MX2008007051A - Improved process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof - Google Patents

Abstract

The invention relates to a process for preparing an optionally substituted 4-benzimidazol- 2-ylmethylamino)-benzamidine, characterised in that (a) an optionally correspondingly substituted diaminobenzene is condensed with 2 [4- (1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, (b) i) the product thus obtained is hydrogenated and ii) optionally the amidino group is carbonylated, without isolating theintermediate product of the hydrogenation beforehand;as well as a process for preparing a salt of an optionally substituted 4(benzimidazol-2-ylmethylamino)-benzamidine, wherein (a) an optionally correspondingly substituted diaminobenzene is condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, (b) the product thus obtained is hydrogenated, and (c) i) optionally the amidino group is carbonylated and ii) without prior isolation of the intermediate product of the carbonylation the desired salt is isolated.

Description

IMPROVED PROCEDURE FOR THE PREPARATION OF 4- (BENZYMIDAZOLYL-METHYLAMIN) -BENZAMIDINS AND THEIR SALTS Background of the invention 1. TECHNICAL FIELD The invention relates to a process for the preparation of an optionally substituted 4- (benzimidazol-2-ylmethylamino) -benzamidine, wherein (a) an optionally substituted diaminobenzene is condensed correspondingly with 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid and (b) i) the product thus obtained is hydrogenated and ii) optionally the amidino group is carbonylated, without previously isolating the intermediate product from the hydrogenation. The 4- (benzimidazol-2-ylmethylamino) -benzamidine thus obtained can then be converted into a salt. In addition, the invention relates to a process for the preparation of a salt of an optionally substituted 4- (benzimidazol-2-ylmethylamino) -benzamidine, in which (a) a diaminobenzene optionally substituted by a corresponding 2-way is condensed. [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic, (b) the product thus obtained is hydrogenated and (c) i) the amidino group is optionally carbonyl and ii) Without prior isolation of the carbonylation intermediate, the desired salt is isolated. 2. PREVIOUS TECHNIQUE 4- (Benzimidazol-2-ylmethylamino) -benzamidines substituted, in particular / - (2-pyridyl) -? / - (2-ethoxycarbonylethyl) -amide of 1-methyl-2 - [? / - [4- (A / -hexyloxycarbonylamine-dino) phenyl] -amino-methyl ] -benzimidazol-5-yl-carboxylic acid are already known from the international patent application WO 98/37075 as active substances with a thrombin inhibitory effect and thrombin time extender. Main types of indication of the compound of chemical formula I are the postoperative prophylaxis of deep vein thrombosis and the prophylaxis of apoplexy (prevention of stroke due to atrial fibrillation, abbreviated SPAF -prevention of apoplexy due to atrial fibrillation). In WO 98/37075 it is proposed to prepare the substituted 4- (benzimidazol-2-ylmethylamino) -benzamidines by reaction with ammonia of the corresponding substituted (4-benzimidazol-2-ylmethylamino) -benzonitriles. This process is very complex from the point of view of the production technique and leads to a high load of acids to be eliminated. The purpose of the present invention was to indicate an alternative method for the preparation of the substituted 4- (benzimidazol-2-ylmethylamino) -benzamidines, in which this step of the complex process can be avoided from the point of view of the production technique . BRIEF SUMMARY OF THE INVENTION Surprisingly, it has now been found that substituted 4- (benzimidazol-2-ylmethylamino) -benzamidines can be prepared in high yields and with the use of inexpensive adjuvants, if (a) an optionally substituted diaminobenzene of correspondingly with 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid and (b) i) the product thus obtained is hydrogenated and ii) the amidino group is optionally carbonyl, preferably with an alkyl halogenoformate in the presence of a base, in particular with n-hexyl chloroformate, without previously isolating the intermediate product from the hydrogenation. The 4- (benzimidazol-2-ylmethylamino) -benzamidine thus obtained can then be converted into a salt. Furthermore, surprisingly, it was found that the salts of optionally substituted 4- (benzimidazol-2-ylmethylamino) -benzamidines can be prepared in high yields and with the use of inexpensive adjuvants, if (a) an optionally substituted diaminobenzene is condensed correspondingly with 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid, (b) the product thus obtained is hydrogenated and (c) i) the amidino group is optionally carbonylated and ii) without prior isolation of the carbonylation intermediate product the desired salt is isolated. DETAILED DESCRIPTION OF THE INVENTION A process for the preparation of an optionally substituted 4- (benzimidazol-2-ylmethylamino) -benzamidine of the formula (I) is preferred.

R1 represents a C3-6alkyl or C3- (C3) alkyl group (i) represents a C -? - 6 alkyl group, a C3-7 cycloalkyl group optionally substituted with a C -? - 3 alkyl group, wherein the C? -3 alkyl group may be further substituted with a carboxyl group or with an in-vivo transformable group in a carboxy group, or (ii) represents a group R21NR22, wherein R21 means a C? -6 alkyl group, which may be substituted with a carboxy group, C? -6-carbonyl alkoxy, benzyloxycarbonyl, C?-3-sulfonylaminocarbonyl alkyl, phenylsulfonylaminocarbonyl, trifluorosulfonyl-amino, trifluorosulfonylaminocarbonyl or 1H-tetrazoyl, a C 2-4 alkyl group, substituted with a hydroxy group, phenyl-C?-3 alkoxy, carboxy-C C alkyl- 3-amino, C 1 -3-carbonyl-C 1 -C 3 -alkylamino, N- (C 1 -C 3 alkylcarboxy-C 1 -3-amino or N- (C 1-3 alkyl) alkoxy alkoxy C? -3-carbonyl-C? -3-amino alkyl, wherein in the groups mentioned above the carbon atom in the a position with respect to the neighboring nitrogen atom can not be substituted, or a upo piperidinyl optionally substituted with an alkyl group C? -3, and R22 means a hydrogen atom, a C1-6 alkyl group) a C3- cycloalkyl group, optionally substituted with a C-? -3 alkyl group, a C3-6 alkenyl group or a C3-6 alkynyl group, wherein the unsaturated moiety can not be directly linked to the nitrogen atom of the group R21NR22, a phenyl group optionally substituted with a fluorine, chlorine or bromine atom, with a C -? - 3 alkyl or C -? - 3 alkoxy group , a benzyl, oxazolyl, isoxazolyl, thiazolyl group, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl or imidazolyl optionally substituted with a C 1-3 alkyl group, or R 21 and R 22, together with the nitrogen atom located therebetween, represent a cycloalkyleneimino group of 5 to 7 members , optionally substituted with a carboxy or C? -4-carbonyl alkoxy group, to which a phenyl ring may additionally be condensed, and R 3 represents a hydrogen atom, a d-carbonyl, cyclohexyloxycarbonyl, phenyl-C 1 alkoxy group. 