SULFONAMIDES WITH ANTITHROMBOTIC ACTIVITY The invention relates to novel sulphonamides of the general formula I in which R1, R independently of one another can be a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl radical, a heteroaryl radical, an alkoxy group, an aralkyloxy group, an alkenyloxy group, an alkynyloxy group, a carboxyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, a hydroxyalkyl group, an alkoxyalkyl group, a carboxyalkyl group, an alkyloxycarbonylalkyl group, an alkenyloxycarbonylalkyl group or an alkynyloxycarbonylalkyl group; R3 can be a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aralkyl radical, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, a carboxyalkyl group, an alkyloxycarbonylalkyl group, an alkenyloxycarbonylalkyl group or an alkynyloxycarbonylalkyl group, an alkylcarbonyl radical, an arylcarbonyl group, a carboxyalkyl- sulphonyl group, an alkyloxycarbonylalkyl- sulphonyl group, a dihydroxyborylalkyl group, a dialkoxyborylalkyl group or an optionally substituted 1,3,2-dioxaborolanylalkyl group or an optionally substituted 1,3,2-dioxaborinanyl- alkyl group; R4 is an optionally substituted amino group, an alkyl group, a cycloalkyl radical, an optionally substituted aryl radical or an optionally substituted heteroaryl radical; X is a single bond, a carbonyl group, or an alkylene or an alkylenoxy group; n is the number 1 or 2 and m is an integer between 1 and 4, and hydrates, solvates and physiologically tolerable salts thereof. The invention also relates to the optically active forms, the racemates and the diastereomer mixtures of these compounds.

The invention also relates to processes for the preparation of the above compounds, medicaments which contain such compounds, and the use of these compounds in the production of medicaments, preferably those with antithromboembolic activity.

Moreover, the invention relates to a method for the prevention and treatment of diseases such as thrombosis, apoplexy, cardiac infarct, inflammations and arteriosclerosis, which comprises the administration of an effective amount of a compound of the formula I.

Further, the invention also relates to pharmaceutical preparations containing at least one compound of the formula I besides conventional carriers and adjuvants.

The sulphonamides of the general formula I, their solvates and their salts intervene by means of reversible inhibition of factor Xa in the process of blood clotting and thus prevent the formation of hyaline thrombi. They can therefore be used in the control and prevention of diseases, such as thrombosis, apoplexy, cardiac infarct, inflammations and arteriosclerosis.

Factor Xa is a serine protease of the clotting system, which catalyses the proteolytic conversion of prothrombin into thrombin. Thrombin, as the last enzyme in the clotting cascade, on the one hand cleaves fibrinogen to fibrin, which after crosslinking by means of factor XIIIa becomes an insoluble gel and forms the matrix for a thrombus, and on the other hand, by proteolysis of its receptor on the blood platelets, activates platelet aggregation and in this way likewise contributes to thrombus formation. On injury of a blood vessel, these processes are necessary to stop bleeding.

Under normal circumstances, measurable thrombin concentrations are not present in the blood plasma. An increase in the thrombin concentration can lead to the formation of thrombi and thus to thromboembolic diseases, which occur very frequently, especially in the industrial nations. As a result of the inhibition of factor Xa, the formation of thrombin can be prevented.

It has recently been reported that amidinoaryl- propanoic acid derivatives such as (+)- (2S)-2- [4- [[(3S)-1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl]-3-(7- amidino-2-naphthyl) propanoic acid hydrochloride pentahydrate (DX-9065a; formula IIa) inhibits factor Xa (J. Med. Chem. 1994,37,1200-1207; Thrombosis and Haemostasis EP-0-540-051-A-1).

Further known factor Xa inhibitors are 1,2-bis (5- amidino-2-benzofuranyl) ethane (DABE, formula IIb, Thrombosis Research or alternatively phenylaminomethylnaphthamidines of the general formula IIc(W096/16940).

The novel sulphonamides of the general formula I according to the invention and hydrates, solvates and physiologically tolerable salts thereof are potent and selective factor Xa inhibitors.

In the general formula I, the substituents R' and R2 can be identical or different.

If R, R in the general formula I is a halogen atom, this can in each case be a fluorine, chlorine, bromine or iodine atom, but fluorine, chlorine or bromine substituents are preferred.

If R, R2, R3, R4 in the general formula I is an alkyl group, this can be straight-chain or branched and can contain 1 to 8 carbon atoms. The methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl and the hexyl group are preferred.

If R1, R2, R3, R4 in the general formula I is a cycloalkyl group, this can be substituted or unsubstituted and can contain 3 to 8 carbon atoms. The cyclopropyl, cyclopentyl, cyclohexyl and the cyclooctyl group are preferred.

If R1, R2, R3 in the general formula I is an alkenyl group, this can be straight-chain or branched and can contain 2 to 8 carbon atoms. The vinyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, 1-butenyl, 1-pentenyl and the 1-hexenyl group are preferred.

If R1, R in the general formula I is an alkynyl group, this can be straight-chain or branched and can contain 2 to 8 carbon atoms. The ethynyl and propargyl group are preferred.

If R, R2, R4 in the general formula I is an aryl radical, this is understood as meaning the phenyl, a biphenyl or a naphthyl group. The aryl radical can be unsubstituted or can optionally carry one or more C1-C8- alkyl substituents, preferably methyl, one or more C1-C8-alkyloxy substituents, preferably methoxy, one or more carboxyl groups, one or more C1-C8-alkoxycarbonyl substituents, preferably methoxycarbonyl or ethoxy- carbonyl, or one or more halogen substituents. The specification C1-C8 here in each case stands for a straight-chain or branched alkyl chain having 1 to 8 carbon atoms. Halogens as substituents of the aryl radical can be fluorine, chlorine, bromine and iodine atoms, but preferably fluorine, chlorine or bromine atoms.

If R1, R2, R3 in the general formula I is a heteroaryl radical, this is understood as meaning a thiophenyl, a benzothiophenyl, a furanyl, a benzofuranyl, a quinolinyl or an isoquinolinyl radical.

The heteroaryl radical can be unsubstituted or can optionally carry one or more C1-C8-alkyl substituents, preferably methyl, one or more C1-C8-alkyloxy substituents, preferably methoxy, one or more carboxyl groups, one or more Cl-C8-alkoxycarbonyl substituents, preferably methoxycarbonyl or ethoxycarbonyl, or one or more halogen substituents. The specification C1-C8 here in each case stands for a straight-chain or branched alkyl chain having 1 to 8 carbon atoms. Halogens as substituents of the heteroaryl radical can be fluorine, chlorine, bromine and iodine atoms, but preferably fluorine, chlorine or bromine atoms.

Alkoxy groups as substituents R R in the general formula I contain 1 to 8 carbon atoms and are straight-chain or branched. The methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, tert-butyloxy, pentyloxy and the hexyloxy group are preferred.

If R R in the general formula I is an aralkyloxy group, this contains a phenyl group linked to a straight-chain or branched C1-Ce-alkyl chain, a naphthyl group linked to a straight-chain or branched C1-C8-alkyl chain or a biphenyl group linked to a straight-chain or branched Cl-cs-alkyl chain. The benzyloxy group, the p-phenylbenzyloxy group and the naphthylmethyloxy group are preferred here.

Alkenyloxy groups as substituents R1, R2 in the general formula I contain 3 to 8 carbon atoms and are straight-chain or branched. The vinyloxy and allyloxy group are preferred.

Alkynyloxy groups as substituents R1, R2 in the general formula I contain 3 to 8 carbon atoms and are straight-chain or branched. The propargyloxy group is preferred.

Alkoxycarbonyl groups as substituents R1, R2 in the general formula I contain straight-chain or branched alkyl chains having 1 to 8 carbon atoms. The methoxycarbonyl and the ethoxycarbonyl group and also the i-propyloxycarbonyl and the tert-butyloxycarbonyl group are preferred.

If R R in the general formula I is an alkenyloxycarbonyl group, this contains straight-chain or branched alkenyls having 3 to 8 carbon atoms. The allyloxycarbonyl group is preferred.

If R R in the general formula I is an alkynyloxycarbonyl group, this contains straight-chain or branched alkynyls having 3 to 8 carbon atoms. The proparyloxycarbonyl group is preferred. <BR> <BR> <BR> <P> 1 2<BR> If R, R in the general formula I is a hydroxyalkyl group, this can be straight-chain or branched and can contain 1 to 8 carbon atoms. The hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and the hydroxyhexyl group are preferred.

If R, R2, R3 in the general formula I is an alkoxyalkyl group, the alkyl radicals concerned are in each case to be understood as meaning straight-chain or branched alkyl chains having 1 to 8 carbon atoms. The methoxymethyl, ethoxymethyl, methoxyethyl and the ethoxyethyl group are preferred.

Carboxyalkyl groups as substituents R1, R2 in the general formula I contain alkyl groups having 1 to 8 carbon atoms and are straight-chain or branched. The carboxymethyl, the carboxyethyl and the carboxypropyl group are preferred.

