CA2229903A1

CA2229903A1 - New cyclic guanidines, process for preparing the same and medicaments

Info

Publication number: CA2229903A1
Application number: CA002229903A
Authority: CA
Inventors: Ralf Kucznierz; Wolfgang Von Der Saal; Herbert Leinert; Frank Grams; Karlheinz Stegmeier
Original assignee: Individual
Current assignee: Roche Diagnostics GmbH
Priority date: 1995-08-23
Filing date: 1996-08-21
Publication date: 1997-03-06
Also published as: WO1997008165A1; DE19530996A1; EP0846115A1; AU6926496A; JPH11511445A

Abstract

Compounds are disclosed having the formula (I), in which R1, R2, R3 independently represent a hydrogen atom, a halogen atom, a hydroxy group, a hydroxyalkyl group, an alkyl group, an alkenyl group, an alkinyl group, an alkoxy group, an aralkyloxy group, an alkenyloxy group, an alkinyloxy group, a carboxyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an alkinyloxycarbonyl group, a carboxyalkyl group, an alkyloxycarbonylalkyl group, an alkenyloxycarbonylalkyl group or an allkinyloxycarbonylalkyl group;
A stands for a straight- or branched-chain alkylene group that optionally bears substituents such as hydroxyl, carboxyl, alkoxycarbonyl groups or halogen atoms; X stands for a simple bond, an alkylene or alkylenoxy group; Y
stands for a simple bond, a chalkogen atom or a carbonyl group; Z stands for a saturated or unsaturated, optionally substituted, heterocyclic or carbocyclic ring system, an optionally substituted amino group, an hydroxyl group, a carboxyl group, an alkoxycarbonyl group or an alkyl group; n equals 1 or 2;
and m equals an integer from 0 to 4. Also disclosed are hydrates, solvates, physiologically tolerable salts of these compounds and their optical isomers, a process for preparing the same and medicaments that contain these compounds and are useful for treating thromboembolitic diseases.

Description

New cyclic qruaniaines, process for producinq them and pharmaceutical preparations The invention concerns new cyclic guanidines of the general formula I

Rl R2 ~ ~ O - A ~ Y -(C~ m-Z (I

in which ~1, R2, R3 independently of one another can be a hydrogen atom, a halogen atom, a hydroxy group, a hydroxyalkyl group, an alkyl group, an alkenyl group, an alkinyl group, an alkoxy group, an aralkyloxy group, an alkenyloxy group, an alkinyloxy group, a carboxyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an alkinyloxy-carbonyl group, a carboxyalkyl group, an alkyloxycarbonylalkyl group, an alkenyloxy-carbonylalkyl group or an alkinyloxy-carbonylalkyl group;

A denotes a straight-chain or branched alkylene group which is optionally provided with substituents such as hydroxyl, - .

carboxyl, alkoxycarbonyl groups or halogen atoms;

X denotes a single bond, an alkylene or alkylenoxy group;

Y can be a single bond, a chalcogen atom or a carbonyl group;

Z denotes a saturated or unsaturated optionally substituted, heterocyclic or carbocyclic ring system, an optionally substituted amino group, a hydroxyl group, a carboxyl group, an alkoxycarbonyl group or an alkyl group;

n denotes 1 or 2 and m denotes an integer between O and 4, as well as hydrates, solvates and physiologically tolerated salts thereof. The invention also concerns the optically active forms, racemates and diastereomer mixtures of these compounds.

The invention also concerns processes for the production of the above-mentioned compounds, pharmaceutical preparations which contain such compounds as well as the use of these compounds for the production of pharmaceutical preparations.

The cyclic guanidines of the general formula I, their solvates and salts intervene in the process of blood -coagulation by the reversible inhibition of factor Xa and thus prevent the formation of hyaline thrombi. They can therefore be used to treat and prevent diseases such as thrombosis, apoplexy, cardiac infarction, inflammations and arteriosclerosis.

Factor Xa is a serine protease of the coagulation system which catalyses the proteolytic conversion of prothrombin into thrombin. Thrombin, as the last enzyme of the coagulation cascade, on the one hand cleaves fibrinogen to fibrin which becomes an insoluble gel after cross-linking by means of factor XIIIa and forms the matrix for a thrombus; on the other hand it activates platelet aggregation by proteolysis of its receptor on the blood platelets and in this manner also contributes to thrombus formation. When a blood vessel is damaged these processes are necessary to stop bleeding. Under normal circumstances no measurable thrombin concentrations are present in blood plasma. An increase in the thrombin concentration can lead to the formation of thrombi and hence to thromboembolic diseases which occur very frequently above all in industrial countries. The formation of thrombin can be prevented by inhibition of factor Xa.

It was recently reported that amidinoarylpropionic acid derivatives such as (+)-(2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl]-propionic acid hydrochloride pentahydrate (DX-9065a;
formula II) are ~actor Xa inhibitors (~. Med. Chem.
1994, 37, 1200-1207; Thrombosis and Haemostasis 1994, 71, 314-319; EP-0-540-051-A-1).

COOH

N
NH~ o The new cyclic guanidines of the general formula I
according to the invention as well as hydrates, solvates and physiologically tolerated salts thereof are effective factor Xa inhibitors.

In the general formula I the substituents R1, R2 and R3 can be the same or different.

Halogens as substituents Rl; R2, R3 in the general formula I denote fluorine, chlorine, bromine and iodine atoms, but preferably fluorine, chlorine and bromine atoms.

I~ Rl, R2, R3 in the general formula I denotes a hydroxyalkyl group then this can be straight-chained or branched and contain 1 to 6 carbon atoms. The hydroxy-methyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and hydroxyhexyl group are preferred.

If R1, R2, R3 in the general formula I denotes an alkyl group then this can be straight-chained or branched and contain 1 to 6 carbon atoms. The methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl and hexyl group are preferred.

If R1, R2, R3 in the general formula I denotes an alkenyl group then this can be straight-chained or branched and contain 2 to 6 carbon atoms. The vinyl, l-propenyl, 2-propenyl, 2-methyl-2-propenyl, 1-butenyl, l-pentenyl and l-hexenyl group are preferred.

If R1, R2, R3 in the general formula I denotes an alkinyl group then this can be straight-chained or branched and contain 2 to 6 carbon atoms. The ethinyl and propargyl group are preferred.

Alkoxy groups as substituents R1, R2, R3 in the general formula I contain 1 to 6 carbon atoms and are straight-chained or branched. The methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, tert.-butyloxy, pentyloxy and hexyloxy group are preferred.

If Rl, R2, R3 in the general formula I denotes an aralkyloxy group then this contains a phenyl group linked to a straight-chain or branched C1-C6 alkyl chain. The benzyloxy group is in this case preferred.

Alkenyloxy groups as substituents Rl, R2, R3 in the general formula I contain 2 to 6 carbon atoms and are straight-chained or branched. The vinyloxy and allyloxy group are preferred.

Alkinyloxy groups as substituents Rl, R2, R3 in the general formula I contain 2 to 6 carbon atoms and are straight-chained or branched. The propargyloxy group is preferred.

Alkoxycarbonyl groups as substituents Rl, R2, R3 in the general formula I contain straight-chain or branched alkyl chains with 1 to 6 carbon atoms. The methoxy-carbonyl and ethoxycarbonyl group are preferred.

.

If Rl, R2, R3 in the general formula I denotes an alkenyloxycarbonyl group then this contains straight-chain or branched alkenyls with 3 to 6 carbon atoms. The allyloxycarbonyl group is preferred.

If Rl, R2, R3 in the general formula I denotes an alkinyloxycarbonyl group then this contains straight-chain or branched alkinyls with 3 to 6 carbon atoms. The propargyloxycarbonyl group is preferred.

Carboxyalkyl groups as substituents Rl, R2, R3 in the general formula I contain alkyls with 1 to 6 carbon atoms and are straight-chained or branched. The carboxy-methyl, carboxyethyl and the carboxypropyl group are preferred.

If Rl, R2, R3 in the general formula I denotes an alkyloxycarbonylalkyl group then the alkyl residues are each understood to be straight-chain or branched alkyl chains with 1 to 6 carbon atoms. The methoxycarbonyl-methyl, ethoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, methoxycarbonylpropyl and ethoxy-carbonylpropyl group are preferred.

If R1, R2, R3 in the general formula I denotes an alkenyloxycarbonylalkyl group then the alkenyl residues are straight-chained or branched with 3 to 6 carbon atoms and the alkyl groups are straight-chained or branched with 1 to 6 carbon atoms. The allyloxycarbonyl-methyl, allyloxycarbonylethyl and allyloxycarbonyl-propyl group are preferred.

If Rl, R2, R3 in the general formula I denotes an alkinyloxycarbonylalkyl group then the alkinyl residues are straight-chained or branched with 3 to 6 carbon atoms and the alkyl groups are straight-chained or branched with 1 to 6 carbon atoms. The propargyloxy-carbonylmethyl, propargyloxycarbonylethyl and propargyloxycarbonylpropyl group are preferred.

In the general formula I the group named A can denote a single bond or a methylene group which can be unsubstituted or substituted with a carboxyl group or alkoxycarbonyl group or it can be a straight-chain or branched alkylene group with 2 to 6 carbon atoms and can optionally carry substituents such as hydroxyl, carboxyl, alkoxycarbonyl groups or halogen atoms.

Alkoxycarbonyl groups as substituents of the methylene or alkylene group of the group A contain straight-chain or branched alkoxy residues with 1 to 6 carbon atoms the methoxycarbonyl and the ethoxycarbonyl group being preferred.

Halogens as substituents of the straight-chain or branched alkylene group of the group A can be fluorine, chlorine, bromine and iodine atoms but preferably chlorine or bromine atoms.

In the general formula I the group named X can denote a single bond, an alkylene group with 1 or 2 carbon atoms or a methylenoxy fragment.

In the general formula I Y can be a single bond, a chalcogen atom, in particular oxygen or sulphur, or a carbonyl group.

If the group Z in the compounds of the general formula I
is a saturated or unsaturated heterocyclic ring system, then this is understood to be a ring system with 5 to 7 ring members which contains one or two identical or different heteroatoms such as nitrogen, oxygen and sulphur and is preferably pyrrolidine, piperidine, piperazine, morpholine, hexahydroazepine, tetrahydrofuran, tetra-hydropyrane, tetrahydrothiophene, 4,5-dihydroimidazole, pyrrole, imidazole, pyrazine, pyrimidine, pyridazine, lN-azepine, 3H-azepine, 1,2-diazepine, 1,4-diazepine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, pyrollidinone, imidazolidinone, piperidinone, in particular pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, tetrahydropyrane, 4,5-dihydroimidazole, pyrrole, imidazole. If the group Z in the compounds of the general formula I is a saturated or unsaturated carbocyclic ring system then this is understood to be a ring system with 3 to 7 carbon atoms, preferably cyclopropyl, cyclopentyl, cyclohexyl, cyclo-heptyl or phenyl. The heterocyclic or carbocyclic residues Z can optionally carry one or two substituents such as nitrile, carboxyl, C1-C6 carboxyalkyl, C1-C6-alkyloxy-carbonyl-C1-C6 alkyl, C1-C6 alkyl, C3-C6 alkenyl, imino, C1-C6 alkylimino, carboxylimino, amidino, formimidoyl, C1-C6 alk~n;~;doyl, C3-C6 cycloalkanimidoyl, benzimidoyl (optionally C1-C6 alkoxy substituted), C1-C6 alkyl-carbonyl, C1-C6 alkyloxycarbonyl, C3-C6 alkenyloxy-carbonyl, benzyloxycarbonyl, carbamoyl, mono or di-(C1-C6)-alkylcarbamoyl, aminocarbonyl, mono-(C1-C6) alkylaminocarbonyl, di-(C1-C6)-alkylaminocarbonyl or 1-(5,5-dimethyl-3-oxo-cyclohexen-1-enyl, preferably carboxyl, C1-C6 carboxyalkyl, C1-C6-alkyloxycarbonyl-C1-C6-alkyl, C3-C6 alkenyl, amidino, formimidoyl, C1-C6 alk~n; ;doyl, C3-C6 cycloalkanimidoyl, benzimidoyl (optionally C1-C6 alkoxy substituted), C1-C6 alkyl-carbonyl, C1-C6 alkyloxycarbonyl, C3-C6 alkenyloxy-carbonyl, benzyloxycarbonyl, 1-(5,5-dimethyl-3-oxo-cyclohexen-l-enyl, wherein the specification (Cl-C6) in each case represents a straight-chain or branched alkyl chain with 1 to 6 carbon atoms whereas (C3-C6) can optionally represent a cycloalkyl group with 3 to 6 carbon atoms or a straight-chain or branched alkenyl group with 3 to 6 carbon atoms.

