CA2319494A1 - 5-membered heterocyclic condensed benzoderivatives, the preparation thereof and their use as pharmaceuticals - Google Patents

5-membered heterocyclic condensed benzoderivatives, the preparation thereof and their use as pharmaceuticals Download PDF

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CA2319494A1
CA2319494A1 CA002319494A CA2319494A CA2319494A1 CA 2319494 A1 CA2319494 A1 CA 2319494A1 CA 002319494 A CA002319494 A CA 002319494A CA 2319494 A CA2319494 A CA 2319494A CA 2319494 A1 CA2319494 A1 CA 2319494A1
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methyl
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Uwe Ries
Norbert Hauel
Gerhard Mihm
Henning Priepke
Klaus Binder
Jean Marie Stassen
Wolfgang Wienen
Rainer Zimmermann
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Boehringer Ingelheim Pharma GmbH and Co KG
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Priority claimed from DE1998134325 external-priority patent/DE19834325A1/en
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    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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Abstract

The invention relates to new five-membered, heterocyclic condensed benzoderivatives of the general formula (I), in which Ra to Rc, A, Ar, X and Y
have the meanings assigned in claim 1, and their tautomers, stereoisomers, mixtures and salts, especially their physiologically compatible salts with inorganic or organic acids or bases, which have valuable properties. The compounds of the general formula (I) above, in which Rc is a cyano group, present valuable intermediate products for the production of the remaining compounds of the general formula (I), and the compounds of the above general formula (I), in which Rc is one of the following amidino groups, as well as their tautomers and stereoisomers, have valuable pharmacological properties, especially an antithrombotic activity.

Description

Boehringer Ingelheim Pharma KG Case 5/1227-FL
D-55216 INGELHEIM Auslandstext 5-Membered heterocyclic condensed benzoderivatives, the preparation thereof and their use as pharmaceuticals The present invention relates to new 5-membered heterocyclic condensed benzoderivatives of general formula Ra Rb I ~~A Ar R~ , ( I ) \ Y
their tautomers, stereoisomers, mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable properties.
The compounds of the above general formula I wherein R denotes a cyano group are valuable intermediates for the preparation of the other compounds of general formula I, and the compounds of the above general formula I wherein R denotes one of the following amidino groups, and the tautomers and stereoisomers thereof have valuable pharmacological properties, particularly an antithrombotic activity.
The present application thus relates to the new compounds of the above general formula I and the preparation thereof, phar-maceutical compositions containing the pharmacologically effec-tive compounds and the use thereof.
In the above general formula A denotes an oxygen or sulphur atom, a carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C1_,-alkyl group or a methylene group optionally mono- or disubstituted by a carboxy-Cl_3-alkyl- or C1_3-alkoxycarbonyl-Cl_3-alkyl group, Ar denotes a phenylene or naphthylene group each optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C -alkyl- or C -alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group each optionally substituted in the carbon skeleton by a C -alkyl group, X denotes a nitrogen atom or an -R1C= group wherein R1 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a C1_3-alkyl or C1_3-alkoxy group, Y denotes an oxygen or sulphur atom or an -RZN- group, wherein RZ denotes a hydrogen atom or a C1_5-alkyl group, a C1_3-alkyl group, which is substituted by a phenyl group optionally substituted by a carboxy or C1_3-alkoxycarbonyl group, a C1_5-alkyl group, which is substituted by a carboxy, C1_3-alk-oxycarbonyl, carboxy-C1_3-alkoxycarbonyl, C1_3-alkoxycarbonyl-Cl_3-alkoxycarbonyl, carboxy-C1_3-alkyl-aminocarbonyl or Cl_3-alk-oxycarbonyl-C1_3-alkylaminocarbonyl group, or an n-Cz_4-alkyl group, which is terminally substituted by a di (C1_3-alkyl)-amino, pyrrolidino, piperidino, morpholino, pipe-razino or N-C1_3-alkyl-piperazino group, whilst the abovemen-tioned cyclic groups may additionally be substituted by one or two C1_3-alkyl groups, Ra denotes a hydrogen atom or a C1_3-alkyl group, denotes a R3-CO-C3_5-cycloalkylene, Rj-SOZ-NR4, R3-CO-NR4, RSNR6-CO, RSNR6-SOz- or RSNR6-CO-C3_5-cycloalkylene group, wherein R3 denotes a Cl_6-alkyl- or CS_,-cycloalkyl group, a C1_3-alkyl group, which is substituted by a CS_,-cyclo-alkyl, phenyl, C1_3-alkyl amino, di- (Cl_3-alkyl) -amino, carboxy-C1_3-al-kylamino, C1_3-alkoxycarbonylamino, phenylsulphonylamino or te-trazolyl group, a Cl_3-alkyl group, which is substituted by a carboxy, Cl_3-alk-~- oxycarbonyl, carboxy-C1_3-alkoxy or Cl_3-alkoxy-carbonyl-C1_j-alk-oxy group, a C1_3-alkyl group, which is substituted by an imidazolyl or benzimidazolyl group, whilst the imidazole moiety of the above-mentioned groups may be substituted by one or two C1_3-alkyl groups or by a carboxy-Cl_3-alkyl or Cl_3-alkoxycarbonyl-Cl_3-al-kyl group, a phenyl group optionally mono or disubstituted by C1_3-alkyl, C1_3-alkoxy, trifluoromethyl, carboxy or Cl_3-alkoxycarbonyl groups, wherein the substituents may be identical or different, a phenyl group substituted by 3 or 4 methyl groups, a naphthyl, ~25 pyridinyl, pyrazolyl, quinolyl or isoquinolyl group each optio-nally substituted by a C1_3-alkyl group, R4 denotes a hydrogen atom, a Cl_5-alkyl or CS_~-cycloalkyl group, a C1_5-alkyl group, which is substituted by a carboxy group or by a C1_5-alkoxycarbonyl group wherein the alkoxy moiety in the 2 or 3 position may additionally be substituted by a hydroxy group, a C1_3-alkyl group, which is substituted by an aminocarbonyl, hydroxyaminocarbonyl, C1_3-alkylamino-carbonyl, di-(C1_3-alkyl)-aminocarbonyl or CS_,-alkylene-iminocarbonyl group, whilst the C6_,-alkyleneimino moiety may additionally be substituted in the 4 position by a di-(C1_3-alkyl)-amino group, an optionally phenyl-substituted C1_3-alkyl group, which is sub-stituted in the alkyl moiety by a carboxy-C1_3-alkoxy-carbonyl, C1_3-alkoxycarbonyl-Cl_3-alkoxycarbonyl, carboxy-Cl_3-alkylamino-carbonyl, N- (C1_3-alkyl) -carboxy-C1_3-alkyl-aminocarbonyl, C1_3-alkoxycarbonyl-Cl_3-alkylaminocarbonyl, N- (Cl_3-alkyl) -C1_3-alkoxycarbonyl-C1_3-alkylaminocarbonyl, morpholinocarbonyl or 4-(C1_3-alkyl)-piperazinocarbonyl group, a Cl_3-alkyl group, which is substituted by a carboxy-Cl_3-alkyl-aminocarbonyl, N- (C1_3-alkyl) -carboxy-Cl_3-alkyl-aminocarbonyl, Cl_3-alkoxycarbonyl-Cl_3-alkylaminocarbonyl or N- (Cl_3-alkyl) -C1_3-alkoxycarbonyl-C1_3-alkylamino-carbonyl group, which are additionally substituted at a carbon atom of the alkylamino moiety by a carboxy or C1_3-alkoxycarbonyl group, a C1_3-alkyl group, which is substituted by a di- (C1_3-alkyl) -aminocarbonyl group wherein an alkyl moiety may additionally be substituted in the 2 or 3 position by a di-(C1_3-alkyl)-amino group, a C1_3-alkyl group, which is substituted by a 4-(morpholinocar-bonyl-Cl_3-alkyl) -piperazinocarbonyl, N- (C1_3-alkyl) -pyrrolidinyl or N- (C1_3-alkyl) -piperidinyl group, or an n-CZ_4-alkyl group, which is terminally substituted by a di-(C1_3-alkyl) -amino, CS_.,-alkyleneimino or morpholino group, RS denotes a C1_5-alkyl or CS_,-cycloalkyl group, a phenyl-C1_3-alkyl group, which may be substituted in the alkyl moiety by a carboxy or C1_3-alkoxycarbonyl group, _ 5 _ an n-C2_4-alkyl group, which is substituted in the 2, 3 or 4 po-sition by a hydroxy, C1_3-alkylamino or di- (C1_3-alkyl) -amino group, a phenyl group optionally mono or disubstituted by a C1_3-alkyl, Cl_3-alkoxy, trifluoromethyl, carboxy or C1_3-alkoxycarbonyl group, wherein the substituents may be identical or different, a phenyl group substituted by 3 or 4 methyl groups, a naphthyl, pyridinyl, quinolyl or isoquinolyl group, R6 denotes a C1_5-alkyl group optionally substituted by a carb-oxy or C1_3-alkoxycarbonyl group, a C1_3-alkyl group, which is substituted in the alkyl moiety by a Cl_3-alkylaminocarbonyl, di- (C1_3-alkyl) -aminocarbonyl, carb-oxy-Cl_3-alkylaminocarbonyl or C1_3-alkyloxycarbonyl-C1_3-alkyl-aminocarbonyl group, or an n-Cz_4-alkyl group, which is substituted in the 2, 3 or 4 position by a hydroxy, C1_3-alkyl amino or di- (C1_3-alkyl) -amino group, or one of the groups RS or R6 denotes a hydrogen atom, whilst the other one of the groups has the meanings given for RS and R6 hereinbefore, or RS and R6 together with the nitrogen atom between them denote a pyrrolidino or piperidino group optionally substituted by one or two C1_3-alkyl groups, which may additionally be substituted by a carboxy-C1_3-alkyl or Cl_3-alkoxy-C1_3-alkyl group or on to which a benzene ring may be condensed via two adjacent carbon atoms, or Rb denotes an amino, C1_3-alkyl amino or CS_,-cycloalkyl-amino group, which may be substituted at the nitrogen atom by a phe-nylaminocarbonyl, N-phenyl-C1_3-alkylaminocarbonyl, phenylsul-phonylamino-C1_3-alkylcarbonyl, C1_3-alkyloxy-carbonyl-C1_,-alkyl, N- (C3_5-cycloalkyl) -C1_3-alkylamino-carbonyl, N- (hydroxycarbonyl-C1_3-alkyl) -aminocarbonyl, N- (Cl_j-alkoxycarbonyl-Cl_3-alkyl) -aminocarbonyl-C3_5-cyclo-alkylamino group, a piperidino group substituted in the 4 position by a di-(C1_3-alkyl) -amino group, a piperazino group substituted in the 4 position by a C1_3-alkyl group, a CZ_4-alkylsulphonyl group, which is substituted in the 2, 3 or 4 position by a di-(C1_3-alkyl)-amino group, a 4-oxo-3,4-dihydro-phthalazinyl-1-yl or 4-oxo-2,3-diaza-spiro[5.5]undec-1-en-1-yl group, a methyl group substituted by a CS_,-cycloalkyleneimino-carbonyl group wherein the methyl group is substituted by a carboxy-C1_3-alkyl or C1_3-alkoxy-C1_3-alkyl group, a carbonyl or methyl group substituted by a C3_5-cycloalkyl or C3_5-alkyl group, whilst the cycloalkyl moiety may additionally be substituted by a C1_3-alkyl, carboxy-Cl_3-alkyl or C1_3-alkoxy-carbonyl-C1_3-alkyl group and the methyl moiety is substituted z5 by a C1_3-alkoxy or C1_4-alkyl amino group, a CS_.,-cycloalkyl-N- (carboxy-C1_3-alkoxy) -iminomethylene or CS_.,-cycloalkyl-N- (C1_3-alkoxycarbonyl-Cl_j-alkoxy) -iminomethylene group, which may additionally be substituted in the cycloalkyl moiety by a C1_3-alkyl group, a phosphinyl group, which is substituted by a C1_6-alkyl or CS_.,-cycloalkyl group and by a hydroxy, C1_3-alkoxy, carboxy-C1_3-alkoxy or C1_3-alkoxycarbonyl-C1_3-alkoxy group, a piperidino group wherein in the 2 position a methylene group is replaced by a carbonyl or sulphonyl group, -a tetrazolyl group optionally substituted by a C1_5-alkyl group, a phenyl or phenylsulphonyl group optionally mono or disubsti-tuted by a C1_3-alkyl, Cl_3-alkoxy, trifluoromethyl, carboxy or C1_3-alkoxycarbonyl group, wherein the substituents may be iden-tical or different, a sulphimidoyl group, which is substituted at the sulphur atom by a CS_.,-cycloalkyl group and may additionally be substituted at the nitrogen atom by a Cz_4-alkanoyl, carboxy-Cl_3-alkyl, Cl_3-alkoxycarbonyl-Cl_3-alkyl, carboxy-C2_4-alkanoyl or Cl_3-alk-oxycarbonyl-C2_4-alkanoyl group, an imidazolyl group substituted in the 1 position by a carboxy-Cl_j-alkyl or Cl_3-alkoxycarbonyl-C1_3-alkyl group, which may additionally be substituted by a C1_5-alkyl group, a C1_3-alkoxycarbonyl-Cl_3-alkyl group, which is substituted in the alkyl moiety by a CS_.,-cycloalkylaminocarbonyl group, a C1_3-alkyl group, which is substituted by a 1-imidazolyl group, whilst the imidazolyl moiety may additionally be substi-tuted by one or two C1_3-alkyl groups, or in the 2 position by a 1-benzimidazolyl group substituted by a carboxy-C1_3-alkyl or C1_3-alkoxycarbonyl-Cl_3-alkyl group, or a furanyl-1-pyrazolyl group optionally substituted by a C1_3-al-kyl group, and R~ denotes a cyano group or an amidino group, which may be sub-stituted by a hydroxy group, by one or two C1_3-alkyl groups, by one or two C1_e-alkoxycarbonyl groups or by a group which can be cleaved in vivo, especially those compounds wherein A, X, Y and Ra to Rd are with the proviso as hereinbefore defi-ned that _ g _ Ar represents a 1,4-phenylene group, R3 does not represent a pyrazolyl group or a naphthyl, pyridi nyl, pyrazolyl, quinolyl or isoquinolyl group each substituted by a Cl_3-alkyl group and Rb does not represent a furanyl-1-pyrazolyl group optionally substituted by a C1_3-alkyl group.
The term "a group which can be cleaved in vivo from an imino or amino group" may refer, for example, to a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a C1-ls-alkanoyl group such as the formyl, acetyl, propionyl, bu-tanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C1_16-alkoxycarbonyl group such as the methoxycarbonyl, eth-oxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbo-nyl, tert. butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyl-oxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C1_6-alkoxycarbonyl group such as the benzyloxycar-bonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a Cl_3-alkylsulphonyl-C2_4-alkoxycarbonyl, C__3-alkoxy-C2_4-alkoxy-CZ_4-alkoxycarbonyl or RICO-O- (ReCR9) -O-CO group, wherein ~._ .,.. 2 5 R., denotes a Cl_8-alkyl , CS_.,-cycloalkyl , phenyl or phenyl-C1_3-alkyl group, RB denotes a hydrogen atom, a C1_3-alkyl, CS_,-cycloalkyl or phenyl group and R9 denotes a hydrogen atom or a C1_3-alkyl group.
Moreover, the saturated alkyl and alkoxy moieties mentioned in the above definitions which contain more than 2 carbon atoms also include the branched isomers thereof, such as the isopro-pyl, tert.butyl, isobutyl group etc.

