DE19962329A1 - New substituted 2-(phenylaminomethyl)-benzimidazoles, used as thrombin inhibitors, serine protease inhibitors, antithrombotic agents and intermediates - Google Patents

Abstract

1-Alkyl-2-(4-substituted phenylaminomethyl)-benzimidazole derivatives (I) are new. 1-Alkyl-2-(4-substituted phenylaminomethyl)-benzimidazole derivatives of formula (I) and their tautomers, stereoisomers, mixtures, prodrugs, derivatives (having carboxy groups replaced by groups which are negatively charged under physiological conditions) and salts are new. Ra = 1-3C n-alkyl (optionally substituted by one or more F), which is substituted in the 1-position by (a) (i) pyrrolidinocarbonyl or 2,5-dihydropyrrolocarbonyl (both optionally substituted by 1-3C alkyl) plus (ii) NHQ1 or (b) 1-3C alkyl terminally substituted by Q2; Q1 = carboxy-(1-4C) alkyl, cyano-(1-4C) alkyl or tetrazolyl-(1-4C) alkyl; Q2 = N-(carboxy-(1-3C) alkylaminocarbonyl)-amino (optionally substituted by 1-3C alkyl on either or both amino group(s)), carboxy-(1-3C) alkoxy, N-(carboxy-(1-3C) alkyl)-amino, N-(1-3C alkyl)-N-(carboxy-(1-3C) alkyl)-amino, N-(carboxy-(1-3C) alkylsulfonyl)-amino, N-(1-3C alkyl)-N-(carboxy-(1-3C) alkylsulfonyl)-amino or tetrazolyl-(1-3C) alkyl; Rb = 1-3C alkyl; Rc = amidino, CN or 5-(Q3)-1,2,4-oxadiazol-3-yl, and Q3 = 1-3C alkyl or phenyl (optionally substituted by F, Cl, Br or 1-3C alkyl). An Independent claim is included for the preparation of (I).

Description

The present invention relates to benzimidazoles of the general formula

their tautomers, their stereoisomers, their mixtures, their Prodrugs, their derivatives, in place of a carboxy group a group negatively charged under physiological conditions and their salts, especially their physiological compatible salts with inorganic or organic acids or bases which have valuable properties.

The compounds of the above general formula I, in which R _{a is} a straight-chain C _1-3 alkyl group, in the 1-position by an optionally substituted by a C _1-3 alkyl group Pyrro lidinocarbonyl- or 2,5-Dihydropyrrolocarbonylgruppe and by a Amino group which is monosubstituted by a cyano-C _1-4 -alkyl group, and / or R _{c is} a cyano group or a 1,2,4-oxadiazole substituted in the 5-position by a C _1-3 -alkyl or phenyl group. Represents 3-yl group, wherein the phenyl substituent can be substituted by a fluorine, chlorine or bromine atom or by a C _1-3 alkyl group, are valuable intermediates for the preparation of the remaining compounds of general formula I, and the compounds the above general formula I, in which R _{c is} one of the following amidino groups, and their tautomers, their stereoisomers, their mixtures, their prodrugs, their derivatives, which instead of a carboxy group under physiological Bedin contain negatively charged group, and their salts, in particular their physiologically acceptable salts with inorganic or organic salts, and their stereoisomers have valuable pharmacological properties, in particular an anti-thrombotic effect.

The subject of the present application are thus the new ones Compounds of the above general formula I and their forth position ent. the pharmacologically active compounds ent medicines, their manufacture and use.

In the above general formula
R _{a is} a straight-chain C _1-3 alkyl group in which the hydrogen atoms may be wholly or partially replaced by fluorine atoms and in the 1-position
by a pyrrolidinocarbonyl or 2,5-dihydropyrrolo carbonyl group optionally substituted by a C _1-3 alkyl group and
by an amino group monosubstituted by a carboxy-C _1-4 -alkyl, cyano-C _1-4 -alkyl or tetrazolyl-C _1-4 -alkyl group,
or by a C _1-3 alkyl group, the terminal by an optionally each at one or both Aminstick atoms by a C _1-3 alkyl substituted N- (carboxy-C _1-3 alkylaminocarbonyl) amino group, by a carboxy -C _1-3 alkoxy, N- (carboxyC _1-3 alkyl) amino, N- (C _1-3 alkyl) -N- (carboxyC _1-3 alkyl) amino -, N- (carboxy-C _1-3 -alkylsulfonyl) -amino, N- (C _1-3 -alkyl) -N- (carboxy-C _1-3 -alkenylsulfonyl) -amino or tetrazolyl-C _{1 3-} alkyl group is substituted,
R _{b is} a C _1-3 alkyl group and
R _{c is} an amidino group, a cyano group or a substituted in the 5-position by a C _1-3 alkyl or phenyl group 1,2,4-oxadiazol-3-yl group, wherein the phenyl substituent by a fluorine, chlorine or Bromatom or substituted by a C _1-3 alkyl group.

The carboxy groups mentioned in the definition of the above-mentioned groups may also be replaced by a group convertible in vivo into a carboxy group or by a group negatively charged under physiological conditions, or
The amino and imino groups mentioned in the definition of the abovementioned radicals may also be substituted by an in vivo cleavable radical. Such groups are described, for example, in WO 98/46576 and by NM Nielson et al. in International Journal of Pharmaceutics 39, 75-85 (1987).

By way of example, a group which can be converted into a carboxy group in vivo is a hydroxymethyl group, an alcohol group esterified with an alcohol, in which the alcoholic part is preferably a C _1-6 -alkanol, a phenyl-C _1-3 -alkanol, a C _{3 -9-} cycloalkanol, wherein a C _5-8 -cycloalkanol may additionally be substituted by one or two C _1-3 -alkyl groups, a C _5-8 -cycloalkanol in which a methylene group in 3- or 4-Stel ment by a Oxygen atom or by an optionally substituted by a C _1-3 alkyl, phenyl-C _1-3 alkyl, phenyl-C _1-3 alkoxy carbonyl or C _2-6 alkanoyl substituted imino group and the Cycloalkanolteil additional may be substituted by one or two C _1-3 alkyl groups, a C _4-7 cycloalkenene, a C _3-5 alkenol, a phenyl C _3-5 alkenol, a C _3-5 allyol or phenyl -C _3-5 alkynol with the proviso that no bond to the oxygen atom emanates from a carbon atom which is a double or triple carries a C _3-8 -cycloalkyl C _1-3 alkanol, a bicycloalkanol having a total of 8 to 10 carbon atoms, which may be substituted in the bicycloalkyl additionally by one or two C _1-3 alkyl groups, a 1,3 Dihydro-3-oxo-1-isobenzfuranol or an alcohol of the formula

R _d -CO-O- (R _e CR _f ) -OH,

in that
R _{d is} a C _1-8 alkyl, C _5-7 cycloalkyl, phenyl or phenyl C _1-3 alkyl group,
R _{e is} a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl or phenyl group and
R _{f represents} a hydrogen atom or a C _1-3 alkyl group,
under a group negatively charged under physiological conditions, such as tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C _1-6 alkylsulfonylamino, phenylsulfonylamino, benzylsulfonylamino, trifluoromethylsulfonylamino, C _1-6 alkylsulfonylaminocarbonyl , Phenylsulfonylaminocarbonyl, benzylsulfonylaminocarbonyl or perfluoroC _1-6 -alkylsulfonylaminocarbonyl group
and under a residue cleavable in vivo from an imino or amino group, for example, a hydroxy group, an acyl group such as an optionally fluorine, chlorine, bromine or iodine atoms, by C _1-3 alkyl or C _1-3 Alkoxy groups mono- or di-substituted benzoyl group, wherein the substituents may be the same or different, a pyridinoyl group or a C _1-16 alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3, 3,3-trichloropropionyl or allyloxycarbonyl group, a C _1-16 -alkoxycarbonyl or C _1-16 -alkylcarbonyloxy group in which hydrogen atoms may be wholly or partly replaced by fluorine or chlorine atoms, such as the methoxycarbonyl, ethoxycarbonyl, Propoxycarbonyl, isopropoxycarbonyl, Butoxycar bonyl, tert.Butoxycarbonyl-, pentoxycarbonyl-, Hexoxycar bonyl-, octyloxycarbonyl, Nonyloxycarbonyl-, Decyloxycarbonyl, Undecyloxycarbonyl-, Dodecyloxycarbonyl-, Hexadecyloxy carbonyl-, Methylcarbo nyloxy, ethylcarbonyloxy, 2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyl oxy, butylcarbonyloxy, tert-butylcarbonyloxy, pentylcarboxynyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyl oxy, decylcarbonyloxy, undecylcarbonyloxy , Dodecylcarbonyl oxy- or Hexadecylcarbonyloxygruppe, a phenyl-C _1-6 alkoxy carbonyl group such as the Benzyloxycarbonyl-, Phenylethoxycarbo nyl- or Phenylpropoxycarbonylgruppe, a 3-amino-propionyl group, in which the amino group by C _1-6 alkyl or C _3-7 cycloalkyl groups mono- or disubstituted and the substituents may be the same or different, a C _1-3 alkylsulfonyl- C _2-4 alkoxycarbonyl, C _1-3 alkoxy-C _2-4 alkoxy-C _2-4 -alkoxycarbonyl, R _d -CO-O- (R _d CR _f) -O-CO-, C _1-6 alkyl-CO-NH- (R _g CR _h) -O-CO- or C _1-6 -alkyl-CO-O (R _g CR _h ) - (R _g CR _h ) -O-CO- group in which R _d to R _f are defined as mentioned above,
R _g and R _h , which may be identical or different, represent hydrogen atoms or C _1-3 -alkyl groups,
to understand.

Furthermore, those in the definition of the above include mentioned saturated alkyl and alkoxy moieties exceeding 2 Contain carbon atoms, including their branched isomers such as for example, the isopropyl, tert-butyl, isobutyl group etc.

Preferred compounds of general formula I mentioned above are those in which
R _b and R _c are defined as mentioned above and
R _{a is} as defined above, that a substituent represents a C _1-3 non-branched alkyl group or a 2,5-dihydropyrrolocarbonyl group optionally substituted by a C _1-3 alkyl group,
or R _{a is} an ethyl group which is in the 1-position
by a pyrrolidinocarbonyl group and
is substituted by an amino group, wherein the amino group by an ethoxycarbonylmethyl group which is substituted in the ethoxy part in the 2-position by a methoxy, dimethylamino or tolyl, by a carboxymethyl, C _3-4 alkoxycarbonylmethyl, cyclohexyloxycarbonyl methyl , 3- (C _2-3 alkoxycarbonyl) -propyl or tetrazolylmethyl group is substituted,
R _{b is} a methyl group and
R _c is an amidino group substituted by a benzoyl, methylbenzoyl, fluorobenzoyl or trifluoromethylbenzoyl group
or
R _{a is} an ethyl group in the 1-position
by a substituted in 2-position by a methyl group pyrrolidinocarbonyl group and
is substituted by an amino group, wherein the amino group is substituted by a carboxymethyl or ethoxycarbonylmethyl group,
R _{b is} a methyl group and
R _{c is} an amidino group or
R _{a is} an ethyl group in the 1-position
by a pyrrolidinocarbonyl group and
by an amino group substituted by a carboxymethyl, C _3-4 -alkoxycarbonyl-methyl or tetrazolylmethyl group or
is substituted by a methyl group, wherein the methyl group is substituted by a tetrazolyl, carboxymethoxy, ethoxycarbonylmethoxy, ethoxycarbonylmethylamino, N- (2-carboxyethyl) -N-methylamino, N- [2- (C _1-3 Alkoxycarbonyl) -ethyl] -N-methylamino, N- (carboxymethylaminocarbonyl) -N-methylamino, N- (C _1-3 -alkoxycarbonylmethylaminocarbonyl) -N-methylamino, N- (carboxymethylsulfonyl) -N- methyl-amino or N- (C _1-3 alkoxycarbonylmethylsulfonyl) -N-methyl-amino group is substituted,
R _{b is} a methyl group and
R _{c is} an amidino group,
their tautomers, their isomers and their salts.

Particularly preferred compounds of the above general formula I are the above-mentioned compounds of general formula I except
(1) 2- [4- (N-phenylcarbonyl-amidino) -phenylaminomethyl] -1-methyl-5- [1- (n-butyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole, and
(2) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (tetrazol-5-ylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole,
their tautomers, their isomers and their salts.