3-carbonyl, benzoyl, p-alkyl d-3-benzoyl or pyridinoyl, wherein the ethoxy moiety in the 2-position of the aforementioned d-carbonyl alkoxy group can be further substituted with a C 1 -C 3 -sulfonyl or 2-alkyl group - (C 1 -3) -ethyl alkoxy, wherein in step (a) a phenyldiamine of the formula (II) wherein R1 and R2 have the indicated meanings for formula (I), is reacted with 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid, the product obtained from the formula (III) where R and R2 have the meaning indicated for the formula (D- is hydrogenated in step (b) i) and then, without previous isolation of the hydrogenation product, optionally the compound of the formula (I), thus obtained, wherein R3 means hydrogen, is reacted in the step (b) ii) with a compound of the formula (IV) R3-X (IV) wherein R3 has the meaning indicated for the formula (I), and X represents a suitable leaving group. The 4- (benzimidazol-2-ylmethylamino) -benzamidine thus obtained can be converted, if desired, then in a further step (c) into a salt, in particular into a pharmaceutically acceptable salt. Another preferred process for the preparation of a salt of an optionally substituted 4- (benzimidazol-2-ylmethylamino) -benzamidine of the formula (I) wherein R1 to R3 are defined as mentioned above, it comprises the following steps: (a) Reacting a phenyldiamine of the formula (II) (II) wherein R1 and R2 have the meaning indicated for formula (I), with 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid, (b) hydrogenate the product of the formula (III) thus obtained wherein R1 and R2 have the meaning indicated for formula (I), and (c) i) reacting the compound of formula (I), thus obtained, wherein R 3 signifies hydrogen, with a compound of the formula (IV) R 3 -X (IV) wherein R 3 has the meaning indicated for the formula (I), and X represents a suitable leaving group, and ii) precipitating the desired salt of the compound of the formula (I) thus obtained, without previously isolating the carbonylation product. Particularly preferred are the processes according to the invention for the preparation of the compounds of the formula (I) or their salts, wherein R 1 represents a C 1-3 alkyl group, R 2 represents a group R 21 NR 22, wherein R 21 represents a group alkyl d-3, which may be substituted with a carboxy group, C 1 -3-carbonyl alkoxy, and R 22 signifies a hydrogen atom, a d 3 alkyl group, a pyridinyl group optionally substituted with a d 3 alkyl group, and R3 represents a hydrogen atom, a C? -8-carbonyl alkoxy group.

Processes according to the invention for the preparation of the compound of the formula (I) or its salts, where R 1 represents a methyl group, R 2 represents a group R 21 NR 22, in which R 21 means an ethyl group, which is substituted with an ethoxycarbonyl group, and R22 means a pyridin-2-yl group, and R3 represents an n-hexyloxycarbonyl group. Preferred salts are the methanesulfonate, chloride, maleinate, tartrate, salicylate, citrate and malonate of the compound of the formula (I). A particularly preferred salt is methanesulfonate. The following embodiments (A) to (F) of the process according to the invention are preferred: (A) The condensation of step (a) is carried out in the presence of an inert diluent and a water-binding agent . The diaminobenzenes of the correspondingly substituted formula (II) of the formula (II) are known, eg. eg, of the international patent application WO 98/37075, for example of Example 25 (steps a and b), or can be prepared in analogy to those described therein. For the hydrogenation of the nitro precursor compound for the preparation of the diaminobenzene of the formula (II), there can be used as solvents, for example, toluene, isopropanol, triethylamine, ethanol, butyl acetate, ethyl acetate, methanol or mixtures of these solvents. Preferably, it is hydrogenated at a hydrogen pressure of 1 to 20 bar, but higher pressures are also possible. The concentration of the nitroaromatic compound (educt) conveniently amounts to 10 to 40% by weight; preferably, it is present in a concentration of 20 to % by weight. As a catalyst, for example, 5-10% palladium on carbon can be used, preferably palladium catalyst at 2-20% by weight - wet carbon, based on the nitroaromatic compound being used, which corresponds to palladium at approximately 0.05 - 1% in weight based on the nitroaromatic compound. Particular preference is given to using 3-amino-4-methylaminobenzoic acid amides, in particular? / - (2-pyridyl) -? / - (2-ethoxycarbonylethyl) -amide of 3-amino-4-methylaminobenzoic acid. The inert diluents used can be both apolar aprotic solvents - such as, for example. eg, aliphatic or aromatic hydrocarbons, optionally halogenated - or polar aprotic solvents such as, e.g. ethers and / or amides or lactams and / or mixtures thereof. As apolar aprotic solvents, aliphatic Cs-Cs alkanes, C4-C-10 cycloalkanes are preferably used. aliphatic d-Cβ haloalkanes, Ce-Cι aromatic, branched or unbranched alkanes, or mixtures thereof. Particularly preferred are alkanes such as pentane, hexane or heptane, cycloalkanes such as cyclohexane or methylcyclohexane, haloalkanes such as dichloromethane, aromatic alkanes such as benzene, toluene or xylene or mixtures thereof. Suitable aprotic solvents are polar ethers such as, for example, tetrahydrofuran (THF), methyltetrahydrofuran, dioxane, tert-butyl methyl ether or dimethoxyethyl ether, or amides such as, for example, dimethylformamide, or lactams, such as, for example, N -methylpyrrolidone. Water-binding agents which can be used are hygroscopic salts, inorganic or organic acids or their acid chlorides, anhydrides of inorganic or organic acids, anhydrides of alkanephosphonic acids, molecular sieves or urea derivatives. 1,1 '-carbonyldiimidazole and alkanephosphonic anhydrides are preferred, alkanephosphonic acid anhydrides are particularly preferred. In a preferred embodiment, 1,1 '-carbonyldiimidazole is suspended in THF and heated. 2- [4- (1, 2,4-Oxadiazol-5-on-3-yl) -phenylaminoj-acetic acid is added. The correspondingly substituted diaminobenzene is added in THF. The reaction mixture is stirred at about 50 ° C and then concentrated after the addition of acetic acid, mixed with water and the solid substance is filtered off., wash and dry. In a particularly preferred second embodiment, anhydrides of alkanephosphonic acid are added, in the presence of an organic base, preferably a tertiary amine such as, for example, eg, DIPEA, to a solution of 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid and diaminobenzene correspondingly substituted in THF. The reaction mixture is stirred, preferably at temperatures between -10 and 50 ° C, and then concentrated after the addition of acetic acid. It is mixed with ethanol / water and optionally a filtration aid, for example diatomaceous earth (eg Clarcel®), and filtered hot. The precipitated substance is then filtered off from the cooled solution, washed and dried. (B) The hydrogenation of step (b) ¡) or (b) is carried out in the presence of an inert diluent and a hydrogenation catalyst. Particularly preferred is a