WO1999042462A1

WO1999042462A1 - Sulfonamides with antithrombotic activity

Info

Publication number: WO1999042462A1
Application number: PCT/EP1999/000914
Authority: WO
Inventors: Frank Grams; Ralf Kucznierz; Herbert Leinert; Karlheinz Stegmeier; Wolfgang Von Der Saal
Original assignee: Roche Diagnostics GmbH
Current assignee: Roche Diagnostics GmbH
Priority date: 1998-02-18
Filing date: 1999-02-12
Publication date: 1999-08-26
Anticipated expiration: 2000-08-18
Also published as: AR015233A1; EP0937723A1; AU3140799A; ZA991268B

Abstract

The invention relates to novel sulphonamides of general formula (I) in which R1 to R4 have the meaning indicated, and their hydrates, solvates and physiologically tolerable salts, optically active forms, racemates and diastereomer mixtures, processes for their preparation and medicaments which contain these compounds, for the treatment of thromboembolic disorders.

Description

SULFONAMIDES WITH ANTITHROMBOTIC ACTIVITY

The invention relates to novel sulphonamides of the general formula I

(I)

in which

R¹ , R² 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;

X 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 - 2 - 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 - 3 - 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. Thro bin, as the last enzyme in the clotting cascade, on the one hand cleaves fibrinogen to fibrin, which after crosslinking by means of factor Xllla 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) -l-acetimidoyl-3-pyrrolidinyl] oxy]phenyl] -3- (7- amidino-2-naphthyl) propanoic acid hydrochloride pentahydrate (DX-9065a; formula Ila) inhibits factor Xa (J. Med. Chem . 1994, 31, 1200-1207; Thrombosis and Haemostasis 1994, 71, 314-319; EP-0-540-051-A-1) . Further known factor Xa inhibitors are 1,2-bis (5- amidino-2-benzofuranyl) ethane (DABE, formula lib, Thrombosis Research 1980, 19 , 339-349) or alternatively - 4 phenylaminomethylnaphthamidines of the general formula He (WO96/16940) .

(Ila)

(lib)

(lie)

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 R¹ and R² can be identical or different.

If R¹, R² 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 R¹, 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, /.-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, 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 , - 5 -

1-propenyl, 2-propenyl, 2-methyl-2-propenyl , 1-butenyl, 1-pentenyl and the 1-hexenyl group are preferred.

If R¹, R² 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 R¹, 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 C_I-CR- alkyl substituents, preferably methyl, one or more Cι-C₈~alkyloxy substituents, preferably methoxy, one or more carboxyl groups, one or more Cι-C₈-alkoxycarbonyl substituents, preferably methoxycarbonyl or ethoxy- carbonyl , or one or more halogen substituents. The specification C_α-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 Ci-Cs-alkyl substituents, preferably methyl, one or more Ci-Cs-alkyloxy substituents, preferably methoxy, one or more carboxyl groups, one or more Ci-Cs-alkoxycarbonyl substituents, preferably methoxycarbonyl or ethoxycarbonyl , or one or more halogen substituents. The specification Ci-Cβ 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 R¹ , R² in the general formula I contain 1 to 8 carbon atoms and are - 6 - 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 R¹, R² in the general formula I is an aralkyloxy group, this contains a phenyl group linked to a straight-chain or branched Ci-Cs-alkyl chain, a naphthyl group linked to a straight-chain or branched Ci-Cs-alkyl chain or a biphenyl group linked to a straight-chain or branched Ci-Cg-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 R¹, R² 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 R¹, R² 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.

If R¹, R² 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 , - 7 - hydroxybutyl , hydroxypentyl and the hydroxyhexyl group are preferred.

If R¹, 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 R¹, 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. - 8 -

An aralkyl radical as a subεtituent R³ in the general formula I is understood as meaning a phenyl group linked to a straight-chain or branched Ci-Cβ-alkyl chain, a naphthyl group linked to a straight-chain or branched Ci-Ce-alkyl chain or a biphenyl group linked to a straight-chain or branched Ci-Cs-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 hydroxyalkyl 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 Ci-Cs- alkyl substituents, preferably methyl, one or more Ci-Cs-alkyloxy substituents, preferably methoxy, one or more carboxyl groups, one or more Ci-Cs-alkoxycarbonyl substituents, preferably methoxycarbonyl or ethoxycarbonyl, or one or more halogen substituents. The specification Cι-C₈ here in each case stands for a straight-chain or branched alkyl chain having 1 to 8 - 9 - 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 carboxyalkylsulphonyl 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 carboxyethy1sulphonyl and the carboxy- propylsulphonyl group are preferred.

If R³ in the general formula I is an alkyloxycarbonylalkylsulphonyl 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 , ethoxycarbonyl ethyl- sulphonyl, methoxycarbonylethylsulphonyl, ethoxy- carbonylethy1sulphonyl , 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. - 10 -

If R⁴ in the general formula I is an amino group, this can be unsubstituted or alternatively substituted, namely by one or two Cι-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-C₈-alkynyl groups, preferably propargyl , or by one or two aralkyl groups, preferably benzyl. The specification Cι-C₈-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 Ci-Cg-alkyl chain, a naphthyl group linked to a straight-chain or branched Cι-C₈-alkyl chain or a biphenyl group linked to a straight-chain or branched Cι-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^a,R² are identical or different and are a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxyl group, a methyl group, an ethyl group, - 11 - a methoxy group, a benzyloxy group, an allyloxy group, a carboxyl group, a methoxy- or ethoxycarbonyl 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 ethoxycarbonylethylεulphonyl group, an ethoxycarbonylpropylsulphonyl group, a dihydroxyborylmethyl group, a dihydroxyboryl- propyl group, a 4 , 4 , 5 , 5-tetramethyl-l, 3 , 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. - 12 -

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 tartrateε or alkanesulphonates having up to 10 carbon atoms or p-toluenesulphonateε or salicylateε or trifluoro- acetateε or εaltε of phyεiologically tolerable mineral acidε such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulphuric acid, phosphoric acid. The compounds of the formula I having one or two free acid groupε on the phosphonate fragment can also form saltε with physiologically tolerable bases. Examples of such salts are alkali metal, alkaline earth metal, ammonium and alkylammonium εaltε, εuch aε the sodium, potaεεium, calcium or tetramethylammonium salt.

The compounds of the formula (I) can be solvated, in particular hydrated. Hydration can be carried out in the courεe of the preparation or can occur gradually aε a reεult of hygroscopic properties of an initially anhydrouε compound of the formula I.

The invention alεo relateε to the optically active formε, the racemates and the diastereomer mixtures of compounds of the general formula I.

For the production of medicamentε, the εubεtances of the general formula I are mixed with suitable pharmaceutical carrier εubεtanceε, aromatic εubεtances, flavourings and colourants and are shaped, for example, as tablets or coated tablets or are suεpended 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 saltε can be adminiεtered orally, enterally or parenterally in liquid or εolid form. The oral adminiεtration form is preferred. The injection medium used iε preferably water, which containε the additiveε cuεtomary in injection εolutions such as stabilizing agents, solubilizerε or buffers. Additives of this type - 13 - are, for example, tartrate and citrate buffers, complexing agentε (εuch aε ethylenediaminetetraacetic acid and itε non-toxic εaltε) and high molecular weight polymerε εuch as liquid polyethylene oxide for viscosity regulation. Solid excipients are, for example, starch, lactoεe, mannitol, methylcelluloεe, talc, highly disperse silicic acids, high molecular weight fatty acidε (such as stearic acid), animal and vegetable fats and solid high molecular weight polymers (such aε polyethylene glycolε) . If deεired, preparations suitable for oral administration can contain flavourings and εweetenerε .

The compoundε are customarily administered in amounts of 1-1500 mg per day baεed 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 alεo 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 alεo be given by injection 1-8 times per day or by continuous infusion, 5-2000 mg per day normally being sufficient.

Compoundε 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

(111)

in which R , R , R and m have the meanings indicated above, with a guanylating reagent in an inert solvent in the presence of an auxiliary base. - 14 - In detail, the compoundε of formula I can be prepared, for example, by reacting a compound of the general formula III

R2 /7

(III)

-NH m in which R¹ , R², R³ and m have the meaningε given above, with a guanylating reagent εuch as, for example, S- alkylisothiourea, preferably S-methylisothiourea, or lH-pyrazole-1-carboxamidine (εee e.g.: M.S. Bernatowicz, Y. u, G.R. Matεeuda, J. Org. Chem. 1992, 57, 2497-2505) in an inert εolvent such as e.g. dimethylformamide, dioxan, dimethyl sulphoxide or toluene at temperatureε between 0°C and the boiling point of the solvent, preferably at 0 to 30°C in the presence of an auxiliary baεe εuch as e.g. triethylamine, N-methylmorpholine, pyridine or ethyldiisopropylamine .

The compoundε of the general formula III are prepared by reacting a compound of the general formula IV

PG1

(IV) πi ^VPG1

in which R¹ , R² R and m have the meaningε indicated above and PG iε a protective group εuch aε, for example, the benzyloxycarbonyl group, the t-butyloxy- carbonyl group or the allyloxycarbonyl group, with a 15 reagent removing the protective group. The protective group removal iε carried out according to generally cuεtomary methodε (εee, for example, T.W. Green, P.G.M. Wutε, "Protective Groupε in Organic Synthesiε", 2nd ed. , John Wiley and Sonε Inc. 1991) by meanε of acidic reagentε εuch aε, for example, hydrogen bromide in glacial acetic acid or trifluoroacetic acid or ethereal HC1 εolution or hydrogenolytically or by meanε of palladium- or rhodium-catalyεed cleavage.