If R, R2, R3 in the general formula I is an alkyloxycarbonylalkyl group, the alkyl radicals are in each case to be understood as meaning straight-chain or branched alkyl chains having 1 to 8 carbon atoms. The methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxy- carbonylethyl, ethoxycarbonylethyl, methoxycarbonyl- propyl and the ethoxycarbonylpropyl group are preferred.

If R1, R2, R3 in the general formula I is an alkenyloxycarbonylalkyl group, the alkenyl radicals are straight-chain or branched having 3 to 8 carbon atoms and the alkyl groups are straight-chain or branched having 1 to 8 carbon atoms. The allyloxycarbonylmethyl, allyloxycarbonylethyl and the allyloxycarbonylpropyl group are preferred.

If R1, R2, R3 in the general formula I is an alkynyloxycarbonylalkyl group, the alkynyl radicals are straight-chain or branched having 3 to 8 carbon atoms and the alkyl groups are straight-chain or branched having 1 to 8 carbon atoms. The propargyloxycarbonylmethyl, propargyloxycarbonylethyl and the propargyloxycarbonylpropyl group are preferred.

If R3 in the general formula I is an alkynyl group, this can be straight-chain or branched and can contain 3 to 8 carbon atoms. The propargyl group is preferred.

An aralkyl radical as a substituent R3 in the general formula I is understood as meaning a phenyl group linked to a straight-chain or branched Cl-C8-alkyl chain, a naphthyl group linked to a straight-chain or branched Ci-C8-alkyl chain or a biphenyl group linked to a straight-chain or branched Cl-C8-alkyl chain. The benzyl group, the p-phenylbenzyl group and the naphthylmethyl group are preferred here.

If R3 in the general formula I is a hydroxy- alkyl group, this can be straight-chain or branched and can contain 2 to 8 carbon atoms. The hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and the hydroxyhexyl group are preferred.

If R3 in the general formula I is an aminoalkyl group, this can be straight-chain or branched and can contain 2 to 8 carbon atoms. The aminoethyl, aminopropyl, aminobutyl, aminopentyl and the aminohexyl group are preferred.

A carboxyalkyl group as a substituent R3 in the general formula I contains an alkyl chain having 1 to 8 carbon atoms and is straight-chain or branched. The carboxymethyl, the carboxyethyl and the carboxypropyl group are preferred.

If R3 in the general formula I is an alkylcarbonyl radical, the alkyl group can be straight- chain or branched and can contain 1 to 8 carbon atoms.

The acetyl and the propionyl group are preferred.

As an aryl fragment, an arylcarbonyl group as a radical R3 in the general formula I contains a phenyl, a biphenyl or optionally a naphthyl group, but preferably a phenyl group. The aryl radical can be unsubstituted or can optionally carry one or more C1-C8- alkyl substituents, preferably methyl, one or more Cl-C$-alkyloxy substituents, preferably methoxy, one or more carboxyl groups, one or more Cl-C8-alkoxycarbonyl substituents, preferably methoxycarbonyl or ethoxy- carbonyl, or one or more halogen substituents. The specification C1-C8 here in each case stands for a straight-chain or branched alkyl chain having 1 to 8 carbon atoms. Halogens as substituents of the aryl radical can be fluorine, chlorine, bromine and iodine atoms, but preferably fluorine, chlorine or bromine atoms.

If R3 in the general formula I is a carboxy- alkylsulphonyl group, this contains an alkyl chain having 1 to 8 carbon atoms, which is straight-chain or alternatively can be branched. The carboxymethyl- sulphonyl, the carboxyethylsulphonyl and the carboxy- propylsulphonyl group are preferred.

If R3 in the general formula I is an alkyloxy- carbonylalkylsulphonyl group, the alkyl radicals are in each case to be understood as meaning straight-chain or branched alkyl chains having 1 to 8 carbon atoms. The methoxycarbonylmethylsulphonyl, ethoxycarbonylmethyl- sulphonyl, methoxycarbonylethylsulphonyl, ethoxy- carbonylethylsulphonyl, methoxycarbonylpropylsulphonyl and the ethoxycarbonylpropylsulphonyl group are preferred.

If R3 in the general formula I is a dihydroxy- borylalkyl group, this contains a straight-chain or branched alkyl chain having 1 to 8 carbon atoms. The dihydroxyborylmethyl and the dihydroxyborylpropyl group are preferred.

If R3 in the general formula I is a dialkoxy- borylalkyl group, the respective alkyl radicals can independently of one another be straight-chain or branched and can contain 1 to 8 carbon atoms. The dimethoxyborylmethyl and the dimethoxyborylpropyl group are preferred.

If R3 in the general formula I is a 1,3,2- dioxaborolanylalkyl group, the alkyl radical can be straight-chain or branched and can contain 1 to 8 carbon atoms. If appropriate, the 1,3,2-dioxaborolanyl radical can be substituted in the 4-and 5-position, namely by up to four methyl groups. The 1,3,2-dioxa- borolanylmethyl group and the 4,4,5,5-tetramethyl- 1,3,2-dioxaborolanylmethyl group are preferred.

If R4 in the general formula I is an amino group, this can be unsubstituted or alternatively substituted, namely by one or two Cl-C8-alkyl groups, preferably methyl or ethyl, by one or two C3-C8- cycloalkyl groups, preferably cyclopropyl, cyclopentyl, cyclohexyl or cyclooctyl, by one or two C2-C8-hydroxy- alkyl groups, preferably hydroxyethyl or hydroxypropyl, by one or two C3-C8-alkenyl groups, preferably allyl, by one or two C3-Cs-alkynyl groups, preferably propargyl, or by one or two aralkyl groups, preferably benzyl. The specification Cl-C$-alkyl refers here to a straight- chain or branched alkyl chain having 1 to 8 carbon atoms. C3-C8-cycloalkyl refers here to a branched or unbranched cycloalkyl group having 3 to 8 carbon atoms.

C2-C8-Hydroxyalkyl refers here to a straight-chain or branched alkyl chain having 2 to 8 carbon atoms, which can be substituted by one or more hydroxyl groups.

C3-C8-Alkenyl here denotes a straight-chain or branched unsaturated chain of 3 to 8 carbon atoms. C3-C8-Alkynyl here denotes a straight-chain or branched chain of 3 to 8 carbon atoms. Aralkyl here denotes a phenyl group linked to a straight-chain or branched Cl-C$-alkyl chain, a naphthyl group linked to a straight-chain or branched Cl-C8-alkyl chain or a biphenyl group linked to a straight-chain or branched Cl-C8-alkyl chain.

If X in the general formula I is an alkylene group, this can be straight-chain or branched and can contain 1 to 8 carbon atoms. The methylene group and the ethylene group are preferred.

If X in the general formula I is an alkylenoxy group, this can be straight-chain or branched and can contain 1 to 8 carbon atoms. The methylenoxy fragment is preferred.

Particularly preferred compounds of the general formula I are those in which R, R are identical or different and are a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxyl group, a methyl group, an ethyl group, a methoxy group, a benzyloxy group, an allyloxy group, a carboxyl group, a methoxy-or ethoxy- carbonyl group, a hydroxymethyl or hydroxyethyl group or a carboxymethyl group; R3 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclohexyl group, an allyl group, a propargyl group, a benzyl group, a hydroxyethyl group, a hydroxypropyl group, a methoxyethyl group, an aminoethyl group, a carboxymethyl group, a carboxyethyl group, a carboxypropyl group, an ethoxycarbonylmethyl group, an ethoxycarbonyl- ethyl group, an ethoxycarbonylpropyl group, an acetyl group, a 4-methoxybenzoyl group, a carboxymethylsulphonyl group, a carboxyethyl- sulphonyl group, a carboxypropylsulphonyl group, an ethoxycarbonylmethylsulphonyl group, an ethoxycarbonylethylsulphonyl group, an ethoxycarbonylpropylsulphonyl group, a dihydroxyborylmethyl group, a dihydroxyboryl- propyl group, a 2- dioxaborolanylmethyl group; R4 is an amino group, a methyl group, an ethyl group, a cyclopropyl group, a cyclohexyl group, a 4-methoxyphenyl group or a thienyl group; X is a methylene group; n is the number 1 and m can be the number 1 or the number 2.

Particularly preferred compounds are also those in which R1, R2 and R3 are hydrogen, R4 is the group NH2, X is the methylene group, n is the number 1 and m is the number 2.

The physiologically tolerable salts of the general formula I are understood as meaning, for example, formates, acetates, caproates, oleates, lactates or salts of carboxylic acids having up to 18 carbon atoms or salts of dicarboxylic acids and tricarboxylic acids such as citrates, malonates and tartrates or alkanesulphonates having up to 10 carbon atoms or p-toluenesulphonates or salicylates or trifluoro- acetates or salts of physiologically tolerable mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulphuric acid, phosphoric acid. The compounds of the formula I having one or two free acid groups on the phosphonate fragment can also form salts with physiologically tolerable bases. Examples of such salts are alkali metal, alkaline earth metal, ammonium and alkylammonium salts, such as the sodium, potassium, calcium or tetramethylammonium salt.

