DE19937494A1 - New carboxylic acid amides are Factor Xa and serine protease inhibitors, useful for the treatment and prevention of thrombotic disorders, tumors and fibrin-dependent inflammation - Google Patents

Abstract

The present invention relates to carboxamides of the general formula DOLLAR F1 in the DOLLAR AR 1 to R 5, Ar, m and n are as defined in claim 1, their tautomers, their stereoisomers, their mixtures, their prodrugs and their salts, which have valuable properties , DOLLAR A The compounds of the above general formula I, in which R 5 represents a cyano group, are valuable intermediates for the preparation of the remaining compounds of the general formula I, and the compounds of the above general formula I, in which R 5 is as defined in claim 1 represents amidino groups mentioned, have valuable pharmacological properties, in particular an antithrombotic effect and a factor Xa-inhibiting effect.

Description

The present invention relates to carboxylic acid amides 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 _{5 represents} a cyano group, are valuable intermediates for the preparation of the remaining compounds of the general For mel I, and the compounds of the above general formula I, in which R _{5 represents} one of the following amidino groups, as well as their tautomers, their stereoisomers, their mixtures, their prodrugs, their derivatives containing in place of a carboxy group a negatively charged group under physiological conditions, and their salts, in particular their physio logically acceptable salts with inorganic or organic salts, and their stereoisomers have valuable pharmacological properties, in particular an antithrombotic effect and a factor Xa-inhibiting action.

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
one of the radicals m or n is the number 0 and the other radical m or n is the number 1,
Ar is an optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl, hydroxy, C _1-3 alkoxy, phenyl C _1-3 alkoxy, amino, C _1-3 -alkylamino or di (C _1-3 -alkyl) -amino group substituted phenylene or Naphthylengrup pe, wherein the phenylene group by another fluorine, chlorine or bromine atom or by another C _1-3 Alkyl group can be substi tuiert,
a thienylene, thiazolylene, pyridinyl, pyrimidinyl, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C _1-3 -alkyl group,
R _{1 is} a hydrogen atom, an optionally substituted by an amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, phenyl, naphthyl or heteroaryl substituted C _1-3 alkyl group,
a C _3-7 cycloalkyl group substituted in the 1-position by a 5- to 7-membered cycloalkyleneiminocarbonyl group,
a 4- to 7-membered cycloalkyleneiminocarbonyl group,
an optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy substituted phenyl group,
a C _1-3 alkoxy, phenylC _1-3 -alkoxy, heteroaryloxy or heteroaryloxyC _1-3 -alkoxy group in which the alkoxy moiety in each case in the 2- or 3-position is also denoted by an amino, C _1-3 alkyl-amino or di (C _1-3 -alkyl) -amino group may be substituted,
a C _3-7 -cycloalkoxy group, wherein the methylene group in the 3- or 4-position in a C _5-7 -cycloalkoxy group may be replaced by an -NH-group, where the -NH-group is represented by an arylcarbonyl or arylsulfonyl group, by a C _1-3 alkylcarbonyl group in which the oxygen atom of the carbonyl group is replaced by an imino group and the alkanoyl part by an amino, C _1-3 alkylamino or di (C _1-3 alkyl) amino group substitui may be substituted by a C _1-3 alkyl group which may be substituted in the 2- or 3-position by an amino, C _1-3 alkylamino or di (C _1-3 alkyl) amino group .
R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, a C _1-3 -alkyl, hydroxy or C _1-3 -alkoxy group,
R _{3 is} a hydrogen atom or a C _1-3 -alkyl group,
R _{4 is} a hydrogen atom or an optionally substituted by a carboxy group C _1-3 alkyl group and
R _{5 is} a cyano group or an optionally substituted by one or two C _1-3 alkyl groups amidino 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 -cycloalkenol, a C _3-5 -alkenol, a phenyl-C _3-5 -alkenol, a C _3-5 -alkenyl or Phenyl- _3-5 -alkynol with the proviso that no binding to the oxygen atom from a carbon atom, wel ches a double or Dreifa a C _3-8 -cycloalkyl-C _1-3 -alkanol, a bicycloalkanol having a total of 8 to 10 carbon atoms, which may be additionally substituted in the bicycloalkyl moiety by one or two C _1-3 alkyl groups, a 1,3 Dihydro-3-oxo-1-isobenzfuranol or an alcohol of the formula

R _a -CO-O- (R _b CR _c ) -OH,

in that
R _{a represents} a C _1-8 alkyl, C _5-7 cycloalkyl, phenyl or phenyl C _1-3 alkyl group,
R _{b is} a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl or phenyl group and
R _{c 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, methylcarbonyloxy, Ethylcarbonyloxy-, 2,2,2-tri chlorethylcarbonyloxy-, Propylcarbonyloxy-, isopropylcarbonyl oxy, butylcarbonyloxy, tert-butylcarbonyloxy, pentylcarboxynyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy or hexadecylcarbonyloxy, a phenylC _1-6 alkoxycarbonyl group such as benzyloxycarbonyl -, Phenylethoxycarbo nyl- or Phenylpropoxycarbonylgruppe, a 3-amino-propionyl group in which the amino group mono- or disubstituted by C _1-6 alkyl or C _3-7 cycloalkyl groups and the substituents may be identical or different, a C _1-3 -alkylsulfonyl-C _2-4 -alkoxycarbonyl, C _1-3 -alkoxy-C _2-4 -alkoxy-C _2-4 -alkoxycarbonyl, R _a -CO-O- (R _b CR _c ) -O-CO-, C _1-6 -alkyl-CO-NH- (R _d CR _e ) -O-CO- or C _1-6 alkyl CO-O- (R _d CR _e ) - (R _d CR _e ) -O-CO- group in which R _a to R _c are defined as mentioned above,
R _d and R _e , 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 the above general formula I are those in which
one of the radicals m or n is the number 0 and the other radical m or n is the number 1,
Ar is an optionally substituted by a fluorine, chlorine or bromine atom, by a methyl, hydroxy, methoxy or benzyloxy substituted phenylene group, which may be substituted by another Me methyl group,
R _{1 is} a phenyl, dimethylaminomethyl, cyclopentylamino, benzylamino, N- (carboxymethyl) benzylamino, N- (C _1-3 -alkoxycarbonylmethyl) -benzylamino, 1-imidazolylamino, benzoylamino or phenylsulfonylamino group,
a cyclopropyl group substituted in the 1-position by a 5- to 7-membered cycloalkyleneiminocarbonyl group,
a 4- to 7-membered cycloalkyleneiminocarbonyl group,
a C _1-3 alkoxy group in which the alkoxy moiety in each case in the 2- or 3-position may be substituted by an amino, C _1-3 -alkylamino or di (C _1-3 -alkyl) -amino group, a phenyl-C _1-3 alkoxy or pyridinyloxy group,
a C _5-7 -cycloalkoxy group in which the methylene group in the 3- or 4-position can be replaced by an -NH group, where the -NH group is substituted by an optionally substituted by an amino group C _1-3 alkylcarbonyl group, in which the oxygen atom of the carbonyl group may be replaced by an imino group and the alkyl moiety may be substituted by an amino group, or may be substituted by a methyl group,
R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxy or methoxy group,
R _{3 is} a hydrogen atom or a methyl group,
R _{4 is} a hydrogen atom or an optionally substituted by a carboxy or C _1-3 alkoxycarbonyl methyl or ethyl group and
R _{5 represents} a cyano group or an amidino group,
their isomers and their salts.

Particularly preferred compounds of general formula I are those in which
one of the radicals m or n is the number 0 and the other radical m or n is the number 1,
Ar is an optionally substituted by a methyl, hydroxy, methoxy or benzyloxy substituted phenylene group,
R _{1 represents} a cyclopropyl group substituted in the 1-position by a 5- to 7-membered cycloalkyleneiminocarbonyl group, or a 4- to 7-membered cycloalkyleneiminocarbonyl group,
R _{2 is} a hydrogen, fluorine, chlorine or bromine atom or a methyl group,
R _{3 is} a hydrogen atom,
R _{4 is} a hydrogen atom or a substituted by a carboxy, meth oxycarbonyl or ethoxycarbonyl methyl or ethyl group and
R _{5 is} an amidino group,
their isomers and their salts.