- g _ Preferred compounds of the abovementioned invention are those of general formula Ra X
Rb I ~~-A ~ ~ R° , ( I a ) \ Y
wherein A, X, Y and Ra to R~ are as hereinbefore defined, especially those compounds of general formula Ia wherein A denotes a methylene group optionally substituted by a carb-oxy-Cl_3-alkyl or Cl_3-alkoxycarbonyl-Cl_3-alkyl group, or a carbonyl or imino group, X denotes a nitrogen atom or an -R1C= group, wherein R1 denotes a hydrogen, fluorine, chlorine or bromine atom, a Cl_3-alkyl or Cl_3-alkoxy group, Y denotes an oxygen or sulphur atom or an -RZN- group, wherein Rz denotes a hydrogen atom or a C1_5-alkyl group, a benzyl group, which may be substituted in the phenyl moiety by a carboxy or C1_3-alkoxycarbonyl group, a C1_5-alkyl group, which is substituted by a carboxy or C1_3-alkoxycarbonyl group, a C1_3-alkyl group, which is substituted by a carboxy-Cl_3-alk-oxycarbonyl, carboxy-C1_3-alkylaminocarbonyl or C1_3-alkoxycar-bonyl-C1_3-alkylaminocarbonyl group, or an n-CZ_4-alkyl group, which is terminally substituted by a di-(C1_3-alkyl) -amino or morpholino group, Ra denotes a hydrogen atom or a methyl group, Rb denotes an R3-CO-C3_S-cycloalkylene, R3-SOZ-NR4, R3-CO-NR4, RSNR6-CO, RSNR6-S02 or RSNR6-CO-C3_5-cycloalkylene group, wherein R3 denotes a C1_4-alkyl, cyclopentyl, cyclohexyl or benzyl group, a C1_3-alkyl group, which is substituted by a tetrazolyl, carb-oxy, Cl_3-alkoxycarbonyl, carboxy-C1_3-alkoxy, Cl_3-alkoxycarbo-nyl-Cl_3-alkoxy, carboxy-Cl_3-alkylamino, C1_3-alkoxycarbonylamino group, a phenyl group optionally mono or disubstituted by methyl, methoxy, trifluoromethyl, carboxy or methoxycarbonyl groups, wherein the substituents may be identical or different, a phe-nyl group substituted by 3 or 4 methyl groups, a 5-pyrazolyl group optionally substituted by a C1_3-alkyl group, a naphthyl, pyridinyl, quinolyl or isoquinolyl group, R4 denotes a hydrogen atom, a C1_5-alkyl or CS_.,-cycloalkyl group, a C1_5-alkyl group, which is substituted by a carboxy group or ~'25 by a C1_5-alkoxycarbonyl group wherein the alkoxy moiety in the 2 or 3 position may additionally be substituted by a hydroxy group, a C1_3-alkyl group, which is substituted by an aminocarbonyl, hydroxyaminocarbonyl or piperidinocarbonyl group, whilst the piperidino moiety may additionally be substituted in the 4 po-sition by a dimethylamino group, a C1_3-alkyl group, which is substituted by a carboxy-Cl_3-alkyl-aminocarbonyl, N-(C1_3-alkyl)-carboxy-C1_3-alkyl-aminocarbonyl, Cl_3-alkoxycarbonyl-C1_3-alkylaminocarbonyl, N- (C1_3-alkyl) -C1_3-alkoxycarbonyl-C1_3-alkylaminocarbonyl, morpholinocarbonyl or 4-(C1_3-alkyl)-piperazinocarbonyl group, a Cl_3-alkyl group, which is substituted by a carboxy-Cl_3-alkyl-aminocarbonyl, N- (C1_3-alkyl) -carboxy-Cl_3-alkyl-aminocarbonyl, Cl_3-alkoxycarbonyl-Cl_3-alkylaminocarbonyl or N- (Cl_3-alkyl) -C1_3-alkoxycarbonyl-C1_3-alkylamino-carbonyl group, which are additionally substituted at a carbon atom of the alkylamino moiety by a carboxy or C1_3-alkoxycarbonyl group, a C1_3-alkyl group, which is substituted in the alkyl moiety by ._.. a di- (C1_3-alkyl) -aminocarbonyl group wherein an alkyl moiety may additionally be substituted in the 2 or 3 position by a di-(C1_3-alkyl) -amino group, a C1_3-alkyl group, which is substituted in the alkyl moiety by a 4-(morpholinocarbonyl-C1_3-alkyl)-piperazinocarbonyl or N- (C1_3-alkyl) -pyrrolidinyl group, or an n-C2_3-alkyl group, which is terminally substituted by a di (C1_3-alkyl) -amino, CS_,-alkyleneimino or morpholino group, RS denotes a C1_5-alkyl or CS_.,-cycloalkyl group, "~'25 a phenyl-C1_3-alkyl group, which may be substituted in the alkyl moiety by a carboxy or C1_3-alkoxycarbonyl group, a phenyl, naphthyl, pyridinyl, quinolyl or isoquinolyl group and R6 denotes a C1_5-alkyl group optionally substituted by a carb-oxy or C1_3-alkoxycarbonyl group, a C1_3-alkyl group, which is substituted in the alkyl moiety by a C1_3-alkylaminocarbonyl, di-(C1_j-alkyl)-aminocarbonyl, carb-oxy-C1_3-alkylaminocarbonyl or C1_3-alkyloxycarbonyl-C1_3-alkyl-aminocarbonyl group, an n-C2_3-alkyl group, which is substituted in the 2 or 3 posi-tion by a Cl_3-alkyl amino or di- (C1_3-alkyl) -amino group, or one of the groups RS or R6 denotes a hydrogen atom, whilst the other one of the groups has the meanings given for RS and R6 hereinbefore, or RS and R6 together with the nitrogen atom between them denote a pyrrolidino or piperidino group optionally substituted by a Cl_3-alkyl, carboxy-C1_3-alkyl or Cl_3-alkoxy-C1_3-alkyl group, -~ onto which a benzene ring may additionally be condensed via two adjacent carbon atoms, or Rb denotes an amino, methylamino, cyclopentylamino or cyc-lohexylamino group, substituted at the nitrogen atom by a phe-nylaminocarbonyl, N-phenyl-methylaminocarbonyl, phenylsulpho-nylaminomethylcarbonyl, hydroxycarbonyl-methylaminocarbonyl or C1_3-alkyloxycarbonylmethylamino-carbonyl group, a piperidino group substituted in the 4 position by a di-(C1_3-alkyl) -amino group, a piperazino group substituted in the 4 position by a C1_3-alkyl "~' 25 group, a CZ_3-alkylsulphonyl group, which is substituted in the 2 or 3 position by a di- (C1_3-alkyl) -amino group, a 4-oxo-3,4-dihydro-phthalazinyl-1-yl or 4-oxo-2,3-diaza-spiro[5.5]undec-1-en-1-yl group, a carbonyl or methyl group substituted by a cyclopentyl, cyclo-hexyl or C3_5-alkyl group wherein the methyl moiety is substi-tuted by a C1_3-alkoxy or C1_4-alkyl amino group and the cyclo-alkyl moiety may additionally be substituted by a methyl, carb-oxymethyl or C1_3-alkoxycarbonylmethyl group, a cyclohexyl-N-(carboxymethoxy)-iminomethylene or cyclohexyl-N-(C1_3-alkoxycarbonylmethoxy)-iminomethylene group, which may additionally be substituted by a methyl group in the cyclohexyl moiety, a phosphinyl group, which is substituted by a C3_6-alkyl group and by a hydroxy, C1_3-alkoxy, carboxymethoxy or Cl_3-alkoxycar-bonylmethoxy group, a piperidino group wherein in the 2 position a methylene group is replaced by a carbonyl or sulphonyl group, a tetrazolyl group optionally substituted by a C1_5-alkyl group, a phenyl or phenylsulphonyl group optionally substituted by a methyl group, a sulphimidoyl group, which is substituted at the sulphur atom by a cyclohexyl group and may additionally be substituted at the nitrogen atom by a Cz_4-alkanoyl, carboxymethyl, C1_3-alkoxy-carbonylmethyl, carboxy-Cz_3-alkanoyl or C1_3-alkoxycarbonyl-Cz_3-alkanoyl group, ~25 an imidazolyl group substituted in the 1 position by a carboxy-methyl or C1_3-alkoxycarbonylmethyl group, which may additional-ly be substituted by a C1_S-alkyl group, a Cl_3-alkoxycarbonyl-C1_3-alkyl group, which is substituted in the alkyl moiety by a CS_.,-cycloalkylaminocarbonyl group, a C1_3-alkyl group, which is substituted by a 1-imidazolyl group, whilst the imidazolyl moiety may additionally be sub-stituted by one or two C1_j-alkyl groups, or by a 1-benzimi-dazolyl group substituted in the 2 position by a carboxy-C1_j-alkyl or C1_3-alkoxycarbonyl-C1_,-alkyl group, or a 5-furanyl-1-pyrazolyl group optionally substituted by a Cl_j-alkyl group and R~ denotes a cyano group or an amidino group, which may be substituted by one or two C1_3-alkyl groups, by one or two C1_8-alkoxycarbonyl groups or by a hydroxy group, the tautomers, stereoisomers and salts thereof.
Particularly preferred compounds of general formula I are those wherein A denotes a methylene or imino group, X denotes a nitrogen atom or an -R1C= group, wherein R1 denotes a hydrogen, fluorine, chlorine or bromine atom or a methyl group, Y denotes an oxygen or sulphur atom or an -RzN- group, wherein R2 denotes a hydrogen atom, a methyl, benzyl, 4-carboxybenzyl or 4-methoxycarbonylbenzyl group, ~25 a C1_3-alkyl group, which is substituted by a carboxy or C1_3-alkoxycarbonyl group, a methyl group, which is substituted by a carboxymethylamino-carbonyl or C1_3-alkoxycarbonylmethylaminocarbonyl group or an n-C2_3-alkyl group, which is terminally substituted by a morpholino group, Ra denotes a hydrogen atom, Rb denotes an R3-CO- (1, 1-cyclopropylene) , R3-S02-NR4, R3-CO-NR4, RSNR6-CO, RSNR6-SO2 or RSNR6-CO-C3_5- (1, 1-cyclopropylene) group, wherein R3 denotes a C1_3-alkyl, cyclopentyl or cyclohexyl group, a methyl group, which is substituted by a tetrazolyl, carboxy-methoxy, C1_3-alkoxycarbonylmethoxy, carboxy-C1_3-alkylamino, C1_3-alkoxycarbonylamino group, a phenyl, naphthyl, pyridinyl, 1-methyl-5-pyrazolyl, quinolyl °~ or isoquinolyl group, R4 denotes a hydrogen atom, a C1_3-alkyl or cyclopentyl group, a C1_5-alkyl group, which is substituted by a carboxy group or by a C1_3-alkoxycarbonyl group, a methyl group, which is substituted by a 4-dimethylamino-pipe-ridinocarbonyl, morpholinocarbonyl, 4-methylpiperazino or 4-morpholinocarbonylmethyl-piperazinocarbonyl group, a C1_3-alkyl group, which is substituted by a carboxy-methyl-aminocarbonyl, N-(C1_3-alkyl)-carboxymethyl-aminocarbonyl, ~?5 C1_3-alkoxycarbonylmethylaminocarbonyl or N- (C1_3-alkyl) -C1_3-alk-oxycarbonylmethylaminocarbonyl group, a C1_3-alkyl group, which is substituted by a di- (C1_3-alkyl) -aminocarbonyl group wherein an alkyl moiety is additionally substituted in the 2 or 3 position by a di-(C1_3-alkyl)-amino group, a C1_3-alkyl group, which is substituted by a carboxy-methyl aminocarbonyl or C1_3-alkoxycarbonylmethylamino-carbonyl group wherein the methyl group of the methylamino moiety is additio-nally substituted by an aminocarbonyl-methyl group, an n-CZ_j-alkyl group, which is terminally substituted by a di-(C1_3-alkyl)-amino, pyrrolidino or morpholino group, RS denotes a C1_5-alkyl, cyclopentyl, cyclohexyl, phenyl, naph-thyl, pyridinyl, quinolyl or isoquinolyl group, R6 denotes a C1_5-alkyl group optionally substituted by a carb-oxy or C1_3-alkoxycarbonyl group, a Cl_3-alkyl group, which is substituted by a C1_3-alkylamino-carbonyl, carboxymethylaminocarbonyl or C1_j-alkyl-oxycarbon-ylmethylaminocarbonyl group, or RS and R6 together with the nitrogen atom between them denote a pyrrolidino group substituted by a carboxymethyl or C1_3-alk-oxymethyl group or a pyrrolidino group onto which a benzene ring is additionally condensed via two adjacent carbon atoms, or Rb denotes an N-pyrrolidinocarbonyl-methylamino, phenylsul-phonyl, 4-oxo-2,3-diaza-spiro[5.5]undec-1-en-1-yl or C3_5-alkyl-tetrazolyl group, a cyclohexylcarbonyl group, which is substituted by a methyl, carboxymethyl or C1_3-alkoxycarbonylmethyl group, '~ ~' 2 5 a cyclohexyl-N-(carboxymethoxy)-iminomethylene or cyclohexyl-N-(C1_3-alkoxycarbonylmethoxy)-iminomethylene group, which is additionally substituted by a methyl group in the cyclohexyl moiety, a phosphinyl group, which is substituted by a C3_6-alkyl group and by a C1_3-alkoxymethoxy group a sulphimidoyl group, which is substituted at the sulphur atom by a cyclohexyl group and additionally at the nitrogen atom by a C2_4-alkanoyl group, or a 3-methyl-5-(furan-2-yl)-1-pyrazolyl group, and R~ denotes an amidino group, the tautomers, stereoisomers and salts thereof.
Most particularly preferred compounds of general formula I are those wherein A denotes a methylene group, X denotes a nitrogen atom or an -HC= group, Y denotes an oxygen or sulphur atom or an -RzN- group, wherein R2 denotes a hydrogen atom, a methyl, benzyl or C1_3-alkoxycar-bonylmethyl group, Ra denotes a hydrogen atom, Rb denotes a RSNR6-SO2, RSNR6-CO, R3-SOZ-NR4, R3-CO-NR4 or RSNR6-CO-C3_5- (1, 1-cyclopropylene) group, wherein R3 denotes a cyclopentyl, cyclohexyl, phenyl, naphthyl, 1-me-~~"25 thyl-pyrazolyl, quinolyl or isoquinolyl group or a methyl group, which is substituted by a carboxymethylamino, C1_3-alk-oxycarbonyl-methylamino, carboxymethoxy, C1_3-alkoxycarbonyl-methoxy or tetrazolyl group, R4 denotes a hydrogen atom or a methyl group, substituted by a carboxy, C1_3-alkoxycarbonyl, morpholinocarbonyl, 4-dimethyl-amino-piperidinocarbonyl, 4-methyl-piperazino-carbonyl, 4-mor-pholinocarbonylmethyl-piperazinocarbonyl, carboxymethylamino-carbonyl, N-methyl-carboxymethylamino-carbonyl, C1_3-alkoxycar-bonylmethylaminocarbonyl, N-methyl-Cl_3-alkoxycarbonylmethyl-aminocarbonyl, N-(C1_3-alkyl)-N-(2-dimethylamino-ethyl)-aminocarbonyl, N-(1-carboxy-2-aminocarbonyl-ethyl)-amino-carbonyl or N-(1-C1_3-alkoxy-carbonyl-2-aminocarbonyl-ethyl)-aminocarbonyl group, or a cyclopentyl group, RS denotes a C1_5-alkyl, phenyl or pyridyl group and R6 denotes a C1_5-alkyl group, which may be terminally substi-tuted by a carboxy or Cl_3-alkoxycarbonyl group, or a Cl_3-alkyl group substituted by a methylaminocarbonyl, carboxymethylamino-carbonyl or C1_3-alkoxycarbonylmethylaminocarbonyl group or sub-stituted in the 2 or 3 position by a dimethylamino group, or RS together with R6 and the nitrogen atom between them denotes a 1-methyl-5-pyrazolyl group, a pyrrolidino group optionally substituted by a C1_3-alkoxycarbonyl group or a pyrrolidino group onto which a benzene ring is condensed via two adjacent carbon atoms, or Rb denotes a N-pyrrolidinocarbonyl-methylamino, phenylsul-phonyl, 4-oxo-2,3-diaza-spiro[5.5]undec-1-en-1-yl or C3_5-alkyl-tetrazolyl group, a cyclohexylcarbonyl group, which is substituted in the 1 posi-tion by a methyl, carboxymethyl or C1_3-alkoxycarbonyl-methyl group ~~ 2 5 a cyclohexyl-N-(carboxymethoxy)-iminomethylene or cyclohexyl-N-(C1_3-alkoxycarbonylmethoxy)-iminomethylene group, which is additionally substituted in the cyclohexyl moiety by a methyl group, or a phosphinyl group, which is substituted by a C3_6-alkyl group and by a C1_3-alkoxymethoxy group, and R~ denotes an amidino group, particularly those compounds of general formula I wherein A denotes a methylene group, X denotes a nitrogen atom or an -HC= group, Y denotes an oxygen or sulphur atom or an -R2N- group, wherein RZ denotes a hydrogen atom, a methyl, benzyl or C1_3-alkoxycar-bonylmethyl group, Ra denotes a hydrogen atom, - Rb denotes an RSaNR6a-SOz group, wherein Rsa denotes a C1_3-alkyl or phenyl group and Rsa denotes a C1_5-alkyl group, which is terminally substituted by a carboxy or C1_3-alkoxycarbonyl group or is substituted in the 2 or 3 position by a dimethylamino group, or Rsa together with Rsa and the nitrogen atom between them denotes a pyrrolidino group optionally substituted by a C1_3-alkoxycar-bonyl group or a pyrrolidino group onto which a benzene ring is condensed via two adjacent carbon atoms, -'~25 or an R3a-SOZ-NR4a group, wherein R3a denotes a cyclopentyl, cyclohexyl, phenyl, naphthyl, quino-lyl or isoquinolyl group and R4a denotes a hydrogen atom or a methyl group which is substi-tuted by a carboxy, C1_3-alkoxycarbonyl, morpholinocarbonyl, 4-dimethylamino-piperidinocarbonyl, 4-methyl-piperazino-carbonyl, 4-morpholinocarbonylmethyl-piperazinocarbonyl, carboxymethylaminocarbonyl, N-methyl-carboxymethylaminocar-bonyl, C1_3-alkoxycarbonylmethyl-aminocarbonyl, N-methyl-C1_3-alkoxycarbonylmethyl-aminocarbonyl, N- (C1_3-alkyl) -N-(2-dimethylamino-ethyl)-aminocarbonyl, N-(1-carboxy-2-aminocarbonyl-ethyl)-aminocarbonyl or N-(1-C1_3-alkoxy-carbonyl-2-aminocarbonyl-ethyl)-aminocarbonyl group, or a RSbNR6b-CO group, wherein Rsb denotes a C3_5-alkyl, phenyl or pyridyl group and R6b denotes a C1_5-alkyl group or a C1_3-alkyl group, which is substituted by a carboxy, C1_3-alkoxycarbonyl, methylamino-carbonyl, carboxymethylaminocarbonyl or C1_3-alkoxycarbonyl-methylaminocarbonyl group or in the 2 or 3 position is also substituted by a dimethylamino group, or an R3b-CO-NR4b group, wherein R3b denotes a phenyl group and R4b denotes a C1_3-alkyl group, which is substituted by a carboxy or C1_3-alkoxycarbonyl group, or R3b denotes a methyl group, which is substituted by a carboxy-methylamino, C1_3-alkoxycarbonylmethylamino, carboxymethoxy, C1_3-alkoxycarbonylmethoxy or tetrazolyl group, and R4b denotes a cyclopentyl group, or a RS~NR6~-CO-C3_5- (1, 1-cyclopropylene) group, wherein R5~ together with R6~ and the nitrogen atom between them denotes a 1-methyl-5-pyrazolyl group, a pyrrolidino group optionally substituted by a C1_3-alkoxycarbonyl group or a pyrrolidino group onto which a benzene ring is condensed via two adjacent carbon atoms, or Rb denotes a N-pyrrolidinocarbonyl-methylamino, phenylsul-phonyl, 4-oxo-2,3-diaza-spiro[5.5]undec-1-en-1-yl or C3_5-alkyl-tetrazolyl group, a cyclohexylcarbonyl group, which is substituted in the 1 posi-tion by a methyl, carboxymethyl or C1_3-alkoxycarbonyl-methyl group a cyclohexyl-N-(carboxymethoxy)-iminomethylene or cyclohexyl-N-(C1_3-alkoxycarbonylmethoxy)-iminomethylene group, which is additionally substituted in the cyclohexyl moiety by a methyl group, a phosphinyl group, which is substituted by a C3_6-alkyl group --, and by a Cl_3-alkoxymethoxy group, and R~ denotes an amidino group, the tautomers, the stereoisomers and the salts thereof.
The following are examples of particularly preferred compounds:
(a) 4-[(5-(N-Carboxymethyl-quinolin-8-yl-sulphonylamino)-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine, (b) 4-[(5-(N-Carboxymethylaminoacetyl-quinolin-8-yl-sulphonyl-amino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine, '~"25 (c) 4-[(5-(N-(2-Dimethylamino-ethyl)-benzenesulphonylamino)-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzamidine, (d) 4-[(5-(N-(2-Diethylamino-ethyl)-benzenesulphonylamino)-1-(carboxymethylaminocarbonyl)-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine, (e) 4-[(5-Pyrrolidinosulphonyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine, (f) 4-[(5-(N-Cyclopentyl-methanesulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine, (g) 4-[(5-(N-Cyclopentyl-3-carboxypropionylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine, (h) 4-[(5-Pyrrolidinocarbonylcyclopropyl-1-methyl-1H-benzimida-zol-2-yl)-methyl]-benzamidine and (i) 4-[(5-(N-Carboxymethyl-quinolin-8-yl-sulphonylamino-benzo-thiazol-2-yl)-methyl]-benzamidine and the salts thereof.
According to the invention the compounds of general formula I
are obtained using known methods, e.g. the following processes:
a) In order to prepare a compound of general formula I wherein R~ denotes a cyano group and X denotes a nitrogen atom:
cyclising a compound of general formula Ra z\ /z2 NH - C/-A - Ar - R~ , ( I I ) Rb YH
optionally formed in the reaction mixture wherein Ra, Rb, A, Ar and Y are as hereinbefore defined, Z1 and ZZ, which may be identical or different, denote amino, hydroxy or mercapto groups optionally substituted by alkyl groups having 1 to 6 carbon atoms or Z1 and Z2 together denote an oxygen or sulphur atom, an imino group optionally substituted by an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms.

The cyclisation is appropriately carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial ace-tic acid, benzene, chlorobenzene, toluene, xylene, glycol, gly-colmonomethylether, diethylenglycol dimethylether, sulpholane, dimethylformamide, tetraline or in an excess of the acylating agent used to prepare the compound of general formula II, e.g.
in the corresponding nitrile, anhydride, acid halide, ester or amide, for example at temperatures between 0 and 250°C, but preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phos-phorus oxychloride, thionylchloride, sulphurylchloride, sul-phuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride or optionally also in the presence of a base such as potassium ethoxide or potassium tert.butoxide. The cyclising may also, however, be carried out without a solvent and/or con-densing agent.
However, it is particularly advantageous to carry out the rea-ction by preparing a compound of general formula II in the reaction mixture by reduction of a corresponding o-nitro com-pound optionally in the presence of a carboxylic acid of gene-ral formula 2 5 HOCO ~ A - Ar - CN , ( I I I ) wherein A and Ar are as hereinbefore defined, by acylating a correspon-ding amino compound formed in the reaction mixture.
b) In order to prepare a compound of general formula I wherein Rb denotes a Rj-SOz-NR4, R3-CO-NR4 or (RSNR6) CO-NR4 group and R
denotes a cyano group:
acylating a compound of general formula Ra X
R4NH \ I ~~A Ar -CN , ( IV) _Y
wherein Ra, R4, A, Ar, X and Y are as hereinbefore defined, with an acid of general formula Rlo - W - OH , (V) wherein Rlo has the meanings given for R3 to R6 hereinbefore and W denotes a carbonyl or sulphonyl group, or with the reactive derivatives thereof.
The reaction of an acid of general formula V is optionally carried out in a solvent or mixture of solvents such as methy-lene chloride, dimethylformamide, benzene, toluene, chloro-benzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan, optionally in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysi-lane, thionylchloride, trimethylchlorosilane, phosphorus tri-chloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, ..., N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-di-cyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-benzo-triazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluo-roborate/1-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopy-ridine, N-methyl-morpholine or triethylamine appropriately at temperatures, between 0 and 150°C, preferably at temperatures between 0 and 100°C.
The reaction of a corresponding reactive compound of general formula V such as an ester, imidazolide or halide thereof is preferably carried out in a solvent such as methylene chloride or ether and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-me-thyl-morpholine at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.
c) In order to prepare a compound of general formula I wherein Rb denotes a R3-SOz-NR4 group and R~ denotes a cyano group reacting a compound of general formula Ra ..... X
R3-S02-NH ~ I ~~-A Ar-CN , (VI) \ Y
wherein Ra, R3, A, Ar, X and Y are as hereinbefore defined, with a compound of general formula R4 - Z3 , (VII) wherein R4 is as hereinbefore defined and Z3 denotes a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a sulphonic acid '"", ester group, e.g. a trifluoromethane-sulphonyloxy, methanesul-phonyloxy or p-toluenesulphonyloxy group.
The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, tolu-ene, dioxan, dimethylsulphoxide or dimethylformamide optionally in the presence of an inorganic or tertiary organic base such as sodium hydride, potassium carbonate, potassium-tert.butoxide or N-ethyl-diisopropylamine at temperatures between 20°C and the boiling temperature of the solvent used, preferably at tem-peratures between 0 and 60°C.
d) In order to prepare a compound of general formula I wherein Rb denotes one of the groups mentioned for Rb hereinbefore, which contains an alkylated phosphinyl and sulphimidoyl group, and R~ denotes a cyano group:
reacting a compound of general formula Ra X
Rb' \ I ~~A Ar-CN , (VIII) _Y
wherein Ra, R3, A, Ar, X and Y are as hereinbefore defined and Rb~ denotes one of the groups mentioned for Rb hereinbefore which contains a phosphinyl and sulphimidoyl group, with a compound of general formula z4 - Rm ( IX) wherein Z4 denotes a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, and R11 denotes one of the alkyl moieties which were mentioned in the definition of the alkylated phosphinyl and sulphimidoyl groups mentioned for the group Rb hereinbefore.
,._ The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, tolu-ene, dioxan, dimethylsulphoxide or dimethylformamide, optio-nally in the presence of an inorganic or tertiary organic base such as sodium hydride, potassium carbonate, potassium-tert.-butoxide or N-ethyl-diisopropylamine at temperatures between 20°C and the boiling temperature of the solvent used, preferab-ly at temperatures between 0 and 60°C.
e) In order to prepare a compound of general formula I wherein Rb denotes one of the groups given for Rb hereinbefore which contains an acylated sulphimidoyl group:
reacting a compound of general formula Ra X
Rb ~~ \ I ~~A Ar -CN ~ ( X ) ~Y
wherein Ra, R~, A, Ar, X and Y are as hereinbefore defined and Rb~ denotes one of the groups given for Rb hereinbefore, which contains a sulphimidoyl group, with a compound of general for-mula HO - R12 , (XI) wherein Rlz denotes one of the acyl moieties which were mentioned in the definition of the acylated sulphimidoyl groups given for the group Rb hereinbefore, or with the reactive derivatives thereof.
The reaction of an acid of general formula XI is optionally carried out in a solvent or mixture of solvents such as methy-lene chloride, dimethylformamide, benzene, toluene, chloroben-zene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan optio-nally in the presence of a dehydrating agent, e.g. in the pre-sence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxy-silane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodi-imide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-dicyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetra-fluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,N'-car-bonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine appropriately at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C.

The reaction of a corresponding reactive compound of general formula XI such as an ester, imidazolide or halide thereof is preferably carried out in a solvent such as methylene chloride or ether and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-me-thyl-morpholine at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.
f) In order to prepare a compound of general formula I wherein Rb denotes a RSNR6-CO, RSNR6-SOz, RSNR6-CO-C3_5-cycloalkylene or RSNR6-CO-NR4 group and R~ denotes a cyano group reacting a compound of general formula Ra X
U I ~~A Ar-CN , (XII) Y
wherein Ra, A, Ar, X and Y are as hereinbefore defined and U denotes a HO-CO-C3_5-cycloalkylene, HO-CO or HO-SOz, or with the reactive derivatives thereof, with an amine of general for-mula (RSNR6) - H (XIII) wherein RS and R6 are as hereinbefore defined.
The reaction of an acid of general formula XII is optionally carried out in a solvent or mixture of solvents such as methy-lene chloride, dimethylformamide, benzene, toluene, chloro-benzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan, optionally in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxy-silane, thionylchloride, trimethylchlorosilane, phosphorus tri-chloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-di-cyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-benzo-triazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetra-fluoroborate/1-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopy-ridine, N-methyl-morpholine or triethylamine appropriately at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C.
The reaction of a corresponding reactive compound of general formula XII such as an ester, imidazolide or halide thereof is preferably carried out in a solvent such as methylene chloride or ether and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-me-thyl-morpholine at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.
g) In order to prepare a compound of general formula I wherein Rb denotes a R3-CO-C3_5-cycloalkylene group and R~ denotes a cyano group:
Oxidising a compound of general formula Ra X
Rb~ ~~ I ~~-A Ar-CN , (XIV) \ Y
wherein Ra, A, Ar, X and Y are as hereinbefore defined and Rbf: denotes a R3- (HCOH) -C3_5-cycloalkylene group.
The oxidation is preferably carried out in a solvent such as ether, tetrahydrofuran, methylene chloride, glacial acetic acid or acetonitrile in the presence of an oxidising agent such as manganese dioxide, potassium permanganate, potassium dichro-mate, dimethylsulphoxide/oxalyl chloride or dimethylsulph-oxide/dicyclohexylcarbodiimide at temperatures between 0 and 50°C, preferably at temperatures between 15 and 25°C.
h) In order to prepare a compound of general formula I wherein Rb denotes one of the groups mentioned for Rb hereinbefore which contains a methyl group linked to the adjacent bicyclic moiety substituted with an optionally substituted amino group:
Reductive amination of a ketone of general formula .... Ra X
Rb " " I ~~-A Ar R° , ( XV ) \ Y
wherein Ra, R~, A, Ar, X and Y are as hereinbefore defined and Rb"" denotes one of the groups mentioned for Rb hereinbefore which is linked via a carbonyl group to the adjacent bicyclic moiety, with an amine of general formula H - R13 (XVI ) wherein R13 denotes an optionally substituted amino group, such as the one mentioned for Rb hereinbefore, if Re is linked to the adja-cent bicyclic moiety via a methyl group optionally substituted by an amino group.
The reductive amination is carried out in the presence of a solvent such as methanol, methanol/water, diethylether, tetra-hydrofuran or dioxan in the presence of a reducing agent such as a complex metal hydride, e.g. with sodium borohydride, li-thium borohydride or sodium cyanoborohydride, preferably at a pH of between 6 and 7 or with catalytically activated hydrogen, e.g. with hydrogen in the presence of palladium, at tempera-tures between 0 and 50°C, preferably at temperatures between 15 and 30°C,.