The compounds of the general formula IV are prepared by reacting a compound of the general formula

V

R1

PG1

(V)

^NPG1

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, meεylate or triflate, in an inert solvent εuch aε dioxane, tetrahydrofuran, N,N-dimethyIformamide, N-methylpyrrolidone or toluene in the preεence of a baεe εuch aε, for example, εodium 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 εolvent, preferably between room temperature and 80°C. Compoundε 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 16 -

PG1

(VI)

in which R¹, R², PG¹ and m have the meaningε indicated above, to a catalytic hydrogenation in inert εolventε εuch aε, for example, methanol, ethanol, tetrahydro- furan or dioxane in the preεence of a catalyst, preferably palladium on carbon. The benzyl group iε replaced here by a hydrogen atom. The removal of the benzyl group iε alεo carried out by reaction with a εtrong acid εuch as trifluoroacetic acid in the presence of mesitylene, anisole or thioaniεole at temperatures between 0 and 50°C, preferably at room temperature, or by treatment with Lewis acidε 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 εolvent.

The compoundε of the general formula VI are prepared by condenεing a compound of the general formula VII

(VII)

in which PG¹ and m have the meaningε indicated above, with a compound of the general formula VIII 17 -

PG1 (VIII)

in which R , R and PG have the meaningε indicated above, in an inert εolvent εuch aε dioxane, tetrahydrofuran or toluene in the preεence of diethyl azodicarboxylate and triphenylphoεphine, 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 PG¹ have the meanings indicated above are either commercially available or are known from the literature or can be prepared according to procesεeε which are known from the literature (εee, 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 1993, 13 , 1421-1424; T.W. Green, P.G.M. Wutε "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

°⁰ cr ^'xⁱ (IX)

in which R² haε the meaning indicated above, with a compound of the general formula X - 1 !

PG1 (X)

in which R¹ and PG¹ have the meaningε indicated above, in an inert εolvent εuch aε N,N-dimethyIformamide, 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- tureε between -20°C and the boiling point of the εolvent, preferably between 0°C and 80°C. Compoundε of the type IX are either commercially available or are known from the literature or can be prepared according to standard methods from precurεors which are commercially available or are known from the literature (see, for example, M. Sato, Y. Kawaεhima, J. Goto, Y. Yamane, Y. Chiba et al., £ur. J. Med. Chem . Chim . Ther . 1995, 30, 403-414; W. Loewe, T. Braden, Arch . Pharm . (Weinheim Ger . ) 1995, 328 , 283-286; R. Cremlin, F. Swinbourne, J. Atherall, L. Courtney, T. Cronje et al. Phosphorus Sulphur 1980, 9, 155-164; 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

R1

(XI)

PG1

- 19 - in which R¹ and PG¹ have the meaningε indicated above, in an inert εolvent εuch aε dichloroethane, tetrahydrofuran, dioxane, ethanol, methanol or diglyme, in the presence of a reducing agent such aε, for example, εodium borohydride, εodium cyanoborohydride or εodium triacetoxyborohydride, at temperatureε 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

R1

(XII)

PG1

in which R¹ and PG have the meanings indicated above, in an inert solvent εuch as methanol, ethanol, tetrahydrofuran or dioxane in the preεence of a catalyεt, for example palladium on carbon, tris- triphenylphoεphine-rhodium chloride or Raney nickel. If appropriate, the reduction can alεo be carried out uεing reducing agentε other than hydrogen, e.g. uεing lithium aluminium hydride, εodium borohydride/cobalt dichloride, sodium borohydride/nickel dichloride, triethylεilane/tris-triphenylphosphine-rhodium chloride or using base metals εuch 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

R1

(XIII)

in which R¹ has the meaning indicated above, in an inert solvent such as methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide or water at tempera- 20 - 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 Synthesiε", 2nd ed. , John Wiley and Sonε Inc. 1991), the preεence of baεeε εuch aε alkali metal or alkaline earth metal hydroxideε, 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 methodε 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 Chejn. 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

(XIV)

in which R¹ , R , R and m have the meanings indicated above, with aliphatic or aromatic imidate ester hydrochlorides in an inert εolvent εuch as tetrahydrofuran, diethyl ether, ethanol, dimethylform- - 21 - 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

(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 cuεtomary methodε (εee, for example, T.W. Green, P.G.M. Wutε, "Protective Groupε in Organic Syntheεiε", 2nd ed. , John Wiley and Sonε 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 R1

(XVI)

in which R¹, R², R³ , m and PG² have the meanings indicated above, with a guanylating reagent such aε, for example, lH-pyrazole-1-carboxamidine or S-methyl- 22 isothiourea in an inert εolvent εuch aε, for example, dimethylformamide, dioxane, dimethyl εulphoxide or toluene at temperatureε between 0°C and the boiling point of the εolvent, preferably at 0 to 30°C in the preεence of an auxiliary baεe εuch aε, 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

PG3

(XVII)

in which R¹ , R², R³ , m and PG² have the meanings indicated above and PG² is not equal to PG³ , where PG³ is a protective group εuch aε, for example, the benzyloxycarbonyl group, the t-butyloxycarbonyl group or the allyloxycarbonyl group, with a reagent εelectively removing the PG² protective group. The removal of the protective groupε iε carried out according to generally cuεtomary methodε (εee, for example, T.W. Green, P.G.M. Wutε, "Protective Groupε in Organic Synthesis", 2nd ed. , John Wiley and Sons Inc. 1991), e.g. by acidic reagentε εuch aε hydrogen bromide in glacial acetic acid or trifluoroacetic acid or ethereal HC1 εolution or hydrogenolytically .

The compoundε of the general formula XVII can be prepared from the appropriate precurεorε analogouεly 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 - 23

(XVIII)

PG3

in which R¹, R³ and PG have the meaningε indicated above, with a compound of the general formula XIX

(XIX)

in which R², m and PG² have the meanings indicated above. The reaction is carried out in an inert solvent such aε N,N-dimethylformamide, N-methylpyrrolidone, dioxane, tetrahydrofuran, dichloromethane or toluene in the presence of a base such aε, for example, εodium carbonate, potaεεium carbonate, 1 , 5-diazabicyclo- [5.4.0] undec-5-ene, triethylamine, N-methylmorpholine or ethyldiiεopropylamine 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

R1

(XX)

PG3

in which R and PG have the meanings indicated above, by alkylation with compoundε of the type R³-Y, in which R³ haε the meaning indicated above and Y iε halogen, tosylate, meεylate or triflate, in an inert εolvent εuch aε dioxane, tetrahydrofuran, N,N-dimethyl- formamide, N-methylpyrrolidone or toluene in the preεence of a base such aε, for example, sodium carbonate, potasεium carbonate, 1 , 5-diazabicyclo- - 24 - [5. .0] undec-5-ene or ethyldiiεopropylamine at temperatureε between 0°C and the boiling point of the εolvent, preferably between room temperature and 80°C. Compoundε 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 alεo 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 preεence of a reducing agent εuch aε, for example, sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, at temperatureε 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 precurεorε which are commercially available or are known from the literature. The compoundε of the general formula XX can be prepared from the corresponding precurεorε analogously to the compounds of the general formula XI.

The compounds of the general formula XIX can be prepared by εulphochlorinating a compound of the general formula XXI

(XXI)

Mil PG2

in which R², m and PG² have the meaningε indicated above. Thiε iε carried out in an inert εolvent εuch aε dichloromethane, chloroform or carbon tetrachloride using a sulphochlorinating reagent εuch as - 25 - chloroεulphonic acid, if appropriate in the preεence of thionyl chloride, εulphuryl chloride or phoεphoryl chloride at temperatureε between -20°C and the boiling point of the εolvent, preferably between 0°C and 40°C.

The compoundε of the general formula XXI are prepared by condenεing a compound of the general formula XXII

HO-

-N. (XXII)

L Jm \ PG2

in which PG² and m have the meanings indicated above, with a compound of the general formula XXIII

R2

(XXIII)

in which R² has the meaning indicated above, in an inert εolvent εuch aε dioxane, tetrahydrofuran or toluene in the preεence of diethyl azodicarboxylate and triphenylphoεphine, 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 processeε known from the literature (εee, 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. Robertε, S.H. Wright, J. Chem . Soc . Perkin Trans . 1 1993, 13 , 1421-1424; T.W. Green, P.G.M. Wutε, "Protective Groups in Organic Synthesiε", 2nd ed. , John Wiley and Sons Inc. 1991) .

Compounds of the general formula XXIII in which R² haε the meaning indicated are either commercially available or are known from the literature or can be prepared according to standard methods from precursors - 26 - which are commercially available or are known from the literature.

Certain compoundε of the general formula I can εubεequently be converted into other compoundε of the general formula I .

Thiε relateε to compoundε of the general formula I in which R¹ , R², R³ , R⁴, n and m have the meaningε indicated above and one or more of the radicals R¹ , R², R³ is or compriseε a methoxy group. By meanε of treatment with cuεtomary reagents removing the methyl group (see, for example, T.W. Green, P.G.M. Wuts, "Protective Groups in Organic Synthesiε", 2nd ed., John Wiley and Sonε Inc. 1991) εuch aε , for example, trimethylεilyl iodide or boron tribromide in an inert solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, acetone, acetonitrile at temperatureε between 0°C and the boiling point of the εolvent, preferably between 0°C and 60°C, these compounds can be converted into the corresponding compoundε of the general formula I having a free hydroxyl group .

Thiε alεo relateε 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 εuch as tetrahydrofuran, dioxane, acetone, ethanol, methanol or water at temperatureε 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 alεo relates to compounds of the general formula I in which R¹ , R², R³ , R , n and m have the meanings indicated above and one or more of the radicals R¹, R² is a benzyloxy group. By means of catalytic hydrogenation in inert εolventε εuch aε, for - 27 - example, methanol, ethanol, tetrahydrofuran or dioxane in the presence of a catalyst, preferably palladium on carbon, the benzyl group iε in thiε caεe replaced by a hydrogen atom (εee, for example, T.W. Green, P.G.M. Wutε, "Protective Groupε in Organic Syntheεiε", 2nd ed. , John Wiley and Sonε Inc. 1991) . The removal of the benzyl group is alεo carried out by reaction with a strong acid such as trifluoroacetic acid in the presence of mesitylene, aniεole 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 εolvent εuch as toluene, acetonitrile, diethyl ether or tetrahydrofuran at temperatures between 0°C and the boiling point of the εolvent, preferably between room temperature and the boiling point of the εolvent.

