DE19530996A1 - Cyclic guanidines, process for their preparation and pharmaceuticals - Google Patents

Abstract

Compounds are disclosed having the formula (I), in which R<1>, R<2>, R<3> 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

The invention relates to new cyclic guanidines of the general formula I.

in the
R¹, R², R³ independently represent a hydrogen atom, a halogen atom, a hydroxy group, a hydroxyalkyl group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aralkyloxy group, an alkenyloxy group, an alkynyloxy group, a carboxyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, one Alkynyloxycarbonyl group, a carboxyalkyl group, an alkyloxycarbonylalkyl group, an alkenyloxycarbonylalkyl group or an alkynyloxycarbonyl alkyl group,
A represents a straight-chain or branched alkylene group which, if desired, is provided with substituents such as hydroxyl, carboxyl, alkoxycarbonyl groups or halogen atoms;
X represents a single bond, an alkylene or alkyleneoxy group;
Y can be a single bond, a chalcogen atom or a carbonyl group;
Z represents 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 is an integer between 0 and 4,
and hydrates, solvates, physiologically acceptable salts thereof. The invention also relates to the optically active forms, the racemates and the diastereome mixtures of these compounds.

The invention also relates to processes for the preparation of the above compounds, Arz drugs containing such compounds and the use of this compound in the manufacture of pharmaceuticals.

The cyclic guanidines of the general formula I, their solvates and their salts intervene in the process of blood coagulation by reversibly inhibiting factor Xa and thus prevent the formation of coagulation thrombi. You can therefore in fighting and preventing diseases such as thrombosis, Apoplexy, heart attack, inflammation and arteriosclerosis can be used.

Factor Xa is a serine protease of the coagulation system that is the proteolytic Catalyzed conversion of prothrombin to thrombin. Thrombin, as the last enzyme the coagulation cascade, on the one hand splits fibrinogen to fibrin, which after Cross-linking using factor XIIIa becomes an insoluble gel and the matrix for a thrombus, on the other hand it activates by proteolysis of its receptor platelet aggregation on the platelets and also carries in this way for thrombus formation. When a blood vessel is injured, these are processes necessary to stop bleeding. Under normal circumstances, none are measured There are thrombin concentrations in the blood plasma. Increase in thrombin Concentration can lead to thrombus formation and thus thromboembolic Lead diseases that occur very often, especially in the industrialized countries. By Inhibition of factor Xa can prevent the formation of thrombin.  

Recently it was reported that amidinoarylpropanoic acid derivatives such as (+) - (2S) -2- [4- [[(35) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2- naphthyl] propanoic acid hydrochloride pentahydrate (DX-9065a; Formula II) factor Xa- Inhibitors are (J. Med. Chem. 1994, 37, 1200-1207; Thrombosis and Haemostasis 1994, 71, 314-319; EP-0-540-051-A1).

The novel cyclic guanidines according to the invention of the general formula I and Hydrates, solvates and physiologically acceptable salts thereof are effective factors Xa inhibitors.

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

Halogens as substituents R¹, R², R³ in the general formula I are fluorine, Chlorine, bromine and iodine atoms, but preferably fluorine, chlorine or bromine atoms.

R¹, R², R³ in the general formula I represents a hydroxyalkyl group, so these are straight-chain or branched and contain 1 to 6 carbon atoms. The hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, Hydroxypentyl and the hydroxyhexyl group.

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

R¹, R², R³ in the general formula I means an alkenyl group, this can straight-chain or branched and contain 2 to 6 carbon atoms. Prefers are the vinyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, 1-butenyl, 1- Pentenyl and the 1-hexenyl group.

R¹, R², R³ in the general formula I represents an alkynyl group, this can straight-chain or branched and contain 2 to 6 carbon atoms. Prefers are the ethynyl and the propargyl group.

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

R¹, R², R³ in the general formula I means an aralkyloxy group, contains this one linked with a straight-chain or branched C₁-C₆ alkyl chain Phenyl group. The benzyloxy group is preferred.

Alkenyloxy groups as substituents R¹, R², R³ in the general formula I. contain 2 to 6 carbon atoms and are straight-chain or branched. Prefers are the vinyloxy and allyloxy groups.

Alkynyloxy groups as substituents R¹, R², R³ in the general formula I. contain 2 to 6 carbon atoms and are straight-chain or branched. Prefers is the propargyloxy group.

Alkoxycarbonyl groups as substituents R¹, R², R³ in the general formula I. contain straight-chain or branched alkyl chains with 1 to 6 carbon atoms. The methoxycarbonyl and the ethoxycarbonyl group are preferred.

In the general formula I R¹, R², R³ is an alkenyloxycarbonyl group, so contains these straight-chain or branched alkenyls with 3 to 6 carbon atoms The allyloxycarbonyl group is preferred.  

In the general formula I R¹, R², R³ is an alkynyloxycarbonyl group, so contains these straight-chain or branched alkynyls with 3 to 6 carbon atoms. The propargyloxycarbonyl group is preferred.

Carboxyalkyl groups as substituents R¹, R², R³ in the general formula I. contain alkyls with 1 to 6 carbon atoms and are straight-chain or branched. The carboxymethyl, the carboxyethyl and the Carboxypropyl group.

R¹, R², R³ in the general formula I denotes an alkyloxycarbonylalkyl group, straight-chain or branched alkyl chains with 1 to 6 carbon atoms. Preferred are the methoxycarbonylmethyl, Ethoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, Methoxycarbonylpropyl and the ethoxycarbonylpropyl group.

R¹, R², R³ in the general formula I means one Alkenyloxycarbonylalkylgruppe, the alkenyl radicals are straight-chain or branched with 3 to 6 carbon atoms and the alkyl groups straight-chain or branched with 1 up to 6 carbon atoms. The allyloxycarbonylmethyl, Allyloxycarbonylethyl and the allyloxycarbonylpropyl group.

R¹, R², R³ in the general formula I denotes an alkynyloxycarbonylalkyl group, the alkynyl radicals are straight-chain or branched with 3 to 6 carbon atoms and the alkyl groups are straight-chain or branched with 1 to 6 carbon atoms. The propargyloxycarbonylmethyl, propargyloxycarbonylethyl and the Propargyloxycarbonylpropyl group.

In the general formula I, the group denoted by A can be a single bond mean or a methylene group which is unsubstituted or with a carboxyl group or alkoxycarbonyl group may be substituted or a straight chain or branched alkylene group with 2 to 6 carbon atoms, if appropriate Substituents such as hydroxyl, carboxyl, alkoxycarbonyl groups or Halogen atoms can carry.  

Alkoxycarbonyl groups as substituents of the methylene or alkylene group Group A contain straight-chain or branched alkoxy radicals with 1 to 6 Carbon atoms, the methoxycarbonyl and the ethoxycarbonyl group are preferred.

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

In the general formula I, the group denoted by X can be a single bond, an alkylene group having 1 or 2 carbon atoms or a methyleneoxy fragment mean.