Very particularly preferred compounds of the above general formula I are those in which
R _{a is} an ethyl group which is in the 1-position by a substituent optionally substituted by a methyl group 2,5-dihydropyrrolocarbonyl and
by an amino group which may be substituted by a C _1-4 alkoxycarbonylC _1-4 alkyl group in which the C _2-4 alkoxy part may be terminally substituted by a methoxy, dimethylamino, phenyl or tolyl group Carboxy-C _1-4 -alkyl, cyclohexyloxycarbonyl-C _1-4 -alkyl or tetrazolyl C _1-4 -alkyl group is monosubstituted, or
by a C _1-3 alkyl group which is terminally substituted by one or more of one or both amine nitrogen atoms by a C _1-3 alkyl group-substituted N- (carboxy-C _1-3 alkylaminocarbonyl) amino or N - (C _1-3 -alkoxycarbonyl-C _1-3 -alkylaminocarbonyl) -amino group, by a carboxy-C _1-3 -alkoxy, C _1-3 -alkoxycarbonyl-C _1-3 -alkoxy-, N- (C _1-3 -alkyl) -N- (carboxy-C _1-3 -alkyl) -amino, N- (C _1-3 -alkyl) -N- (C _1-3 -alkoxycarbonyl-C _{1- 3-} alkyl) -amino, N- (C _1-3 -alkyl) -N- (carboxy-C _1-3 -alkylsulfonyl) -amino or N- (C _1-3 -alkyl) -N- (C _1-3 -alkoxycarbonyl-C _1-3 -alkylsulfonyl) -amino or tetra-zolyl-C _1-3 -alkyl group is substituted,
R _{b is} a methyl group and
R _c is an amidino group optionally substituted by a benzoyl, methylbenzoyl, fluorobenzoyl or trifluoromethylbenzoyl group
or R _{a is} an ethyl group which is in the 1-position
by a pyrrolidinocarbonyl group and
is substituted by an amino group, wherein the amino group is replaced by an ethoxycarbonylmethyl group which is substituted in the 2-position by a methoxy, dimethylamino or tolyl group by a carboxymethyl, propyl oxycarbonylmethyl, isopropyloxycarbonylmethyl, isobutyl oxycarbonylmethyl, cyclohexyloxycarbonylmethyl , 3- (C _2-3 alkoxycarbonyl) -propyl or tetrazolylmethyl group is substituted,
R _{b is} a methyl group and
R _c is an amidino group substituted by a benzoyl, methylbenzoyl, fluorobenzoyl or trifluoromethylbenzoyl group or
R _{a is} an ethyl group in the 1-position
by a pyrrolidinocarbonyl group substituted in the 2-position by a methyl group and
is substituted by an amino group, wherein the amino group is substituted by a carboxymethyl or ethoxycarbonylmethyl group,
R _{b is} a methyl group and
R _{c is} an amidino group or
R _{a is} an ethyl group in the 1-position
by a pyrrolidinocarbonyl group and
by an amino group substituted by a carboxymethyl or C _3-4 alkoxycarbonylmethyl group or
is substituted by a methyl group, wherein the methyl group by a tetrazolyl, carboxymethoxy, Ethoxycar bonylmethoxy-, Ethoxycarbonylmethylamino-, N- (2-carboxy ethyl) -N-methyl-amino, N- [2- (C _{1- 3-} alkoxycarbonyl) -ethyl] -N-methylamino, N- (carboxymethylaminocarbonyl) -N-methylamino, N- (C _1-3 alkoxycarbonylmethylaminocarbonyl) -N-methylamino, N- (carboxymethylsulfonyl ) -N-methyl-amino or N- (C _1-3 -alkoxycarbonylmethylsulfonyl) -N-methyl-amino group is substituted,
R _{b is} a methyl group and
R _{c is} an amidino group,
their tautomers, their isomers and their salts.

As particularly preferred compounds, the following may be mentioned, for example:

• 1. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycar bonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] -benz imidazole,
• 2. 2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-me thyl-5- [1- (ethoxycarbonylmethylamino) -1- (2,5-dihydropyrrolo carbonyl) -ethyl] -benzimidazole,
• 3. (R) -2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] - 1-methyl-5- [1- (isobutyloxycarbonylmethylamino) -1- (pyrroli dinocarbonyl) -ethyl] -benzimidazole,
• 4. (R) -2- [4- (N-phenylcarbonylamidino) -phenylaminomethyl] - 1-methyl-5- [1- (n-propyloxycarbonylmethylamino) -1- (pyrroli dinocarbonyl) -ethyl] -benzimidazole,
• 5. (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxy methylamino) -1 - [(R, S) -1-methyl-pyrrolidinocarbonyl] ethyl] - benzimidazole,
• 6. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethyl methylamino) -1- (2,5-dihydropyrrolocarbonyl) -ethyl] -benzimidazole and  
• 7. (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (cyclohexyloxycarbonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] benzimidazole,
  their isomers and their salts.

According to the invention, the compounds of the general Formula I according to known methods, for example according to following procedures:

a) for the preparation of a compound of the general formula I in which R _{c represents} a cyano group or a 1,2,4-oxadiazol-3-yl group substituted in the 5-position by a C _1-3 -alkyl or phenyl group, wherein the phenyl substituent may be substituted by a fluorine, chlorine or bromine atom or by a C _1-3 alkyl group:
Cyclization of an optionally in the reaction mixture th compound of the general formula

in the
R _a and R _b are defined as mentioned above,
R _c 'is a cyano group or a 5-position by a C _1-3 alkyl kyl- or phenyl substituted 1,2,4-oxadiazol-3-yl group, wherein the phenyl substituent by a fluorine, chlorine or bromine atom or may be substituted by a C _1-3 alkyl group,
Z ₁ and Z ₂ , which may be the same or different, if appropriate substituted by alkyl groups having 1 to 6 carbon atoms substituted amino, hydroxy or mercapto or
Z ₁ and Z ₂ , together represent an oxygen or sulfur atom, an optionally substituted by an alkyl group having 1 to 3 carbon atoms imino group, an alkylenedioxy or Al kylendithiogruppe each having 2 or 3 carbon atoms be interpreted.

The cyclization is conveniently carried out in a solvent or solvent mixture such as ethanol, isopropanol, glacial acetic acid, Benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylform amide, tetralin or in an excess of that for preparing the Compound of general formula II used acylation medium, z. B. in the corresponding nitrile, anhydride, Säureha halide, ester or amide, for example at temperatures between 0 and 250 ° C, but preferably at the boiling point the reaction mixture, optionally in the presence of a Kon densationsmittels such as phosphorus oxychloride, thionyl chloride, Sul furyl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulf fonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, vinegar acid, acetic anhydride, N, N-dicyclohexylcarbodiimide or optionally also in the presence of a base such as potassium ethoxide or potassium tert-butylate. The cyclization can but also without solvents and / or condensing agents be performed.

b) For the preparation of a compound of general formula I in which R _{c represents} an amidino group:
Reaction of a compound of the general formula which may be formed in the reaction mixture

in the
R _a and R _b are defined as mentioned above and
Z _{4 represents} an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthio group such as the methylthio, ethylthio, n-propylthio or benzylthio group, with ammonia or with its salts.

The reaction is conveniently carried out in a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane at temperatures between 0 and 150 ° C, preferably at Tempe between 0 and 80 ° C, with ammonia or one of its Salts such as ammonium carbonate or ammonium acetate carried out.

A compound of general formula III is obtained at For example, by implementation of a corresponding Cyanoverbin with an appropriate alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of a Acid such as hydrochloric acid or by reaction of a corresponding Amides with a trialkyloxonium salt such as triethyloxonium tetra fluoroborate in a solvent such as methylene chloride, tetra hydrofuran or dioxane at temperatures between 0 and 50 ° C, but preferably at 20 ° C, or a corresponding Ni trils with hydrogen sulfide expediently in a Lö such as pyridine or dimethylformamide and in the presence a base such as triethylamine and subsequent alkylation of the formed thioamide with a corresponding alkyl or Aralkyl.

c) For the preparation of a compound of the general formula I, in which R _a contains a carboxy group and R _c is defined as mentioned at the beginning:
Transfer of a compound of the general formula

in the
R _b and R _c are defined as mentioned above and
R _a 'has the meanings mentioned above for R _a , with the proviso that R _a contains a group which can be converted into a carboxy group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis,
by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis in a compound of general formula I in which R _a contains a carboxy group, is converted.

As a group which can be converted into a carboxy group, for example, a carboxyl group protected by a protective group, such as its functional derivatives, eg. B. their unsubsti tuierte or substituted amides, esters, thioesters, trimethyl silyl esters, orthoesters or imino esters, which are conveniently converted by means of hydrolysis in a carboxyl group,
their esters with tertiary alcohols, eg. B. the tert-butyl ester, which are conveniently converted by treatment with an acid or thermolysis in a carboxyl group, and
their esters with aralkanols, eg. As the benzyl ester, which are conveniently converted by means of hydrogenolysis in a carboxyl group, into consideration.

The hydrolysis is conveniently carried out either in the presence an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, Es  acetic acid, trichloroacetic acid, trifluoroacetic acid or their Mixtures or in the presence of a base such as lithium hydroxide, Sodium hydroxide or potassium hydroxide in a suitable Lö such as water, water / methanol, water / ethanol, what water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane at temperatures between -10 and 120 ° C, z. B. at temperatures between room temperature and the boiling point temperature of the reaction mixture, carried out.

Contains a compound of formula IV, for example, the tert-butyl or tert-butyloxycarbonyly group, these may also by treatment with an acid such as trifluoroacetic acid, Formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, Phosphoric acid or polyphosphoric acid optionally in one inert solvents such as methylene chloride, chloroform, benzene, Toluene, diethyl ether, tetrahydrofuran or dioxane, preferably at temperatures between -10 and 120 ° C, z. At temperatures between 0 and 60 ° C, or thermally optionally in an inert solvent such as methylene chloride, chloroform, Benzene, toluene, tetrahydrofuran or dioxane, and preferably in the presence of a catalytic amount of an acid such as p-To sulfonic acid, sulfuric acid, phosphoric acid or polyphos phosphoric acid, preferably at the boiling point of the used Solvent, e.g. At temperatures between 40 and 120 ° C, be split off.

For example, if a compound of Formula IV contains the Ben Zyloxy- or benzyloxycarbonyl group, so they can hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as Me ethanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate ester, dioxane or dimethylformamide, preferably at tempera between 0 and 50 ° C, z. At room temperature, and a Hydrogen pressure of 1 to 5 bar are split off.  

d) For the preparation of a compound of general formula I in which R _{c represents} an amidino group which is substituted by an in vivo cleavable radical:
Reaction of a compound of the general formula

in the
R _a and R _{b are} as defined above, with a compound of the general formula Ver

Z ₅ - R ₉ (VII),

in the
R _{9 is} the acyl radical of one of the abovementioned in vivo cleavable radicals and
Z _{5 is} a nucleophilic leaving group such as a halogen atom, e.g. As a chlorine, bromine or iodine atom, or a p-nitrophenyl group.

The reaction is preferably carried out in a solvent such as Me ethanol, methylene chloride, tetrahydrofuran, toluene, di oxane, dimethyl sulfoxide or dimethylformamide, optionally in Presence of an inorganic or a tertiary organic Base, preferably at temperatures between 20 ° C and the you Detemperatur of the solvent used, carried out.

With a compound of general formula VII in which Z _{5 represents} a nucleofuge leaving group, the reaction is preferably before in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone / water, dimethylformamide or dimethylsulphoxide optionally in the presence of a base such as sodium hydride , Potassium carbonate, potassium tert-butylate or N-ethyl-diisopropylamine at temperatures between 0 and 60 ° C., carried out.

e) For the preparation of a compound of the general formula I, in which R _{c represents} one of the abovementioned amidino groups:
Catalytic hydrogenation of a compound of the general formula

in the
R _a and R _b are defined as mentioned above and
R _{c represents} a 1,2,4-oxadiazol-3-yl group substituted in the 5-position by a C _1-3 alkyl or phenyl group, in which the phenyl substituent is replaced by a fluorine, chlorine or bromine atom or by a C _1-3 alkyl group may be substituted, and he may require subsequent hydrolysis of a compound thus obtained.

The catalytic hydrogenation is preferably in a suitable solvents such as methanol, ethanol, ethanol / water, Glacial acetic acid, ethanol / glacial acetic acid, ethyl acetate, dioxane or Dimethylformamide in the presence of a hydrogenation catalyst such as palladium / carbon, preferably at temperatures between 0 and 50 ° C, z. At room temperature, and a hydrogen pressure from 1 to 5 bar.