i) In order to prepare a compound of general formula I wherein Rb denotes one of the optionally substituted phenyl groups men-tioned for Rb hereinbefore and R~ denotes a cyano group:
reacting a compound of general formula Ra X
V I ~~A Ar-CN , (XVII) \ Y
wherein Ra, A, Ar, X and Y are as hereinbefore defined and V denotes a trifluoromethanesulphonyloxy group, a bromine or iodine atom, with a compound of general formula Ria - Zs (XVI I I ) wherein R14 denotes one of the optionally substituted phenyl groups mentioned for Rb hereinbefore and ZS denotes a boric acid group or a tri-(C1_3-alkyl)-tin group.
The reaction is preferably carried out in a solvent such as ,_..... toluene/water, dimethoxyethane or dimethylformamide in the pre-sence of a phosphine such as bis(triphenyl-phosphine)-palla-dium(II)choride or tetrakis-(triphenyl-phosphine)-palladium(0) in the presence of a base such as sodium carbonate at tempera-tures between 20 and 100°C, preferably at temperatures between 40 and 80°C.
j) In order to prepare a compound of general formula I wherein R~ denotes an amidino group, which may be substituted by one or two C1_3-alkyl groups Reacting a compound of general formula Ra X
Rb ~ I ~~-A Ar-C (=NH) Z6 , (XIX) \ Y
optionally formed in the reaction mixture wherein Ra, Rb, A, Ar, X and Y are as hereinbefore defined and Z6 denotes 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 of general formula H - R15NR16 ~ ( XX ) wherein R15 and R16, which may be identical or different, each denote a hydrogen atom or a C1_3-alkyl group, or with a salt thereof.
The reaction is appropriately carried out in a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxan at temperatures between 0 and 150°C, preferably at temperatures between 0 and 80°C, with an amine of general formula XX or with a corresponding acid addition salt such as for example ammonium carbonate or ammonium acetate.
A compound of general formula XIX is obtained for example by reacting a corresponding cyano compound with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzylalcohol in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a trialkyloxo-nium salt such as triethyloxonium-tetrafluoroborate in a sol-vent such as methylene chloride, tetrahydrofuran or dioxan at temperatures between 0 and 50°C, but preferably at 20°C, or a corresponding nitrite with hydrogen sulphide appropriately in a solvent such as pyridine or dimethylformamide and in the pre-sence of a base such as triethylamine and subsequent alkylation of the resulting thioamide with a corresponding alkyl or aral-kylhalide.
k) In order to prepare a compound of general formula I wherein R~ denotes an amidino group which is substituted by a hydroxy group:
reacting a nitrile of general formula Ra X
Rb I ~~-A Ar - CN , ( XX I ) \ Y
wherein Ra, Rb, A, Ar, X and Y are as hereinbefore defined, with hy-droxylamine or the salts thereof.
The reaction is appropriately carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol/water, tetra-hydrofuran, tetrahydrofuran/water, dioxan or dioxan/water at temperatures between 0 and 150°C, preferably at temperatures between 0 and 80°C.
1) In order to prepare a compound of general formula I wherein Rb contains a carboxy group and R~ is as hereinbefore defined or Rb is as hereinbefore defined and R~ denotes an amidino group optionally substituted by a hydroxy group or by one or two C1_3-alkyl groups Converting a compound of general formula Ra X
Rb' "" ~ I ~~A Ar R°' , (XIV) \ Y
wherein Ra, A, Ar, X and Y are as hereinbefore defined and Rb" " ' and R~' have the meanings given for Rb and R~ hereinbefore with the proviso that Rb contains a group which can be conver-ted into a carboxy group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and R~ is as hereinbe-fore defined or R~ denotes a group which can be converted into an amidino group optionally substituted by a hydroxy group or by one or two C1_3-alkyl groups by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and R~ is as here-inbefore defined, is converted, by hydrolysis, treatment with an acid or base, "'~ thermolysis or hydrogenolysis, into a compound of general for-mula I wherein Rb contains a carboxy group and R~ is as herein-before defined or Rb is as hereinbefore defined and R~ denotes an amidino group optionally substituted by a hydroxy group or by one or two Cl_3-alkyl groups .
An example of a group which may be converted into a carboxy group might be, for example, a carboxyl group protected by a protecting group, such as a functional derivative thereof, e.g.
an unsubstituted or substituted amide, ester, thioester, trime-thylsilylester, orthoester or iminoester thereof, which are appropriately converted into a carboxyl group by hydrolysis, ~z5 the esters thereof with tertiary alcohols, e.g. the tert. butyl ester, which are appropriately converted into a carboxyl group by treatment with an acid or thermolysis, and the esters thereof with aralkanols, e.g. the benzyl ester, which are appropriately converted into a carboxyl group by hy-drogenolysis.
The hydrolysis is appropriately carried out either in the pre-sence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloracetic acid, trifluor-acetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hy-droxide in a suitable solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/te-trahydrofuran or water/dioxan at temperatures between -10 and 120°C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.
If, for example, a compound of formula XXII contains the tert.-butyl or tert.butyloxycarbonyl group, this may also by cleaved by treating with an acid such as trifluoracetic acid, formic acid, p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethylether, tetrahydrofuran or dioxan preferably at temperatures between -10 and 120°C, e.g. at temperatures bet-ween 0 and 60°C, or also thermally, optionally in an inert sol-vent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxan and preferably in the presence of a catalytic amount of an acid such as p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid prefe-rably at the boiling temperature of the solvent used, e.g. at temperatures between 40 and 120°C.
If, for example, a compound of formula XXII for example con-tains the benzyloxy or benzyloxycarbonyl group, these may also ~~25 be cleaved hydrogenolytically in the presence of a hydrogena-tion catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxan or dimethylformamide, preferably at tem-peratures between 0 and 50°C, e.g. at ambient temperature, and at a hydrogen pressure of 1 to 5 bar.
m) In order to prepare a compound of general formula I wherein R~ denotes an amidino group which is substituted by one or two C1_8-alkoxycarbonyl groups or by a group which can be cleaved in vivo:
reacting a compound of general formula I

Ra X
Rb ~ I ~~A Ar R°" , (XXI I I ) \ Y
wherein Ra, Rb, A, Ar, X and Y are as hereinbefore defined and R°,,~'~ denotes an amidino group, with a compound of general formula Z., - Rl., , (XXIV) wherein Rl., denotes a C1_8-alkoxycarbonyl group or the acyl group of one of the groups which can be cleaved in vivo mentioned herein-before and Z., denotes a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a p-nitrophenyl group.
The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, tolu-ene, dioxan, dimethylsulphoxide or dimethylformamide optionally in the presence of an inorganic or tertiary organic base, pre-~~~ ferably at temperatures between 20°C and the boiling tempera-ture of the solvent used.
In the case of a compound of general formula XXIV wherein Z3 denotes a nucleofugic leaving group, the reaction is preferably carried out in a solvent such as methylene chloride, acetoni-trile, tetrahydrofuran, toluene, dimethylformamide or dimethyl-sulphoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium-tert.butoxide or N-ethyl-diisopropylamine at temperatures between 0 and 60°C.
If according to the invention a compound of general formula I
is obtained wherein R' denotes an amidino group, this may be converted, by reacting with a haloacetic acid derivative, by subsequent hydrolysis and decarboxylation, into a corresponding amidino compound substituted by one or two methyl groups, and/-or if a compound of general formula I is obtained wherein R~ de-notes a hydroxyamidino group, this can be converted by cataly-tic hydrogenation into a corresponding amidino compound and/or if a compound of general formula I is obtained wherein Rb con-tams a carboxy group, this can be converted by esterification into a corresponding ester and/or if a compound of general formula I is obtained wherein Rb con-tains an O-alkyl-phosphinyl group, this can be converted by ether splitting into a corresponding phosphinyl compound and/or if a compound of general formula I is obtained wherein Rb con-tains a halogen atom, this can be converted by dehalogenation into a corresponding dehalogenated compound and/or if a compound of general formula I is obtained wherein Rb con-tains a quinolyl group, this may be converted by catalytic hydrogenation into a corresponding tetrahydroquinolyl compound.
The subsequent alkylation is appropriately carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxan, dimethylsulphoxide, dimethylformamide or acetone optionally in the presence of a reaction accelerator such as sodium or po-tassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which may simultaneously serve as the solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100°C, but pre-ferably at temperatures between -10 and 80°C.

The subsequent hydrolyse is appropriately carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloracetic acid, tri-fluoracetic 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, water/te-trahydro or water/dioxan and the subsequent decarboxylation is performed in the presence of an acid as described hereinbefore at temperatures between -10 and 120°C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.
The subsequent esterification is carried out with a correspon-ding alcohol appropriately in a solvent or mixture of solvents such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan, but pre-ferably in an excess of the alcohol used, optionally in the presence of an acid such as hydrochloric acid or in the pre-sence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydro-chloric acid, sulphuric acid, methanesulphonic acid, p-to-luenesulphonic acid, phosphorus trichloride, phosphorus pent-oxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexyl-~'25 carbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole, triphenylphosphine/carbon tetrachlo-ride or triphenylphosphine/diethyl azodicarboxylate, optionally in the presence of a base such as potassium carbonate, N-ethyl-diisopropylamine or N,N-dimethylamino-pyridine appropriately at temperatures between 0 and 150°C, preferably at temperatures between 0 and 80°C, or with a corresponding halide in a solvent such as methylene chloride, tetrahydrofuran, dioxan, dimethyl-sulphoxide, dimethylformamide 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 or in the presence of a ter-tiary organic base such as N-ethyl-diisopropylamine or N-me-thyl-morpholine, which may simultaneously serve as the solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100°C, but preferably at temperatures between -10 and 80°C.
The subsequent dehalogenation and catalytic hydrogenation is carried out with hydrogen in the presence of a catalyst such as palladium/charcoal or platinum in a solvent such as methanol, ethanol, 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, but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
The subsequent ether splitting is carried out for example with iodotrimethylsilane, bromotrimethylsilane or chloromethylsi-lane/sodium iodide in a solvent such as methylene chloride, chloroform or acetonitrile at temperatures between 0°C and the boiling temperature of the reaction mixture, but preferably at temperatures between 20 and 60°C.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, the protecting group for a hydroxy group may be the trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group, the protecting groups for a carboxyl group may be the trime-thylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyra-nyl group and the protecting group for an amino, alkylamino or imino group may be the acetyl, trifluoracetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group the phtha-lyl group is another possibility.
The optional subsequent cleaving of any protecting group used is carried out for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or di-oxan/water, in the presence of an acid such as trifluoracetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydro-xide or potassium hydroxide or by means of ether splitting, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C.
A benzyl, methoxybenzyl or benzyloxycarbonyl group may, how-ever, be cleaved hydrogenolytically for example, e.g. with hydrogen in the presence of a catalyst such as palladium/-charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydro-chloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
z5 A methoxybenzyl group can also be cleaved in the presence of an oxidising agent such as cerium(IV) ammonium nitrate in a sol-vent such as methylene chloride, acetonitrile or acetonitrile/-water at temperatures between 0 and 50°C, but preferably at am-bient temperature.
A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoracetic acid in the presence of anisole.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoracetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxan or ether.

A phthalyl group is preferably cleaved in the presence of hy-drazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopro-panol, toluene/water or dioxan at temperatures between 20 and 50°C.
An allyloxycarbonyl group is cleaved by treating with a cataly-tic amount of tetrakis-(triphenylphosphine)-palladium(O), pre-ferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100°C, preferably at ambient temperature and under an inert gas, or by treating with a catalytic amount of tris-(triphenylphosphine)-rhodium(I)chlo-ride in a solvent such as aqueous ethanol and 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 of general formulae II to XXIV used as starting materials, some of which are known from the literature, are obtained by methods known from the literature, and furthermore their preparation is described in the Examples.
The chemistry of the compounds of general formula III is des-cribed, for example, by Jack Robinson in J. Chem. Soc. 1941, 744, that of the benzimidazoles is described by Katritzky and Rees in Comprehensive Heterocyclic Chemistry, Oxford, Pergamon Press, 1984, that of the benzothiazoles and benzoxazoles is described by Schaumann in Hetarene III, Methoden der orga-nischen Chemie (Houben-Weyl), 4t'' Edition, Verlag Thieme, Stuttgart 1993, that of the benzofurans by Mustafa in Chemistry of Heterocyclic Compounds, Vol. 29, New York, Wiley 1974, that of the sulphoximides by Johnson in Accounts in Chemical Re-search 6, 341 (1973), that of the phosphinic acids by Regitz in Phosphor-Verbindungen 1 and 2, Methoden der organischen Chemie (Houben-Weyl), Vol. 12, Verlag Thieme, Stuttgart 1993, and that of the boric acids by Sieckus in Pure and Applied Chemistry 66, 2155 (1994) .
Thus, for example, a compound of general formula II is obtained by acylating a corresponding o-diamino compound with a corres-ponding reactive derivative of a compound of general formula III, a compound of general formulae IV, XV, VIII, X, XII, XIV and XVII is obtained by cyclising a corresponding substituted com-pound and if necessary subsequently reducing a nitro group pre-sent in the phenyl moiety, acylation, amidation and/or haloge-nation, a compound of general formula VI is obtained by sulphonylation of a compound of general formula IV, a compound of general formulae XIX, XXI, XXII and XXIII is appropriately obtained by one of the methods described above.
Furthermore the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers.
Thus, for example, the compounds of general formula I obtained ~25 which occur in the form of racemates may be resolved into their optical antipodes by methods known per se (cf. Allinger N. L.
and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) and compounds of general formula I with at least 2 asymmetric carbon atoms may be separated into their diastereomers on the basis of their physico-chemical differen-ces using methods known per se, e.g. by chromatography and/or fractional crystallisation, and if they occur in racemic form they may subsequently be separated into their enantiomers, as mentioned above.
Enantiomer separation is preferably carried out by column sepa-ration on chiral phases or by recrystallisation from an opti-cally active solvent or by reacting with an optically active substance which forms salts or derivatives, such as e.g. esters or amides, with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric salt mixture or derivative thus obtained, e.g. on the basis of their different solubilities, whilst the free antipodes can be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Parti-cularly common, optically active acids include e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyl-tartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol might be, for example, (+) or (-)-menthol and an optically active acyl group in amides might be, for example, the (+) or (-)-menthyloxycarbonyl group.
In addition the compounds of formula I obtained may be conver-ted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorga-nic or organic acids. Examples of suitable acids for this pur-pose include hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or malefic acid.
~z5 Furthermore, the new compounds of formula I thus obtained, if they contain a carboxy group, may subsequently, if desired, be converted into the salts thereof with inorganic or organic ba-ses, particularly into the physiologically acceptable salts thereof for pharmaceutical use. Examples of suitable bases in-clude sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
As already mentioned hereinbefore, the new compounds of general formula I and the salts thereof have valuable properties. Thus, the compounds of general formula I wherein R~ denotes a cyano group are valuable intermediate products for preparing the other compounds of general formula I, and the compounds of ge-neral formula I wherein R~ denotes one of the amidino groups mentioned hereinbefore, as well as the tautomers, stereoisomers and the physiologically acceptable salts thereof, have valuable pharmacological properties, particularly an antithrombotic effect which is preferably based on a thrombin- or factor Xa-influencing activity, for example a thrombin-inhibiting or fac-tor Xa-inhibiting activity, an aPTT-time-extending activity and an inhibitory effect on related serine proteases such as e.g.
trypsin, urokinase factor VIIa, factor IX, factor XI and factor XII.
For example, the following compounds A = 4-[(5-(N-Carboxymethyl-quinolin-8-yl-sulphonylamino)-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride, B = 4-[(5-(N-Carboxymethylaminoacetyl-quinolin-8-yl-sulphonyl-amino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hy-drochloride, C = 4-[(5-(N-(2-Dimethylamino-ethyl)-benzenesulphonylamino)-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydro-chloride, z5 D = 4-[(5-(N-(2-Diethylamino-ethyl)-benzenesulphonylamino-1-(carboxymethylaminocarbonylmethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride, E = 4-[(5-Pyrrolidinosulphonyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride, F = 4-[(5-(N-Cyclopentyl-methanesulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride, G = 4-[(5-(N-Cyclopentyl-3-carboxypropionylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride, H = 4-[(5-(1-Pyrrolidinocarbonylcyclopropyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and I - 4-[(5-(N-Carboxymethyl-quinolin-8-yl-sulphonylamino)-benzo-thiazol-2-yl)-methyl]-benzamidine-hydrochloride were investigated for their effect on extending the aPTT time as follows:
Material:-Plasma, from human citrated blood, -PTT-reagent, Boehringer Mannheim (524298), "' -Calcium solution (0.025 mol/1), Behring Werke, Marburg (ORH 056/57), -diethylbarbiturate acetate buffer, Behring Werke, Marburg (ORWH 60/61), -Biomatic B10 coagulometer, Desaga, Wiesloch.
Method:
The aTTP [sic] time is determined with a Biomatic B10-coagulo-meter made by Messrs Desaga.
The test substance was placed in the test tubes prescribed by the manufacturer with 0.1 ml of human citrated plasma and 0.1 ~_~ 25 ml of PTT-reagent. The mixture was incubated for three minutes at 37°C. The coagulation reaction was started by the addition of 0.1 ml of calcium solution. The time taken for the mixture to coagulate from the addition of the calcium solution is mea-sured using the equipment. Mixtures to which 0.1 ml of DBA buf-fer had been added were used as the control.
The effective concentration of substance with which the aPTT
time was double that of the control was defined by means of a dosage/activity curve.
The following Table contains the results obtained:

Substance aTTP time (EDZOa in ~M) A 0.92 B 0.55 C 5.60 D 3.80 E 0.25 F 0.35 G 0.82 H 0.50 I 1.00 The compounds prepared according to the invention are well tolerated as no toxic side effects can be observed at thera-peutic doses.
In view of their pharmacological properties the new compounds and the physiologically acceptable salts thereof are suitable for the prevention and treatment of venous and arterial throm-botic diseases, such as for example the treatment of deep leg vein thrombosis, the prevention of reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral .~ arterial diseases such as pulmonary embolism, disseminated intravascular clotting, the prevention of coronary thrombosis, stroke prevention and the preventing the occlusion of shunts.
In addition the compounds according to the invention are sui-table for antithrombotic support in thrombolytic treatment, such as for example with rt-PA or streptokinase, to prevent long-term restenosis after PT(C)A, to prevent metastasis and the growth of clot-dependent tumours and fibrin-dependent in-flammatory processes.
The dosage required to achieve a corresponding activity is appropriately 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg, by intravenous route and 0.1 to 50 mg/kg, preferably 0.3 to mg/kg, by oral route, 1 to 4 times a day. For this purpose the compounds of formula I prepared according to the invention, optionally in conjunction with other active substances, may be formulated together with one or more conventional inert car-riers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyr-rolidone, citric acid, tartaric acid, water, water/ethanol, wa-ter/glycerol, water/sorbitol, water/polyethyleneglycol, pro-pyleneglycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The following Examples are intended to illustrate the invention more fully:

4-[(5-benzenesulphonylamino-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzamidine-hydrochloride a . ~- f ( 5-ni ro-l H-b n . i mi da of - -~,1 ) -~m ~h~l 1 -bPn on i t-ri 1 P
3.1 g (0.02 mol) of 4-nitro-o-phenylenediamine and 3.7 g (0.023 mol) of 4-cyanophenylacetic acid are refluxed for 2 hours in 30 ml of phosphorus oxychloride. After cooling the mixture is neutralised with concentrated ammonia and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulphate and concentrated by evaporation. The re-sidue is chromatographed on silica gel, eluting with methylene chloride/methanol (50:1). The desired fractions are concentra-ted by evaporation, the residue is triturated with ethyl aceta-te/ether, suction filtered and dried.
Yield: 2.1 g (38 0 of theory) , Rf value: 0.25 (Silica gel; methylene chloride/methanol = 19:1) CisHioNa~2 ( 2 78 . 3 ) Mass spectrum: M' - 278 b. 4-[(5-nitro-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzo-nitrile and 4-[(6-nitro-1-methyl-1H-benzimidazol-2-yl)-methyl]-ben .oni ri 1 1.4 g (5.0 mmol) of 4-[(5-nitro-1H-benzimidazol-2-yl)-methyl]-benzonitrile, 2.6 g (15 mmol) of potassium carbonate x 2 H20 and 0.84 g (6.0 mmol) of methyl iodide are dissolved in 60 ml acetone and stirred for 1 hour at ambient temperature. The sol-vent is evaporated off, the residue is mixed with water, the product precipitated is suction filtered and dried.
Yield: 1.1 g (75 0 of theory), Rf value: 0.2 (Silica gel; methylene chloride/methanol = 19:1) c. 4-[(5-amino-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzo-nitrilP
1.1 g (37.6 mmol) of 4-[(5-nitro-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and 4-[(6-nitro-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzonitrile are dissolved in 30 ml methanol and 40 ml methylene chloride and after the addition of 0.2 g palladium on activated charcoal (10%) hydrogenated for 60 minutes at ambient temperature. Then the catalyst is filte-red off and the filtrate is concentrated by evaporation. The residue is chromatographed on silica gel and eluted with methy-lene chloride/methanol (30:1).
Yield: 0.3 g (30 0 of theory), Rf value: 0.4 (silica gel; methylene chloride/methanol = 9:1) C16H14N4 ( 2 6 2 . 3 ) Mass spectrum: M+ - 262 d. 4-[(5-benzenesulphonylamino-1-methyl-1H-benzimidazol-2-yl)-meth~rl_-b n .oni ri 1 300 mg (11.4 mmol) of 4-[(5-amino-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and 200 mg (11.4 mmol) of benzene-sulphonic acid chloride are stirred into 10 ml pyridine for one hour at ambient temperature. Then 1 ml water is added and the mixture is concentrated by evaporation. The residue is combined with water and ethyl acetate and stirred for one hour at ambi-ent temperature, whilst the substance slowly crystallises. The ethyl acetate is evaporated off and the crystalline residue is suction filtered.
Yield: 380 mg (83 % of theory), '.~ 25 Rf value: 0.5 (silica gel; methylene chloride/methanol = 9:1) e. 4-[(5-benzenesulphonylamino-1-methyl-1H-benzimidazol-2-yl)-430 mg (1.07 mmol) of 4-[(5-benzenesulphonylamino-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile are dissolved in 30 ml saturated ethanolic hydrochloric acid and stirred for 5 hours at ambient temperature. The solvent is distilled off, the resi-due is dissolved in 30 ml absolute ethanol and combined with 1.0 g (10.7 mmol) of ammonium carbonate. After 60 hours at am-bient temperature the mixture is evaporated to dryness. The residue is chromatographed on silica gel and eluted with methy-lene chloride/methanol (5:1). Corresponding fractions are eva-porated down, triturated with ether and suction filtered.
Yield: 170 mg (29 0 of theory), Rf value: 0.2 (silica gel; methylene chloride/methanol - 5:1) C22H21NSOzS x HCl (419.50/455.96) Mass spectrum: (M+H)' - 420 4-[(5-benzenesulphonylamino-1H-benzimidazol-2-yl)-methyl]-benz-amidine-hydrochloride Prepared analogously to Example le from 4-[(5-benzenesulphonyl-amino-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochlo-ric acid/ammonium carbonate in ethanol.
Yield: 59 % of theory, CzlHlsIVs02S x HC1 (405.48/441.95) Mass spectrum: (M+H)+ - 406 Exam 4-[(6-benzenesulphonylamino-4-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(6-benzenesulphonyl-amino-4-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 38 0 of theory.
C22HZ1NSOZS x HCl (419.50/455.96) Mass spectrum: (M+H)' - 420 4-[(6-benzenesulphonylamino-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(6-benzenesulphonyl-amino-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 23 0 of theory Rf value: 0.25 (silica gel; methylene chloride/methanol = 5:1) C22HZ1NSO2S x HC1 (419.50/455.96) Mass spectrum: (M+H)' - 420 4-[(5-benzenesulphonylamino-1-n-propyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-benzenesulphonyl-amino-1-n-propyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 43 0 of theory, C24H25N502S x HC1 (447.55/484.02) ._. Mass spectrum: (M+H)' - 448 4-[(6-benzenesulphonylamino-1-n-propyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(6-benzenesulphonyl-amino-1-n-propyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 39 0 of theory, C24H25N502S x HCl (447.55/484.02) Mass spectrum: (M+H)' - 448 4-[(5-phenylaminosulphonyl-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzamidine-hydrochloride a. 4-phPn~rlaminos~lmhonyl-2-ni ro- hlorobPn~PnP
Prepared analogously to Example ld from aniline and 4-chlorine-3-nitro-benzenesulphonic acid chloride in pyridine.
Yield: 97 0 of theory, Rf value: 0.5(silica gel; methylene chloride/ethanol = 19:1) b. 4-~~Pri~rl mi noml p hon~sl-2-ni ro-N-m hyl -ani 1 i n 6.0 g (0.019 mol) of 4-phenylaminosulphonyl-2-nitro-chloroben zene and 40 ml methylamine solution (40o in H20) are heated to 130~C in a bomb for two hours. The contents are diluted with water and neutralised with hydrochloric acid. The precipitated product is suction filtered and dried.
Yield: 5.0 g (86 0 of theory), Rf value: 0.45 (silica gel; methylene chloride/ethanol = 19:1) C . 4-z hPn~rl mi o~~z hon~rl-2-ami no-N-m hurl -ani 1 i n 5.0 g (0.016 mol) of 4-phenylaminosulphonyl-2-nitro-N-methyl-aniline are dissolved in 300 ml ethyl acetate and 30 ml metha-,w" nol and after the addition of 1.0 g Raney nickel hydrogenated with hydrogen at 60~C. The catalyst is removed by suction fil-tering, 40 ml methanolic hydrochloric acid are added and the solution is evaporated down. The residue is crystallised with ether/ethyl acetate, suction filtered and dried.
Yield: 5.0 g (89 0 of theory), Rf value: 0.41 (silica gel; methylene chloride/ethanol = 9:1) d. 4-[(5-phenylaminosulphonyl-1-methyl-1H-benzimidazol-2-yl)-Prepared analogously to Example la from 4-phenylaminosulphonyl-2-amino-N-methyl-aniline-hydrochloride and 4-cyano-phenylacetic acid in phosphorus oxychloride.
Yield: 36 0 of theory, e. 4-[(5-phenylaminosulphonyl-1-methyl-1H-benzimidazol-2-yl)-me-thyl1 -b n .ami i nP-h~rdrn~-hl r,r; ~70 Prepared analogously to Example le from 4-[(5-phenylaminosul-phonyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 11 % of theory, C22HZ1NSOZS x HCl (419.5/456.0) Mass spectrum: (M+H)' - 420 Exa Tr~l P 8 4-[(5-benzenesulphonylamino-1-ethyl-1H-benzimidazol-2-yl)-me-thyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-benzenesulphonyl-amino-1-ethyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 35 0 of theory, C23H23NSOzS x HC1 (433.53/469.99) Mass spectrum: (M+H)' - 434 4-[(5-(N-methyl-benzenesulphonylamino)-1-methyl-IH-benzimi-dazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-methyl-ben-zenesulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 27 % of theory, Cz3H2jN5O2S x HC1 (433.53/469.99) Mass spectrum: (M+H)' - 434 4-[(5-benzenesulphonylamino-1-ethoxycarbonylmethyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-benzenesulphonyl-amino-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 68 0 of theory, CZSHZSN504S x HC1 (491.58/528.05) Mass spectrum: (M+H)' - 492 4-[(5-benzenesulphonylamino-1-carboxymethyl-1H-benzimidazol-2-yl)-methyl]-benzamidine 200 mg (0.379 mmol) of 4-[(5-benzenesulphonylamino-1-ethoxy-carbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hy-drochloride are dissolved in 10 ml ethanol and stirred at 40~C
for 90 minutes after the addition of 1 ml 2N sodium hydroxide solution. The solvent is distilled off, the residue diluted with 20 ml water and acidified with glacial acetic acid. The precipitated product is suction filtered and dried.
Yield: 160 mg (91 0 of theory), C23H21N5~4'S (463.53) Mass spectrum: (M+H)' - 464 4-[(5-(N-ethoxycarbonylmethyl-benzenesulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride a. 4-[(5-(N-ethoxycarbonylmethyl-benzenesulphonylamino)-1-me-th~rl-1 H-b .i mi da .ol - -girl ) -mp hurl 1 -b n .oni ri 1 P
Prepared analogously to Example lb from 4-[(5-benzenesulphonyl-amino-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and ethyl bromoacetate in potassium carbonate/acetone.
Yield: 99 0 of theory, Rf value: 0.3 (silica gel; methylene chloride/methanol = 9:1) b. 4-[(5-(N-ethoxycarbonylmethyl-benzenesulphonylamino)-1-me-thvl-1H-berizimidazol-2-vl l -mPt-hvl l -hanzami r3i na-h~rr~rnrhl nr; ~A
Prepared analogously to Example le from 4-[(5-(N-ethoxycar-bonylmethyl-benzenesulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 41 0 of theory, CZ4H23N504S x HCl (505.62/542.06) Mass spectrum: (M+H)' - 506 (3M + 2H)+' - 758.8 z5 Rxam 4-[(5-(N-carboxymethyl-benzenesulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride 0.6 g (1.1 mmol) of 4-[(5-(N-ethoxycarbonylmethyl-benzene-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benz-amidine-hydrochloride and 0.22g (5.5 mmol) of sodium hydroxide are stirred in 15 ml water and 10 ml ethanol for two hours at ambient temperature. The mixture is diluted with water and ad-justed to pH 4 with hydrochloric acid. The solvent is concen-trated by evaporation, the residue is triturated with ether, suction filtered and dried.