If the group Z in the general formula I denotes an amino group then this can be substituted and namely with one or two C1-C6 alkyl groups, preferably methyl or ethyl, with one or two aralkyl groups, preferably benzyl, with a C1-C6 alkyloxycarbonyl group preferably t-butyloxy-carbonyl, with a C3-C6 alkenyloxycarbonyl group preferably allyloxycarbonyl or with an aralkyloxycarbonyl group preferably benzyloxycarbonyl. In this case the specification (C1-C6) in each case represents a straight-chain or branched alkyl chain with 1 to 6 carbon atoms, whereas (C3-C6) optionally denotes a straight-chain or branched alkenyl group with 3 to 6 carbon atoms.

If the group z in the general formula I denotes an alkoxycarbonyl group then this can contain straight-chain or branched alkoxy residues with 1 to 6 carbon atoms, the methoxycarbonyl and the ethoxycarbonyl group being preferred.

If the group Z in the general formula I denotes an alkyl chain then this is straight-chained or branched and contains 1 to 6 carbon atoms which can carry one or several hydroxy groups which can in turn be independently of one another etherified with Cl-C6 alkyl groups preferably methyl or with aralkyl groups -.
.

preferably benzyl or with C3-C6 alkenyl groups, preferably allyl. In this case the specification (Cl-C6) represents a straight-chain or branched alkyl chain with 1 to 6 carbon atoms whereas (C3-C6) optionally denotes a straight-chain or branched alkenyl group with 3 to 6 carbon atoms.

The number n denotes 1 or 2 and the number m denotes an integer between O and 4.

Compounds of the general formula I are particularly preferred in which Rl denotes a hydrogen atom, a hydroxy group, a methoxy group, a benzyloxy group, a carboxyl group, a methoxycarbonyl or an ethoxycarbonyl group;

R2, R3 are the same or different and denote a hydrogen atom, a hydroxyl group, a methoxy group, a benzyloxy group, a carboxyl group, a carboxy-methyl group, a carboxyethyl group, a carboxy-methyloxy group, a methoxycarbonyl or ethoxy-carbonyl group, a methoxycarbonylmethyl or ethoxycarbonylmethyl group, a methoxycarbonyl-ethyl or ethoxycarbonylethyl group, a methoxy-carbonylmethyloxy or ethoxycarbonylmethyloxy group;

A denotes a methylene group which can optionally be substituted with a carboxyl, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, allyloxy-carbonyl or hydroxymethyl group;
-X denotes a single bond, a methylene group, an ethylene group or the fragment -CH2-O-;

Y denotes an oxygen atom;

Z denotes a 4-tetrahydropyranyl residue, a 2-tetrahydrofuranyl residue, a 3-tetrahydrofuranyl residue, an amino group, a hydroxy group, a methoxy group, a carboxyl group, an ethoxy-carbonyl group, a guanidino group, a free or optionally ethylene-bridged amidino group, a 4-imidazolyl residue, a 5-hexahydropyrimidine residue imino-substituted or ethoxycarbonyl-imino-substituted in the 2-position, or a 2-pyrrolidinyl residue which is unsubstituted or substituted on the nitrogen or an unsubstituted or nitrogen-substituted 3-pyrrolidinyl residue or an unsubstituted or nitrogen-substituted 4-piperidinyl residue in which the substituent can be an amidino group, a formimidoyl group, an acetimidoyl group, an ethylimidoyl group, an n-butylimidoyl group, a cyclopropylimidoyl group, an N-methylacetimidoyl group, an optionally C1-C6-alkoxy-substituted benzimidoyl group, an acetyl group, an allyl group, an allyloxycarbonyl group, a tert.-butyloxycarbonyl group, a 1-(5,5-dimethyl-3-oxo-cyclohex-1-enyl) group or an N,N-dimethylaminocarbonyl group;

n can be 1 or 2 and m can be 0, 1, 2 or 3.

Physiologically tolerated salts of the general formula I

are understood to be for example formates, acetates, caproates, oleates, lactates or salts of carboxylic acids with up to 18 carbon atoms or salts of dicarboxylic acids and tricarboxylic acids such as citrates, malonates and tartrates or alkanesulfonates with up to 10 carbon atoms or p-toluenesulfonates or salicylates or trifluoroacetates or salts of physiologically tolerated mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulphuric acid, phosphoric acid. The compounds of formula I with a free carboxyl group can also form salts with physiologically tolerated bases. Examples of such salts are alkali metal, alkaline earth metal, ammonium and alkylammonium salts such as the sodium, potassium, calcium or tetraethylammonium salt.

The compounds of formula I can be solvated and in particular hydrated. The hydration can occur during the production or gradually occur as a result of hygroscopic properties of a compound of formula I that is at first anhydrous.

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

For the production of pharmaceutical preparations the substances of the general formula I are mixed with suitable pharmaceutical carrier substances, aromatics, flavourings and dyes and for example formed as tablets or dragées or are suspended or dissolved in water or oil such as olive oil with addition of appropriate auxiliary substances.

-The substances of the general formula I and their salts can be administered enterally or parenterally in a liquid or solid form. Water is preferably used as the injection medium which contains the usual additives for injection solutions such as stabilizers, solubilizers or buffers. Such additives are for example tartrate and citrate buffers, complexing agents (such as ethylene-diamine tetraacetic acid and non-toxic salts thereof) and high molecular polymers such as liquid polyethylene oxide to regulate viscosity. Solid carrier substances are for example starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acids, high molecular fatty acids (such as stearic acid), animal and vegetable fats and solid high molecular polymers (such as polyethylene glycols). Suitable preparations for oral administration can optionally contain flavourings and sweeteners.

The compounds are usually administered in amounts of 10 - 1500 mg per day relative to 75 kg body weight. It is preferable to administer 1-2 tablets with a content of active substance of 5 - 500 mg 2-3 times per day. The tablets may also be retarded and as a result of which only 1-2 tablets containing 20 - 700 mg active substance have to be administered once per day. The active substance can also be administered by injection 1-8 times per day or by continuous infusion in which case 50 - 2000 mg per day are normally sufficient.

Compounds of the general formula I are produced by known methods.

The compounds of the general formula I are produced by reacting a compound of the general formula III

Rl R2 HN~ ~ 0--A ~ Y--(CH2)m--Z (~

in which R1-R3, A, X, Y! Z, n, m have the above-mentioned meanings with a guanylation reagent such as for example lH-pyrazole-1-carboxamidine or S-methylthio-urea in an inert solvent such as e.g. dimethylformamide, dioxane, dimethylsulfoxide 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.

If the compound of the general formula III also contains a free amino group at other positions such as in group Z
then this is also guanylated under the reaction conditions according to the aforementioned procedure.

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

Rl R2 ~ ~0--A~Y--(CH~)m--Z (IV) in which Rl-R3, A, X, Y, Z, n and m have the above-mentioned me~n; ngs and pG1 denotes a protective group such as the benzyloxycarbonyl group, the t-butyloxy-carbonyl group or the allyloxycarbonyl group, with a reagent that cleaves protective groups. The protective groups are cleaved by common methods in peptide chemistry using acidic reagents such as e.g. hydrogen bromide in glacial acetic acid or trifluoro-acetic acid or etherial HCl solution or hydrogenolytically or by palladium-catalysed or rhodium-catalysed cleavage.

If the compound of the general formula IV also contains a group analogous to pG1 at other positions, for example within the group Z, then this is also cleaved under the reaction conditions according to the above-mentioned procedure.

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

~ ~ OH (V~
1 ~N ~ (CH ~

in which Rl, PG1, X and n have the above-mentioned meanings, with a compound of the general formula VI

R4 - A Y - (CH2)m- Z (~1) CA 02229903 l998-02-l8 in which R2, R3, A, Y, Z and m have the above-mentioned meanings and R4 denotes halogen, tosylate, mesylate or triflate, in an inert solvent such as dioxane, tetra-hydrofuran, dimethylformamide, N-methyl-pyrrolidone or toluene in the presence of a base such as for example sodium carbonate, potassium carbonate, 1,5-diazabi-cyclo[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 general formula VI are produced by methods known in the literature.

The compounds of the general formula V are produced by conventional methods in peptide chemistry by reacting compounds of the type VII

R

HN~ ~ OH (Vl~

in which Rl, X and n have the above-mentioned meanings, with the appropriate reagents such as e.g. di-tert-butyldicarbonate or chloroformic acid esters in inert solvents such as tetrahydrofuran, dioxane, dimethyl-formamide or water in the presence of bases such as alkali hydroxides or alkaline earth hydroxides, sodium carbonate, potassium carbonate, N-methylmorpholine, diisopropylethylamine, triethylamine or 1,5-diazabi-cyclo[5.4.0]undec-5-ene at temperatures between 0~C and the boiling point of the solvent preferably between room temperature and 50~C.

-CA 02229903 l998-02-l8 Compounds of the general formula VII are produced by known methods of heterocycle synthesis (2,3-dihydro-lH-indoles and 2, 3,4, 5-tetrahydro-lH-benzo[c]azepines:
Ch.S.J. Walpole, J. Med. Chem. 1994, 37, 1942-1954;
1,2,3,4--tetrahydroisoquinolines: J. M. Bobbitt, K.L.
Khanna, J.M. Kiely, Chem. Ind. 1964, 1950-1951; 2,3,4,5-tetrahydro-lH-benzo[d]azepines: H. Wikstrom, B.
Andersson, T. Elebring, S. Lagerkvist, G. Hallnemo, I.
Petterson, P.-A. Jovall, K. Swensson, A. Ekman, A.
Carlsson, J. Med. Chem. 1992, 35, 3984-3990: 2,3,4,5-tetrahydro-benzo[f][ 1,4] oxazepines: A.H. Robins, DE
1696552, 29.04.1971).

Compounds of the general formula IV can also be obtained by reacting compounds of the general formula V in which R1, PG1, X and n have the above-mentioned meanings, with compounds of the general formula VI in which R2, R3, A, Y, Z and m have the above-mentioned meanings and R4 denotes a hydroxyl group, in an inert solvent such as dioxane, tetrahydrofuran or toluene in the presence of diethylazodicarboxylate and trimethylphosphite or triethylphosphite at temperatures between O and 50~C
preferably at room temperature.

Compounds of the type IV' R! R2 pGl,N~ (CH~O--A~Y--(CH~)m--Z (~V ) in which R1-R3, A, X, Z, n, m and pG1 have the above-- .

mentioned meanings and Y' denotes an oxygen atom can also be produced by condensing a compound of the general formula VIII

Rl R2 ~ ; ~ 0--A ~ OH (V m) in which Rl-R3, A, X, pGl and n have the above-mentioned meanings with a compound of the general formula IX

HC~----(CH2)m--Z (IX) in which Z and m have the above-mentioned meanings in an inert solvent such as dioxane, tetrahydrofuran or toluene in the presence of diethylazodicarboxylate and trimethylphosphite or triethylphosphite at temperatures between 0 and 50~C, preferably at room temperature.

Compounds of the general formula IX are either commercially available or can be produced by methods known in the literature (see e.g.: K.L. Bhat, D.M.
Flanagan, M.M. Jouillé, Synth. Commun. 1985, 15, 587-598).

Compounds of the general formula VIII are prepared by reacting a compound of the general formula X

.

Rl R2 PGl- N~( ~ ~ O - A ~ o _ pG2 (X) in which R1-R3, A, X, pGl and n have the above-mentioned meanings and pG2 can be a further protective group such as e.g. a methyl, benzyl or allyl group, with a reagent that cleaves the protective group PG2. The protective groups are cleaved by common methods using acidic or Lewis acid reagents such as e.g. hydrogen bromide in glacial acetic acid, trifluoroacetic acid, etherial HCl solution or boron trifluoride etherate, titanium tetra-chloride, trimethylsilyl iodide or by hydrogenolysis or by palladium-catalysed or rhodium-catalysed cleavage and namely in a manner such that the protective group pGl is retained.

Compounds of the general formula X can be produced by reacting a compound of the general formula V with a compound of the general formula XI

R5 A ~ O _ pG2 (X~

in which R2, R3, A, pG2 have the above-mentioned meanings and R5 denotes a nucleofuge such as halogen, tosylate, mesylate or triflate in an inert solvent such as tetrahydrofuran, dioxane, 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 ethyldiisopropylamine at temperatures between 0~C and the boiling point of the solvent, preferably between room temperature and 100~C.

Compounds of the general formula XI can be produced by known methods from the corresponding alcohols of the general formula XII

HO - A ~ o _ pG2 ( ~

in which R2, R3, A, pG2 have the above-mentioned meanings by for example chlorinating an alcohol of the general formula XII using phosphorus pentachloride in an inert solvent such as benzene, toluene or mesitylene at temperatures between room temperature and the boiling point of the solvent that is used, preferably between room temperature and 60~C.

Compounds of the general formula XII are either commercially available or known from the literature or can be produced by standard methods from commercially available precursors or precursors known in the literature.