This alεo relateε to compoundε of the general formula I in which R¹, R , R³ , R , 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 triε-triphenyl- phoεphine-rhodiu chloride or of a palladium catalyst such as tetrakis-triphenylphoεphine-palladium in an inert solvent εuch aε tetrahydrofuran or dioxane, if appropriate in the presence of a nucleophile such aε, for example, diethyl malonate, tributyltin hydride, 5, 5-dimethylcyclohexane-l, 3-dione or piperidine at temperatureε between 0°C and 50°C, preferably at room temperature, the allyl group iε in thiε caεe 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 enantiomerε of the compounds of the formula I are obtained either by resolution (via salt formation with optically active acidε or baεeε) or by employing optically active starting substances in the synthesis or by enzymatically hydrolysing them. - 28 -

Apart from the compounds mentioned in the examples, the following compoundε are preferred within the meaning of the invention:

1. 7- {4- [1- (l-Iminoethyl)piperidin-4-yloxy]benzene- εulphonylamino}-3 , 4-dihydro-lH-iεoquinoline-2- carboxamidine

2. 7- { 4- t 1- (l-Iminopropyl)piperidin-4-yloxy]benzene- εulphonylamino}-3 , 4-dihydro-lH-iεoquinoline-2- carboxamidine

3. 7- {4- [1- (Cyclopropyliminomethyl)piperidin-4- yloxy.benzeneεulphonylamino} -3 , 4-dihydro-lH- isoquinoline-2-carboxamidine

4. 7- (4- {1- [Imino- ( 4-methoxyphenyl) methyl] iperidin- 4-yloxy}benzeneεulphonylamino} -3 , 4-dihydro-lH- iεoquinoline-2-carboxamidine

5. 7- {4- [1- (Iminothiophen-2-ylmethyl)piperidin-4- yloxy] benzeneεulphonylamino} -3 , 4-dihydro-lH- isoquinoline-2-carboxamidine

6. 7-{ [4- (l-Carbamimidoylpiperidin-4-yloxy)benzene- εulphonyljmethylamino} -3 , 4-dihydro-lH-iεoquino- line-2-carboxamidine

7. 7- ( {4- [1- (l-Iminoethyl)piperidin-4-yloxy]benzene- εulphonyljmethylamino} -3 , 4-dihydro-lH-iεoquino- line-2-carboxamidine

8. 7- ( {4- [1- (l-Iminopropyl)piperidin-4-yloxy] - benzeneεulphonyl }methylamino) -3 , 4-dihydro-lH- iεoquinoline-2-carboxamidine - 29 -

9. 7-({4-[l- (Cyclopropyliminoethyl)piperidin-4- yloxy]benzeneεulphonyl}methylamino) -3 , 4-dihydro- lH-iεoquinoline-2-carboxamidine

10. 7-[(4-{l- [Imino- (4-methoxyphenyl)methy1] piperidin- 4-yloxy}benzeneεulphonyl)methylamino] -3 , 4-dihydro- lH-iεoquinoline-2-carboxamidine

11. 7- ( {4- [1- (Iminothiophen-2-ylmethyl)piperidin-4- yloxy]benzeneεulphonyl}methylamino) -3, 4-dihydro- lH-iεoquinoline-2-carboxamidine

12. 7-{ [4- (l-Carbamimidoylpiperidin-4-yloxy)benzene- εulphonyl] ethylamino} -3 , 4-dihydro-lH-iεoquinoline- 2-carboxamidine

13. 7- (Ethyl- {4- [1- (1-Iminoethyl) piperidin-4-yloxy] - benzeneεulphonyl) amino) -3, 4-dihydro-lH-isoquino- 1ine-2-carboxamidine

14. 7- (Ethyl-{4- [1- (l-Iminopropyl)piperidin-4-yloxy] - benzenesulphonyl}amino) -3 , 4-dihydro-lH-isoquino- line-2-carboxamidine

15. 7- ( {4- [ 1- (Cyclopropyliminomethyl)piperidin-4- yloxy]benzeneεulphonyl} ethylamino} -3 , 4-dihydro-lH- isoquinoline-2-carboxamidine

16. 7- [Ethyl- (4-{l- [Imino (4-methoxyphenyl) methyl] - piperidin-4-yloxy}benzenesulphonyl) amino] -

3 , 4-dihydro-lH-iεoquinoline-2-carboxamidine

17. 7- (Ethyl-{4- [1- (Iminothiophen-2-ylmethyl) - piperidin-4-yloxy] benzeneεulphonyl} amino) -

3 , 4-dihydro-lH-iεoquinoline-2-carboxamidine

18. 7-{ [4- ( l-Carbamimidoyl)piperidin-4-yloxy) benzene- εulphonyl] cyclopropylamino) -3 , 4-dihydro-lH-iεo- quinoline-2-carboxamidine - 30 -

19. 7- (Cyclopropyl- {4- [1- (1-iminoethyl) piperidin-4- yloxy]benzenesulphonyl} amino) -3 , 4-dihydro-lH- isoquinoline-2-carboxamidine

20. 7- (Cyclopropyl- {4- [1- ( 1-iminopropyl) piperidin-4- yloxy] benzeneεulphonyl} amino) -3 , 4-dihydro-lH- iεoquinoline-2-carboxamidine

21. 7- (Cyclopropyl- {4- [1- (cyclopropyliminomethyl) - piperidin-4-yloxy] benzeneεulphonyl } amino) -

3 , 4-dihydro-lH-iεoquinoline-2-carboxamidine

22. 7- [Cyclopropyl- (4-{l- [Imino- (4-methoxyphenyl) - methyl ]piperidin-4-yloxy}benzeneεulphonyl) amino] - 3 , 4-dihydro-lH-iεoquinoline-2-carboxamidine

23. 7- (Cyclopropyl- {4- [1- (iminothiophen-2-ylmethyl) - piperidin-4-yloxy] benzeneεulphonyl} amino) -

3 , 4-dihydro-lH-iεoquinoline-2-carboxamidine

24. 7- {Allyl- [4- (l-carbamimidoylpiperidin-4-yloxy) - benzeneεulphonyl] amino} -3 , 4-dihydro-lH-isoquino- line-2-carboxamidine

25. 7- (Allyl- {4- [1- (l-iminoethyl)piperidin-4-yloxy] - benzenesulphonyl}amino}-3 , 4-dihydro-lH-isoquino- line-2-carboxamidine

26. 7- (Allyl- {4- [1- ( 1-iminopropyl) iperidin-4-yloxy] - benzeneεulphonyl} amino) -3 , 4-dihydro-lH-isoquino- line-2-carboxamidine

27. 7- (Allyl- { 4- [ 1- ( cyclopropyliminomethyl ) piperidin- 4-yloxy] enzeneεulphonyl} amino) -3 , 4-dihydro-lH- iεoquinoline-2-carboxamidine - 31 -

28. 7- [Allyl- (4-{l- [imino- (4-methoxyphenyl) methyl] - piperidin-4-yloxy}benzenesulphonyl) amino] - 3 , 4-dihydro-lH-isoquinoline-2-carboxamidine

29. 7- (A.^'lyl-{4- [1- (iminothiophen-2-ylmethyl) - piperidin-4-yloxy] benzeneεulphonyl } amino) - 3 , 4-dihydro-lH-iεoquinoline-2-carboxamidine

30. 7-{Benzyl- [4- (l-carbamimidoylpiperidin-4-yloxy) - benzeneεulphonyl] amino} -3 , 4-dihydro-lH-isoquino- line-2-carboxamidine

31. 7- (Benzyl- {4- [1- (1-iminoethyl) piperidin-4-yloxy] - benzenesulphonyl} amino) -3 , 4-dihydro-lH-isoquino- line-2-carboxamidine

32. 7- (Benzyl- {4- [1- (1-iminopropyl ) piperidin-4- yloxy] benzeneεulphonyl} amino) -3 , 4-dihydro-lH- iεoquinoline-2-carboxamidine

33. 7- (Benzyl- {4- [1- (cyclopropyliminomethyl) piperidin- 4-yloxy] enzenesulphonyl} amino) -3, 4-dihydro-lH- isoquinoline-2-carboxamidine

34. 7- [Benzyl- (4-{l- [imino- (4-methoxyphenyl) methyl] - piperidin-4-yloxy}benzenesulphonyl) mino] -

3 , 4-dihydro-lH-isoquinoline-2-carboxamidine

35. 7- (Benzyl- {4- [1- (iminothiophen-2-ylmethyl) - piperidin-4-yloxy] benzeneεulphonyl} amino) -

3 , 4-dihydro-lH-iεoquinoline-2-carboxamidine

36. 7- [ [4- (1-Carbamimodoylpiperidin-4-yloxy) benzeneεulphonyl] - (2-hydroxyethyl) amino] -3 , 4-dihydro-lH- iεoquinoline-2-carboxamidine

37. 7- ( (2-Hydroxyethyl) -{4- [1- ( l-iminoethyl)piperidin- 4-yloxy] benzeneεulphonyl} amino) -3 , 4-dihydro- lH-iεoquinoline-2-carboxamidine - 32 -

38. 7- ( ( 2-Hydroxyethyl ) - { 4- [ 1- ( 1-iminopropyl ) - piperidin-4-yloxy] benzeneεulphonyl} amino) -

3 , 4-dihydro-lH-iεoquinoline-2-carboxamidine

39. 7-[{4-[l- (Cyclopropyliminomethyl) piperidin-4- yloxy] benzenesulphonyl}- (2-hydroxyethyl) amino] - 3 , 4-dihydro-lH-isoquinoline-2-carboxamidine