The optional subsequent hydrolysis becomes more convenient Example, either in the presence of an acid such as hydrochloric acid, Schwe hydrochloric acid, phosphoric acid, acetic acid, trichloroacetic acid, tri fluoroacetic acid or mixtures thereof or in the presence of a Base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol,  Water / ethanol, water / isopropanol, methanol, ethanol, what or tetrahydrofuran or water / dioxane at temperatures between between -10 and 120 ° C, z. B. at temperatures between Raumtempe temperature and the boiling temperature of the reaction mixture, carried out leads.

f) For the preparation of a compound of the general formula I in which R _{a represents} an aminoC _1-3 alkyl group in which the amino group is replaced by a carboxyC _1-4 -alkyl or tetrazolylC _1-4 -alkyl group is monosubstituted:
Alkylation of a compound of the general formula

in the
R _b and R _c are defined as mentioned above and
R _a "represents an amino C _1-3 alkyl group, with a compound of the general formula

R _a '''- Z ₇ (X)

in the
R _a '''is a carboxy C _1-4 alkyl or tetrazolyl C _1-4 alkyl group and
Z _{7 is} a nucleophilic leaving group such as a halogen atom or a sulfonic acid ester radical, eg. As a chlorine, bromine or iodine atom, or a p-nitrophenyl group.

The alkylation is conveniently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulf oxide, dimethylformamide or acetone, optionally in the presence a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate  or potassium carbonate or in the presence of a tertiary organi base such as N-ethyl-diisopropylamine or N-methyl-morpho lin, which can also serve as a solvent at the same time, or optionally in the presence of silver carbonate or Sil oxide at temperatures between -30 and 100 ° C, preferably but at temperatures between -10 and 80 ° C, carried out.

If, according to the invention, a compound of the general formula I in which R _a contains a carboxy group can subsequently be converted into the corresponding compound by esterification in which R _{a contains} an esterified carboxy group, and / or
a compound of the general formula I, in which R _{a contains} an esterified carboxy group, it may then be converted by means of transesterification into a corresponding compound in which R _a contains another esterified carboxy group, whoever and / or
a compound of the general formula I in which R _{a contains} a cyano group, then this can then be converted into a corre sponding compound in which R _a contains a tetrazolyl group.

The subsequent esterification is with a corresponding Alcohol suitably in a solvent or solution medium mixture such as methylene chloride, benzene, toluene, chloroben zol, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, before but preferably in an excess of the alcohol used, optionally in the presence of an acid such as hydrochloric acid or in Presence of a dehydrating agent, e.g. In the presence of isobutyl chloroformate, thionyl chloride, trimethyl chlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodi imide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole, triphenylphosphine / carbon tetrachloride  or triphenylphosphine / diethyl azodicarboxylate if appropriate in the presence of a base such as potassium carbonate, N-ethyldiisopropylamine or N, N-dimethylaminopyridine moderately at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, or with an ent speaking halide in a solvent such as methylene chloride chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylform amide or acetone, optionally in the presence of a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate nat or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which can also serve as a solvent at the same time, or gege optionally in the presence of silver carbonate or silver oxide Temperatures between -30 and 100 ° C, but preferably at Temperatures between -10 and 80 ° C, performed.

Subsequent transesterification is carried out with a corresponding Al kohol expediently in a solvent or solution medium mixture such as methylene chloride, benzene, toluene, chloroben zol, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, before but preferably in an excess of the alcohol used, conveniently, the presence of an acid such as hydrochloric acid or in Presence of a compound such as 2,8,9-trimethyl-1-phosphate 2,5,8,9-tetraazabicyclo [3.3.3] undecane at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, performed.

The subsequent transfer of a cyano group into a tetra zolylgruppe is preferably in a solvent such as Ben zol, toluene or dimethylformamide at temperatures between 80 and 150 ° C, preferably at 120 and 130 ° C performed. here at is conveniently the required nitrogen water substance acid during the reaction of an alkali azide, z. B. from sodium azide, in the presence of a weak acid such as ammo released. The implementation can also be done with a other salt or derivative of hydrazoic acid, before  preferably with aluminum azide or tributyltin azide, where then the optionally obtained Tetrazolver Binding from the salt contained in the reaction mixture by An acidify with a dilute acid such as 2 N hydrochloric acid or Releases 2N sulfuric acid.

In the reactions described above can be given if existing reactive groups such as carboxy, amino or Alkylamino groups during the reaction by conventional protection be protected, which after the implementation again from be split.

For example, as a protective group for a carboxy group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group and
as a protecting group for an amino or alkylamino group, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and, additionally, the phthalyl group in the amino group consideration.

The optional subsequent cleavage of a used Protective residue is, for example, hydrolytically in an aqueous trigen solvent, z. In water, isopropanol / water, Te trahydrofuran / water or dioxane / water, in the presence of a Acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as lithium hydroxide, Na triumhydroxide or potassium hydroxide or by ether cleavage, z. B. in the presence of iodotrimethylsilane, at temperatures zwi 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

The cleavage of a benzyl, methoxybenzyl or benzyloxy However, carbonyl radical is hydrogenolytically, for example, z. B. with hydrogen in the presence of a catalyst such as Pal ladium / coal in a solvent such as methanol, ethanol, Es  ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid optionally with the addition of an acid such as Hydrochloric acid at temperatures between 0 and 50 ° C, preferably but at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

The cleavage of a methoxybenzyl group can also in counter an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or Ace tonitrile / water at temperatures between 0 and 50 ° C, preferably However, at room temperature, done.

However, the cleavage of a 2,4-dimethoxybenzyl radical takes place preferably in trifluoroacetic acid in the presence of anisole.

The cleavage of a tert-butyl or tert-butyloxycarbonyl The rest is preferably carried out by treatment with an acid as trifluoroacetic acid or hydrochloric acid optionally under Use of a solvent such as methylene chloride, dioxane or ether.

The cleavage of a phthalyl radical is preferably carried out in Presence of hydrazine or a primary amine such as methyl amine, ethylamine or n-butylamine in a solvent such as Methanol, ethanol, isopropanol, toluene / water or dioxane Temperatures between 20 and 50 ° C.

The cleavage of an allyloxycarbonyl radical is carried out by Be treatment with a catalytic amount of tetrakis (triphenyl phosphine) -palladium (O) preferably in a solvent such as Tetrahydrofuran and preferably in the presence of an over shot of a base such as morpholine or 1,3-dimedone Temperatures between 0 and 100 ° C, preferably at room temp under inert gas, or by treatment with a catalytic amount of tris (triphenylphosphine) rhodium (I) - chloride in a solvent such as aqueous ethanol and Gege  if appropriate in the presence of a base such as 1,4-diazabicyclo- [2.2.2] octane at temperatures between 20 and 70 ° C.

The compounds used as starting materials of the general NEN Formulas II to X, which are partially known from the literature, is obtained by literature methods, furthermore their preparation is described in the examples.

The chemistry of the compounds of general formula II becomes for example, by Jack Robinson in J. Chem. Soc. 1941, 744, that of Benzimidazole by Katritzky and Rees in Comprehensive Heterocyclic Chemistry, Oxford, Pergamon Press, 1984, by Schaumann in Hetarene III, Methods of Organic Chemistry (Houben-Weyl), 4th edition, Verlag Thieme, Stuttgart 1993, described.

Thus, for example, a compound of general formula II is obtained by acylating a corresponding o-diamino compound with a corresponding reactive acyl derivative,
a compound of the general. Formulas III, IV, VI, VIII and IX by cyclization of a corresponding substituted Ver compound according to method a) and, if necessary, subsequently ßende conversion of a cyano compound thus obtained into the desired starting compound by known methods.

Further, the obtained compounds of the general For mel I separated into their enantiomers and / or diastereomers become.

Thus, for example, the compounds obtained the general formula I, which occur in racemates, according to known methods (see Allinger N.L. and Eliel E.L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of the general my formula I with at least 2 asymmetric carbonato due to their physicochemical differences  known methods, for. B. by chromatography and / or fractionated crystallization, into their diastereomers which, if they occur in racemic form, on closing as mentioned above in the enantiomers separated who you can.

The enantiomer separation is preferably carried out by columns separation on chiral phases or by recrystallization an optically active solvent or by reacting with one, with the racemic compound salts or derivatives like z. As esters or amides-forming optically active substance, ins particular acids and their activated derivatives or alcohols, and separating the diastereomers thus obtained Salt mixture or derivative, e.g. B. due to different Solubilities, wherein from the pure diastereomeric salts or Derivatives the free antipodes by action appropriate Funds can be released. Especially common, optically active acids are, for. B. the D and L forms of wine acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, apple acid, mandelic acid, camphorsulfonic acid, glutamic acid, Aspa ricinic acid or quinic acid. As optically active alcohol comes for example, (+) - or (-) - menthol and as optically active Acyl radical in amides, for example, the (+) - or (-) - menthyl oxycarbonylrest into consideration.

Furthermore, the compounds of the formula I can be obtained in their salts, in particular for pharmaceutical use in their physiologically acceptable salts with inorganic or organic acids are transferred. When acids come for example, hydrochloric acid, hydrobromic acid, sw felsic acid, methanesulfonic acid, phosphoric acid, fumaric acid, Bern tartaric acid, lactic acid, citric acid, tartaric acid or malein acid into consideration.

In addition, the new compounds thus obtained can be Formula I, if they contain a carboxy group, desired then in their salts with inorganic or or  ganic bases, in particular for pharmaceutical applications into their physiologically acceptable salts. The bases used here are, for example, sodium hydroxide, Ka liumhydroxid, cyclohexylamine, ethanolamine, diethanolamine and Triethanolamine into consideration.

As already mentioned, the novel compounds of the general formula I and their salts have valuable properties. Thus, the compounds of general formula I in which R _{c represents} a cyano group, valuable Zwischenpro products for the preparation of the other compounds of general formula I, and the compounds of general formula I, in which R _{c represents} one of the aforementioned amidino groups , As well as their tautomers, their stereoisomers and their physiologically acceptable salts have valuable pharmacological properties, in particular an antithrombo tical effect, which is preferably based on a thrombin or factor Xa influencing effect, for example on a thrombin-inhibiting or factor Xa-inhibiting effect, on a the aPTT-prolonging effect and an inhibitory effect on related serine proteases such. Trypsin, urokinase factor VIIa, factor IX, factor XI and factor XII.

For example, the compounds were
A = 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] benzimidazole dihydrochloride,
B = (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- (1- (carboxymethylamino) -1 - [(R, S) -2-methylpyrrolidinocarbonyl] ethyl] benzimidazole dihydrochloride and
C = (2) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] benzimidazole dihydrochloride
examined for their effect on the aPTT time extension as follows:

material

• - plasma, from human citrated blood,
• PTT Reagent, Boehringer Mannheim (524298),
• - Calcium solution (0.025 mol / l), Behring Werke, Marburg (ORH 056/57),
• - Diethyl barbiturate buffer, Behring Werke, Mar castle (ORWH 60/61),
• - Biomatic B10 coagulometer, Desaga, Wiesloch.

execution

The aPTT time was determined using a biomatic B10 coagulometer from Desaga.

The test substance was in the manufacturer's prescribed Test vessels containing 0.1 ml of human citrated plasma and 0.1 ml of PTT Reagent given. The batch was at 37 ° C for three minutes incubated. By adding 0.1 ml of calcium solution was the Coagulation reaction started. Device-related takes place with the Entering the calcium solution measuring the time to Gerin tion of the approach. As a control approaches were used in those 0.1 ml of DBA buffer was added.

According to the definition, the dose-response curve was effective substance concentration at which the aPTT Time was doubled over control.

The following table contains the found values:

substance aPTT time (ED ₂₀₀ in μM) A 12:13 B 12:12 C 12:22

The compounds according to the invention are well ver tolerable, since at therapeutic doses no toxic side In addition, the ent speaking prodrugs, for example, the compounds of Bei play 1 (6), 2, 3 (2) and 3 (5) a good oral absorption.

Due to their pharmacological properties are the new compounds and their physiologically acceptable salts for the prevention and treatment of venous and arterial thrombo diseases, such as the treatment of tie fen vein thrombosis, the prevention of reocclusions after bypass surgery or angioplasty (PT (C) A), as well as the Occlusion in peripheral arterial diseases such as lungs Embolism, the disseminated intravascular coagulation, the Prophylaxis of coronary thrombosis, prophylaxis of stroke and preventing the occlusion of shunts. Zusätz Lich, the compounds of the invention are antithromes botische assistance with a thrombolytic treatment, such as with rt-PA or streptokinase, to prevent it long-term restenosis according to PT (C) A, to prevent the Metastasis and the growth of coagulation-dependent Tumors and fibrin-dependent inflammatory processes, e.g. B. in the treatment of pulmonary fibrosis.

The necessary to achieve a corresponding effect Dosage is expediently when administered intravenously 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg, and in the case of oral Administration 0.1 to 50 mg / kg, preferably 0.3 to 30 mg / kg, respectively 1 to 4 times a day. For this purpose, the invention can be forth Asked compounds of formula I, optionally in Kom Combination with other active substances, together with one or several inert customary carriers and / or dilution average, z. B. with corn starch, lactose, cane sugar, micro crystalline cellulose, magnesium stearate, polyvinylpyrrolidone, Citric acid, tartaric acid, water, water / ethanol, water / Gly cerin, water / sorbitol, water / polyethylene glycol, propylene glycol  col, cetylstearyl alcohol, carboxymethylcellulose or fat containing substances such as hard fat or their suitable Ge in common galenical preparations such as tablets, Dragees, capsules, powders, suspensions or suppositories einar BEITEN.