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

In the compounds of the general formula I, the group Z is a saturated or unsaturated heterocyclic ring system, that is a ring system with 5 to 7 ring links, which one or two identical or different Contains heteroatoms such as nitrogen, oxygen and sulfur, preferably pyrrolidine, Piperidine, piperazine, morpholine, hexahydroazepine, tetrahydrofuran, Tetrahydropyran, tetrahydrothiophene, 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, especially pyrrolidine, piperidine, piperazine, morpholine, Tetrahydrofuran, tetrahydropyran, 4,5-dihydroimidazole, pyrrole, imidazole. Is in the Compounds of general formula I a group Z a saturated or unsaturated carbocyclic ring system, this means a ring system with 3 to 7 carbon atoms, preferably cyclopropyl, cyclopentyl, cyclohexyl, Cycloheptyl, or phenyl. The heterocyclic or carbocyclic radicals Z can if desired one or two substituents such as nitrile, carboxyl, C₁-C₆- Carboxyalkyl, C₁-C₆-alkyloxycarbonyl-C₁-C₆-alkyl, C₁-C₆-alkyl, imino, C₁-C₆- Alkylimino, carboxylimino, amidino, formimidoyl, C₁-C₆-alkanimidoyl, C₃-C₆- Cycloalkanimidoyl, benzimidoyl, C₁-C₆-alkylcarbonyl, C₁-C₆-alkyloxycarbonyl,  C₃-C₆-alkenyloxycarbonyl, benzyloxycarbonyl, carbamoyl, mono- or di- (C₁- C₆) alkylcarbamoyl, aminocarbonyl, mono- or di- (C₁-C₆) alkylaminocarbonyl, preferably carboxyl, C₁-C₆-carboxyalkyl, C₁-C₆-alkyloxycarbonyl-C₁-C₆-alkyl, Amidino, formimidoyl, C₁-C₆-alkanimidoyl, C₃-C₆-cycloalkanimidoyl, Benzimidoyl, C₁-C₆-alkyloxycarbonyl, C₃-C₆-alkenyloxycarbonyl, Wear benzyloxycarbonyl, the specification (C₁-C₆) each having a straight chain or branched alkyl chain having 1 to 6 carbon atoms, while (C₃-C₆) optionally for a cycloalkyl grouping with 3 to 6 carbon atoms or a straight-chain or branched alkenyl grouping with 3 to 6 Carbon atoms can stand.

If the group Z in the general formula I denotes an amino group, then these be substituted, 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-butyloxycarbonyl, with a C₃-C₆ alkenyloxycarbonyl group, preferably allyloxycarbonyl or with an aralkyloxycarbonyl group, preferably benzyloxycarbonyl. The Specification (C₁-C₆) stands here for a straight-chain or branched Alkyl chain with 1 to 6 carbon atoms, while (C₃-C₆) optionally one straight-chain or branched alkenyl grouping with 3 to 6 carbon atoms indicates.

The group Z in the general formula I denotes an alkoxycarbonyl group, so these can be straight-chain or branched alkoxy radicals having 1 to 6 carbon atoms contain the methoxycarbonyl and the ethoxycarbonyl group preferred are.

If the group Z in the general formula I denotes an alkyl chain, this is straight-chain or branched and contains 1 to 6 carbon atoms, one or can carry several hydroxy groups, which in turn independently of one another with C₁- C₆-alkyl groups, preferably methyl or with aralkyl groups, preferably Benzyl or with C₃-C₆ alkenyl groups, preferably allyl, may be etherified. The specification (C₁-C₆) stands for a straight-chain or branched Alkyl chain with 1 to 6 carbon atoms, while (C₃-C₆) optionally one  straight-chain or branched alkenyl grouping with 3 to 6 carbon atoms indicates.

The number n means 1 or 2 and the number m means an integer between 0 and 4th

Compounds of the general formula I in which
R¹ represents a hydrogen atom, a hydroxy group, a methoxy group, a benzyloxy group, a carboxyl group, a methoxy carbonyl or an ethoxycarbonyl group;
R², R³ are the same or different and are 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 methoxy or ethoxycarbonyl group, a methoxy or ethoxy carbonylmethyl group, a methoxy or ethoxycarbonylethyl group, a methoxycarbonylmethyloxy or ethoxycarbonylmethyloxy group;
A represents a methylene group which can optionally be substituted by a carboxyl, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl or hydroxymethyl group;
X represents a single bond, a methylene group, an ethylene group or the fragment -CH₂-O-;
Y represents an oxygen atom;
Z is a 4-tetrahydropyranyl radical, a 2-tetrahydrofuranyl radical, a 3-tetrahydrofuranyl radical, an amino group, a hydroxyl group, a methoxy group, a carboxyl group, an ethoxycarbonyl group, a guanidino group, a free or optionally ethylene-bridged amidino group, a 4-imidazolyl group, a 4-imidazole group, a 4-imidazole group The position imino- or ethoxycarbonylimino-substituted 5-hexahydropyrimidine radical means, or a 2-pyrrolidinyl radical which is unsubstituted or substituted on the nitrogen or a 3-pyrrolidinyl radical which is unsubstituted or substituted on the nitrogen or a 4-piperidinyl radical which is unsubstituted or substituted on the nitrogen, the substituent being an amidino group , a formimidoyl group, an acetimidoyl group, an ethylimidoyl group, an n-butylimidoyl group, a cyclopropylimidoyl group, an N-methylacetimidoyl group, a benzimidoyl group, an acetyl group or an N, N-dimethyl aminocarbonyl group;
n 1 or 2 and
m can be 0, 1, 2 or 3.

The physiologically tolerable salts of the general formula I are understood 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 compatible mineral acids such as hydrochloric acid, Hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid. The Compounds of formula I with a free carboxyl group can also be salts with form physiologically acceptable bases. Examples of such salts are alkali metal, Alkaline earth metal, ammonium and alkylammonium salts, such as the sodium, potassium, Calcium or tetramethyl ammonium salt.

The compounds of the formula I can be solvated, in particular hydrated. The hydration can take place during manufacture or gradually as a result hygroscopic properties of an initially anhydrous compound of the formula I. occur.

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

The substances of the general formula I with suitable pharmaceutical carriers, aroma, taste and color mixed substances and shaped for example as tablets or dragees or under  Add appropriate auxiliaries in water or oil, e.g. B. suspended in olive oil or solved.

The substances of general formula I and their salts can be in liquid or solid ter form can be applied enterally or parenterally. Occurs as an injection medium preferably water for use, which is the usual addition to injection solutions contains sets such as stabilizers, solubilizers or buffers. Such To sentences are e.g. B. tartrate and citrate buffers, complexing agents (such as ethylenediaminetetraes acetic acid and its non-toxic salts) and high molecular weight polymers such as liquid Po ethylene oxide for viscosity regulation. Solid carriers are e.g. B. starch, Lactose, mannitol, methyl cellulose, talc, highly disperse silicas, high molecular weight re fatty acids (such as stearic acid), animal and vegetable fats and solid high moles kular polymers (such as polyethylene glycols). Preparation suitable for oral application If desired, flavorings and sweeteners can be included.

The compounds are usually used in amounts of 10-1500 mg per day applied based on 75 kg body weight. It is preferable to 1-2 2-3 times a day To administer tablets with an active substance content of 5-500 mg. The tablets can also be delayed, which means that 1-2 tablets with 20- 700 mg of active ingredient must be given. The active ingredient can also be given by injection 1-8 times a day or by continuous infusion, taking 50-2000 mg per Day is usually sufficient.

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

The compounds of general formula I are prepared by one Compound of the general formula III

in which R¹-R³, A, X, Y, Z, n and m have the meanings given above, with a guanylation reagent such as 1H-pyrazole-1-carboxamidine or S- Methylthiourea in an inert solvent such as e.g. B. dimethylformamide, Dioxane, dimethyl sulfoxide or toluene at temperatures between 0 ° C and Boiling point of the solvent, preferably at 0 to 30 ° C in the presence of a Auxiliary base such as B. triethylamine, N-methylmorpholine, pyridine or Ethyldiisopropylamin brings to reaction.

If the compound of the general formula III also contains at other points, for example in group Z, a free amino group, this is among the Reaction conditions also guanylated according to the above method.