For example, the following preferred compounds are mentioned:

• a) 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (pyrrolidin lidin-1-yl-carbonyl) -phenyl] -acetamide,
• b) 2- (2-benzyloxy-5-carbamimidoyl-phenyl) -N- (2-ethoxycarbo nyl-ethyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) phenyl] - acetamide,
• c) 2- (2-hydroxy-5-carbamimidoyl-phenyl) -N- (2-ethoxycarbonyl ethyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acet amid and
• d) 2- (2-hydroxy-5-carbamimidoyl-phenyl) -N- (2-carboxy-ethyl) - N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide

and their salts.

According to the invention, the compounds of general formula I are obtained by processes known per se, for example by the following processes:

• a) Acylation of a compound of the general formula
  in the
  R ₁ to R ₄ and m are defined as mentioned above, with a carboxylic acid of the general formula
  HO-CO- (CH ₂ ) _n -Ar-R ₅ (III),
  in the
  Ar, R ₅ and n are defined as mentioned above, or with their reactive derivatives.
  The acylation is conveniently carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane, if appropriate in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C performed.
  However, the acylation may also be carried out with the free acid, if appropriate in the presence of an acid activating agent or a dehydrating agent, e.g. Example, in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus oxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodi imide / N-hydroxysuccinimide or 1-hydroxy -benzotriazole, N, N'-Car bonyldiimidazol or N, N'-thionyldiimidazole or triphenyl phosphine / carbon tetrachloride, at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C, performed.
• b) for the preparation of a compound of general formula I in which R _{5 is} an amidino group which may be substituted by one or two C _1-3 -alkyl groups:
  Reaction of a compound of the general formula which may be formed in the reaction mixture
  in the
  R ₁ to R ₄ , Ar and n are defined as mentioned above and
  Z _{1 represents} an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkyl thio or aralkylthio group such as the methylthio, ethylthio, n-propylthio or benzylthio group, with an amine the general formula
  HR ₆ NR ₇ (V)
  in the
  R ₆ and R ₇ , which may be the same or different, each represents a hydrogen atom or a C _1-3 alkyl group, 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 an amine of general Formula V or with a corresponding acid addition salt such as For example, ammonium carbonate or ammonium acetate Runaway leads.

A compound of general formula IV 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.

If, according to the invention, a compound of the general formula I which contains an amino or imino group is obtained, this can then be converted with a corresponding acyl derivative into a corresponding acyl compound of the general formula I and / or
a compound of the general formula I which contains an esterified carboxy group, this can be converted by hydrolysis into a corresponding carboxylic acid of the general formula I and / or
a compound of general formula I which contains a carboxy group, this can then be converted by esterification in a corresponding ester.

The subsequent acylation is conveniently carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ethers, Tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or Sulfolane optionally in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C, carried out. However, this can also ge with the free acid if necessary in the presence of an acid activating mit  or a dehydrating agent, eg. In the presence of isobutyl chloroformate, thionyl chloride, trimethyl chlorosilane, hydrogen chloride, sulfuric acid, methanesulfone acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcar bodiimide / N-hydroxysuccinimide or 1-hydroxybenzotriazole, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or Triphenylphosphine / carbon tetrachloride, at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C, are performed.

The subsequent hydrolysis is expediently either in Presence of an acid such as hydrochloric acid, sulfuric acid, phosphorus acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or their mixtures or in the presence of a base such as lithium hy hydroxide, sodium hydroxide or potassium hydroxide in a suitable manner solvents such as water, water / methanol, water / ethanol, Water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane and subsequent decarboxylation in Presence of an acid as described above at Tempera between -10 and 120 ° C, eg. B. at temperatures between Room temperature and the boiling temperature of the reaction mixture, carried out.

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.

In the reactions described above can be given if existing reactive groups such as hydroxy, carboxy, amino no, alkylamino or imino groups during the reaction conventional protecting groups are protected, which after Umset be split off again.

For example, the protective group for a hydroxy group is the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group,
as protecting groups for a carboxyl group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyra nylgruppe and
as a protective group for an amino, alkylamino or imino group, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxy benzyl or 2,4-dimethoxybenzyl group and for the amino group additionally the Phthalyl group into 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, Ethyl acetate, dimethylformamide, dimethylformamide / Ace clay or glacial acetic acid, if appropriate 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.

The removal of a methoxy is advantageously carried out in Present boron tribromide in a solvent such as methylene chloride at temperatures between -35 and -25 ° C.

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 optionally 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 formulas II to V, which are 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 Schroter in nitrogen compounds II, Pages 341-730, Methods of Organic Chemistry (Houben-Weyl), 4th edition, publisher Thieme, Stuttgart 1957, and the general my formula III by J.F. Hartwig in Angew. Chem. 110, 2154- 2157 (1998).

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 _{5 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 _{5 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- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (pyrrolidinyl-1-yl-carbonyl) -phenyl] -acetamide,
B = 2- (2-Benzyloxy-5-carbamimidoyl-phenyl) -N- (2-ethoxycarbonyl-ethyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide .
C = 2- (2-hydroxy-5-carbamimidoyl-phenyl) -N- (2-ethoxycarbonyl-ethyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide;
D = 2- (2-hydroxy-5-carbamimidoyl-phenyl) -N- (2-carboxy-ethyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide
investigated for their effect on the inhibition of the factor Xa as follows:

methodology Enzyme kinetic measurement with chromogenic substrate

The amount of p-nitroaniline (pNA) released by the human factor Xa from the colorless chromogenic substrate is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used. The inhibition of the enzyme activity by the test substance (based on the solvent control) is determined at various test substance concentrations and from this the IC _{50 is} calculated as the concentration which inhibits the factor Xa used by 50%.

material

Tris (hydroxymethyl) -aminomethane buffer (100 mmol) and sodium chloride (150 mmol), pH 8.0
Factor Xa (Roche), specific activity: 10 U / 0.5 ml, final concentration: 0.175 U / ml per reaction mixture
Substrate Chromozyme X (Roche), final concentration: 200 μmol / l per reaction batch
Test substance: final concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 μmol / l

execution

10 μl of a 23.5 fold more concentrated starting Solution of the test substance or solvent (control), 175 μl Tris (hydroxymethyl) -aminomethane buffer and 25 μl of factor Xa-Ge Use solution of 1.65 U / ml is incubated for 10 minutes at 37 ° C biert. After adding 25 μl Chromozym X-use solution (1.88 μmol / l), the sample is included in the photometer (SpectraMax 250) 405 nm measured for 150 seconds at 37 ° C.

evaluation

• 1. Determine the maximum increase (deltaOD / minutes) 3 measuring points.
• 2. Determination of the% inhibition based on the solvent con trolls.
• 3. Create a dose response curve (% inhibition vs substance concentration).
• 4. Determination of the IC ₅₀ by interpolation of the X value (substance concentration) of the dose-response curve at Y = 50% inhibition.

The following table contains the found values:

The compounds according to the invention are well ver tolerable, since at therapeutic doses no toxic side effects could be observed.  

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 BEITEN.  

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

example 1 2- (3-carbamimidoyl-phenyl) -N- [2-chloro-5- (1- (pyrrolidin-1-yl- carbonyl) cyclopropyl) phenyl] acetamide hydrochloride a. 1- (4-chloro-3-nitro-phenyl) -cyclopropanecarboxylic