The compounds of the formula (I) can be solvated, in particular hydrated. Hydration can be carried out in the course of the preparation or can occur gradually as a result of hygroscopic properties of an initially anhydrous compound of the formula I.

The invention also relates to the optically active forms, the racemates and the diastereomer mixtures of compounds of the general formula I.

For the production of medicaments, the substances of the general formula I are mixed with suitable pharmaceutical carrier substances, aromatic substances, flavourings and colourants and are shaped, for example, as tablets or coated tablets or are suspended or dissolved in water or oil, e. g. in olive oil, with addition of appropriate auxiliaries.

The substances of the general formula I and their salts can be administered orally, enterally or parenterally in liquid or solid form. The oral administration form is preferred. The injection medium used is preferably water, which contains the additives customary in injection solutions such as stabilizing agents, solubilizers or buffers. Additives of this type are, for example, tartrate and citrate buffers, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts) and high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation. Solid excipients are, for example, starch, lactose, mannitol, methylcellulose, talc, highly disperse silicic acids, high molecular weight fatty acids (such as stearic acid), animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols). If desired, preparations suitable for oral administration can contain flavourings and sweeteners.

The compounds are customarily administered in amounts of 1-1500 mg per day based on a body weight of 75 kg. It is preferred to administer 1-2 tablets having an active compound content of 1-500 mg 2-3 times per day. The tablets can also be delayed release, as a result of which only 1-2 tablets containing 2-700 mg of active compound have to be given once per day. The active compound can also be given by injection 1-8 times per day or by continuous infusion, 5-2000 mg per day normally being sufficient.

Compounds of the general formula I are prepared by methods known per se.

The compounds of the general formula I are prepared, for example, by reacting a compound of the general formula III in which Ru, R2, R3 and m have the meanings indicated above, with a guanylating reagent in an inert solvent in the presence of an auxiliary base.

In detail, the compounds of formula I can be prepared, for example, by reacting a compound of the general formula III in which Ru, R, R'and m have the meanings given above, with a guanylating reagent such as, for example, S- alkylisothiourea, preferably S-methylisothiourea, or 1H-pyrazole-l-carboxamidine (see e. g. : M. S.

Bernatowicz, Y. Wu, G. R. Matseuda, J. Org. Chem. 1992, 57,2497-2505) in an inert solvent such as e. g. dimethylformamide, dioxan, dimethyl sulphoxide or toluene at temperatures between 0°C and the boiling point of the solvent, preferably at 0 to 30°C in the presence of an auxiliary base such as e. g. triethylamine, N-methylmorpholine, pyridine or ethyldiisopropylamine.

The compounds of the general formula III are prepared by reacting a compound of the general formula IV in which R1, R2, R3 and m have the meanings indicated above and PG1 is a protective group such as, for example, the benzyloxycarbonyl group, the t-butyloxy- carbonyl group or the allyloxycarbonyl group, with a reagent removing the protective group. The protective group removal is carried out according to generally customary methods (see, for example, T. W. Green, P. G. M.

Wuts,"Protective Groups in Organic Synthesis", 2nd ed., John Wiley and Sons Inc. 1991) by means of acidic reagents such as, for example, hydrogen bromide in glacial acetic acid or trifluoroacetic acid or ethereal HC1 solution or hydrogenolytically or by means of palladium-or rhodium-catalysed cleavage.

The compounds of the general formula IV are prepared by reacting a compound of the general formula V in which R1, R2, PG1 and m have the meanings indicated above, with compounds of the type R3-Y, in which R3 has the meaning indicated above and Y is halogen, tosylate, mesylate or triflate, in an inert solvent such as dioxane, tetrahydrofuran, N, N-dimethylformamide, N-methylpyrrolidone or toluene in the presence of a base such as, for example, sodium carbonate, potassium carbonate, 1,5-diazabicyclo [5.4.0] undec-5-ene or ethyl- diisopropylamine at temperatures between 0°C and the boiling point of the solvent, preferably between room temperature and 80°C. Compounds of the type R3-Y are either commercially available or are known from the literature or can be prepared according to standard methods from precursors which are commercially available or are known from the literature.

The compounds of the general formula V are prepared by subjecting a compound of the general formula VI in which Ru, R2, PG and m have the meanings indicated above, to a catalytic hydrogenation in inert solvents such as, for example, methanol, ethanol, tetrahydro- furan or dioxane in the presence of a catalyst, preferably palladium on carbon. The benzyl group is replaced here by a hydrogen atom. The removal of the benzyl group is also carried out by reaction with a strong acid such as trifluoroacetic acid in the presence of mesitylene, anisole or thioanisole at temperatures between 0 and 50°C, preferably at room temperature, or by treatment with Lewis acids such as BF3 etherate in an inert solvent such as toluene, acetonitrile, diethyl ether or tetrahydrofuran at temperatures between 0°C and the boiling point of the solvent, preferably between room temperature and the boiling point of the solvent.

The compounds of the general formula VI are prepared by condensing a compound of the general formula VII in which PG1 and m have the meanings indicated above, with a compound of the general formula VIII in which R1, R2 and PG1 have the meanings indicated above, in an inert solvent such as dioxane, tetrahydrofuran or toluene in the presence of diethyl azodicarboxylate and triphenylphosphine, trimethyl or triethyl phosphite at temperatures between 0 and 50°C, preferably at room temperature.

Compounds of the general formula VII in which m and p51 have the meanings indicated above are either commercially available or are known from the literature or can be prepared according to processes which are known from the literature (see, for example, K. L. Bhat, D. M. Flanagan, M. M. Jouille, Synth. Commun. 1985,15, 587-598; P. G. Houghton, G. R. Humphrey, D. J. Kennedy, D. C. Roberts, S. H. Wright, J. Chem. Soc. Perkin Trans. <BR> <BR> <BR> <P>1 1993, 13,1421-1424; T. W. Green, P. G. M. Wuts "Protective Groups in Organic Synthesis", 2nd ed., John Wiley and Sons Inc. 1991).

The compounds of the general formula VIII are prepared by reacting a compound of the general formula IX in which R2 has the meaning indicated above, with a compound of the general formula X in which R1 and PG1 have the meanings indicated above, in an inert solvent such as N, N-dimethylformamide, N- methylpyrrolidone, dioxane, tetrahydrofuran, dichloro- methane or toluene in the presence of a base such as, for example, sodium carbonate, potassium carbonate, 1,5-diazabicyclo [5.4.0] undec-5-ene, triethylamine, N-methylmorpholine or ethyldiisopropylamine at tempera- tures between-20°C and the boiling point of the solvent, preferably between 0°C and 80°C. Compounds of the type IX are either commercially available or are known from the literature or can be prepared according to standard methods from precursors which are commercially available or are known from the literature (see, for example, M. Sato, Y. Kawashima, J. Goto, Y.

Yamane, Y. Chiba et al., Eur. J. Med. Chem. Chim. Ther.

1995,30,403-414; W. Loewe, T. Braden, Arch. Pharm.

(Weinheim Ger.) 1995,328,283-286; R. Cremlin, <BR> <BR> F. Swinbourne, J. Atherall, L. Courtney, T. Cronje et al. Phosphorus Sulphur R. W. Campbell, H. W. Hill, J. Org. Chem. 1973,38,1047, Stewart J.

Chem. Soc. 1922,121,2559).

The compounds of the general formula X are prepared by reacting a compound of the general formula XI in which R'and PG'have the meanings indicated above, in an inert solvent such as dichloroethane, tetrahydrofuran, dioxane, ethanol, methanol or diglyme, in the presence of a reducing agent such as, for example, sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, at temperatures between -20°C and the boiling point of the solvent, preferably between 0°C and 60°C.

The compounds of the general formula XI are prepared by hydrogenating a compound of the general formula XII in which R'and PG'have the meanings indicated above, in an inert solvent such as methanol, ethanol, tetrahydrofuran or dioxane in the presence of a catalyst, for example palladium on carbon, tris- triphenylphosphine-rhodium chloride or Raney nickel. If appropriate, the reduction can also be carried out using reducing agents other than hydrogen, e. g. using lithium aluminium hydride, sodium borohydride/cobalt dichloride, sodium borohydride/nickel dichloride, triethylsilane/tris-triphenylphosphine-rhodium chloride or using base metals such as iron or tin in the presence of acid.

The compounds of the general formula XII are prepared by reacting a compound of the general formula XIII in which R1 has the meaning indicated above, in an inert solvent such as methanol, ethanol, tetrahydro- furan, dioxane, dimethylformamide or water at tempera- tures between 0°C and the boiling point of the solvent, preferably between room temperature and 50°C, with the appropriate commerically available reagents introducing the protective group, such as, for example, di-tert- butyl dicarbonate or chloroformic acid esters. The introduction of the appropriate protective group is carried out according to the generally known methods of protective group chemistry (see, for example, T. W. Green, P. G. M. Wuts,"Protective Groups in Organic Synthesis", 2nd ed., John Wiley and Sons Inc. 1991), the presence of bases such as alkali metal or alkaline earth metal hydroxides, sodium carbonate, potassium carbonate, N-methylmorpholine, diisopropylethylamine, triethylamine or 1,5-diazabicyclo [5.4.0] undec-5-ene optionally being necessary.