The compounds of general formula III are prepared by one Compound of the general formula IV

in which R¹-R³, A, X, Y, Z, n and m have the meanings given above and PG¹ is a protective group such as the benzyloxycarbonyl group, the t  Butyloxycarbonylgruppe or the allyloxycarbonyl group means with a Protector splitting reagent brings about the reaction. The Deprotection takes place according to the methods customary in peptide chemistry by acidic reagents such as B. hydrogen bromide in glacial acetic acid or trifluoroacetic acid or ethereal HCl solution or hydrogenolytically or by palladium or rhodium-catalyzed cleavage.

The compounds of general formula IV are prepared by one Compound of the general formula V

in which R¹, PG¹, X and n have the meanings given above, with a Compound of the general formula VI

in which R², R³, A, Y, Z, and m have the meanings given above and R⁴- Halogen, tosylate, mesylate or triflate means in an inert solvent such as Dioxane, tetrahydrofuran, dimethylformamide, N-methyl-pyrrolidone or toluene in Presence of a base such as sodium carbonate, potassium carbonate, 1,5- Diazabicyclo [5.4.0] undec-5-ene or ethyldiisopropylamine at temperatures between 0 ° C and boiling point of the solvent, preferably between room temperature and 80 ° C, implemented.  

Compounds of the general formula VI are prepared by methods known from the literature produced.

The compounds of the general formula V are prepared according to the method described in Methods commonly used in peptide chemistry by implementing compounds of the Type VII,

in the R₁, X, and n have the meanings given above with the appropriate reagents such as. B. di-tert-butyl dicarbonate or Chloroformic acid esters in inert solvents such as tetrahydrofuran, dioxane, Dimethylformamide or water in the presence of bases such as alkali or Alkaline earth metal hydroxides, sodium carbonate, potassium carbonate, N-methylmorpholine, Diisopropylethylamine, triethylamine or 1,5-diazabicyclo [5.4.0] undec-5-ene Temperatures between 0 ° C and boiling point of the solvent, preferably between Room temperature and 50 ° C.

Compounds of the general formula VII are prepared per se known methods of heterocycle synthesis (2,3-dihydro-1H-indoles and 2,3,4,5- Tetrahydro-1H-benzo [c] azepine: 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-1H-benzo [d] azepine: H. Wikström, B. Andersson, T. Elebring, S. Lagerkvist, G. Hallnemo, 1. Petterson, P.-Å. Jovall, K. Svensson, 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 16 95 652, April 29, 1971).

Compounds of general formula IV can also by reacting Compounds of general formula V in which R¹, PG¹, X and n are the above have the meanings given, with compounds of the general formula VI, in  the R², R³, A, Y, Z, and m have the meanings given above and R⁴ one Hydroxyl function means, in an inert solvent such as dioxane, tetrahydro furan or toluene in the presence of diethyl azodicarboxylate and trimethyl or Triethyl phosphite at temperatures between 0 and 50 ° C, preferably at Room temperature.

Type IV ′ compounds,

in which R¹-R³, A, X, Z, n, m and PG¹ have the meanings given above and Y 'means an oxygen atom can also be prepared by one Compound of the general formula VIII

in which R¹-R³, A, X, PG¹ and n have the meanings given above, with a compound of the general formula IX,

HO- (CH₂) _m -Z (IX)

in which Z and m have the meanings given above in an inert Solvents such as dioxane, tetrahydrofuran or toluene in the presence of Diethyl azodicarboxylate and trimethyl or triethyl phosphite at temperatures between 0 and 50 ° C, preferably at room temperature.  

Compounds of the general formula IX are either commercially available or can be processes known from the literature (see, for example: K.L. Bhat, D.M. Flanagan, M. M. Jouill´, Synth. Commun. 1985, 15,587-598).

The compounds of general formula VIII are prepared by using a Compound of the general formula X,

in which in R¹-R³, A, X, PG¹, n have the meanings given above and PG² another protective group such. B. the methyl, the benzyl or the Allyl group can, with a reagent which cleaves the protective group PG² to Brings reaction. The deprotection takes place according to the usual methods acidic or Lewis acidic reagents, such as e.g. B. hydrogen bromide in glacial acetic acid, Trifluoroacetic acid, ethereal HCl solution or boron trifluoride etherate, Titanium tetrachloride, trimethylsilyl iodide or hydrogenolytically or by palladium or rhodium-catalyzed cleavage in such a way that the protective group PG¹ preserved.

Compounds of the general formula X can be prepared by using a Compound of the general formula V with a compound of the general formula XI,

in which R², R³, A, PG² have the meanings given above and R⁵ one Leaving group such as halogen, tosylate, mesylate or triflate means in an inert Solvents such as tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone or toluene in the presence of a base such as sodium carbonate, Potassium carbonate, 1,5-diazabicyclo [5.4.0] undec-5-ene or ethyldiisopropylamine Temperatures between 0 ° C and boiling point of the solvent, preferably between room temperature and 100 ° C.

Compounds of the general formula XI can be obtained from the corresponding alcohols of the general formula XII,

in which R², R³, A, PG² have the meanings given above be, for example, by chlorination of an alcohol general formula XII using phosphorus pentachloride in an inert solvent such as benzene, toluene or mesitylene at temperatures between room temperature and Boiling temperature of the solvent 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 obtained from precursors that are commercially available or known Standard methods are made.

Compounds of the general formula X ′,

in which R¹-R³, X, PG¹, PG², n have the meanings given above and A ′ is a hydroxymethyl substituted methylene group can also be prepared in which a compound of the general formula X ′ ′,

in which R¹-R³, X, PG¹, PG², n have the meanings given above and A ′ ′ is a methoxy, ethoxy or allyloxycarbonyl substituted methylene group, by basic or palladium-catalyzed saponification and subsequent reduction of the free carboxyl function with mild reducing agents such. B. sodium borohydride in inert solvents such as ethanol, tetrahydrofuran, dioxane in the corresponding Alcohol convicted.

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

This relates to compounds of the general formula I which are in one or more Fragments of R¹-R³, A or Z one or more carboxylic ester function carry. By standard methods such as B. by aqueous alkaline hydrolysis or by treatment with trimethylsilyl iodide at temperatures between 0 ° C and Boiling point of the solvent, preferably inert at room temperature Solvents such as methylene chloride or by enzymatic hydrolysis, for example in the presence of an esterase, these compounds can in Compounds of general formula I converted with free carboxyl groups will.

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

This also applies to compounds of the general formula I in which one or more of the substituents R¹-R³ contains one or more benzyloxy groups. By catalytic hydrogenation in the presence of a catalyst, preferably Palladium on carbon, the benzyl group is replaced by the hydrogen atom. The benzyl group can also be removed by reaction with a strong one Acid such as trifluoroacetic acid in the presence of mesitylene, anisole or thioanisole Temperatures between 0 and 50 ° C, preferably at room temperature or through 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 boiling point of the solvent, preferably between room temperature and boiling point of the solvent or by treatment with trimethylsilyl iodide 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.

Pure enantiomers of the compounds of the formula I can either be obtained Resolution (via salt formation with optically active acids or bases), or in which one uses in the synthesis optically active starting materials or by enzymatically hydrolyzed.