process, in which the hydrogenation is carried out in a temperature range from 0 ° C to 100 ° C, preferably from 15 ° C to 75 ° C, in particular from 30 ° C to 60 ° C. In addition, a process is preferred, wherein the hydrogenation it is carried out at a pressure of more than 0.5 bar at 100 bar, preferably at a pressure of 1 bar at 10 bar, in particular at about 1-4 bar. Inert diluents can be used both protic solvents - such as, for example. eg, alcohols, carboxylic acids and / or water - or polar aprotic solvents such as, e.g. ethers and / or amides or lactams and / or mixtures thereof. Water may optionally be added to all solvents. Preferred protic solvents are preferably branched or unbranched Ci-Cs alkanes, C 1 -C 3 carboxylic acids or mixtures thereof. Particularly preferred are lower alcohols such as methanol, ethanol, n-propanol and isopropanol, carboxylic acids such as formic acid, acetic acid and propionic acid or their mixtures. Ethanol and / or acetic acid are preferably used as the reaction medium, where they can optionally contain water. Suitable aprotic solvents are polar ethers, such as, for example, tetrahydrofuran, dioxane or dimethoxyethyl ether, or amides such as, for example, dimethylformamide, or lactams, such as, for example, N-methylpyrrolidone. Preferably solvents are used that tend little to combustion. Suitable hydrogenation catalysts are, in general, transition metals such as, for example, nickel, platinum or palladium or their salts or oxides. Raney nickel, platinum oxide and palladium are preferred over an inert support material, in particular palladium on active carbon (Pd / C). Processes are preferred in which the product of step (a) to give the hydrogenation catalyst is used in a weight ratio of 1: 1 to 1000: 1, preferably 5: 1 to 100: 1. In a preferred embodiment of step (b) the product of step (a) is taken up in ethanol and, after addition of acetic acid and 2 bar of hydrogen, hydrogenated with 10% Pd / C wet at room temperature. It is filtered from the catalyst and p-toluenesulfonic acid, dissolved in 90 ml of ethanol or in 90 ml of water, is added. Preferably, an aqueous solution of p-toluenesulfonic acid is used. Precipitate the tosylate of the 4- (benzimidazol-2-ylmethylamino) -benzamidine obtained, separate by filtration and continue washing in several portions with ethanol. In a particularly preferred embodiment of step (b) the product of step (a) is taken up in ethanol / water and hydrogenated at 4 bar of hydrogen with 10% Pd / C wet at 60 ° C. It is filtered from the catalyst and p-toluenesulfonic acid (solid or dissolved in 90 ml of ethanol or in 90 ml of water) is added. Preferably, p-toluenesulfonic acid is used. Precipitate the tosylate of 4- (benzimidazol-2-ylmethylamino) -benzamidine, separate by filtration and continue washing in several portions with ethanol. In a preferred embodiment of step (b) i) the product of step (a) is collected in a mixture based on THF and water (approximately 7: 3 based on volume) and hydrogenated at 4 bar hydrogen with 10% Pd / C humid at approx. 40 ° C. The hydrogenation solution is filtered and the filter is further washed with THF / water (7: 3). The filtrate is diluted with THF and water and mixed with potassium carbonate. Then, according to a variant of the process, carbonylation can be carried out directly in step (b) ii). For this purpose, after separation of the catalyst and without intermediate isolation of the hydrogenation product, the filtrate is mixed with an auxiliary base and reacted with a carbonylation agent. Carbonylation agents and bases, as well as possible solvents and suitable temperature ranges that can be used are described in (E) in greater detail. The reaction is preferably carried out with potassium carbonate and at temperatures between 10-50 ° C, preferably 10-20 ° C. After the reaction is complete, the suspension is heated, for example, to approx. 50 ° C, so that a transparent two-phase mixture results. The lower aqueous phase is strongly charged inorganically and can be separated before distilling THF off and a change of solvent to acetone takes place, from which, by the addition of water, the compound of the formula (I) crystallizes. Possible treatment variant: In a variant of the reaction, after removal of the inorganically charged aqueous phase and distillation of THF, a change of solvent to butyl acetate takes place. The crystallization of the compound of the formula (I) is then carried out after the aqueous extraction of the organic phase and azeotropic removal of the residual moisture. (C) For the preparation of 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylaminoj-acetic acid, 2- [4- (1, 2,4-oxadiazole-5 -on-3-yl) -aniline is reacted with a 2-halogenoacetic acid ester, preferably bromoacetic acid ethyl ester, in the presence of a weak base, preferably a tertiary amine such as, for example, triethylamine or a carbonate of alkali metal such as, for example, sodium carbonate, in an inert solvent, and the ethyl ester of 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] is saponified] -acetic obtained. The inert diluents used can be both protic solvents - such as, for example. eg, alcohols and / or water - or polar aprotic solvents such as, e.g. ethers and / or amides or lactams and / or mixtures thereof. To all solvents may be added water. Protic solvents used are preferably water or branched or unbranched C? -C8 alkanols, or mixtures thereof. Particularly preferred are water or lower alcohols such as methanol, ethanol, n-propanol and isopropanol or their mixtures. Very particularly preferably ethanol is used as the reaction medium, where it may optionally contain water. Likewise, isopropanol can be used, possibly together with water. However, the most suitable solvent is water. Suitable aprotic solvents are polar ethers, such as, for example, tetrahydrofuran or dimethoxyethyl ether, or amides, such as, for example, dimethylformamide, or lactams, such as, for example, N-methylpyrrolidone. In a particularly preferred embodiment, ethyl bromoacetate is metered into a suspension of 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -aniline and sodium carbonate in water / isopropanol or , preferably, in water / ethanol and stirred at 35-45X. The cooled suspension is filtered with suction, washing in several portions with water and ethanol is continued and dried. The saponification is preferably carried out in a protic solvent with an alkali metal or alkaline earth metal hydroxide, in particular with lithium, sodium or potassium hydroxide. In a particularly preferred embodiment, 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid ester is suspended in water or, preferably, in water / ethanol and it is mixed at room temperature, slowly, with an aqueous solution of NaOH. The suspension is transformed into a solution and heated to 45 to 75 ° C. To the solution, thus obtained, is added HCl until approximately pH 5 or, preferably, pH 3 has been reached. The solid is isolated and washed with cold water, as well as cold ethanol and MtBE. (D) For the preparation of 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -aniline, 4-aminophenyl-amidoxime is reacted with a dialkyl carbonate, preferably dimethyl carbonate or diethyl carbonate, in the presence of a base, preferably of an alkali metal alcoholate, in particular sodium methylate, sodium ethylate or potassium tert-butanolate. 