Compounds of the type XIII are either commercially available or are known from the literature or can be prepared according to standard methods from precursors which are commercially available or are known from the literature (see, for example, J. F. Ajao, C. W. Bird, J. Heterocycl. Chem. 1985,22,329-331; E. Ochai, T. Nakagomo Chem. Pharm. Bull. 1958,6,497; A. McCoubrey, D. W. Mathieson, J. Chem. Soc. 1951, 2851).

Compounds of the general formula I can also be prepared by reacting, for example, a compound of the general formula XIV in which R, R2, R3 and m have the meanings indicated above, with aliphatic or aromatic imidate ester hydrochlorides in an inert solvent such as tetrahydrofuran, diethyl ether, ethanol, dimethylform- amide or dioxane at temperatures between-20°C and the boiling point of the solvent, preferably between 0°C and 40°C, in the presence of an auxiliary base such as triethylamine, diisopropylethylamine or N-methylmorpho- line.

Compounds of the general formula XIV can be prepared by reacting, for example, a compound of the general formula XV in which R1, R2, R3 and m have the meanings indicated and pG2 is a protective group, such as, for example, the allyloxycarbonyl group, with a reagent removing the protective group. The protective group removal is carried out according to generally customary methods (see, for example, T. W. Green, P. G. M. Wuts,"Protective Groups in Organic Synthesis", 2nd ed., John Wiley and Sons Inc. 1991), e. g. by means of palladium-or rhodium-catalysed cleavage.

Compounds of the general formula XV can be prepared by reacting, for example, a compound of the general formula XVI in which R1, R2, R3, m and pG2 have the meanings indicated above, with a guanylating reagent such as, for example, 1H-pyrazole-l-carboxamidine or S-methyl- isothiourea in an inert solvent such as, for example, dimethylformamide, dioxane, dimethyl sulphoxide or toluene at temperatures between 0°C and the boiling point of the solvent, preferably at 0 to 30°C in the presence of an auxiliary base such as, for example, triethylamine, N-methylmorpholine, pyridine or ethyldiisopropylamine.

The compounds of the general formula XVI are prepared by reacting a compound of the general formula XVII in which Ri, R2, R3, m and pG2 have the meanings indicated above and PG is not equal to PG3, where PG3 is a protective group such as, for example, the benzyloxycarbonyl group, the t-butyloxycarbonyl group or the allyloxycarbonyl group, with a reagent selectively removing the pG2 protective group. The removal of the protective groups is carried out according to generally customary methods (see, for example, T. W. Green, P. G. M. Wuts,"Protective Groups in Organic Synthesis", 2nd ed., John Wiley and Sons Inc.

1991), e. g. by acidic reagents such as hydrogen bromide in glacial acetic acid or trifluoroacetic acid or ethereal HC1 solution or hydrogenolytically.

The compounds of the general formula XVII can be prepared from the appropriate precursors analogously to the compounds of the general formula IV.

Alternatively, the compounds of the general formula XVII can also be prepared by reacting a compound of the general formula XVIII in which R1, R3 and PG3 have the meanings indicated above, with a compound of the general formula XIX in which R2, m and PG have the meanings indicated above. The reaction is carried out in an inert solvent such as N, N-dimethylformamide, N-methylpyrrolidone, dioxane, tetrahydrofuran, dichloromethane or toluene in the presence of a base such as, for example, sodium carbonate, potassium carbonate, 1,5-diazabicyclo- [5.4.0] undec-5-ene, triethylamine, N-methylmorpholine or ethyldiisopropylamine at temperatures between-20°C and the boiling point of the solvent, preferably between 0°C and 80°C.

The compounds of the general formula XVIII can be prepared from compounds of the general formula XX in which R1 and PG3 have the meanings indicated above, by alkylation with compounds of the type R3-Y, in which R3 has the meaning indicated above and Y is halogen, tosylate, mesylate or triflate, in an inert solvent such as dioxane, tetrahydrofuran, N, N-dimethyl- formamide, N-methylpyrrolidone or toluene in the presence of a base such as, for example, sodium carbonate, potassium carbonate, 1,5-diazabicyclo- [5.4.0] undec-5-ene or ethyldiisopropylamine at temperatures between 0°C and the boiling point of the solvent, preferably between room temperature and 80°C.

Compounds of the type R3-Y are either commercially available or are known from the literature or can be prepared from precursors which are commercially available or are known from the literature according to standard methods. Alternatively, the compounds of the general formula XVIII can also be obtained starting from compounds of the general formula XX, by reductive amination of the corresponding aldehyde. These reactions are carried out in an inert solvent such as dichloroethane, tetrahydrofuran, dioxane, ethanol, methanol or diglyme, in the presence of a reducing agent such as, for example, sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, at temperatures between-20°C and the boiling point of the solvent, preferably between 0°C and 60°C. The corresponding aldehydes are either commercially available or are known from the literature or can be prepared according to standard methods from precursors which are commercially available or are known from the literature. The compounds of the general formula XX can be prepared from the corresponding precursors analogously to the compounds of the general formula XI.

The compounds of the general formula XIX can be prepared by sulphochlorinating a compound of the general formula XXI in which R2, m and pG2 have the meanings indicated above. This is carried out in an inert solvent such as dichloromethane, chloroform or carbon tetrachloride using a sulphochlorinating reagent such as chlorosulphonic acid, if appropriate in the presence of thionyl chloride, sulphuryl chloride or phosphoryl chloride at temperatures between-20°C and the boiling point of the solvent, preferably between 0°C and 40°C.

The compounds of the general formula XXI are prepared by condensing a compound of the general formula XXII in which pG2 and m have the meanings indicated above, with a compound of the general formula XXIII in which R2 has the meaning indicated above, in an inert solvent such as dioxane, tetrahydrofuran or toluene in the presence of diethyl azodicarboxylate and triphenylphosphine, trimethyl or triethyl phosphite at temperatures between 0 and 50°C, preferably at room temperature.

Compounds of the general formula XXII in which m and PG2 have the meanings indicated above are either commercially available or are known from the literature or can be prepared according to processes known from the literature (see, for example, K. L. Bhat, D. M. Flanagan, M. M. Jouille, Synth. Commun. 1985,15, 587-598; P. G. Houghton, G. R. Humphrey, D. J. Kennedy, D. C. Roberts, S. H. Wright, J. Chem. Soc. Perkin Trans.

1 T. W. Green, P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2nd ed., John Wiley and Sons Inc. 1991).

Compounds of the general formula XXIII in which R2 has the meaning indicated are either commercially available or are known from the literature or can be prepared according to standard methods from precursors which are commercially available or are known from the literature.

Certain compounds of the general formula I can subsequently be converted into other compounds of the general formula I.

This relates to compounds of the general formula I in which Ru, R, R3, R4, n and m have the meanings indicated above and one or more of the radicals Ru, R2, R3 is or comprises a methoxy group. By means of treatment with customary reagents removing the methyl group (see, for example, T. W. Green, P. G. M. Wuts,"Protective Groups in Organic Synthesis", 2nd ed., John Wiley and Sons Inc. 1991) such as, for example, trimethylsilyl iodide or boron tribromide in an inert solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, acetone, acetonitrile at temperatures between 0°C and the boiling point of the solvent, preferably between 0°C and 60°C, these compounds can be converted into the corresponding compounds of the general formula I having a free hydroxyl group.

This also relates to compounds of the general formula I in which R1, R2, R3, R4, n and m have the meanings indicated above and one or more of the radicals R1, R2 is or comprises an ethoxy-or methoxycarbonyl group. By means of acidic or alkaline hydrolysis in an inert solvent such as tetrahydrofuran, dioxane, acetone, ethanol, methanol or water at temperatures between 0°C and the boiling point of the solvent, preferably between room temperature and 60°C, these compounds can be converted into the corresponding compounds of the general formula I having a free carboxyl group.

This also relates to compounds of the general formula I in which R1, R2, R3, R4, n and m have the meanings indicated above and one or more of the radicals Ru, R 2 is a benzyloxy group. By means of catalytic hydrogenation in inert solvents such as, for example, methanol, ethanol, tetrahydrofuran or dioxane in the presence of a catalyst, preferably palladium on carbon, the benzyl group is in this case replaced by a hydrogen atom (see, for example, T. W. Green, P. G. M. Wuts,"Protective Groups in Organic Synthesis", 2nd ed., John Wiley and Sons Inc. 1991). The removal of the benzyl group is also carried out by reaction with a strong acid such as trifluoroacetic acid in the presence of mesitylene, anisole or thioanisole at temperatures between 0 and 50°C, preferably at room temperature, or by treatment with Lewis acids such as boron trifluoride etherate in an inert solvent such as toluene, acetonitrile, diethyl ether or tetrahydrofuran at temperatures between 0°C and the boiling point of the solvent, preferably between room temperature and the boiling point of the solvent.