For the purposes of the invention, preference is given to those mentioned in the examples Connections the following:

1. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- piperidin-4-yloxy) phenyl] acetic acid
2. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- piperidin-4-yloxy) phenyl] acetic acid ethyl ester
3. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 1-imino-methyl-piperidin-4-yloxy) phenyl] - acetic acid
4. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 1-imino methyl-piperidin-4-yloxy) phenyl] - ethyl acetate
5. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 1-imino ethyl-piperidin-4-yloxy) phenyl] - acetic acid
6. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 1-imino ethyl-piperidin-4-yloxy) phenyl] - ethyl acetate
7. [4- (1-Acetyl-piperidin-4-yloxy) phenyl] - [2- (amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] acetic acid
8. [4- (1-Acetyl-piperidin-4-yloxy) phenyl] - [2- (amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] ethyl acetate
9. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - {4- [1- (dimethyl-carbamoyl) piperidin-4-yloxy] phenyl }-acetic acid
10. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - {4- [1- (dimethyl-carbamoyl) piperidin-4-yloxy] phenyl } ethyl acetate
11. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - {- 4- [1- (1-methyl-imino-ethyl) piperidine-4 -yloxy] -phenyl -} - acetic acid
12. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - {4- [1- (1-methyl-imino-ethyl) piperidine-4- yloxy] phenyl} ethyl acetate
13. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - {4- [1- (cyclopropyl-imino-methyl) -piperidin-4-yloxy] -phenyl} -acetic acid
14. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - {4- [1- (cydopropyl-imino-methyl) piperidin-4-yloxy] -phenyl} ethyl acetate
15. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - {4- [1- (1- imino-hexyl) piperidin-4-yloxy] -phenyl} -acetic acid
16. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - {4- [1- (1- imino-hexyl) piperidin-4-yloxy] -phenyl} ethyl acetate
17. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - {4- [1- (imino-phenyl-methyl) -piperidin-4-yloxy] - phenyl} acetic acid
18. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - {4- [1- (imino-phenyl-methyl) -piperidin-4-yloxy] - phenyl} ethyl acetate
19. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4- (pyrrolidin-3-yloxy) phenyl] acetic acid
20. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4- (pyrrolidin-3-yloxy) phenyl] acetic acid ethyl ester
21. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - {4- [1- (1-imino-ethyl) pyrrolidin-3-yloxy] -phenyl} -acetic acid
22. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - {4- [1- (1-imino-ethyl) pyrrolidin-3-yloxy] -phenyl} ethyl acetate
23. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4- (pyrrolidin-2-ylmethoxy) phenyl] acetic acid
24. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4- (pyrrolidin-2-ylmethoxy) phenyl] acetic acid ethyl ester
25. {4- [1- (Amino-imino-methyl) pyrrolidin-2-ylmethoxy] phenyl} - [2- (amino-imino methyl) -1,2,3,4-tetrahydro-isoquinoline-7- yloxy] acetic acid
26. {4- [1- (Amino-imino-methyl) pyrrolidin-2-ylmethoxy] phenyl} - [2- (amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinoline-7- yloxy] ethyl acetate
27. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - {4- [1- (1- imino-ethyl) -pyrrolidin-2-ylmethoxy ] -phenyl} -acetic acid
28. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] {4- [1- (1-imino-ethyl) -pyrrolidin-2-ylmethoxy] - phenyl} ethyl acetate
29. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 4,5-dihydro-1H-imidazol-2-ylmethoxy-) -phenyl] -acetic acid
30. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 4,5-dihydro-1H-imidazol-2-ylmethoxy-) -phenyl] -acetic acid ethyl ester
31. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 3H-imidazol-4-ylmethoxy -) - phenyl] acetic acid
32. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 3H-imid-ol-4-ylmethoxy -) - phenyl] - ethyl acetate
33. [4- (2-Amino-ethoxy) phenyl] - [2- (amino-imino-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy] acetic acid
34. [4- (2-Amino-ethoxy) phenyl] - [2- (amino-imino-methyl) -1,2,3,4-tetrahydro-ro-isoquinolin-7-yloxy] -acetic acid ethyl ester
35. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 2-hydroxy-ethoxy) phenyl] acetic acid
36. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 2-hydroxy-ethoxy) phenyl] acetic acid ethyl ester
37. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 3-hydroxy-propoxy) phenyl] acetic acid
38. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 3-hydroxy-propoxy) -phenyl] -acetic acid, ethyl ester
39. [2- (Amino-imino-methyl) -1,2,3 4-tetrahydro-isoquinolin-7-yloxy] - [4- (tetrahydro-pyran-4-yloxy) phenyl] acetic acid
40. [2- (Amino-imino-methyl) -1,2,3 4-tetrahydro-isoquinolin-7-yloxy] - [4- (tetrahydro-pyran-4-yloxy) phenyl] acetic acid ethyl ester
41. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 2-imino-hexahydro-pyrimidin-5-yloxy) phenyl] - acetic acid
42. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 2-imino-hexahydro-pyrimidin-5-yloxy) phenyl] - ethyl acetate
43. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 2-ethoxycarbonyl-imino-hexahydro-pyrimidin-5-yloxy) - phenyl] acetic acid
44. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 2-ethoxycarbonyl-imino-hexahydro-pyrimidin-5-yloxy) - phenyl] ethyl acetate
45. [2- (Amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (- 2-guanidino-ethoxy) phenyl] acetic acid
46. [2- (Amino-imino-methyl) -1, w2,3,4-tetrahydro-isoquinolin-7-yloxy] - [4 - (2-guanidino-ethoxy) phenyl] ethyl acetate
47. [3- (Amino-imino-methyl) -8-methoxy-2,3,4,5-tetrahydro-1H-benzo [d] azep-in-7-yloxy] - {4- [1- (amino -imino-methyl) -piperidin-4-yloxy] phenyl} acetic acid
48. [3- (Amino-imino-methyl) -8-methoxy-2,3,4,5-tetrahydro-1H-benzo [d] azep-in-7-yloxy] - {4- [1- (amino -imino-methyl) -piperidin-4-yloxy] phenyl} ethyl acetate
49. [3- (Amino-imino-methyl) -8-methoxy-2,3,4,5-tetrahydro-1H-benzo [d] azep-in-7-yloxy] - {4- [1- (amino -imino-methyl) -pyrrolidin-3-yloxy] -phenyl} -acetic acid
50. [3- (Amino-imino-methyl) -8-methoxy-2,3,4,5-tetrahydro-1H-benzo [d] azep-in-7-yloxy] - {4- [1- (amino -imino-methyl) -pyrrolidin-3-yloxy] -phenyl} - ethyl acetate
51. [(7- {4- [1- (Amino-imino-methyl) -piperidin-4-yloxy] benzyloxy} -8-methoxy-1,2,4,5-tetrahydro-benzo [d] azepine 3-yl) imino methyl] amine