40. 7- [ (2 -Hydroxyethyl) - (4-{l- [imino- ( 4-methoxyphenyl) methyl]piperidin-4-yloxy}benzeneεulphonyl) - amino] -3 , 4-dihydro-lH-iεoquinoline-2-carboxamidine

41. 7- ( (2-Hydroxyethyl) -{4- [1- (iminothiophen-2- ylmethyl)piperidin-4-yloxy] benzeneεulphonyl} - amino) -3 , 4-dihydro-lH-isoquinoline-2-carboxamidine

42. [ [4- (l-Carbamimidoylpiperidin-4-yloxy) benzeneεulphonyl] - (2-carbamimidoyl-l, 2,3, 4-tetrahydro- iεoquinolin-7-yl) amino] acetic acid

43. ( (2-Carbamimidoyl-l, 2,3, 4-tetrahydroiεoquinolin-7- yl) - {4- [1- (l-iminoethyl)piperidin-4-yloxy] - benzenesulphonyl} amino) acetic acid

44. ( (2-Carbamimidoyl-l ,2,3, 4-tetrahydroisoquinolin-7- yl ) - { 4- [ 1- ( 1-iminopropyl ) piperidin-4-yloxy] - benzenesulphonyl} amino) acetic acid

45. ( (2-Carbamimidoyl-l, 2,3, 4-tetrahydroisoquinolin-7- yl) - {4- [1- ( cyclopropyliminomethyl ) piperidin-4- yloxy] benzeneεulphonyl}amino) acetic acid

46. [ (2-Carbamimidoyl-l, 2,3, 4-tetrahydroiεoquinolin-7- yl) - (4- {1- [imino- (4-methoxyphenyl) methyl] - piperidin-4-yloxy}benzeneεulphonyl) amino] acetic acid - 33 -

47. ( (2-Carbamimidoyl-l, 2,3, 4-tetrahydroiεoquinolin-7- yl) -{4- [1- ( iminothiophen-2-ylmethy1) piperidin-4- yloxy] benzeneεulphonyl} amino) acetic acid

48. 4- [ [4- (l-Carbamimidoylpiperidin-4-yloxy) benzeneεulphonyl] - (2-carbamimidoyl-l ,2,3, 4-tetrahydro- iεoquinolin-7-yl) amino] butyric acid

49. 4- ( (2-Carbamimidoyl-l , 2,3, 4-tetrahydroisoquinolin- 7-yl) -{4- [1- (l-iminoethyl)piperidin-4-yloxy] - benzeneεulphonyl} amino) butyric acid

50. 4- ( (2-Carbamimidoyl-l , 2,3, 4-tetrahydroisoquinolin- 7-yl) - {4- [1- (l-iminopropyl)piperidin-4-yloxy] - benzeneεulphonyl}amino) butyric acid

51. 4- ( (2-Carbamimidoyl-l ,2,3, 4-tetrahydroisoquinolin- 7-yl) -{4- [1- (cyclopropyliminomethyl) piperidin-4- yloxy] benzeneεulphonyl } amino) butyric acid

52. 4- [ (2-Carbamimidoyl-l , 2,3, 4-tetrahydroiεoquinolin- 7-yl) - (4-{l- [imino- (4-methoxyphenyl) methyl] - piperidin-4-yloxy}benzeneεulphonyl) amino] utyric acid

53. 4- ( (2-Carbamimidoyl-l, 2,3, 4-tetrahydroiεoquinolin- 7-yl) - {4- [1- (iminothiophen-2-ylmethyl)piperidin-4- yloxy] benzenesulphonyl } mino) butyric acid

54. Ethyl [ [4- ( l-carbamimidoylpiperidin-4-yloxy) - benzeneεulphonyl] - (2-carbamimidoyl-l , 2,3,4- tetrahydroisoquinolin-7-yl ) amino] acetate

55. Ethyl ( (2-carbamimidoyl-l , 2 , 3 , 4-tetrahydroiso- quinolin-7-yl) -{4- [1- ( 1-iminoethyl) piperidin-4- yloxy] benzeneεulphonyl } amino ) acetate - 34 -

56. Ethyl ( (2-carbamimidoyl-l, 2 , 3 , 4-tetrahydroiεo- quinolin-7-yl) -{4- [1- ( 1-iminopropyl) piperidin-4- yloxy] benzeneεulphonyl }amino) acetate

57. Ethyl ( (2-carbamimidoyl-l, 2 , 3 , 4-tetrahydroiεo- quinolin-7-yl) - {4- [1- (cyclopropyliminomethyl) - piperidin-4-yloxy] benzeneεulphonyl} mino) acetate

58. Ethyl [ (2-carbamimidoyl-l , 2 , 3 , 4-tetrahydroiεo- quinolin-7-yl) - (4- {1- [imino- (4-methoxyphenyl) - methyl]piperidin-4-yloxy}benzenesulphonyl) - amino] acetate

59. Ethyl ( (2-carbamimidoyl-l , 2 , 3 , 4-tetrahydroiso- quinolin-7-yl) - {4- [1- (iminothiophen-2-ylmethyl) - piperidin-4-yloxy] benzenesulphonyl } amino) acetate

60. 7- {Acetyl- [4- (l-carbamimidoylpiperidin-4-yloxy) - benzeneεulphonyl] amino} -3 , 4-dihydro-lH- iεoquinoline-2-carboxamidine

61. 7- (Acetyl-{4- [1- (l-iminoethyl)piperidin-4-yloxy] - benzeneεulphonyl} amino) -3 , 4-dihydro-lH-isoquino- 1ine-2-carboxamidine

62. 7- (Acetyl- {4- [1- (1-iminopropyl) piperidin-4- yloxy] enzenesulphonyl} amino) -3 , 4-dihydro-lH- isoquinoline-2-carboxamidine

63. 7- (Acetyl- {4- [1- (cyclopropyliminomethyl) piperidin- 4-yloxy] enzeneεulphonyl} amino) -3 , 4-dihydro-lH- isoquinoline-2-carboxamidine

64. 7- [Acetyl- (4- {1- [imino- (4-methoxyphenyl) methyl] - piperidin-4-yloxy}benzeneεulphonyl ) amino] -

3 , 4-dihydro-lH-iεoquinoline-2-carboxamidine - 35 -

65. 7- (Acetyl- {4- [1- (iminothiophen-2-ylmethyl) - piperidin-4-yloxy] benzeneεulphonyl} amino) -

3 , 4-dihydro-lH-iεoquinoline-2-carboxamidine

66. 7- [ [4- (l-Carbamimidoylpiperidin-4-yloxy) enzenesulphonyl] - (4-methoxybenzoyl) amino] -3 , 4-dihydro- lH-iεoquinoline-2-carboxamidine

67. 7-[{4-[l- (1-Iminoethyl) piperidin-4-yloxy] benzeneεulphonyl}- (4-methoxybenzoyl) amino] -3 , 4-dihydro- lH-iεoquinoline-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] benzeneεulphonyl} - (4-methoxybenzoyl) amino] - 3 , 4-dihydro-lH-iεoquinoline-2-carboxamidine

70. 7- [ (4- {1- [Imino- (4-methoxyphenyl) methyl ]piperidin- 4-yloxy}benzeneεulphonyl) - (4-methoxybenzoyl) - amino] -3 , 4-dihydro-lH-iεoquinoline-2-carboxamidine

71. 7- [ {4- [1- (Iminothiophen-2-ylmethyl)piperidin-4- yloxy] benzeneεulphonyl } - (4-methoxybenzoyl) amino] - 3 , 4-dihydro-lH-isoquinoline-2-carboxamidine

72. [ [4- (l-Carbamimidoylpiperidin-4-yloxy) benzenesulphonyl] - (2-carbamimidoyl-l, 2,3, 4-tetrahydro- iεoquinolin-7-yl ) amino] sulphonylacetic acid

73. ( (2-Carbamimidoyl-l, 2,3, 4-tetrahydroisoquinolin-7- yl) -{4- [1- (l-iminoethyl)piperidin-4-yloxy] - benzeneεulphonyl} amino) sulphonylacetic acid

74. ( (2-Carbamimidoyl-l, 2,3, 4-tetrahydroiεoquinolin-7- yl) -{4- [1- (l-iminopropyl)piperidin-4-yloxy] - benzeneεulphonyl} amino) εulphonylacetic acid - 36 -

75. ( (2-Carbamimidoyl-l, 2,3, 4-tetrahydroisoquinolin-7- yl) - {4- [1- ( cyclopropyliminomethyl ) piperidin-4- yloxy] benzenesulphonyl} amino) sulphonylacetic acid

76. [ (2-Carbamimidoyl-l, 2,3, 4-tetrahydroiεoquinolin-7- yl) - (4-{l- [imino- (4-methoxyphenyl) methyl] - piperidin-4-yloxy}benzeneεulphonyl) amino] - εulphonylacetic acid

77. ( (2-Carbamimidoyl-l , 2,3, 4-tetrahydroiεoquinolin-7- yl) -{4- [1- ( iminothiophen-2-ylmethy1) piperidin-4- yloxy] benzeneεulphonyl}amino) sulphonylacetic acid

78. [ [4- (l-Carbamimidoylpiperidin-4-yloxy)benzoyl- sulphonyl] - (2-carbamimidoyl-l, 2,3, 4-tetrahydro- iεoquinolin-7-yl) amino]methylboronic acid

79. ( (2-Carbamimidoyl-l , 2,3, 4-tetrahydroisoquinolin-7- yl) - {4- [1- (l-iminoethyl)piperidin-4-yloxy] benzenesulphonyl } amino) ethylboronic acid

80. ( (2-Carbamimidoyl-l , 2,3, 4-tetrahydroisoquinolin-7- yl) - {4- [1- (l-iminopropyl)piperidin-4-yloxy] - benzenesulphonyl} amino) methylboronic acid

81. ( (2-Carbamimidoyl-l , 2,3, 4-tetrahydroisoquinolin-7- yl) -{4- [1- ( cyclopropyliminomethyl ) piperidin-4- yloxy] benzeneεulphonyl } amino) methylboronic acid