Yield: 0.3 g (53 % of theory), Cz4Hz3N504S x HCl (477.54/514.00) Mass spectrum: (M+H)+ - 478 Examr~l_e 14 4-[(5-(N-benzyl-methanesulphonylamino)-1-methyl-1H-benzimi-dazol-2-yl)-methyl]-benzamidine-hydrochloride a. 4-[(5-methanesulphonylamino-1-methyl-1H-benzimidazol-2-yl)-Prepared analogously to Example ld from 4-[(5-amino-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and methanesulphonic acid chloride in pyridine.
Yield: 62 0 of theory, Rf value: 0.6 (silica gel; methylene chloride/methanol - 9:1) b. 4-[(5-(N-benzyl-methanesulphonylamino)-1-methyl-1H-benzimi-da .ol - -girl 1 -meth~rl ] -b -n .on; r; 1 Prepared analogously to Example lb from 4-[(5-methanesulphonyl-amino-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile, benzylchloride and potassium carbonate in acetone.
Yield: 79 % of theory, Rf value: 0.7 (silica gel; methylene chloride/methanol = 9:1) c. 4-[(5-(N-benzyl-methanesulphonylamino)-1-methyl-1H-benzimi-Prepared analogously to Example le from 4-[(5-(N-benzyl-me-thanesulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 54 0 of theory, C24HZSN5025 x HC1 (447.55/484.01) Mass spectrum: (M+H)' - 448 - 57 _ 4-[(5-(N-(naphthalen-1-yl-methyl)-methanesulphonylamino)-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-(naphthalen-1-yl-methyl)-methanesulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium car-bonate in ethanol.
Yield: 11 0 of theory, C28HZ.,NSOZS x HC1 (497.62/534.08) Mass spectrum: (M+H)+ - 498 4-[(5-(naphthalen-1-yl-sulphonylamino)-1-methyl-1H-benzimida-zol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(naphthalen-1-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzo-nitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 66 0 of theory, CzsHz3NsOzS x HCl (469 . 57/506 . 03 ) Mass spectrum: (M+H)' - 470 4-[(5-(naphthalen-2-yl-sulphonylamino)-1-methyl-1H-benzimida-zol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(naphthalen-2-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzo-nitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 74 % of theory, CZ6H23NSOzS x HC1 (469 . 57/506 . 03 ) Mass spectrum: (M+H)' - 470 4-[(5-benzylsulphonylamino-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-benzylsulpho-nylamino-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 68 a of theory, C23H23N5~2S x HCl (433.53/469. 99) Mass spectrum: (M+H)' - 434 4-[(5-(Quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzo-nitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 65 % of theory, CzsHzaNsO2s x HCl (470.55/507.01) Mass spectrum: (M+H)' - 471 F.~amp~ 2 ~~
4-[(5-(3,5-Bis-trifluoromethylphenylsulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(3,5-Bis-tri-fluoromethylphenylsulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 63 0 of theory, C24H19F6NSOZS x HC1 (555.51/591.97) Mass spectrum: (M+H)' - 556 4-[(5-(2,5-dimethoxyphenylsulphonylamino)-1-methyl-1H-benzimi-dazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(2,5-dimethoxy-phenylsulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 83 % of theory, C24H25N5~4S x HC1 ( 4 7 9 . 5 5 / 516 . O l ) Mass spectrum: (M+H)' - 480 4-[(5-(2,3,5,6-tetramethylphenylsulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(2,3,5,6-tetra-methylphenylsulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: l7 0 of theory, °° C26H29NSOZS x HCl (475.61/512.08) Mass spectrum: (M+H)' - 476 4-[(5-phenylsulphonylaminoacetylamino-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-phenylsulphonyl-aminoacetylamino-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzo-nitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 65 % of theory, C24H24N6O3S x HC1 (476.56/513.03) Mass spectrum: (M+H)' - 477 4-[(5-(N-methyl-naphthalen-1-yl-aminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride a. 4- hl oro-'~-ni ro-bPn~oi r ari c~Hl Sri ~7a 20.1 g (0.1 mol) of 4-chloro-3-nitro-benzoic acid, 11 ml thionyl chloride and 1 drop of dimethylformamide are mixed together and refluxed for two hours. The thionyl chloride is evaporated off.
Yield: 21.9 g (100 % of theory).
b. 4-chl oro-~-ni ro-N- (n"yhtl-,al Pn-1 -girl ) b n ami c~P
To a solution of 2.8 g (0.02 mol) of 1-naphthylamine and 2.0 g (0.02 mol) of triethylamine in 50 ml tetrahydrofuran is added dropwise at 15-20~C a solution of 4.4 g (0.02 mol) of 4-chloro-3-nitro-benzoic acid chloride in 20 ml tetrahydrofuran. The so-lution is stirred for 30 minutes at ambient temperature. Then the solvent is evaporated off and the residue is chromatogra-phed on silica gel, eluting with methylene chloride. The desi-red fractions are concentrated by evaporation, triturated with ether, suction filtered and dried.
Yield: 5.9 g (90 0 of theory).
c . 4- _hl oro-~-ni ro-N-m hurl -N- (nanht-ral Pn ~ yl ) bPn ami ~3P
3.2 g (0.01 mol) of 4-chloro-3-nitro-N-(naphthalen-1-yl)-benz-amide and 1.1 g (0.01 mol) of potassium-tert.-butoxide are dissolved in 50 ml dimethylsulphoxide and stirred for 30 mi-nutes at ambient temperature. Then 1 ml methyl iodide is added thereto and the mixture is stirred for a further 3 hours at ambient temperature. The solution is poured onto saturated sodium chloride solution and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulphate and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with methylene chloride.

Yield: 3.2 g (94% of theory), Melting point: 118-120°C.
d. 4-met_h_~rl ami no-'~-ni ro-N-mP hurl -N- (nanht-hal Pn 1 girl ) ami ~3P
3.0 g (8.83 mmol) of 4-chloro-3-nitro-N-methyl-N-(naphthalen-1-yl)-benzamide and 30 ml methylamine solution (40% in H20) are heated to 130'C in a bomb for 14 hours. After cooling the solu tion is poured onto water, the residue is suction filtered and chromatographed on silica gel, eluting with methylene chloride.
Yield: 2.9 g (98 a of theory), Rf value: 0.3 (silica gel; methylene chloride/ethanol = 50:1) a . ~-meth~rl_ami no- -ami no-N-m hurl -N- (nar~hthal Pn-~ -girl ) -bPn ami c~P
2.9 g (8.6 mmol) of 4-methylamino-3-nitro-N-methyl-N-(naphtha len-1-yl)-benzamide are dissolved in 100 ml methanol and after the addition of 0.5 g palladium on activated charcoal (20 0) hydrogenated for two hours at ambient temperature. Then the catalyst is filtered off and the filtrate is concentrated by evaporation.
Yield: 2.6 g (98 % of theory), Rf value: 0.15 (silica gel; methylene chloride/ethanol = 50:1) f. 4-[(5-(N-methyl-naphthalen-1-yl-aminocarbonyl)-1-methyl-1H-ben2i_mi dazol - -girl ) -~~rl 1 -bPnzoni firi 1 P
'.~~25 483 mg (3.0 mmol) of 4-cyanophenylacetic acid and 486 mg (3.0 mmol) of carbonyldiimidazole are dissolved in 20 ml tetra-hydrofuran and stirred for 1 hour at 50'C. Then 916 mg 5-(naph-thalen-1-yl-methylaminocarbonyl)-2-methylamino-aniline are ad-ded thereto and stirring is continued for a further 3 hours at 50'C. The solvent is concentrated by evaporation, the residue is combined with 30 ml glacial acetic acid and refluxed for 1 hour. After evaporation of the solvent the filtrate is chroma-tographed on silica gel, eluting with methylene chloride/etha-nol 99:1, 98:1 and 97:1. The desired fractions are concentrated by evaporation, the residue is triturated with acetone/ether, suction filtered and dried.

Yield: 970 mg (75 0 of theory), Melting point: 266-268°C
g. 4-[(5-(N-methyl-naphthalen-1-yl-aminocarbonyl)-1-methyl-1H-b~nzimidazol -~-vl 1 -mPrh~T1 1 -han~am; rai no_1-,mi-7,...-.l.l,l .~".~ .7,-, Prepared analogously to Example le from 4-[(5-(N-methyl-naph-thalen-1-yl-aminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 82 % of theory, C28HZSN50 x HCl (447.55/484.01) ~~ Mass spectrum: M+ - 447 4-[(5-phenylmethylaminocarbonyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-phenylmethyl-aminocarbonyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzoni-trile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 95.50 of theory, C24HasNsO x HCl (397.49/433.96) Mass spectrum: M' - 397 4-[(5-(N-phenyl-n-butylaminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-phenyl-n-bu-tylaminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzo-nitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 95 0 of theory, CZ.,HZ9N50 x HC1 (439.57/476.03) Mass spectrum: (M+H)+ - 440 4-[(4-benzenesulphonylamino-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(4-benzenesulphonyl-amino-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 63 % of theory, CZ2HZ1N502S x HC1 (419.50/455.96) Mass spectrum: (M+H)+ - 420 4-[(5-(N-methylaminocarbonyl-N-phenyl-aminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-mesylate 700 mg (1.6 mmol) of 4-[(5-(N-methylaminocarbonyl-N-phenyl-aminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzo-nitrile, 222 mg (3.2 mmol) of hydroxylamine-hydrochloride and 170 mg (1.6 mmol) of sodium carbonate are refluxed in 100 ml methanol and 4 ml water for 16 hours. After the addition of 150 mg methanesulphonic acid and 500 mg Raney nickel the mix-ture is hydrogenated at ambient temperature and with 5 atm.
hydrogen. The catalyst is filtered off, the residue is concen-trated by evaporation and chromatographed on silica gel, elu-ting with methylene chloride/ethanol (8:2).
Yield: 680 mg (77 0 of theory), Cz6HasNsOz x CH3S03H (454.54/550.64) Mass spectrum: (M+H)' - 455 4-[(6-(naphthalen-2-yl-sulphonylamino)-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(6-(naphthalen-2-yl-sulphonylamino)-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 63 % of theory, C29HZ~N504S x HCl (541.64/578.1) Mass spectrum: (M+H)+ - 542 4-[('4-(naphthalen-2-yl-sulphonylamino)-1-methyl-1H-benzimida-zol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(4-(naphthalen-2-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzo-nitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 66 % of theory, Ca6H2aNsOzS x HCl (469.57/506.03) Mass spectrum: (M+H)' - 470 4-[(5-(N-(2-morpholino-ethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydro-chloride Prepared analogously to Example le from 4-[(5-(N-(2-morpholino-ethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 66 0 of theory, C31H33N.,O3S x 2 HCl (583.72/656.63) Mass spectrum: (M+H)+ - 584 4-[(5-(N-(2-morpholino-ethyl)-quinolin-8-yl-amino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-morpholino-ethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 96 0 of theory, C31H31N7O45 x HCl (597.70/634.17) Mass spectrum: (M+H)+ - 598 4-[(5-(N-(3-ethoxycarbonyl-n-propyl)-quinolin-8-yl-sulphonyl-amino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-(3-ethoxy-m.... carbonyl-n-propyl)-quinolin-8-yl)-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 58 % of theory, C31H32N6O4S x HC1 (584.71/621.17) Mass spectrum: (M+H)+ - 585 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydro-chloride Prepared analogously to Example le from 4-[(5-(N-ethoxycar-bonylmethyl-quinolin-8-yl-sulphonylamino-1-methyl-1H-benzimida-zol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 68 % of theory, C29HZgN6O4S x HC1 (556.65/593.12) Mass spectrum: (M+H)+ - 557 (M+Na)+ - 579 (M+2H)++ - 279 4-[(5-(N-ethoxycarbonylmethyl-benzoylamino)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-ethoxycar-bonylmethyl-benzoylamino)-1-methyl-1H-benzimidazol-2-yl)-me--... thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 47 0 of theory, C2,HZ.,N503 x HCl ( 4 6 9 . 5 5 / 5 0 6 . 0 ) Mass spectrum: (M+H)+ - 470 3 0 Rxamz l 4-[(5-(N-(3-ethoxycarbonyl)-phenylsulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-(3-ethoxy-carbonyl)-phenylsulphonylamino-1-methyl-1H-benzimidazol-2-yl)-- 6~ -methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 24 % of theory, CZSHasNs~4s x HC1 (491.6/528.0) Mass spectrum: (M+H)+ - 492 4-[(5-(N-methyl-pyridine-3-ylaminocarbonyl)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-methyl-pyri-dine-3-ylaminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 49 0 of theory, C23HZZN6O x HCl (398.48/434.94) Mass spectrum: (M+H)+ - 399 Rxa tzol~ ~8_ 4-[(5-(N-methyl-pyridine-2-ylaminocarbonyl)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-methyl-pyri-dine-2-yl-aminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 49 % of theory, Cz3H22N60 x HC1 (398.48/434.94) Mass spectrum: (M+H)' - 399 4-[(5-(N-phenyl-N-ethoxycarbonylmethyl-aminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-phenyl-N-ethoxycarbonylmethyl-aminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium car-bonate in ethanol.
Yield: 65 % of theory, C2,Hz.,N503 x HC1 (469.55/506.02) Mass spectrum: (M+H)+ - 470 4-[(5-(N-phenyl-N-(2-dimethylamino-ethyl)-aminocarbonyl)-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-phenyl-N-(2-dimethylamino-ethyl)-aminocarbonyl)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/-ammonium carbonate in ethanol.
Yield: 24 % of theory, ( C2.,H3oN6O x 2 HCl (454.59/527.50) Mass spectrum: (M+H)' - 455 4-[(5-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in etha-nol/water.
Yield: 56 % of theory, CZ,Hz4N604S x HC1 (528.60/565.05) Mass spectrum: (M+H)+ - 529 (M+Na)' - 551 Exam~l P~4 4-[(5-(N-(3-carboxy-n-propyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydro-chloride Prepared analogously to Example 13 from 4-[(5-(N-(3-carboxy-.r, n-propyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol/water.
Yield: 46 0 of theory, C29HZgN6O4S x HC1 (556.65/593.10) Mass spectrum: (M+H)' - 557 (M+Na)' - 579 2 0 Fxamz l ~4 ~
4-[(5-(N-(2-morpholino-ethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-carbonyl]-benzamidine-dihydro-chloride ~ ,~. 2 5 Prepared analogously to Example le from 4-[(5-(N-(2-morpholino-ethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-carbonyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
30 Yield: 37 % of theory, C31H31N.,~4S x 2 HCl ( 597 . 7/670 . 62 ) Mass spectrum: (M+H)' - 598 4-[(5-(N-(3-dimethylamino-n-propyl)-quinolin-8-yl-sulphonyl-amino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(3-dimethyl-amino-n-propyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 78 % of theory, C30H33N7O2S x 2 HCl (555 . 71/663 . 07) Mass spectrum: (M+H)+ - 556 (M+2H)" - 278.8 4-[(5-(N-(2-dimethylamino-ethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydro-chloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/-ammonium carbonate in ethanol.
Yield: 81 0 of theory, Cz9H31N,OzS x 2HC1 (541.68/612.59) Mass spectrum: (M+H)' - 542 Ex_amml 46 4-[(5-(N-benzoyl-N-carboxymethyl-amino)-1-methyl-1H-benzimida-zol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-benzoyl-N-eth oxycarbonylmethyl-amino)-1-methyl-1H-benzimidazol-2-yl)-me thyl]-benzamidine-hydrochloride and sodium hydroxide in etha-nol/water.
Yield: 98 0 of theory, C25H23NSO3 x HC1 (441. 50/447.95) Mass spectrum: (M+H)' - 442 (M+Na) + - 464 4-[(5-(3-carboxyphenylsulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(3-ethoxycar-bonylphenylsulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol/water.
Yield: 82 0 of theory, C23H21NSO4S x HCl (463.50/499.95) Mass spectrum: (M+H)' - 464 4-[(5-(N-phenyl-N-carboxymethyl-aminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride i "~ 25 Prepared analogously to Example 13 from 4-[(5-(N-phenyl-N-eth-oxycarbonylmethyl-aminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol/water.
Yield: 68 % of theory CzsHzaNs~a (441.50/477.95) Mass spectrum: (M+H)' - 442 . - 72 -4-[(5-benzenesulphonylamino-1-n-propyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-benzenesulphonyl-amino-1-n-propyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 62 % of theory, C25Hz.,N502S x HC1 (461 . 58/498 . 04 ) Mass spectrum: (M+H)' - 462 4-[(5-(N-ethoxycarbonylmethyl-benzenesulphonylamino)-1-n-pro-pyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-ethoxycar-bonylmethyl-benzenesulphonylamino)-1-n-propyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium car-bonate in ethanol.
Yield: 45 % of theory, Cz9H33N5O4S x HC1 (547.68/584.14) Mass spectrum: (M+H)' - 548 4-[(5-(N-methyl-benzenesulphonylamino)-1-n-propyl-1H-benzimida-zol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-methyl-ben-zenesulphonylamino)-1-n-propyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 45 0 of theory, CZ6Hz9N502S x HCl (475.62/512.08) Mass spectrum: (M+H)' - 476 4-[(5-(N-carboxymethyl-benzenesulphonylamino)-1-n-propyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-ethoxycar-bonylmethyl-benzenesulphonylamino)-1-n-propyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol/water.
Yield: 62 0 of theory °~ CZ.,H29NSO4S x HC1 (519.63/556.08) Mass spectrum: (M+H)' - 520 Exams 4-[(5-(N-phenyl-N-(3-ethoxycarbonyl-n-propyl)-aminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochlo-ride Prepared analogously to Example le from 4-[(5-(N-phenyl-N-(3-ethoxycarbonyl-n-propyl)-aminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/-ammonium carbonate in ethanol.
Yield: 70 a of theory, C29H31NSO3 x HC1 (497.61/534.07) Mass spectrum: (M+H)' - 498 4-[(5-((N-pyridin-3-yl-carbonyl)-N-methyl-amino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-((N-pyridin-3-yl-carbonyl)-N-methyl-amino)-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.