52. [(7- {4- [1- (Amino-imino-methyl) pyrrolidin-3-yloxy] benzyloxy} -8-methoxy-1,2,4,5-tetrahydro-benzo [d] azepine 3-yl) imino methyl] amine
53. (Imino- {7-methoxy-8- [4- (pyrrolidin-3-yloxy) benzyloxy] -1,2,4,5-tetrahydro benzo [d] azepin-3-yl} methyl) amine
54. (Imino- {7-methoxy-8- [4- (piperidin-4-yloxy) benzyloxy] -1,2,4,5-tetrahydro benzo [d] azepin-3-yl} methyl) amine
55. [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
56. [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
57. [3- (Amino-imino-methyl) -8-methoxy-2,3,4,5-tetrahydro-1H-benzo [d] azep-in-7- yloxy] - {4- [1- (1 -imino-ethyl) -pyrrolidin-3-yloxy] -phenyl} -acetic acid
58. [3- (Amino-imino-methyl) -8-methoxy-2,3,4,5-tetrahydro-1H-benzo [d] azep-in-7- yloxy] - {4- [1- (1 -imino-ethyl) -pyrrolidin-3-yloxy] -phenyl} -acetic acid ethyl ester
59. [3- (Amino-imino-methyl) -8-methoxy-2,3,4,5-tetrahydro-1H-benzo [d] azep-in-7-yloxy] - {4- [1- (1 -imino-ethyl) -piperidin-4-yloxy] phenyl} acetic acid
60. [3- (Amino-imino-methyl) -8-methoxy-2,3,4,5-tetrahydro-1H-benzo [d] azep-in-7- yloxy] - {4- [1- (1 -imino-ethyl) -piperidin-4-yloxy] -phenyl} -acetic acid ethyl ester
61. {4- [1- (Amino-imino-methyl) -pyrrolidin-3-yloxy] phenyl} - [3- (amino-imino-methyl) -2,3,4,5-tetrahydro-1H-benzo [ d] azepin-6-yloxy] acetic acid
62. {4- [1- (Amino-imino-methyl) -pyrrolidin-3-yloxy] phenyl} - [3- (amino-imino-methyl) -2,3,4,5-tetrahydro-1H-benzo [ d] azepin-6-yloxy] ethyl acetate
63. {4- [1- (Amino-imino-methyl) -piperidin-4-yloxy] phenyl} - [3- (amino-imino-methyl) -2,3,4,5-tetrahydro-1H-benzo [ d] azepin-6-yloxy] acetic acid
64. {4- [1- (Amino-imino-methyl) -piperidin-4-yloxy] phenyl} - [3- (amino-imino-methyl) -2,3,4,5-tetrahydro-1H-benzo [ d] azepin-6-yloxy] ethyl acetate
65. [3- (Amino-imino-methyl) -2,3,4,5-tetrahydro-1H-benzo [d] azepin-6-yloxy -] - {4- [1- (1-imino-ethyl) -piperidin-4-yloxy] phenyl} acetic acid
66. [3- (Amino-imino-methyl) -2,3,4,5-tetrahydro-1H-benzo [d] azepin-6-yloxy -] - {4- [1- (1-imino-ethyl) -piperidin-4-yloxy] phenyl} ethyl acetate
67. [3- (Amino-imino-methyl) -2,3,4,5-tetrahydro-1H-benzo [d] azepin-6-yloxy -] - {4- [1- (1-imino-ethyl) -pyrrolidin-3-yloxy] phenyl} acetic acid
68. [3- (Amino-imino-methyl) -2,3,4,5-tetrahydro-1H-benzo [d] azepin-6-yloxy -] {4- [1- (1-imino-ethyl) - pyrrolidin-3-yloxy] phenyl} acetic acid ethyl ester
69. [(6- {4- [1- (Amino-imino-methyl) -piperidin-4-yloxy] benzyloxy} -1,2,4,5-tetrahydro-benzo [d] azepin-3-yl) -imino-methyl] -amine
70. [(6- {4- [1- (Amino-imino-methyl) -pyrrolldin-3-yloxy] benzyloxy} -1,2,4,5-tetrahydro-benzo [d] azepin-3-yl) -imino-methyl] -amine
71. {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
72. {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] ethyl acetate
73. {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
74. {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] ethyl acetate
75. [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
76. [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
77. [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
78. [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
79. [(7- {4- [1- (Amino-imino-methyl) pyrrolidin-3-yloxy] benzyloxy} -3,5-dihydro-2H-benzo [f] [1,4-] oxazepine 4-yl) imino methyl] amine
80. [(7- {4- [1- (Amino-imino-methyl) -piperidin-4-yloxy] benzyloxy} -3,5-dihydro-2H-benzo [f] [1,4-] oxazepine 4-yl) imino methyl] amine
81. [2- (Amino-imino-methyl) -6-methoxy-2,3-dihydro-1H-isoindol-5-yloxy] - {4- [1- (amino-imino-methyl) piperidine-4- yloxy] phenyl} acetic acid
82. [2- (Amino-imino-methyl) -6-methoxy-2,3-dihydro-1H-isoindol-5-yloxy] - {- 4- [1- (amino-imino-methyl) piperidine-4 -yloxy] -phenyl} -acetic acid ethyl ester
83. [2- (Amino-imino-methyl) -6-methoxy-2,3-dihydro-1H-isoindol-5-yloxy] {4- [1- (amino-imino-methyl) pyrrolidin-3-yloxy ] -phenyl} -acetic acid
84. [2- (Amino-imino-methyl) -6-methoxy-2,3-dihydro-1H-isoindol-5-yloxy] {4- [1- (amino-imino-methyl) pyrrolidin-3-yloxy ] -phenyl} -acetic acid ethyl ester
85. [2- (Amino-imino-methyl) -6-methoxy-2,3-dihydro-1H-isoindol-5-yloxy] - {4- [1- (1-imino-ethyl) piperidine-4- yloxy] phenyl} acetic acid
86. [2- (Amino-imino-methyl) -6-methoxy-2,3-dihydro-1H-isoindol-5-yloxy] {4- [1- (1-imino-ethyl) piperidin-4-yloxy ] -phenyl} -acetic acid ethyl ester
87. [2- (Amino-imino-methyl) -6-methoxy-2,3-dihydro-1H-isoindol-5-yloxy] - {4- [1- (1-imino-ethyl) pyrrolidin-3- yloxy] phenyl} acetic acid
88. [2- (Amino-imino-methyl) -6-methoxy-2,3-dihydro-1H-isoindol-5-yloxy] - {4- [1- (1-imino-ethyl) pyrrolidin-3- yloxy] phenyl} ethyl acetate
89. [(5- {4- [1- (Amino-imino-methyl) -piperidin-4-yloxy] benzyloxy} -6-methoxy-1,3-dihydro-isoindol-2-yl) -imino-methyl ] -amin
90. [(5- {4- [1- (Amino-imino-methyl) pyrrolidin-3-yloxy] benzyloxy} -6-methoxy-1,3-dihydro-isoindol-2-yl) -imino-methyl ] -amin
91. {4- [1- (Amino-imino-methyl) pyrrolidin-3-yloxy] phenyl} - [2- (amino-imino-methyl) -2,3,4,5-tetrahydro-1H-benzo [ c] azepin-8-yloxy] acetic acid
92. {4- [1- (Amino-imino-methyl) pyrrolidin-3-yloxy] phenyl} - [2- (amino-imino-methyl) -2,3,4,5-tetrahydro-1H-benzo [ c] azepin-8-yloxy] ethyl acetate
93. {4- [1- (Amino-imino-methyl) -piperidin-4-yloxy] phenyl} - [2- (amino-imino-methyl) -2,3,4,5-tetrahydro-1H-benzo [ c] azepin-8-yloxy] acetic acid
94. {4- [1- (Amino-imino-methyl) -piperidin-4-yloxy] phenyl} - [2- (amino-imino-methyl) -2,3,4,5-tetrahydro-1H-benzo [ c] azepin-8-yloxy] ethyl acetate
95. [2- (Amino-imino-methyl) -2,3,4,5-tetrahydro-1H-benzo [c] azepin-8-yloxy -] - {4- [1- (1-imino-ethyl) -piperidin-4-yloxy] phenyl} acetic acid
96. [2- (Amino-imino-methyl) -2,3,4,5-tetrahydro-1H-benzo [c] azepin-8-yloxy -] {4- [1- (1-imino-ethyl) - piperidin-4-yloxy] phenyl} ethyl acetate
97. [2- (Amino-imino-methyl) -2,3,4,5-tetrahydro-1H-benzo [c] azepin-8-yloxy -] - {4- [1- (1-imino-ethyl) -pyrrolidin-3-yloxy] phenyl} acetic acid
98. [2- (Amino-imino-methyl) -2,3,4,5-tetrahydro-1H-benzo [c] azepin-8-yloxy -] - {4- [1- (1-imino-ethyl) -pyrrolidin-3-yloxy] phenyl} ethyl acetate
99. [(7 - {- 4- [1- (Amino-imino-methyl) -piperidin-4-yloxy] benzyloxy} -6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl) - imino-methyl] amine
100. [(7- {4- [1- (Amino-imino-methyl) pyrrolidin-3-yloxy] benzyloxy} -3,4-dihydro-1H-isoquinolin-2-yl) -imino-methyl] - amine
101. [(7- {4- [1- (Amino-imino-methyl) -piperidin-4-yloxy] benzyloxy} -3,4-dihydro-1H-isoquinolin-2-yl) -imino-methyl] - amine
102. [Imino- (7- {4- [1- (1-imino-ethyl) piperidin-4-yloxy] benzyloxy} -3,4-dihydro-1H-isoquinolin-2-yl) methyl] - amine