350 ml fuming nitric acid are added at -25 to -30 ° C por tionwise with 50.0 g (0.21 mol) of 1- (4-chloro-phenyl) -cyclopro pancarbonsäure. After completion of the addition is stirred for 15 minutes at -25 ° C and then poured onto ice. The precipitated substance is filtered off with suction, washed with water and dried.
Yield: 58.5 g (95% of theory),
R _f value: 0.43 (silica gel, methylene chloride / methanol = 9.5: 0.5)

b. 5- [1- (pyrrolidin-1-yl-carbonyl) cyclopropyl) -2-chloro-nitro benzene

2.4 g (0.01 mol) of 1- (4-chloro-3-nitro-phenyl) -cyclopropanecarboxylic acid are dissolved in 25 ml of tetrahydrofuran and, after addition of 3.2 g (0.01 mol) of O- (benzotriazol-1-yl) -N, N, N ', N'-tetra methyluronium tetrafluoroborate, 1.1 ml (0.01 mol) of N-methyl-mor pholine and 1.0 ml (0.012 mol) of pyrrolidine stirred for 16 hours at room temperature. The solvent is distilled off, the residue is poured into ice-water, made alkaline with ammonia ge and extracted with ethyl acetate. The organic phase is dried and evaporated.
Yield: 2.5 g (85% of theory),
R _f value: 0.18 (silica gel, cyclohexane / ethyl acetate = 1: 1)

c. 5- [1- (pyrrolidin-1-yl-carbonyl) -cyclopropyl] -2-chloro-aniline

1.8 g (8.14 mmol) of 5- [1- (pyrrolidin-1-yl-carbonyl) cyclopropyl] -2-chloro-nitrobenzene are dissolved in 30 ml of ethyl acetate and 30 ml of ethanol and after addition of 0.8 g of palladium on activated carbon (10%) 3 hours at room temperature with hydrogen hy driert. Subsequently, the catalyst is filtered off and evaporated.
Yield: 2.0 g (92.8% of theory),
R _f value: 0.24 (silica gel, cyclohexane / ethyl acetate / ammonia = 1: 1: 0.01)
C ₁₄ H ₁₇ ClN ₂ O (264.75)
Mass spectrum: M ⁺ = 264/6 (Cl)

d. 2- (3-cyano-phenyl) -N- [2-chloro-5- (1- (pyrrolidin-1-yl-carbo nyl) cyclopropyl) -phenyl] -acetamide

Prepared analogously to Example 1b from 5- [1- (pyrrolidin-1-yl-carbonyl) -cyclopropyl] -2-chloroaniline, O- (benzotriazol-1-yl) -N, N, N ', N'- tetramethyluronium tetrafluoroborate, N-methyl-morpholine and 3-cyanophenylacetic acid in dimethylformamide.
Yield: 43% of theory,
R _f value: 0.21 (silica gel, cyclohexane / ethyl acetate = 1: 2)

e. 2- (3-carbamimidoyl-phenyl) -N- [2-chloro-5- (1- (pyrrolidin 1-yl-carbonyl) cyclopropyl) -phenyl] -acetamide hydrochloride

400 mg (0.1 mmol) of 2- (3-cyano-phenyl) -N- [2-chloro-5- (1- (pyrrolidinyl-1-yl-carbonyl) -cyclopropyl) -phenyl] -acetamide are dissolved in 60 ml saturated ethanolic hydrochloric acid and stirred for 17 hours at room temperature. The solvent is distilled off, the residue is dissolved in 50 ml of absolute ethanol and admixed with 1.5 g (15.6 mmol) of ammonium carbonate. After 22 hours at room temperature, it is evaporated to dryness. The residue is chromatographed on silica gel, eluting with methylene chloride / methanol / glacial acetic acid (9: 1: 0.01).
Yield: 50 mg (11% of theory),
R _f value: 0.59 (silica gel, methylene chloride / methanol / ammonia = 4: 1: 0.01)
C ₂₃ H ₂₅ ClN ₄ O ₂ × HCl (424.94 / 461.4)
Mass spectrum: (M + H) ⁺ = 425/7 (Cl)

Example 2 3-Carbamimidoyl-N- [3- (1- (pyrrolidin-1-yl-carbonyl) -cyclopro pyl) -benzyl] -benzamide hydrochloride a. 1- (3-bromo-phenyl) -1-cyclopropane-nitrile

25 g (0.13 mol) of 3-bromo-benzyl cyanide are taken up in 32 ml (0.38 mol) of 1-bromo-2-chloro-ethane and treated with 0.6 g (2.6 mmol) Ben zyltriethylammoniumchlorid. Subsequently, a solution of 105.8 g (2.65 mol) of sodium hydroxide in 106 ml of water at 10 to 25 ° C is added dropwise. After 20 hours at 55 ° C, the reaction solution is poured into ice water and extracted with ethyl acetate ex trahiert. The organic extracts are dried and evaporated. The residue is triturated with petroleum ether, filtered off with suction and dried.
Yield: 19.3 g (68% of theory),
R _f value: 0.69 (petroleum ether / ethyl acetate = 4: 1)

b. 1- (3-Bromo-phenyl) -cyclopropanecarboxylic

7.6 g (0.135 mol) of potassium hydroxide are dissolved in 60 ml of ethylene glycol, treated portionwise with 10 g (0.045 mol) of 1- (3-bromo-phenyl) - cyclopropane nitrile and heated after addition of 30 ml of water for 4.5 hours at 140 ° C. , After cooling, it is poured onto 600 ml of ice-water and extracted with ether. The aqueous phase is on ice / conc. Hydrochloric acid poured, the precipitated product is filtered off with suction and dried.
Yield: 10.1 g (93% of theory),
R _f value: 0.85 (silica gel, cyclohexane / ethyl acetate / glacial acetic acid = 1: 1: 0.01)

c. 3- [1- (pyrrolidin-1-yl-carbonyl) cyclopropyl] -bromo-benzene

Prepared analogously to Example 1b from 1- (3-bromo-phenyl) -cyclopro pancarbonsäure, pyrrolidine, O- (benzotriazol-1-yl) -N, N, N ', N' - tetramethyluronium tetrafluoroborate and N-methyl-morpholine in tetrahydrofuran.
Yield: 98% of theory,
R _f value: 0.55 (silica gel, cyclohexane / ethyl acetate / glacial acetic acid = 1: 1: 0.01)

d. 3- [1- (pyrrolidin-1-yl-carbonyl) cyclopropyl] -benzonitrile

6 g (20.4 mmol) of 3- [1- (pyrrolidin-1-yl-carbonyl) -cyclopropyl] bromobenzene are dissolved in 25 ml of dimethylformamide and, after addition of 2.7 g (30.6 mmol) of copper I-cyanide, 0.3 g ( 0.216 mmol) of tetrakis-triphenylphosphine-palladium (0) and 5 g of alumina were stirred at 140 ° C. for 30 hours. The insoluble material is filtered off and the solution is evaporated. The residue is chromatographed on silica gel, eluting with cyclohexane / ethyl acetate (1: 2).
Yield: 1.8 g (36% of theory),
R _f value: 0.32 (silica gel, cyclohexane / ethyl acetate / glacial acetic acid = 1: 1: 0.01)

e. 3- [1- (pyrrolidin-1-yl-carbonyl) cyclopropyl] benzylamine

1.8 g (7.5 mmol) of 3- [1- (pyrrolidin-1-yl-carbonyl) -cyclopropyl] - benzonitrile are hydrogenated in 50 ml of methanolic ammonia with addition of 300 mg of Raney nickel for 3 hours at 70 ° C with hydrogen , It is then filtered off from the catalyst and evaporated.
Yield: 1.8 g (98% of theory),
R _f value: 0.94 (silica gel, methylene chloride / methanol / ammonia = 4: 1: 0.01)

f. 3-Cyano-N- [3- (1- (pyrrolidin-1-yl-carbonyl) cyclopropyl) - benzyl] benzamide

Prepared analogously to Example 1b from 3- [1- (pyrrolidin-1-ylcarbonyl) cyclopropyl] benzylamine, 3-cyanobenzoic acid, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetra fluoroborate and N-methylmorpholine in tetrahydrofuran.
Yield: 96% of theory,
R _f value: 0.56 (silica gel, ethyl acetate / ethanol = 9: 1)

G. 3-Carbamimidoyl-N- [3- (1- (pyrrolidin-1-yl-carbonyl) -cyclo propyl) -benzyl] -benzamide hydrochloride

Prepared analogously to Example 1e from 3-cyano-N- [3- (1- (pyrrolidinyl-1-yl-carbonyl) -cyclopropyl) benzyl] benzamide and hydrochloric acid / ammonium carbonate in ethanol.
Yield: 58% of theory,
R _f value: 0.19 (reversed phase RP 8; 5% sodium chloride solution / methanol = 1: 1)
C ₂₃ H ₂₆ N ₄ O ₂ × HCl (390.48 / 426.95)
Mass spectrum: (M + H) ⁺ = 391
(M -H + HCl) ^- = 425/7 (Cl)

The following compound is prepared analogously to Example 2:
(1) 3-Carbamimidoyl-N- [4- (1- (pyrrolidin-1-yl-carbonyl) -cyclopropyl) -benzyl] -benzamide hydrochloride
Yield: 68% of theory,
C ₂₃ H ₂₆ N ₄ O ₂ × HCl (390.48 / 426.95)
Mass spectrum: (M + H) ⁺ = 391
(M + 2H) ⁺⁺ = 196