4-aminophenyl-amidoxime can also be prepared, e.g. eg, by reaction of 4-aminobenzonitrile with hydroxylamine hydrochloride. In a particularly preferred embodiment, sodium methoxide or, preferably, sodium ethoxide is added at 65-75 ° C, preferably at 70-75 ° C, to a suspension of 4-aminophenyl-amidoxime in ethanol and further clarification with ethanol After stirring for 15 min, diethyl carbonate or, preferably, dimethyl carbonate is added dropwise. After a reaction time of 2-4 hours, the mixture is cooled and ethanol is distilled off at 120 mbar and 40 ° C. The residue is taken up in water and, after heating, is adjusted to pH 10-12 by semi-concentrated sodium hydroxide solution, then, by acidification with concentrated hydrochloric acid, adjusted to pH < 6, preferably at pH < 4, particularly preferably at pH 2-3 and cooled slowly. The solution is transformed into a suspension, which is filtered and continued to be washed several times with cold water and ethanol. (E) For the preparation of a salt of a compound of the formula (I), wherein R 3 has a meaning other than hydrogen, by carbonylation of a compound of the formula (I), wherein R 3 is hydrogen, and precipitation of the desired salt without previous isolation of the product from carbonylation, in a first partial step (c) i), the compound of the formula (I), in which R3 signifies hydrogen, is reacted with a carbonylating agent R3-X, wherein R3 has the meanings indicated above, except hydrogen, and X means a labile group. Preferably, X can mean a halogen such as, for example, chlorine or bromine or a p-toluenesulfonyl group, methanesulfonyl or trifluoromethanesulfonyl. Very particular preference is given to n-hexyl chloroformate for the preparation of a compound of the formula (I), in which R 3 denotes n-hexyl. The reaction is preferably carried out at a temperature of 10 to 50 ° C, in particular at 10 to 20 ° C, in the presence of a base. As a base, alkali metal carbonates, such as, for example, potassium carbonate or sodium carbonate, alkali metal hydrogen carbonates such as, for example, sodium hydrogen carbonate or potassium hydrogen carbonate, can conveniently be used. or tertiary amines such as, for example, triethylamine. Preferably, potassium carbonate is used. The reaction is carried out, for example, in mixtures based on water and acetone or water and THF; A water / acetone mixture is preferred. After completion of the reaction, it can be achieved, by heating the suspension, p. ex. up to approx. 50 ° C, the formation of a transparent biphamixture, so that the aqueous phase containing a large part of the inorganic components can be easily separated. Then, a solvent change can be made. Suitable solvents include, for example, ketones or esters such as, for example, MIBK, butyl acetate, ethyl acetate, propyl acetate, isopropyl acetate or isobutyl acetate. MIBK and butyl acetate are particularly preferred. The organic phase is washed in aqueous conditions, in order to separate polar impurities. Remnant remnants of moisture are then separated by azeotropic distillation before crystallizing and isolating the product, or, without intermediate isolation for partial stage c) ii), it is mixed, e.g. With acetone and then, by adding the corresponding acid, for example methanesulfonic acid, for the preparation of the methanesulfonate, the desired salt is directly precipitated and isolated. (F) For the precipitation of a given salt, starting from the compound of the formula (I), a solution of the compound of the formula (I) is prepared, optionally under heating, and then the corresponding acid is added, optionally in the form of a solution. . For the crystallization of the salt, it can be cooled. Next, the salt is isolated. Suitable solvents are, for example, acetone or a mixture based on acetone and ethanol. Optionally, the amount of solvent used for the preparation of the substrate solution can be increased. This enables a transparent filtration of the solution before the addition of the acid. The preparation of 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid, required as an intermediate product, from 4-aminobenzonitrile is shown in the following scheme Reactions: Diagram I (The non-isolated intermediate steps, indicated by brackets, may optionally vary between the various variants of the procedure.) A preferred embodiment is indicated.) (1A) to O Br R-0 (2B1 (2A) The preparation of a 4- (benzimidazol-2-ylmethylamino) -benzamidine is represented by way of example in the following reaction scheme: Scheme The elaboration of the different reactions can be carried out in a customary manner, for example by separating the reaction coadjuvant, separating the solvent and isolating the pure final product by crystallization, distillation, extraction or chromatography.

Following the procedure described above, the compound of formula (I), thus obtained, can be transformed into a physiologically compatible salt. In the case of the physiologically compatible salts, it may be salts with inorganic or organic acids or, if the compound contains a carboxy group, with inorganic or organic bases. Suitable acids are, for example, methanesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine. The compound of the formula (6) is preferably transformed into its mesylate. The procedure according to the invention must now be explained by the following examples. The person skilled in the art is aware that the examples are only for illustration and are not to be considered as limiting. EXAMPLES The following abbreviations are used above and in the following: AcOH acetic acid AMBPA? / - (2-pyridyl) -? / - (2-ethoxycarbonylethyl) -amide of 3-amino-4-methylaminobenzoic acid CDI 1 , 1 '-carbonyldiimidazole DIPEA diisopropylethylamine EE ethyl acetate EtOH ethanol HCl hydrochloric acid MIBK methyl isobutyl ketone (4-methyl-2-pentanone) MtBE methyl-tert-butyl ether NaOH sodium hydroxide NMP N-methylpyrrolidone PPA propanophosphonic acid anhydride PTSA p-toluenesulfonic acid TA room temperature THF tetrahydrofuran desc. decomposition Example 1 Preparation of 2- [4- (1,2,4-oxadiazol-5-on-3-yl) -aniline (1): Variant 1: LIA) 118.6 g (1 mol) are placed in the reaction vessel ) of 4-aminobenzonitrile and 68.9 g (0.65 mol) of sodium carbonate in 500 ml of ethanol and 100 ml of water and heated to 60 ° C. 76.4 g (1.1 mol) of hydroxylamine hydrochloride, dissolved in 100 ml of water, are added slowly, dropwise, to this suspension. The mixture is then stirred overnight at 60 ° C. When cooling to 0-5 ° C, the substance precipitates, it is separated by filtration and it is continued to wash several times with a total of 150 ml of cold water and 100 ml of cold ethanol.