The following examples are intended to illustrate the invention in more detail purify:

example 1 (R) -2- [4- [N- (4-methyl phenylcarbonyl) -amidino] -phenylaminome thyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrroli dinonarbonyl) -ethyl] -benzimidazole a. (R) -5- (4-chloro-3-nitro-phenyl) -5-methyl-imidazolidine- 2,4-dione

To 50 ml of fuming nitric acid are added portionwise at -25 to -35 ° C 10.0 g (4.45 mmol) of (R) -5- (4-chloro-phenyl) -5-methyl-imidazolidine-2,4-dione. After 45 minutes at -25 to -20 ° C, the reaction mixture is poured into ice water ge. The crystalline product is filtered off with suction, washed with water and dried.
Yield: 10.5 g (100% of theory),
Melting point: 173-178 ° C
R _f value: 0.30 (silica gel, cyclohexane / ethyl acetate = 1: 1)

b. (R) -2-amino-2- (4-chloro-3-nitro-phenyl) -propionic acid

10.5 g (0.044 mol) of (R) -5- (4-chloro-3-nitro-phenyl) -5-methyl-imidazolidine-2,4-dione are refluxed in 200 ml of dioxane and 700 ml of 6N hydrochloric acid for 5 days heated. The solution is evaporated, the residue taken up in water and extracted with ethyl acetate. The aqueous phase is evaporated, treated with toluene and evaporated to dryness. The residue is triturated with ether, filtered off with suction and dried.
Yield: 6.8 g (63% of theory),
R _f value: 0.24 (Reversed phase RP8, 5% saline / methanol = 1: 1)

c. (R) -2-tert.Butyloxycarbonylamino-2- (4-chloro-3-nitro-phe nyl) propanoic acid

72.5 g (0.296 mol) of (R) -2-amino-2- (4-chloro-3-nitrophenyl) propionic acid are dissolved in 850 ml of dioxane and 200 ml of water and after addition of 108.7 ml (0.78 mol) of triethylamine and 136 g (0.623 mol) of di-tert-butyl dicarbonate stirred for 18 hours at room temperature. After addition of 800 ml of 1 N sodium hydroxide solution, the solution is stirred for 30 minutes and then extracted 3 times with 500 ml of ether. The aqueous phase is adjusted to pH 7 with 1 N hydrochloric acid and then adjusted to pH 4 with 5% citric acid. After 4-fold extraction with 500 ml of ethyl acetate who washed the combined organic phases with water, filtered with suction and evaporated by evaporation over magnesium sulfate.
Yield: 86.8 g (85% of theory),
R _f value: 0.3 (silica gel, methylene chloride / methanol = 4: 1 + 1% ammonia)
C ₁₄ H ₁₇ ClN ₂ O ₆ (344. 7)
Mass spectrum: (MH) ^- = 343

d. (R) -2-tert.Butyloxycarbonylamino-2- (4-methylamino-3-nitro- phenyl) propionic acid

96 g (0.278 mol) of (R) -2-tert-butyloxycarbonylamino-2- (4-chloro-3-nitro-phenyl) -propionic acid and 440 ml of methylamine solution (40% solution in water) are left in a pressure vessel for seven hours Heated to 90 ° C. After cooling, the reaction solution is adjusted to pH 3.5 with ice cooling by addition of glacial acetic acid and extracted with ethyl acetate. After evaporation of the solvent, the remaining residue is washed with ether and dried.
Yield: 70 g (74% of theory),
R _f value: 0.30 (silica gel, methylene chloride / ethanol = 19: 1 + 1% glacial acetic acid)
C ₁₅ H ₂₁ N ₃ O ₆ (339.3)
Mass spectrum: (MH) ^- = 338

e. (R) -2- (4-Methylamino-3-nitro-phenyl) -2-tert.butyloxycar carbonylamino-1-pyrrolidino-propanone

50 g (0.147 mol) of (R) -2-tert-butyloxycarbonylamino-2- (4-methylamino-3-nitro-phenyl) -propionic acid are dissolved in 275 ml of dimethylformamide and after addition of 47.5 g (0.147 mol) O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, 24.5 g (0.334 mol) pyrrolidine and 30 ml (0.273 mol) N-methylmorpholine stirred for 20 hours at room temperature. The solution is poured onto ice-water and acidified with citric acid (pH 5-6). The precipitate formed is filtered off with suction, washed with water and dried.
Yield: 45.5 g (79% of theory),
R _f value: 0.6 (silica gel, petroleum ether / ethyl acetate = 1: 1)

f. (R) -2- {4-methylamino-3-amino-phenyl) -2-tert.butyloxycar carbonylamino-1-pyrrolidino-propanone

25.5 g (65 mmol) of (R) -2- (4-methylamino-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1-pyrrolidino-propanone are dissolved in 650 ml of methanol and, after addition of 4.0 g of palladium Activated carbon (20%) hydrogenated at room temperature for 2 hours. At closing, the catalyst is filtered off and evaporated.
Yield: 21.4 g (91% of theory),
R _f value: 0.31 {silica gel; Ethyl acetate + 1% ammonia)

G. (R) -2- [4-methylamino-3- (4-cyanophenylaminomethylcarbonyl amino) phenyl] -2-tert.butyloxycarbonylamino-1-pyrrolidino propanone

Prepared analogously to Example 1e from (R) -2- (4-methylamino-3-amino-phenyl) -2-tert. butyloxycarbonylamino-1-pyrrolidinopropanone, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and N-methylmorpholine in dimethylformamide.
Yield: 100% of theory,
R _f value: 0.47 (silica gel, ethyl acetate)

H. (R) -2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (N-tert- butyloxycarbonylamino) -1- (pyrrolidinocarbonyl) -ethyl] benz imidazole

47.7 g (0.042 mol) of (R) -2- [4-methylamino-3- (4-cyanophenylamino-methylcarbonylamino) -phenyl] -2-tert-butyloxycarbonylamino-1-pyrrolidino-propanone are refluxed in 300 ml of glacial acetic acid for 2 hours , The reaction mixture is added to water on ice and treated with conc. Brought ammonia to pH 8. The precipitate formed is filtered off, washed with water and dried.
Yield: 46 g (100% of theory),
R _f value: 0.3 (silica gel, ethyl acetate + 1% ammonia)

i. (R) -2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1-amino- 1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

25.1 g (50 mmol) of (R) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (N-tert -butyloxycarbonylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole are dissolved in 500 ml of 6 Hydrochloric acid at 35 ° C ge dissolves and stirred for one hour at this temperature. The solution is mixed with ice, made alkaline with ammonia and extracted with ethyl acetate. The combined organic extracts are dried and evaporated.
Yield: 17.8 g (88% of theory),
R _f value: 0.5 (silica gel, methylene chloride / ethanol = 4: 1 + 1% ammonia)

k. (R) -2- (4-Cyanophenylaminomethyl) -1-methyl-5- (1-ethoxycar bonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

4.2 g (10.44 mmol) of (R) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1-amino-1- (pyrrolidinocarbonyl) ethyl] benzimidazole are dissolved in 100 ml of acetone and treated with 2.3 g ( 16.65 mmol) potassium carbonate and 2.25 ml (20.2 mmol) of ethyl bromoacetate. The suspension is heated to 60 ° C for 5 hours. After cooling, the reaction mixture is stirred into 400 ml of ice water, the precipitate formed is filtered off, washed with water and dried. The crude product is chromatographed on silica gel, eluting with methylene chloride / ethanol (19: 1 and 9: 1). The uniform fractions are united and evaporated.
Yield: 3.1 g (61% of theory),
R _f value: 0.4 (silica gel, ethyl acetate / ethanol = 9: 1)

l. (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (1-ethoxy carbonylethylamino) -1- (pyrrolidinocarbonyl) -ethyl-benzimida zole hydrochloride

6.8 g (1.3.8 mmol) of (R) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1-ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole are dissolved in 400 ml of saturated ethanolic hydrochloric acid and stirred at room temperature for 23 hours. The solvent is distilled off, the residue is dissolved in 200 ml of absolute ethanol and treated with 20 g (0.21 mol) of ammonium carbonate. After 20 hours at room temperature, 100 ml of ethanol are added and after stirring for a further 10 hours at room temperature, filtered and evaporated to dryness. The residue is stirred in 200 ml of acetone, filtered off, washed with ether and dried.
Yield: 7.6 g (100% of theory),
R _f value: 0.61 (reversed phase RPB; 5% sodium chloride solution / methanol = 3: 2)
C ₂₇ H ₃₆ N ₇ O ₃ × HCl (505.64 / 542.09)
Mass spectrum: (M + H) ⁺ = 506

m. (R) -2- [4- [N- (4-methylphenylcarbonyl) -amidino] -phenylamino methyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrroli dinocarbonyl) -ethyl] -benzimidazole

A suspension of 0.7 g (1.2 mmol) of (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole dihydrochloride in 25 ml of methylene chloride is reacted with 4.0 ml (28 mmol) of triethylamine and 0.8 g (3.0 mmol) of 4-methylbenzoic acid 4-nitrophenyl ester and heated to 50 ° C. for 3.5 hours to give a clear solution. After cooling, it is washed with sodium bicarbonate solution, brine and water, dried over magnesium sulfate and evaporated. The crude product is purified on silica gel, eluting with ethyl acetate / ethanol (50: 1 and 9: 1). The uniform fractions are combined, evaporated, triturated with ether, filtered off with suction and dried.
Amount: 0.5 g (66% of theory),
R _f value: 0.50 (silica gel, ethyl acetate / ethanol = 9: 1)
C ₃₆ H ₄₁ N ₇ O ₄ (623.75)
Mass Spectrum:
(M + H) ⁺ = 624
(M + Na) ⁺ = 646
(M - H) ^- = 622

Analogously to Example 1, the following compounds are obtained:

(1) (R) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (isoproxyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole acetate
Yield: 69% of theory,
R _f value: 0.2 (silica gel, methylene chloride / ethanol = 7: 3 + 1% glacial acetic acid)
C ₂₈ H ₃₇ N ₇ O ₃ · CH ₃ COOH (519.65 / 579.70)
Mass Spectrum:
(M + H) ⁺ = 520
(M - H) ^- = 518

(2) (R) -2- [4- [N- (4-Fluoro-phenylcarbonyl) amidino] -phenylamino methyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl ] benzimidazole
Yield: 40% of theory,
R _f value: 0.4 (silica gel, ethyl acetate / ethanol = 9: 1 + 1% ammonia)
C ₃₄ H ₃₈ FN ₇ O ₄ (627.72)
Mass Spectrum:
(M + H) ⁺ = 628
(M + Na) ⁺ = 650
(M - H) ^- = 626

(3) (R) -2- [4- [N- (4-trifluoromethylphenylcarbonyl) amidino] phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] - benzimidazole
Yield: 47% of theory,
R _f value: 0.53 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 0.9: 0.1)
C ₃₅ H ₃₈ F ₃ N ₇ O ₄ (677.73)
Mass Spectrum:
(M + H) ⁺ = 678
(M + Na) ⁺ = 700
(M - H) ^- = 676

(4) (R) -2- [4- (N-phenylcarbonylamidino) -phenylaminomethyl] - 1-methyl-5- [1- (tetrazol-5-yl-methylamino) -1- (pyrrolidinocar carbonyl) -ethyl] -benzimidazole

(5) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- (1- (ethoxycarbonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] -benzimidazole dihydrochloride
Yield: 94% of theory,
R _f value: 0.2 (reversed phase RP8; 5% saline / methanol = 2: 3)
C ₂₇ H ₃₃ N ₇ O ₃ × 2 HCl (503.6 / 576.51)
Mass Spectrum:
(M + H) ⁺ = 504
(M - H + HCl) ^- = 538/540 (Cl)

(6) 2- (4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (2,5-dihydropyrrolo-carbonyl) -ethyl] -benzimidazole
Yield: 71% of theory,
R _f value: 0.3 (silica gel, ethyl acetate / ethanol = 9: 1)
C ₃₄ H ₃₇ N ₇ O ₄ (607.72)
Mass Spectrum:
(M + H) ⁺ = 608
(M + Na) ⁺ = 630
(M - H) ^- = 606

(7) (R) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1 - [(R, S) -1-methyl-pyrrolidinocarbonyl] -ethyl] -benzimidazole dihydrochloride (mixture of diastereomers)
Yield: 88% of theory,
R _f value: 0.3 (Reversed Phase RP8; 5% saline / methanol = 3: 2)
C ₂₈ H ₃₇ N ₇ O ₃ × 2 HCl (519.65 / 592.56)
Mass Spectrum:
(M + H) ⁺ = 520
(M + Cl) ^- = 554/6 (CI)