Yield: 54 % of theory, C23HZZN60 x HC1 (398.5/434.95) Mass spectrum: M+ - 398 Exams 4-[(5-((N-pyridin-4-yl-carbonyl)-N-methyl-amino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-((N-pyridin-4-yl-carbonyl)-N-methyl-amino)-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 53 % of theory, C23Hz2N60 x HCl (398.5/434.95) Mass spectrum: (M+H)' - 399 4-[(5-(pyridin-3-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(pyridin-3-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzo-~.-nitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 48 0 of theory, CzlH2oN602S x HC1 (420.5/456.95) Mass spectrum: (M+H)' - 421 3 0 Examz 1 a 5 7 4-[(5-(N-ethoxycarbonylmethyl-benzenesulphonylamino)-1-eth-oxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-ethoxycar-bonylmethyl-benzenesulphonylamino)-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 64.5 0 of theory, C29H31NSO6S x HCl (577.67/614.14) Mass spectrum: (M+H)+ - 578 4-[(5-(N-(2-dimethylamino-ethyl)-benzenesulphonylamino)-1-eth-oxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-di-hydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl)-benzenesulphonylamino)-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: ll.lo of theory, CZ8H3zN6O4S x 2 HCl (548.68/621.6) Mass spectrum: (M+H)' - 549 (M+2H)++ - 275.1 4-[(6-benzenesulphonylamino-1-ethoxycarbonylmethyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(6-benzenesulphonyl-amino-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 90 % of theory, CzsHzsNs04s x HCl (491.58/528.05) Mass spectrum: (M+H)' - 492 - 76 _ 4-[(5-(3-ethoxycarbonyl-n-propylamino)-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(3-ethoxycar-bonyl-n-propylamino)-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbo-nate in ethanol.
Yield: 41.7 % of theory, C25H31N504 x HCl (465 . 56/502 . 03 ) Mass spectrum: (M+H)+ - 466 4-[(5-(ethoxycarbonylmethylamino)-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(ethoxycarbonyl-methylamino)-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 56.4 a of theory, C23H2,NSO4 x HCl (437.51/473.98) j ._ Mass spectrum: (M+H)' - 438 4-[(5-(N-methyl-piperidin-1-yl-carbonylamino)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-methyl-pipe-ridin-1-yl-carbonylamino)-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 55 0 of theory, _ 77 _ Cz3H28N6O x HCl (404.52/440.98) Mass spectrum: M' - 404 4-[(5-(N-methyl-2,3-dihydroindol-1-yl-carbonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-methyl-2,3-di-hydroindol-1-yl-carbonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 78 % of theory, C2sHzsNsO x HC1 (438.54/475.00) Mass spectrum: M' - 438 4-[(5-(N-(3-ethoxycarbonyl-n-propyl)-benzenesulphonylamino)-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benz-amidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-(3-ethoxy-carbonyl-n-propyl)-benzenesulphonylamino)-1-ethoxycarbonyl-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 59.5 % of theory, C3iHasNsOss x HCl (605.9/641.4) Mass spectrum: (M+H)' - 606 4-[(6-(N-methyl-benzenesulphonylamino)-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(6-(N-methyl-ben-zenesulphonylamino)-1-ethoxycarbonylmethyl-1H-benzimidazol-2-_ 78 _ yl)-methyl]-benzonitrile and hydrochloric acid/ammonium car-bonate in ethanol.
Yield: 45 0 of theory, C26Hz.,N504S x HC1 (505.61/542.07 ) Mass spectrum: (M+H)+ - 506 4-[(5-benzenesulphonylamino-1-(3-ethoxycarbonyl)-n-propyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride ~...- Prepared analogously to Example le from 4-[(5-benzenesulphonyl-amino-1-(3-ethoxycarbonyl)-n-propyl-1H-benzimidazol-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 58 0 of theory, C2~H29NSO4S x HCl (519.6/556.1) Mass spectrum: (M+H)' - 520 Exa~rol_e 67 4-[(5-benzenesulphonylamino-1-benzyl-1H-benzimidazol-2-yl)-me-thyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-benzenesulphonyl-amino-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 63 % of theory, CZBH25NSOzS x HC1 (495.6/532.1) Mass spectrum: (M+H)+ - 496 4-[(5-benzenesulphonylamino-1-(2-morpholino-ethyl)-1H-benzimid-azol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-benzenesulphonyl-amino-1-(2-morpholino-ethyl)-1H-benzimidazol-2-yl)-methyl]-ben-zonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 96 0 of theory, CZ~H3aN603S x 2 HCl (518.65/591.56) Mass spectrum: (M+H)' - 519 4-[(5-benzenesulphonylamino-1-(2-dimethylamino-ethyl)-1H-benz-imidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-benzenesulpho-nylamino-1-(2-dimethylamino-ethyl)-1H-benzimidazol-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 38 0 of theory, C25H28N6O2S x 2 HC1 (476. 6/549.56) Mass spectrum: (M+H)' - 477 ~''~~ 25 4-[(5-(N-ethoxycarbonylmethyl-benzenesulphonylamino)-1-(3-eth-oxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzami-dine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-ethoxycarbo-nylmethyl-benzenesulphonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 61 0 of theory, C31H35NSO6S x HC1 ( 605 . 7/642 . 2 ) Mass spectrum: (M+H)+ - 606 4-[(5-(N-ethoxycarbonylmethyl-benzenesulphonylamino)-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-ethoxycarbon-ylmethyl-benzenesulphonylamino)-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 43 0 of theory, C32H31NSO4S x HCl ( 581 . 7/618 . 2 ) Mass spectrum: (M+H)' - 582 4-[(5-(N-(N'-phenyl-methylaminocarbonyl)-methylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-(N'-phenyl-methylaminocarbonyl)-methylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium car--~ 25 bonate in ethanol.
Yield: 43 0 of theory, CzsHzsNsO x HCl (426.52/462.98) Mass spectrum: (M+H)' - 427 3 0 Examz 1 P 7'~
4-[(5-(N-(ethoxycarbonylmethylaminoacetyl)-quinolin-8-yl-sul-phonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzami-dine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-(ethoxycar-bonylmethylaminoacetyl)-quinolin-8-yl-sulphonylamino)-1-methyl-, _ 81 _ 1H-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 80 0 of theory, C31H31N.,OSS x HCl (613.70/650.16) Mass spectrum: (M+H)' - 614 4-[(5-(N-(4-dimethylaminopiperidinocarbonylmethyl)-quinolin 8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]
benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(4-dimethyl-aminopiperidinocarbonylmethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 78 0 of theory, C34H38NeO3S x 2 HC1 ( 63 8 . 8 /711 . 73 ) Mass spectrum: (M+H)' - 639 4-[(5-(N-ethoxycarbonylmethyl-benzenesulphonylamino)-1-(2-mor pholino-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihy drochloride Prepared analogously to Example le from 4-[(5-(N-ethoxycar-bonylmethyl-benzenesulphonylamino)-1-(2-morpholino-ethyl)-1H-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 68 0 of theory, C31H36N6OSS x 2 HCl (604.7/677.66) Mass spectrum: (M+H)' - 605 4-[(5-(N-aminocarbonylmethyl-benzenesulphonylamino)-1-(3-eth-oxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzami-dine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-aminocarbo-nylmethyl-benzenesulphonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 49 a of theory, CZ9H32N6OSS x HCl (576.7/613.1) Mass spectrum: (M+H)+ - 577 Exams l a 77 4-[(5-(N-aminocarbonylmethyl-benzenesulphonylamino)-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-aminocarbo-nylmethyl-benzenesulphonylamino)-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 61 0 of theory, C3oH28N603S x HC1 (552.7/588.2) Mass spectrum: (M+H)' - 553 4-[(5-(N-aminocarbonylmethyl-benzenesulphonylamino)-1-(2-mor-pholino-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-di-hydrochloride Prepared analogously to Example le from 4-[(5-(N-aminocarbo-nylmethyl-benzenesulphonylamino)-1-(2-morpholino-ethyl)-1H-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.

Yield: 78 0 of theory, C29H33N.,O4S x HCl (575.7/648.6) Mass spectrum: (M+H)' - 576 E~=
4-[(5-(N-carboxymethyl-benzenesulphonylamino)-1-(2-morpholino-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochlo-ride Prepared analogously to Example 13 from 4-[(5-N-(ethoxycarbo-nylmethyl-benzenesulphonylamino)-1-(2-morpholino-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-di-hydrochloride and sodium hydroxide in ethanol/water.
Yield: 87 % of theory, C29H32N6OSS x 2 HC1 (576.7/649.62) Mass spectrum: (M+H)' - 577 4-[(5-(N-ethoxycarbonylmethyl-benzenesulphonylamino-1-(2-di-methylamino-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride ~~25 Prepared analogously to Example le from 4-[(5-(N-ethoxycarbo-nylmethyl-benzenesulphonylamino)-1-(2-dimethylamino-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/-ammonium carbonate in ethanol.
Yield: 60 % of theory, 3O C29H34N6~4S x 2 HCl (562.7/635.66) Mass spectrum: (M+H)' - 563 (M+2H) " - 282 4-[(5-(N-carboxymethyl-benzenesulphonylamino)-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-ethoxycar-bonylmethyl-benzenesulphonylamino)-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol/water.
Yield: 84 0 of theory, C3oH2.,N504S x HCl (553.65/590.11) Mass spectrum: (M+H)+ - 554 4-[(5-(N-(carboxymethylaminoacetyl)-quinolin-8-yl-sulphonyl-amino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-(ethoxycar-bonylmethylaminoacetyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol/water.
Yield: 74 % of theory, "° 25 Cz9H2~N,O5S x HC1 (585.65/622.11) Mass spectrum: (M+H)+ - 586 (M+Na)' - 608 4-[(5-(N-carboxymethyl-benzenesulphonylamino)-1-(2-dimethyl-amino-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihy-drochloride Prepared analogously to Example 13 from 4-[(5-(N-ethoxycar-bonylmethyl-benzenesulphonylamino)-1-(2-dimethylamino-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride and sodium hydroxide in ethanol/water.
Yield: 62 % of theory, CZ.,H3oN604S x 2 HCl (534.65/607.56) Mass spectrum: (M+H)' - 535 4-[(5-(N-(4-methylpiperazinocarbonylmethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benz-amidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(4-methyl-piperazinocarbonylmethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 86 % of theory, C32H34N8~3s x 2 HCl (610.74/683.67) Mass spectrum: (M+H)' - 611 4-[(5-(N-(N'-(2-dimethylaminoethyl)-ethylaminocarbonylmethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 5-(N-(N'-(2-dimethyl-aminoethyl)-ethylaminocarbonylmethyl)-quinolin-8-yl-sulphonyl-amino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 95 % of theory, C33H38NBO3S x 2 HC1 (626.79/699.71) Mass spectrum: (M+H)' - 627 4-((5-[(1-ethoxycarbonyl-2-aminocarbonyl-ethylamino)-carbonyl-methyl]-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-[(1-ethoxycar-bonyl-2-aminocarbonyl-ethylamino)-carbonylmethyl]-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-ben-zonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 63 0 of theory, C33H34NBO6'S x HCl (670.75/707.21) Mass spectrum: (M+H)+ - 671 Exarryl~87 4-[(5-(N-(4-(2-morpholino-2-oxo-ethyl)-piperazinocarbonylme-thyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(4-(2-morpho-lino-2-oxo-ethyl)-piperazinocarbonylmethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzo-nitrile and hydrochloric acid/ammonium carbonate in ethanol.
-~~?5 Yield: 81 % of theory, C3.,H41N9OSS x 2 HC1 (723.87/796.79) Mass spectrum: (M+H)' - 724 4-[(5-(N-(2-dimethylamino-ethyl)-benzenesulphonylamino)-1-eth-oxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-((5-(N-(2-dimethyl-amino-ethyl)-benzenesulphonylamino)-1-ethoxycarbonylmethyl-1H-_ 87 _ benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/-ammonium carbonate in ethanol.
Yield: 84 % of theory, C29H34N6O4S x 2 HCl (562.71/635.63) Mass spectrum: (M+H)' - 563 4-[(5-(N-(2-dimethylamino-ethyl)-quinolin-8-yl-sulphonylamino-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benz-amidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl)-quinolin-8-yl-sulphonylamino)-1-ethoxycarbonyl-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 86 % of theory, C32H35N,04S x 2 HCl (613.75/686.68) Mass spectrum: (M+H)' - 614 4-[(5-(N-aminocarbonylmethyl-benzenesulphonylamino)-1-(2-di-°'°' methylamino-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-aminocarbo-nylmethyl-benzenesulphonylamino)-1-(2-dimethylamino-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 83 0 of theory, C2.,H31N.,O3S x 2 HC1 (533.7/606.56) Mass spectrum: (M+H)' - 534 4-[(5-(N-(2-dimethylamino-ethyl)-benzenesulphonylamino-1-(2-morpholino-ethyl)-1H-benzimidazol-2-yl)-methyl]-benz-amidine-trihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl)-benzenesulphonylamino)-1-(2-morpholino-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 76 0 of theory, C31H39N7O3'S x 3 HCl (589.8/699.18) Mass spectrum: (M+H)+ - 590 (M+2H)" - 295.8 4-[(5-(N-(2-dimethylamino-ethyl)-benzenesulphonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl)-benzenesulphonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 70 0 of theory, C31H38N6O4S x 2 HC1 (590.7/663.62) Mass spectrum: (M+H)' - 591 3 0 F~xam= l P 9'~
4-[(5-(N-(2-dimethylamino-ethyl)-benzenesulphonylamino)-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydro-chloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl)-benzenesulphonylamino)-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 55 0 of theory, C32H34N6OZS x 2 HCl (566.7/639.62) Mass spectrum: (M+H)+ - 567 4-[(5-(N-[(1-carboxy-2-aminocarbonyl-ethylamino)-carbonylme-thyl]-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-[(1-ethoxy-carbonyl-2-aminocarbonyl-ethylamino)-carbonylmethyl]-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol/-water.
Yield: 55 % of theory, CaiHaoNe~ss x HCl ( 642 . 70/679 . 16 ) Mass spectrum: (M+H)+ - 643 4-[(5-(N-(2-dimethylamino-ethyl)-n-butanesulphonylamino)-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benz-amidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl)-n-butanesulphonylamino)-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/-ammonium carbonate in ethanol.
Yield: 77 % of theory, C2.,H3gN604S x 2 HC1 ( 542 . 72/615 . 64 ) Mass spectrum: (M+H)' - 543 4-[(5-(N-methoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydro-chloride Prepared analogously to Example le from 4-[(5-(N-methoxycarbo-nylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimida-zol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in methanol.
Yield: 67 a of theory, C2gHz6N6O4S x HCl (542.63/579.09) Mass spectrum: (M+H)' - 543 (M+2H)+' - 272 ( M+H+Na ) 2' - 2 8 3 4-[(5-(N-methoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-N'-methoxycarbonyl-benzamidine 0.7 g (1.2 mmol) of 4-[(5-(N-methoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benz-z5 amidine-hydrochloride and 0.66 g (4.8 mmol) of potassium carbo-nate are dissolved in 5 ml water and 20 ml acetone and after the addition of 0.12 g (1.3 mmol) of methylchloroformate the mixture is stirred for 30 minutes at ambient temperature. The solvent is evaporated off, the residue chromatographed on sili-ca gel and eluted with methylene chloride/methanol 40:1. The desired fractions are concentrated by evaporation, the residue is triturated with ether and suction filtered.
Yield: 0.26 g (36 0 of theory), C3aH28N6O6S ( 6 0 0 . 6 6 ) Mass spectrum: (M+H)' - 601 (M+Na)' - 623 4-[(5-(N-(2-dimethylamino-ethyl)-quinolin-8-yl-sulphonylamino)-1-carboxymethyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hy-drochloride Prepared analogously to Example 13 from 4-[(5-(N-(2-dimethyl-amino-ethyl)-quinolin-8-yl-sulphoamino)-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and so-ium hydroxide in ethanol/water.
Yield: 60 0 of theory, C3oH31N,O4S x HC1 (585.67/622.13) Mass spectrum: (M+H)' - 586 Examral P A ~
z 4-[(5-(N-(2-dimethylamino-ethyl)-benzenesulphonylamino)-1-(eth-oxycarbonylmethylaminocarbonylmethyl)-1H-benzimidazol-2-yl)-me-thyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl)-benzenesulphonylamino-1-(ethoxycarbonylmethyl-aminocarbonylmethyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 85 0 of theory, C31H3,N.,OSS x 2 HC1 ( 619 . 76/692 . 68 ) Mass spectrum: (M+H)' - 620 (M+2H)" - 310.8 3 0 Examp_l_,~ ~ 0 0 4-[(5-(N-(3-dimethylamino-n-propyl)-benzenesulphonylamino)-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydro-chloride Prepared analogously to Example le from 4-[(5-(N-(3-dimethyl-amino-n-propyl)-benzenesulphonylamino)-1-benzyl-1H-benzimida-zol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 83 % of theory, C33H36N6~2s x 2 HC1 (580. 8/653 .7) Mass spectrum: (M+H)' - 581 (M+2H)" - 291 4-[(5-(N-(2-dimethylamino-ethyl)-benzenesulphonylamino)-1-(carboxymethylaminocarbonylmethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example 13 from 4-[(5-(N-(2-dimethyl-amino-ethyl)-benzenesulphonylamino)-1-(ethoxycarbonylmethyl-aminocarbonylmethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride and sodium hydroxide in ethanol/water.
Yield: 94 % of theory, C29H33N.,OSS x 2 HCl (591.71/664.64) Mass spectrum: (M+H)' - 592 4-[(5-(N-(2-methyl-propyloxycarbonylmethyl)-quinolin-8-yl-sul-phonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-N'-meth-oxycarbonyl-benzamidine Prepared analogously to Example 97 from 4-[(5-(N-(2-methyl-propyloxycarbonylmethyl)-quinolin-8-yl-sulphonylamino)-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and methyl chloroformate in acetone/water.
Yield: 25 0 of theory, C33H34N6O6'S ( 642 . 74 ) Mass spectrum: (M+H)' - 643 (M+Na)' - 665 4-[(5-(N-ethoxycarbonylmethyl-isoquinolin-5-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochlo-ride Prepared analogously to Example le from 4-[(5-(N-ethoxycarbo-nylmethyl-isoquinolin-5-yl-sulphonylamino)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/-ammonium carbonate in ethanol.
Yield: 98 0 of theory, Cz9H28N6O4S x HC1 (556.65/593.11) Mass spectrum: (M+H)' - 557 Examz l P 1 04 4-[(5-(isoquinolin-5-yl-sulphonylamino)-1-methyl-1H-benzimida-zol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(isoquinolin-5-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 48 0 of theory, C25H22N60zS x HCl (470.55/507.02) Mass spectrum: (M+H)' - 471 4-[(5-(N-(2-pyrrolidino-ethyl)-benzenesulphonylamino-1-benzyl 1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-pyrroli-dino-ethyl)-benzenesulphonylamino)-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.

Yield: 53 0 of theory, C34H36N6~2'S x 2 HCl (592. 8/665. 7) Mass spectrum: (M+H)+ - 593 (M+2H) '+ - 297 4-[(5-(N-(2-pyrrolidino-ethyl)-benzenesulphonylamino-1-(3-eth-oxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzami-dine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-pyrroli-dino-ethyl)-benzenesulphonylamino)-1-(3-ethoxycarbonyl-n-pro-pyl)-1H-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 33 % of theory, C33H40N6~4'S x 2 HCl ( 616 . 8 / 6 8 9 . 7 ) Mass spectrum: (M+H)' - 617 (M+2H)" - 309 4-[(5-(N-(3-piperidino-n-propyl)-benzenesulphonylamino)-1-ben-zyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(3-piperidino-n-propyl)-benzenesulphonylamino)-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 56 % of theory, C36H40N6~2s x 2 HCl (620.8/693 .7) Mass spectrum: (M+H)' - 621 4-[(5-benzenesulphonylamino-1-(2-ethoxycarbonyl-ethyl)-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-benzenesulpho-nylamino-1-(2-ethoxycarbonyl-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 67 0 of theory, CZ6Hz.,N504S x HCl (505.60/542.06) Mass spectrum: (M+H)' - 506 4-[(5-(N-carboxymethyl-isoquinolin-5-yl-sulphonylamino)-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-ethoxycarbo-nylmethyl-isoquinolin-5-yl-sulphonylamino)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol/water.
Yield: 90 0 of theory, Cz.,HZ4N6O4S x HC1 (528.60/565.06) Z5 Mass spectrum: (M+H)' - 529 4-[(5-(N-(3-dimethylamino-n-propyl)-benzenesulphonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(3-dimethyl-amino-n-propyl)-benzenesulphonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.

Yield: 78 0 of theory, C32H4oN6O4S x 2 HC1 (604.8/677.7) Mass spectrum: (M+H)' - 605 Rxamp 4-[(5-(N-(3-piperidino-n-propyl)-benzenesulphonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(3-piperidino-n-propyl)-benzenesulphonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 72 0 of theory, C35H44N6O4S x 2 HC1 (644 .8/717. 7) Mass spectrum: (M+H)' - 645 4-[(5-(N-(3-dimethylamino-n-propyl)-benzenesulphonylamino)-1-(3-carboxy-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benz-amidine-dihydrochloride Prepared analogously to Example 13 from 4-[(5-(N-(3-dimethyl-amino-n-propyl)-benzenesulphonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydro-chloride and sodium hydroxide in ethanol/water.
Yield: 79 % of theory, C3oH36N604S x 2 HC1 (576.7/649.6) Mass spectrum: (M+H)' - 577 4-[(5-(N-(3-piperidino-n-propyl)-benzenesulphonylamino)-1-(3-carboxy-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example 13 from 4-[(5-(N-(3-piperidino-n-propyl)-benzenesulphonylamino)-1-(3-ethoxycarbonyl-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride and sodium hydroxide in ethanol/water.
Yield: 64 0 of theory, C33H4oN6O4S x 2 HCl (616.8/689.7) Mass spectrum: (M+H)+ - 617 Examp 4-[(5-(N-(2-dimethylamino-ethyl)-benzenesulphonylamino)-1-(4-methoxycarbonyl-benzyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl-benzenesulphonylamino)-1-(4-methoxycarbonyl-ben-zyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochlo-ric acid/ammonium carbonate in ethanol.
Yield: 78 0 of theory, C34H36N6O4S x 2 HCl (624.8/697.7) Mass spectrum: (M+H)' - 625 4-[(5-(N-(2-dimethylamino-ethyl)-benzenesulphonylamino-1-(2-ethoxycarbonyl-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl)-benzenesulphonylamino)-1-(2-ethoxycarbonyl-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 84 % of theory, C3aH36N6O4S x 2 HC1 (576.73/651.65) Mass spectrum: (M+H)+ - 577 4-[(5-(N-(3-dimethylamino-n-propyl)-benzenesulphonylamino)-1-(2-ethoxycarbonyl-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(3-dimethyl-amino-n-propyl)-benzenesulphonylamino)-1-(2-ethoxycarbonyl-ethyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 81 % of theory, C31H38N6O4S x 2 HCl (590.75/663.67) Mass spectrum: (M+H)' - 591 (M+2H) +' - 296 4-[(5-(N-(2-dimethylamino-ethyl)-benzenesulphonylamino)-1-(2-carboxy-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example 13 from 4-[(5-(N-(2-dimethyl-amino-ethyl)-benzenesulphonylamino)-1-(2-ethoxycarbonyl-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride and sodium hydroxide in ethanol/water.
Yield: 92 % of theory, CzeH32N604S x 2 HC1 (548.67/621.59) Mass spectrum: (M+H)' - 549 _ 99 _ 4-[(5-(N-(3-dimethylamino-n-propyl)-benzenesulphonylamino)-1-(2-carboxy-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example 13 from 4-[(5-(N-(3-dimethyl-amino-n-propyl)-benzenesulphonylamino)-1-(2-ethoxycarbonyl-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochlori-de and sodium hydroxide in ethanol/water.
Yield: 42 % of theory, C29H34N6O4S x 2 HCl (548.67/621.59) Mass spectrum: (M+H)+ - 549 Exampl 4-[(5-(N-phenyl-N-(3-carboxy-n-propyl)-aminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-phenyl-N-(3-ethoxycarbonyl-n-propyl)-aminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol/water.
Yield: 78 % of theory, Cz~Hz~N503 x HCl (469 . 55/506 . 02 ) Mass spectrum: (M+H)+ - 470 4-[(5-(N-(3-dimethylamino-n-propyl)-methanesulphonylamino-1-(2-ethoxycarbonyl-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(3-dimethyl-amino-n-propyl)-methanesulphonylamino)-1-(2-ethoxycarbonyl-ethyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydro-chloric acid/ammonium carbonate in ethanol.