Finally, it is washed with 50 ml of MtBE and 178.4 g of wet product are obtained. It is dried at 35 ° C under vacuum. Yield: 135.4 g of light beige substance (89.5% of theory), melting point: from 169.5 ° C (dec); purity: > 98% peak surface area by HPLC (1B) To a suspension of 60.5 g of (1A) (0.4 mol) in 400 ml of ethanol are added in portions, at 70-75 ° C, 25.02 g (0.46 mol) of sodium methylate and continue rinsing with 20 ml of ethanol . After stirring for 15 min, 47.25 g (0.4 mol) of diethyl carbonate are added dropwise. After a reaction time of 3 hours, it is cooled to 40 ° C and the ethanol is distilled off at 120 mbar and 40 ° C. A dark residue is obtained. This is dissolved at 40-45 ° C in 350 ml of water and, after heating up to 70 ° C, it is adjusted to pH 11 first by slow addition of semi-concentrated soda lye; then it is adjusted to pH 5.5 by acidification with concentrated hydrochloric acid and cooled slowly. The solution is transformed into a suspension, which is filtered and continued to be washed several times with a total of 150 ml of cold water and 50 ml of ethanol. 88.7 g of wet substance are obtained, which is dried at 35 ° C under vacuum. Yield: 62 g of dark colored substance (87.5% of theory); melting point: from 178 ° C (dec.); purity: > 98% peak surface by HPLC Variant 2: ÜA) 41.3 g (0.35 mole) of 4-aminobenzonitrile and 36.5 g (0.53 mole) of hydroxylamine hydrochloride in 175 ml of ethanol and heated to 60 are placed in the reaction vessel. ° C. 170.1 g (0.53 mol) of sodium ethylate solution (~ 21% in ethanol) are added slowly, dropwise, to this suspension. The mixture is then stirred overnight at 60 ° C. Upon cooling to 0-5 ° C, the substance precipitates, it is separated by filtration and it is continued to wash several times with a total of 70 ml of cold ethanol. Approx. 86 g of wet product. This continues to be elaborated directly. (1B) To a suspension of 86 g of (1A) in 270 ml of ethanol is added 32 g (0.35 mol) of dimethyl carbonate. At 65-75 ° C, 125 g (0.38 mol) of sodium ethylate solution (~ 21% in ethanol) are added and the mixture is further rinsed with 20 ml of ethanol. After a reaction time of 3 hours, the mixture is cooled to 40 ° C and the ethanol is distilled off at 120 mbar and 40 ° C. A dark residue is obtained. This is dissolved at 40-45 ° C in 280 ml of water and, after heating to 70 ° C, it is adjusted to pH 11 first by slow addition of semi-concentrated sodium hydroxide solution; then, by acidification with concentrated hydrochloric acid, it is adjusted to pH 3-4 or, preferably, to pH 2-3 and cooled slowly. The solution is transformed into a suspension, which is filtered and continued to be washed several times with a total of 50 ml of cold water and 20 ml of ethanol. Approx. 88 g of wet substance, which is dried at max. 50 ° C in vacuum. Yield: 48 g of beige substance (77.5% of theory); melting point: from 178 ° C (dec.); purity: > 98% peak surface by HPLC Example 2 Preparation of 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid (2): Variant 1: (2A) A At room temperature, 83.5 g (0.5 mol) of ethyl bromoacetate are added portionwise to a suspension of 70.86 g (0.4 mol) of (1B) and 26.5 g (0.25 mol) of sodium carbonate in 600 ml of water / isopropanol and stirred during one night. The reaction mixture turns brownish-red to orange. The suspension cooled to 0 ° C is suctioned, washed in several portions with 300 ml of water and 150 ml of ethanol (106 g of wet clear brown substance) and dried at 35 ° C under vacuum. Yield: 92.44 g of brownish substance (87.7% of theory); melting point: from 186.1 ° C (dec.); purity: > 98% peak surface area by HPLC The ester (2A) (86.9 g, 0.33 mol), thus obtained, is suspended in 400 ml of water and, at RT, 120 g of 45% NaOH are slowly added dropwise. The suspension becomes a solution and turns reddish (pH 12.5). Heat to ~ 60 ° C and saponify for 1 h. The solution obtained is mixed in portions with HCl (at 37% or, preferably, with concentrated HCl), until a pH of 5 is reached. It is cooled to 0 ° C. The solid is filtered with suction and washed in several portions with a total of 400 ml of cold water, as well as in each case 40 ml of cold ethanol and MtBE. 81.4 g of dark, moist substance are obtained. This is dried at 35 ° C under vacuum. Yield: 76.7 g of substance (98% of theory) Melting point: from 193 ° C (dec.) Purity: >; 99% Peak Surface by HPLC Variant 2: (2A) At 45 ° C, 60.2 g (0.36 mol) of ethyl bromoacetate are metered in to a suspension of 53.2 g (0.3 mol) of (1B) and 19.1 g (0.18 mol) of sodium carbonate in 500 ml of water / ethanol (90:10 to 95: 5) and, if necessary, stir overnight. The reaction mixture becomes brown-reddish orange The suspension cooled to 0 ° C is suctioned, washed in several portions with 100 ml of ethanol and dried at max. 50 ° C in vacuum. Yield: 69.5 g of beige-brown substance (87.7% of theory); melting point: from 186.1 ° C (dec.); purity: > 98% peak area per HPLC (2B) The ester (2A) (86.9 g, 0.33 mol), thus obtained, is suspended in 400 ml of water or, preferably, ethanol / water (1: 1) and at RT are added slowly, dropwise, 120 g of 45% NaOH. The suspension becomes a solution and turns reddish (pH 12.5). Heat to ~ 60 ° C and saponify for 1 h.

The solution obtained is mixed in portions with HCl (37% or, preferably, with concentrated HCl), until a pH of 3 is reached. It is cooled to 0 ° C. The solid is filtered with suction and washed in several portions with a total of 400 ml of cold water, as well as in each case 40 ml of cold ethanol. 81.4 g of wet substance are obtained. This is dried at 35 ° C under vacuum. Yield: 76.7 g of substance (98% of theory) Melting point: from 193 ° C (dec.) Purity: > 99% peak area by HPLC Example 3 Preparation of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide of 3-amino-4-methylaminobenzoic acid (AMBPA) (3) Variant A: 5% Pd / C In a hydrogenation autoclave 150 g (0.4 mol) of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide of 4-methylamino-3-nitrobenzoic acid are placed, 12 g of 5% palladium on carbon catalyst and 627 ml of ethyl acetate. The mixture is hydrogenated under a hydrogen atmosphere of 3-4 bar at 35-55 ° C until constancy of hydrogen uptake (1-2 h). After cooling to 20 ° C, the hydrogenation solution is filtered off from the catalyst and concentrated in vacuo on the rotary evaporator. The residue is taken up in 650 ml of isopropanol, distilled to half the initial volume and cooled to 5-10 ° C. After 4 h the resulting suspension is filtered, and the precipitate, thus isolated, is further washed in portions with a total of 100 ml of isopropanol.

The solid obtained is dried in the vacuum drying oven at 50 ° C. Yield: 114.2 g (corresponding to 83% of theory). Variant B: 10% Pd / C In a hydrogenation autoclave, 25 g (0.07 mol) of N- (2-pyridyl) -N- (2- 4-methylamino-3-nitrobenzoic acid ethoxycarbonylethyl) -amide, 2. 5 g of 10% palladium on carbon catalyst and 83 ml of ethyl acetate.