82. [ (2-Carbamimidoyl-l , 2,3, 4-tetrahydroisoquinolin-7- yl) - (4- {1- [imino- (4-methoxyphenyl) methyl] - piperidin-4-yloxy}benzenesulphonyl) amino] methylboronic acid

83. ( (2-Carbamimidoyl-l , 2,3, 4-tetrahydroisoquinolin-7- yl) - {4- [1- (iminothiophen-2-ylmethy1) piperidin-4- yloxy] benzeneεulphonyl } amino ) methylboronic acid - 37 -

84. 7- [4- (l-Carbamimidoylpyrrolidin-3- (S) -yloxy) - benzenesulphonylamino] -3 , 4-dihydro-lH- iεoquinoline-2-carboxamidine

85. [ [4- (l-Carbamimidoylpyrrolidin-3- (S) -yloxy) - benzeneεulphonylamino] - (2-carbamimidoyl-l , 2,3,4- tetrahydroiεoquinolin-7-yl) amino] εulphonylacetic acid

86. ( (2-Carbamimidoyl-l, 2,3, 4-tetrahydroiεoquinolin-7- yl) -{4- [1- (1-iminoethyl) pyrrolidin-3- (S) -yloxy] - benzeneεulphonyl} amino) sulphonylacetic acid

87. [ [4- (l-Carbamimidoylpyrrolidin-3- (S) -yloxy) - benzenesulphonyl] - (2-carbamimidoyl-l , 2,3,4- tetrahydroiεoquinolin-7-yl ) amino] acetic acid

88. ( (2-Carbamimidoyl-l, 2,3, 4-tetrahydroisoquinolin-7- yl) -{4- [1- (l-iminoethyl)pyrrolidin-3- (S) -yloxy] - benzeneεulphonyl} amino) acetic acid

The following exampleε illuεtrate the invention, without restricting it thereto.

Example 1 :

7- [4 - (l -Carbamimidoylpiperidin~4-yloxy) benzenesulphonylamino] -3 , 4-dihydro-lH-isoquinoline-2- carboxamidine dihydrochloride

1. tert-Butyl 7-nitro-3 , 4-dihydro-lH-isoqumoline-2- carboxylate

A εolution 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 suspenεion of 8.6 g (0.040 mol) of 7-nitro-l,2, 3, 4-tetrahydro- iεoquinoline hydrochloride (J.F. Ajao, C.W. Bird, Heterocyclo . Chem . 1985, 22, 239-331) and 16.6 ml - 38 -

(0.170 mol) of triethylamine in 100 ml of methylene chloride. After stirring at room temperature for 24 hours, the resulting clear solution is εuccessively extracted 3 x in each caεe with 50 ml each of water, 1 N acetic acid and saturated sodium bicarbonate solution. After drying and concentrating, the residue is triturated with iεohexane, 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 aε a brownish solid; El-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-iεoquinoline-2-carboxylate are diεεolved in 100 ml of ethyl acetate and hydrogenated in the preεence 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 aε a light brown εolid of m.p. 75-77°C; EI-MS: 248 (M⁺) .

3. tert-Butyl 7-benzylamino-3 , 4-dihydro-lH-iso- quinoline-2-carboxylate

A εolution of 5.0 g (0.020 mol) of tert-butyl 7-amino-3 , 4-dihydro-lH-iεoquinoline-2-carboxylate in 50 ml of methanol iε treated with 2.40 ml (0.022 mol) of benzaldehyde and εtirred at room temperature for 16 h. The reεulting reaction mixture iε cooled to 5°C and 0.76 g (0.021 mol) of εodium borohydride is added in portions. After stirring at room temperature for 24 hours, the methanol is removed by diεtillation and the solid - 39 - reεidue iε triturated with water, filtered off with εuction and dried. 5.80 g (86%) of the title compound are obtained aε a white εolid. M.p. 110°C; (+)-FAB-MS: 339 (MH⁺).

4. tert-Butyl 7- [benzyl- (4-hydroxybenzeneεulphonyl) - amino] -3 , 4-dihydro-lH-iεoquinoline-2-carboxylate

A εolution of 9.1 g (0.027 mol) of tert-butyl 7- benzylamino-3 , 4-dihydro-lH-iεoquinoline-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 . 1973, 38 , 1047) and stirred at room temperature for 16 h. The pyridine is diεtilled off and the reεidue iε diεεolved in 150 ml of ethyl acetate. It iε extracted εucceεεively 2 x in each caεe with 50 ml each of water, 1 N acetic acid and εaturated εodium bicarbonate solution, and the organic phase is dried over sodium sulphate. After concentrating, the residue iε 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 fractionε, 10.9 g (82%) of the title compound are obtained aε a white, cryεtalline εolid of m.p. 172-175°C EI-MS:495 (M⁺) .

5. tert-Butyl 7- {benzyl- [4- (1-tert-butoxycarbonyl- piperidin-4-yloxy) benzeneεulphonyl] amino} -3 , 4- dihydro-lH-iεoquinoline-2-carboxylate

A εolution of 9.2 g (0.019 mol) of tert-butyl 7- [benzyl- (4-hydroxybenzeneεulphonyl) amino] -3,4- dihydro-lH-iεoquinoline-2-carboxylate, 4.1 g (0.021 mol) of tert-butyl 4-hydroxypiperidine-l- carboxylate (analogously to K.L. Bhat, D.M. Flanagan, M.M. Jouille, Synth. Commun . 1985, - 40 -

15, 587-598) and 5.4 g (0.021 mol) of triphenylphosphine in 150 ml of tetrahydrofuran iε treated at 5°C with 3.3 ml (0.021 mol) of diethyl azodicarboxylate and εtirred at room temperature for 24 h. After concentrating, the reεidue iε 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- ( 1-tert-butoxy- carbonylpiperidin-4-yloxy) benzenesulphonyl] - amino} -3 , 4-dihydro-lH-isoquinoline-2-carboxylate (0.013 mol) are diεεolved in 250 ml of ethyl acetate and hydrogenated in the preεence 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: iεohexane/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 colourlesε oil. ( + )-FAB-MS: 588 (MH⁺) .

7. 4- (Piperidin-4-yloxy) -N- (1,2,3, 4-tetrahydro- iεoquinolin-7-yl ) benzeneεulphonamide dihydrochloride

A solution of 2.5 g (0.004 mol) of tert-butyl 7- { [4- (l-tert-butoxycarbonylpiperidin-4-yloxy) - benzenesulphonyl] amino} -3 , 4-dihydro-lH- iεoquinoline-2-carboxylate in 50 ml of diethyl - 41 - 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; 70.1%); m.p. 107-109°C; EI-MS: 387 (M⁺) .

8. 7- [4- (l-carbamimidoylpiperidin-4-yloxy) -benzene- εulphonylamino] -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-tetrahydroiεoquinolin-7-yl- benzeneεulphona ide dihydrochloride and 1.2 g (0.008 mol) of lH-pyrazole-1-carboxamidine hydrochloride (ref.: M.S. Bernatowicz, Y. Wu, G.R. Matεueda, J. Org . Chem . 1992, 51, 2497-2502) in 2 ml of dimethylformamide iε treated at 5°C with 4.2 ml of diiεopropylethylamine. After εtirring at room temperature for 24 hourε, it iε 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: H₂0, pH 3; H₂0/CH₃OH 6:4, pH 3) by means of preparative HPLC (RP-18 column, 15-25μm) . ^' After concentrating the appropriate column fractions and drying in vacuo (10^~2 torr) , 0.8g (74%) of the title compound iε obtained aε a white εolid of m.p. 150°C (dec); ( + ) -FAB-MS: 472 (MH⁺).

Example 2 :

Deεcription of pharmacological teεt

Obtainment of plaεma

Nine partε of freεh blood from healthy donors are mixed with one part of sodium citrate solution

(0.11 mol/1) and centrifuged at about 3000 rpm for - 42 -

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 μl of citrate plasma and 100 μl of APTT reagent (Diagnostica Stago/Boehringer Mannheim GmbH; containε lyophiliεate cephalin with microcryεtalline kieselguhr activator) are incubated at 37 °C for 3 minutes together with 10 μl of dimethyl εulphoxide (DMSO) or 10 μl of a solution of the active substance in DMSO in a ball coagulometer (KC10 from Amelung) . With addition of 100 μl of 0.025 M calcium chloride solution, a stopclock is started and the time until the occurrence of clotting iε determined. In the control measurements , the APTT is about 28-35 seconds and is prolonged by active subεtanceε. If no clotting occurred after 5 minutes during the measurementε, the teεt waε εtopped (>300).

The meaεured APTT timeε in seconds are indicated as the difference from the control in Table 1. The concentrations of the active subεtanceε in the final volume waε 1000 μM (APTT 1000) , 100 μM (APTT 100), 10 μM (APTT 10), 1 μM (APTT 1).

Thrombin time

200 μl of citrate plaεma are incubated at 37°C for 2 minutes in a ball coagulometer (KC10 from Amelung) . lOμl of dimethyl εulphoxide (DMSO) or a εolution of the active subεtance in DMSO are/iε added to 190 μl of thrombin reagent whoεe temperature haε previouεly been adjuεted (Boehringer Mannheim GmbH; containε about 3 U/ml of equine thrombin and 0.0125 M Ca⁺⁺ . With addition of thiε 200 μl of εolution to the plaεma, a - 43 - εtopclock iε εtarted and the time until the occurrence of clotting is determined. In the control measurementε, the thrombin time iε about 24 seconds and is prolonged by active εubstances . If no clotting occurred after 5 minuteε during the meaεurementε, the teεt waε stopped (>300) .

The meaεured thrombin timeε in seconds are indicated as the difference from the control in Table 1. The concentrations of the active substanceε in the final volume were 500 μM (TT 500) .