(8) (R) -2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (3-ethoxycarbonyl-propylamino) -1- (pyrrolidino carbonyl) ethyl] benzimidazole
Yield: 19% of theory,
R _f value: 0.44 (silica gel, methylene chloride / methanol = 4: 1 + 1% glacial acetic acid)
C ₃₆ H ₄₃ N ₇ O ₄ (637.79)
Mass Spectrum:
(M + H) ⁺ = 638
(M - H) ^- = 636

(9) (R) -2- [4- (Nn-Hexyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (n-propyloxycarbonylmethylamino) -1- (pyrrolidino carbonyl) ethyl] benzimidazole
Yield: 70% of theory,
R _f value: 0.37 (silica gel, ethyl acetate / ethanol = 9: 1)
C ₃₅ H ₄₉ N ₇ O ₅ (647.82)
Mass Spectrum:
(M + Na) ⁺ = 670
(M - H) ^- = 646

Example 2 (R) -2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-me thyl-5- [1- (n-butyloxycarbonylmethylamino) -1- (pyrrolidino carbonnyl) -ethyl] -benzimidazole

A solution of 0.3 g (0.53 mmol) of (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole in 5 ml of n-butanol is treated with 0.1 g (0.46 mmol) of 2,8,9-trimethyl-1-phospha-2,5,8,9-tetraazabicyclo [3.3.3] undecane and stirred for 1 hour at room temperature , The reaction mixture is purified on silica gel, using ethyl acetate / ethanol / conc. Ammonia (50: 0.95: 0.05 and 20: 0.95: 0.05). The uniform fractions are combined and evaporated.
Yield: 0.19 g (57% of theory,
R _f value: 0.45 (silica gel, ethyl acetate / ethanol = 9: 1 + 1% ammonia)
C ₃₆ H ₄₃ N ₇ O ₄ (637.78)
Mass Spectrum:
(M + H) ⁺ = 638
(M + Na) ⁺ = 660
(M - H) ^- = 636

Analogously to Example 2, the following compounds are obtained:

(1) (R) -2- [4- (N-Phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (isobutyloxycarbonylmethylamino) -1- (pyrrolinedinocarbonyl) ethyl] benzimidazole
Yield: 16% of theory,
R _f value: 0.48 (silica gel, ethyl acetate / ethanol = 9: 1 + 1% ammonia)
C ₃₆ H ₄₃ N ₇ O ₄ (637.78)
Mass Spectrum:
(M + H) ⁺ = 638
(M + Na) ⁺ = 660
(M - H) ^- = 636

(2) (R) -2- [4- (N-Phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (2-methoxyethyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole
Yield: 43% of theory,
R _f value: 0.31 (silica gel, ethyl acetate / ethanol = 9: 1 + 1% ammonia)
C ₃₅ H ₄₂ N ₇ O ₅ (639.76)
Mass Spectrum:
(M + H) ⁺ = 640
(M - H) ^- = 638

(3) (R) -2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (2-dimethylamino-ethyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole
Yield 23% of theory,
R _f value: 0.26 (silica gel, methylene chloride / methanol / ammonia = 9: 0.9: 0.1)
C ₃₆ H ₄₄ N ₈ O ₄ (652.8)
Mass Spectrum:
(M + H) ⁺ = 651
(M - H) ^- = 653

(4) (R) -2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (2- (2-methylphenyl) -ethyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl ] benzimidazole
Yield: 23% of theory,
R _f value: 0.52 (silica gel, ethyl acetate / ethanol / ammonia = 9: 0.95: 0.05)
C ₄₁ H ₄₅ N ₇ O ₄ (699.86)
Mass Spectrum:
(M + H) ⁺ = 700
(M + Na) ⁺ = 722
(M - H) ^- = 698

(5) (R) -2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (cyclohexyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethylbenzimidazole
Yield: 34% of theory,
1% value: 0.49 (silica gel, ethyl acetate / ethanol = 9: 1 + 1% ammonia)
C ₃₈ H ₄₇ N ₇ O ₄ (663.83)
Mass Spectrum:
(M + H) ⁺ = 664
(M + Na) ⁺ = 686
(M - H) ^- = 662

Example 3 (R) -2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-me ethyl 5- [1- (isopropyloxycarbonylmethylamino) -1- (2, 5-dihydro pyrrolocarbonyl) -ethyl] -benzimidazole

To a solution of 0.5 g (0.82 mmol) of (R) -2- [4- (N-phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (2,5-) dihydropyrrolocarbonyl) -ethyl] -benz imidazole in 12.3 ml of isopropanol are added 2.1 ml of conc. Sulfuric acid added dropwise. After 4 hours at 85 ° C, the solution is cooled and poured onto 250 ml of ice water. By adding conc. Ammonia, the pH is adjusted to 8.5. The precipitate formed is filtered off, dried and purified on silica gel, eluting with methylene chloride + 2% methanol + 0.01% ammonia. The uniform fractions are combined and evaporated, the residue is triturated with ether, filtered off and dried.
Yield: 0.19 g (37% of theory),
R _f value: 0.46 (silica gel, ethyl acetate / ethanol = 9: 1 + 1% ammonia)
C ₃₅ H ₃₉ N ₇ O ₄ (621.75)
Mass Spectrum:
(M + H) ⁺ = 622
(M + Na) ⁺ = 644
(M - H) ^- = 620

Analogously to Example 3, the following compounds are obtained:

(1) (R) -2- [4- (N-phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (n-propyloxycarbonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) -ethyl] - benzimidazole
Yield: 33% of theory,
R _f value: 0.46 (silica gel, ethyl acetate / ethanol = 9: 1 + 1% ammonia)
C ₃₅ H ₃₉ N ₇ O ₄ (621.75)
Mass Spectrum:
(M + H) ⁺ = 622
(M + Na) ⁺ = 644
(M - H) ^- = 620

(2) (R) -2- [4- (N-Phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (n-propyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole
Yield: 36% of theory,
R _f value: 0.45 (silica gel, ethyl acetate / ethanol = 9: 1 + 1% ammonia)
C ₃₅ H ₄₁ N ₇ O ₄ (623.76)
Mass Spectrum:
(M + H) ⁺ = 624
(M + Na) ⁺ = 646
(M - H) ^- = 622

(3) (R) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (n -butyl oxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole dihydrochloride
Yield: 8% of theory,
R _f value: 0.44 (silica gel, methylene chloride / methanol = 4: 1 + 1% ammonia)
C ₂₉ H ₃₉ N ₇ O ₃ × 2 HCl (533.69 / 606.6)
Mass Spectrum:
(M + H ⁺ = 534
(M - H) ^- = 532

(4) (R) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (n-pro-p-xyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole sulfate
Yield: 7% of theory,
R _f value: 0.36 (silica gel, methylene chloride / methanol = 4: 1 + 1% ammonia)
C ₂₈ H ₃₇ N ₇ O ₃ × H ₂ SO ₄ (519.65 / 617.7)
Mass Spectrum:
(M + H) ⁺ = 520

(5) (R) -2- [4- (N-Phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (cyclohexyloxycarbonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] benzimidazole
Yield: 22% of theory,
R _f value: 0.60 (silica gel, ethyl acetate / ethanol = 9: 1 + 1% ammonia)
C ₃₈ H ₄₃ N ₇ O ₄ (661.81)
Mass Spectrum:
(M + H) ⁺ = 662
(M + Na) ⁺ = 684
(M - H) ^- 660

(6) (R) -2- [4- (N-phenylcarboriylamidino) -phenylaminomethyl] - 1-methyl-5- [1- (3- (isopropyloxycarbonyl) propylamino) -1- (pyr rolidinocarbonyl) -ethyl] -benzimidazole

(7) (R) -2- [4- (N-phenylcarbonylamidino) -phenylaminomethyl] - 1-methyl-5- [1- (3- (n-propyloxycarbonyl) propylamino) -1- (pyr rolidinocarbonyl) -ethyl] -benzimidazole  

Example 4 (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (tetrazol- 5-yl-methylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole a. 4 (5-methyl-1,2,4-oxadiazol-3-yl) phenylamino-acetic acid ethyl ester

Prepared analogously to Example 1k from 4- (5-methyl-1,2,4-oxadia zol-3-yl) -aniline and ethyl bromoacetate in N-ethyl-di isopropylamine.
Yield: 78% of theory,
R _f value: 0.60 (silica gel, ethyl acetate / petroleum ether = 1: 1)

b. 4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl-N-tert.butyloxy- carbonylamino-acetic acid

Prepared analogously to Example 1c of 4- (5-methyl-1,2,4-oxadia-zol-3-yl) -phenylamino-acetic acid ethyl ester and di-tert-butyl dicarbonate / N-ethyl-diisopropylamine in dioxane.
Yield: 63% of theory,
R _f value: 0.48 (silica gel, ethyl acetate / cyclohexane = 1: 2)

c. 4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl-N-tert.butyloxy- carbonyl-aminoacetic

A solution of 3.5 g (9.7 mmol) of ethyl 4- (5-methyl-1,2,4-oxadiazol-3-yl) -phenyl-N-tert-butyloxycarbonylaminoacetate in 10 ml of tetrahydrofuran and 4 ml of methanol is added 9.7 ml 1 N sodium hydroxide solution (9.7 mmol) and stirred for 3 hours at room temperature. The reaction mixture is evaporated to half its volume and treated with water. The pH is adjusted to 4-5 by addition of glacial acetic acid, the precipitate formed is filtered off, washed with water and dried.
Yield: 2.8 g (87% of theory),
R _f value: 0.5 (Reversed Phase RP8; 5% saline / methanol = 1: 3)

d. (R) -2- [4- (5-methyl-1,2,4-oxadiazol-3-yl) -phenyl-N-t-Bu tyloxycarbonyl-aminomethyl] -1-methyl-5- [2-tert.butyloxycar carbonylamino-1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Prepared analogously to Example 1g / h from (R) -2- (4-methylamino-3-amino-phenyl) -2-tert-butyloxycarbonylamino-1-pyrrolidino-propanone, 4- (5-methyl-1,2,4-oxadiazole 3-yl) -phenyl-N-tert-butylbenzyloxycarbonyl-aminoacetic acid and carbonyldiimidazole in Te trahydrofuran and subsequent treatment with glacial acetic acid.
Yield: 47% of theory,
R _f value: 0.46 (silica gel, ethyl acetate)

e. (R) -2- [4- (5-methyl-1,2,4-oxadiazol-3-yl) -phenylaminome thyl] -1-methyl-5- [1-amino-1- (pyrrolidinocarbonyl) -ethyl] - benzimidazole

Prepared analogously to Example 1i from (R) -2- [4- (5-methyl-1,2,4-oxadiazol-3-yl) -phenyl-N-tert-butyloxycarbonyl-aminomethyl] -1-methyl-5- [ 2-tert-butyloxycarbonyl-amino-1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole and 6N hydrochloric acid.
Yield: 91% of theory,
R _f value: 0.44 (silica gel, methylene chloride / methanol / ammonia = 9: 0.9: 0.1)

f. (R) -2- [4- (5-methyl-1,2,4-oxadiazol-3-yl) -phenylaminome thyl] -1-methyl-5- [1-cyanomethylamino-1- (pyrrolidinocarbonyl) - ethyl] benzimidazole

Prepared analogously to Example 1k from (R) -2- [4- (5-methyl-1,2,4-oxadiazol-3-yl) -phenylaminomethyl] -1-methyl-5- [1-amino-1- (pyr rolidinocarbonyl) ethyl] benzimidazole and bromoacetonitrile / potassium carbonate in acetone.
Yield: 72% of theory,
R _f value: 0.54 (silica gel, ethyl acetate / ethanol = 9: 1 + 1% ammonia)
C ₂₇ H ₃₀ N ₈ O ₂ (498.59)
Mass Spectrum:
(M + H) ⁺ = 499
(M - H) ^- = 497
(M + Na) ⁺ = 521

G. (R) -2- [4- (5-methyl-1,2,4-oxadiazol-3-yl) -phenylaminome thyl] -1-methyl-5- [1- (tetrazol-5-yl-methylamino) -1- (pyrroli dinocarbonyl-ethyl) -benzoimidazol

1.1 g (2.2 mmol) of (R) -2- (4- (5-methyl-1,2,4-oxadiazol-3-yl) -phenylaminomethyl] -1-methyl-5- [1-cyanomethylamino-1-one pyrrolinedinocarbonyl) -ethyl] -benzimidazole are suspended in 20 ml of toluene and 60 ml of dioxane and treated with 2.2 g (6.6 mmol) of tributyltin azide The reaction mixture is heated for 6 hours at 130 ° C. After evaporation of the solvent, the residue is treated with petroleum ether triturated, filtered, washed with petroleum ether and dried The crude product is purified on silica gel, eluting with methylene chloride / methanol 20: 1 and 9: 1. The unitary fractions are combined and evaporated.
Yield: 0.7 g (59% of theory)
R _f value: 0.33 (silica gel, methylene chloride (methanol = 9: 1)
C ₂₇ H ₃₁ N ₁₁ O ₂ (541.6)
Mass Spectrum:
(M - H) ^- = 540
(M + Na) ⁺ = 564