103. [Imino- (7 - {- 4- [1- (1-imino-ethyl) pyrrolidin-3-yloxy] benzyloxy} -3,4-dihydro-1H-isoquinolin-2-yl) methyl] -amin
104. (Imino- {7- [4- (piperidin-4-yloxy) benzyloxy] -3,4-dihydro-1H-isoquinolin-2-yl} methyl) amine
105. (Imino- {7- [4- (pyrrolidin-3-yloxy) benzyloxy] -3,4-dihydro-1H-isoquinolin-2-yl-} methyl) amine
106. {3- [1- (Amino-imino-methyl) -piperidin-4-yloxy] phenyl} - [2- (amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinoline-7- yloxy] acetic acid
107. {3- [1- (Amino-imino-methyl) -piperidin-4-yloxy] phenyl} - [2- (amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinoline-7- yloxy] ethyl acetate
108. 5- [1- (Amino-imino-methyl) -piperidin-4-yloxy] -2- [2- (amino-imino-methyl-1) -1,2,3,4-tetrahydro-isoquinolin-7 -yloxymethyl] benzoic acid
109. 5- [1- (Amino-imino-methyl) -piperidin-4-yloxy] -2- [2- (amino-imino-methy-l-1,2,3,4-tetrahydro-isoquinoline-7- yloxymethyl] benzoic acid ethyl ester
110. {5- [1- (Amino-imino-methyl) -piperidin-4-yloxy] -2- [2- (amino-imino-methyl-1) -1,2,3,4-tetrahydro-isoquinoline- 7-yloxymethyl] phenyl} acetic acid
111. {5- [1- (Amino-imino-methyl) -piperidin-4-yloxy] -2- [2- (amino-imino-methyl-1) -1,2,3,4-tetrahydro-isoquinoline- 7-yloxymethyl] phenyl} acetic acid ethyl ester
112. {5- [1- (Amino-imino-methyl) -piperidin-4-yloxy] -2- [2- (amino-imino-methyl-1- 1,2,3,4-tetrahydro-isoquinoline-7 -yloxymethyl] -phenoxy} acetic acid
113. {5- [1- (Amino-imino-methyl) -piperidin-4-yloxy] -2- [2- (amino-imino-methyl-1) -1,2,3,4-tetrahydro-isoquinoline- 7-yloxymethyl] phenoxy} ethyl acetate
114. 3- {5- [1- (Amino-imino-methyl) -piperidin-4-yloxy] -2- [2- (amino-imino-methyl-1- 1,2,3,4-tetrahydro-isoquinoline -7-yloxymethyl] phenyl} propionic acid
115. 3- {5- [1- (Amino-imino-methyl) -piperidin-4-yloxy] -2- [2- (amino-imino-methyl-1) -1,2,3,4-tetrahydro- isoquinolin-7-yloxymethyl] phenyl} propionic acid ethyl ester
116. 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
117. 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-r
118. 2- {4- [1- (Amino-imino-methyl) -piperidin-4-yloxy] phenyl} -2- [2- (amino-imino-methyl) -1,2,3,4-tetrahydro- isoquinolin-7-yloxy] ethanol
119. [2- (Amino-imino-methyl) -6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-y-loxy] - {4- [1- (amino-imino-methyl) - piperidin-4-yloxy] phenyl} acetic acid
120. [2- (Amino-imino-methyl) -6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-y-loxy] - {4- [1- (amino-imino-methyl) - piperidin-4-yloxy] phenyl} ethyl acetate
121. [2- (Amino-imino-methyl) -6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-y-loxy] - {4- [1- (1-imino-ethyl) - piperidin-4-yloxy] phenyl} acetic acid
122. [2- (Amino-imino-methyl) -6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-y-loxy] - {4- [1- (1-imino-ethyl) - piperidin-4-yloxy] phenyl} ethyl acetate
123. [2- (Amino-imino-methyl) -6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-y-loxy] - [4- (piperidin-4-yloxy) phenyl] - acetic acid
124. [2- (Amino-imino-methyl) -6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-y-loxy] - [4- (piperidin-4-yloxy) phenyl] - ethyl acetate
125. {4- [1- (Amino-imino-methyl) -piperidin-4-yloxy] phenyl} - [2- (amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinoline-6- yloxy] acetic acid
126. {4- [1- (Amino-imino-methyl) -piperidin-4-yloxy] phenyl} - [2- (amino-imino-methyl) -1,2,3,4-tetrahydro-isoquinoline-6- yloxy] ethyl acetate
127. [2- (Amino-imino-methyl) -7-methoxy-1,2,3,4-etrahydro-isoquinolin-6-yl-oxy] - {4- [1- (amino-imino-methyl) - piperidin-4-yloxy] phenyl} acetic acid
128. [2- (Amino-imino-methyl) -7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-y-loxy] - {4- [1- (amino-imino-methyl) - piperidin-4-yloxy] phenyl} ethyl acetate
129. [2- (Amino-imino-methyl) -7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-y-loxy] - {4- [1- (amino-imino-methyl) - pyrrolidin-3-yloxy] phenyl} acetic acid
130. [2- (Amino-imino-methyl) -7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-y-loxy] - {4- [1- (amino-imino-methyl) - pyrrolidin-3-yloxy] phenyl} acetic acid ethyl ester
131. [2- (Amino-imino-methyl) -7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-y-loxy] - {4- [1- (1-imino-ethyl) - pyrrolidin-3-yloxy] phenyl} acetic acid
132. [2- (Amino-imino-methyl) -7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-y-loxy] - {4- [1- (1-imino-ethyl) - pyrrolidin-3-yloxy] phenyl} acetic acid ethyl ester
133. [2- (Amino-imino-methyl) -7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-y-loxy] - {4- [1- (1-imino-ethyl) - piperidin-4-yloxy] phenyl} acetic acid
134. [2- (Amino-imino-methyl) -7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-y-loxy] - {4- [1- (1-imino-ethyl) - piperidin-4-yloxy] phenyl} ethyl acetate
135. [2- (Amino-imino-methyl) -7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-y-loxy] -4- (piperidin-4-yloxy) phenyl] acetic acid
136. [2- (Amino-imino-methyl) -7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-y-loxy] -4- (piperidin-4-yloxy) phenyl] ethyl acetate
137. [2- (Amino-imino-methyl) -7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-y-loxy] -4- (pyrrolidin-3-yloxy) phenyl] acetic acid
138. [2- (Amino-imino-methyl) -7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-y-loxy] -4- (pyrrolidin-3-yloxy) phenyl] -acetic acid, ethyl ester
139. [(6- {4- [1- (Amino-imino-methyl) pyrrolidin-3-yloxy] benzyloxy} -7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl) imino -methyl] amine
140. [(6- {4- [1- (Amino-imino-methyl) -piperidin-4-yloxy] benzyloxy} -7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl) imino -methyl] amine
141. {4- [1 (Amino-iminomethyl) piperidin-4-yloxy] -3-hydroxyphenyl} - [2- (aminoimino-methyl) -1,2,3,4-tetrahydro-isoquinoline -7-yloxy] acetic acid
142. {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 ethyl ester
143. 2- (Amino-imino-methyl) -7- {4- [1- (amino-imino-methyl) -piperidin-4-yloxy] benzyloxy} -1,2,3,4-tetrahydro-isoquinoline- 6-carboxylic acid
144. 2- (Amino-imino-methyl) -7- {4- [1- (amino-imino-methyl) -piperidin-4-yloxy] benzyloxy} -1,2,3,4-tetrahydro-isoquinoline- 6-carboxylic acid ethyl ester
145. 2- (amino-imino-methyl) -7- (1- {4- [1- (amino-imino-methyl) piperidin-4-yloxy] phenyl} -2-hydroxy-ethoxy) -1, 2,3,4-tetrahydro-isoquinoline-6-carboxylic acid
146. 2- (Amino-imino-methyl) -7- (1- {4- [1- (amino-imino-methyl) piperidin-4-yloxy] phenyl} -2-hydroxy-ethoxy) -1.2 , 3,4-tetrahydro-isoquinoline-6-carboxylic acid ethyl ester.