This also relates to compounds of the general formula I in which R1, R2, R3, R4, n and m have the meanings indicated above and one or more of the radicals R1, R2 is an allyloxy group. By means of transition metal-catalysed cleavage, for example in the presence of a rhodium catalyst such as tris-triphenyl- phosphine-rhodium chloride or of a palladium catalyst such as tetrakis-triphenylphosphine-palladium in an inert solvent such as tetrahydrofuran or dioxane, if appropriate in the presence of a nucleophile such as, for example, diethyl malonate, tributyltin hydride, or piperidine at temperatures between 0°C and 50°C, preferably at room temperature, the allyl group is in this case replaced by a hydrogen atom (see, for example, T. W. Green, P. G. M. Wuts,"Protective Groups in Organic Synthesis", 2nd ed., John Wiley and Sons Inc. 1991).

Pure enantiomers of the compounds of the formula I are obtained either by resolution (via salt formation with optically active acids or bases) or by employing optically active starting substances in the synthesis or by enzymatically hydrolysing them.

Apart from the compounds mentioned in the examples, the following compounds are preferred within the meaning of the invention: 1.7- {4- [l- (l-Iminoethyl) piperidin-4-yloxy] benzene- sulphonylamino}-3,4-dihydro-lH-isoquinoline-2- carboxamidine 2.7- {4- [l- (l-Iminopropyl) piperidin-4-yloxy] benzene- sulphonylamino}-3,4-dihydro-lH-isoquinoline-2- carboxamidine 3.7- {4- [1- (Cyclopropyliminomethyl) piperidin-4- yloxy] benzenesulphonylamino}-3, 4-dihydro-lH- isoquinoline-2-carboxamidine 4.7- (4- {l- [Imino- (4-methoxyphenyl) methyl] piperidin- 4-yloxy}benzenesulphonylamino}-3,4-dihydro-1H- isoquinoline-2-carboxamidine 5.7- {4- [l- (Iminothiophen-2-ylmethyl) piperidin-4- yloxy] benzenesulphonylamino}-3, 4-dihydro-lH- isoquinoline-2-carboxamidine 6.7-{[4-(1-Carbamimidoylpiperidin-4-yloxy) benzene- sulphonyl] methylamino}-3, 4-dihydro-lH-isoquino- line-2-carboxamidine 7.7- (f4- [l- (l-Iminoethyl) piperidin-4-yloxylbenzene- sulphonyl}methylamino}-3,4-dihydro-1H-isoquino- line-2-carboxamidine 8. 7-({4-[1-(1-Iminopropyl)piperidin-4-yloxy]- benzenesulphonyl} methylamino)-3,4-dihydro-lH- isoquinoline-2-carboxamidine 9.7- (4- [l- (Cyclopropyliminoethyl) piperidin-4- yloxy] benzenesulphonyl}methylamino)-3,4-dihydro- 1H-isoquino]ine-2-carboxamidine 10.7- [ (4- {l- [Imino- (4-methoxyphenyl) methyl] piperidin- 4-yloxy} benzenesulphonyl) methylamino]-3,4-dihydro- lH-isoquinoline-2-carboxamidine 11. 7-({4-[1-(Iminothiophen-2-ylmethyl)piperidin-4- yloxy] benzenesulphonyl} methylamino)-3,4-dihydro- 1H-isoquinoline-2-carboxamidine 12.7- { [4- (I-Carbamimidoylpiperidin-4-yloxy) benzene- sulphonyl] ethylamino}-3, 4-dihydro-lH-isoquinoline- 2-carboxamidine 13. 7-(Ethyl-(4-[1-(1-Iminoethyl)piperidin-4-yloxy]- benzenesulphonyl} amino)-3,4-dihydro-lH-isoquino- line-2-carboxamidine 14. 7-(Ethyl-{4-[1-(1-Iminopropyl)piperidin-4-yloxy]- benzenesulphonyl} amino)-3,4-dihydro-lH-isoquino- line-2-carboxamidine 15. 7-({4-[1-(Cyclopropyliminomethyl)piperidin-4- yloxy] benzenesulphonyl} ethylamino}-3, 4-dihydro-lH- isoquinoline-2-carboxamidine 16.7- [Ethyl- (4- {1- [Imino (4-methoxyphenyl) methyl]- piperidin-4-yloxy}benzenesulphonyl)amino]- 3,4-dihydro-lH-isoquinoline-2-carboxamidine 17. 7-(Ethyl-{4-[1-(Iminothiophen-2-ylmethyl)- piperidin-4-yloxy] benzenesulphonyl} amino)- 3,4-dihydro-lH-isoquinoline-2-carboxamidine 18.7- { [4- (l-Carbamimidoyl) piperidin-4-yloxy) benzene- sulphonyl] cyclopropylamino}-3, 4-dihydro-lH-iso- quinoline-2-carboxamidine 19.7- (Cyclopropyl- {4- [l- (l-iminoethyl) piperidin-4- yloxy] benzenesulphonyl}amino)-3,4-dihydro-lH- isoquinoline-2-carboxamidine 20.7- (Cyclopropyl- {4- [l- (l-iminopropyl) piperidin-4- yloxy] benzenesulphonyl}amino)-3,4-dihydro-lH- isoquinoline-2-carboxamidine 21.7- (Cyclopropyl- {4- [1- (cyclopropyliminomethyl)- piperidin-4-yloxy] benzenesulphonyl} amino)- 3,4-dihydro-lH-isoquinoline-2-carboxamidine 22.7- [Cyclopropyl- (4- {l- [Imino- (4-methoxyphenyl)- methyl] piperidin-4-yloxy} benzenesulphonyl) amino]- 3,4-dihydro-lH-isoquinoline-2-carboxamidine 23.7- (Cyclopropyl- {4- [l- (iminothiophen-2-ylmethyl)- piperidin-4-yloxy] benzenesulphonyl} amino)- 3,4-dihydro-lH-isoquinoline-2-carboxamidine 24.7- {Allyl- [4- (l-carbamimidoylpiperidin-4-yloxy)- benzenesulphonyl] amino}-3, 4-dihydro-lH-isoquino- line-2-carboxamidine 25.7- (Allyl- {4- [l- (l-iminoethyl) piperidin-4-yloxy]- benzenesulphonyl} amino}-3,4-dihydro-lH-isoquino- line-2-carboxamidine 26.7- (Allyl- {4- [1- (1-iminopropyl) piperidin-4-yloxy]- benzenesulphonyl} amino)-3,4-dihydro-lH-isoquino- line-2-carboxamidine 27. 7-(Allyl-{4-[1-(cyclopropyliminomethyl)piperidin- 4-yloxy] benzenesulphonyl} amino)-3,4-dihydro-lH- isoquinoline-2-carboxamidine 28. 7-[Allyl-(4-{1-[imino-(4-methoxyphenyl)methyl]- piperidin-4-yloxy} benzenesulphonyl) amino]- 3,4-dihydro-lH-isoquinoline-2-carboxamidine 29.7- (Allyl- {4- [1- (iminothiophen-2-ylmethyl)- piperidin-4-yloxy] benzenesulphonyl} amino)- 3,4-dihydro-lH-isoquinoline-2-carboxamidine 30. 7-{Benzyl-[4-(1-carbamimidoylpiperidin-4-yloxy)- benzenesulphonyl] amino}-3, 4-dihydro-lH-isoquino- line-2-carboxamidine 31.7- (Benzyl- {4- [1- (1-iminoethyl) piperidin-4-yloxy]- benzenesulphonyl}amino)-3,4-dihydro-1H-isoquinol- line-2-carboxamidine 32. 7-(Benzyl-{4-[1-(1-iminopropyl)piperidin-4- yloxy] benzenesulphonyl} amino)-3,4-dihydro-lH- isoquinoline-2-carboxamidine 33. 7-(Benzyl-{4-[1-(cyclopropyliminomethyl)piperidin- 4-yloxy]benzenesulphonyl)amino)-3,4-dihydro-1H- isoquinoline-2-carboxamidine 34.7- [Benzyl- (4- {l- [imino- (4-methoxyphenyl) methyl]- piperidin-4-yloxy}benzenesulphonyl)amino]- 3,4-dihydro-lH-isoquinoline-2-carboxamidine 35. 7-(Benzyl-(4-[1-(iminothiophenyl-2-ylmethyl)- piperidin-4-yloxy] benzenesulphonyl} amino)- 3,4-dihydro-lH-isoquinoline-2-carboxamidine 36.7- [ [4- (l-Carbamimodoylpiperidin-4-yloxy) benzene- sulphonyl]-(2-hydroxyethyl) amino]-3, 4-dihydro-lH- isoquinoline-2-carboxamidine 37.7- ( (2-Hydroxyethyl)- {4- [l- (l-iminoethyl) piperidin- 4-yloxy] benzenesulphonyl} amino)-3,4-dihydro- 1H-isoquinoline-2-carboxamidine 38.7- ( (2-Hydroxyethyl)- {4- [l- (l-iminopropyl)- piperidin-4-yloxy] benzenesulphonyl} amino)- 3,4-dihydro-lH-isoquinoline-2-carboxamidine 39.7- [ {4- [1- (Cyclopropyliminomethyl) piperidin-4- yloxy] benzenesulphonyl}-(2-hydroxyethyl) amino]- 3,4-dihydro-lH-isoquinoline-2-carboxamidine 40.7- [ (2-Hydroxyethyl)- (4- {l- [imino- (4-methoxy- phenyl) methyl] piperidin-4-yloxy} benzenesulphonyl)- amino]-3,4-dihydro-lH-isoquinoline-2-carboxamidine 41.7- ( (2-Hydroxyethyl)- {4- [1- (iminothiophen-2- ylmethyl) piperidin-4-yloxy] benzenesulphonyl}- amino)-3,4-dihydro-lH-isoquinoline-2-carboxamidine 42. [ [4- (1-Carbamimidoylpiperidin-4-yloxy) benzene- sulphonyl]-(2-carbamimidoyl-1,(2-carbamimidoyl-1, 2,3,4-tetrahydro- isoquinolin-7-yl) amino] acetic acid 43. ((2-Carbamimidoyl-1,2,3,4-tetrahydroisoquinolin-7- yl)- {4- [l- (l-iminoethyl) piperidin-4-yloxy]- benzenesulphonyl} amino) acetic acid 44. ((2-Carbamimidoyl-1, 2,3,4-tetrahydroisoquinolin-7- yl)- {4- [l- (l-iminopropyl) piperidin-4-yloxy]- benzenesulphonyl} amino) acetic acid 45. ((2-Carbamimidoyl-1, 2,3,4-tetrahydroisoquinolin-7- yl)- {4- [1- (cyclopropyliminomethyl) piperidin-4- yloxy] benzenesulphonyl} amino) acetic acid 46. [(2-Carbamimidoyl-1,2,3,4-tetrahydroisoquinolin-7- yl)- (4- {l- [imino- (4-methoxyphenyl) methyl]- piperidin-4-yloxy} benzenesulphonyl) amino] acetic acid 47. ((2-Carbamimidoyl-1, 2,3,4-tetrahydroisoquinolin-7- yl)- {4- [l- (iminothiophen-2-ylmethyl) piperidin-4- yloxy] benzenesulphonyl} amino) acetic acid 48. 