H. (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (tetrazole) 5-yl-methylamino-1- (pyrrolidinocarbonyl) -ethyl) -benzimidazole

Prepared analogously to Example 1h from (R) -2- [4- (5-methyl-1,2,4-oxadiazol-3-yl) -phenylaminomethyl] -1-methyl-5- (1- (tetrazol-5-yl -methylamino) -1- (pyrrolidinocarbonyl) -ethyl) -benzimidazole and hydrogen / palladium (20% on charcoal) in ethanol / ice.
Yield: 63% of theory,
R _f value: 0.35 (reversed phase RP8; 5% saline / methanol = 4: 3)
C ₂₅ H ₃₁ N ₁₁ O (501.6)
Mass Spectrum:
(M + H) ⁺ = 502
(M - H) ^- = 500

Example 5 2- (4-amidinophenylaminomethyl) -1-methyl-5- (1- (ethoxycarbonyl methyloxymethyl) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole acetate a. 2- (4-chloro-phenyl) -3-hydroxy-2-methyl-propionsäuremethyl ester

35 ml of a 1.6 molar solution of n-butyllithium in hexane (61 mmol) are added dropwise at -78 ° C. to a solution of 8.1 ml of diisopropylamine (85 mmol) in 20 ml of tetrahydrofuran. At closing, a solution of 10.0 g (50 mmol) of 2- (4-chloro-phenyl) -propionate in 30 ml of tetrahydrofuran is added dropwise at -78 ° C. Gaseous formaldehyde is introduced into the reaction mixture at -20 ° C. for 30 minutes. After addition of 5% citric acid and glacial acetic acid is ex tracted with ethyl acetate. The organic phases are washed with 1 N sulfuric acid, water, saturated sodium bicarbonate solution and brine and dried over magnesium sulfate. The crude product is purified on silica gel, eluting with cyclohexane / ethyl acetate (19: 1, 9: 1, 4: 1, 1: 1 and 0: 1). The uniform fractions are combined and evaporated.
Yield: 9.7 g of yellow oil (84% of theory),
R _f value: 0.25 (silica gel, petroleum ether / ethyl acetate = 4: 1)

b. 2- (4-chloro-phenyl) -3-hydroxy-2-methyl-propionic acid

Prepared analogously to Example 8 from 2- (4-chloro-phenyl) -3-hydroxy-2-methyl-propionate and sodium hydroxide in ethanol.
Yield: 83% of theory,
R _f value: 0.55 (silica gel, ethyl acetate / cyclohexane = 2: 1 + 1% glacial acetic acid)

c. 2- (4-chloro-3-nitro-phenyl) -2-methyl-3-nitrooxy-propionic acid

Prepared analogously to Example 1a from 2- (4-chloro-phenyl) -3-hydroxy-2-methyl-propionic acid and nitric acid.
Yield: 90% of theory,
Melting point: 129-132 ° C
C ₁₀ H ₉ ClN ₂ O ₇ , (304.64)

d. 2- (4-chloro-3-nitro-phenyl) -2-methyl-3-hydroxy-propionic acid

Prepared analogously to Example 1i from 2- (4-chloro-3-nitro-phenyl) -3-nitrooxy-2-methyl-propionic acid and 6 N hydrochloric acid in dioxane.
Yield: 98% of theory,
C ₁₀ H ₁₀ ClNO ₅ (259.65)
Mass Spectrum:
(M - H) ^- 258/60 (Cl)
(2M - H) ^- = 517/9 (Cl ₂ )

e. 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-hy droxy-propionic acid

Prepared analogously to Example 1e from 2- (4-chloro-3-nitro-phenyl) -3-hydroxy-2-methyl-propionic acid and N-methyl-benzylamine.
Yield: 81% of theory,
C ₁₈ H ₂ OClN ₂ O ₅ (344.37)
Mass Spectrum:
M ⁺ = 344

f. 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-hy droxy-1-pyrrolidine-1-propane-1-one

Prepared analogously to Example 1e from 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -3-hydroxy-2-methyl-propionic acid and pyrrolidine.
Yield: 96% of theory,
C ₂₂ H ₂₇ N ₃ O ₄ (397.48)
Mass Spectrum:
M ⁺ = 398
(M + Na) ⁺ = 420

G. 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-eth oxycarbonylmethyloxy-1-pyrrolidino-propane-1-one

A solution of 8.0 g (20 mmol) of 2- [4- (N-benzylmethylamino) -3-nitro-phenyl] -2-methyl-3-hydroxy-1-pyrrolidino-propan-1-one and 5 ml ( 48 mmol) Diazoessigester in 50 ml of methylene chloride is added at room temperature with 2.0 ml boron trifluoride-diethyl ether complex (16 mmol) and heated for 14 hours under reflux he. After cooling, the reaction solution is stirred into ice water and the organic phase separated. The aqueous phase is extracted three times with methylene chloride, the combined organic phases are washed with brine, dried over sodium sulphate and evaporated. The residue is dissolved in ethyl acetate and purified on silica gel, initially with petroleum ether, then extracted with petroleum ether / ethyl acetate (1: 1). The uniform fractions are combined and evaporated.
Yield: 2.5 g (26% of theory),
R _f value: 0.6 (silica gel, ethyl acetate)
C ₂₆ H ₃₃ N ₃ O ₆ (483.57)
Mass spectrum: (M + H) ⁺ = 484

H. 2- (4-methylamino-3-amino-phenyl) -2-methyl-3-ethoxycarbonyl methyloxy-1-pyrrolidino-propane-1-one

Prepared analogously to Example 1f from 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-ethoxymethyloxy-1-pyrrolidin-1-yl-propan-1-one and hydrogen / Palladium on activated carbon.
Yield: 81% of theory,
R _f value: 0.40 (silica gel, methylene chloride / ethanol = 19: 1)

i. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonyl methyloxymethyl) -1- (pyrrolidinocarbonyl) -ethyl-benzimidazole

Prepared analogously to Example 1g / h from 2- (4-methylamino-3-amino-phenyl) -2-methyl-3-ethoxycarbonylmethyloxy-1-pyrrolidino-pro pan-1-one, 4-cyano-phenylglycine / O- (benzotriazole) 1-yl) - N, N, N ', N'-tetramethyluronium tetrafluoroborate and subsequent treatment with glacial acetic acid.
Yield: 77% of theory,
R _f value: 0.40 (silica gel, methylene chloride / ethanol = 19: 1)
C ₂₈ H ₃₃ N ₅ O ₄ (503.61)
Mass Spectrum:
(M + H) ⁺ = 504
(M + Na) ⁺ = 526

k. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycar bonylmethyloxymethyl) -1- (pyrrolidinocarbonyl) -ethyl] benz imidazole-acetate

Prepared analogously to Example 11 from 2- (4-cyanophenylamino methyl) -1-methyl-5- [1- (ethoxycarbonylmethyloxymethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole and hydrochloric acid / ammonium carbonate in ethanol.
Yield: 64% of theory,
R _f value: 0.25 (silica gel, methylene chloride / ethanol = 4: 1 + 1% glacial acetic acid)
C ₂₈ H ₃₆ N ₆ O ₄ · CH ₃ COOH (520.63 / 580.69)
Mass spectrum: (M + H) ⁺ = 521

Example 6 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (1H-tetrazol- 5-yl-methyl) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole hydrochloride a. 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-me thansulfonyloxy-1-pyrrolidino-propane-1-one

A solution of 1.2 g (3.0 mmol) of 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-hydroxy-1-pyrrolidino-propan-1-one in 20 ml of tetrahydrofuran 1.3 ml (9.3 mmol) of triethylamine are added at room temperature. Subsequently, 0.27 ml (3.5 mmol) of methanesulfonyl chloride are added dropwise at 2-5 ° C. After 2 hours at room temperature, the precipitate formed is filtered off with suction and the filtrate is evaporated. The crude product is reacted further without purification.
Yield: 1.4 g (98% of theory).

b. 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-cy ano-1-pyrrolidin-propane-1-one

A solution of 8.2 g (17 mmol) of 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-methanesulfonyloxy-1-pyrrolidino-propan-1-one in 125 ml of dimethylformamide with 1.8 g (27 mmol) of potassium cyanide and heated for 2 hours at 100 ° C he. After cooling, the reaction solution is stirred into ice-water and extracted 3 × with ethyl acetate. The combined organic phases are washed with brine and dried over sodium sulfate. The crude product is dissolved in methylene chloride and purified on silica gel, eluting initially with methylene chloride, later with methylene chloride / ethanol (50: 1 and 25: 1). The uniform fractions are combined and evaporated.
Yield: 5.0 g (72% of theory)
R _f value: 0.45 (silica gel, methylene chloride / ethanol = 19: 1)
C ₂₃ H ₂₆ N ₄ O ₃ (406.49)
Mass Spectrum:
M ⁺ = 406
(M + Na) ⁺ = 429

c. 2 16352 00070 552 001000280000000200012000285911624100040 0002019962329 00004 16233- [4- (N-Benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3- (1H tetrazol-5-yl) -1-pyrrolidino-pronan-1-one

Prepared analogously to Example 4 g of 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-cyano-1-pyrrolidino-propan-1-one and tributyltin azide.
Yield: 37% of theory,
R _f value: 0.55 (silica gel, methylene chloride / ethanol 9: 1)
C ₂₃ H ₂₇ N ₇ O ₃ (449.52)
Mass Spectrum:
(M + Na) ⁺ = 472
(M - H) ^- = 448

d. 2- [4- (N-methylamino) -3-amino-phenyl] -2-methyl-3- (1H-tetra zol-5-yl) -1-pyrrolidino-propan-1-one

Prepared analogously to Example 1f from 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3- (1H-tetrazol-5-yl) -1-pyrrolidino-propane-1 -on and hydrogen / palladium on charcoal.
Yield: 48% of theory,
R _f value: 0.3 (silica gel, methylene chloride / ethanol = 9: 1)
C ₁₆ H ₂₃ N ₇ O (329.41)
Mass Spectrum:
(M + H) ⁺ = 330
(M - H) ^- = 328

e. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (1H-tetrazol- 5-yl-methyl) -1- (pyrrolidinocarbonyl) -ethyl] -benzimdazol

Prepared analogously to Example 1g / h from 2- [4- (N-methylamino) -3-amino-phenyl] -2-methyl-3- (1H-tetrazol-5-yl) -1-pyrrolidino-propan-1-one, 4-Cyano-phenylglycine / O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate and subsequent treatment with glacial acetic acid.
Yield: 17% of theory,
R _f value: 0.25 (silica gel, methylene chloride / ethanol 9: 1) C ₂₅ H ₂₇ N ₉ O (469.55)
Mass spectrum: (M - H) ^- = 468

f. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (1H-tetrazol- 5-yl-methyl) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole-hy hydrochloride

Prepared analogously to Example 11 from 2- (4-cyanophenylamino methyl) -1-methyl-5- [1- (1H-tetrazol-5-ylmethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole and hydrochloric acid / ammonium car- tar carbonate in ethanol.
Yield: 25% of theory,
R _f value: 0.35 (reversed phase RP8; 5% saline / methanol = 1: 1)
C ₂₅ H ₃₀ N ₁₀ O x HCl (486.58 / 523.05)
Mass spectrum: (M + H) ⁺ = 487

Example 7 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonyl methylaminomethyl) -1- (pyrrolidinocarbonyl) -ethyl] -benzimida zol diacetate a. 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl- 3-azido-1-pyrrolidino-propan-1-one

Prepared analogously to Example 6b from 2- [4- (N-benzyl-methyl-amino) -3-nitro-phenyl] -2-methyl-3-methanesulphonyloxy-1-pyrrolidino-propan-1-one and sodium azide in dimethylformamide.
Yield: 100% of theory,
R _f value: 0.75 (silica gel, ethyl acetate / petroleum ether = 1: 1)
C ₂₂ H ₂₆ N ₆ O ₃ (422.49)
Mass spectrum: M ⁺ = 422

b. 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl- 3-amino-1-pyrrolidino-propan-1-one