Example 3 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [2-methyl-5- (1- (pyrrolysine lidin-1-carbonyl) -cyclopropyl) -phenyl] -acetamide hydrochloride a. 5-Cyano-2-methoxy-phenylacetic acid

Prepared analogously to Example 2d from 5-bromo-2-methoxy-phenyl acetic acid, copper-I-cyanide, tetrakis-triphenylphosphine-pal ladium- (0) and alumina in dimethylformamide.
Yield: 37% of theory,
R _f value: 0.26 (silica gel, cyclohexane / ethyl acetate / glacial acetic acid = 1: 1: 0.01)

b. 2- (5-cyano-2-methoxy-phenyl) -N- [2-methyl-5- (1- (pyrrolidin 1-carbonyl) -cyclopropyl) -phenyl] -acetamide

0.6 g (3.3 mmol) of 3-cyano-6-methoxyphenylacetic acid are dissolved in 10 ml of dimethylformamide and, after addition of 0.5 g (3.3 mmol) of N, N-carbonyldiimidazole, stirred at room temperature for 10 minutes. Then 0.8 g (3.3 mmol) of 5- (pyrrolidinyl-1-yl-carbonyl) -cyclopropyl) -2-methyl-aniline are added. The reaction mixture is stirred for 4 hours at 80 ° C, cooled to room temperature, treated with ice water, made alkaline with ammonia and extracted several times with ethyl acetate. The combined organic extracts are dried and evaporated. The residue is chromatographed on silica gel, eluting with cyclohexane / ethyl acetate (7: 3).
Yield: 73% of theory,
R _f value: 0.30 (silica gel, ethyl acetate)

c. 2- (5-cyano-2-hydroxy-phenyl) -N- [2-methyl-5- (1- (pyrrolidin 1-carbonyl) -cyclopropyl) -phenyl] -acetamide

0.7 g (1.67 mmol) of 2- (5-cyano-2-methoxy-phenyl) -N- (2-methyl-5- (1- (pyrrolidine-1-carbonyl) -cyclopropyl) -phenyl] -acetamide are added in 35 10 ml of a 1 molar solution of boron tribromide in methylene chloride (10 mmol) are added dropwise at -35 to -25 ° C. After stirring for 1 hour at 20 ° C., ice is added followed by 20 ml of 2N The aqueous phase is extracted several times with methylene chloride, and the combined organic extracts are dried and evaporated The residue is chromatographed on silica gel, eluting with methylene chloride / ethanol (100: 1).
Yield: 81% of theory,
R _f value: 0.14 (silica gel, methylene chloride / ethanol = 49: 1)

d. 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [2-methyl-5- (1- (pyr rolidin-1-carbonyl) -cyclopropyl) -phenyl] -acetamide hydrochloride

Prepared analogously to Example 1e from 2- (5-cyano-2-hydroxy-phenyl) -N- [2-methyl-5- (1- (pyrrolidine-1-carbonyl) -cyclopropyl) -phenyl] -acetamide, and hydrochloric acid / Ammonium carbonate in ethanol.
Yield: 80% of theory,
R _f value: 0.39 (silica gel, methylene chloride / methanol / glacial acetic acid = 4: 1: 0.01)
C ₂₄ H ₂₈ N ₄ O ₃ · HCl (420.51 / 456.98)
Mass spectrum: (M + H) ⁺ = 421
(M + Cl) ^- = 455/7 (Cl)

The following compound is prepared analogously to Example 3:
(1) 2- (5-Carbamimidoyl-2-methoxy-phenyl) -N- [2-methyl-5- (1- (pyrrolidine-1-carbonyl) -cyclopropyl) -phenyl] -acetamide hydrochloride
Yield: 92% of theory,
R _f value: 0.33 (silica gel, methylene chloride / methanol / glacial acetic acid = 4: 1: 0.01)
C ₂₅ H ₃₀ N ₄ O ₃ × HCl (434.55 / 471.01)
Mass spectrum: (M + H) ⁺ = 435

Example 4 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (pyrroli din-1-yl-carbonyl) -phenyl] -acetamide hydrochloride a. 2- (5-cyano-2-methoxy-phenyl) -N- [3-methyl-4- (pyrrolidin 1-yl-carbonyl) -phenyl] -acetamide

0.4 g (2 mmol) of 3-methyl-4- (pyrrolidin-1-yl-carbonyl) -aniline are dissolved in 15 ml of tetrahydrofuran and, after addition of 0.3 ml (2 mmol) of triethylamine and 0.4 g (2 mmol) of 3-cyano - 5-methoxy-phenylacetyl chloride stirred for 48 hours at room temperature. Then it is mixed with water, made alkaline with ammonia and extracted with ethyl acetate. The combined organic extracts are washed with 1N hydrochloric acid, dried and evaporated.
Yield: 0.45 g (59% of theory),
R _f value: 0.18 (silica gel, ethyl acetate)

b. 2- (5-carbamimidoyl-2-methoxy-phenyl) -N- [3-methyl-4- (pyrrolidin lidin-1-yl-carbonyl) -phenyl] -acetamide hydrochloride

Prepared analogously to Example 1e from 2- (5-cyano-2-methoxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide and hydrochloric acid / ammonium carbonate in ethanol.
Yield: 36% of theory,
R _f value: 0.33 (reversed phase RP 8; 5% sodium chloride solution / methanol = 1: 1)
C ₂₂ H ₂₆ N ₄ O ₃ × HCl (394.48 / 430.94)
Mass spectrum: (M + H) ⁺ = 395,
(M-H + HCl) ^- = 429

c. 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (pyrrolidin lidin-1-yl-carbonyl) -phenyl] -acetamide hydrochloride

Prepared analogously to Example 3c from 2- (5-carbamimidoyl-2-methoxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] - acetamide hydrochloride and boron tribromide in dichloromethane.
Yield: 19% of theory,
R _f value: 0.38 (reversed phase RP 8; 5% sodium chloride solution / methanol = 1: 1)
C ₂₁ H ₂₄ N ₄ O ₃ × HCl (380.45 / 416.91)
Mass spectrum: (M + H) ⁺ = 381
(MH) ^- = 379

The following compounds are prepared analogously to Example 4:
(1) 2- (3-Carbamimidoyl-phenyl) -N- [3-methyl-4- (pyrrolidin-1-ylcarbonyl) -phenyl] -acetamide hydrochloride
Yield: 12% of theory,
C ₂₁ H ₂₄ N ₄ O ₂ × HCl (364.45 / 400.92)
Mass spectrum: (M + H) ⁺ = 365
(2) 2- (5-Carbamimidoyl-2-methoxy-phenyl) -N- [3-methyl-4- (pyrrolidinyl-1-yl-carbonyl) -phenyl] -acetamide hydrochloride
Yield: 36% of theory,
C ₂₂ H ₂₆ N ₄ O ₃ × HCl (394.48 / 430.94)
Mass spectrum: (M + H) ⁺ = 395
(M-H + HCl) ^- = 429
(3) 2- (5-Carbamimidoyl-2-hydroxy-phenyl) -N-methyl-N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide hydrochloride
Yield: 99% of theory,
C ₂₂ H ₂₆ N ₄ O ₃ × HCl (394.48 / 430.94)
Mass spectrum: (M + H) ⁺ = 395
(MH) ^- = 393
(4) 2- (5-carbamimidoyl-2-phenoxy-phenyl) -N-methyl-N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide hydrochloride
Yield: 90% of theory,
C ₂₉ H ₃₂ N ₄ O ₃ · HCl (484.60 / 521.06)
Mass spectrum: (M + H) ⁺ = 485
(M-H + HCl) ^- = 519/21 (Cl)

Example 5 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [2,5-dimethyl-4- (pyrrolidin lidin-1-yl-carbonyl) -phenyl] -acetamide hydrochloride a. 2,5-Dimethyl-4- (pyrrolidin-1-yl-carbonyl) bromobenzene