The batch is hydrogenated under a hydrogen atmosphere of 3-4 bar at 50 ° C until constancy of hydrogen uptake (4-5 h). After cooling to 20 ° C, the hydrogenation solution is filtered off from the catalyst and concentrated in vacuo on the rotary evaporator. The residue dissolves hot in a little ethyl acetate and mixed with 68 ml of toluene. After cooling to 5 ° C, stirring is continued for 1 h, then the precipitate is filtered off and washed with toluene. The product obtained is dried in the vacuum drying oven at 40 ° C. Yield: 20.9 g (corresponding to 91% of theory) Example 4 Preparation of 1 / Methyl-2- [α / - [4-] 2- (2-pyridyl) -? / - (2-ethoxycarbonylethyl) -amide (1, 2,4-oxadiazol-5-on-3-yl) phenyl] -amino-methyl] -benzimidazol-5-yl-carboxylic acid (4): Variant A: CDI as coupling reagent 11.35 g (70 mmol) of 1, 1 '-carbonyldiimidazole are suspended in 100 ml of THF and heated to 50 ° C. 14.23 g (60.5 mmol) of (2B) are added in portions. 17.1 g (50 mmol) of AMPBA are dissolved in 37 ml of THF under heating to 50 ° C. After approx. 90 min, the suspension is added to the AMPBA solution metered and it is further clarified with 20 ml of THF. The reaction mixture is stirred for approx. 18 h and then heating to reflux after the addition of 100 ml of acetic acid, so that the THF is distilled off. After approx. 1 h is mixed with 400 ml of water and stirred. The solution is cooled, the precipitated pink solid is separated by filtration and it is further washed with 20 ml of water in 2 portions and dried at maximum 50 ° C in vacuum. Yield: 24.8 g of substance (75% of theoretical) melting point: from 167 ° C with dec. (DSC); purity: > 95% peak surface area by HPLC Variant B: PPA as a coupling reagent 34.2 g (0.1 mole) of AMBPA, 27.5 g (0.12 mole) of (2B) and 30.3 g (0.23 mole) of DIPEA are placed in 170 ml of THF and cooled to something below of the room temperature. Thereto is now added 85 g (0.13 mol) of PPA (in the form of a -50% solution in ethyl acetate). The mixture is stirred for 90 min. And then the solvent is distilled off. Towards the end, 73.5 g of acetic acid are added and heated to an internal temperature of 90CC. It is then mixed with 400 ml of ethanol or, preferably, with 400 ml of ethanol / water (about 85: 15) and diatomaceous earth filtering aid (eg Clarcel®), and filtered hot. The solution is cooled, the precipitated solid is filtered off and the mixture is washed with 50 ml of ethanol in 2 portions and dried at max. 50 ° C in vacuum. Yield: 56 g of substance (85% of theory); melting point: from 167 ° C with dec. (DSC); purity: > 95% peak surface by HPLC Variant C: Pivaloyl chloride as coupling reagent 96 g (0.41 mol) of (2B) are suspended at 0 ° C in 250 ml of NMP and 550 ml of THF. The liquid suspension is successively mixed with 48 g (0.4 mol) of pivaloyl chloride and 52 g (0.4 mol) of DIPEA and stirring is continued for 30 minutes. Then, 125 g (0.36 mol) of AMBPA dissolved in 800 ml of acetic acid are added, and the reaction mixture is heated to reflux for 3 h. THF is removed by distillation under a slight vacuum and, in hot, 1600 ml of water are metered in. The solid is isolated at 5 ° C, washed with 550 ml of water and dried overnight in the drying oven. by circulating air max. 50 ° C. Yield: 183 g (76%) Purity: > 95% peak surface by HPLC Example 5 Preparation of 1 / methyl-2- [α / - [4-amidinophenyl] - [2- (pyridyl) -] - (2-ethoxycarbonylethyl) -amide of 1-methyl-2- [α / - [4-amidinophenyl] ] -amino-methyl] -benzimidazole-5-yl-carboxylic acid (5A) Alternative A: Hydrogenation of (4) in ethanol 37.3 g (56.4 mmol) of (4) are dissolved in 900 ml of ethanol and, after adding 10 ml of acetic acid and 2 bar of hydrogen, the mixture is hydrogenated with 4 g of 10% Pd / C wet at RT. Filter from the catalyst and add 17 g (89.4 mmol) of PTSA, dissolved in 180 ml of ethanol. Precipitate the tosylate from (5A), separate by filtration and continue washing in several portions with 150 ml of ethanol. A moist substance is obtained, which is dried at 35 ° C under vacuum. Yield: 34.5 g of light beige substance (91.3% of theory); melting point: 187 ° C (DSC); purity: > 98% peak surface by HPLC Variant B: Hydrogenation of (4) in ethanol / water 37.3 g (56.4 mmol) of (4) are dissolved in 400 ml of ethanol / water (90:10) and hydrogenated at 4 bar of hydrogen with 4 g of 10% PD / C humid at 60 ° C. Separate from the catalyst and add 11.5 g (60.6 mmol) of PTSA. By concentrating, the tosylate of (5A) precipitates. The suspension is cooled, the substance is separated by filtration and washing is continued in several portions with 150 ml of ethanol / water. A moist substance is obtained, which is dried at 35 ° C under vacuum. Yield: 33.7 g of light beige substance (89% of theory); Point of melting: 187 ° C (DSC); purity: > 98% peak surface by HPLC Variant C: Hydrogenation of (4) in THF / water 30.0 g (45.3 mmol) of (4J) are dissolved at room temperature in 90 ml of THF / water (1: 1), mixed with 4 g of Pd at 10% / C wet and hydrogenated at 4 bar and 60 ° C. The catalyst is separated by filtration, washing is continued with about 40 ml of THF / water (1: 1) and the filtrate is added. , without treatment, to the next step or is isolated, as above, by the addition of 13.6 g (72 mmol) of PTSA, dissolved in 100 ml of water and cooling Example 6 Preparation of α- (2-pyridyl) - ? / - (2-Ethoxycarbonylethyl) -amide of 1-methyl-2- [? - [4 - (? / - n-hexyloxycarbonylamidin) phenyl] -amino-methyl] -benzimidazol-5-yl-carboxylic acid (2-ethoxycarbonylethyl) -amide. 6A) The compound obtained according to Example 4 is reacted, in a manner known per se, with n-hexyl chloroformate in the presence of a base. Variant A: Acylation of (5A) in acetone / water 55 g (81.9 mmol) of (5A), dissolved in 437 ml of acetone and 273 ml of water, are mixed in the presence of 34 g (246 mmol) of potassium carbonate , at a temperature of approx. 15 ° C with 16.4 g (99.6 mmol) of n-hexyl chloroformate. At the end of the reaction, the precipitated product is filtered off and washed with acetone / water. If necessary, it can be dissolved again under heating in approx. 270 ml of acetone and then filter. After filtration, by adding 220 ml of water, the substance crystallizes again. The isolated substance is dried at 45 ° C in vacuo. Yield: 42 - 48 g (82 - 94%) Variant B: Acylation of (5A) in acetone / water with phase separation 50 g (74.4 mmol) of 5A, suspended in 380 ml of acetone and 248 ml of water are mixed in the presence of 63 g (447 mmol) of sodium carbonate. potassium, at a temperature of approx. 15 ° C with 13.48 g (81.9 mmol) of n-hexyl chloroformate. At the end of the reaction the suspension is heated to about 50 ° C. After phase separation, the aqueous phase is discarded and the acetone is mixed with 450 ml of butyl acetate. The aqueous phase, then separated, is discarded and the organic phase is washed in several portions with water. After drying the organic phase by azeotropic distillation, the product crystallizes at approx. 60-80 ° C, is isolated and continued to be washed with butyl acetate. The product is dried under vacuum at 60 ° C. Yield: 47 g (87%) Purity: > 99% peak surface by HPLC Variant C: Acylation of (5A) in acetone / water with phase separation at the scale of 40 kg kg (59.5 mole) of 5A are suspended together with 50.4 kg (365 mole) of potassium carbonate in 300 I of acetone and 200 I of water. To the suspension, 10.8 kg (65.6 mol) of n-hexyl chloroformate are added in a space of 1 h to ca. 15 ° C, and the suspension is heated to 50 ° C after a subsequent agitation time of 30 min. After separation of the aqueous phase, butyl acetate is replaced by acetone. The aqueous phase that separates is discarded and the organic phase is extracted twice with water. After drying the organic phase by azeotropic distillation, the product 6B crystallizes, is isolated and is further washed with butyl acetate. The product is dried under vacuum at 60 ° C.