Inhibition conεtantε

The kinetic meaεurementε were carried out in 0.1 M phoεphate buffer containing 0.2 M εaline εolution and 0.5% polyethylene glycol 6000 (preparation εee below) at pH 7.5 and 25°C in polyεtyrene εemimicro cuvetteε in a total volume of 1 ml . The reactionε were εtarted by addition of enzyme to preincubated εolutionε, which either contained dimethyl εulphoxide (control) or solutions of the test subεtance in DMSO (inhibitor εtock εolutionε: 10 mM in DMSO) . The increaεe in the extinction at 405 rim aε a reεult of the releaεe of 4-nitroaniline from the substrate was monitored photometrically over a period of 12 minuteε . Meaεured valueε (extinction vε time) were determined at an interval of 20 seconds and these data were εtored by computer .

The procedure for the determination of the inhibition constants _x was aε followε : the velocities Vo (change in extinction per second; measurementε without inhibitor) and V_λ (change in extinction per εecond; meaεurementε with inhibitor) were determined by linear regreεεion, only the meaεuring points at which the subεtrate - 44 - concentration decreaεed by leεε than 15% being taken into account. K_M and V_maχ were determined from a series of measurementε (conεtant inhibitor concentration, variable εubstrate concentrations) by non-linear fit to the equation

V = ^Vπ x ^X ^

[S] + K_M

The Ki value was obtained from the complete εerieε of meaεurementε with 16 data εetε (meaεurementε at 4 different εubstrate concentrations and in each case 4 different inhibitor concentrations) by nonlinear regreεεion from the equation

V x [S]

K_M X (1 + [I] / K + [S]

V_πi_ax being the maximum velocity in the abεence of an inhibitor, K_M the Michaeliε conεtant and [S] the εubεtrate concentration.

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

FXa:

Stock solution: 990 μl of phosphate buffer solution (preparation see below) are treated with 10 μl of human factor Xa (Boehringer Mannheim GmbH; 10 U; εuεpenεion) and εtored on ice for at moεt 4 hourε .

For meaεurement, 850 μl of phosphate buffer are thermostated (25°C) with 100 μl of subεtrate [N-methoxycarbonyl- (D) -norleucyl-glycyl- (L) -argi- nine-4-nitroaniline acetate; Chromozym X;

Boehringer Mannheim GmbH; εubεtrate concentrationε uεed 800, 600, 400 and 200 μM; K_M 400 μM] and

25 μl of inhibitor solution or 25 μl of DMSO (control) in a photometer. The reaction iε started by addition of 25 μl of εtock εolution. - 45 -

Thrombin :

Human -thrombin (Sigma; 100 U; specific activity: 2000 NIH units/mg) iε diεεolved in 1 ml of water and εtored at -18°C in portionε of 20 μl . Stock solution: 1480 μl of phosphate buffer εolution

(preparation see below) are treated with 20 μl of the α-thrombin solution prepared as above and εtored on ice for at most 4 hours . For measurement, 850 μl of phosphate buffer are thermoεtated

(25°C) with 100 μl of substrate [H- (D) -Phe-Pip- Arg-4-nitroaniline dihydrochloride; S-2238; Kabi; substrate concentrations used 100, 50, 30 and 20 μM; K_M 4 μM) and 25 μl of inhibitor solution or 25 μl of DMSO (control) in a photometer. The reaction iε εtarted by addition of 25 μl of εtock εolution.

Trypεin:

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 μl of 1 mM hydrochloric acid are treated with 10 μl of the trypεin εolution prepared aε above and εtored on ice for at moεt 4 hourε . For measurement, 850 μl of phoεphate buffer are ther ostated (25°C) with 100 μl of εubεtrate [H- (D) -Phe-Pip-Arg-4-nitroaniline dihydrochloride; S-2238; Kabi; εubεtrate concentrationε uεed 100, 50, 30 and 20 μM; K_M 45 μM) and 25 μl of inhibitor εolution or 25 μl of DMSO (control) in a photometer. The reaction iε εtarted by addition of 25 μl of εtock solution.

Preparation of the 0.1 M phosphate buffer solution (pH 7.5, 0.2 M NaCl) :

8.90 g of Na₂HP0₄ ^■ 2 H₂0, 5.84 g of NaCl and 2.50 g of polyethylene glycol 6000 are diεεolved in 400 ml of distilled water and made up to a 46 total volume of 500 ml with distilled water (solution I). 1.36 g of KH₂P0 , 1.17 g of NaCl and 0.50 g of polyethylene glycol 6000 are disεolved in 80 ml of distilled water and made up to a total volume of 100 ml with distilled water (solution II) . Sufficient εolution II (about 85 ml) is then added to εolution I until the pH is 7.5. The buffer solution is always freshly prepared (can be kept at 4°C for at most 10 dayε when εtored in a refrigerator) .

Table 1 : Pharmacological data of Example Compound I

Example Ki Ki Ki APTT APTT APTT APTT T No. (fXa) (thrombin) (trypsin) 1000 100 10 1 500

1 0.010 2 0.1 > 300 140 50 12 40

Claims

- 47 - Claimε

1. Compoundε of general formula I

(I)

in which

R¹, R² 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;

R can be a hydrogen atom, eine 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 carboxyalkylεulphonyl group, an alkyloxy- carbonylalkylεulphonyl group, a - 48 - dihydroxyborylalkyl group, a dialkoxyborylalkyl group or an optionally substituted 1,3,2- dioxaborolanylalkyl group or an optionally substituted 1, 3 , 2-dioxaborinanylalkyl group;

4

R is an optionally substituted ammo group, an alkyl group, a cycloalkyl radical, an optionally subεtituted aryl radical or an optionally subεtituted heteroaryl radical;

X iε a εingle bond, a carbonyl group, or an alkylene or an alkyleneoxy group; n iε the number 1 or 2 and m iε an integer between 1 and 4, aε well aε hydrates, solvates and physiologically tolerable εalts thereeof, optically active forms, racemates and diastereomer mixtures.

2. Compounds according to claim 1, in which

1 2

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 ethoxycarbonyl group, a hydroxymethyl- or hydroxyethyl group or a carboxymethyl group;

₃ R iε a hydrogen atom, a methyl group, an ethyl group, an iεopropyl 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 ethoxycarbonylethyl group, an ethoxy- carbonylpropyl group, an acetyl group, a 4- methoxybenzoyl group, a carboxymethylεulphonyl group, a carboxyethylεulphonyl group, a carboxypropylεulphonyl group, an - 49 - ethoxycarbonylmethylεulphonyl group , an ethoxycarbonylethylεulphonyl group , an ethoxycarbonylpropy1sulphonyl group , a dihydroxyborylmethyl

group, a dihydroxyborylpropyl group or. a 4,4,5,5- tetramethyl-1 , 3 , 2-dioxaborolanylmethyl group;

R⁴ iε an amino group, a methyl group, an ethyl group, a cyclopropyl group, a cyclohexyl group, a 4-methoxyphenyl group or a thienyl group;

X iε a methylene group; n iε the number 1 and m can be the number 1 or 2.

3. The compoundε according to claim 1, εelected from

7- {4- [1- (1-imino-ethyl) -piperidin-4-yloxy] -benzene- sulphonylamino} -3 , 4-dihydro-lH-isoquinoline-2-carbox- amidine,

7- {4- [1- (1-imino-propyl) -piperidin-4-yloxy] -benzene- εulphonylamino} -3 , 4-dihydro-lH-iεoquinoline-2-carbox- amidine,

7- {4- [1- (cyclopropyl-imino-methyl) -piperidin-4-yloxy] - benzeneεulphonylamino} -3 , 4-dihydro-lH-isoquinoline-2- carboxamidine ,

7- (4-{l- [imino- (4-methoxy-phenyl) -methyl] -piperidin-4- yloxy} -benzenesulphonylamino) -3 , 4-dihydro-lH-iso- quinoline-2-carboxamidine,

7- {4- [1- ( imino-thiophen-2-yl-methyl) -piperidin-4- yloxy] -benzeneεulphonylamino} -3 , 4-dihydro-lH-iεo- quinoline-2-carboxamidine,

7-{ [4- (l-carbamimidoyl-piperidin-4-yloxy) -benzeneεulphonyl] -methyl-amino} -3 , 4-dihydro-lH-iεoquinoline-2- carboxamidine , - 50 - 7- ( {4- [1- (1-imino-ethyl) -piperidin-4-yloxy] -benzenesulphonyl} -methyl-amino) -3 , 4-dihydro-lH-iεoquinoline-2- carboxamidine ,

7- ( {4- [1- (1-imino-propyl) -piperidin-4-yloxy] -benzenesulphonyl} -methyl-amino) -3 , 4-dihydro-lH-isoquinoline-2- carboxamidine ,

7- ( {4- [1- (cyclopropyl-imino-methyl) -piperidin-4-yloxy] - benzeneεulphonyl} -methyl-amino) -3 , 4-dihydro-lH-iεo- quinoline-2-carboxamidine,

7- [ (4-{l- [imino- (4-methoxy-phenyl) -methyl] -piperidin-4- yloxy} -benzeneεulphonyl) -methyl-amino] -3, 4-dihydro-lH- iεoquinoline-2-carboxamidine,

7- ( {4- [1- ( imino-thiophen-2-yl-methyl) -piperidin-4- yloxy] -benzenesulphonyl} -methyl-amino) -3 , 4-dihydro-lH- iεoquinoline-2-carboxamidine,

7-{ [4- (l-carbamimidoyl-piperidin-4-yloxy) -benzeneεulphonyl] -ethyl-amino}-3 , 4-dihydro-lH-isoquinoline-2- carboxamidine,

7- (ethyl- {4- [1- ( 1-imino-ethyl) -piperidin-4-yloxy] - benzenesulphonyl} -amino) -3 , 4-dihydro-lH-isoquinoline-2- carboxamidine ,

7- (ethyl- {4- [1- (1-imino-propyl) -piperidin-4-yloxy] - benzenesulphonyl} -amino) -3 , 4-dihydro-lH-isoquinoline-2- carboxamidine ,