Compounds of the general formula X' CA 02229903 l998-02-l8 Rl R2 l~N~(CH ~ O - A' ~ o _ pG2 in which R1-R3, X, PGl, pG2 and n have the above-mentioned meanings and A' is a hydroxymethyl-substituted methylene group, can also be produced by converting a compound of the general formula X'' Rl ' R2 ~ ~ O - A ~ o _ pG2 in which Rl-R3, X, PG1, pG2 and n have the above-mentioned meanings and A'' is a methoxycarbonyl-substituted, ethoxycarbonyl-substituted or allyloxy-carbonyl-substituted methylene group, into the corresponding alcohol by basic or palladium-catalysed saponification and subsequent reduction of the free carboxyl group with mild reducing agents such as e.g.
sodium borohydride in inert solvents such as ethanol, tetrahydrofuran or dioxane.

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

This relates to compounds of the general formula I which carry one or several carboxylic acid ester functions in one or several fragments of Rl-R3, A or Z. These can be converted into compounds of the general formula I with free carboxyl groups by standard methods such as e.g. by aqueous alkaline hydrolysis or by treatment with trimethylsilyl iodide at temperatures between 0~C and the boiling point of the solvent, preferably at room temperature in inert solvents such as methylene chloride or by enzymatic hydrolysis for example in the presence of an esterase.

This also relates to compounds of the general formula I
in which the fragment A contains an allyloxycarbonyl group. The free carboxylic acid is obtained by transition metal-catalysed cleavage for example by palladium-catalysed allyl cleavage in an inert solvent such as tetrahydrofuran or dioxane in the presence of a nucleophile such as e.g. 5,5-dimethyl-cyclohexane-1,3-dione or piperidine at temperatures between 0 and 50~C
preferably at room temperature.

This also relates to compounds of the general formula I
in which one or several of the substituents R1-R3 contains one or several benzyloxy groups. In this process the benzyl group is replaced by a hydrogen atom by catalytic hydrogenation in the presence of a catalyst, preferably palladium on carbon. The benzyl group can also be removed 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 or by treatment with trimethylsilyl iodide at temperatures between 0~C and the boiling point of the solvent, preferably at room temperature in inert solvents such as diethyl ether, tetrahydrofuran, methylene chloride or chloroform.

This also relates to compounds of the general formula I
in which the group Z denotes a 2-pyrrolidinyl residue allyloxycarbonyl-substituted on the nitrogen or a 3-pyrrolidinyl residue allyloxycarbonyl-substituted on the nitrogen or a 4-piperidinyl residue allyloxycarbonyl-substituted on the nitrogen. The corresponding free amine, the N-allyl-substituted amine or the N-(1-[5,5-dimethyl-3-oxo-cyclohex-1-enyl])-substituted amine can be obtained depending on the choice of the nucleophile or of the reaction temperature by palladium-catalysed reactions in an inert solvent such as tetrahydrofuran or dioxane in the presence of a nucleophile such as 5,5-dimethyl-cyclohexane-1,3-dione, tributyltin hydride, diethyl malonate or piperidine.

This also relates to compounds of the general formula I
in which the group Z denotes a 2-pyrrolidinyl residue or a 3-pyrrolidinyl residue or a 4-piperidinyl residue. The corresponding N-iminoalkyl-substituted or N-iminoaryl-substituted derivatives of the respective starting compound can be obtained by reaction with aliphatic or aromatic imidic acid ester-hydrochlorides in an inert solvent such as tetrahydrofuran, diethyl ether, ethanol, dimethylformamide or dioxane in the presence of an auxiliary base such as triethylamine, diisopropyl-ethylamine or N-methylmorpholine.

..

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

In addition to the compounds mentioned in the examples the following are preferred within the sense of the invention:

1. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(1-imino-methyl-piperidin-4-yloxy)-phenyl]-acetic acid 2. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(1-imino-methyl-piperidin-4-yloxy)-phenyl]-acetic acid ethyl ester 3. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(dimethyl-carbamoyl)-piperidin-4-yloxy]-phenyl}-acetic acid 4. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(dimethyl-carbamoyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester 5. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(1-methyl-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid 6. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(1-methyl-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester 7. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(cyclopropyl-imino-methyl)-piperidin-4-yloxy]-phenyl}-acetic acid 8. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(cyclopropyl-imino-methyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester 9. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(imino-hexyl)-piperidin-4-yloxy]-phenyl}-acetic acid 10. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(1-imino-hexyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester 11. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(imino-phenyl-methyl)-piperidin-4-yloxy]-phenyl}-acetic acid 12. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(imino-phenyl-methyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester 13. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(pyrrolidin-2-ylmethoxy)-phenyl]-acetic acid 14. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(pyrrolidin-2-ylmethoxy)-phenyl]-acetic acid ethyl ester 15. {4-[1-(amino-imino-methyl)-pyrrolidin-2-ylmethoxy]-phenyl}-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-acetic acid 16. {4-[1-(amino-imino-methyl)-pyrrolidin-2-ylmethoxy]-phenyl}-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-acetic acid ethyl ester 17. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(1-imino-ethyl)-pyrrolidin-2-ylmethoxy]-phenyl}-acetic acid 18. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(1-imino-ethyl)-pyrrolidin-2-ylmethoxy]-phenyl}-acetic acid ethyl ester 19. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(4,5-dihydro-lH-imidazol-2-ylmethoxy-)-phenyl]-acetic acid 20. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(4,5-dihydro-lH-imidazol-2-ylmethoxy-)-phenyl]-acetic acid ethyl ester 21. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(3H-imidazol-4-ylmethoxy-)-phenyl]-acetic acid 22. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(3H-imidazol-4-ylmethoxy-)-phenyl]-acetic acid ethyl ester 23. [4-(2-(Amino-ethoxy)-phenyl]-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-acetic acid 24. [4-(2-(Amino-ethoxy)-phenyl]-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-acetic acid ethyl ester 25. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(2-hydroxy-ethoxy)-phenyl]-acetic acid 26. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester 27. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(3-hydroxy-propoxy)-phenyl]-acetic acid 28. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(3-hydroxy-propoxy)-phenyl]-acetic acid ethyl ester 29. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(2-imino-hexahydro-pyrimidin-5-yloxy)-phenyl]-acetic acid 30. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(2-imino-hexahydro-pyrimidin-5-yloxy)-phenyl]-acetic acid ethyl ester 31. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(2-ethoxycarbonyl-imino-hexahydro-pyrimidin-5-yloxy)-phenyl]-acetic acid 32. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(2-ethoxycarbonyl-imino-hexahydro-pyrimidin-5-yloxy)-phenyl]-acetic acid ethyl ester 33. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(2-guanidino-ethoxy)-phenyl]-acetic acid 34. [2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(2-guanidino-ethoxy)-phenyl]-acetic acid ethyl ester 35. [3-(Amino-imino-methyl)-8-methoxy-2,3,4,5-tetrahydro-lH-benzo[d]azepin-7-yloxy]-{4-[1-(amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-acetic acid 36. [3-(Amino-imino-methyl)-8-methoxy-2,3,4,5-tetrahydro-lH-benzo[d]azepin-7-yloxy]-{4-[1-(amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester 37. [3-(Amino-imino-methyl)-8-methoxy-2,3,4,5-tetrahydro-lH-benzo[d]azepin-7-yloxy]-{4-[1-(amino-imino-methyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid .

38. [3-(Amino-imino-methyl)-8-methoxy-2,3,4,5-tetrahydro-lH-benzo[d]azepin-7-yloxy]-{4-[1-(amino-imino-methyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid ethyl ester 39. [(7-{4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-benzyloxy}-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-imino-methyl]-amine 40. [(7-{4-[1-(Amino-imino-methyl)-pyrrolidin-3-yloxy]-benzyloxy}-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-imino-methyl]-amine 41. (Imino-{7-methoxy-8-[4-(pyrrolidin-3-yloxy)-benzyloxy]-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-methyl)-amine 42. (Imino-{7-methoxy-8-[4-(piperidin-4-yloxy)-benzyloxy]-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-methyl)-amine 43. [Imino-(7-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-benzyloxy}-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-methyl]-amine 44. [Imino-(7-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-benzyloxy}-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-methyl]-amine 45. [3-(Amino-imino-methyl)-8-methoxy-2,3,4,5-tetrahydro-lH-benzo[d]azepin-7-yloxy]-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid 46. [3-(Amino-imino-methyl)-8-methoxy-2,3,4,5-tetrahydro-lH-benzo[d]azepin-7-yloxy]-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid ethyl ester 47. [3-(Amino-imino-methyl)-8-methoxy-2,3,4,5-tetrahydro-lH-benzo[d]azepin-7-yloxy]-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid 48. [3-(Amino-imino-methyl)-8-methoxy-2,3,4,5-tetrahydro-lH-benzo[d]azepin-7-yloxy]-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester 49. {4-[1-(Amino-imino-methyl)-pyrrolidin-3-yloxy]-phenyl}-[3-(amino-imino-methyl)-2,3,4,5-tetrahydro-lH-benzo[d]azepin-6-yloxy]-acetic acid 50. {4-[1-(Amino-imino-methyl)-pyrrolidin-3-yloxy]-phenyl}-[3-(amino-imino-methyl)-2,3,4,5-tetrahydro-lH-benzo[d]azepin-6-yloxy]-acetic acid ethyl ester 51. {4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-[3-(amino-imino-methyl)-2,3,4,5-tetrahydro-lH-benzo[d]azepin-6-yloxy]-acetic acid 52. {4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-[3-(amino-imino-methyl)-2,3,4,5-tetrahydro-lH-benzo[d]azepin-6-yloxy]-acetic acid ethyl ester 53. [3-(Amino-imino-methyl)-2,3,4,5-tetrahydro-lH-benzo[d]azepin-6-yloxy]-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid ;