Prepared analogously to Example 1b from 4-bromo-3,5-dimethyl-benzoic acid, pyrrolidine, O- (benzotriazol-1-yl) -N, N, N ', N'-tetra methyluronium tetrafluoroborate and triethylamine in dimethylformamide.
Yield: 63% of theory,
R _f value: 0.45 (silica gel, methylene chloride / ethanol = 19: 1)

b. 2,5-Dimethyl-4- (pyrrolidin-1-yl-carbonyl) -benzylanilin

2.3 g (0.01 mol) of 2,5-dimethyl-4- (pyrrolidin-1-yl-carbonyl) bromobenzene and 1.3 g (0.012 mol) of benzylamine are dissolved in 25 ml of toluene and after addition of 4.6 g of cesium carbonate, 100 mg of palladium -II-acetate and 200 mg of 2,2'-bis (-diphenylphosphino) - 1,1'-binaphthyl for 7 hours under argon atmosphere at 100 ° C stirred. After cooling, it is diluted with ice-water and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. The residue is chromatographed on silica gel, eluting with methylene chloride / ethanol (50: 1 and 25: 1).
Yield: 60% of theory,
R _f value: 0.30 (silica gel, methylene chloride / ethanol = 9: 1)

c. 2,5-Dimethyl-4- (pyrrolidin-1-yl-carbonyl) -aniline

Prepared analogously to Example 1c from 2,5-dimethyl-4- (pyrrolidin-1-yl-carbonyl) benzylaniline and palladium on activated carbon in methanol.
Yield: 94% of theory,
R _f value: 0.30 (silica gel, ethyl acetate / petroleum ether = 1: 1)

d. 2-benzyloxy-5-bromo-phenylacetic acid

12.4 g (0.053 mol) of 2-hydroxy-5-bromo-phenylacetic acid are dissolved in 125 ml of dimethylformamide and stirred for 15 minutes at room temperature after addition of 14 g (0.125 mol) of potassium tert-butylate. Subsequently, 18.5 g (0.108 mol) of benzyl bromide are added, and the reaction solution is stirred for 3 hours at room temperature. After cooling to room temperature, the solution is poured onto ice-water and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. The residue is dissolved in 100 ml of ethanol and stirred for 3 hours at room temperature after addition of 50 ml of 2N sodium hydroxide solution. The solvent is distilled off, the residue is adjusted to pH 4 with 2N hydrochloric acid. After extraction with ethyl acetate, the organic phases are dried and evaporated. The residue is chromatographed on silica gel and eluted with petroleum ether / ethyl acetate (8: 2).
Yield: 6.7 g (38% of theory),
R _f value: 0.50 (silica gel, ethyl acetate / petroleum ether = 1: 1)

e. 2-benzyloxy-5-cyano-phenylacetic acid

Prepared analogously to Example 2d from 2-benzyloxy-5-bromo-phenyl acetic acid, copper-1-cyanide, tetrakis-triphenylphosphine-pal ladium- (0) and alumina in dimethylformamide.
Yield: 26% of theory,
R _f value: 0.45 (silica gel, methylene chloride / ethanol = 19: 1)

f. 2- (5-cyano-2-benzyloxy-phenyl) -N- [2,5-dimethyl-4- (pyrroli din-1-yl-carbonyl) -phenyl] -acetamide

Prepared analogously to Example 1b from 2-benzyloxy-5-cyano-phenylacetic acid, 2,5-dimethyl-4- (pyrrolidin-1-yl-carbonyl) -aniline, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate and N-methylmorpholine in tetrahydrofuran.
Yield: 44% of theory,
R _f value: 0.75 (silica gel, ethyl acetate / ethanol = 9: 1)

G. 2- (5-carbamimidoyl-2-benzyloxy-phenyl) -N- [2,5-dimethyl- 4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide

Prepared analogously to Example 1e from 2- (5-cyano-2-benzyloxy-phenyl) -N- [2,5-dimethyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide and hydrochloric acid / ammonium carbonate in ethanol.
Yield: 86% of theory,
R _f value: 0.20 (silica gel, methylene chloride / ethanol / glacial acetic acid = 8: 2: 0.01)

H. 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [2,5-dimethyl- 4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide hydrochloride

355 mg (0.68 mmol) of 2- (5-carbamimidoyl-2-benzyloxyphenyl) -N- [2,5-dimethyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide are dissolved in 40 ml of methanol dissolved and hydrogenated after addition of 250 mg of palladium on activated carbon for 15 minutes with hydrogen. It is then filtered off from the catalyst and evaporated.
Yield: 145 mg (49% of theory),
R _f value: 0.10 (silica gel, methylene chloride / ethanol / glacial acetic acid = 8: 2: 0.01)
C ₂₂ H ₂₆ N ₄ O ₃ × HCl (394.48 / 430.94)
Mass spectrum: (M + H) ⁺ = 395
(MH) ^- 393

Example 6 2- (2-benzyloxy-5-carbamimidoyl-phenyl) -N- (2-ethoxycarbonyl ethyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acet amide hydrochloride a. N- (2-methoxycarbonyl-ethyl) -3-methyl-4- (pyrrolidin-1-yl- carbonyl) -aniline

1.5 g (7.3 mmol) of 3-methyl-4- (pyrrolidin-1-yl-carbonyl) -aniline, 20 ml (220 mmol) of methyl acrylate, 1 ml (2.2 mmol) of triton B and 60 mg (0.27 mmol) of 2 5-di-tert-butyl-hydroquinone who the 22 hours at 85 ° C is carried out. Subsequently, the reac tion mixture is evaporated, the residue is chromatographed on silica gel, eluting with methylene chloride +0 to 5% ethanol.
Yield: 1.6 g (76% of theory),
R _f value: 0.70 (silica gel, methylene chloride / ethanol = 9: 1)

b. 2- (2-benzyloxy-5-cyano-phenyl) -N- (2-ethoxycarbonyl-ethyl) - N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide

0.8 g (2.88 mmol) of N- (2-methoxycarbonyl-ethyl) -3-methyl-4- (pyrrolidin-1-yl-carbonyl) -aniline are dissolved in 50 ml of tetrahydrofuran and after addition of 1.1 ml (7.86 mmol) Triethylamine with 0.8 g (2.62 mmol) of 2-benzyloxy-5-cyano-phenylessigsäurechlorid stirred for 8 hours at room temperature. It is then diluted with water and extracted with methylene chloride. The combined organic extracts are dried and evaporated. The residue is chromatographed on silica gel, eluting with methylene chloride.
Yield: 1.0 g (71% of theory),
R _f value: 0.72 (silica gel, methylene chloride / ethanol = 9: 1)

c. 2- (2-benzyloxy-5-carbamimidoyl-phenyl) -N- (2-ethoxycarbonyl ethyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acet amide hydrochloride

Prepared analogously to Example 1e from 2- (2-benzyloxy-5-cyano-phenyl) -N- (2-ethoxycarbonyl-ethyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] - acetamide and hydrochloric acid / ammonium carbonate in ethanol.
Yield: 44% of theory,
R _f value: 0.17 (silica gel, methylene chloride / ethanol = 4: 1)
C ₃₃ H ₃₈ N ₄ O ₅ × HCl (570.69 / 607.16)
Mass spectrum: (M + H) ⁺ = 571

Example 7 2- (2-hydroxy-5-carbamimidoyl-phenyl) -N- (2-ethoxycarbonyl ethyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) phenyl] - acetamide hydrochloride

Prepared analogously to Example 5h from 2- (2-benzyloxy-5-carbaminediylphenyl) -N- (2-ethoxycarbonylethyl) -N- [3-methyl-4- (pyrrolidinyl-1-ylcarbonyl) - phenyl] -acetamide hydrochloride and palladium on charcoal in methanol.
Yield: 96% of theory,
R _f value: 0.45 (Reversed phase RP 8, methanol / 5% sodium chloride solution = 6: 4)
C ₂₆ H ₃₂ N ₄ O ₅ × HCl (480.57 / 517.04)
Mass spectrum: (M + H) ⁺ = 481

Example 8 2- (2-hydroxy-5-carbamimidoyl-phenyl) -N- (2-carboxy-ethyl) - N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamid- hydrochloride

0.3 g (0.58 mmol) of 2- (2-hydroxy-5-carbamimidoyl-phenyl) -N- (2-ethoxycarbonyl-ethyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl ] -acetamide hydrochloride are stirred in a mixture of 3.2 ml (3.2 mmol) of 1 molar lithium hydroxide solution, 6.2 ml of water and 7.6 ml of tetrahydrofuran for 2 hours at room temperature. After addition of 74 mg of ammonium chloride, the solution is evaporated. The residue is chromatographed on reversed phase and eluted with water.
Yield: 0.2 g (71% of theory),
R _f value: 0.62 (Reversed phase RP 8, methanol / 5% sodium chloride solution = 6: 4)
C ₂₄ H ₂₈ N ₄ O ₅ · HCl (452.52 / 488.97)
Mass spectrum: (M + H) ⁺ = 453
(MH) ^- = 451