4-[[4-(1-Carbamimidoylpiperidin-4-yloxy)benzene- sulphonyl]- (2-carbamimidoyl-l,2,3,4-tetrahydro- isoquinolin-7-yl) amino] butyric acid 49. 4-((2-Carbamimidoyl-1, 2,3,4-tetrahydroisoquinolin- 7-yl)- {4- [1- (1-iminoethyl) piperidin-4-yloxy]- benzenesulphonyl} amino) butyric acid 50. 4-((2-Carbamimidoyl-1, 2,3,4-tetrahydroisoquinolin- 7-yl)- {4- [1- (1-iminopropyl) piperidin-4-yloxy]- benzenesulphonyl} amino) butyric acid 51. 4-((2-Carbamimidoyl-1, 2,3,4-tetrahydroisoquinolin- 7-yl)- {4- [l- (cyclopropyliminomethyl) piperidin-4- yloxy] benzenesulphonyl} amino) butyric acid 3,4-tetrahydroisoquinolin- 7-yl)- (4- {1- [imino- (4-methoxyphenyl) methyl]- piperidin-4-yloxy}benzenesulphonyl)amino]butyric acid 53. 4-((2-Carbamimidoyl-1, 2,3,4-tetrahydroisoquinolin- 7-yl)- {4- [1- (iminothiophen-2-ylmethyl) piperidin-4- yloxy] benzenesulphonyl} amino) butyric acid 54. Ethyl [ [4- (1-carbamimidoylpiperidin-4-yloxy)- benzenesulphonyl]- (2-carbamimidoyl-1,2,3,4- tetrahydroisoquinolin-7-yl) amino] acetate 55. Ethyl ((2-carbamimidoyl-1, 2,3,4-tetrahydroiso- quinolin-7-yl)- {4- [1- (1-iminoethyl) piperidin-4- yloxy] benzenesulphonyl} amino) acetate 56. Ethyl ((2-carbamimidoyl-1, 2,3,4-tetrahydroiso- quinolin-7-yl)- {4- [l- (l-iminopropyl) piperidin-4- yloxy] benzenesulphonyl} amino) acetate 57. Ethyl ((2-carbamimidoyl-1, 2,3,4-tetrahydroiso- quinolin-7-yl)- {4- [l- (cyclopropyliminomethyl)- piperidin-4-yloxy] benzenesulphonyl} amino) acetate 58. Ethyl [(2-carbamimidoyl-1, 2,3,4-tetrahydroiso- quinolin-7-yl)- (4- {l- [imino- (4-methoxyphenyl)- methyl] piperidin-4-yloxy} benzenesulphonyl)- amino] acetate 59. Ethyl ((2-carbamimidoyl-1, 2,3,4-tetrahydroiso- quinolin-7-yl)- {4- [1- (iminothiophen-2-ylmethyl)- piperidin-4-yloxy] benzenesulphonyl} amino) acetate 60. 7-{Acetyl-[4-(1-carbamimidoylpiperidin-4-yloxy)- benzenesulphonyl] amino}-3, 4-dihydro-lH- isoquinoline-2-carboxamidine 61.7- (Acetyl- {4- [l- (l-iminoethyl) piperidin-4-yloxy]- benzenesulphonyl} amino)-3,4-dihydro-lH-isoquino- line-2-carboxamidine 62.7- (Acetyl- {4- [l- (l-iminopropyl) piperidin-4- yloxy] benzenesulphonyl} amino)-3,4-dihydro-lH- isoquinoline-2-carboxamidine 63.7- (Acetyl- {4- [1- (cyclopropyliminomethyl) piperidin- 4-yloxy] benzenesulphonyl} amino)-3,4-dihydro-lH- isoquinoline-2-carboxamidine 64.7- [Acetyl- (4- {1- [imino- (4-methoxyphenyl) methyl]- piperidin-4-yloxy} benzenesulphonyl) amino]- 3,4-dihydro-lH-isoquinoline-2-carboxamidine 65.7- (Acetyl- {4- [1- (iminothiophen-2-ylmethyl)- piperidin-4-yloxy] benzenesulphonyl} amino)- 3,4-dihydro-lH-isoquinoline-2-carboxamidine 66. 7-[[4-(1-Carbamimidoylpiperidin-4-yloxy)benzene- <BR> <BR> <BR> sulphonyl]- (4-methoxybenzoyl) amino]-3,4-dihydro-<BR> <BR> <BR> <BR> lH-isoquinoline-2-carboxamidine 67.7- [ {4- [l- (l-Iminoethyl) piperidin-4-yloxy] benzene- <BR> <BR> <BR> sulphonyl}- (4-methoxybenzoyl) amino]-3,4-dihydro-<BR> <BR> <BR> <BR> lH-isoquinoline-2-carboxamidine 68.7- [ {4- [l- (l-Iminopropyl) piperidin-4-yloxy]- benzenesulphonyl}- (4-methoxybenzoyl) amino]- 3,4-dihydro-lH-isoquinoline-2-carboxamidine 69.7- [ {4- [l- (Cyclopropyliminomethyl) piperidin-4- yloxy] benzenesulphonyl}- (4-methoxybenzoyl) amino]- 3,4-dihydro-lH-isoquinoline-2-carboxamidine 70.7- [ (4- {l- [Imino- (4-methoxyphenyl) methyl] piperidin- 4-yloxy} benzenesulphonyl)- (4-methoxybenzoyl)- amino]-3,4-dihydro-lH-isoquinoline-2-carboxamidine 71.7- [ {4- [l- (Iminothiophen-2-ylmethyl) piperidin-4- yloxy] benzenesulphonyl}- (4-methoxybenzoyl) amino]- 3,4-dihydro-lH-isoquinoline-2-carboxamidine 72. [ [4- (l-Carbamimidoylpiperidin-4-yloxy) benzene- sulphonyl]-(2-carbamimidoyl-1,(2-carbamimidoyl-1, 2,3,4-tetrahydro- isoquinolin-7-yl) amino] sulphonylacetic acid 73. ((2-Carbamimidoyl-1,2,3,4-tetrahydroisoquinolin-7- yl)- {4- [1- (l-iminoethyl) piperidin-4-yloxy]- benzenesulphonyl} amino) sulphonylacetic acid 74. ((2-Carbamimidoyl-1, 2,3,4-tetrahydroisoquinolin-7- yl)- {4- [l- (l-iminopropyl) piperidin-4-yloxy]- benzenesulphonyl} amino) sulphonylacetic acid 75. ((2-Carbamimidoyl-1,2,3,4-tetrahydroisoquinolin-7- yl)- {4- [l- (cyclopropyliminomethyl) piperidin-4- yloxy] benzenesulphonyl} amino) sulphonylacetic acid 76. [(2-Carbamimidoyl-1,2,3,4-tetrahydroisoquinolin-7- yl)- (4- {l- [imino- (4-methoxyphenyl) methyl]- piperidin-4-yloxy) benzenesulphonyl) amino]- sulphonylacetic acid 77. ((2-Carbamimidoyl-1,2,3,4-tetrahydroisoquinolin-7- yl)- {4- [1- (iminothiophen-2-ylmethyl) piperidin-4- yloxy] benzenesulphonyl} amino) sulphonylacetic acid 78. [ [4- (l-Carbamimidoylpiperidin-4-yloxy) benzoyl- sulphonyl]-(2-carbamimidoyl-1,(2-carbamimidoyl-1, 2,3,4-tetrahydro- isoquinolin-7-yl) amino] methylboronic acid 79. ((2-Carbamimidoyl-1, 2,3,4-tetrahydroisoquinolin-7- yl)- {4- [l- (l-iminoethyl) piperidin-4-yloxy] benzene- sulphonyl} amino) methylboronic acid 80. ((2-Carbamimidoyl-1, 2,3,4-tetrahydroisoquinolin-7- yl)- {4- [l- (l-iminopropyl) piperidin-4-yloxy]- benzenesulphonyl} amino) methylboronic acid 81. ((2-Carbamimidoyl-1, 2,3,4-tetrahydroisoquinolin-7- yl)- {4- [1- (cyclopropyliminomethyl) piperidin-4- yloxy] benzenesulphonyl} amino) methylboronic acid 82. [(2-Carbamimodyl-1, 2,3,4-tetrahydroisoquinolin-7- yl)- (4- {l- [imino- (4-methoxyphenyl) methyl]- piperidin-4-yloxy} benzenesulphonyl) amino] methyl- boronic acid 83. ((2-Carbamimodyl-1, 2,3,4-tetrahydroisoquinolin-7- yl)- {4- [l- (iminothiophen-2-ylmethyl) piperidin-4- yloxy] benzenesulphonyl} amino) methylboronic acid 84.7- [4- (l-Carbamimidoylpyrrolidin-3- (S)-yloxy)- benzenesulphonylamino]-3,4-dihydro-lH- isoquinoline-2-carboxamidine 85. [ [4- (I-Carbamimidoylpyrrolidin-3- (S)-yloxy)- benzenesulphonylamino]-(2-carbamimidoyl-1,(2-carbamimidoyl-1 , 2,3,4- tetrahydroisoquinolin-7-yl) amino] sulphonylacetic acid 86. ((2-Carbamimidoyl-1, 2,3,4-tetrahydroisoquinolin-7- yl)- {4- [l- (1-iminoethyl) pyrrolidin-3- (S)-yloxy]- benzenesulphonyl} amino) sulphonylacetic acid 87. [ [4- (l-Carbamimidoylpyrrolidin-3- (S)-yloxy)- benzenesulphonyl]-(2-carbamimidoyl-1,(2-carbamimidoyl-1, 2,3,4- tetrahydroisoquinolin-7-yl) amino] acetic acid 88. ((2-Carbamimidoyl-1, 2,3,4-tetrahydroisoquinolin-7- yl)- {4- [l- (l-iminoethyl) pyrrolidin-3- (S)-yloxy]- benzenesulphonyl} amino) acetic acid The following examples illustrate the invention, without restricting it thereto.