7- ( {4- [1- (cyclopropyl-imino-methyl) -piperidin-4-yloxy] - benzeneεulphonyl} -ethyl-amino) -3 , 4-dihydro-lH-iεoquino- line-2-carboxamidine,

7- [ethyl- (4- {1- [imino- (4-methoxy-phenyl ) -methyl] - piperidin-4-yloxy} -benzeneεulphonyl ) -amino] -3,4- dihydro-lH-iεoquinoline-2-carboxamidine,

7- (ethyl- {4- [1- ( imino-thiophen-2-yl-methyl) -piperidin- 4-yloxy] -benzeneεulphonyl } -amino) -3 , 4-dihydro-lH-iso- quinoline-2-carboxamidine, - 51 - 7-{ [4- (l-carbamimidoyl-piperidin-4-yloxy) -benzeneεulphonyl] -cyclopropyl-amino} -3 , 4-dihydro-lH-iεo- quinoline-2-carboxamidine,

7- (cyclopropyl- {4- [1- (1-imino-ethyl) -piperidin-4- yloxy] -benzeneεulphonyl} -amino) -3 , 4-dihydro-lH- iεoquinoline-2-carboxamidine,

7- (cyclopropyl- {4- [1- (1-imino-propyl) -piperidin-4- yloxy] -benzeneεulphonyl} -amino) -3 , 4-dihydro-lH- iεoquinoline-2-carboxamidine,

7- (cyclopropyl- {4- [1- (cyclopropyl-imino-methyl) - piperidin-4-yloxy] -benzenesulphonyl} -amino) -3,4- dihydro-lH-iεoquinoline-2-carboxami ine,

7- [cyclopropyl- (4- {1- [imino- (4-methoxy-phenyl) -methyl] - piperidin-4-yloxy} -benzeneεulphonyl) -amino] -3 , 4- dihydro-lH-iεoquinoline-2-carboxamidine,

7- (cyclopropyl- {4- [1- ( imino-thiophen-2-yl-methyl) - piperidin-4-yloxy] -benzeneεulphonyl} -amino) -3 , 4- dihydro-lH-isoquinoline-2-carboxamidine,

7- {allyl- [4- (l-carbamimidoyl-piperidin-4-yloxy) - benzenesulphonyl] -amino} -3 , 4-dihydro-lH-isoquinoline-2- carboxamidine ,

7- (allyl- {4- [1- (1-imino-ethyl) -piperidin-4-yloxy] - benzenesulphonyl} -amino) -3 , 4-dihydro-lH-iεoquinoline-2- carboxamidine ,

7- (allyl- {4- [1- (1-imino-propyl ) -piperidin-4-yloxy] - benzeneεulphonyl} -amino) -3 , 4-dihydro-lH-isoquinoline-2- carboxamidine ,

7- (allyl- {4- [1- (cyclopropyl-imino-methyl) -piperidin-4- yloxy] -benzenesulphonyl} -amino) -3 , 4-dihydro-lH- iεoquinoline-2-carboxamidine,

7- [allyl- (4- {1- [imino- (4-methoxy-phenyl) -methyl] - piperidin-4-yloxy} -benzeneεulphonyl) -amino] -3 , 4- dihydro-lH-isoquinoline-2-carboxamidine, - 52 - 7- (allyl- {4- [1- ( imino-thiophen-2-yl-methyl) -piperidin-

4-yloxy] -benzenesulphonyl} -amino) -3, 4-dihydro-lH- iεoquinoline-2-carboxamidine,

7-{benzyl- [4- (l-carbamimidoyl-piperidin-4-yloxy) - benzeneεulphonyl] -amino} -3 , 4-dihydro-lH-isoquinoline-2- carboxamidine,

7- (benzyl- {4- [1- (1-imino-ethyl) -piperidin-4-yloxy] - benzeneεulphonyl} -amino) -3 , 4-dihydro-lH-isoquinoline-2- carboxamidine ,

7- (benzyl- {4- [1- ( 1-imino-propyl) -piperidin-4-yloxy] - benzenesulphonyl} -amino) -3 , 4-dihydro-lH-isoquinoline-2- carboxamidine,

7- (benzyl- {4- [1- (cyclopropyl-imino-methyl) -piperidin-4- yloxy] -benzeneεulphonyl} -amino) -3 , 4-dihydro-lH-iεo- quinoline-2-carboxamidine,

7- [benzyl- (4-{l- [imino- (4-methoxy-phenyl) -methyl] - piperidin-4-yloxy} -benzeneεulphonyl) -amino] -3 , 4- dihydro-lH-iεoquinoline-2-carboxamidine,

7- (benzyl- {4- [1- (imino-thiophen-2-yl-methyl) -piperidin- 4-yloxy] -benzeneεulphonyl} -amino) -3 , 4-dihydro-lH- iεoquinoline-2-carboxamidine ,

7- [ [4- (l-carbamimidoyl-piperidin-4-yloxy) -benzeneεulphonyl] - (2-hydroxy-ethyl) -amino] -3 , 4-dihydro-lH- iεoquinoline-2-carboxamidine,

7- ( (2-hydroxy-ethyl) - {4- [1- (1-imino-ethyl) -piperidin-4- yloxy] -benzeneεulphonyl} -amino) -3 , 4-dihydro-lH-iso- quinoline-2-carboxamidine,

7- ( (2-hydroxy-ethyl) -{4- [1- (1-imino-propyl) -piperidin- 4-yloxy] -benzenesulphonyl} -amino) -3 , 4-dihydro-lH-iso- quinoline-2-carboxamidine,

7- [ {4- [1- (cyclopropyl-imino-methyl) -piperidin-4-yloxy] - benzeneεulphonyl}- (2-hydroxy-ethyl) -amino] -3 , 4-dihydro- lH-isoquinoline-2-carboxamidine, - 53 - 7 - [ ( 2 -hydroxy-ethyl ) - ( 4 - { l- [ imino- ( 4-methoxy-phenyl ) - methyl] -piperidin-4-yloxy} -benzeneεulphonyl) -amino] -

3 , 4-dihydro-lH-isoquinoline-2-carboxamidine,

7- ( (2-hydroxy-ethyl) -{4- [1- (imino-thiophen-2-yl- methyl) -piperidin-4-yloxy] -benzeneεulphonyl} -amino) - 3 , 4-dihydro-lH-iεoquinoline-2-carboxamidine,

[ [4- (l-carbamimidoyl-piperidin-4-yloxy) -benzeneεulphonyl] - (2-carbamimidoyl-l ,2,3, 4-tetrahydro- iεoquinolin-7-yl) -amino] -acetic acid,

( (2-carbamimidoyl-l, 2,3, 4-tetrahydro-iεoquinolin-7-yl) - {4- [1- (1-imino-ethyl) -piperidin-4-yloxy] -benzeneεulphonyl} -amino) - acetic acid,

( (2-carbamimidoyl-l ,2,3, 4-tetrahydro-iεoquinolin-7-yl ) - {4- [1- (1-imino-propyl) -piperidin-4-yloxy] -benzeneεulphonyl} -amino) - acetic acid,

( (2-carbamimidoyl-l , 2,3, 4-tetrahydro-iεoquinolin-7-yl) - {4- [1- (cyclopropyl-imino-methyl) -piperidin-4-yloxy] - benzeneεulphonyl} -amino) - acetic acid,

[ (2-carbamimidoyl-l, 2,3, 4-tetrahydro-iεoquinolin-7-yl) - (4-{l- [imino- (4-methoxy-phenyl) -methyl] -piperidin-4- yloxy} -benzenesulphonyl ) -amino] - acetic acid,

( (2-carbamimidoyl-l , 2,3, 4-tetrahydro-iεoquinolin-7-yl) - {4- [1- (imino-thiophen-2-yl-methyl) -piperidin-4-yloxy] - benzeneεulphonyl} -amino) - acetic acid,

4- [ [4- (l-carbamimidoyl-piperidin-4-yloxy) -benzeneεulphonyl] - (2-carbamimidoyl-l ,2,3, 4-tetrahydro-iεo- quinolin-7-yl) -amino] -butyric acid,

4- ( (2-carbamimidoyl-l , 2,3, 4-tetrahydro-isoquinolin-7- yl) -{4- [1- (1-imino-ethyl) -piperidin-4-yloxy] -benzenesulphonyl} -amino) - butyric acid,

4- ( (2-carbamimidoyl-l , 2,3, 4-tetrahydro-isoquinolin-7- yl) - {4- [1- (1-imino-propyl) -piperidin-4-yloxy] -benzeneεulphonyl} -amino) - butyric acid, - 54 - 4- ( (2-carbamimidoyl-l , 2,3, 4-tetrahydro-isoquinolin-7- yl) - {4- [ 1- (cyclopropyl-imino-methyl) -piperidin-4- yloxy] -benzeneεulphonyl} -amino) - butyric acid,

4- [ (2-carbamimidoyl-l, 2,3, 4-tetrahydro-isoquinolin-7- yl) - (4-{l- [imino- (4-methoxy-phenyl) -methyl] -piperidin- 4-yloxy} -benzeneεulphonyl) -amino] - butyric acid,