Example 9 3-Carbamimidoyl-N- [4- (pyrrolidin-3-yl-oxy) -benzyl] -benzamide dihydrochloride a. N-t-butyloxycarbonyl-3-pyrrolidinol

5.8 g (66.5 mmol) of 3-pyrrolidinol and 6.7 g (67 mmol) of triethylamine are dissolved in 80 ml of methylene chloride and treated dropwise with a solution of 15.3 g (70 mmol) of di-tert-butyl-dicarbonate in 40 ml of methylene chloride. The mixture is then stirred for 16 hours at room temperature and stirred with water. The organic phase is dried and evaporated.
Yield: 12.4 g (100% of theory),
R _f value: 0.75 (silica gel, ethyl acetate / methanol = 9: 1)

b. 4 - [(N-t-butoxycarbonyl) -pyrrolidin-3-yl-oxy] -benzoni tril

3.8 g (20 mmol) of N-tert-butyloxycarbonyl-3-pyrrolidinol are dissolved in 100 ml of tetrahydrofuran and, after addition of 2.4 g (20 mmol) of 4-hydroxybenzonitrile, 5.7 g (22 mmol) of triphenylphosphine and 3.9 g (22 mmol) Diethylazodicarbonsäurediethylester stirred for 18 hours at room temperature. The solvent is distilled off and the residue is chromatographed on silica gel, eluting with cyclohexane / ethyl acetate (10: 5).
Yield: 4.5 g (78% of theory),
R _f value: 0.40 (silica gel, cyclohexane / ethyl acetate = 10: 5)

c. 4 - [(N-t-butoxycarbonyl) -pyrrolidin-3-yl-oxy] benzyl amine

4.5 g (15.6 mmol) of 4 - [(N-tert-butyloxycarbonyl) -pyrrolidin-3-yl-oxy] -benzonitrile are dissolved in 100 ml of methanol and 50 ml of methanolic ammonia and after addition of 1 g of Raney nickel for 2 hours at Hydrogenated at 50 ° C with hydrogen. Subsequently ßend is filtered off from the catalyst and evaporated.
Yield: 4.2 g (92% of theory),
R _f value: 0.08 (silica gel, ethyl acetate / methanol = 4: 1)

d. 3-Cyano-N- [4- (N'-t-butyloxycarbonyl-pyrrolidin-3-yl oxy) benzyl] benzamide

1.1 g (3.8 mmol) of 4 - [(N-tert-butyloxycarbonyl) -pyrrolidin-3-yl-oxy] -benzylamine are dissolved in 30 ml of methylene chloride and after addition of 0.9 g (9 mmol) of triethylamine in portions with 1.6 g (3.8 mmol) of 3-cyanobenzoic acid chloride. After 4 hours at room temperature, the solution is mixed with water ver, the organic phase is dried and evaporated.
Yield: 1.5 g (94% of theory),
R _f value: 0.27 (silica gel, methylene chloride / ethyl acetate = 9: 1)

e. 3-Carbamimidoyl-N- [4- (pyrrolidin-3-yl-oxy) -benzyl] -benz amide dihydrochloride

Prepared analogously to Example 1e from 3-cyano-N- [4- (N'-tert-butyl-tyloxycarbonylpyrrolidin-3-yl-oxy) benzyl] benzamide and hydrochloric acid / ammonium chloride in ethanol.
Yield: 100% of theory,
Melting point: from 180 ° C (decomposition)
C ₁₉ H ₂₂ N ₄ O ₂ × 2 HCl (338.41 / 411.41)
Mass spectrum: (M + H) ⁺ = 339

The following compounds are prepared analogously to Example 9:
(1) 3-Carbamimidoyl-N- [4- (cyclopentyloxy) benzyl] benzamide hydrochloride
Yield: 86% of theory
R _f value: 0.42 (silica gel, methylene chloride / ethanol = 8: 2)
C ₂₀ H ₂₃ N ₃ O ₂ × HCl (337.43 / 373.89)
Mass spectrum: (M + H) ⁺ = 338
(2) 3-Carbamimidoyl-N- [4- (benzyloxy) -benzyl] -benzamide hydrochloride
Yield: 63% of theory
R _f value: 0.28 (silica gel, methylene chloride / ethanol = 17: 1)
C ₂₂ H ₂₁ N ₃ O ₂ × HCl (359.43 / 395.89)
Mass spectrum: (M + H) ⁺ = 360
(3) 3-Carbamimidoyl-N- [4- (N'-acetyl-pyrrolidin-3-yl-oxy) -benzyl] -benzamide hydrochloride
Yield: 100% of theory,
R _f value: 0.08 (silica gel, methylene chloride / ethanol = 9: 1)
C ₂₁ H ₂₄ N ₄ O ₃ × HCl (380.45 / 416.91)
Mass spectrum: (M + H) ⁺ = 381
(4) 3-Carbamimidoyl-N- [4- (N'-methyl-pyrrolidin-3-yl-oxy) -benzyl] -benzamide hydrochloride
Yield: 29% of theory,
R _f value: 0.07 (silica gel, methylene chloride / ethanol = 7: 3)
C ₂₀ H ₂₄ N ₄ O ₂ × HCl (352.44 / 388.91)
Mass spectrum: (M + H) ⁺ = 353
(5) 3-Carbamimidoyl-N- [4- (N '- (aminomethylcarbonyl) -pyrrolidin-3-yl-oxy) -benzyl] -benzamide dihydrochloride
Yield: 82% of theory,
Melting point: from 160 ° C (decomposition)
C ₂₁ H ₂₅ N ₅ O ₃ x 2 HCl (395.54 / 468.46)
Mass spectrum: (M + H) ⁺ = 396
(6) 3-Carbamimidoyl-N- [4- (N '- (2-aminoethyl-carbonyl) -pyrrolinedin-3-yl-oxy) -benzyl] -benzamide dihydrochloride
Yield: 88% of theory,
Melting point: from 165 ° C (decomposition)
C ₂₂ H ₂₇ N ₅ O ₃ x 2 HCl (409.48 / 482.48)
Mass spectrum: (M + H) ⁺ = 410
(7) 3-Carbamimidoyl-N- [4- (3-amino-propyloxy) -benzyl] -benzamide dihydrochloride
Yield: 82% of theory,
Melting point: from 122 ° C (decomposition)
C ₁₈ H ₂₂ N ₄ O ₂ × 2 HCl (326.40 / 399.4)
Mass spectrum: (M + H) ⁺ = 327
(8) 3-Carbamimidoyl-N- [4- (2-dimethylamino-ethyloxy) -benzyl] -benzamide dihydrochloride
Yield: 85% of theory,
Melting point: from 65 ° C (decomposition)
C ₁₉ H ₂₄ N ₄ O ₂ x 2 HCl (340.43 / 413.43)
Mass spectrum: (M + H) ⁺ = 341
(9) 3-Carbamimidoyl-N- [4- (pyridin-4-yl-oxy) -benzyl] -benzamide hydrochloride
Yield: 66% of theory,
Melting point: 115 ° C (decomposition)
C ₂₀ H ₁₈ N ₄ O ₂ × HCl (346.39 / 382.89)
Mass spectrum: (M + H) ⁺ = 347
(10) 3-Carbamimidoyl-N- [4- (piperidin-4-yl-oxy) -benzyl] -benzamide hydrochloride
Yield: 62% of theory
Melting point: from 170 ° C (decomposition)
C ₂₀ H ₂₄ N ₄ O ₂ × HCl (352.44 / 388.89)
Mass spectrum: (M + H) ⁺ = 353

Example 10 3-Carbamimidoyl-N- [4- (1- (1-imino-ethyl) -pyrrolidin-3-yl-oxy) - benzyl] benzamide dihydrochloride a. 3-Cyano-N- [4- (pyrrolidin-3-yl-oxy) -benzyl] -benzamide