Example 1: <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 7- (4- (1-Carbamimidoylpiperidin-4-yloxy) benzene-<BR> <BR> <BR> <BR> <BR> <BR> <BR> sulphonylamino]-3, 4-dihydro-lH-isoquinoline-2- carboxamidine dihydrochloride 1. tert-Butyl 7-nitro-3,4-dihydro-lH-isoquinoline-2- carboxylate A solution of 9.6 g (0.044 mol) of di-tert-butyl dicarbonate in 100 ml of methylene chloride is added dropwise at 5°C to a suspension of 8.6 g (0.040 mol) of 7-nitro-1,2,3,4-tetrahydro- isoquinoline hydrochloride (J. F. Ajao, C. W. Bird, Heterocyclo. Chem. 1985,22,239-331) and 16.6 ml (0.170 mol) of triethylamine in 100 ml of methylene chloride. After stirring at room temperature for 24 hours, the resulting clear solution is successively extracted 3 x in each case with 50 ml each of water, 1 N acetic acid and saturated sodium bicarbonate solution. After drying and concentrating, the residue is triturated with isohexane, filtered off with suction and dried. 10.9 g (0.039 mol; 98%) of the title compound of m. p. 137-139°C are obtained as a brownish solid; EI-MS: 278 (M+).

2. tert-Butyl 7-amino-3,4-dihydro-lH-isoquinoline-2- carboxylate 8.3 g (0.030 mol) of tert-butyl 7-nitro-3,4- dihydro-lH-isoquinoline-2-carboxylate are dissolved in 100 ml of ethyl acetate and hydrogenated in the presence of 1.0 g of palladium/carbon (10%) under normal pressure for 5 h at room temperature. After absorption of 2160 ml of hydrogen, the catalyst is removed by filtration and the solvent is stripped off. As a residue, 7.3 g (0.029 mol; 98%) of the title compound are obtained as a light brown solid of m. p. 75-77°C; EI-MS: 248 (M+).

3. tert-Butyl 7-benzylamino-3, 4-dihydro-lH-iso- quinoline-2-carboxylate A solution of 5.0 g (0.020 mol) of tert-butyl 7-amino-3,4-dihydro-lH-isoquinoline-2-carboxylate in 50 ml of methanol is treated with 2.40 ml (0.022 mol) of benzaldehyde and stirred at room temperature for 16 h. The resulting reaction mixture is cooled to 5°C and 0.76 g (0. 021 mol) of sodium borohydride is added in portions. After stirring at room temperature for 24 hours, the methanol is removed by distillation and the solid residue is triturated with water, filtered off with suction and dried. 5.80 g (86%) of the title compound are obtained as a white solid. M. p.

110°C; (+)-FAB-MS: 339 (MH+).

4. tert-Butyl 7- [benzyl- (4-hydroxybenzenesulphonyl)- amino]-3,4-dihydro-lH-isoquinoline-2-carboxylate A solution of 9.1 g (0.027 mol) of tert-butyl 7- benzylamino-3,4-dihydro-lH-isoquinoline-2- carboxylate in 150 ml of abs. pyridine is treated in portions at 5°C with 6.24 g (0.030 mol) of 4-hydroxybenzenesulphonyl chloride (R. W. Campbell, H. W. Hill, J. Org. Chem. and stirred at room temperature for 16 h. The pyridine is distilled off and the residue is dissolved in 150 ml of ethyl acetate. It is extracted successively 2 x in each case with 50 ml each of water, 1 N acetic acid and saturated sodium bicarbonate solution, and the organic phase is dried over sodium sulphate. After concentrating, the residue is chromatographed on a silica gel column for purification (eluent: isohexane/ethyl acetate 8: 2,7: 3,6: 4,1: 1). After concentrating the appropriate column fractions, 10.9 g (82%) of the title compound are obtained as a white, crystalline solid of m. p. 172-175°C EI-MS: 495 (M+).

5. tert-Butyl {benzyl- [4- (l-tert-butoxycarbonyl- piperidin-4-yloxy) benzenesulphonyl] amino}-3,4- dihydro-lH-isoquinoline-2-carboxylate A solution of 9.2 g (0.019 mol) of tert-butyl 7- [benzyl- (4-hydroxybenzenesulphonyl) amino]-3,4- dihydro-lH-isoquinoline-2-carboxylate, 4.1 g (0.021 mol) of tert-butyl 4-hydroxypiperidine-1- carboxylate (analogously to K. L. Bhat, D. M. Flanagan, M. M. Jouille, Synth. Commun. 1985, 15,587-598) and 5.4 g (0.021 mol) of triphenylphosphine in 150 ml of tetrahydrofuran is treated at 5°C with 3.3 ml (0.021 mol) of diethyl azodicarboxylate and stirred at room temperature for 24 h. After concentrating, the residue is chromatographed on a silica gel column for purification (eluent: isohexane/ethyl acetate 9: 1, 8: 2,7: 3). After concentrating the appropriate column fractions, 9.0 g (71%) of the title compound are obtained as a white solid. M. p. 142- 144°C; (+)-FAB-MS: 678 (MH+).

6. tert-Butyl 7-{[4-(1-tert-butoxycarbonylpiperidin- 4-yloxy) benzenesulphonyl] amino}-3, 4-dihydro-lH- isoquinoline-2-carboxylate 8.9 g of tert-butyl 7- {benzyl- [4- (l-tert-butoxy- carbonylpiperidin-4-yloxy) benzenesulphonyl]- amino}-3,4-dihydro-lH-isoquinoline-2-carboxylate (0.013 mol) are dissolved in 250 ml of ethyl acetate and hydrogenated in the presence of 2.0 g of palladium/carbon (10%) under normal pressure for 10 d at room temperature. The catalyst is removed by filtration and the filtrate is concentrated. The residue is chromatographed on a silica gel column for purification (eluent: isohexane/ethyl acetate 9: 1,8: 2,7: 3). After concentrating the appropriate column fractions, 5.3 g (69%) of the title compound are obtained as a colourless oil. (+)-FAB-MS: 588 (MH+).