4- ( (2-carbamimidoyl-l, 2,3, 4-tetrahydro-isoquinolin-7- yl) -{4- [1- (imino-thiophen-2-yl-methyl) -piperidin-4- yloxy] -benzenesulphonyl} -amino) -butyric acid, ethyl [ [4- ( l-carbamimidoyl-piperidin-4-yloxy) -benzeneεulphonyl] - (2-carbamimidoyl-l ,2,3, 4-tetrahydro-iso- quinolin-7-yl) -amino] -acetate, ethyl ( (2-carbamimidoyl-l , 2 , 3 , 4-tetrahydro-iεoquinolin- 7-yl ) - { 4- [ 1- ( 1-imino-ethyl ) -piperidin-4-yloxy] -benzeneεulphonyl} -amino) -acetate, ethyl ( (2-carbamimidoyl-l, 2,3, 4-tetrahydro-iεoquinolin- 7-yl) -{4- [1- (1-imino-propyl) -piperidin-4-yloxy] - benzeneεulphonyl} -amino) -acetate, ethyl ( (2-carbamimidoyl-l, 2 , 3 , 4-tetrahydro-iεoquinolin- 7-yl) -{4- [1- (cyclopropyl-imino-methyl) -piperidin-4- yloxy] -benzenesulphonyl} -amino) -acetate, ethyl [ (2-carbamimidoyl-l, 2 , 3 , 4-tetrahydro-iεoquinolin- 7-yl) - (4- {1- [imino- (4-methoxy-phenyl) -methyl] -piperi- din-4-yloxy} -benzeneεulphonyl) -amino] -acetate, ethyl ( (2-carbamimidoyl-l , 2 , 3 , 4-tetrahydro-iεoquinolin- 7-yl) -{4- [1- ( imino-thiophen-2-yl-methyl) -piperidin-4- yloxy] -benzenesulphonyl} -amino) -acetate,

7- {acetyl- [4- ( l-carbamimidoyl-piperidin-4-yloxy) - benzenesulphonyl] -amino} -3 , 4-dihydro-lH-isoquinoline-2- carboxamidine ,

7- (acetyl- {4- [1- (1-imino-ethyl) -piperidin-4-yloxy] - benzeneεulphonyl}_,-amino) -3 , 4-dihydro-lH-iεoquinoline-2- carboxamidine , - 55 - 7- (acetyl- {4- [1- (1-imino-propyl) -piperidin-4-yloxy] - benzeneεulphonyl} -amino) -3 , -dihydro-lH-iεoquinoline-2- carboxamidine ,

7- (acetylτ_#{4- [1- (cyclopropyl-imino-methyl) -piperidin-4- yloxy] -benzenesulphonyl} -amino) -3 , 4-dihydro-lH-iso- quinoline-2-carboxamidine,

7- [acetyl- (4-{l- [imino- (4-methoxy-phenyl) -methyl] - piperidin-4-yloxy} -benzenesulphonyl) -amino] -3,4- dihydro-lH-iεoquinoline-2-carboxamidine,

7- (acetyl- {4- [1- ( imino-thiophen-2-yl-methyl) -piperidin- 4-yloxy] -benzeneεulphonyl} -amino) -3 , 4-dihydro-lH-iεo- quinoline-2-carboxamidine,

7- [ [4- (l-carbamimidoyl-piperidin-4-yloxy) -benzeneεulphonyl] - (4-methoxy-benzoyl) -amino] -3 , 4-dihydro-lH- isoquinoline-2-carboxamidine,

7- [ {4- [1- (1-imino-ethyl) -piperidin-4-yloxy] -benzenesulphonyl}- (4-methoxy-benzoyl) -amino] -3, 4-dihydro-lH- iεoquinoline-2-carboxamidine,

7- [ {4- [1- (1-imino-propyl) -piperidin-4-yloxy] -benzenesulphonyl}- (4-methoxy-benzoyl) -amino] -3 , 4-dihydro-lH- iεoquinoline-2-carboxamidine,

7- [ {4- [1- (cyclopropyl-imino-methyl) -piperidin-4-yloxy] - benzenesulphonyl} - (4-methoxy-benzoyl) -amino] -3,4- dihydro-lH-iεoquinoline-2-carboxamidine,

7- [ (4-{l- [imino- (4-methoxy-phenyl) -methyl] -piperidin-4- yloxy} -benzeneεulphonyl) - (4-methoxy-benzoyl) -amino] - 3 , 4-dihydro-lH-isoquinoline-2-carboxamidine,

7- [ {4- [1- (imino-thiophen-2-yl-methyl) -piperidin-4- yloxy] -benzenesulphonyl}- (4-methoxy-benzoyl) -amino] - 3 , 4-dihydro-lH-isoquinoline-2-carboxamidine,

[ [4- (l-carbamimidoyl-piperidin-4-yloxy) -benzenesulphonyl] - (2-carbamimidoyl-l ,2,3, 4-tetrahydro- iεoquinolin-7-yl ) -amino] -εulphonylacetic acid, - 56 - ( (2-carbamimidoyl-l , 2,3, 4-tetrahydro-isoquinolin-7-yl) -

{4- [1- (1-imino-ethyl) -piperidin-4-yloxy] -benzenesulphonyl} -amino) -sulphonylacetic acid,

( (2-carbamimidoyl-l, 2,3, 4-tetrahydro-isoquinolin-7-yl) - {4- [1- (1-imino-propyl) -piperidin-4-yloxy] -benzenesulphonyl } -amino) -sulphonylacetic acid,

( (2-carbamimidoyl-l, 2,3, 4-tetrahydro-isoquinolin-7-yl) - {4- [1- (cyclopropyl-imino-methyl) -piperidin-4-yloxy] - benzenesulphonyl} -amino) -sulphonylacetic acid,

[ (2-carbamimidoyl-l, 2,3, 4-tetrahydro-isoquinolin-7-yl) - (4- {1- [imino- (4-methoxy-phenyl) -methyl] -piperidin-4- yloxy} -benzeneεulphonyl ) -amino] -sulphonylacetic acid,

( (2-carbamimidoyl-l, 2,3, 4-tetrahydro-isoquinolin-7-yl) - {4- [1- ( imino-thiophen-2-yl-methyl) -piperidin-4-yloxy] - benzenesulphonyl} -amino) -εulphonylacetic acid,

[ [4- (l-carbamimidoyl-piperidin-4-yloxy) -benzeneεulphonyl] - (2-carbamimidoyl-l ,2,3, 4-tetrahydro-iεoquino- lin-7-yl) -amino] -methylboronic acid,

( (2-carbamimidoyl-l , 2,3, 4-tetrahydro-iεoquinolin-7-yl) - {4- [1- (1-imino-ethyl) -piperidin-4-yloxy] -benzeneεulphonyl} -amino) -methylboronic acid,

( (2-carbamimidoyl-l ,2,3, 4-tetrahydro-iεoquinolin-7-yl) - {4- [1- (1-imino-propyl) -piperidin-4-yloxy] -benzeneεulphonyl} -amino) -methylboronic acid,

( (2-carbamimidoyl-l ,2,3, 4-tetrahydro-iεoquinolin-7-yl) - {4- [1- (cyclopropyl-imino-methyl) -piperidin-4-yloxy] - benzeneεulphonyl} -amino) -methylboronic acid,

[ (2-carbamimidoyl-l ,2,3, 4-tetrahydro-iεoquinolin-7-yl) - (4- {1- [imino- (4-methoxy-phenyl) -methyl] -piperidin-4- yloxy} -benzeneεulphonyl) -amino] -methylboronic acid,

( (2-carbamimidoyl-l, 2,3, 4-tetrahydro-iεoquinolin-7-yl) - {4- [1- ( imino-thiophen-2-yl-methyl) -piperidin-4-yloxy] - benzeneεulphonyl} -amino) -methylboronic acid, - 57 - 7- [4- (l-carbamimidoyl-pyrrolidin-3- (S) -yloxy) -benzeneεulphonylamino] -3 , 4-dihydro-lH-iεoquinoline-2-carbox- amidine,

[ [4- (l-carbamimidoyl-pyrrolidin-3- (S) -yloxy) -benzeneεulphonyl] - (2-carbamimidoyl-l, 2,3, 4-tetrahydro-iεo- quinolin-7-yl) -amino] -εulphonylacetic acid,

( (2-carbamimidoyl-l ,2,3, 4-tetrahydro-iεoquinolin-7-yl) - {4- [1- (1-imino-ethyl) -pyrrolidin-3- (S) -yloxy] -benzeneεulphonyl} -amino) -εulphonylacetic acid,

[ [4- (l-carbamimidoyl-pyrrolidin-3- (S) -yloxy) -benzeneεulphonyl] - (2-carbamimidoyl-l , 2,3, 4-tetrahydro-iεo- quinolin-7-yl) -amino] -acetic acid,

( (2-carbamimidoyl-l ,2,3, 4-tetrahydro-iεoquinolin-7-yl) - {4- [1- (1-imino-ethyl) -pyrrolidin-3- (S) -yloxy] -benzeneεulphonyl} -amino) -acetic acid and

7- [4- (l-carbamimidoyl-piperidin-4-yloxy) -benzenesul- phonylamino] -3 , 4-dihydro-lH-isoquinoline-2-carbox- amidine dihydrochloride.

4. Compounds according to any one of claims 1-3 for the prevention and treatment of diseaεeε εuch aε thrombosis, apoplexy, cardiac infarct, inflammation and arteriosclerosiε .

5. Pharmaceutical preparations, containing at least one compound according to any one of claims 1-3 in addition to usual carriers and adjuvants.

6. Uεe of compoundε according to any one of claimε 1-3 for the production of medicaments with antithromboembolic activity.

7. Method for the prevention and treatment of diεeases such as thrombosis, apoplexy, cardiac infarct, inflammation and arterioscleroεiε, which compriεes the - 58 - administration of an effective amount of a compound according to any one of claims 1-3.

8. Process for the preparation of compounds of the formula I, which compriseε the reaction of a compound of the formula III

(III)

in which R¹ , R , R³ and m have the meaningε indicated in claim 1, with a guanylating reagent in an inert solvent in the presence of an auxiliary base.

9. Procesε according to claim 8, in which 1H- pyrazole-1-carboxamidine or an S-alkyliεothiourea iε uεed aε the guanylating reagent.

10. Process according to claim 8 or claim 9, in which dimethylformamide, dioxan, dimethyl sulphoxide or toluene is used as the solvent.

11. Process according to any one of claims 8-10, in which triethylamine, N-methylmorpholine, pyridine or ethyldiiεopropylamine iε uεed as the auxiliary base.

12. The compounds according to claims 1-3 when prepared according to a process of claims 8-11.

13. The compoundε, use, methods and process as described above.