2.4 g (5.7 mmol) of 3-cyano-N- [4- (N-tert-butyloxycarbonylpyrrolidin-3-yl-oxy) benzyl] benzamide are dissolved in 30 ml of methylene chloride, at 0 ° C with 8 ml of trifluoroacetic acid and then stirred for 1 hour at room temperature. The sol vens is distilled off, the residue taken in methylene chloride, made alkaline with ammonia and ver with water. The combined organic extracts are dried and evaporated.
Yield: 1.4 g (76% of theory),
R _f value: 0.29 (silica gel, methylene chloride / methanol / ammonia = 7: 3: 0.2)

b. -ben 3-Cyano-N- [4- (1- (1-imino-ethyl) -pyrrolidin-3-yl-oxy) cyl] -benzamide

0.7 g (2.17 mmol) of 3-cyano-N- [4- (pyrrolidin-3-yl-oxy) benzyl] benzamide, 0.4 g (3.2 mmol) of ethyl acetimidine hydrochloride and 1 g (10 mmol) of triethylamine are dissolved in 70 ml of ethanol ge and stirred for 6 days at room temperature. The solvent is distilled off, the residue taken up in water and made alkaline with sodium carbonate. Then it is extracted with methylene chloride, the combined organic extracts who dried and evaporated. The residue is triturated with ether and filtered with suction.
Yield: 0.6 g (76% of theory),
R _f value: 0.37 (silica gel, methylene chloride / methanol / ammonia = 7: 3: 0.2)
Melting point: from 80 ° C (decomposition)

c. 3-Carbamimidoyl-N- [4- (1- (1-imino-ethyl) -pyrrolidin-3-yl oxy-benzyl] benzamide dihydrochloride

Prepared analogously to Example 1e from 3-cyano-N- [4- (1- (1-imino ethyl) -pyrrolidin-3-yl-oxy) benzyl] benzamide and hydrochloric acid / ammonium carbonate in ethanol.
Yield: 64% of theory,
Melting point: from 100 ° C (decomposition)
C ₂₁ H ₂₅ N ₅ O ₂ × 2 HCl (379.46 / 452.46)
Mass spectrum: (M + H) ⁺ = 380

The following compound is prepared analogously to Example 10:
(1) 3-Carbamimidoyl-N- [4- (1-carbamimidoyl-pyrrolidin-3-yl-oxy) -benzyl] -benzamide dihydrochloride
Yield: 88% of theory,
Melting point: from 160 ° C (decomposition)
C ₂₀ H ₂₄ N ₆ O ₂ × 2 HCl (380.45 / 453.38)
Mass spectrum: (M + 2H) ⁺⁺ = 191

Example 11 3-Carbamimidoyl-N- [4- (benzoylamino) -benzyl] -benzamide hydrochloride chloride a. 3-Cyano-N- (4-amino-benzyl) -benzamide

6 g (0.05 mol) of 4-aminobenzylamine and 10 g (0.1 mol) of triethylamine are dissolved in 150 ml of methylene chloride and treated at room temperature dropwise with a solution of 8.3 g (0.05 mol) of 3-cyanobenzoyl chloride in 20 ml of methylene chloride. After one hour, 150 ml of water and 20 ml of methanol are added. After extraction, the combined organic extracts are dried and evaporated. The residue is chromatographed on silica gel and eluted with ethyl acetate.
Yield: 4.4 g (35% of theory),
R _f value: 0.69 (silica gel, ethyl acetate)

b. 3-Cyano-N- [4- (benzoylamino) benzyl] benzamide

To a solution of 1 g (4 mmol) of 3-cyano-N- (4-amino-benzyl) -benzamide and 0.6 g (6 mmol) of triethylamine in 30 ml of methylene chloride at room temperature, a solution of 0.6 g (4.2 mmol) Benzoyl chloride in 10 ml of methylene chloride was added dropwise. After 8 hours at room temperature, the crystallized product is dissolved in methylene chloride and methanol. After extraction with water, the combined organic extracts are dried and evaporated.
Yield: 1.2 g (84% of theory),
Melting point: 210 ° C

c. 3-Carbamimidoyl-N- [4- (benzoylamino) -benzyl] -benzamide hydrochloride chloride

Prepared analogously to Example 1e from 3-cyano-N- [4- (benzoylamino) benzyl] benzamide and hydrochloric acid / ammonium carbonate in ethanol.
Yield: 65% of theory,
Melting point: 190-215 ° C
C ₂₂ H ₂₀ N ₄ O ₂ × HCl (372.43 / 408.93)
Mass spectrum: (M + H) ⁺ = 373

The following compounds are prepared analogously to Example 11:
(1) 3-Carbamimidoyl-N- [4- (phenylsulfonylamino) -benzyl] -benz amide hydrochloride
Yield: 80% of theory,
Melting point: 266 ° C
C ₂₁ H ₂₀ N ₄ O ₃ S x HCl (408.48 / 444.98)
Mass spectrum: (M + H) ⁺ = 409
(2) 3-Carbamimidoyl-N- [4- (benzylamino) -benzyl] -benzamide hydrochloride
Yield: 69% of theory,
C ₂₂ H ₂₂ N ₄ O x HCl (358.44 / 394.94)
Mass spectrum: (M + H) ⁺ = 359
(3) 3-Carbamimidoyl-N- [4- (N-benzyl-N-ethoxycarbonylmethyl-amino) -benzyl] -benzamide hydrochloride
Yield: 79% of theory,
Melting point: from 100 ° C
C ₂₆ H ₂₈ N ₄ O ₃ · HCl (444.54 / 481.04)
Mass spectrum: (M + H) ⁺ = 445
(4) 3-carbamimidoyl-N- [4-biphenyl-methyl] -benzamide
Yield: 79% of theory,
Melting point: from 160 ° C (decomposition)
C ₂₁ H ₁₉ N ₃ O (329.40)
Mass spectrum: (M + H) ⁺ = 330
(5) 3-Carbamimidoyl-N- [4- (cyclopentylamino) -benzyl] -benzamide hydrochloride
Yield: 80% of theory,
Melting point: from 135 ° C (decomposition)
C ₂₀ H ₂₄ N ₄ O x HCl (336.44 / 372.94)
Mass spectrum: M ⁺ = 336

Example 12 3-carbamimidoyl-N- (4-dimethylaminomethyl-benzyl) -benzamide di hydrochloride a. 4-cyano-N, N-dimethyl-benzylamine

A solution of 7.3 g (0.16 mol) of dimethylamine in 100 ml of ether is added dropwise at -5 ° C. to a solution of 10 g (0.05 mol) of 4-cyanobenzyl bromide in 400 ml of ether. Subsequently, the reaction mixture is stirred for 2 hours at -5 ° C and 20 hours at room temperature. After addition of 200 ml of water and 200 ml of conc. Hydrochloric acid, the aqueous solution is separated, made alkaline with sodium hydroxide solution and hiert extra with methylene chloride. The combined organic extracts are dried and evaporated.
Yield: 8 g (100% of theory),
R _f value: 0.58 (silica gel, methylene chloride / ethanol = 9: 1)

b. 4-dimethylaminomethyl-benzylamine

Prepared analogously to Example 9c from 4-cyano-N, N-dimethyl benzylamine, methanolic ammonia and Raney nickel / hydrogen.
Yield: 94% of theory,
R _f value: 0.13 (silica gel, methylene chloride / ethanol = 9: 1)

c. 3-Cyano-N- (4-dimethylaminomethyl-benzyl) -benzamide

Prepared analog Example 9d from 4-dimethylaminomethylbenzylamine, 3-cyanobenzoyl chloride and triethylamine in Me methylene chloride.
Yield: 73% of theory,
Melting point: 100 ° C

d. 3-carbamimidoyl-N- (4-dimethylaminomethyl-benzyl) -benzamide dihydrochloride

Prepared analogously to example 1e from 3-cyano-N- (4-dimethylaminomethylbenzyl) benzamide and hydrochloric acid / ammonium carbonate in ethanol.
Yield: 100% of theory,
Melting point: from 101 ° C (decomposition)
C ₁₈ H ₂₂ N ₄ O x 2 HCl (310.40 / 383.40)
Mass spectrum: (M + H) ⁺ = 311

The following compound is prepared analogously to Example 12:
(1) 3-Carbamimidoyl-N- [4- (imidazol-1-yl) -methyl-benzyl] -benz amide hydrochloride
Yield: 86% of theory,
Melting point: from 152 ° C (decomposition)
C ₁₉ H ₁₉ N ₅ O. HCl (333.39 / 369.89)
Mass spectrum: (M + H) ⁺ = 334

Example 13 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 the use solution eR _f olgt with water for injections.

Example 14 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 15 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 16 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 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: 12 mm.