54. [3-(Amino-imino-methyl)-2,3,4,5-tetrahydro-lH-benzo[d]azepin-6-yloxy]-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester 55. [3-(Amino-imino-methyl)-2,3,4,5-tetrahydro-lH-benzo[d]azepin-6-yloxy]-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid 56. [3-(Amino-imino-methyl)-2,3,4,5-tetrahydro-lH-benzo[d]azepin-6-yloxy]-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid ethyl ester 57. [(6-{4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-benzyloxy}-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-imino-methyl]-amine 58. [(6-{4-[1-(Amino-imino-methyl)-pyrrolidin-3-yloxy]-benzyloxy}-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-imino-methyl]-amine 59. {4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-[4-(amino-imino-methyl)-2,3,4,5-tetrahydro-benzo[f][l,4]oxazepin-7-yloxy]-acetic acid 60. {4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-[4-(amino-imino-methyl)-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-yloxy]-acetic acid ethyl ester 61. {4-[1-(Amino-imino-methyl)-pyrrolidin-3-yloxy]-phenyl}-[4-(amino-imino-methyl)-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-yloxy]-acetic acid 62. {4-[1-(Amino-imino-methyl)-pyrrolidin-3-yloxy]-phenyl}-[4-(amino-imino-methyl)-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-yloxy]-acetic acid ethyl ester 63. [4-(Amino-imino-methyl)-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-yloxy]-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid 64. [4-(Amino-imino-methyl)-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-yloxy]-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid ethyl ester 65. [4-(Amino-imino-methyl)-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-yloxy]-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid 66. [4-(Amino-imino-methyl)-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-yloxy]-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester 67. [(7-{4-[1-(Amino-imino-methyl)-pyrrolidin-3-yloxy]-benzyloxy}-3,5-dihydro-2H-benzo[f][1,4]oxazepin-4-yl)-imino-methyl]-amine 68. [(7-{4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-benzyloxy}-3,5-dihydro-2H-benzo[f][1,4]oxazepin-4-yl)-imino-methyl]-amine _ 69. [2-(Amino-imino-methyl)-6-methoxy-2,3-dihydro-lH-isoindol-5-yloxy]-{4-[1-(amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-acetic acid 70. [2-(Amino-imino-methyl)-6-methoxy-2,3-dihydro-lH-isoindol-5-yloxy]-{4-[1-(amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester 71. [2-(Amino-imino-methyl)-6-methoxy-2,3-dihydro-lH-isoindol-5-yloxy]-{4-[1-(amino-imino-methyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid 72. [2-(Amino-imino-methyl)-6-methoxy-2,3-dihydro-lH-isoindol-5-yloxy]-~4-[1-(amino-imino-methyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid ethyl ester 73. [2-(Amino-imino-methyl)-6-methoxy-2,3-dihydro-lH-isoindol-5-yloxy]-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid 74. [2-(Amino-imino-methyl)-6-methoxy-2,3-dihydro-lH-isoindol-5-yloxy]-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester 75. [2-(Amino-imino-methyl)-6-methoxy-2,3-dihydro-lH-isoindol-5-yloxy]-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid 76. [2-(Amino-imino-methyl)-6-methoxy-2,3-dihydro-lH-isoindol-5-yloxy]-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid ethyl ester 77. [(5-{4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-benzyloxy}-6-methoxy-1,3-dihydro-isoindol-2-yl)-imino-methyl]-amine 78. [(5-{4-[1-(Amino-imino-methyl)-pyrrolidin-3-yloxy]-benzyloxy}-6-methoxy-1,3-dihydro-isoindol-2-yl)-imino-methyl]-amine 79. {4-[1-(Amino-imino-methyl)-pyrrolidin-3-yloxy]-phenyl}-[2-(amino-imino-methyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepin-8-yloxy]-acetic acid 80. {4-[1-(Amino-imino-methyl)-pyrrolidin-3-yloxy]-phenyl}-[2-(amino-imino-methyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepin-8-yloxy]-acetic acid ethyl ester 81. {4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-[2-(amino-imino-methyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepin-8-yloxy]-acetic acid 82. {4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-[2-(amino-imino-methyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepin-8-yloxy]-acetic acid ethyl ester 83. [2-(Amino-imino-methyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepin-8-yloxy]-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid 84. [2-(Amino-imino-methyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepin-8-yloxy]-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester 85. [2-(Amino-imino-methyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepin-8-yloxy]-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid 86. [2-(Amino-imino-methyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepin-8-yloxy]-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid ethyl ester 87. [(7-{4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-benzyloxy}-6-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-imino-methyl]-amine 88. [(7-{4-[1-(Amino-imino-methyl)-pyrrolidin-3-yloxy]-benzyloxy}-3,4-dihydro-lH-isoquinolin-2-yl)-imino-methyl]-amine 89. [(7-{4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-benzyloxy}-3,4-dihydro-lH-isoquinolin-2-yl)-imino-methyl]-amine 90. [Imino-(7-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-benzyloxy3-3,4-dihydro-lH-isoquinolin-2-yl)-methyl]-amine 91. [Imino-(7-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-benzyloxy}-3,4-dihydro-lH-isoquinolin-2-yl)-methyl]-amine 92. (Imino-{7-[4-(piperidin-4-yloxy)-benzyloxy]-3,4-dihydro-lH-isoquinolin-2-yl}-methyl)-amine 93. (Imino-{7-[4-(pyrrolidin-3-yloxy)-benzyloxy]-3,4-dihydro-lH-isoquinolin-2-yl}-methyl)-amine 94. {3-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-acetic acid 95. {3-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-acetic acid ethyl ester 96. 5-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-2-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxymethyl]-benzoic acid 97. 5-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-2-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxymethyl]-benzoic acid ethyl ester 98. {5-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-2-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxymethyl]-phenyl}-acetic acid 99. {5-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-2-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxymethyl]-phenyl}-acetic acid ethyl ester 100. {5-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-2-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxymethyl]-phenoxy}-acetic acid 101. {5-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-2-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxymethyl]-phenoxy}-acetic acid ethyl ester 102. 3-{5-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-2-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxymethyl]-phenyl}-propionic acid lQ3. 3-{5-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-2-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxymethyl]-phenyl}-propionic acid ethyl ester 104. 4-{4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-4-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-butyric acid 105. 4-{4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-4-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-butyric acid ethyl ester 106. 2-{4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-2-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-ethanol 107. [2-(Amino-imino-methyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-acetic acid 108. [2-(Amino-imino-methyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester -109. [2-(Amino-imino-methyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid 110. [2-(Amino-imino-methyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester 111. [2-(Amino-imino-methyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(piperidin-4-yloxy)-phenyl]-acetic acid 112. [2-(Amino-imino-methyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(piperidin-4-yloxy)-phenyl]-acetic acid ethyl ester 113. {4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-acetic acid 114. {4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-acetic acid ethyl ester 115. [2-(Amino-imino-methyl)-7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-{4-[1-(amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-acetic acid 116. [2-(Amino-imino-methyl)-7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-{4-[1-(amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester 117. [2-(Amino-imino-methyl)-7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-{4-[1-(amino-imino-methyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid 118. [2-(Amino-imino-methyl)-7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-{4-[1-(amino-imino-methyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid ethyl ester 119. [2-(Amino-imino-methyl)-7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid 120. [2-(Amino-imino-methyl)-7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-acetic acid ethyl ester 121. [2-(Amino-imino-methyl)-7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid 122. [2-(Amino-imino-methyl)-7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester 123. [2-(Amino-imino-methyl)-7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-4-(piperidin-4-yloxy)-phenyl]-acetic acid 124. [2-(Amino-imino-methyl)-7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6 yloxy]-4-(piperidin-4-yloxy)-phenyl]-acetic acid ethyl ester 125. [2-(Amino-imino-methyl)-7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-4-(pyrrolidin-3-yloxy)-phenyl]-acetic acid 126. [2-(Amino-imino-methyl)-7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-4-(pyrrolidin-3-yloxy)-phenyl]-acetic acid ethyl ester 127. [(6-{4-[1-(Amino-imino-methyl)-pyrrolidin-3-yloxy]-benzyloxy}-7-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-imino-methyl]-amine 128. [(6-{4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-benzyloxy}-7-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-imino-methyl]-amine 129. {4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-3-hydroxy-phenyl}-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-acetic acid 130. {4-[1-(Amino-imino-methyl)-piperidin-4-yloxy]-3-hydroxy-phenyl}-[2-(amino-imino-methyl)-1,2,3f4-tetrahydro-isoquinolin-7-yloxy]-acetic acid ethyl ester 131. 2-(Amino-imino-methyl)-7-{4-[1-(amino-imino-methyl)-piperidin-4-yloxy]-benzyloxy}-1,2,3,4-tetrahydro-isoquinolin-6-carboxylic acid 132. 2-(Amino-imino-methyl)-7-{4-[1-(amino-imino-methyl)-piperidin-4-yloxy]-benzyloxy}-1,2,3,4-tetrahydro-isoquinolin-6-carboxylic acid ethyl ester 133. 2-(Amino-imino-methyl)-7-(1-{4-[1-(amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-2-hydroxy-ethoxy)-1,2,3,4-tetrahydro-isoquinolin-6-carboxylic acid 134. 2-(Amino-imino-methyl)-7-(1-{4-[1-(amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-2-hydroxy-ethoxy)-1,2,3,4-tetrahydro-isoquinolin-6-carboxylic acid ethyl ester Example 1:

~4~ r 1 - (amino-imino-methyl)-piperidin-4-yloxyl-Phenyl~-~2-(amino-imino-methyl)-1 2 3 4-tetrahydro-isoquinolin-7-yloxy]-acetic acid ethyl ester-dihydrochloride 1. 7-Hydroxy-3 4-dihydro-lH-isoquinoline-2-carboxYlic acid-tert.-butYl ester A solution of 17.1 g (0.079 mol) di-tert-butyl dicarbonate in 170 ml methylene chloride is added dropwise at 5~C to a suspension of 16.4 g (0.079 mol) 7-hydroxy-1,2,3,4-tetrahydro-isoquinoline hydroacetate (analogously to J.M. Bobbitt, K.L.~h~nn~, J.M. Kiely, Chem. Ind. 1964, 1950--1951) and 32.6 ml (0.235 mol) triethylamine in 164 ml methylene chloride. After stirring for 1 hour at 5~C the resulting clear solution is evaporated, the =

residue is dissolved in ethyl acetate and subsequently extracted by shaking in each case three times with 50 ml 1 N acetic acid, saturated sodium bicarbonate solution and a saturated solution of sodium chloride in succession. After drying and evaporating, the residue is triturated with isohexane, suction filtered and dried. 17.S g (0.070 mol; 88.9 %) of the title compound with a melting point of 140-142.5~C is obtained as a white solid.

2. (4-BenzyloxY-phenyl)-chloro-acetic acid ethyl ester 10.4 g phosphorus pentachloride (0.050 mol) is added at 5~C to a solution of 14.3 g (4-benzyloxy-phenyl)-hydroxy-acetic acid ethyl ester (0.050 mol) in 250 ml methylene chloride and stirred for 24 h at room temperature. After evaporating the residue is purified by chromatography on a silica gel column (mobile solvent: isohexane/ethyl acetate 9:1). After evaporation of the appropriate column fractions, 13.0 g (0.043 mol; 85.3 %) of the title compound is obtained as a yellow crystalline solid with a melting point of 45-47~C.

3. 7-~(4-Benzyloxy-phenYl)-ethoxYcarbonyl-methoxyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert.-butyl ester 8.4 g (0.060 mol) potassium carbonate is added to a solution of 11.4 g (4-benzyloxy-phenyl)-chloro-acetic acid ethyl ester (0.037 mol) and 7.5 g (0.030 mol) 7-hydroxy-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester in 150 ml acetonitrile and heated for 24 h under reflux.
After filtration the filtrate is evaporated and the residue is purified by chromatography on a silica gel column (mobile solvent: isohexane/ethyl acetate 9:1, 8:2, 7:3). After evaporation of the appropriate column fractions, 15.2 g (97.9 %) of the title compound is obtained as a white crystalline solid with a melting point of 85-87~C.

4. 7- r Ethoxycarbonyl-(4-hydroxy-phen,yl)-methoxy~-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester 10.8 g (0.020 mol) 7-[(4-benzyloxy-phenyl)-ethoxy-carbonyl-methoxy]-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester is dissolved in 200 ml ethyl acetate and hydrogenated for 3 h at room temperature under normal pressure in the presence of 2.0 g palladium/carbon (10 %). After the uptake of 480 ml hydrogen the catalyst is removed by filtration and the solvent is evaporated. 7.8 g (0.018 mol; 91.2 %) of the title compound is obtained as a residue in the form of a white crystalline solid with a melting point of 152-155~C.

5. 7-~[4-(1-tert-Butoxvcarbonyl-piperidin-4-yloxY)-phenyll-ethoxycarbonyl-methoxY~-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester A solution of 4.3 g (0.010 mol) 7-[ethoxycarbonyl-(4-hydroxy-phenyl)-methoxy]-3,4-dihydro-lH-isoquinoline-2-carboxylic acid-tert-butyl ester, 2.2 g (0.011 mol) 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (analogously to K.L. Bhat, D.M. Flanagan, M.M. Jouillé, Synth. Commun. 1985, 15, 587-598) and 3.3 g (0.013 mol) triphenyl-phosphine in 100 ml tetrahydrofuran is admixed at 5~C with 2.0 ml (0.013 mol) azodicarboxylic acid diethyl ester and stirred for 24 h at room temperature. After evaporation the residue is purified by chromatography on a silica gel column (mobile solvent: isohexane/ethyl acetate 9:1, 8:2, 7:3). After evaporating the appropriate column fractions 4.6 g (0.0075 mmol; 75.3 %) of the title compound is obtained as a yellow oil. EI-MS: 610 (M+) 6. r 4-(Piperidin-4-yloxY)-phenyl~-[(1 2 3 4-tetrahydro-isoquinolin-7-yloxy)]-acetic acid ethyl ester dihydrochloride 50 ml etherial HCl solution is added at 5~C to a solution of 4.6 g (0.0075 mol) 7-{[4-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-phenyl]-ethoxy-carbonylmethoxy}-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester in 50 ml ethanol and subsequently stirred for 5 h at 5~C. After addition of 50 ml diethyl ether the precipitated white solid is filtered and dried. Yield: 2.6 g (0.0054 mol;
71.7 %). Melting point: 215-222~C.

7 ~4~ r 1- (Amino-imino-methyl)-Piperidin-4-yloxyl-phenyl~- r 2-(amino-imino-methyl)-1 2 3,4-tetrahydro-isoquinolin-7-Yloxy~-acetic acid ethyl ester dihydrochloride A solution of 1.65 g (0.0034 mol) [4-(piperidin-4-yloxy)-phenyl]-[(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)]-acetic acid ethyl ester-dihydrochloride and 2.00 g (0.0136 mol) lH-pyrazole-1-carboxamidine hydrochloride (lit.: M.S. Bernatowicz, Y.Wu, G.R.
Matsueda, ~. Org. Chem. 1992, 57, 2497-2502) in 2.5 ml dimethylformamide is admixed at 5~C with 9.3 ml (0.0544 mol) diisopropylethylamine. After stirring for 48 h at room temperature 25 ml diethyl ether is added and decanted four times. The remaining residue is dissolved in 25 ml water, adjusted to pH 3 with 2 N HCl and chromatographed by means of preparative HPLC (RP-18 column, 15 -25 ~m) (mobile solvent: H2O; pH 3; H2O/CH3OH 8:2, pH 3). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr) 1.5 g (0.0026 mol; 77.7 %) of the title compound is obtained as a white solid with a melting point of 120~C.

Example 2:

~4- r 1-Amino-imino-methyl)-piperidin-4-yloxy~-phenyl~- r 2-(amino-imino-methyl)-1 2 3,4-tetrahydro-isoquinolin-7-yloxy~-acetic acid dihydrochloride A solution of 567 mg (0.0010 mol) {4-[1-(amino-imino-methyl)-piperidin-4-yloxy]-phenyl}-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-acetic acid ethyl ester dihydrochloride is dissolved in a mixture of 10 ml water and 10 ml ethanol and admixed at 5~C with 4 ml 1 N NaOH solution. After stirring for 1 h at room temperature it is adjusted to pH 3 with 2 N HCl and evaporated. The residue is dissolved in 20 ml water and chromatographed by means of preparative HPLC (RP-18 column, 15-25 ~m) (mobile solvent: H20, pH 3; H20/CH3CN
7:3, pH 3). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr) 400 mg (0.0007 mol; 74.1 %) of the title compound is obtained as a white solid with a melting point of 95~C.