3,4-tetrahydro- isoquinolin-7-yl) benzenesulphonamide dihydrochloride A solution of 2.5 g (0.004 mol) of tert-butyl <BR> <BR> <BR> <BR> 7-{[4-(1-tert-butoxycarbonylpiperidin-4-yloxy)-<BR> <BR> <BR> <BR> <BR> <BR> benzenesulphonyl] amino}-3, 4-dihydro-lH- isoquinoline-2-carboxylate in 50 ml of diethyl ether is treated at 5°C with 50 ml of ethereal HC1 solution and then stirred at 5°C for 5 h. The precipitated white solid is removed by filtration and dried: 1.9 g (0.0126 mmol; m. p.

107-109°C; EI-MS: 387 (M+).

8.7- [4- (l-carbamimidoylpiperidin-4-yloxy)-benzene- sulphonylamino]-3,4-dihydro-lH-isoquinoline-2- carboxamidine dihydrochloride A solution of 0.9 g (0.002 mol) of 4- (piperidin-4- yloxy)-N- (1,2,3,4-tetrahydroisoquinolin-7-yl- benzenesulphonamide dihydrochloride and 1.2 g (0.008 mol) of 1H-pyrazole-l-carboxamidine hydrochloride (ref.: M. S. Bernatowicz, Y. Wu, G. R. Matsueda, J. Org. Chem. 1992,57,2497-2502) in 2 ml of dimethylformamide is treated at 5°C with 4.2 ml of diisopropylethylamine. After stirring at room temperature for 24 hours, it is treated 4 x with 25 ml of diethyl ether each time and the ether is decanted off. The residue which remains is dissolved in 15 ml of water, adjusted to pH 3 using 2 N HC1 and chromatographed (eluent: H2O, pH 3; H20/CH30H 6: 4, pH 3) by means of preparative HPLC (RP-18 column, 15-25m). After concentrating the appropriate column fractions and drying in vacuo (10-2 torr), 0.8g (74%) of the title compound is obtained as a white solid of m. p. 150°C (dec.); (+)-FAB-MS: 472 (MH+).

Example 2: Description of pharmacological test Obtainment of plasma Nine parts of fresh blood from healthy donors are mixed with one part of sodium citrate solution (0.11 mol/1) and centrifuged at about 3000 rpm for 10 minutes at room temperature. The plasma is removed by pipette and can be stored at room temperature for about 8 h.

Activated partial thromboplastin time (APTT) 100 Rl of citrate plasma and 100 il of APTT reagent (Diagnostica Stago/Boehringer Mannheim GmbH; contains lyophilisate cephalin with microcrystalline kieselguhr activator) are incubated at 37°C for 3 minutes together with 10 Rl of dimethyl sulphoxide (DMSO) or 10 au ouf a solution of the active substance in DMSO in a ball coagulometer (KC10 from Amelung). With addition of 100 au ouf 0.025 M calcium chloride solution, a stopclock is started and the time until the occurrence of clotting is determined. In the control measurements, the APTT is about 28-35 seconds and is prolonged by active substances. If no clotting occurred after 5 minutes during the measurements, the test was stopped (>300).

The measured APTT times in seconds are indicated as the difference from the control in Table 1. The concentrations of the active substances in the final volume was 1000 FM (APTT 1000), 100 M (APTT 100), 10 FM (APTT 10), 1 RM (APTT 1).

Thrombin time 200 Al of citrate plasma are incubated at 37°C for 2 minutes in a ball coagulometer (KC10 from Amelung). 10p1 of dimethyl sulphoxide (DMSO) or a solution of the active substance in DMSO are/is added to 190 ll of thrombin reagent whose temperature has previously been adjusted (Boehringer Mannheim GmbH; contains about 3 U/ml of equine thrombin and 0.0125 M Ca++. With addition of this 200 p. l of solution to the plasma, a stopclock is started and the time until the occurrence of clotting is determined. In the control measurements, the thrombin time is about 24 seconds and is prolonged by active substances.

If no clotting occurred after 5 minutes during the measurements, the test was stopped (>300).

The measured thrombin times in seconds are indicated as the difference from the control in Table 1. The concentrations of the active substances in the final volume were 500 AM (TT 500).

Inhibition constants The kinetic measurements were carried out in 0.1 M phosphate buffer containing 0.2 M saline solution and 0.5% polyethylene glycol 6000 (preparation see below) at pH 7.5 and 25°C in polystyrene semimicro cuvettes in a total volume of 1 ml. The reactions were started by addition of enzyme to preincubated solutions, which either contained dimethyl sulphoxide (control) or solutions of the test substance in DMSO (inhibitor stock solutions: 10 mM in DMSO). The increase in the extinction at 405 nm as a result of the release of 4-nitroaniline from the substrate was monitored photometrically over a period of 12 minutes. Measured values (extinction vs time) were determined at an interval of 20 seconds and these data were stored by computer.

The procedure for the determination of the inhibition constants Ki was as follows: the velocities Vo (change in extinction per second; measurements without inhibitor) and Vi (change in extinction per second; measurements with inhibitor) were determined by linear regression, only the measuring points at which the substrate concentration decreased by less than 15% being <BR> <BR> <BR> <BR> taken into account. KM and Vmax were determined from a series of measurements (constant inhibitor concentration, variable substrate concentrations) by non-linear fit to the equation V = V, ax x [S] [S] + KM The Ki value was obtained from the complete series of measurements with 16 data sets (measurements at 4 different substrate concentrations and in each case 4 different inhibitor concentrations) by non- linear regression from the equation <BR> <BR> <BR> <BR> <BR> <BR> [S]VmaxX <BR> Vi = KM X (1 + [I] / Ki) + [S] <BR> <BR> <BR> <BR> <BR> <BR> Vmax being the maximum velocity in the absence of an inhibitor, KM the Michaelis constant and [S] the substrate concentration.

The measured Ki values are indicated in [uM] in Table 1.

FXa: Stock solution: 990 pi of phosphate buffer solution (preparation see below) are treated with 10 pi of human factor Xa (Boehringer Mannheim GmbH; 10 U; suspension) and stored on ice for at most 4 hours.

For measurement, 850 ul of phosphate buffer are thermostated (25°C) with 100 ul of substrate <BR> <BR> <BR> <BR> [N-methoxycarbonyl- (D)-norleucyl-glycyl- (L)-argi- nine-4-nitroaniline acetate; Chromozym X; Boehringer Mannheim GmbH; substrate concentrations <BR> <BR> <BR> <BR> used 800,600,400 and 200 uM; KM 400 uM] and 25 ul of inhibitor solution or 25 ul of DMSO (control) in a photometer. The reaction is started by addition of 25 pi of stock solution.

Thrombin: Human a-thrombin (Sigma; 100 U; specific activity: 2000 NIH units/mg) is dissolved in 1 ml of water and stored at-18°C in portions of 20 pi. Stock solution: 1480 ul of phosphate buffer solution (preparation see below) are treated with 20 pi of the a-thrombin solution prepared as above and stored on ice for at most 4 hours. For measure- ment, 850 ul of phosphate buffer are thermostated (25°C) with 100 pi of substrate [H- (D)-Phe-Pip- Arg-4-nitroaniline dihydrochloride; S-2238; Kabi; substrate concentrations used 100,50,30 and 20 uM; KM 4 uM) and 25 pi of inhibitor solution or 25 pi of DMSO (control) in a photometer. The reaction is started by addition of 25 ul of stock solution.

Trypsin: 10 mg of bovine pancreatic trypsin (Sigma) are dissolved in 100 ml of 1 mM hydrochloric acid and stored at 2-8°C in a refrigerator. Stock solution: 990 ul of 1 mM hydrochloric acid are treated with 10 pi of the trypsin solution prepared as above and stored on ice for at most 4 hours. For measurement, 850 ul of phosphate buffer are thermostated (25°C) with 100 ul of substrate [H- (D)-Phe-Pip-Arg-4-nitroaniline dihydrochloride; S-2238; Kabi; substrate concentrations used 100, 50,30 and 20 uM; KM 45 uM) and 25 ul of inhibitor solution or 25 pi of DMSO (control) in a photometer. The reaction is started by addition of 25 ul of stock solution.

Preparation of the 0.1 M phosphate buffer solution (pH 7.5,0.2 M NaCl): 8.90 g of Na2HP04-2 2 H2O, 5.84 g of NaCl and 2.50 g of polyethylene glycol 6000 are dissolved in 400 ml of distilled water and made up to a total volume of 500 ml with distilled water (solution I). 1.36 g of KH2PO4,1.17 g of NaCl and 0.50 g of polyethylene glycol 6000 are dissolved in 80 ml of distilled water and made up to a total volume of 100 ml with distilled water (solution II). Sufficient solution II (about 85 ml) is then added to solution I until the pH is 7.5. The buffer solution is always freshly prepared (can be kept at 4°C for at most 10 days when stored in a refrigerator).

Table 1: Pharmacological data of Example Compound I ExampleKi Ki Ki APTT APTT APTT APTT TT No. (fXa) (thrombin) (trypsin) 1000 100 10 1 500 1 0.010 2 0. 1 > 300 140 50 12 40