Yield: 30.5 kg (82%) Purity: > 99% peak surface by HPLC Example 7 Preparation of 1-methyl-2 - [? - [4 - (? / - n-) / V- (2-pyridyl) - / V- (2-ethoxycarbonylethyl) -amide hexyloxycarbonylamino) phenyl] -amino-methyl] -benzimidazol-5-yl-carboxylic acid (6B) from? - (2-pyridyl) -? - (2-ethoxycarbonylethyl) -amide of 1-methyl-2- [? - [4- (1,2,4-Oxadiazol-5-on-3-yl) phenyl] -amino-methyl] -benzimidazol-5-yl-carboxylic acid (4) 60 g (91 mmol) of? / - ( 2-pyridyl) -? / - (2-ethoxycarbonylethyl) -amide of 1-methyl-2 - [? / - [4- (1, 2,4-oxadiazol-5-on-3-yl) phenyl] - amino-methyl] -benzimidazol-5-yl-carboxylic acid (4) are hydrogenated with 3.0 g of 10% palladium on charcoal (moistened with water) in 126 ml of THF and 54 ml of water at 40 ° C and a pressure of hydrogen of 4 bar during 25 min. The hydrogenation solution is filtered and the filter is washed with 75 g of THF / water (7: 3). The filtrate is successively mixed with 56 ml of THF, 260 ml of water and in portions with 75.2 g (544 mmol) of potassium carbonate at room temperature. Next, 14.2 g (86 mmol) of n-hexyl chloroformate are metered in over 40 min. After control of the conversion, another 1.2 g (7.3 mmol) of n-hexyl chloroformate is metered in, so that all the starting material has been reacted. The suspension is heated to approx. 45 ° C. A transparent two-phase mixture is formed. The aqueous phase is discarded and THF is widely separated by distillation. To the suspension, 150 ml of acetone are added, the mixture is heated to 50 ° C. and filtered to clarity. The filter is further clarified with 100 ml of acetone. The filtrate is cooled to room temperature and the product is precipitated by slowly adding 100 ml of water. The product wet is washed with 150 ml of acetone / water (1: 1) and 150 ml of water and dried in vacuo. Yield: 56.9 g (94%) Purity by HPLC: > 98.8% Example 8 Preparation of acid? / - (2-pyridyl) -? / - (2-ethoxycarbonylethyl) -amide acid mesylate 1 - . 1-methyl-2 - [? / - [4 - (? / - n-hexyloxycarbonylamido) phenyl] -amino-methyl] -benzimidazol-5-yl-carboxylic acid (7) 100 g (0.16 mol) of the compound (6B) they are dissolved in 890 ml of acetone under heating and mixed with a solution of 15 g (0.16 mol) of methanesulfonic acid in 200 ml of acetone. The solution is filtered and, after the addition of 77 ml of acetone, it is cooled to approx. 20 ° C. The precipitated product is isolated and continued to be washed with acetone. Then, it is dried in the drying oven at max. 50 ° C. Yield: 90-98 g (103-113 g) Example 9 Preparation of 1 / methyl-2 - [? / -] - [2-pyridyl] -? / - (2-ethoxycarbonylethyl) -amide [4 - (? / - n-hexyloxycarbonylamino) phenyl] -amino-methyl] -benzimidazole-5-yl-carboxylic acid (7) from? / - (2-pyridyl) -? / - (2-ethoxycarbonylethyl) ) - 1-methyl-2- [? - [4-amidinophenyl] -amino-methyl] -benzimidazol-5-yl-carboxylic acid (5A) 50.0 g (74.4 mmol) of suspension are suspended in the reaction vessel. 5A and 63.0 g (446.6 mmol) of potassium carbonate in 380 ml of acetone and 248 ml of water and 13.48 g are metered in over the space of 1 h and at 20 ° C. (81.9 mmol) of n-hexyl chloroforomonate. After a reaction time of 30 min, the suspension is heated to ca. 50 ° C. A transparent biphasic mixture is formed in which 0.12 g (0.7 mmol) of n-hexyl chloroformate are metered in after a conversion control, so that all of the starting material has reacted. The aqueous phase is separated, the organic phase is filtered until clear and the filter is washed with 50 ml of acetone. Under a slight vacuum, 300 ml of acetone are distilled off and replaced with 250 ml of MIBK. The aqueous phase that is deposited is separated and the organic phase is extracted at 50-60 ° C with 50 ml of water. Subsequently, 300 ml of solvent are removed by distillation and replaced with 500 ml of acetone. The reaction solution is cooled to 30-36 ° C, mixed with 7 inoculation crystals (which, for example, were obtained from a reaction previously carried out according to Example 7 or according to the procedure described in Example 3 of the document WO 03/074056) and a previously prepared solution of 6.44 g (67 mmol) of methanesulfonic acid in 50 ml of acetone was added dropwise. The suspension is continued stirring for 20 min, the product is isolated by filtration and washed with 300 ml of acetone. The isolated substance is dried at 45 ° C in vacuo. Yield: 48.0 g (89%) Purity: > 99% peak surface area by HPLC

Claims (14)

1. CLAIMS 1. Process for the preparation of an optionally substituted 4- (benzimidazol-2-ylmethylamino) -benzamidine, characterized in that ((a) a diaminobenzene is optionally suitably substituted with 2- [4- (1, 2 , 4-oxadiazol-5-on-3-yl) -phenylamino] -acetic and (b) i) the product thus obtained is hydrogenated and ii) optionally the amidino group is carbonylated, without previously isolating the intermediate product from the hydrogenation. 2. Process according to claim 1 for the preparation of an optionally substituted 4- (benzimidazol-2-ylmethylamino) -benzamidine of the formula (I) wherein R1 represents a C1-6 alkyl or C3- cycloalkyl group, R2 (i) represents a C? -6 alkyl group, a C3-7 cycloalkyl group optionally substituted with a C? -3 alkyl group, wherein the group alkyl d-3 may be further substituted with a carboxyl group or with an in-vivo transformable group in a carboxy group, or (ii) represents a group R21NR22, wherein R21 means a C1-6 alkyl group, which may be substituted with a carboxy group, C?-6-carbonyl alkoxy, benzyloxycarbonyl, C?