Example 3:

~4- r 1- (Amino-imino-methyl)-pyrrolidin-3-(S)-yloxy~-phenyl~- r 2-(amino-imino-methyl)-1,2,3,4-tetrahydro-iso~uinolin-7-yloxy~-acetic acid ethyl ester dihydrochloride 1. 7- r ~ 4-(1-tert-butoxYcarbonYl-pyrrolidin-3-(S)-yloxy)-phenyl]-ethoxycarbonyl-methoxy~-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert.-butyl ester A solution of 3.90 g (0.0091 mol) 7-[ethoxy-carbonyl-(4-hydroxy-phenyl)-methoxy]-3,4-dihydro-lH-isoquinoline-2-carboxylic acid-tert-butyl ester, 1.87 g (0.0100 mol) (R)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (analogously to K.L. Bhat, D.M. Flanagan, M.M. Jouille, Synth.
Commun. 1985, 15, 587-598) and 3.60 g (0.0137 mol) triphenylphosphine in 75 ml tetrahydrofuran is admixed at 5~C with 2.15 ml (0.0137 mol) azodicarboxylic acid diethyl ester and stirred for 24 h at room temperature. After evaporation the residue is purified by chromatography on a silica gel column (mobile solvent: isohexane/ethyl acetate 9:1, 8:2, 7:3). After evaporating the appropriate column fractions 2.20 g (0.0037 mol; 40.5 %) of the title compound is obtained as a colourless oil.
EI-MS: 596 (M+).

2. r4-(Pyrrolidin-3-(S)-yloxy)-phenyl~ - r ( 1 2,3 4-tetrahydro-iso~uinolin-7-yloxy)l-acetic acid ethyl ester dihydrochloride 50 ml etherial HCl solution is added at 5~C to a solution of 2.20 g (0.0037 mol) 7-{[4-(1-tert-butoxycarbonyl-pyrrolidin-3-(S)-yloxy)-phenyl]-ethoxycarbonyl-methoxy}-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester in 25 ml ethanol and subsequently stirred for 5 h at 5~C. After addition of 25 ml ether the precipitated light-brown solid is filtered and dried. Yield: 0.80 g (0.0017 mol; 45.9 %). Melting point: 50~C.

3- ~4~ r 1 - (Amino-imino-methyl)-pyrrolidin-3-(S)-yloxy]-phenyl ~ - r 2-(amino-imino-methyl)-1 2 3 4-tetrahydro-isoquinolin-7-yloxy]-acetic acid ethyl ester dihydrochloride A solution of 0.80 g (0.0017 mol) [4-(pyrrolidin-3-(S)-yloxy)-phenyl]-[(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)]-acetic acid ethyl ester dihydrochloride and 1.00 g (0.0068 mol) lH-pyrazole-l-carboxamidine hydrochloride (lit.: M.S. Bernatowicz, Y.Wu, G.R.
Matsueda, ~. Org. Chem. 1992, 57, 2497-2502) in 1.5 ml dimethylformamide is admixed at 5~C with 4.7 ml (0.0272 mol) diisopropylethylamine. After stirring for 48 h at room temperature 20 ml diethyl ether is added and decanted four times. The remaining residue is dissolved in 50 ml water, adjusted to pH 3 with 2 N HCl and chromatographed by means of preparative HPLC (RP-18 column, 15 - 25 ~m) (mobile solvent: H20; pH 3; H20/CH30H 8:2, pH 3). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr) 0.50 g (0.0009 mol;
52.9 %) of the title compound is obtained as a pale yellow solid with a melting point of 90~C.

Example 4:

~4-[1-Amino-imino-methyl)-pyrrolidin-3-(S)-yloxy]-phenyl~- r 2-(amino-imino-methyl)-1,2,3,4-tetrahYdro-isoquinolin-7-yloxy~-acetic acid dihydrochloride A solution of 280 mg (0.0005 mol) {4-[1-(amino-imino-methyl)-pyrrolidin-3-(S)-yloxy]-phenyl}-[2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-acetic acid ethyl ester dihydrochloride is dissolved in a mixture of 10 ml water and 10 ml ethanol and admixed at 5~C with 4 ml 1 N NaOH solution. After stirring for 2 h at 5~C it is adjusted to pH 3 with 2 N HCl and evaporated. The residue is dissolved in 20 ml water and chromatographed by means of preparative HPLC (RP-18 column, 15-25 ~m) (mobile solvent: H20, pH 3; H20/CH3CN
8:2, pH 3). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr), 180 mg (0.00034 mol; 68.5 %) of the title compound is obtained as a light-brown solid with a melting point of >155~C
(decomposition).

Example 5:

3-(S)-~4-~(2-carbamimidoYl-1,2,3,4-tetrahydro-isoquinolin-7-yloxY)-ethoxycarbonyl-methyl~-phenoxy~-pyrrolidine-1-carboxylic acid allyl ester hydrochloride 1. 3-(R)-hydroxy-pyrrolidin-1-carboxylic acid allyl ester A solution of 2.3 ml (0.022 mol) chloroformic acid allyl ester in 5 ml dichloromethane is added dropwise at 5~C to a solution of 1.62 ml (0.020 mol) 3-(R)-hydroxypyrrolidine and 3.6 ml (0.024 mol) 1,8-diazabicyclo[5.4.0]undec-7-ene in 50 ml dichloromethane. After stirring for 24 h at room temperature it is shaken out twice each time in succession with 40 ml water, 1 N acetic acid and saturated sodium bicarbonate solution. After drying over sodium sulfate and evaporating, 3.0 g (0.0175 mol; 87.6 %) of the title compound is obtained as a yellow oil. EI-MS: 171 (M+).

2. 7-~r4-(1-Allyloxycarbonyl-pyrrolidin-3-(S)-yloxy)-phenyl~-ethoxycarbonyl-methoxy~-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert.-butyl ester A solution of 4.3 g (0.010 mol) 7-[ethoxycarbonyl-(4-hydroxy-phenyl)-methoxy]-3,4-dihydro-lH-isoquinoline-2-carboxylic acid-tert.-butyl ester, 2.2 g (0.0125 mol) 3-(R)-hydroxy-pyrrolidine-l-carboxylic acid allyl ester and 3.3 g (0.0125 mol) triphenylphosphine in 75 ml tetrahydrofuran is admixed at 5~C under a nitrogen atmosphere with 2.0 ml (0.0125 mol) azodicarboxylic acid diethyl ester in 10 ml tetrahydrofuran and stirred for 72 h at room temperature. After evaporation the residue is chromatographed for purification on a silica gel column (mobile solvent: isohexane/ethyl acetate 8:2, 7:3, 6:4, 5:5). After concentrating the appropriate column fractions the crude product is taken up in diethyl ether, the insoluble residue is removed by filtration and evaporated: 5.3 g (0.0091 mmol; 91.0 %) deliquescent crystals. (+)-LSIMS:
579.9 (MH+)-3. 3-(S)-~4-~Ethoxycarbonyl-~1,2,3,4-tetrahydro-isoauinolin-7-yloxy)-methYl~-phenoxy~-pyrrolidine-1-carboxylic acid allyl ester; hydrochloride 75 ml etherial HCl solution is added at 5~C to a solution of 5.3 g (0.0091 mol) 7-{[4-[1-allyloxy-carbonyl-pyrrolidin-3-(S)-yloxy)-phenyl]-ethoxy-carbonyl-methoxy}-3,4-dihydro-lH-isoquinoline-2-carboxylic acid-tert.-butyl ester in 100 ml diethyl ether and it is subsequently stirred for 5 h at 5~C. After evaporating, 5.0 g colourless oil is obtained which can be reacted further as a crude product without further purification steps. EI-MS:
480 (M+)-4. 3-(S)-~4-[(2-Carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-ethoxycarbonyl-methyll-phenoxy~-~yrrolidine-1-carboxylic acid allyl ester;
hydrochloride A solution of 3.75 g (0.0073 mol) 3-(S)-{4-[ethoxy-carbonyl-(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-methyl]-phenoxy}-pyrrolidine-1-carboxylic acid .

allyl ester hydrochloride and 2.11 g (0.0145 mol) lH-pyrazole-l-carboxamidine hydrochloride (lit.:
M.S. Bernatowicz, Y.Wu, G.R. Matsueda, J. Org.
Chem. 1992, 57, 2497-2502) in 7.25 ml dimethylformamide is admixed at 5~C under a nitrogen atmosphere with 10.2 ml (0.0580 mol) diisopropylethylamine. After stirring for 24 h at room temperature, 50 ml diethyl ether is added and decanted four times. The remaining residue is dissolved in 50 ml water, adjusted to pH 3 with 2 N
HCl and chromatographed by means of preparative HPLC (RP-18 column, 15 - 25 ~m) (mobile solvent:
H2O/CH3CN 7:3, pH 3). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr), 3.0 g (0.0054 mol; 74.0 %) of the title compound is obtained as a white solid with a melting point of 80-83~C. (+)FAB-MS: 523 (MH+).

ExamPle 6:

~2-(Amino-imino-methyl)-1 2,3 4-tetrahydro-isoquinolin-7-yloxyl-~4-(pyrrolidin-3-(S)-yloxy)-phenyl~-acetic acid ethyl ester; dihydrochloride 1.50 g (0.0029 mol) 3-(S)-{4-[(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-ethoxycarbonyl-methyl]-phenoxy}-pyrrolidine-1-carboxylic acid allyl ester hydrochloride and 1.56 ml (0.0058 mol) tributyltin hydride in 300 ml dichloromethane is admixed at 5~C with 333 mg (0.0003 mol) tetrakis-triphenylphosphine palladium and stirred for 3 h at 5~C. It is extracted four times with 50 ml 0.1 N HCl, the combined aqueous solutions are filtered and evaporated: 1.37 g (0.0027 mol; 92.4 %) of a colourless solid with a melting point of >170~C (decomposition). (+)-FAB-MS:
439 (MH+)-Example 7:

~2-(Amino-imino-methYl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxY]-r4-(~yrrolidin-3-(s)-yloxy)-phenyl]-acetic acid; dihydrochloride 255 mg (0.0005 mol) t2-amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(pyrrolidin-3-(S)-yloxy)-phenyl]-acetic acid ethyl ester dihydrochloride is dissolved in a mixture of 10 ml water and 10 ml ethanol and admixed at 5~C with 2 ml 1 N NaOH solution.
After stirring for 5 h at 5~C it is adjusted to pH 3 with 2 N HCl and evaporated. The residue is dissolved in 20 ml water and chromatographed by means of preparative HPLC (RP-18 column, 15-25 ~m) (mobile solvent: H2O, pH
3; H2O/CH3CN 9:1, pH 3). A~ter evaporating the appropriate column fractions and drying in a vacuum (10-2 torr), 75 mg (0.00016 mol; 31.0 %) of the title compound is obtained as a yellowish solid with a melting point of 100-105~C. (+)-FAB-MS: 411 (MH+).

Example 8:

r2-(Amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxyl-~4-~1-(1-imino-ethyl)-pyrrolidin-3-(S)-yloxy]-phenyl~-acetic acid ethyl ester dihYdrochloride 2.9 ml (0.028 mol) triethylamine is added dropwise at 5~C under nitrogen to 0.65 g ethyl acetimidate hydrochloride (0.0052 mol) and 1.37 g [2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-[4-(pyrrolidin-3-(S)-yloxy)-phenyl]-acetic acid ethyl ester dihydrochloride (0.0026 mol) in 60 ml ethanol. It is stirred for 2 days at room temperature, evaporated, the residue is dissolved in 20 ml water, adjusted to pH 3 with 2 N HCl and filtered. The filtrate is chromatographed by means of preparative HPLC (RP-18 column, 15-25 ~m) (mobile solvent: H2O, pH 3; H2O/CH3CN
8:2, pH 3). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr), 1.10 g (0.002 mol; 76.6 %) of the title compound is obtained as a yellowish solid with a melting point of >130~C
(decomposition). (+)-FAB-MS: 480 (MH+).

Example 9:

r 2-(Amino-imino-methyl)-1,2 3 4-tetrahydro-isoquinolin-7-yloxyl-~4- r 1- (1-imino-ethYl)-pyrrolidin-3-(S)-yloxy~-phenyl~-acetic acid dihydrochloride 276 mg (0.0005 mol) [2-(amino-imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-{4-[1-(1-imino-ethyl)-pyrrolidin-3-(S)-yloxy]-phenyl}-acetic acid ethyl ester dihydrochloride is dissolved in a mixture of 20 ml water and 20 ml ethanol and admixed at 5~C with 4 ml 1 N NaOH
solution. After stirring for 5 h at 5~C it is ad]usted to pH 3 with 2 N HCl and evaporated. The residue is dissolved in 20 ml water, adjusted to pH 3 with 2 N HCl and chromatographed by means of preparative HPLC (RP-18 column, 15-25 ~m) (mobile solvent: H2O, pH 3; H2O/CH3CN
9:1, pH 3). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr), 250 mg (0.00048 mol; 96.0 %) of the title compound is obtained as a yellowish solid (>180~C decomposition). (+)-FAB-MS:

=

452 (MH+).