Yield: 90 0 of theory, C26H36N6O4S x 2 HC1 (528.68/601.61) Mass spectrum: (M+H)' - 529 Exam_r~l P 'I .'1 4-[(5-(N-(2-dimethylamino-ethyl)-methanesulphonylamino)-1-(2-ethoxycarbonyl-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl)-methanesulphonylamino)-1-(2-ethoxycarbonyl-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 94 % of theory, CZSH34N6O4S x 2 HC1 (514.65/587.57) Mass spectrum: (M+H)+ - 515 4-[(5-(2-dimethylamino-ethylaminosulphonyl)-1-benzyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(2-dimethylamino-ethylaminosulphonyl)-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 84 0 of theory, C26H3oN602S x 2 HCl (490.6/563.6) Mass spectrum: (M+H)' - 491 4-[(5-(N-methyloxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-N~-isobutyloxycarbonyl-benzamidine Prepared analogously to Example 97 from 4-[(5-(N-methyloxy-carbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride and isobutyl chloroformate in acetone/water.
Yield: 41 0 of theory, C33H34N6~6'S ( 642 . 75 ) Mass spectrum: (M+H)' - 643 (M+Na)' - 665 4-[(5-(N-(3-dimethylamino-n-propyl)-methanesulphonylamino)-1-(2-carboxy-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example 13 from 4-[(5-(N-(3-dimethyl-amino-n-propyl)-methanesulphonylamino)-1-(2-ethoxycarbonyl-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydro-chloride and sodium hydroxide in ethanol/water.
Yield: 63 0 of theory, Cz4H3zN6O4S x 2 HC1 (500.62/573.54) Mass spectrum: (M+H)' - 501 3 0 Exam= 1 P ~
4-[(5-(N-(2-dimethylamino-ethyl)-methanesulphonylamino)-1-(2-carboxy-ethyl))-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example 13 from 4-[(5-(N-(2-dimethyl-amino-ethyl)-methanesulphonylamino)-1-(2-ethoxycarbonyl-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride and sodium hydroxide in ethanol/water.
Yield: 72 0 of theory, C23H3oN6O4S x 2 HC1 (486.6/559.52) Mass spectrum: (M+H)+ - 487 4-[(5-(N-ethyloxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-N'-cyclohexyloxycar-bonyl-benzamidine Prepared analogously to Example 97 from 4-[(5-(N-ethyloxy-carbonylmethyl-quinolin-8-yl-sulphonylamino-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride and cyclohexyl chloroformate in acetone/water.
Yield: 61 a of theory, C3sHasNs~ss ( 682 . 81 ) Mass spectrum: (M+H)' - 683 (M+Na)' - 705 4-[(5-(N-ethyloxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-N'-benzyloxycarbonyl-benzamidine Prepared analogously to Example 97 from 4-[(5-(N-ethyloxycar-bonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride and benzyl chloroformate in acetone/water.
Yield: 65 0 of theory, C37H34N6~6s (690.79) Mass spectrum: (M+H)' - 691 (M+Na)' - 713 4-[(5-(4-dimethylamino-piperidino)-1H-benzimidazol-2-yl)-me-thyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(4-dimethylamino-piperidino)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hy-drochloric acid/ammonium carbonate in ethanol.
Yield: 100 % of theory, CZZH28N6 x 2 HC1 (376.51/ 449.42) Mass spectrum: (M+H)' - 377 4-[(5-(4-dimethylamino-piperidino)-1-(2-ethoxycarbonyl-ethyl) 1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(4-dimethylamino-piperidino)-1-(2-ethoxycarbonyl-ethyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 100 0 of theory, CZ.,H36N602 x 2 HC1 (476.63/549.56) Mass spectrum: (M+H)' - 477 ' 25 4-[(5-(N-(2-dimethylamino-ethyl)-methanesulphonylamino)-1-(3-ethoxycarbonylmethylaminocarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl)-methanesulphonylamino)-1-(3-ethoxycarbonylmethyl-aminocarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzo-nitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 98 0 of theory, C28H39N,OSS x 2 HC1 (585.74/658.67) Mass spectrum: (M+H)' - 586 4-[(5-(N-(2-dimethylamino-ethyl)-methanesulphonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl)-methanesulphonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 94 0 of theory, C26H36N604S x 2 HC1 (528.69/601.62) Mass spectrum: (M+H)+ - 529 4-[(5-(N-ethyloxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-N'-ethyloxycarbonyl-benzamidine Prepared analogously to Example 97 from 4-[(5-(N-(2-ethyloxy-carbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride and ethyl chloroformate in acetone/water.
Yield: 63 % of theory, Cj2H32N6O6S ( 62 8 . 71 ) Mass spectrum: (M+H)' - 629 4-[(5-(N-methyl-piperidinocarbonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydro-chloride Prepared analogously to Example le from 4-[(5-(N-methyl-pi-peridinocarbonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benz-imidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/-ammonium carbonate in ethanol.
Yield: 21 0 of theory, CZBHj6N6O3 x HCl ( 504 . 64 /541 . 11 ) Mass spectrum: (M+H)' - 505 (M+2H) " - 253 4-[(5-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-N'-ethyloxycarbonyl-benzamidine Prepared analogously to Example 13 from 4-[(5-(N-ethoxycarbo-nylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimida-zol-2-yl)-methyl]-N'-ethyloxycarbonyl-benzamidine-hydrochloride and sodium hydroxide in ethanol/water.
Yield: 70 % of theory, C3oH28N606S ( 6 0 0 . 6 6 ) Mass spectrum: (M+H)' - 601 (M-H)- - 599 (M+Na)' - 623 4-[(5-(N-methyl-piperidinocarbonylamino)-1-(3-carboxy-n-pro-pyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-methyl-pipe-ridinocarbonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol/water.
Yield: 63 % of theory, C26H32N6~3 x HCl ( 4 7 6 . 5 9 / 513 . 0 5 ) Mass spectrum: (M+H)+ - 477 4-[(5-(N-(2-diethylamino-ethyl)-benzenesulphonylamino) 1-(ethoxycarbonylmethylaminocarbonylmethyl)-1H-benzimidazol 2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-diethyl-amino-ethyl)-benzenesulphonylamino)-1-(ethoxycarbonylmethyl-aminocarbonylmethyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 76 0 of theory, C33H41N705'S x 2 HC1 ( 647 . 81/720 . 74 ) Mass spectrum: (M+H)' - 648 (M+2H)" - 324.8 4-[(5-(N-(2-dimethylamino-ethyl)-N-ethyl-aminosulphonyl)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl)-N-ethyl-aminosulphonyl)-1-(3-ethoxycarbonyl-n-pro-pyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochlo-ric acid/ammonium carbonate in ethanol.
Yield: 64 % of theory, C2.,H38N6OqS x 2 HC1 (542.7/615.6) Mass spectrum: (M+H)' - 543 4-[(5-(N-(2-dimethylamino-ethyl)-aminosulphonyl)-1-(3-ethoxy-carbonyl-n-propyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl)-aminosulphonyl)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 93 0 of theory, C25H34N6~4'S x 2 HC1 (514.7/587. 6) Mass spectrum: (M+H)+ - 515 Fxam= 1_2 13 9 4-[(5-(N-(2-diethylamino-ethyl)-benzenesulphonylamino)-1-(carb-oxymethylaminocarbonylmethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example 13 from 4-[(5-(N-(2-diethyl-amino-ethyl)-benzenesulphonylamino)-1-(ethoxycarbonylmethyl-aminocarbonylmethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride and sodium hydroxide in ethanol/water.
' 25 Yield: 78 0 of theory, C31H3~N.,OSS x 2 HC1 (619.76/692.69) Mass spectrum: (M+H)' - 620 (M+2H)" - 311 ( M+H+Na ) " - 3 2 2 4-[(5-(N-(2-dimethylamino-ethyl)-ethylaminosulphonyl)-1-(3-carboxy-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example 13 from 4-[(5-(N-(2-dimethyl-amino-ethyl)-ethylaminosulphonyl)-1-(3-ethoxycarbonyl-n-pro-pyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride and sodium hydroxide in ethanol/water.
Yield: 86 0 of theory, C25H34N6~4'S x 2 HC1 (514 .7/587.6) Mass spectrum: (M+H)' - 515 Fxam~ l P 1 41 4-[(5-(N-(ethoxycarbonylmethylaminocarbonylmethyl)-phenyl-aminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benz-amidine-hydrochloride Prepared analogously to Example 1 from 4-[(5-(N-(ethoxycarbo-nylmethylaminocarbonylmethyl)-phenylaminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/-ammonium carbonate in ethanol.
Yield: 88 0 of theory, C28H3oN6O4 x HC1 (514.6/551.05) Mass spectrum: (M+H)' - 515 4-[(5-(N-(carboxymethylaminocarbonylmethyl)phenylaminocarbo-nyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydro-chloride Prepared analogously to Example 13 from 4-[(5-(N-(ethoxycarbo-nylmethylaminocarbonylmethyl)-phenylaminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol/water.
Yield: 33 % of theory, CZ.,HZ6N6O4 x HC1 (498.55/535.13) Mass spectrum: (M+H)+ - 499 4-[(5-(2-dimethylamino-ethylaminosulphonyl)-1-(3-carboxy-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydro-chloride Prepared analogously to Example 13 from 4-[(5-(2-dimethylamino-ethylaminosulphonyl)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride and sodium hydroxide in ethanol/water.
Yield: 75 % of theory, C23H30N6~4s x 2 HCl (486.6/559.5) Mass spectrum: (M+H)' - 487 4-[(5-(N-(1-methyl-piperidin-2-yl-methyl)-benzenesulphonyl-.... amino) -1- (ethoxycarbonylmethylarilinocarbonylmethyl) -1H-benz-imidazol-2-yl)-methyl]-benzamidine-dihydrochloride a. 4-[(5-benzenesulphonylamino-1-(ethoxycarbonylmethylamino-carbonvl meth~rl ) -1H-ben .i mi da .ol -2-~1 ) -meth~rl 1-b n oni t-ri 1 a 2.7 g (6.1 mmol) of 4-[(5-benzenesulphonylamino-1-carboxyme-thyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile, 0.85 g (6.1 mmol) of glycine-ethyl ester-hydrochloride and 1.5 g (15 mmol) of triethylamine are dissolved in 80 ml dimethylform-amide and after the addition of 2.4 g (7.5 mmol) of O-(benzo-triazol-1-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate the mixture is stirred for 16 hours at ambient temperature. The solvent is evaporated off, the residue chromatographed on sili-ca gel and eluted with methylene chloride/ethanol 99:1 and 98:2. The desired fractions are concentrated by evaporation, the residue is triturated with ether, suction filtered and dried.
Yield: 1.9 g (59 % of theory), Melting point: 166-168~C.
b. 4-[(5-(N-(1-methyl-piperidin-2-yl-methyl)-benzenesulpho-nylamino)-1-(ethoxycarbonylmethylaminocarbonylmethyl)-1H-b n .i mi da .ol - -girl ) -methyl 1 -b n .oni t-ri 1 P
Prepared analogously to Example lb from 4-[(5-benzenesulphonyl-amino-1-(ethoxycarbonylmethylaminocarbonylmethyl)-1H-benzimi-dazol-2-yl)-methyl]-benzonitrile, 2-(chloromethyl)-N-methyl-pi-peridine and potassium carbonate in acetone.
Yield: 38 0 of theory, C34H38N6O5'S ( 642 . 79 ) Mass spectrum: (M+H)+ - 643 c. 4-[(5-(N-(1-methyl-piperidin-2-yl-methyl)-benzenesulphonyl-amino)-1-(ethoxycarbonylmethylaminocarbonylmethyl)-1H-benzimi-da~~~-v1) -methvll -benzami c3i nP-rli h~r~3rnrhl r"-~; r~A
Prepared analogously to Example le from 4-[(S-(N-(1-methyl-piperidin-2-yl-methyl)-benzenesulphonylamino)-1-(ethoxycarbo-nylmethylaminocarbonylmethyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ~p5 ethanol.
Yield: 100 0 of theory, C34H41N.,OSS x 2 HCl (659.82/732.75) Mass spectrum: (M+H)' - 660 (M+2H) " - 330 . 7 4-[(5-(N-(N'-ethoxycarbonylmethyl-N'-methyl-aminocarbonyl-methyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-(N'-ethoxycar-bonylmethyl-N'-methyl-aminocarbonylmethyl)-quinolin-8-yl-sul-phonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitri-le and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 52 % of theory, C32H33N7~SS x HC1 (627.73/664.19) Mass spectrum: (M+H)' - 628 F,xam 4-[(5-(N-methyl-piperidinocarbonylamino)-1-benzyl-1H-benzimida-zol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-methyl-pi-peridinocarboamino)-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 57 0 of theory, C29H32N60 x HC1 (480 . 62 . /517. 08) Mass spectrum: (M+H)' - 481 4-[(5-(N-(N'-carboxymethyl-N'-methyl-aminocarbonylmethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-(N'-ethoxycar-bonylmethyl-N'-methyl-aminocarbonylmethyl)-quinolin-8-yl-sul-phonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzami-dine-hydrochloride and sodium hydroxide in ethanol/water.

Yield: 69 % of theory, C3oH29N.,O5S x HC1 (599.67/636.13) Mass spectrum: (M+H)+ - 600 Exams l a 1 4 f~
4-[(5-(N-ethoxycarbonylmethylaminocarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-N'-cyc-lohexyloxycarbonyl-benzamidine Prepared analogously to Example 97 from 4-[(5-(N-ethoxycarbo-nylmethylaminocarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochlori-de and cyclohexyl chloroformate in tetrahydrofuran/water.
Yield: 48 0 of theory, C38H41N.,O~S ( 73 9 . 8 6 ) Mass spectrum: (M+H)' - 740 (M+2H)'~ - 370.8 (M+H+Na)+' - 381.6 4-[(5-(N-ethoxycarbonylmethylaminocarbonylmethyl-quinolin-8-yl-,. sulphonylamino)-1-methyl-1H-benzimidazol-2-y1)-methyl]-N'-ben-- 25 zyloxycarbonyl-benzamidine Prepared analogously to Example 97 from 4-[(5-(N-ethoxycarbo-nylmethylaminocarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochlori-de and benzyl chloroformate in tetrahydrofuran/water.
Yield: 38 0 of theory, C39H37N7O7'S ( 747 . 85 ) Mass spectrum: (M+H)' - 748 (M+Na)' - 770 (M+H+Na)" - 385.2 4-[(5-(N-(1-methyl-piperidin-2-yl-methyl)-benzenesulphonylami-no-1-(carboxymethylaminocarbonylmethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example 13 from 4-[(5-(N-(1-methyl-piperidin-2-yl-methyl)-benzenesulphonylamino)-1-(ethoxycarbo-nylmethylaminocarbonylmethyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride and sodium hydroxide in ethanol.
Yield: 83 % of theory, C32H3.,N.,055 x 2 HC1 (631.77/704.7) Mass spectrum: (M+H)' - 632 (M+2H) ++ - 316 . 8 4-[(5-(2-dimethylamino-ethyl)-aminocarbonyl)-1-(ethoxycarbonyl-methylaminocarbonylmethyl)-1H-benzimidazol-2-yl)-methyl]-benz-amidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(2-dimethylamino-ethyl)-aminocarbonyl)-1-(ethoxycarbonylmethylaminocarbonyl-methyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydro-~5 chloric acid/ammonium carbonate in ethanol.
Yield: 95 0 of theory, CzsH33N.,04 x 2 HCl (507.61/580.54) Mass spectrum: (M+H)a - 508 Examr~le 152 4-[(5-(N-(2-dimethylamino-ethyl)-ethylaminosulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl)-ethylaminosulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 82 0 of theory, C22H3oN60zS x 2 HC1 (442.6/515.5) Mass spectrum: (M+H)+ - 443 4-((5-cyclohexylcarbonylamino-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride a. 4-c"~r l o ~ girl arbon~rl ami no- -ni rn-fl »nrnhan~Ana 15.6 g (0.1 mol) of 4-fluoro-3-vitro-aniline and 17.9 g (0.11 mol) of cyclohexylcarboxylic acid chloride are dissolved in 250 ml tetrahydrofuran and after the addition of 12.1 g (0.12 mol) of triethylamine the mixture is stirred for 3 hours at ambient temperature. The solvent is distilled off, the residue is mixed with water and extracted with ethyl acetate. The combined orga-nic extracts are dried over sodium sulphate and concentrated by evaporation.
Yield:17.1 g (64 0 of theory), Rf value: 0.2 (silica gel; methylene chloride/petroleum ether =
9:1) b. tert.butyl 4-[4-(cyclohexylcarbonylamino)-2-vitro-phenyl Prepared analogously to Example 7b from 4-cyclohexylcarbonyl-amino-2-vitro-fluorobenzene, tert.butyl aminobutyrate and potassium carbonate in dimethylsulphoxide.
Yield: 49 0 of theory, Rf value: 0.3 (silica gel; methylene chloride/methanol = 50:1) c. tert.butyl 4-[4-(cyclohexylcarbonylamino)-2-amino-phenylami-nol bLt~r_ratP
Prepared analogously to Example 7c from tert.butyl 4-[4-(cyclo-hexylcarbonylamino)-2-vitro-phenylamino]butyrate and palladium on activated charcoal/hydrogen in methanol.

Yield: 94 0 of theory, Rf value: 0.5 (silica gel; methylene chloride/methanol - 9:1) d. 4-[(5-cyclohexylcarbonylamino-1-(3-tert.butyloxycarbonyl-ri-nrotwl) -1 H-b n . i m i c3a ~nl - -yl~h~ 1 1 -b inn i fi ri 1 a 0.65 g (4.0 mmol) of 4-cyanophenylacetic acid and 0.65 g (4.0 mmol) of N,N'-carbonyldiimidazole are dissolved in 50 ml tetrahydrofuran and refluxed for 30 minutes. After the addition of 1.3 g (3.5 mmol) of tert.butyl 4-[4-(cyclohexylcar-bonylamino)-2-amino-phenylamino]butyrate the mixture is re-fluxed for a further 3 hours. The solvent is concentrated by evaporation and the residue refluxed for 1 hour with 30 ml glacial acetic acid. Then it is evaporated down in vacuo, the residue is poured onto water, made basic with ammonia and ex-tracted with ethyl acetate. The combined organic extracts are dried and evaporated down. The residue is chromatographed on silica gel and eluted with methylene chloride/methanol 50:1.
The desired fractions are combined and concentrated by evapora-tion.
Yield: 0.9 g (52 % of theory), Rf value: 0.4 (silica gel; methylene chloride/methanol - 9:1) e. 4-[(5-cyclohexylcarbonylamino-1-(3-ethoxycarbonyl-n-propyl)-t25 Prepared analogously to Example le from 4-[(5-cyclohexylcar-bonylamino-1-(3-tert.butyloxycarbonyl-n-propyl)-1H-benzimi-dazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 95 0 of theory, C2aH35N503 x HC1 (489.62/526.08) Mass spectrum: (M+H)' - 490 4-[(5-cyclohexylcarbonylamino-1-(4-ethoxycarbonyl-n-butyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-cyclohexylcar-bonylamino-1-(4-ethoxycarbonyl-n-butyl)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 79 0 of theory, C29H3.,NSO3 x HCl (503.64/540.11) Mass spectrum: (M+H)+ - 504 4-[(5-cyclohexylcarbonylamino-1-(3-carboxy-n-propyl)-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-cyclohexylcar-bonylamino-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in etha-nol/water.
Yield: 100 a of theory, .~- C26H31N5~3 x HCl ( 4 61 . 5 7 / 4 9 8 . 0 3 ) '~ 25 Mass spectrum: (M+H)' - 462 4-[(5-cyclohexylcarbonylamino-1-(4-carboxy-n-butyl)-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-cyclohexylcar-bonylamino-1-(4-ethoxycarbonyl-n-butyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in etha-nol/water.
Yield: 98 % of theory, C2,H33NSO3 x HCl (475.59/512.05) Mass spectrum: (M+H)+ - 476 4-[(5-cyclohexylmethylaminocarbonyl-1-(3-ethoxycarbonyl-n-pro-pyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-cyclohexylme-thylaminocarbonyl-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimida-zol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium u._ carbonate in ethanol.
Yield: 67 0 of theory, CzgH3.,N5O3 x HCl (503.66/540.12) Mass spectrum: (M+H)+ - 504 4-[(5-(N-cyclohexyl-methylaminocarbonyl)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydro-chloride Prepared analogously to Example le from 4-[(5-(N-cyclohexyl-methylaminocarbonyl)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimi-dazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 64 a of theory, Cz9H3.,N503 x HC1 (503.66/540.12) Mass spectrum: (M+H)+ - 504 4-[(5-(N-methyl-cyclohexylcarbonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochlo-ride Prepared analogously to Example le from 4-[(5-(N-methyl-cyclo-hexylcarbonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimi-dazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 74 0 of theory, C29H3.,NSO3 x HCl (503.65/540.11) Mass spectrum: (M+H)+ - 504 F-xamp l ~~ 6 0 4-[(5-(N-methyl-cyclohexylcarbonylamino)-1-(4-ethoxycarbonyl-n-butyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochlori-de Prepared analogously to Example le from 4-[(5-(N-methyl-cyclo-hexylcarbonylamino)-1-(4-ethoxycarbonyl-n-butyl)-1H-benzimida-zol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
~-~ 25 Yield: 87 0 of theory, C3oHj9N5O3 x HC1 ( 517 . 68/554 . 15 ) Mass spectrum: (M+H)' - 518 4-[(5-(N-methyl-cyclohexylcarbonylamino)-1-(3-carboxy-n-pro-pyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-methyl-cyclo-hexylcarbonylamino)-1-(3-ethoxycarbonyl-n-propyl)-1H-benzimida-zol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxi-de in ethanol/water.

Yield: 44 % of theory, C2.,H33NSO3 x HC1 (475.59/512.06) Mass spectrum: (M+H)+ - 476 ExarQ~ l 4-[(5-(N-methyl-cyclohexylcarbonylamino)-1-(4-carboxy-n-butyl)-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-methyl-cyclo-hexylcarbonylamino)-1-(4-ethoxycarbonyl-n-butyl)-1H-benzimida-zol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxi-de in ethanol/water.
Yield: 47 0 of theory, C28H35N503 x HC1 (489.62/526.08) Mass spectrum: (M+H)' - 490 4-[(5-(N-(3-ethoxycarbonyl-n-propyl)-ethylaminosulphonyl)-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-(3-ethoxycar-bonyl-n-propyl)-ethylaminosulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium car-bonate in ethanol.
Yield: 61 0 of theory, C24H31N504S x HC1 (485.6/522.1) Mass spectrum: (M+H)' - 486 4-[(5-(N-(4-ethoxycarbonyl-n-butyl)-ethylaminosulphonyl)-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-(4-ethoxycar-bonyl-n-butyl)-ethylaminosulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium car-bonate in ethanol.
Yield: 63 % of theory, C25H33NSO4S x HC1 (499.6/536.1) Mass spectrum: (M+H)+ - 500 4-[(5-(N-(3-carboxy-n-propyl)-ethylaminosulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-(3-ethoxycar-bonyl-n-propyl)-ethylaminosulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol.
Yield: 66 0 of theory, CZZH2.,N504S x HC1 (457.6/494.1) Mass spectrum: (M+H)' - 458 Examr~le 166 4-[(5-(N-(4-carboxy-n-butyl)-ethylaminosulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride - z5 Prepared analogously to Example 13 from 4-[(5-(N-(4-ethoxycar-bonyl-n-butyl)-ethylaminosulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol.
Yield: 66 0 of theory, C23Hz9Ns04s x HC1 (471.6/508.1) Mass spectrum: (M+H)+ - 472 4-[(5-(N-(2-ethoxycarbonyl-ethyl)-ethylaminosulphonyl)-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-ethoxycar-bonyl-ethyl)-ethylaminosulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium car-bonate in ethanol.
Yield: 18 % of theory, C23H29N5~4's x HCl(471.6/508.1) Mass spectrum: (M+H)+ - 472 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl)-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-amino]-benzamidine-hydrochloride a. 2-meth~rlamino-5-ni ro-anilin 12.5 g (0.079 mol) of 2-fluoro-5-nitroaniline and 100 ml me-thylamine (40% in water) are stirred for 48 hours at ambient temperature. The precipitated product is diluted with water, suction filtered, washed and dried.
Yield: 12.0 g (91 % of theory), Rf value: 0.5 (silica gel; ethyl acetate/petroleum ether = 6:4) b . 5 -niro-'i -m hurl-b n . i mi da .ol - -on 3.4 g (0.02 mol) of 2-methylamino-5-nitro-aniline and 3.9 g (0.024 mol) of N,N'-carbonyldiimidazole are dissolved in 100 ml tetrahydrofuran and refluxed for two hours. The solvent is con-centrated by evaporation, the residue is mixed with water, the product precipitated is suction filtered and dried.
Yield: 3.1 g (86 % of theory), CeH.,N303 x HCl ( 193 . 17 ) Mass spectrum: M' - 193 C . 5-ni ro- hl oro-1 -m hyl -b n i mi r-3a ~r,l o 2.1 g (0.01 mol) of phosphorus pentachloride are dissolved in 2.5 ml phosphorus oxychloride and after the addition of 1.9 g (0.01 mol) of 5-vitro-1-methyl-benzimidazol-2-one the mixture is stirred for two hours at 125~C. The solvent is evaporated off, the residue is poured onto ice water and neutralised with ammonia. The precipitate formed is suction filtered and dried.
Yield: 1.6 g (76 a of theory), Rf value: 0.66 (silica gel; ethyl acetate/petroleum ether =
4:1) d.
1.5 g (7.1 mmol) of 5-vitro-2-chloro-1-methyl-benzimidazole and 2.1 g (17.5 mmol) of 4-aminobenzonitrile are melted for two hours at 150'C. The reaction mixture is cooled and diluted with ethyl acetate. The precipitate is suction filtered and dried.
Yield: 2.0 g (95 % of theory), Rf value: 0.6 (silica gel; ethyl acetate/ethanol/ammonia - 90:10:1) e.
Prepared analogously to Example lc from 4-[5-vitro-1-methyl-1H-benzimidazol-2-yl]-amino-benzonitrile and palladium on activa-ted charcoal/hydrogen in dimethylformamide.
Yield: 55 % of theory, Rf value: 0.5 (silica gel; ethyl acetate/ethanol/ammonia - 90:10:1) f. 4-[(5-(quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimida-Zol-2-vl)-aminnl-han~nn;t-r;lc Prepared analogously to Example ld from 4-[5-amino-1-methyl-1H-benzimidazol-2-yl]-amino-benzonitrile and 8-quinolinesulphonic acid chloride in pyridine.
Yield: 91 0 of theory, Rf value: 0.6 (silica gel; ethyl acetate/ethanol/ammonia - 90:10:1) g. 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1.0 g (2.2 mmol) of 4-[(5-(quinolin-8-yl-sulphonylamino)-1-me-thyl-1H-benzimidazol-2-yl)-amino]-benzonitrile and 0.8 g (2.5 mmol) of caesium carbonate are dissolved in 15 ml dime-thylformamide and after the addition of 0.4 g (2.5 mmol) of ethyl bromoacetate stirred for 30 minutes at ambient tempera-ture. The solvent is concentrated by evaporation, the residue is taken up in water and extracted with ethyl acetate. The combined organic extracts are dried and evaporated down.
Yield: 0.8 g (70 % of theory), Rf value: 0.7 (silica gel; ethyl acetate/ethanol/ammonia - 90:10:1) h. 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-Prepared analogously to Example le from 4-[(5-(N-ethoxycarbo-nylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimida-zol-2-yl)-amino]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 86 % of theory, C28HZ.,N.,04S x HCl (557.64/594.11) Mass spectrum: (M+H)' - 558 2 5 F,xamp 1 P 1 6 9 4-[(5-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-amino]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-ethoxycarbo-nylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimida-zol-2-yl)-amino]-benzamidine-hydrochloride and sodium hydroxide in ethanol.
Yield: 78 0 of theory, CZ6H23N,04S x HCl (529.52/565.98) Mass spectrum: (M+H)' - 530 4-[(5-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-N'-tert.butyloxycarbonyl-benz-amidine Prepared analogously to Example 13 from 4-[(5-(N-ethoxycarbo-nylmethylquinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimida-zol-2-yl)-methyl]-N'-tert.butyloxycarbonyl-benzamidine and sodium hydroxide in ethanol.
Yield: 64 0 of theory, -~. C32H32N6O6'S (628 .71) Mass spectrum: (M+H)+ - 629 Examr~le 171 4-[(5-(4-methyl-piperazino)-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(4-methyl-pipe-razino)-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 72 0 of theory, C2oH24N6 x 2 HCl (348.46/421.39) ~~ 25 Mass spectrum: (M+H) + - 349 4-[(5-(N-(5-ethoxycarbonyl-n-pentyl)-ethylaminosulphonyl)-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-(5-ethoxycar-bonyl-n-pentyl)ethylaminosulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium car-bonate in ethanol.
Yield: 60 % of theory, Cz6H35N504S x HCl ( 513 . 7/550 . 1 ) Mass spectrum: (M+H)' - 514 4-[(5-pyrrolidinosulphonyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-pyrrolidinosul-phonyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
-~. Yield: 43 0 of theory, CZOH23N502S x HCl (397.5/434.0) Mass spectrum: (M+H)' - 398 4-[(5-(quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-amino]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-amino]-benzo-nitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 90 0 of theory, C24HZ1N.,02S x 2HC1 (471.54/544.48) Mass spectrum: (M+H)' - 472 4-[(5-(N-(3-ethoxycarbonyl-n-propyl)-phenylaminosulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydro-chloride Prepared analogously to Example le from 4-[(5-(N-(3-ethoxycar-bonyl-n-propyl)-phenylaminosulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.