Example 17 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 mix 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 18 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 19 Suppositories containing 100 mg of active ingredient

AL = L <1 suppository contains: 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           2,000.0 mg         

manufacturing

The polyethylene glycol is used together with Polyethylensorbi tanmonostearat 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 (9)

1. Carboxylic acid amides of the general formula
in the
one of the radicals m or n is the number 0 and
the other radicals m or n are the number 1,
Ar is an optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl, hydroxy, C _1-3 alkoxy, phenyl C _1-3 alkoxy, amino, C _1-3 -alkylamino or di (C _1-3 -alkyl) -amino group substituted phenylene or Naphthylengrup pe, wherein the phenylene group by another fluorine, chlorine or bromine atom or by another C _1-3 Alkyl group can be substi tuiert,
a thienylene, thiazolylene, pyridinyl, pyrimidinyl, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C _1-3 -alkyl group,
R _{1 is} a hydrogen atom, an optionally substituted by an amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, phenyl, naphthyl or heteroaryl substituted C _1-3 alkyl group,
a C _3-7 cycloalkyl group substituted in the 1-position by a 5- to 7-membered cycloalkyleneiminocarbonyl group,
a 4- to 7-membered cycloalkyleneiminocarbonyl group,
an optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy substituted phenyl group,
a C _1-3 alkoxy, phenylC _1-3 -alkoxy, heteroaryloxy or heteroaryloxyC _1-3 -alkoxy group in which the alkoxy moiety in each case in the 2- or 3-position is also denoted by an amino, C _1-3 alkyl-amino or di (C _1-3 -alkyl) -amino group may be substituted,
a C _3-7 -cycloalkoxy group, wherein the methylene group in the 3- or 4-position in a C _5-7 -cycloalkoxy group may be replaced by an -NH-group, where the -NH-group is represented by an arylcarbonyl or arylsulfonyl group, by a C _1-3 alkylcarbonyl group in which the oxygen atom of the carbonyl group is replaced by an imino group and the alkanoyl part by an amino, C _1-3 alkylamino or di (C _1-3 alkyl) amino group substitui may be substituted by a C _1-3 alkyl group which may be substituted in the 2- or 3-position by an amino, C _1-3 alkylamino or di (C _1-3 alkyl) amino group .
R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, a C _1-3 -alkyl, hydroxy or C _1-3 -alkoxy group,
R _{3 is} a hydrogen atom or a C _1-3 -alkyl group,
R _{4 is} a hydrogen atom or an optionally substituted by a carboxy group C _1-3 alkyl group and
R _{5 represents} a cyano group or an amidino group optionally substituted by one or two C _1-3 -alkyl groups,
wherein the carboxy groups mentioned in the definition of the abovementioned radicals are 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 be substituted by a cleavable in vivo radical,
their tautomers, their stereoisomers, their mixtures and their salts. 2. Carbonsäueamide of the general formula I according to claim 1, in which
one of the radicals m or n is the number 0 and the other radical m or n is the number 1,
Ar is an optionally substituted by a fluorine, chlorine or bromine atom, by a methyl, hydroxy, methoxy or benzyloxy substituted phenylene group, which may be substituted by another Me methyl group,
R _{1 is} a phenyl, dimethylaminomethyl, cyclopentylamino, benzylamino, N- (carboxymethyl) -benzylamino, N- (C _1-3 -alkoxycarbonylmethyl) -benzylamino, 1-imidazolylamino, benzoylamino or phenylsulfonylamino group,
a cyclopropyl group substituted in the 1-position by a 5- to 7-membered cycloalkyleneiminocarbonyl group,
a 4- to 7-membered cycloalkyleneiminocarbonyl group,
a C _1-3 alkoxy group in which the alkoxy moiety in each case in the 2- or 3-position may be substituted by an amino, C _1-3 -alkylamino or di (C _1-3 -alkyl) -amino group, a phenyl C _1-3 alkoxy or pyridinyloxy group,
a C _5-7 -cycloalkoxy group in which the methylene group in the 3- or 4-position can be replaced by an -NH group, where the -NH group is substituted by an optionally substituted by an amino group C _1-3 alkylcarbonyl group, in which the oxygen atom of the carbonyl group may be replaced by an imino group and the alkyl moiety may be substituted by an amino group, or may be substituted by a methyl group,
R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxy or methoxy group,
R _{3 is} a hydrogen atom or a methyl group,
R _{4 is} a hydrogen atom or an optionally substituted by a carboxy or C _1-3 alkoxycarbonyl methyl or ethyl group and
R _{5 represents} a cyano group or an amidino group,
their isomers and their salts. 3. Carbonsäueamide of the general formula I according to claim 1, in which
one of the radicals m or n is the number 0 and the other radical m or n is the number 1,
Ar is an optionally substituted by a methyl, hydroxy, methoxy or benzyloxy substituted phenylene group,
R _{1 represents} a cyclopropyl group substituted in the 1-position by a 5- to 7-membered cycloalkyleneiminocarbonyl group, or a 4- to 7-membered cycloalkyleneiminocarbonyl group,
R _{2 is} a hydrogen, fluorine, chlorine or bromine atom or a methyl group,
R _{3 is} a hydrogen atom,
R _{4 is} a hydrogen atom or a substituted by a carboxy, meth oxycarbonyl or ethoxycarbonyl methyl or ethyl group and
R _{5 is} an amidino group,
their isomers and their salts. 4. The following carboxylic acid amides of the general formula I according to claim 1:

• a) 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (pyrrolidinyl-1-yl-carbonyl) -phenyl] -acetamide,
• b) 2- (2-Benzyloxy-5-carbamimidoyl-phenyl) -N- (2-ethoxycarbonyl-ethyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide .
• c) 2- (2-hydroxy-5-carbamimidoyl-phenyl) -N- (2-ethoxycarbonyl-ethyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide and
• d) 2- (2-Hydroxy-5-carbamimidoyl-phenyl) -N- (2-carboxy-ethyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide

and their salts. 5. Physiologically acceptable salts of the compounds according to claims 1 to 4, in which R _{5 represents} one of the amidino groups mentioned in claims 1 to 4. 6. A pharmaceutical composition containing a compound according to at least one of claims 1 to 4, in which R _{5 is} one of the claims 1 to 4 mentioned in the amidino groups, or a salt according to claim 5 besides optionally one or more inert carriers and / or diluents , 7. Use of a compound according to at least one of claims 1 to 4, in which R _{5 is} one of the amidino groups mentioned in claims 1 to 4, or a salt according to claim 5 for the preparation of a medicament having an anti-thrombotic action. 8. A process for the preparation of a medicament according to claim 6, characterized in that non-chemical way a compound according to at least one of claims 1 to 4, in which R _{5 is} one of the mentioned in the claims 1 to 4 Ami dinogruppen, or a salt is incorporated according to claim 5 in one or more inert carriers and / or diluents. 9. A process for the preparation of the compounds according to the entitlements to 1 to 5, characterized in that

• a) a compound of the general formula
  in the
  R ₁ to R ₄ and m are defined as mentioned in claims 1 to 4, with a carboxylic acid of the general formula
  HO-CO- (CH ₂ ) _n -Ar-R ₅ (III),
  in the
  Ar, R ₅ and n are defined as mentioned in claims 1 to 4, or acylated with their reactive derivatives or
• b) for the preparation of a compound of general formula I in which R _{5 is} an amidino group which may be substituted by one or two C _1-3 -alkyl groups, a compound optionally formed in the reaction mixture Re of the general formula
  in the
  R ₁ to R ₄ , Ar and n as mentioned in claims 1 to 4 are de fined and
  Z _{1 represents} an alkoxy, aralkoxy, alkylthio or aralkylthio group with an amine of the general formula
  HR ₆ NR ₇ (V)
  in the
  R ₆ and R _7, which may be the same or different, each represents a hydrogen atom or a C _1-3 alkyl group, or is reacted with its salts, and
  if desired, subsequently a compound of the general formula I thus obtained, which keeps an amino or imino group ent, is converted by means of a corresponding acyl derivative into an ent speaking acyl compound of the general formula I and / or
  a compound of the general formula I thus obtained, which contains an esterified carboxy group, is converted by hydrolysis into a corresponding carboxylic acid of the general formula I and / or
  a compound of the general formula I thus obtained, which contains a carboxy group, is converted by esterification into an ent speaking ester 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.