Examples 10 ana 11:

~4- r l-Allyl-pyrrolidin-3-(s)-yloxy)-phenyll-(2-carbamimidoYl-1 2 3,4-tetrahYdro-isoquinolin-7-yloxy)-acetic acid ethyl ester hydrochloride and (2-carbamimidoyl-1,2 3 4-tetrahydro-isoquinolin-7-yloxy)-~4- r 1- ( 5 5-dimethyl-3-oxo-cYclohex-1-enyl)-pyrrolidin-3-(S)-yloxyl-phenYl~-acetic acid ethYl ester hydrochloride 0.56 g (0.001 mol) 3-(S)-{4-[(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-ethoxycarbonyl-methyl]-phenoxy}-pyrrolidine-1-carboxylic acid allyl ester hydrochloride and 1.40 g (0.010 mol) 5,5-dimethyl-1,3-cyclohexanedione in 50 ml tetrahydrofuran is admixed at 5~C with 240 mg (0.0002 mol) tetrakis-triphenyl-phosphine-palladium and stirred for 72 h at room temperature. It is evaporated, the residue is dissolved in 50 ml water, shaken out twice with 50 ml ethyl acetate each time, filtered and evaporated. The residue is taken up in 50 ml water, adjusted to pH 3 with 2 N
HCl and chromatographed by means of preparative HPLC
(RP-18 column, 15-25 ~m) (mobile solvent: H20, pH 3;
H20/CH3CN 8:2, pH 3; H20/CH3CN 7:3, pH 3). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr) 98 mg (0.0002 mol; 20.0 %) [4-(1-allyl-pyrrolidin-3-(S)-yloxy)-phenyl]-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-acetic acid ethyl ester hydrochloride is obtained as a yellow oil [EI-MS: 478 (M+)] and 230 mg (0.0004 mol;
40.0 %) (2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-{4-[1-(5,5-dimethyl-3-oxo-cyclohex-1-enyl)-pyrrolidin-3-(S)-yloxy]-phenyl}-acetic acid ethyl ester , CA 02229903 1998-02-18 ;

hydrochloride is obtained as a white solid with a melting point of >160~C (decomposition). [(+)-FAB-MS:
561 (MH+)].

ExamPle 12:

(2-Carbamimidoyl-1 2 3 4-tetrahydro-isoquinolin-7-yloxy)-~4- r 1- (5 5-dimethyl-3-oxo-cyclohex-1-enyl)-pyrrolidin-3-(S)-yloxy]-phenyl~-acetic acid hYdrochloride 150 mg (0.00025 mol) (2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-{4-[1-(5,5-dimethyl-3-oxo-cyclohex-l-enyl)-pyrrolidin-3-(S)-yloxy]-phenyl}-acetic acid ethyl ester hydrochloride is dissolved in a mixture of 10 ml water and 10 ml ethanol and admixed at 5~C with 1 ml 1 N NaOH solution. After stirring for 3 h at 5~C it is adjusted to pH 3 with 2 N HCl and evaporated. The residue is dissolved in 10 ml water, adjusted to pH 3 with 2 N HCl and chromatographed by means of preparative HPLC (RP-18 column, 15-25 ~m) (mobile solvent: H2O, pH 3; H2O/CH3CN 8:2, pH 3). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr), 60 mg (0.00011 mol; 42.2 %) of the title compound is obtained as a yellowish solid with a melting point of 175-178~C (> 190~C decomposition).
(+)-FAB-MS: 533 (MH+).

Example 13:

4-~4-~(2-Carbamimidoyl-1,2 3 4-tetrahydro-isoquinolin-7-yloxy)-ethoxycarbonyl-methyll-phenoxy~-piPeridine-1-carboxylic acid allYl ester; hydrochloride 1. 4-Hydroxy-piperidine-l-carboxYlic acid allyl ester A solution of 11.7 ml (0.110 mol) chloroformic acid allyl ester in 20 ml dichloromethane is added dropwise at 5~C to a solution of 10.1 g (0.100 mol) 4-hydroxypiperidine and 18.0 ml (0.120 mol) 1,8-diazabicyclo[5.4.0]undec-7-ene in 200 ml dichloromethane. After stirring for 48 h at room temperature it is shaken out in succession twice with 400 ml water, 1 N acetic acid and saturated sodium bicarbonate solution. After drying over sodium sulfate and evaporation, 18.5 g (0.0999 mol;
99.9 %) of the title compound is obtained as a yellow oil. EI-MS: 185 (M+).

2. 7-~ r 4-(1-Allyloxycarbonyl-piperidin-4-yloxy)-phenyl~-ethoxycarbonyl-methoxy~-3 4-dihydro-lH-isoquinoline-2-carboxylic acid tert.-butYl ester A solution of 8.5 g (0.020 mol) 7-[ethoxycarbonyl-(4-hydroxy-phenyl)-methoxy]-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert.-butyl ester, 4.6 g (0.025 mol) 4-hydroxy-piperidine-1-carboxylic acid allyl ester and 6.6 g (0.025 mol) triphenyl-phosphine in 150 ml tetrahydrofuran is admixed at 5~C under nitrogen with 4.0 ml (0.025 mol) azidocarboxylic acid diethyl ester in 20 ml tetrahydrofuran and stirred for 72 h at room temperature. After evaporation the residue is chromatographed for purification on a silica gel column (mobile solvent: isohexane/ethyl ester 8:2, 7:3, 6:4, 5:5). After evaporating the appropriate column fractions 10.8 g (0.018 mmol; 90.0 %) of the title compound is obtained as an oil. (+)-FAB-MS:
595 (MH+)~

3. 4-~4-~EthoxYcarbonyl-(1,2,3,4-tetrahYdro-isoquinolin-7-yloxy)-methyl~-phenoxy~-piperidine-1-carboxylic acid allyl ester; hydrochloride A solution of 10.8 g (0.018 mol) 7-{[4-(1-allyloxycarbonyl-piperidin-4-yloxy)-phenyl]-ethoxycarbonyl-methoxy}-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert.-butyl ester in 100 ml diethyl ester is admixed at 5~C with 100 ml etherial HCl solution and subsequently stirred for 7 h at 5~C. The precipitated white solid is removed by filtration and dried: 6.7 g (0.0126 mmol; 70.1 %);
melting point 132~C.

4. 4-~4-[(2-Carbamimidoyl-1,2,3,4-tetrahydro-iso~uinolin-7-yloxY)-ethoxycarbonyl-methyl~-phenoxy~-piperidine-1-carboxylic acid allyl ester;
hydrochloride A solution of 2.90 g (0.005 mol) 4-{4-[ethoxy-carbonyl-(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-methyl]-phenoxy}-piperidine-1-carboxylic acid allyl ester-hydrochloride and 1.50 g (0.010 mol) lH-pyrazole-1-carboxamidine-hydrochloride (lit.: M.S.
Bernatowicz, Y.Wu, G.R. Matsueda, ~. Org . Chem .
1992, 57, 2497-2502) in 5 ml dimethylformamide is admixed at 5~C under a nitrogen atmosphere with 5.1 ml (0.029 mol) diisopropylethylamine. After stirring for 24 h at room temperature, 25 ml diethyl ether is added and decanted four times. The remaining residue is dissolved in 25 ml water, adjusted to pH 3 with 2 N HCl and chromatographed by means of preparative HPLC (RP-18 column, 15 - 25 ~m) (mobile solvent: H20, pH 3; H20/CH3CN 7:3, pH 3).
After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr), 2.70 g (0.0047 mol; 94.0 %) of the title compound is obtained as a colourless oil. (+)FAB-MS: 537 (MH+).

Example 14:

~2-Carbamimidoyl-1 2 3 4-tetrahydro-iso~uinolin-7-yloxY)-[4-(piperidin-4-yloxy)-phenyll-acetic acid ethYl ester; dihydrochloride 3.30 g (0.0057 mol) 4-{[(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-ethoxycarbonyl-methyl]-phenoxy}-piperidine-1-carboxylic acid allyl ester hydrochloride and 3.10 ml (0.0114 mol) tributyltin hydride in 200 ml dichloromethane is admixed at 5~C with 655 mg (10 mol%) tetrakis-triphenylphosphine palladium and stirred for 5 h at 5~C. It is extracted four times with 100 ml 0.1 N HCl, the combined aqueous solutions are filtered, evaporated, the residue is digested with a small amount of diethyl ether, filtered and dried. 2.40 g of a yellow solid (0.0046 mol; 80.1 %) with a melting point of 130~C is obtained. (+)FAB-MS: 453 (MH+).

Examplc 15:

(2-Carbamimidoyl-1,2,3,4-tetrahydro-isoauinolin-7-yloxy)- r 4-~piperidin-4-yloxy)-phenyl]-acetic acid:
dihydrochloride 0.53 g (0.001 mol) (2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-[4-(piperidin-4-yloxy)-phenyl]-acetic acid ethyl ester dihydrochloride is dissolved in a mixture of 15 ml water and 15 ml ethanol and admixed at 5~C with 4 ml 1 N NaOH solution. After stirring for 4 h at 5~C it is adjusted to pH 3 with 2 N HCl and evaporated. The residue is chromatographed by means of preparative HPLC (RP-18 column, 15 - 25 ~m) (mobile solvent: H2O, pH 3; H2O/CH3CN 9:1, pH 3). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr), 0.44 g (0.00088 mol; 88.5 ~) of the title compound is obtained as a light-yellow solid with a melting point of >175~C (decomposition). (+)FAB-MS: 425 (MH+).

Example 16:

(2-Carbamimidoyl-1,2,3,4-tetrahydro-iso~uinolin-7-yloxy~-~4- r ~ -imino-ethyl)-piPeridin-4-yloxy~-phenyl~-acetic acid ethyl ester dihydrochloride 2.2 ml (0.016 mol) triethylamine is added dropwise under nitrogen at 5~C to 0.50 g ethyl acetimidate hydrochloride (0.004 mol) and 1.05 g (2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-[4-(piperidin-4-yloxy)-phenyl]-acetic acid ethyl ester dihydrochloride (0.002 mol) in 50 ml ethanol. It is stirred for 2 days at room temperature, evaporated, the residue is dissolved in 20 ml water, adjusted to pH 3 with 2 N HCl and filtered. The filtrate is chromatographed by means of preparative HPLC (RP-18 column, 15 - 25 ~m) (mobile solvent: H2O, pH 3; H2O/CH3CN 8:2, pH 3). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr) 0.60 g (0.0011 mol; 53.0 %) of the title compound is obtained as a light solidified oil. (+)FAB-MS: 494 (MH+).

Example 17:

(2-Carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-~4-rl-(1-imino-ethyl)-piperidin-4-yloxyl-phenyl~-acetic acid dihydrochloride 280 mg (0.0005 mol) (2-carbamimidoyl)-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-acetic acid ethyl ester dihydrochloride is dissolved in a mixture of 15 ml water and 15 ml ethanol and admixed at 5~C with 2 ml 1 N NaOH
solution. After stirring for 5 h at 5~C it is adjusted to pH 3 with 2 N HCl and evaporated. The residue is dissolved in 20 ml water, adjusted to pH 3 with 2 N HCl and chromatographed by means of preparative HPLC (RP-18 column, 15 - 25 ~m) (mobile solvent: H2O, pH 3;
H2O/CH3CN 8:2, pH 3). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr), 200 mg (0.00037 mol; 74.3 %) of the title compound is obtained as a white solid with a melting point of 162~C
(decomposition). (+)FAB-MS: 466 (MH+).

Example 18:

(2-Carbamimidoyl-1 2 3 4-tetrahydro-isoquinolin-7-yloxyl-~4-[1-(1-imino-pro~yl)-piPeridin-4-yloxyl-phenyl~-acetic acid ethyl ester dihydrochloride 1. Propionimidic acid ethyl ester hydrochloride 7.10 ml propionitrile (0.100 mol) and 5.8 ml ethanol (0.100 mol) is dissolved in 10 ml diethyl ether and dry hydrogen chloride passed in at 5~C
until saturation. After standing for 24 h at room temperature it is evaporated, admixed four times with 25 ml diethyl ether each time and decanted.
The solid residue is triturated with diethyl ether, filtered and dried in a vacuum: 10.6 g (0.077 mol;
77.0 %) white solid with a melting point of 96-99~C. EI-MS: 101 (M+).