example 1 {4- [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-1H-isoquinoline-2-carboxylic acid tert-butyl ester

To a suspension of 16.4 g (0.079 mol) 7-hydroxy-1,2,3,4- tetrahydroisoquinoline hydroacetate (analog J.M. Bobbitt, K.L. Khanna, J.M. Kiely, Chem. Ind. 1964, 1950-1951) and 32.6 ml (0.235 mol) triethylamine in 164 ml of methylene chloride is a solution of 17.1 g (0.079 mol) di- at 5 ° C Dropped tert-butyl dicarbonate in 170 ml methylene chloride. After 1 hour stir at 5 ° C the clear solution formed is concentrated, the residue in Dissolved ethyl acetate and successively 3 × each with 50 ml of 1 N acetic acid, saturated sodium bicarbonate solution and saturated saline shaken out. After drying and concentration, the residue is washed with isohexane triturated, suction filtered and dried. 17.5 g (0.070 mol; 88.9%) are obtained the title compound with mp 140-142.5 ° C as a white solid

2. (4-Benzyloxy-phenyl) chloroacetic acid ethyl ester

A solution of 14.3 g (4-benzyloxy-phenyl) -hydroxy-acetic acid ethyl ester (0.050 mol) in 250 ml of methylene chloride is at 5 ° with 10.4 g Phosphorus pentachloride (0.050 mol) added and 24 h at room temperature touched. After concentration, the residue is cleaned on a Chromatographed silica gel column (eluent: isohexane / ethyl acetate 9: 1). After Concentration of the corresponding column fractions gives 13.0 g (0.043 mol; 85.3%) of the title compound as a yellow, crystalline solid with mp. 45- 47 ° C.  

3.7 - [(4-benzyloxyphenyl) ethoxycarbonyl methoxy] -3,4-dihydro-1H-isoquinoline- 2-carboxylic acid tert-butyl ester

A solution of 1 1.4 g (4-benzyloxyphenyl) chloroacetic acid ethyl ester (0.037 mol) and 7.5 g (0.030 mol) of 7-hydroxy-3,4-dihydro-1H-isoquinoline-2- carboxylic acid tert-butyl ester in 150 ml of acetonitrile is mixed with 8.4 g (0.060 mol) Potassium carbonate was added and the mixture was heated under reflux for 24 h. After filtration the filtrate was concentrated and the residue was purified on a silica gel column chromatographed (eluent: isohexane / ethyl acetate 9: 1, 8: 2, 7: 3). After Concentration of the corresponding column fractions gives 15.2 g (97.9%) of the Title compound as a white, crystalline solid with mp. 85-87 ° C.

4. 7- [ethoxycarbonyl- (4-hydroxyphenyl) methoxy] -3,4-dihydro-1H-isoquinol-2-ol carboxylic acid tert-butyl ester

10.8 g (0.020 mol) 7 - [(4-benzyloxyphenyl) ethoxycarbonyl methoxy] -3.4- dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester are in 200 ml Dissolved ethyl acetate and in the presence of 2.0 g palladium / coal (10%) Normal pressure hydrogenated for 3 h at room temperature. After taking 480 ml Hydrogen is filtered off from the catalyst and the solvent is removed. 7.8 g (0.018 mol; 91.2%) of the title compound are obtained as the residue white, crystalline solid with mp. 152-155 ° C.

5. 7 - {[4- (1-tert-Butoxycarbonyl-piperidin-4-yloxy) phenyl] ethoxycarbonyl methoxy} -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

A solution of 4.3 g (0.010 mol) of 7- [ethoxycarbonyl- (4-hydroxyphenyl) methoxy] -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 2.2 g (0.011 mol) 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (analogous to K.L. Bhat, D.M. Flanagan, M.M. Jouill´, Synth. Commun. 1985, 15, 587-598) and 3.3 g (0.013 mol) triphenylphosphine in 100 ml tetrahydrofuran is at 5 ° C. with 2.0 ml (0.013 mol) of diethyl azodicarboxylate and added for 24 h Room temperature stirred. After concentration, the residue is ready for cleaning chromatographed on a silica gel column (mobile phase: isohexane / ethyl acetate 9: 1,  8: 2, 7: 3). After concentration of the corresponding column fractions, 4.6 g are obtained (0.0075 mmol; 75.3%) of the title compound as a yellow oil. EI-MS: 610 (M⁺).

6. [4- (Piperidin-4-yloxy) phenyl] - [(1,2,3,4-tetrahydro-isoquinolin-7-yl-oxy)] - vinegar acid ethyl ester dihydrochloride

A solution of 4.6 g (0.0075 mol) of 7 - {[4- (1-tert-butoxycarbonyl-piperidine-4- yloxy) phenyl] ethoxycarbonyl-methoxy} -3,4-dihydro-1H-isoquinoline-2- Carboxylic acid tert-butyl ester in 50 ml of ethanol is ethereal at 5 ° C with 50 ml HCl solution was added and the mixture was then stirred at 5 ° C. for 5 h. After adding 50 ml of diethyl ether, the precipitated, white solid is filtered off and dried. Yield: 2.6 g (0.0054 mol; 71.7%). Mp: 215-222 ° C.

7. {4- [1- (Amino-imino-methyl) -piperidin-4-yloxy] phenyl} - [2- (amino-imino methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] ethyl acetate- dihydrochloride

A solution of 1.65 g (0.0034 mol) of [4- (piperidin-4-yloxy) phenyl] - [(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)] ethyl acetate dihydrochloride and 2.00 g (0.0136 mol) 1H-pyrazole-1-carboxamidine hydrochloride (Lit .: MS Bernatowicz, Y. Wu, GR Matsueda, J. Org. Chem. 1992, 57, 2497-2502) in 2.5 ml dimethylformamide at 5 ° C treated with 9.3 ml (0.0544 mol) of diisopropylethylamine. After 48 hours Stirring at room temperature is mixed 4 times with 25 ml of diethyl ether and decanted. The remaining residue is dissolved in 25 ml of water, adjusted to pH 3 with 2 N HCl and chromatographed by means of preparative HPLC (RP-18 column, 15-25 µm) (eluent: H₂O, pH 3; H₂O / CH₃OH 8: 2, pH 3). After concentration of the appropriate column fractions and drying i. Vac. (10 ^-2 Torr), 1.5 g (0.0026 mol; 77.7%) of the title compound are obtained as a white solid with a melting point of 120 ° C.