Yield: 41 % of theory, CzaH31N504S x HC1 (533.7/570.1) Mass spectrum: (M+H)' - 534 Rxam=
4-[(5-(N-(4-ethoxycarbonyl-n-butyl)-isobutylaminosulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydro-chloride Prepared analogously to Example le from 4-[(5-(N-(4-ethoxycar-bonyl-n-butyl)-isobutylaminosulphonyl)-1-methyl-1H-benzimida-zol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 41 0 of theory, CZ.,H3.,NSOQS x HCl (527.7/564.2) Mass spectrum: (M+H)' - 528 4-[(5-(2-dimethylamino-ethylsulphonyl)-1-methyl-1H-benzimida-zol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(2-dimethylamino-~25 ethylsulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 78 0 of theory, CZOH25N502S x HC1 (399.52/472.44) Mass spectrum: (M+H)' - 400 4-[(5-(2-ethoxycarbonyl-pyrrolidinosulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(2-ethoxycar-bonyl-pyrrolidinosulphonyl)-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 64 % of theory, Cz3H2.,N504S x HCl (469.6/506.0) Mass spectrum: (M+H)' - 470 4-[(5-(4-oxo-3,4-dihydro-phthalazin-1-yl)-1-methyl-1H-benzimi-dazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(4-oxo-3,4-di-hydro-phthalazin-1-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 90 0 of theory, C24HzoN60 x HCl (408.5/444.9) ~V~25 Mass spectrum: (M+H)' - 409 4-[(5-(2-carboxy-pyrrolidinosulphonyl)-1-methyl-1H-benzimid-azol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(2-ethoxycar-bonyl-pyrrolidinosulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol.
Yield: 85 % of theory, CZ1H23N504S x HC1 (441.5/477.96) Mass spectrum: (M+H)' - 442 4-[(5-benzylaminocarbonyl-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-benzylamino-carbonyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 72 0 of theory, CzaHzsNsO x HC1 (397.49/470.42) Mass spectrum: (M+H)+ - 398 4-[(5-pyrrolidinosulphonyl-1-methyl-1H-benzimidazol-2-yl)-(ethoxycarbonylmethyl)methyl]-benzamidine-hydrochloride a. Nl~th~rl_ 2- (4- Drano h~Pn~rl 1 -t rfi h,~t-girl malo a 1.7 g (0.01 mol) of methyl 4-cyanophenylacetate are dissolved in 30 ml tetrahydrofuran, 0.48 g (0.01 mol) of sodium hydride (60o in oil) are added in batches thereto and stirred for 15 ;~-25 minutes at 60~C. Then 1.5 ml (0.01 mol) of tert.butyl bromo-acetate are added dropwise at ambient temperature. The reaction mixture is refluxed for 5 hours, cooled and poured onto water and extracted with methylene chloride. The combined organic extracts are dried and evaporated down. The residue is chroma-tographed on silica gel and eluted with petroleum ether/ethyl acetate ( 4 : 1 ) .
Yield: 1.5 g (52 0 of theory), Rf value: 0.7 (silica gel; petroleum ether/ethyl acetate = 7:3) b. mQnQ- Prr h»t~r~(~~rano~~rl ) mal onatA
1.5 g (5.2 mmol) of methyl 2-(4-cyanophenyl)-tert.butyl malona-te and 0.6 g (15 mmol) of sodium hydroxide are stirred in 25 ml ethanol and 5 ml water for two hours at ambient temperature.
Then the mixture is acidified with hydrochloric acid and con-centrated by evaporation. The residue is extracted with methy-lene chloride and water, the combined organic extracts are dried and evaporated down. The crude product is chromatographed on silica gel and eluted with methylene chloride + 1-5 o etha-nol.
Yield: 950 mg (67 % of theory), Rf value: 0.40 (silica gel; methylene chloride/ethanol = 19:1) c. 4-[(5-pyrrolidinosulphonyl-1-methyl-1H-benzimidazol-2-yl)-( rt butox~r arbon~rl mP girl ) m~~,l 1 b n oni t-ri 1 P
Prepared analogously to Example 24f from mono-tert.butyl 2-(4-cyanophenyl)-malonate and 4-pyrrolidinosulphonyl-2-amino-N-methylaniline in N,N'-carbonyldiimidazole/tetrahydrofuran and glacial acetic acid.
Yield: 47 0 of theory, Rf value: 0.6 (silica gel; methylene chloride/ethanol = 19:1) d. 4-[(5-pyrrolidinosulphonyl-1-methyl-1H-benzimidazol-2-yl) Prepared analogously to Example le from 4-[(5-pyrrolidinosul phonyl-1-methyl-1H-benzimidazol-2-yl)-(tert.butoxycarbonylme thyl)methyl]-benzonitrile and hydrochloric acid/ammonium car ~'25 bonate in ethanol.
Yield: 63 0 of theory, C24H29NSO4S x HCl (483.6/520.1) Mass spectrum: (M+H)' - 484 ExamDl a 1 8'~
4-[(5-(N-(2-ethoxycarbonyl-ethyl)-quinolin-8-yl-sulphonylami-no)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hy-drochloride Prepared analogously to Example le from 4-[(5-(N-(2-ethoxycar-bonyl-ethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimi-dazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 92 0 of theory, C3aH3oN6O4S x HCl (570.68/607.14) Mass spectrum: (M+H)+ - 571 4-[(5-(~N-(2-ethoxycarbonyl-ethyl)-quinolin-8-yl-sulphonylami no)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydro chloride Prepared analogously to Example 13 from 4-[(5-(N-(2-ethoxycar-bonyl-ethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimi-dazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydro-xide in ethanol.
Yield: 67 0 of theory, CzeH26N604S x HCl (542.63/585.09) Mass spectrum: (M+H)' - 543 4-[(5-cyclohexylcarbonyl-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzamidine-hydrochloride .._ 2 5 Prepared analogously to Example le from 4-[(5-cyclohexylcarbo-nyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 95 0 of theory, Cz3H26N40 x HC1 (374.49/410.95) Mass spectrum: (M+H)' - 375 4-[(5-(a-ethoxycarbonyl)benzylaminocarbonyl-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(a-ethoxycar-bonyl)benzylaminocarbonyl-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 69 0 of theory, C2.,Hz.,N503 x HC1 ( 4 6 9 . 5 5 / 5 0 6 . 01 ) Mass spectrum: (M+H)' - 470 4-[(5-(a-carboxy)benzylaminocarbonyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(a-ethoxycarbo-nyl)benzylaminocarbonyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide.
Yield: 91 % of theory, C25Hz3N503 x HC1 (441.5/477.96) .... Mass spectrum: (M+H)' - 442 4-[(5-pyrrolidinosulphonyl-1-methyl-1H-benzimidazol-2-yl)-(carboxymethyl)methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-pyrrolidinosul-phonyl-1-methyl-1H-benzimidazol-2-yl)-(ethoxycarbonylmethyl)me thyl]-benzamidine-hydrochloride and sodium hydroxide in etha-nol.
Yield: 76 0 of theory, Cz2Hz5N504S x HC1 (455.5/491.96) Mass spectrum: (M+H)' - 456 4-[(5-cyclohexyl-(a-n-propylamino)methyl-1-methyl-1H-benzimi-dazol-2-yl)-methyl]-benzamidine-dihydrochloride a. 4~~r l oh xyl carbonyl ) - hl ornhan~AnA
To a mixture of 80 ml (0.78 mol) of chlorobenzene and 30 g (0.22 mol) of aluminium chloride are added dropwise at 15-20°C
24 ml (0.18 mol) of cyclohexanecarboxylic acid chloride. After one hour at ambient temperature the reaction mixture is heated _. for 5 hours to 50'C. After cooling, the mixture is then decom-posed with ice water/conc. hydrochloric acid and the aqueous phase is extracted with methylene chloride. The combined orga-nic extracts are dried and evaporated down. The residue is di-stilled under high vacuum (2 mm, 105-115'C). The desired frac-tion is combined with water, the precipitate formed is suction filtered and dried.
Yield: 6.6 g (16 a of theory), C13H15C10 (222.72) Mass spectrum: M+ - 222 b. 4-(~~rcl-oh~~rl carbon~rl ) -2-ni rrn- hl ornhPn~onA
To 50 ml fuming nitric acid are added batchwise at -25°C 6.4 g ,'" 25 (28.8 mmol) of 4-(cyclohexylcarbonyl)-chlorobenzene. The solu-tion is stirred for 10 minutes at -25°C and then poured onto ice water. The precipitated product is suction filtered, washed with water and dried.
Yield: 7.3 g (95 0 of theory), Rf value: 0.2 (silica gel, petroleum ether/methylene chloride =
2:1) C . 4- (c~.~ .1~ ph~~rl c~arbon~rl ) -~-ni rn-1~1-m hurl ani l i nP
Prepared analogously to Example 7b from 4-(cyclohexylcarbonyl)-2-nitro-chlorobenzene and methylamine solution.
Yield: 96.5 % of theory, C14H18NZO3 ( 2 6 2 . 31 ) Mass spectrum: M+ - 262 d. 4~~r 1 oh x~rl arbon~rl 1 - -ami n~-N-mAth~r7 ani 1 i nP
2.6 g (0.01 mol) of 4-(cyclohexylcarbonyl)-2-nitro-N-methyl-aniline are dissolved in 100 ml ethyl acetate and 30 ml metha-nol and after the addition of 0.5 g Raney nickel hydrogenated with hydrogen at ambient temperature. Then the catalyst is fil-tered off and the filtrate is concentrated by evaporation.
Yield: 2.2 g (100 0 of theory), Rf value: 0.55 (silica gel; methylene chloride/ethanol = 19:1) e. 4-[(5-cyclohexylcarbonyl-1-methyl-1H-benzimidazol-2-yl)-me~hvl_1 -benzoni t-ri 1 P
Prepared analogously to Example 24f from 4-(cyclohexylcarbo-nyl)-2-amino-N-methyl-aniline, 4-cyanophenylacetic acid and N,N'-carbonyldiimidazole in tetrahydrofuran, and glacial acetic acid.
Yield: 74 0 of theory, Rf value: 0.3 (silica gel; methylene chloride/ethanol = 50:1) f. 4-[(5-cyclohexyl-(a-n-propylamino)methyl-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzonitrile and 4-[(5-cyclohexyl-(hy-droxy)methyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-ben .oni ri 1 715 mg (2.0 mmol) of 4-[(5-cyclohexylcarbonyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile, 1.0 ml n-propylamine and 1.0 g sodium acetate are dissolved in 30 ml methanol, 2 ml water and 2 ml glacial acetic acid and combined batchwise with 1.5 g (39.6 mmol) of sodium borohydride. After 1 hour at ambient temperature the mixture is poured onto water and extracted with ethyl acetate. The combined organic extracts are washed with common salt solution and dried over sodium sulphate. After eva-poration of the solvent in vacuo the residue is chromatographed on silica gel and eluted with methylene chloride + 1-10 °s etha-nol.

Yield: 100 mg (12 % of theory), Rf value: 0.1 and 0.4 (silica gel; methylene chloride/ethanol =
19:1) g. 4-[(5-cyclohexyl-(a-n-propylamino)methyl-1-methyl-1H-benz-Prepared analogously to Example le from 4-[(5-cyclohexyl-(a-n-propylamino)methyl-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 100 0 of theory, C26H35N5 x 2 HCl (417.61/490.54) Mass spectrum: (M+H)' - 418 Exams 190 4-[(5-(cyclohexyl-(methoxy)methyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-)cyclohexyl-(hy-droxy)methyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzoni-trile and hydrochloric acid/ammonium carbonate in methanol.
Yield: 75 0 of theory, C24H3oN40 x HCl (390.54/427.0) Mass spectrum: (M+H)' - 391 4-[(5-(4-oxo-2,3-diaza-spiro[S.5]undec-1-en-1-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride a. f 1 - (4-chl orn-han~r,~rl~~r 1 ohPx~rl 1 ac-Pt i c, a i r7 8.4 g (0.04 mol) of 4-(4-chlorophenyl)-4-oxo-butyric acid are dissolved in 300 ml tetrahydrofuran, combined batchwise with 5.8 g (0.12 mol) of sodium hydride (50a in oil) and refluxed for 90 minutes. After the addition of 8.9 ml ( 0.06 mol) of 1,5-diiodopentane the reaction mixture is refluxed for a further 3 hours. After cooling the reaction mixture is stirred into ice water, the tetrahydrofuran is distilled off and the residue is extracted with methylene chloride. The aqueous phase is acidified with hydrochloric acid and extracted with methy-lene chloride. The combined organic extracts are dried and eva-porated down. The residue is chromatographed on silica gel and eluted with methylene chloride + ethanol (1 to 2 0).
Yield: 6.2 g (55 0 of theory).
b.
Prepared analogously to Example 189b from [1-(4-chloro-benzo-w- yl)-cyclohexyl]-acetic acid and fuming nitric acid.
Yield: 96 0 of theory.
c.
Prepared analogously to Example 7b from [1-(4-chloro-benzoyl)-cyclohexyl]-acetic acid and methylamine solution.
Yield: 93 0 of theory.
d. 4-[(5-(4-oxo-2,3-diaza-spiro[5.5]undec-1-en-1-yl)-3-nitro 2.5 ml hydrazine hydrate are slowly added dropwise to 25 ml glacial acetic acid and then 2.4 g (7.5 mmol) of [1-(4-N-methy-lamino-3-nitro-benzoyl)-cyclohexyl]-acetic acid are added. The '-~'"~25 reaction mixture is refluxed for 3 hours, then cooled and dilu-ted with water. The precipitate formed is suction filtered and dried.
Yield: 2.0 g (85 0 of theory).
e. 4-[(5-(4-oxo-2,3-diaza-spiro[5.5]undec-1-en-1-yl)-3-amino-Prepared analogously to Example lc from 4-[(5-(4-oxo-2,3-diaza-spiro[5.5]undec-1-en-1-yl)-3-nitro-N-methylaniline and palla-dium on activated charcoal/hydrogen in dimethylformamide.
Yield: 80 % of theory.

f. 4-[(5-(4-oxo-2,3-diaza-spiro[5.5]undec-1-en-1-yl)-1-methyl-1I~b n .i mi da .ol - -yl ) -merhyl 1 ben7nni tri l a Prepared analogously to Example 24f from 4-[(5-(4-oxo-2,3-di aza-spiro[5.5]undec-1-en-1-yl)-3-amino-N-methylaniline, 4-cy anophenylacetic acid and N,N'-carbonyldiimidazole in tetrahy drofuran, glacial acetic acid.
Yield: 49 a of theory, Rf value: 0.4 (silica gel; methylene chloride/ethanol = 19:1) g. 4-[(5-(4-oxo-2,3-diaza-spiro[5.5]undec-1-en-1-yl)-1-methyl-- Prepared analogously to Example le from 4-[(5-(4-oxo-2,3-diaza-spiro[5.5]undec-1-en-1-yl)-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 70 0 of theory, CzsHzeNs~ x HCl (428.5/465.0) Mass spectrum: (M+H)' - 429 2 0 Exami 1 4-[(5-(1-ethoxycarbonylmethyl-cyclohexan-1-yl-carbonyl)-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride ~~ 25 a.
4.9 g (0.015 mol) of [1-(4-methylamino-3-nitro-benzoyl)-cyclo-hexyl]-acetic acid are dissolved in 100 ml tetrahydrofuran and after the addition of 2.4 g (0.015 mol) of N,N'-carbonyldi-imidazole the mixture is refluxed for 15 minutes. After con-30 centration of the solution and addition of 30 ml methanol the mixture is refluxed for 3 hours. The solvent is distilled off, the residue chromatographed on silica gel and eluted with me-thylene chloride + methanol (1-5 0). The desired fractions are combined and concentrated by evaporation.
35 Yield: 2.4 g (48 0 of theory).

b. methyl [1-(4-methylamino-3-amino-benzoyl)-cyclohexyl]-ar_et-a Prepared analogously to Example lc from methyl [1-(4-methyl-amino-3-nitro-benzoyl)-cyclohexyl]-acetate and palladium on activated charcoal/hydrogen in methanol.
Yield: 96 0 of theory.
c. 4-[(5-(1-ethoxycarbonylmethyl-cyclohexan-1-yl-carbonyl)-Prepared analogously to Example 24f from methyl [1-(4-methyl-amino-3-amino-benzoyl)-cyclohexyl]-acetate, 4-cyanophenylacetic acid and N,N~-carbonyldiimidazole in tetrahydrofuran/glacial acetic acid.
Yield: 66 0 of theory, Rf value: 0.5 (silica gel; methylene chloride/ethanol = 50:1) d. 4-[(5-(1-ethoxycarbonylmethyl-cyclohexan-1-yl-carbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydro-~hl_o_ri_de Prepared analogously to Example le from 4-[(5-(1-ethoxycarbo-nylmethyl-cyclohexan-1-yl-carbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium car-bonate in ethanol.
Yield: 55 % of theory, "~ 2 5 C2.,H32N403 x HC1 ( 4 6 0 . 6 / 4 9 7 . 0 ) Mass spectrum: (M+H)' - 461 4-[(5-(n-pentyl-O-ethyl-phosphinyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride a. di .hl oro- (4-c-hl orz h~n~rl 1 ~_hos i nr~
To a suspension of 53.3 g (0.4 mol) of aluminium chloride in 40 ml (0.39 mol) of chlorobenzene, 104.8 ml (1.2 mol) of phos-phorus trichloride are added dropwise at ambient temperature.
The reaction mixture is refluxed for three hours. Then within 30 minutes 37.2 ml (0.4 mol) of phosphorus oxychloride are added dropwise at 83°C. After 12 hours at ambient temperature the residue is stirred with petroleum ether and decanted off.
The combined organic extracts are distilled under high vacuum at 57-61°C and 0.048-0.035 mbar.
Yield: 45.6 g (55 0 of theory).
b. l.~ieth~rl (4-c,hl oroz h n~rl 1 -phoSphnnat-P
To a solution of 14.9 ml (0.184 mol) of pyridine and 10.8 ml (0.184 mol) of ethanol in 50 ml tetrahydrofuran is added drop-wise, within one hour, with cooling, a solution of 17.9 g (0.083 mol) of dichloro-(4-chlorophenyl)-phosphine in 20 ml tetrahydrofuran. The suspension is stirred for 72 hours at ambient temperature, suction filtered and concentrated by eva-poration. The residue is distilled at 80-83°C and 0.19 mbar.
Yield: 11.7 g (61 0 of theory), Rf value: 0.4 (silica gel; methylene chloride/ethanol - 50:1) C. ~yl_ (4- .hl oro~rl~ -n-t~Pn girl -nloi nata 3.5 g (15 mmol) of diethyl(4-chlorophenyl)-phosphonate and 3 ml (24.7 mmol) of n-pentylbromide are heated to 150°C for 90 minu-tes with stirring. The cooled clear solution is chromatographed on silica gel and eluted with cyclohexane/ethyl acetate (7:3 to 1:1) .
~~25 Yield: 2.7 g (66 a of theory), C13H2oClO2P ( 274 . 74 ) Mass spectrum: M' - 274 d. eth~rl (4- hl nrn- -ni ro phenyl 1 n Pn girl ~Sp1-~i r~ara Prepared analogously to Example 189b from ethyl(4-chlorophe-nyl)-n-pentyl-phosphinate and fuming nitric acid.
Yield: 56 0 of theory.
e.
Prepared analogously to Example 7b from ethyl(4-chloro-3-nitro-phenyl)-n-pentyl-phosphinate and methylamine solution.
Yield: 100 % of theory.

f.
Prepared analogously to Example lc from ethyl(4-methylamino-3-nitro-phenyl)-n-pentyl-phosphinate and palladium on activated charcoal/hydrogen in ethanol.
Yield: 100 % of theory.
g. 4-[(5-(n-pentyl-O-ethyl-phosphinyl)-1-methyl-1H-benzimida-zol-.-yl~~rll-b nznnitrila Prepared analogously to Example 24f from ethyl(4-methylamino-3-amino-phenyl)-n-pentyl-phosphinate, 4-cyanophenylacetic acid and N,N'-carbonyldiimidazole in tetrahydrofuran and glacial acetic acid.
Yield: 43.7 % of theory.
h. 4-[(5-(n-pentyl-O-ethyl-phosphinyl)-1-methyl-1H-benzimida-znl - .-vl) -mPth~rl 1 -bPn ami rli nP-h~rdrnr-hl nri r3P
Prepared analogously to Example le from 4-[(5-(n-pentyl-O-ethyl-phosphinyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 78 0 of theory, CzaH31N40zP x HC1 (426.51/462.97) Mass spectrum: (M+H)' - 427 4-[(5-(N-(2-dimethylamino-ethyl)-benzenesulphonylamino-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-dimethyl-amino-ethyl)-benzenesulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium car-bonate in ethanol.
Yield: 83 0 of theory, C26H3oN6O2S x 2 HC1 (490.64/563.57) Mass spectrum: (M+H)' - 491 4-[(5-(n-pentyl-phosphinyl)-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzamidine-hydrochloride To a solution of 100 mg (0.2 mmol) of 4-[(5-(n-pentyl-O-ethyl-phosphinyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride in 5 ml methylene chloride are added 1.8 ml (14 mmol) of trimethylsilylbromide. After the addition of 20 ml methylene chloride the reaction mixture is stirred for 6 days -. at ambient temperature. After evaporation of the solvent the residue is triturated with water/2N hydrochloric acid. The so-lid formed is suction filtered, the filtrate is concentrated by evaporation, mixed several times with ethanol and concentrated by evaporation. The residue is triturated with methanol/acetone, suction filtered and dried.
Yield: 70 mg (74 0 of theory) CZ1H2~N40zP x HC1 (398.45/434.91) Mass spectrum: (M+H)' - 399 4-[(5-(n-pentyl-O-ethoxycarbonylmethyl-phosphinyl)-1-methyl-1H-~25 benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride a. [(5-(n-pentyl-phosphinyl)-1-methyl-1H-benzimidazol-2-yl)-methyll -benznn i t-ri 1 a 0.6 g (1.5 mmol) of 4-[(5-(n-pentyl-O-ethyl-phosphinyl)-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile are dissolved in 45 ml methylene chloride, combined with 2 ml (15.4 mmol) of trimethylbromosilane and stirred for 22 hours at ambient tempe-rature. After evaporation of the solvent the residue is com-bined with ice water and adjusted to pH 6 with sodium acetate.
After two hours the precipitate formed is suction filtered and dried.