2. (2-Carbamimidoyl-1 2 3 4-tetrahYdro-iso~uinolin-7-yloxyl-r4-rl-~l-imino-pro~Yl)-piperidin-4-,Yloxy~-phenyl~-acetic acid ethyl ester dihydrochloride 2.2 ml (0.016 mol) triethylamine is added dropwise at 5~C under nitrogen to 0.55 g propionimidic acid ethyl ester hydrochloride (0.004 mol) and 1.05 g (2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-[4-(piperidin-4-yloxy)-phenyl]-acetic acid ethyl ester dihydrochloride (0.002 mol) in 40 ml ethanol. It is stirred for 3 days at room temperature, evaporated, the residue is dissolved in 20 ml water, adjusted to pH 3 with 2 N HCl and filtered. The filtrate is chromatographed by means of preparative HPLC (RP-18 column, 15 - 25 ~m) (mobile solvent: H20, pH 3; H20/CH3CN 8:2, pH 3).
After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr), 0.61 g (0.0011 mol; 52.5 %) of the title compound is obtained as a colourless solid with a melting point of 64-66~C (decomposition starts at 120~C). (+)FAB-MS: 508 (MH+).

~xample 19:

(2-Carbamimidoyl-1 2 3 4-tetrahydro-isoquinolin-7-yloxy)-(4-~1- r 1-imino-(4-methoxy-phenyl)-methYl]-piperidin-4-Yloxy~-phenyl)-acetic acid ethYl ester dihydrochloride 1. 4-Methoxy-benzimidic acid ethyl ester hYdrochloride 6.70 g 4-Methoxybenzonitrile (0.050 mol) and 2.9 ml ethanol (0.050 mol) is dissolved in a mixture of 20 ml diethyl ether and 20 ml dichloromethane and cooled to 5~C. After passing in dry hydrogen chloride until saturation, it is allowed to stand for 24 h at room temperature, evaporated, the solid residue is triturated with diethyl ether, filtered and dried in a vacuum: 10.0 g (0.0464 mol; 92.7 %) light skin-coloured solid with a melting point of 130-132~C. EI-MS: 179 (M+).

2. (2-Carbamimidoyl-1,2 3 4-tetrahydro-isoquinolin-7-yloxy)-(4-~1- r 1-imino-(4-methoxyphenYl)-methyll-piperidin-4-yloxy~-~henyl)-acetic acid ethYl ester dihydrochloride 2.2 ml (0.016 mol) triethylamine is added dropwise at 5~C under nitrogen to 0.86 g (0.004 mol) and 1.05 g (2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-[4-(piperidin-4-yloxy)-phenyl]-acetic acid ethyl ester dihydrochloride (0.002 mol) in 40 ml ethanol. It is stirred for 5 days at room temperature, evaporated, the residue is dissolved in 20 ml water, adjusted to pH 3 with 2 N HCl and filtered. The filtrate is chromatographed by means of preparative HPLC (RP-18 column, 15 - 25 ~m) (mobile solvent: H2O, pH 3; H2O/CH3CN 9:1, pH 3).
After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr), 0.76 g (0.0012 mol; 57.7 %) of the title compound is obtained as a colourless solid with a melting point of 165~C.
(+)FAB-MS: 586 (MH+).

Example 20:

(2-Carbamimidoyl-1 2,3 4-tetrahydro-isoguinolin-7-yloxy)-(4-~ 1-imino-(4-methoxy-phenyl)-methyll-~iperidin-4-yloxy~-~henyl)-acetic acid dihydrochloride 760 mg (0.0011 mol) (2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-(4-{1-[1-imino-(4-methoxyphenyl)-methyl]-piperidin-4-yloxy}-phenyl)-acetic acid ethyl ester dihydrochloride is dissolved in a mixture of 30 ml water and 30 ml ethanol and admixed at 5~C with 4.4. ml 1 N NaOH solution. After stirring for 5 h at 5~C it is adjusted to pH 3 with 2 N HCl and evaporated. The residue is dissolved in 20 ml water, adjusted to pH 3 with 2 N HCl and chromatographed by means of preparative HPLC (RP-18 column, 15 - 25 ~m) (mobile solvent: H2O, pH 3; H2O/CH3CN 8:2, pH 3). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr), 500 mg (0.00079 mol; 72.1 %) of the title compound is obtained as a white solid with a melting point of 223~C (+)-LSIMS: 558.2 (MH+).

Example 21:

(2-Carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-r4-(tetrahYdro-pyran-4-yloxy)-phenyl~-acetic acid ethYl ester hYdrochloride 1. 7-~Ethoxycarbonyl-r4-(tetrahydro-~Yran-4-yloxy)-phenyll-methoxy~-3,4-dihydro-lH-iso~uinoline-2-carboxYlic acid tert.-butyl ester A solution of 2.60 g (0.006 mol) 7-[ethoxycarbonyl-(4-hydroxy-phenyl)-methoxy]-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert.-butyl ester, 0.71 ml (0.0075 mol) tetrahydro-4-H-pyran-4-ol and 3.8 g (0.015 mol) triphenylphosphine in 60 ml tetrahydrofuran is admixed at 5~C with 2.36 ml (0.015 mol) azodicarboxylic acid diethyl ester and it is stirred for 24 h at room temperature. After evaporating, the residue is chromatographed for purification on a silica gel column (mobile solvent: isohexane/ethyl acetate 9:1, 8:2, 7:3).
After evaporating the appropriate column fractions 1.8 g (0.0035 mmol; 58.3 %) of the title compound is obtained as a colourless oil. EI-MS: 511 (M+).

=.

2. r(l 2 3 4-Tetrahydro-isoquinolin-7-yloxy)~-r4-(tetrahYdro-pyran-4-yloxy)-phenyl~-acetic acid ethyl ester hydrochloride A solution of 1.30 g (0.0025 mol) 7-{ethoxy-carbonyl-[4-(tetrahydro-pyran-4-yloxy)-phenyl]-methoxy}-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert.-butyl ester in 50 ml diethyl ester is admixed at 5~C with 50 ml etherial HCl solution, it is stirred for 5 h at 5~C and evaporated. Yield:
1.11 g (0.0024 mol; 99.1 %) wax-like yellow solid.
(+)-FAB-MS: 412 (MH+).

2. (2-Carbamimidoyl-1 2,3 4-tetrahydro-isoquinolin-7-yloxy)-r4-(tetrahydro-pyran-4-yloxy)-phenyll-acetic acid ethYl ester hydrochloride A solution of 1.30 g (0.0029 mol) [(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)]-[4-(tetrahydro-pyran-4-yloxy)-phenyl]-acetic acid ethyl ester hydrochloride and 0.85 g (0.0058 mol) lH-pyrazole-l-carboxamidine hydrochloride (lit.: M.S.
Bernatowicz, Y.Wu, G.R. Matsueda, ~. Org. Chem .
1992, 57, 2497-2502) in 2 ml N,N-dimethylformamide is admixed at 5~C with 4.0 ml (0.023 mol) diisopropylethylamine. After stirring for 24 h at room temperature, 25 ml diethyl ether is added and decanted four times. The remaining residue is dissolved in 25 ml water, adjusted to pH 3 with 2 N
HCl and chromatographed by means of preparative HPLC (RP-18 column, 15 - 25 ~m) (mobile solvent:
H2O, pH 3; H2O/CH3OH 8:2, pH 3; H2O/CH3OH 6:4, pH 3;). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr), 0.60 g (0.0026 mol; 42.2 %) of the title compound is obtained as a light yellow solid with a melting point of 95~C. (+)FAB-MS: 454 (MH+).

ExamPle 22:

(2-Carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)- r 4-(tetrahydro-pyran-4-yloxy)-phenYl]-acetic acid hydrochloride 0.60 g (0.0013 mol) (2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-[4-(tetrahydro-pyran-4-yloxy)-phenyl]-acetic acid ethyl ester hydrochloride is dissolved in a mixture of 20 ml water and 20 ml ethanol and admixed at 5~C with 5.2 ml 1 N NaOH solution. After stirring for 5 h at 5~C, it is adjusted to pH 3 with 2 N
HCl and evaporated. The residue is dissolved in 20 ml water, adjusted to pH 3 with 2 N HCl and chromatographed by means of preparative HPLC (RP-18 column, 15 - 25 ~m) (mobile solvent: H2O, pH 3; H2O/CH3CN 8:2, pH 3). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr), 0.15 g (0.00032 mol; 25.0 %) of the title compound is obtained as a light-yellow solid with a melting point of 112~C (decomposition). (+)-FAB-MS: 426 (MH+).

Example 23:

r 4-(1-Acetyl-piperidin-4-yloxy)-phenyl~-(2-carbamimidoyl-1 2 3 4-tetrahYdro-isoauinolin-7-Yloxy)-acetic acid ethyl ester hydrochloride 1. 1-(4-Hydroxy-piperidin-1-Yl)-ethanone 18.8 ml (0.200 mol) acetic anhydride is added dropwise at 5~C to a solution of 5.60 g (0.050 mol) 4-hydroxy-piperidine in 100 ml methanol. It is stirred for 72 h at room temperature, evaporated and the crude product is crystallized from diethyl ether: 4.10 g (0.029 mol; 58.0 %) white solid with a melting point of 70-73~C. EI-MS: 143 (M+).

2. 7-~ r 4~ r 1-Acetyl-piperidin-4-yloxy)-phenyll-ethoxycarbonyl-methoxY~-3 4-dihydro-lH-isoquinoline-2-carboxYlic acid tert.-butyl ester A solution of 1.71 g (0.004 mol) 7-[ethoxycarbonyl-(4-hydroxy-phenyl)-methoxy]-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert.-butyl ester, 0.63 g (0.0044 mol) 1-(4-hydroxy-piperidin-1-yl)-ethanone and 1.2 g (0.0044 mol) triphenylphosphine in 100 ml tetrahydrofuran is admixed at 5~C under nitrogen with 0.70 ml (0.0044 mol) azodicarboxylic acid diethyl ester in 8 ml tetrahydrofuran and stirred for 120 h at room temperature. After evaporation, the residue is chromatographed for purification on a silica gel column (mobile solvent: isohexane/ethyl acetate 1:1, 4:6, 3:7, 2:8, 1:9; ethyl acetate). After evaporating the appropriate column fractions, 2.00 g (0.0362 mmol;

90.5 %) of the title compound is obtained as a colourless wax-like solid. (+)-FAB-MS: 553 (MH+).

3. [4-(1-Acetyl-piperidin-4-yloxy)-phenyll-[(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)~-acetic acid ethyl ester hYdrochloride 50 ml etherial HCl solution is added at 5~C to a solution of 2.00 g (0.0036 mol) 7-{[(4-(1-acetyl-piperidin-4-yloxy)-phenyl]-ethoxycarbonyl-methoxy}-3,4-dihydro-lH-isoquinoline-2-carboxylic acid-tert.-butyl ester in 50 ml ethanol, stirred for 5 h at 5~C and evaporated: yield: 1.70 g (0.0035 mol;
97.2 %) yellow oil. (+)-FAB-MS: 453 (MH+).

4- r 4-(1-Acetyl-piperidin-4-yloxy)-phenyl~-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-acetic acid ethyl ester hYdrochloride A solution of 1.70 g (0.0035 mol) [4-(1-acetyl-piperidin-4-yloxy)-phenyl]-[(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)]-acetic acid ethyl ester hydrochloride and 1.03 g (0.0070 mol) lH-pyrazole-1-carboxamidine-hydrochloride (lit.: M.S.
Bernatowicz, Y.Wu, G.R. Matsueda, ~. Org. Chem .
1992, 57, 2497-2502) in 3.5 ml N,N-dimethyl-formamide is admixed at 5~C under nitrogen with 4.9 ml (0.028 mol) diisopropylethylamine. After stirring for 48 h at room temperature, 25 ml diethyl ether is added and decanted four times. The remaining residue is dissolved in 25 ml water, adjusted to pH 3 with 2 N HCl and chromatographed by means of preparative HPLC (RP-18 column, 15 -25 ~m) (mobile solvent: H2O, pH 3; H2O/CH3OH 7:3, pH 3). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr), 0.80 g (0.0015 mol; 43.0 %) of the title compound is obtained as a yellow solid with a melting point of 103~C (decomposition). (+)-FAB-MS: 495 (MH+).

~xample 24:

r 4-(1-Acetyl-~iperidin-4-yloxy)-phenyll-(2-carbamimidoyl-1~2~3~4-tetrahYdro-isoquinolin-7-yloxy) acetic acid hydrochloride 0.80 g (0.0015 mol) [4-(1-acetyl-piperidin-4-yloxy)-phenyl]-(2-carbamimidoyl-1,2,3,4-tetrahydro-iso~uinolin-7-yloxy)-acetic acid ethyl ester hydrochloride is dissolved in a mixture of 15 ml water and 15 ml ethanol and admixed at 5~C with 6 ml 1 N NaOH solution. After stirring for 5 h at 5~C it is adjusted to pH 3 with 2 N
HCl and evaporated. The residue is dissolved in 20 ml water/acetonitrile 8:2, adjusted to pH 3 with 2 N HCl and chromatographed by means of preparative HPLC (RP-18 column, 15 - 25 ~m) (mobile solvent: H2O, pH 3;
H2O/CH3CN 8:2, pH 3). After evaporating the appropriate column fractions and drying in a vacuum (10-2 torr), 0.40 g (0.0008 mol; 53.0 %) of the title compound is obtained as a white solid with a melting point of 102~C
(>180~C decomposition). (+)-FAB-MS: 467 (MH+).