-3-sulfonylaminocarbonyl alkyl, phenylsulfonylaminocarbonyl, trifluorosulfonylamino, trifluorosulfonylaminocarbonyl or 1 H-tetrazolyl, a C 2-4 alkyl group, substituted with a hydroxy, phenyl-alkoxy group C? -3, carboxy-alkyl C? -3-amino, alkoxy d-3-carbonyl-C? -3-amino alkyl, N- (C? -3 alkyl) -carboxy-alkyl d-3-amino or N - (alkyl d-3) -alcoxy! C? -3-carbonyl-alkyl d-3-amino, wherein in the groups mentioned above the carbon atom adjacent to the nitrogen atom can not be substituted, or a piperidinyl group optionally substituted with an alkyl group d-3, and R22 signifies a hydrogen atom, a C? -6 alkyl group, a cycloalkyl group 03.7, optionally substituted with an alkyl group d-3, a C3.6 alkenyl group or C3-6 alkynyl, wherein the unsaturated part can not be directly linked to the nitrogen atom of the group R21NR22, a phenyl group optionally substituted with a fluorine, chlorine or bromine atom, with an alkyl group or C alco-3 alkoxy, a benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl or imidazolyl group optionally substituted with an alkyl group d-3, or R21 and R22, together with the nitrogen atom located therebetween, they represent a 5- to 7-membered cycloalkyleneimino group, optionally substituted with a carboxy or C? -4-carbonyl alkoxy group, to which a phenyl ring may additionally be condensed, and R 3 represents a hydrogen, a Ci.g -carbonyl, cyclohexyloxycarbonyl, phenyl-C3-carbonyl, benzoyl, p-alkyl d-3-benzoyl or pyridinoyl group, wherein the part of ethoxy in the 2-position of the alkoxy group The aforementioned g-carbonyl can be further substituted with an alkyl d-3-sulfonyl or 2- (C 1 -3) -ethyl group, wherein in step (a) a phenyldiamine of the formula (II) where R1 and R2 have the meaning indicated for the formula
2. (I), is reacted with 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid, the resulting product of the formula (III) wherein R and R2 have the meanings indicated for the formula (I), hydrogenated in step (b) i) and then, without previous isolation of the hydrogenation product, optionally the compound of the formula (I), obtained, wherein R3 signifies hydrogen, is reacted in step (b) ii) with a compound of the formula (IV) R3-X (IV) wherein R3 has the meaning indicated for the formula (I), and X represents a suitable labile group.
3. 3. Process according to claim 1 or 2, for the preparation of a compound of the formula (I), in which R1 represents an alkyl group -3, R2 represents a group R21NR22, in which R21 means an alkyl group - 3, which may be substituted with a carboxy group, C 1 -C 3 -alkoxy, and R 22 signifies a hydrogen atom, a C 3 -3 alkyl group, a pyridinyl group optionally substituted with an alkyl group d 3, and R 3 represents a hydrogen atom, an alkoxy group d -β-carbonyl.
4. 4. Process according to claim 3, for the preparation of the compound of the formula (I), in which R1 represents a methyl group, R2 represents a group R21NR22, in which R21 means an ethyl group, which is substituted with a ethoxycarbonyl group, and R22 means a pyridin-2-yl group, and R3 represents an n-hexyloxycarbonyl group.
5. 5. Process according to one of the preceding claims, characterized in that the compound of formula (I), thus obtained, is then transformed into a physiologically acceptable salt.
6. 6. Process according to claim 5, characterized in that the physiologically acceptable salt is methanesulfonate.
7. 7. Process for the preparation of a salt of a 4- (benzimidazol-2-ylmethylamino) -benzamidine optionally substituted, in which (a) a diaminobenzene is optionally suitably substituted with 2- [4- (1 , 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid, (b) the product thus obtained is hydrogenated and (c) i) the amidino group is optionally carbonyl and ii) without previous isolation of the product intermediate the carbonylation the desired salt is isolated.
8. 8. Process according to claim 7 for the preparation of a salt of an optionally substituted 4- (benzimidazol-2-ylmethylamino) -benzamidine of the formula (I) wherein R1 to R3 are defined as mentioned in claim 2, it encompasses the following steps: (a) reacting a phenyldiamine of the formula (II) R ' wherein R1 and R2 have the meanings indicated for formula (I), with 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid, (b) hydrogenate the product of the formula (III) thus obtained wherein R1 and R2 have the indicated meaning for formula (I), and (c) i) reacting the compound of formula (I), thus obtained, wherein R3 signifies hydrogen, with a compound of the formula (IV) R3-X (IV) wherein R3 has the meaning indicated for formula (I), and X represents a suitable leaving group, and ii) precipitate the desired salt of the compound of formula (I) thus obtained, without previously isolating the carbonylation product.
9. 9. Process according to claim 7 or 8, for the preparation of a salt of a compound of the formula (I), in which R1 represents an alkyl group d-3, R2 represents a group R21NR22, in which R21 means an alkyl group d-3, which may be substituted with a carboxy group, alkoxy d-3-carbonyl, and R22 signifies a hydrogen atom, an alkyl group d-3, a pyridinyl group optionally substituted with an alkyl group d-3 , and R3 represents a hydrogen atom, a C? -8-carbonyl alkoxy group.
10. 10. Process according to claim 9, for the preparation of a salt of the compound of the formula (I), in which R1 represents a methyl group, R2 represents a group R21NR22, wherein R21 means an ethyl group, which is substituted with an ethoxycarbonyl group, and R22 means a pyridin-2-yl group, R3 represents an n-hexyloxycarbonyl group and the conjugated ion is methanesulfonate.
11. 11. Method according to one of the preceding claims, characterized in that the condensation of stage (a) is carried out in the presence of an inert diluent and a water binding agent.
12. 12. Process according to one of the preceding claims, characterized in that the hydrogenation of step (b) or (b) i) is carried out in the presence of an inert diluent and a hydrogenation catalyst.
13. 13. Method according to one of the preceding claims, characterized in that for the preparation of 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic acid is reacted 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -aniline with an ester of 2-halogenacic acid in the presence of a weak base, and the ethyl ester of 2- [4-] acid is saponified. Obtained (1, 2,4-oxadiazol-5-on-3-yl) -phenylamino] -acetic.
14. 14. Process according to one of the preceding claims, characterized in that 4-aminophenyl-amidoxime is reacted with the preparation of 2- [4- (1, 2,4-oxadiazol-5-on-3-yl) -aniline. a dialkyl carbonate in the presence of a base.