Example 2 {4- [1- (Amino-imino-methyl) -piperidin-4-yloxyl-phenyl} - [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] ethyl acetate dihydrochloride is dissolved in a mixture of 10 ml of water and 10 ml of ethanol and 4 ml of 1N NaOH solution are added at 5 ° C. After 1 hour Stirring at room temperature is adjusted to pH 3 with 2 N HCl and evaporated. The residue is dissolved in 20 ml of water and chromatographed using preparative HPLC (RP-18 column, 15-25 µm) (eluent: H₂O, pH 3; H₂O / CH₃CN 7: 3, pH 3). After concentration of the corresponding column fractions and drying in vacuo (10 ^-2 torr), 400 mg (0.0007 mol; 74.1%) of the title compound are obtained as a white solid with a melting point of 95 ° C.

Example 3 {4- [1- (Amino-imino-methyl) -pyrrolidine-3- (S) -yloxy] phenyl} - [2- (amino-imino methyl) -1,2,3,4-tetrahydro-isoquinolin-7-yloxy] ethyl acetate - dihydrochloride 1. 7 - {[4- (1-tert-Butoxycarbonyl-pyrrolidin-3 (S) -yloxy) phenyl] ethoxycarbonyl methoxy} -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

A solution of 3.90 g (0.0091 mol) of 7- [ethoxycarbonyl- (4-hydroxyphenyl) methoxy] -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 1.87 g (0.0100 mol) (R) -4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (analogous to K. L. Bhat, D.M. Flanagan, M.M. Jouill´, Synth. Commun. 1985, 15, 587-598) and 3.60 g (0.0137 mol) triphenylphosphine in 75 ml tetrahydrofuran is at 5 ° C with 2.15 ml (0.0137 mol) of diethyl azodicarboxylate and added for 24 h Room temperature stirred. After concentration, the residue is ready for cleaning chromatographed on a silica gel column (mobile phase: isohexane / ethyl acetate 9: 1,  8: 2, 7: 3). After concentration of the corresponding column fractions, 2.20 is obtained g (0.0037 mol; 40.5%) of the title compound as a colorless oil. EI-MS: 596 (M⁺).

2. [4- (pyrrolidin-3- (S) -yloxy) phenyl] - [(1,2,3,4-tetrahydro-isoquinoline - 7-yloxy)] ethyl acetate dihydrochloride

A solution of 2.20 g (0.0037 mol) of 7 - {[4- (1-tert-butoxycarbonyl-pyrrolidine 3- (S) -yloxy) -phenyl] -ethoxycarbonyl-methoxy} -3,4-dihydro-1H-isoquinoline-2- Carboxylic acid tert-butyl ester in 25 ml of ethanol is etherified at 5 ° C with 50 ml HCl solution was added and the mixture was then stirred at 5 ° C. for 5 h. After adding 25 ml of ether, the precipitated, light brown solid is filtered off and dried. Yield: 0.80 g (0.0017 mol; 45-9%). Mp: 50 ° C.

3. {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

A solution of 0.80 g (0.0017 mol) of [4- (pyrrolidin-3- (S) -yloxy) phenyl] - [(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)] - ethyl acetate dihy -drochloride and 1.00 g (0.0068 mol) of 1-H-pyrazole-1-carboxamidine hydrochloride (lit .: MS Bernatowicz, Y. Wu, GR Matsueda, J. Org. Chem. 1992, 57, 2497-2502) in 1.5 ml of dimethylformamide is added to 4.7 ml (0.0272 mol) of diisopropylethylamine at 5 ° C. After 48 hours Stirring at room temperature is mixed 4 times with 20 ml of diethyl ether and decanted. The remaining residue is dissolved in 50 ml of water, adjusted to pH 3 with 2 N HCl and chromatographed using preparative HPLC (RP-18 column, 15-25 µm) (eluent: H₂O, pH 3; H₂O / CH₃OH 8: 2, pH 3). After concentration of the corresponding column fractions and drying in vacuo (10 ^-2 torr), 0.50 g (0.0009 mol; 52.9%) of the title compound is obtained as a slightly yellowish solid with a melting point of 90 ° C.

Claims (5)

1. Compounds of formula I. in the
R¹, R², R³ independently represent a hydrogen atom, a halogen atom, a hydroxy group, a hydroxyalkyl group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aralkyloxy group, an alkenyloxy group, an alkynyloxy group, a carboxyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, one Alkynyloxycarbonyl group, a carboxyalkyl group, an alkyloxycarbonylalkyl group, an alkenyloxycarbonylalkyl group or an alkynyloxycarbonyl alkyl group,
A represents a straight-chain or branched alkylene group which, if desired, is provided with substituents such as hydroxyl, carboxyl, alkoxycarbonyl groups or halogen atoms;
X represents a single bond, an alkylene or alkyleneoxy group;
Y can be a single bond, a chalcogen atom or a carbonyl group;
Z represents 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 is an integer between 0 and 4,
as well as hydrates, solvates, physiologically acceptable salts thereof and optical isomers. 2. Compounds of formula I according to claim 1
in the
R¹ represents a hydrogen atom, a hydroxy group, a methoxy group, a benzyloxy group, a carboxyl group, a methoxy carbonyl or an ethoxycarbonyl group;
R², R³ are the same or different and are 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 methoxy or ethoxycarbonyl group, a methoxy or ethoxy carbonylmethyl group, a methoxy or ethoxycarbonylethyl group, a methoxycarbonylmethyloxy or ethoxycarbonylmethyloxy group;
A represents a methylene group which can optionally be substituted by a carboxyl, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl or hydroxymethyl group;
X represents a single bond, a methylene group, an ethylene group or the fragment -CH₂-O-;
Y represents an oxygen atom;
Z is a 4-tetrahydropyranyl radical, a 2-tetrahydrofuranyl radical, a 3-tetrahydrofuranyl radical, an amino group, a hydroxyl group, a methoxy group, a carboxyl group, an ethoxycarbonyl group, a guanidino group, a free or optionally ethylene-bridged amidino group, a 4-imidazolyl group, a 4-imidazole group, a 4-imidazole group The position imino- or ethoxycarbonylimino-substituted 5-hexahydropyrimidine radical means, or a 2-pyrrolidinyl radical which is unsubstituted or substituted on the nitrogen or a 3-pyrrolidinyl radical which is unsubstituted or substituted on the nitrogen or a 4-piperidinyl radical which is unsubstituted or substituted on the nitrogen, the substituent being an amidino group , a formimidoyl group, an acetimidoyl group, an ethylimidoyl group, an n-butylimidoyl group, a cyclopropylimidoyl group, an N-methylacetimidoyl group, a benzimidoyl group, an acetyl group or an N, N-dimethyl aminocarbonyl group;
n 1 or 2 and
m can be 0, 1, 2 or 3. 3. A process for the preparation of compounds of formula I according to claim 1 or 2, characterized in that a compound of formula III in the
R¹-R³, A, X, Y, Z, n and m have the meanings given above, with a guanylation reagent such as 1H-pyrazole-1-carboxamidine or S-methylthiourea in an inert solvent such as. B. dimethylformamide, dioxane, dimethyl sulfoxide or toluene at temperatures between 0 ° C and boiling point of the solvent, preferably at 0 to 30 ° C in the presence of an auxiliary base such as. B. triethylamine, N-methylmorpholine, pyridine or ethyldiisopropylamine to react and, if desired, the compounds obtained in their hydrates, solvates, physiologically acceptable salts or optical isomers. 4. Pharmaceutical objectives containing at least one compound of Formula I according to claim 1 or 2 in addition to conventional carriers and auxiliaries. 5. Use of compounds of formula I according to claim 1 or 2 for Manufacture of drugs with antithromboembolic effects.