ExamPle 25:

(2-Carbamimidoyl-1 2 3 4-tetrahydro-isoquinolin-7-yloxy)-(4-hYdroxy-phenyl)-acetic acid ethyl ester hydrochloride 1. (4-BenzyloxY-phenyl)- r 1 2 3 4-tetrahydro-isoquinolin-7-yloxy)~-acetic acid ethyl ester hydrochloride 5.20 g (0.010 mol) 7-[ethoxycarbonyl-(4-hydroxy-phenyl)-methoxy]-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert.-butyl ester is dissolved in a mixture of 50 ml ethanol and 50 ml dichloromethane, the clear solution is admixed at 5~C with 20 ml etherial HCl solution and subsequently stirred for 24 h at room temperature. It is evaporated, the solid, colourless residue is triturated with ether, filtered and dried: 4.19 g (0.0092 mmol; 92.3 %);
melting point 149-152~C.

2. (4-Hydroxy-phenyl)-~(1,2 3 4-tetrahydro-isoquinolin-7-yloxy)l-acetic acid ethYl ester hydrochloride 3.50 g (0.0077 mol) (4-benzyloxy-phenyl)-[(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)]acetic acid ethyl ester hydrochloride is dissolved in 100 ml ethanol and hydrogenated for 3 h under normal pressure at room temperature in the presence of 1.0 g palladium/carbon (10 %). After taking up 185 ml hydrogen, the catalyst is removed by filtration and it is evaporated. The oily crude product (3.70 g) is reacted further without additional purification ~= - .

steps. (+)-FAB-MS: 328 (MH+).

3. (2-Carbamimidoyl-1 2 3,4-tetrahydro-isoquinolin-7-yloxy)-(4-hydroxy-phenyl)-acetic acid ethyl ester hydrochloride A solution of 3.70 g (crude product) (4-hydroxy-phenyl)-[(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)]-acetic acid ethyl ester hydrochloride and 2.64 g (0.018 mol) lH-pyrazole-1-carboxamidine-hydrochloride (lit.: M.S. Bernatowicz, Y.Wu, G.R.
Matsueda, ~. Org. Chem. 1992, 57, 2497-2502) in 6 ml dimethylformamide is admixed at 5~C under nitrogen with 6.3 ml (0.036 mol) diisopropylethylamine. After stirring for 48 h at room temperature, 25 ml diethyl ether is added and decanted four times. The remaining residue is dissolved in 25 ml water, adjusted to pH 3 with 2 N HCl and chromatographed by means of preparative HPLC (RP-18 column, 15 - 25 ~m) (mobile solvent: H20, pH 3; H20/CH30H 1:1, pH 3).
After evaporating the appropriate column fractions and drying in a vacuum (lo-2 torr), 1.80 g (0.0044 mol; 57.6 % over two steps) of the title compound is obtained as a colourless solid with a melting point of 196~C (decomposition). (+)-FAB-MS: 370 (MH+).

Example 26:

Description of the pharmacological experiments Isolation of plasma 9 parts fresh blood from healthy donors are mixed with one part sodium citrate solution (0.11 mol/l) and centrifuged at ca. 3000 rpm for 10 min at room temperature. The plasma is removed by pipette and can be stored for ca. 8 h at room temperature.

Activated ~artial thromboplastin time (APTT) 100 ~1 citrate plasma and 100 ~1 APTT reagent (Diagnostica Stago/ Boehringer Mannheim GmbH; contains cephalin lyophilisate with a microcrystalline kieselguhr activator) are incubated for 3 min at 37~C in a ball coagulometer (KC10 from the Amelung Company) together with 10 ~1 dimethylsulfoxide (DMS0) or 10 ~1 of a solution of the active substance in DMSO. A stopwatch is started when 100 ~1 0.025 M calcium chloride solution is added and the time point at which coagulation starts is determined. In the control measurements the APTT is ca.
28-35 seconds and is increased by the active substances.
The experiment was stopped after 5 minutes if no coagulation occurred (>300).

The measured APTT times in seconds are stated in table 1 as a difference to the control. The concentrations of the active substances in the final volumes were 100 ~M
(APTT100), 10 ~M (APTT10), 1 ~M (APTTl).

Thrombin time 200 ~1 citrate plasma is incubated for 2 min at 37~C in a ball coagulometer (KC10 from the Amelung Company). 10 ~1 dimethylsulfoxide (DMS0) or a solution of the active substance in DMS0 is added to 190 ~1 preheated thrombin reagent (Boehringer Mannheim, GmbH; contains ca. 3 U/ml horse thrombin and 0.0125 M Ca++). A stopwatch is started when this 200 ~l solution has been added to the plasma and the time point at which coagulation starts is determined. In the control measurements the thrombin time is ca. 24 seconds and is increased by the active substances. If no coagulation occurred in the measurements after 5 minutes the experiment was stopped (>300)~

The measured thrombin times in seconds are stated in table 1 as a difference to the control. The concentration of the active substances in the final volume was 500 ~M (TT500).

Inhibition constants The kinetic measurements were carried out in 0.2 M
sodium chloride and 0.5 % polyethylene glycol 6000 containing 0.1 M phosphate buffer (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 adding enzyme to preincubated solutions which either contained dimethylsulfoxide (control) or solutions of the test substance in DMS0 (inhibitor stock solutions: 10 mM in DMS0). The increase in absorbance at 405 nm caused by the release of 4-nitroaniline from the substrate was monitored photometrically for a time period of 12 min. Measurement points (time versus absorbance) were determined at intervals of 20 sec. and these data were stored by computer The inhibition constants Ki were determined as follows:
rates Vo (change in absorbance per second; measurements without inhibitor) and Vi (change in absorbance per second; measurements with inhibitor) were determined by linear regression using only the measurement points in which the substrate concentration had been reduced by less than 15 %. From one measurement series (constant inhibitor concentration, variable substrate concentrations) Km~ and VmaX were determined by a non-linear fit to the equation Vmax * [S]
V ____________ [S] + Km From the total series of measurements with 16 sets of data (measurements at 4 different substrate concentrations and each with 4 different inhibitor concentrations) the Ki value was determined by non-linear regression from the equation Vmax * [S]
V _________ __ Km * (1 + [S] /Ki) + [S]

in which VMax denotes the maximum rate in the absence of an inhibitor, KM denotes the Michaelis constant and [S]
denotes the substrate concentration.

The r.easured Ki values in [~M] are ~tated in table 1.
The entry Ki = 999 means that the respective enzyme is not inhibited.

FXa:

Stock solution: 990 ~l phosphate buffer solution (preparation see below) was admixed with 10 ~l human factor Xa (Boehringer Mannheim GmbH; 10 U; suspension) and stored on ice for a maximum of 4 hours. For the measurement 850 ,ul phosphate buffer containing 100 ,ul substrate [N-methoxycarbonyl-(D)-norleucyl-glycyl-(L)-arginine-4-nitroaniline acetate; chromozyme X;
Boehringer Mannheim GmbH; substrate concentrations used 800, 600, 400 and 200 ,uM; KM 400 ,(bM] and 25 ,~L1 inhibitor solution or 25 ,~L1 DMSO (control) are incubated in a photometer (25~C). The reaction is started by addition of 25 ,~1 stock solution.

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

8.90 g Na2HPO4 ~ 2 H20, 5.84 g NaCl and 2.50 g polyethylene g1YCO1 6000 are dissolved in 400 ml distilled water and filled up with distilled water to a total volume of 500 ml (solution I). 1. 36 g KH2PO4, 1.17 g NaCl and 0. 50 g polyethylene glycol 6000 are dissolved in 80 ml distilled water and filled up with distilled water to a total volume of 100 ml (solution II). Then an amount of solution II (ca. 85 ml) is added to solution I until the pH value is 7. 5. The buffer solution is freshly prepared every time (can be stored for a maximum of 10 days when stored in a refrigerator at 4~C).

Table 1: Pharmacological data of selected compound~ from the example~

Example No. Ki(fXa) APTT 100 APTT 10 APTT 1 TT500 1 0.028 >300 91 19 106 0.2 26 6 2 19 6 0.4 106 21 2 57 11 0.2 111 22 4 76 16 0.03 277 83 16 107

Claims

1. Compounds of formula I

in which R1, R2, R3 independently of one another denote a hydrogen atom, a halogen atom, a hydroxy group, a hydroxy-C1-C6-alkyl group, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkinyl group, a C1-C6 alkoxy group, a C1-C6 aralkyloxy group, a C2-C6 alkenyloxy group, a C2-C6 alkinyloxy group, a carboxyl group, a C1-C6 alkoxy-carbonyl group, a C3-C6 alkenyloxy-carbonyl group, a C3-C6 alkinyloxy-carbonyl group, a carboxy-C1-C6-alkyl group, a C1-C6-alkyloxycarbonyl-C1-C6-alkyl group, a C3-C6-alkenyloxycarbonyl-C1-C6-alkyl group or a C3-C6 alkinyloxy-carbonyl-C1-C6-alkyl group;

A denotes a methylene group which is optionally provided with substituents such as hydroxyl, carboxyl, C1-C6 alkoxy-carbonyl groups or halogen atoms;

X denotes a methylene group;

Y can be a single bond, a chalcogen atom or a carbonyl group;

Z denotes an optionally substituted pyrrolidine, piperidine, piperazine, morpholine, hexahydroazepine, tetrahydro-furan, tetrahydropyran, tetrahydro-thiophene, 4,5-dihydroimidazole, pyrrole, imidazole, pyrazine, pyrimidine, pyridazine, 1H-azepine, 3H-azepine, 1,2-diazepine, 1,4-diazepine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, pyrollidinone, imidazolidinone, piperidinone, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl residue, an optionally substituted amino group, a hydroxyl group, a carboxyl group, a C1-C6 alkoxycarbonyl group or a C1-C6 alkyl group n denotes the number 1 and m denotes an integer between 0 and 4, as well as hydrates, solvates and physiologically tolerated salts thereof and optical isomers.

2. Compounds of formula I as claimed in claim 1 in which R1 denotes a hydrogen atom, a hydroxy group, a methoxy group, a benzyloxy group, a carboxyl group, a methoxycarbonyl or an ethoxycarbonyl group;

R2, R3 are the same or different and denote a hydrogen atom, a hydroxyl group, a methoxy group, a benzyloxy group, a carboxyl group, a carboxymethyl group, a carboxyethyl group, a carboxymethyloxy group, a methoxycarbonyl or ethoxycarbonyl group, a methoxycarbonyl-methyl or ethoxycarbonylmethyl group, a methoxycarbonylethyl or ethoxycarbonylethyl group, a methoxycarbonylmethyloxy or ethoxy-carbonylmethyloxy group;

A denotes a methylene group which can optionally be substituted with a carboxyl, carboxymethyl, methoxycarbonyl, ethoxy-carbonyl, allyloxycarbonyl or hydroxymethyl group;

X denotes a methylene group, Y denotes an oxygen atom;

Z denotes a 4-tetrahydropyranyl residue, a 2-tetrahydrofuranyl residue, a 3-tetrahydro-furanyl residue, an amino group, a hydroxy group, a methoxy group, a carboxyl group, an ethoxycarbonyl group, a guanidino group, a free or optionally ethylene-bridged amidino group, a 4-imidazolyl residue, a 5-hexa-hydropyrimidine residue imino-substituted or ethoxycarbonylimino-substituted in the 2-position, or a 2-pyrrolidinyl residue which is unsubstituted or substituted on the nitrogen or a 3-pyrrolidinyl residue which is unsubstituted or substituted on the nitrogen or an 4-piperidinyl residue which is unsubstituted or substituted on the nitrogen in which the substituent can be an amidino group, a formimidoyl group, an acetimidoyl group, an ethylimidoyl group, an n-butylimidoyl group, a cyclopropylimidoyl group, an N-methylacetimidoyl group, an optionally C1-C6-alkoxy-substituted benzimidoyl group, an acetyl group, an allyl group, an allyloxycarbonyl group, a tert.-butyloxycarbonyl group, a 1-(5,5-dimethyl-3-oxo-cyclohex-1-enyl) group or an N,N-di-methylaminocarbonyl group;

n can be the number 1 m can be the number 0, 1, 2 or 3.

3. Process for the production of compounds of formula I as claimed in claim 1 or 2, wherein a compound of formula III, (III) in which R1-R3, A, X, Y, Z, n and m have the above-mentioned meanings, is reacted with a guanylation reagent such as for example 1H-pyrazole-1-carboxamidine or S-methylthiourea in an inert solvent such as e.g.
dimethylformamide, dioxane, dimethylsulfoxide 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 and the obtained compounds are optionally converted into hydrates, solvates, physiologically tolerated salts or optical isomers thereof.

4. Pharmaceutical compositions containing at least one compound of formula I as claimed in claim 1 or 2 in addition to common carrier and auxiliary substances.

5. Use of compounds of formula I as claimed in claim 1 or 2 for the production of pharmaceutical preparations having anti-thromboembolic action.