A solution of 24.75 g (59 mmol) of 2- [4- (N-benzylmethylamino) -3-nitro-phenyl] -2-methyl-3-azido-1-pyrrolidino-propan-1-one and 15.7 g ( 60 mmol) of triphenylphosphine in 250 ml of tetrahydrofuran and 1.8 ml of water is stirred for 60 hours at room temperature. After evaporation of the solvent, the residue is purified on silica gel, eluting initially with methylene chloride, later with methylene chloride / ethanol (50: 1, 9: 1, 8: 2 and 7: 3). The uniform fractions are combined and evaporated.
Yield: 21.7 g (93% of theory),
R _f value: 0.25 (reversed phase RP8; 5% saline / methanol = 2: 3)
C ₂₂ H ₂₈ N ₄ O ₃ (396.49)
Mass spectrum: (M + H) ⁺ = 397

c. 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl- 3-tert.butyloxycarbonylamino-1-pyrrolidino-propan-1-one

Prepared analogously to Example 1c from 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-arnino-1-pyrrolidino-propan-1-one and di-tert-butyl dicarbonate / N-ethyl-diisopropylamine in dioxane.
Yield: 98% of theory,
R _f value: 0.55 (silica gel, methylene chloride / ethanol = 19: 1)
C ₂₇ H ₃₆ N ₅ O ₄ (496.61)
Mass Spectrum:
M ⁺ = 496
(M + Na) ⁺ = 519
(M - H) ^- = 495

d. 2- [4- (N-methylamino) -3-amino-phenyl-2-methyl-3-tert-butyl oxycarbonylamino-1-pyrrolidino-propane-1-one

Prepared analogously to Example 1f from 2- [4- (N-benzyl-methyl-amino) -3-nitro-phenyl] -2-methyl-3-tert-butyloxycarbonylamino-1-pyrrolidino-propan-1-one and hydrogen / palladium Activated carbon.
Yield: 23% of theory,
R _f value: 0.4 (silica gel, methylene chloride / ethanol = 19: 1)
C ₂₀ H ₃₂ N ₄ O ₃ (376.5)
Mass Spectrum:
(M + Na) ⁺ = 399
(M - H) ^- = 375

e. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (tert.butyloxy carbonylaminomethyl) -1- (pyrrolidinocarbonyl) -ethyl] -benzimi dazol

Prepared analogously to Example 1g / h from 2- [4- (N-methylamino) -3-amino-phenyl] -2-methyl-3- (tert-butyloxycarbonylamino) -1-pyrrolidino-propan-1-one, Cyano-phenylglycine / carbonyldiimidazole and subsequent treatment with glacial acetic acid.
Yield: 58% of theory,
R _f value: 0.5 (aluminum oxide, methylene chloride / ethanol = 19: 1)
C ₂₉ H ₃₆ N ₆ O ₃ (516.65)
Mass Spectrum:
M ⁺ = 516
(M + Na) ⁺ = 539

f. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1-aminomethyl- 1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Prepared analogously to Example 1i from 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (tert-butyloxycarbonylaminomethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole and 6 N hydrochloric acid in Di oxan.
Yield: 82% of theory,
R _f value: 0.25 (silica gel, methylene chloride / ethanol = 9: 1)

G. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonyl methylaminomethyl) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Prepared analogously to Example 1k from 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1-aminomethyl-1- (pyrrolidinocarbonyl) - ethyl) benzimidazole and ethyl bromoacetate / potassium carbonate in acetone.
Yield: 25% of theory,
R _f value: 0.6 (silica gel, methylene chloride / ethanol = 9: 1)
C ₂₈ H ₃₄ N ₆ O ₃ (502.62)
Mass Spectrum:
(M + H) ⁺ = 503
(M + Na) ⁺ = 525
(M - H) ^- = 501

H. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycar bonylmethylaminomethyl) -1- (pyrrolidinocarbonyl) -ethyl] benz imidazole-diacetate

Prepared analogously to Example 11 from 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylaminomethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole and hydrochloric acid / ammonium carbonate in ethanol.
Yield: 66% of theory,
R _f value: 0.35 (silica gel, methylene chloride / ethanol = 4: 1 + 1% glacial acetic acid)
C ₂₈ H ₃₇ N ₇ O ₃ x 2 CH ₃ COOH (519.65 / 639.76)
Mass Spectrum:
(M + H) ⁺ = 520

The following compounds are obtained analogously to Example 7:

(1) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N- (2-ethoxy carbonyl-ethyl) -N-methyl-aminomethyl) -1- (pyrrolidinocarbonyl) - ethyl] benzimidazole

(2) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N -ethoxycar bonylmethylsulfonyl) -N-methyl-aminomethyl) -1- (pyrrolidinocar carbonyl) -ethyl] -benzimidazole

(3) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N -ethoxycarbonylmethylaminocarbonyl-N-methylaminomethyl) -1- (2,5-dihydropyrrolocarbonyl) ethyl] benzimidazole hydrochloride
Yield: 55% of theory,
R _f value: 0.4 (reversed phase RP8, 5% saline solution / methanol = 1: 1)
C ₃₀ H ₃₈ N ₈ O ₄ × HCl (574.36 / 610.81)
Mass Spectrum:
(M + H) ⁺ = 575
(M - H) ^- = 573
(M + Cl) ^- = 609/611 (CI)

Example 8 (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethyl methylamino) -1 - [(R, S) -2-methyl-pyrrolidinocarbonyl] -ethyl] -benz imidazole dihydrochloride (mixture of diastereomers)

A solution of 500 mg (0.84 mNol) of (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1 - [(R, S) -2-methyl-pyrrolidinocarbonyl] -ethyl] -benzimidazole dihydrochloride (diastereomer mixture) in 4 ml of water is treated with 2.7 ml of 1 N sodium hydroxide solution and stirred for 45 minutes at room temperature. The pH of the solution is adjusted to 3.5 by adding 1 N hydrochloric acid. The solution is evaporated with the addition of toluene and the residue is treated with a little methanol nol. After filtering off the undissolved inorganic material, the filtrate is evaporated and treated with ether Verrie ben. The solid formed is filtered off and dried.
Yield: 480 mg (100% of theory),
R _f value: 0.5 (Reversed Phase RP8; 5% saline / methanol = 1: 1)
C ₂₆ H ₃₃ N ₇ PO ₃ × 2 HCl (491.6 / 564.51)
Mass Spectrum:
(M + H) ⁺ = 492
(M + Na) ⁺ = 514

The following compounds are obtained analogously to Example 8:

(1) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylaminomethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole dihydrochloride
Yield: 70% of theory,
R _f value: 0.45 (reversed phase RP8; 5% saline / methanol = 1: 1)
C ₂₆ H ₃₃ N ₇ O ₃ x 2 HCl (491.6 / 564.51)
Mass spectrum: (M + H) ⁺ = 492

(2) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] benzimidazole dihydrochloride
Yield: 100% of theory,
R _f value: 0.5 (Reversed Phase RP8; 5% saline / methanol = 1: 1)
C ₂₅ H ₂₉ N ₇ O ₃ x 2 HCl (475.55 / 548.46)
Mass Spectrum:
(M + H) + = 476
(M - H) ^- = 474

(3) (R) -2- [4- (N-Phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole
Yield: 67% of theory,
R _f value: 0.46 (silica gel, 5% methylene chloride / methanol / concentrated ammonia = 4: 0.9: 0.1)
C ₃₂ H ₃₅ N ₇ O ₄ (581.67)
Mass Spectrum:
(M + H) ⁺ = 582
(M - H) ^- 580
(M + Na) ⁺ = 604

(4) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethyl-oxymethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole hydrochloride
Yield: 45% of theory,
R _f value: 0.4 (Reversed Phase RP8; 5% saline / methanol = 1: 1)
C ₂₆ H ₃₂ N ₆ O ₄ · HCl (492.58 / 529.03)
Mass Spectrum:
(M + H) ⁺ = 493
(M - H) ^- = 491

(5) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N- (2-carb oxyethyl) -N-methyl-aminomethyl) -1- (pyrrolidinocarbonyl) - ethyl] benzimidazole

(6) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxy methylsulfonyl-N-methyl-aminomethyl) -1- (pyrrolidinocarbonyl) - ethyl] benzimidazole

(7) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxy-methylaminocarbonyl) -N-methyl-aminomethyl) -1- (2,5-dihydro-pyrrolocarbonyl) -ethyl] -benzimidazole hydrochloride
Yield: 15% of theory,
R _f value: 0.5 (Reversed Phase RP8; 5% saline / methanol = 1: 1)
C ₂₈ H ₃₄ N ₈ O ₄ × HCl (546.62 / 583.09)
Mass Spectrum:
(M + H) ⁺ = 547
(M - H) ^- = 545
(M + Cl) ^- = 581/583 (CI)

Example 9 Dry ampoule containing 75 mg of active ingredient per 10 ml

composition active substance 75.0 mg mannitol 50.0 mg Water for injections ad 10.0 ml

manufacturing

Active substance and mannitol are dissolved in water. After bottling is freeze-dried. The resolution for ready to use Solution is with water for injections.  

Example 10 Dry ampoule containing 35 mg of active ingredient per 2 ml

composition active substance 35.0 mg mannitol 100.0 mg Water for injections ad 2.0 ml

manufacturing

Active substance and mannitol are dissolved in water. After bottling is freeze-dried.

The solution to the ready-to-use solution is water for injections.

Example 11 Tablet with 50 mg active ingredient

composition (1) Active substance 50.0 mg (2) lactose 98.0 mg (3) corn starch 50.0 mg (4) polyvinylpyrrolidone 15.0 mg (5) magnesium stearate 2.0 mg           215.0 mg         

manufacturing

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are mixed (5). From this mixture tablets are pressed, biplan with double-sided facet and one-sided part score.
Diameter of the tablets: 9 mm.

Example 12 Tablet with 350 mg active ingredient

composition (1) Active substance 350.0 mg (2) lactose 136.0 mg (3) corn starch 80.0 mg (4) polyvinylpyrrolidone 30.0 mg (5) magnesium stearate 4.0 mg           600.0 mg         

manufacturing

(1), (2) and (3) are mixed and treated with an aqueous solution granulated by (4). The dried granules are added (5) mixed. From this mixture tablets are pressed biplan with double-sided facet and one-sided part notch.

Diameter of the tablets: 12 mm.

Example 13 Capsules with 50 mg active ingredient

composition (1) Active substance 50.0 mg (2) dried corn starch 58.0 mg (3) powdered milk sugar 50.0 mg (4) magnesium stearate 2.0 mg           160.0 mg         

manufacturing

(1) is triturated with (3): This trituration becomes the mixture from (2) and (4) with intensive mixing.  

This powder mixture is placed on a capsule filling machine in Hard gelatine capsules size 3 bottled.

Example 14 Capsules with 350 mg active ingredient

composition (1) Active substance 350.0 mg (2) dried corn starch 46.0 mg (3) powdered milk sugar 30.0 mg (4) magnesium stearate 4.0 mg           430.0 mg         

manufacturing

(1) is triturated with (3). This trituration becomes the mix from (2) and (4) with intensive mixing.

This powder mixture is placed on a capsule filling machine in Hard gelatine capsules size 0 filled.

Example 15 Suppositories containing 100 mg of active ingredient

Contains 1 suppository active substance 100.0 mg Polyethylene glycol (M.G. 1500) 600.0 mg Polyethylene glycol (M. G. 6000) 460.0 mg polyethylene sorbitan monostearate 840.0 mg           2000.0 mg         

manufacturing

The polyethylene glycol is used together with polyethylene sorbitan monostearate melted. At 40 ° C, the milled Wirk substance homogeneously dispersed in the melt. It is at 38 ° C  cooled and in weakly pre-cooled suppository forms cast.

Claims (10)

1. Benzimidazoles of the general formula
in the
R _{a is} a straight-chain C _1-3 alkyl group in which the hydrogen atoms may be wholly or partially replaced by fluoro atoms and in the 1-position
by a pyrrolidinocarbonyl or 2,5-dihydropyrrolo carbonyl group optionally substituted by a C _1-3 alkyl group and
by an amino group monosubstituted by a carboxy-C _1-4 -alkyl, cyano-C _1-4 -alkyl or tetrazolyl-C _1-4 -alkyl group,
or by a C _1-3 alkyl group, the terminal by an optionally each at one or both Aminstick atoms by a C _1-3 alkyl substituted N- (carboxy-C _1-3 alkylaminocarbonyl) amino group, by a carboxy -C _1-3 alkoxy, N- (carboxyC _1-3 alkyl) amino, N- (C _1-3 alkyl) -N- (carboxyC _1-3 alkyl) amino , N- (carboxyC _1-3 alkylsulphonyl) amino, N- (C _1-3 alkyl) -N- (carboxyC _1-3 alkylsulphonyl) amino or tetrazolylC _{1. 3-} alkyl group is substituted,
R _{b is} a C _1-3 -aryl group and
R _{c is} an amidino group, a cyano group or a substituted in the 5-position by a C _1-3 alkyl or phenyl group 1,2,4-oxadiazol-3-yl group, wherein the phenyl substituent by a fluorine, chlorine or Bromine atom or may be substituted by a C _1-3 alkyl group, mean
their tautomers, their stereoisomers, their mixtures, their prodrugs, their derivatives containing in place of a carboxy group a group negatively charged under physiological conditions, and salts thereof. 2. Benzimidazoles of the general formula I according to claim 1, in which
R _b and R _{c are defined} as mentioned in claim 1 and
R _{a is} as defined above, that a substituent represents a C _1-3 non-branched alkyl group or a 2,5-dihydropyrrolocarbonyl group optionally substituted by a C _1-3 alkyl group,
or R _{a is} an ethyl group which is in the 1-position
by a pyrrolidinocarbonyl group and
is substituted by an amino group, wherein the amino group by an ethoxycarbonylmethyl group which is substituted in the ethoxy part in the 2-position by a methoxy, dimethylamino or tolyl, by a carboxymethyl, C _3-4 alkoxycarbonylmethyl, cyclohexyloxycarbonyl methyl , 3- (C _2-3 alkoxycarbonyl) -propyl or tetrazolylmethyl group is substituted,
R _{b is} a methyl group and
R _c is an amidino group substituted by a benzoyl, methylbenzoyl, fluorobenzoyl or trifluoromethylbenzoyl group or
R _{a is} an ethyl group in the 1-position
by a substituted in 2-position by a methyl group pyrrolidinocarbonyl group and
is substituted by an amino group, wherein the amino group is substituted by a carboxymethyl or ethoxycarbonylmethyl group,
R _{b is} a methyl group and
R _{c is} an amidino group or
R _{a is} an ethyl group in the 1-position
by a pyrrolidinocarbonyl group and
by an amino group substituted by a carboxymethyl, C _3-4 -alkoxycarbonyl-methyl or tetrazolylmethyl group or
is substituted by a methyl group, wherein the methyl group is substituted by a tetrazolyl, carboxymethoxy, ethoxycarbonylmethoxy, ethoxycarbonylmethylamino, N- (2-carboxyethyl) -N-methylamino, N- [2- (C _1-3 Alkoxycarbonyl) -ethyl] -N-methylamino, N- (carboxymethylaminocarbonyl) -N-methylamino, N- (C _1-3 -alkoxycarbonylmethylaminocarbonyl) -N-methylamino, N- (carboxymethylsulfonyl) -N- methyl-amino or N- (C _1-3 alkoxycarbonylmethylsulfonyl) -N-methyl-amino group is substituted,
R _{b is} a methyl group and
R _{c is} an amidino group,
their tautomers, their isomers and their salts. 3. Benzimidazoles of the general formula I according to claim 2 with the exception of
(1) 2- [4- (N-phenylcarbonyl-amidino) -phenylaminomethyl] -1-methyl-5- [1- (n-butyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole, and
(2) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (tetrazol-5-yl-methylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole, their tautomers, their isomers and their salts. 4. Benzimidazoles of the general formula I according to claim 1, in which
R _{a is} an ethyl group in the 1-position
by a substituent optionally substituted by a methyl group 2,5-dihydropyrrolocarbonyl and
by an amino group which may be substituted by a C _1-4 alkoxycarbonyl C _1-4 alkyl group in which the C _2-4 alkoxy part may be terminally substituted by a methoxy, dimethylamino, phenyl or tolyl group, by a carboxy C _1-4 alkyl, cyclohexyloxycarbonylC _1-4 alkyl or tetrazolylC _1-4 alkyl group is monosubstituted, or
by a C _1-3 alkyl group which is terminally substituted by one or more of one or both amine nitrogen atoms by a C _1-3 alkyl group-substituted N- (carboxy-C _1-3 alkylaminocarbonyl) amino or N - (C _1-3 -alkoxycarbonyl-C _1-3 -alkylaminocarbonyl) -amino group, by a carboxy-C _1-3 -alkoxy, C _1-3 -alkoxycarbonyl-C _1-3 -alkoxy-, N- (C _1-3 -alkyl) -N- (carboxy-C _1-3 -alkyl) -amino, N- (C _1-3 -alkyl) -N- (C _1-3 -alkoxycarbonyl-C _{1- 3-} alkyl) -amino, N- (C _1-3 -alkyl) -N- (carboxy-C _1-3 -alkylsulfonyl) -amino or N- (C _1-3 -alkyl) -N- (C _1-3 -alkoxycarbonyl-C _1-3 -alkylsulfonyl) -amino or tetra-zolyl-C _1-3 -alkyl group is substituted,
R _{b is} a methyl group and
R _c is an amidino group optionally substituted by a benzoyl, methylbenzoyl, fluorobenzoyl or trifluoromethylbenzoyl group
or R _{a is} an ethyl group which is in the 1-position
by a pyrrolidinocarbonyl group and
is substituted by an amino group, wherein the amino group by an ethoxycarbonylmethyl group which is substituted in the 2-position by a methoxy, dimethylamino or tolyl group, by a carboxymethyl, propyl oxycarbonylmethyl, Isopropyloxycarbonylmethyl-, isobutyl oxycarbonylmethyl, Cyclohexyloxycarbonylmethyl- , 3- (C _2-3 alkoxycarbonyl) -propyl or tetrazolylmethyl group is substituted,
R _{b is} a methyl group and
R _c is an amidino group substituted by a benzoyl, methylbenzoyl, fluorobenzoyl or trifluoromethylbenzoyl group or
R _{a is} an ethyl group in the 1-position
by a substituted in 2-position by a methyl group pyrrolidinocarbonyl group and
is substituted by an amino group, wherein the amino group is substituted by a carboxymethyl or ethoxycarbonylmethyl group,
R _{b is} a methyl group and
R _{c is} an amidino group or
R _{a is} an ethyl group in the 1-position
by a pyrrolidinocarbonyl group and
by an amino group substituted by a carboxymethyl or C _3-4 alkoxycarbonylmethyl group or
is substituted by a methyl group, wherein the methyl group by a tetrazolyl, carboxymethoxy, Ethoxycar bonylmethoxy-, Ethoxycarbonylmethylamino-, N- (2-carboxy ethyl) -N-methyl-amino, N- [2- (C _{1- 3-} alkoxycarbonyl) -ethyl] -N-methylamino, N- (carboxymethylaminocarbonyl) -N-methylamino, N- (C _1-3 -alkoxycarbonylmethylaminocarbonyl) -N-methylamino, N- (carboxymethylsulfonyl) - N-methyl-amino or N- (C _1-3 alkoxycarbonylmethylsulfonyl) -N-methyl-amino group is substituted,
R _{b is} a methyl group and
R _{c is} an amidino group,
their tautomers, their isomers and their salts. 5. The following benzimidazoles of the general formula I according to claim 1:
(1) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] benzimidazole,
(2) 2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (2,5-dihydropyrrolo carbonyl) ethyl] benzimidazole,
(3) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (isobutyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole,
(4) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (n-propyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole,
(5) (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1 - [(R, S) -1-methylpyrrolidinocarbonyl] ethyl] benzimidazole,
(6) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethylbenzimidazole and
(7) (R) -2- [4- (N-phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (cyclohexyloxycarbonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] benzimidazole,
their isomers and their salts. 6. Physiologically acceptable salts of the compounds according to claims 1 to 6, in which R _{c represents} one of the amidino groups mentioned in claims 1 to 5. 7. A pharmaceutical composition containing a compound according to at least one of claims 1 to 5, in which R _{c is} one of the claims 1 to 5 mentioned in the amidino groups, or a salt according to claim 6 in addition to optionally one or more inert carriers and / or diluents , 8. Use of a compound according to at least one of claims 1 to 5, in which R _{c represents} one of the amidino groups mentioned in claims 1 to 5, or a salt according to claim 6 for the preparation of a medicament having a thrombin time-prolonging action, a Thrombinhemmender effect and an inhibitory effect on related serine proteases. 9. A process for the preparation of a medicament according to claim 7, characterized in that non-chemical way a compound according to at least one of claims 1 to 5, in which R _{c is} one of the mentioned in the claims 1 to 5 Ami dinogruppen, or a salt is incorporated according to claim 6 in one or more inert carriers and / or diluents. 10. A process for the preparation of the compounds according to the entitlements to 1 to 6, characterized in that

• a) for the preparation of a compound of the general formula I in which R _{c represents} a cyano group or a 1,2,4-oxadiazol-3-yl group substituted in the 5-position by a C _1-3 -alkyl or phenyl group, wherein the phenyl substituent may be substituted by a fluorine, chlorine or bromine atom or by a C _1-3 alkyl group,
  an optionally formed in the reaction mixture compound of the general formula
  in the
  R _a and R _{b are defined} as mentioned in claims 1 to 5,
  R _c 'is a cyano group or a 5-position by a C _1-3 alkyl kyl- or phenyl substituted 1,2,4-oxadiazol-3-yl group, wherein the phenyl substituent by a fluorine, chlorine or bromine atom or may be substituted by a C _1-3 alkyl group,
  Z ₁ and Z ₂ , which may be the same or different, if appropriate substituted by alkyl groups having 1 to 6 carbon atoms substituted amino, hydroxy or mercapto or
  Z ₁ and Z ₂ , together an oxygen or sulfur atom, an optionally substituted by an alkyl group having 1 to 3 carbon atoms imino group, an alkylenedioxy or Al kylendithiogruppe each having 2 or 3 carbon atoms be interpreted, is cyclized or
• b) for the preparation of a compound of general formula I in which R _{c represents} an amidino group,
  an optionally formed in the reaction mixture compound of the general formula
  in the
  R _a and R _{b are} as defined in claims 1 to 5 mentioned and
  Z _{4 is} an alkoxy, aralkoxy, alkylthio or aralkylthio group, is reacted with ammonia or with its salts, or
• c) for the preparation of a compound of the general formula I in which R _a contains a carboxy group and R _{c is defined} as mentioned in claims 1 to 5,
  a compound of the general formula
  in the
  R _b and R _{c are defined} as mentioned in claims 1 to 5 and
  R _a 'has the meanings mentioned for R _a in claims 1 to 5, with the proviso that R _a contains a group convertible by hydrolysis, treating with an acid or base, thermolysis or hydrogenolysis into a carboxy group,
  by hydrolysis, treatment with an acid or base, Ther molysis or hydrogenolysis in a compound of general formula I in which R _a contains a carboxy group is converted or
• d) for the preparation of a compound of general formula I in which R _{c represents} an amidino group which is substituted by an in vivo cleavable radical,
  a compound of the general formula
  in the
  R _a and R _{b are} as defined in claims 1 to 5 mentioned, with a compound of the general formula
  Z ₅ - R ₉ (VII),
  in the
  R _{9 is} the acyl radical of one of the in vivo cleavable radicals mentioned in claims 1 to 5 and
  Z _{5 is} a nucleofuge leaving group, is reacted or
• e) for the preparation of a compound of general formula I in which R _{c is} one of the amidino groups mentioned in claims 1 to 5,
  a compound of the general formula
  in the
  R _a and R _{b are} as defined in claims 1 to 5 mentioned and
  R _{c represents} a 1,2,4-oxadiazol-3-yl group substituted in the 5-position by a C _1-3 alkyl or phenyl group, in which the phenyl substituent is replaced by a fluorine, chlorine or bromine atom or by a C _1-3 alkyl group may be substituted, kata lytically hydrogenated and, if necessary, then a resulting compound is hydrolyzed or
• f) for the preparation of a compound of general formula I wherein R _{a represents} an aminoC _1-3 alkyl group in which the amino group is substituted by a carboxyC _1-4 alkyl or tetrazolylC _1-4 alkyl group is monosubstituted,
  a compound of the general formula
  in the
  R _b and R _{c are defined} as mentioned in claims 1 to 5 and
  R _a "represents an amino C _1-3 alkyl group, with a compound of the general formula
  R _a '''- Z ₇ (X)
  in the
  R _a '''is a carboxy C _1-4 alkyl or tetrazolyl C _1-4 alkyl group and
  Z _{7 is} a nucleofuge leaving group, is alkylated and
  then, if desired, subsequently converting a compound of general formula I in which R _a contains a carboxy group by esterification into a corresponding compound in which R _{a contains} an esterified carboxy group, and / or
  a compound of the general formula I in which R _{a contains} an esterified carboxy group is converted by means of transesterification into a corresponding compound in which R _a contains another esterified carboxy group, and / or
  a compound of general formula I, in which R _a contains a cyano group, is converted by means of hydrazoic acid into a corresponding compound in which R _{a contains} a tetrazolyl group, and / or
  a protective moiety used during the reactions for the protection of reactive groups is split off and / or
  a compound of general formula I thus obtained is separated into its stereoisomers and / or
  a compound of the general formula I thus obtained is converted into its salts, in particular for the pharmaceutical application into its physiologically tolerated salts with an inorganic or organic acid or base.