Yield: 0.37 g (66 % of theory), Rf value: 0.35 (Reversed Phase, 5% sodium chloride solution/me-thanol = 1:2) b. 4-[(5-n-pentyl-O-ethoxycarbonylmethyl-phosphinyl)-1-methyl-To a solution of 370 mg (0.97 mmol) of 4-[(5-(n-pentyl-phos-phinyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile in 7 ml dimethylformamide are added 170 mg (1.2 mmol) of potassium carbonate and 130 mg (1.2 mmol) of ethyl bromoacetate. The re-action mixture is heated to 50°C for 20 minutes, cooled and then poured onto ice water and extracted with ethyl acetate.
The organic extracts are washed with citric acid and sodium carbonate solution, dried over sodium sulphate and evaporated down. The residue is chromatographed on silica gel and eluted with ethyl acetate/ethanol (25:1 and 10:1).
Yield: 0.4 g (88 0 of theory), Rf value: 0.4 (silica gel; methylene chloride/ethanol = 50:1) c. 4-[(5-n-pentyl-O-ethoxycarbonylmethyl-phosphinyl)-1-methyl Prepared analogously to Example le from 4-[(5-n-pentyl-O-eth oxycarbonylmethyl-phosphinyl)-1-methyl-1H-benzimidazol-2-yl) methyl]-benzonitrile and hydrochloric acid/ammonium carbonate ~25 in ethanol.
Yield: 76 0 of theory, CzsH3aN404P x HCl (484.55/521.01) Mass spectrum: (M+H)' - 485 3 0 Exam= 1 P 'I 9 7 4-[(5-(n-pentyl-O-carboxymethyl-phosphinyl)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride 35 Prepared analogously to Example 13 from 4-[(5-(n-pentyl-O-eth-oxycarbonylmethyl-phosphinyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in etha-nol.
Yield: 74 % of theory, Cz3Hz9N404P x HCl (456.49/492.95) Mass spectrum: (M+H)' - 457 4-[(5-(1-carboxymethyl-cyclohexan-1-yl-carbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine To a solution of 160 mg (4 mmol) of sodium hydroxide in 5 ml water and 20 ml ethanol are added 400 mg (0.8 mmol) of 4-[(5-(1-ethoxycarbonylmethyl-cyclohexan-1-yl-carbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydro-chloride. After two hours at ambient temperature the solution is evaporated down, the residue is dissolved in water and acidified with glacial acetic acid. The precipitate is suction filtered and dried.
Yield: 250 mg (72 % of theory), CZSHzeNa~s (432.5) Mass spectrum: (M+H)+ = 433 4-[(5-(2-oxo-piperidin-1-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride a. 4- 1 Toro- -ni ro-N-( -bromobmt~rlc~x~r)~~
After the addition of 3 ml triethylamine to a solution of 3.7 g (0.024 mol) of 4-fluoro-3-nitro-aniline in 100 ml tetrahydrofu-ran at ambient temperature, 4.8 g (0.024 mol) of S-bromovaleric acid chloride are added dropwise. Then the mixture is stirred for two hours at ambient temperature and concentrated by evapo-ration. The residue is chromatographed on silica gel and eluted with methylene chloride. The desired fractions are combined and evaporated down.

Yield: 7.0 g (92 0 of theory), Rf value: 0.6 (silica gel; petroleum ether/ethyl acetate = 3:7) b. ~(2-oxo-~i_t~ ri c7i n-'1 -girl ) -?-ni t'rn l ~nrnhPn~ona To a suspension of 1.0 g (21.9 mmol) of sodium hydride (50o in oil) in 200 ml tetrahydrofuran is added dropwise at ambient temperature a solution of 7.0 g (21.9 mmol) of 4-fluoro-3-ni-tro-N-(5-brombutyloxy)-aniline in 50 ml tetrahydrofuran. After 30 minutes it is poured onto ice water, the tetrahydrofuran is distilled off and the aqueous phase is extracted with methylene chloride. The combined organic extracts are dried and evapora-ted down. The residue is chromatographed on silica gel and elu-ted with petroleum ether/ethyl acetate (7:3).
Yield: 4.1 g (79 % of theory), Rf value: 0.4 (silica gel; petroleum ether/ethyl acetate = 3:7) C. 4- (2-oxo-~i_t~Pric7in-1 -girl ) -2-nitre-N-math~r] ani 1 inP
Prepared analogously to Example 7b from 4-(2-oxo-piperidin-1-yl)-2-nitro-fluorobenzene and aqueous methylamine solution.
Yield: 92 0 of theory, Rf value: 0.35 (silica gel; petroleum ether/ethyl acetate =
1:9) d. 4- (2-oxo-~i pPri r3i n-'1 -girl ) -~-ami no-N-m hurl ani 1 i nP
''._"'25 Prepared analogously to Example lc from 4-(2-oxo-piperidin-1-yl)-2-nitro-N-methyl-aniline and palladium on activated char-coal/hydrogen in methanol.
Yield: 97 % of theory, Rfvalue: 0.25 (silica gel; methylene chloride/ethanol - 19:1) e. 4-[(5-(2-oxo-piperidin-1-yl)-1-methyl-1H-benzimidazol-2-yl)-Prepared analogously to Example 24f from 4-(2-oxo-piperidin-1-yl)-2-amino-N-methyl-aniline, 4-cyanophenylacetic acid and N,N'-carbonyldiimidazole in tetrahydrofuran/glacial acetic acid.

Yield: 35 % of theory, Rf value: 0.23 (silica gel, methylene chloride/ethanol = 19:1) f. 4-[(5-(2-oxo-piperidin-1-yl)-1-methyl-1H-benzimidazol-2-yl)-me-thyl 1 -b n~ami chi na-h~rdroc'~hl c~ri r3P
Prepared analogously to Example le from 4-[(5-(2-oxo)piperidin-1-yl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 87 % of theory, 1O CzlHa3NsO x HC1 (361.5/397.9) Mass spectrum: (M+H)+ = 362 4-[(5-(n-butane-sultam-2-yl)-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(n-butane-sultam-2-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 77 % of theory, CZOH23N50zS x HC1 (397.5/434.0) Mass spectrum: (M+H)+ - 398 . '"" 2 5 F,xamn 1 0 ~
4-[(5-(N-cyclohexyl-methanesulphonylamino)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-N-cyclohexyl-methanesulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 52 0 of theory, Cz3H29N502S x HCl (439.59/476.06) Mass spectrum: (M+H)' - 440 4-[(5-(1-methyl-cyclohexan-1-yl-carbonyl)-1-methyl-1H-benzimi-dazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(1-methyl-cyclo-hexan-1-yl-carbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 63 0 of theory, C24HZBN4O x HCl (388.5/425.0) Mass spectrum: (M+H)' - 389 4-[(5-(1-isobutyl-tetrazol-5-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride a. 4- hl oro- i ro-b n of ~ a i d-i ~~hW~l a-mi d~
Prepared analogously to Example 24b from 4-chloro-3-nitro-ben-zoylchloride, isobutylamine and triethylamine in tetrahydro-furan.
Yield: 88 0 of theory.
a "''25 b.
10.3 g (0.04 mol) of 4-chloro- 3-nitro-benzoic acid-isobutyl-amide are dissolved in 200 ml methylene chloride and combined with 2.6 g (0.04 mol) of sodium azide. Then 6.7 ml (0.04 mol) of trifluoromethanesulphonic acid anhydride are added dropwise at O'C. The reaction is then stirred for 40 hours at ambient temperature and combined with 5o sodium carbonate solution. The organic phase is separated off, dried and evaporated down. The residue is chromatographed on silica gel and eluted with methy-lene chloride + ethanol (0-la). The desired fractions are com-bined and evaporated down.
Yield: 3.6 g (32 % of theory), C11H12C1NSOz ( 2 81 . 7 ) Mass spectrum: M+ - 281 C.
Prepared analogously to Example 7b from 4-[(5-(1-isobutyl-te-trazol-5-yl)-2-nitro-chlorobenzene and methylamine solution.
Yield: 100 0 of theory, Rf value: 0.3 (silica gel; methylene chloride/ethanol = 50:1) d.
Prepared analogously to Example 24e from 4-[(5-(1-isobutyl-_, tetrazol-5-yl)-2-nitro-N-methyl-aniline and palladium on acti-vated charcoal/hydrogen in methanol.
Yield: 100 0 of theory, Rf value: 0.3 (silica gel; methylene chloride/ethanol = 19:1) e. 4-[(5-(1-isobutyl-tetrazol-5-yl-1-methyl-1H-benzimidazol-2-vl)-mP hull-b n~nnit-rile Prepared analogously to Example 24f from 4-[(5-(1-isobutyl-tetrazol-5-yl)-2-amino-N-methyl-aniline, 4-cyanophenylacetic acid and N,N~-carbonyldiimidazole in tetrahydrofuran, glacial acetic acid.
Yield: 86 0 of theory, Rf value: 0.4 (silica gel; methylene chloride/ethanol - 19:1) ''- ~"' 2 5 f. 4-[(5-(1-isobutyl-tetrazol-5-yl-1-methyl-1H-benzimidazol-Prepared analogously to Example le from 4-[(5-(1-isobutyl-tetrazol-5-yl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzoni trile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 44 % of theory, CmH24Ne x HCl ( 3 8 8 . 5 / 4 2 5 . 0 ) Mass spectrum: (M+H)+ - 389 4-[(5-phenyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzami-dine-hydrochloride a. 2-nitro-4-i henyl-N-meth~rl-acetanilide 3.0 g (11.7 mmol) of 2-vitro-4-phenylacetanilide are dissolved in 70 ml dimethylformamide and combined batchwise with 576 mg (12 mmol) of sodium hydride (50o in oil) at ambient tempera-ture. After 30 minutes at 65~C the reaction mixture is cooled to ambient temperature, combined with 3 ml methyl iodide and stirred for 30 minutes. The mixture is stirred into saturated sodium chloride solution and extracted with ethyl acetate. The combined organic extracts are washed with water, dried and eva-porated down. The residue is chromatographed on silica gel and eluted with methylene chloride + ethanol (0-5 0). The desired fractions are combined and evaporated down.
Yield: 3.2 g (100 % of theory), Rf value: 0.43 (silica gel; methylene chloride/ethanol = 19:1) b. 2-vitro-4-~h -n~rl-N-me ~yl-aniline 3.2 g (11.7 mmol) of 2-vitro-4-phenyl-N-methyl-acetanilide are refluxed in 99 ml semiconcentrated hydrochloric acid for 7 hours. The solution is cooled and extracted with methylene ~25 chloride. The organic phase is washed with water and sodium hy-drogen carbonate solution, dried over sodium sulphate and eva-porated down. The residue is chromatographed on silica gel and eluted with methylene chloride. The desired fractions are com-bined and evaporated down.
Yield: 2.0 g (75 % of theory), Rf value: 0.8 (silica gel; methylene chloride) c. 2-amino-4- Fnyl-N-meth~rl-aniline Prepared analogously to Example lc from 2-vitro-4-phenyl-N-me-thyl-aniline and palladium on activated charcoal/hydrogen in methanol.

Yield: 91 0 of theory, Rf value: 0.4 (silica gel; methylene chloride/ethanol = 19:1) d. 4-[(5-phenyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzo-nitrile Prepared analogously to Example 24f from 2-amino-4-phenyl-N-methyl-aniline, 4-cyanophenylacetic acid and N,N~-carbonyldi-imidazole in tetrahydrofuran and glacial acetic acid.
Yield: 100 0 of theory, e. 4-[(5-phenyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benz-'""" amic3i n -h~rdroc~hl c>ri ~3P
Prepared analogously to Example le from 4-[(5-phenyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 60 a of theory, CZZHzON4 x HC1 (340.4/376.9) Mass spectrum: (M+H)' - 341 Fxam_t~ol~~0 4-[(5-((1-methyl-cyclohexan-1-yl)-ethoxycarbonylmethyloxyimino-methylene)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride a. 4-[(5-((1-methyl-cyclohexan-1-yl)-ethoxycarbonylmethyloxy-imino-methylene)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzo-750 mg (2 mmol) of 4-[(5-(1-methyl-cyclohexan-1-yl-carbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile (prepared analogously to Example 194) and 645 mg (3 mmol) of carboxymeth-oxylamine are refluxed for two hours in 10 ml methanol and 1 ml water. The solvent is distilled off, the residue is chromato-graphed on silica gel and eluted with methylene chloride +
ethanol (5-10 0). The desired fractions are combined and evapo-rated down.

Yield: 450 mg (54 % of theory), Rf value: 0.5 (silica gel; methylene chloride/ethanol = 9:1) b. 4-[(5-((1-methyl-cyclohexan-1-yl)-ethoxycarbonylmethyloxy imino-methylene)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benz amidine-h~rdrochloride Prepared analogously to Example le from 4-[(5-((1-methyl-cyclo-hexan-1-yl)-ethoxycarbonylmethyloxyimino-methylene)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 41 0 of theory, C28H35NSO3 x HC1 (489.6/526.1) Mass spectrum: (M+H)+ - 490 Example 206 4-[(5-(N-cyclopentyl-methanesulphonylamino)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-cyclopentyl-methanesulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 65 % of theory, C2zH2.,N50zS x HCl (425.56/462.02) Mass spectrum: (M+H)' - 426 4-[(5-(N-(2-ethoxycarbonyl-ethyl)-isobutylaminocarbonyl)-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-(2-ethoxycar-bonyl-ethyl)-isobutylaminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium car-bonate in ethanol.

Yield: 54 % of theory, C26H33N5~3 x HCl (463 .59/500.06) Mass spectrum: (M+H)' - 464 F~nl_e 208 4-[(5-(N-(2-carboxy-ethyl)-isobutylaminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine Prepared analogously to Example 198 from 4-[(5-(N-(2-ethoxycar-bonyl-ethyl)-isobutylaminocarbonyl-1-methyl-1H-benzimidazol-2-'~ yl)-methyl]-benzamidine-hydrochloride) and sodium hydroxide in ethanol.
Yield: 72 0 of theory, C24Hz 9N503 ( 4 3 5 . 5 ) Mass spectrum: (M+H)' - 436 4-[(5-tert.butylcarbonyl-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-tert.butylcar-m. bonyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 50 0 of theory, C21Hz4N40 x HC1 (348.5/384.9) Mass spectrum: (M+H)' - 349 Fxam=le ~~0 4-[(5-(1-methyl-cyclopentan-1-yl-carbonyl)-1-methyl-1H-benzimi-dazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(1-methyl-cyclo-pentan-1-yl-carbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 55 0 of theory, C23HZ6N40 x HC1 ( 3 74 . 5 /411 . 0 ) Mass spectrum: (M+H)+ - 375 4-[(5-(S-cyclohexyl-sulphimidoyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride a . 1-chlo_ro-~~rc~l_oh xan ~m 1 ~~1 - -p i rObPn ~PnP
16.4 g (0.095 mol) of 4-chloro-3-nitroaniline are suspended in 150 ml hydrochloric acid (120) and at 2-5~C combined with a so lution of 6.55 g (0.095 mol) of sodium nitrite in 12 ml water.
The reaction mixture is added dropwise to a suspension of 11.6 ml (0.095 mol) of cyclohexylmercaptan in 175 ml sodium hydro-xide solution (150), combined with 10 g of copper powder and then heated to 80'C for 1 hour. After cooling to ambient tempe-rature the mixture is extracted with methylene chloride, the organic extracts are washed with hydrochloric acid and water, dried and evaporated down. The residue is chromatographed on aluminium oxide and eluted with cyclohexane/ethyl acetate (9:1 and 4:1). The desired fractions are combined and concentrated by evaporation.
Yield: 15.7 g (61 % of theory), Rf value: 0.3 (aluminium oxide, petroleum ether) b. 1- -hl oro- ~r .1 oh xan~ ~1 r~hi n~rl-7-ni rob n . n 11.6 g (0.043 mol) of 1-chloro-4-cyclohexanesulphanyl-2-nitro-benzene are dissolved in 200 ml acetic anhydride and at 10~C
combined with 4.4 g (0.038 mol) of perhydrol. The solution is stirred for 48 hours at ambient temperature and concentrated by evaporation. The residue is combined with ice and ammonia and extracted with ethyl acetate. The organic extracts are washed with sodium chloride solution, dried and concentrated by eva-poration. The residue is chromatographed on silica gel and elu-ted with cyclohexane/ethyl acetate 7:3 and 1:2.
Yield: 6.7 g (54 0 of theory), Rf value: 0.9 (silica gel; cyclohexane/ethyl acetate = 2:1) C . 1-~hl oro-4- ~ l~~rl ~»1 z hi mi do~rl - -ni robPn~Pna 8.4 g (0.029 mol) of 1-chloro-4-cyclohexansulphinyl-2-nitro-benzene, 24.8 g (0.086 mol) of ethyl O-mesitylene-sulphonyl-acetohydroxamate and 28.6 g (0.15 mol) of p-toluenesulphonic acid are dissolved in 160 ml dimethylformamide and stirred for 90 hours at ambient temperature. Then the mixture is diluted .w~ with ice water and combined with sodium carbonate. After ex-traction with ethyl acetate the combined organic phases are washed with sodium chloride, dried and evaporated down. The residue is chromatographed on silica gel and eluted with methy-lene chloride/ethanol (50:1 and 30:1). The desired fractions are combined and concentrated by evaporation.
Yield: 7.1 g (81 0 of theory), Rf value: 0.3 (silica gel; cyclohexane/ethyl acetate = 2:1) d. 1-chloro-4-cyclohexyl-N-tert.butoxycarbonyl-sulphimidoyl-2-n' ro n .Pn To a solution of 3.1 g (0.01 mol) of 1-chloro-4-cyclohexylsul-phimidoyl-2-nitrobenzene in 10 ml tetrahydrofuran is added dropwise at 5'C a solution of 1.4 g (0.012 mol) of potassium-tert.butoxide in 5 ml tetrahydrofuran. After 20 minutes a solu-tion of 4.4 g (0.02 mol) of di-tert.butyldicarbonate in 30 ml tetrahydrofuran is added. After 3 hours at ambient temperature the mixture is stirred with ammonium chloride solution and ex-tracted with ethyl acetate. The organic extracts are washed with water and sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The residue is chro-matographed on silica gel and eluted with ethyl acetate/cyclo-hexane (9:1 and 4:1).
Yield: 2.7 g (65 0 of theory), Rf value: 0.5 (silica gel; petroleum ether/ethyl acetate = 4:1) e. 1-methylamino-4-cyclohexyl-N-tert.butoxycarbonyl-sulphimido-y7 -2-ni trnhan~r~na Prepared analogously to Example 7b from 1-chloro-4-cyclohexyl-N-tert.butoxycarbonyl-sulphimidoyl-2-nitrobenzene and methyl-amine solution.
Yield: 92 0 of theory, Rf value: 0.6 (silica gel; cyclohexane/ethyl acetate = 1:1) f. 1-methylamino-2-amino-4-cyclohexyl-N-tert.butoxycarbonyl-sulmhimidovl-benzPnP
Prepared analogously to Example lc from 1-methylamino-4-cyclo--~ hexyl-N-tert.butoxycarbonyl-sulphimidoyl-2-nitrobenzene and palladium on activated charcoal/hydrogen in methanol. The crude product is further reacted without being purified.
g. 4-[(5-(cyclohexyl-N-tert.butoxycarbonyl-sulphimidoyl)-1-me-Prepared analogously to Example 24f from 1-methylamino-2-amino-4-cyclohexyl-N-tert.butoxycarbonyl-sulphimidoyl-benzene, 4-cy-anophenylacetic acid and N,N~-carbonyldiimidazole in tetrahy-drofuran/glacial acetic acid.
Yield: 40.6 0 of theory, Rf value: 0.5 (silica gel; ethyl acetate) h. 4-[(5-(cyclohexyl-sulphimidoyl)-1-methyl-1H-benzimidazol-1.3 g (2.6 mmol) of 4-[(5-(cyclohexyl-N-tert.butoxycarbonyl-sulphimidoyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzo-nitrile are dissolved in 15 ml dioxan and after the addition of 10 ml 6N hydrochloric acid the mixture is stirred for 8 hours at ambient temperature. The solution is diluted with ice, com-bined with ammonia and extracted with ethyl acetate. The orga-nic phase is washed with water and sodium chloride solution, dried and concentrated by evaporation.
Yield: 1.0 g (98 0 of theory), Rf value: 0.65 (silica gel; methylene chloride/ethanol - 9:1) i. 4-[(5-(cyclohexyl-sulphimidoyl)-1-methyl-1H-benzimidazol-2-girl ) -mPt-h~rl_1 -b n . mi di n -h~rdro hl nri c3P
Prepared analogously to Example le from 4-[(5-(cyclohexyl-sulphimidoyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzo-nitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 90 % of theory, CZ2H2.,NSOS x HC1 (409.56/446.02) Mass spectrum: (M+H)' - 410 Fxamz 4-[(5-(N-ethoxycarbonylmethyl-cyclohexylsulphimidoyl)-1-methyl-1H-benzimidazol-2-yl)-(ethoxycarbonylmethyl)-methylene]-benzamidine-hydrochloride a. 4-[(5-(N-ethoxycarbonylmethyl-cyclohexylsulphimidoyl)-1-me-thyl-1H-benzimidazol-2-yl)-(ethoxycarbonylmethyl)-methylene]-benzonitrile and 4-[(5-(cyclohexyl-sulphimidoyl)-1-methyl-1H-benzimidazol-2-yl)-(ethoxycarbonylmethyl)methylene]-benzoni-0.7 g (1.78 mmol) of 4-[(5-(cyclohexylsulphimidoyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and 1 g (7.25 mmol) of potassium carbonate are dissolved in 100 ml acetone and after the addition of 0.45 ml (4.0 mmol) of ethyl bromoacetate the mixture is refluxed for 95 hours. The precipitate formed is suction filtered, the mother liquor concentrated by evaporation and the residue chromatographed on silica gel, eluting with ethyl acetate/ethanol (1:0 and 9:1).
Yield: 0.2 g (20 0 of theory) 4-[(5-(N-ethoxycarbonylmethyl-cyclohexylsulphimidoyl)-1-methyl-1H-benzimidazol-2-yl)-(ethoxy-carbonylmethyl)methylene]-benzonitrile, C30H36N4~Ss ( 564 ) , Mass spectrum: M' - 564 and 0.2 g (200 of theory), 4-[(5-(cyclohexylsulphimidoyl)-1-me-3S thyl-1H-benzimidazol-2-yl)-(ethoxycarbonylmethyl)methylene]-benzonitrile, CzsH3oNs~3s (478.6) , Mass spectrum: M+= 478 b. 4-[(5-(N-ethoxycarbonylmethyl-cyclohexylsulphimidoyl)-1-me-thyl-1H-benzimidazol-2-yl)-(ethoxycarbonylmethyl)-methylene]-Prepared analogously to Example le from 4-[(5-(N-ethoxycar-bonylmethyl-cyclohexylsulphimidoyl)-1-methyl-1H-benzimidazol-2-yl)-(ethoxycarbonylmethyl)methylene]-benzonitrile and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 31 0 of theory, CsoHasNsCss x HCl (581.75/618.21) Mass spectrum: (M+H)' - 582 Exam= 1 P ~'t 4-[(5-(cyclohexyl-sulphimidoyl)-1-methyl-1H-benzimidazol-2-yl)-(ethoxycarbonylmethyl)methylene]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(cyclohexyl-sulphimidoyl)-1-methyl-1H-benzimidazol-2-yl)-(ethoxycarbonyl-methyl)methylene]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 70 0 of theory, C26H33N503S x HC1 (495.66/532.12) Mass spectrum: (M+H)' - 496 4-[(5-(N-cyclopentyl-3-methoxycarbonylpropionylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-cyclopentyl-3-methoxycarbonylpropionylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.

Yield: 81 % of theory, Cz6H31Ns03 x HC1 (461.57/498.04) Mass spectrum: (M+H)+ - 462 (M+2H)'+ - 231.7 (M+H+Na)++ - 242.8 4-[(5-(N-acetyl-cyclohexylsulphimidoyl)-1-methyl-1H-benzimida-zol-2-yl)-methyl]-benzamidine-hydrochloride 150 mg (0.29 mmol) of 4-[(5-(N-acetyl-cyclohexylsulphimidoyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochlo-ride are suspended in 5 ml glacial acetic acid and after the addition of 3 ml acetic anhydride stirred for 75 minutes at 40'C. The reaction mixture is concentrated by evaporation at 70'C, the residue is triturated with ether, suction filtered and dried.
Yield: 150 mg (100 0 of theory), C24H29NSOZS x HCl (451.6/488.06) Mass spectrum: (M+H)' - 452 4-[(5-(N-(3-carboxypropionyl)-cyclohexylsulphimidoyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride 210 mg (0.4 mmol) of 4-[(5-(cyclohexylsulphimidoyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride are dissolved in 5 ml glacial acetic acid and after the addition of 61 mg (0.6 mmol) of succinic anhydride stirred at 70'C for 1 hour. The glacial acetic acid is distilled off, the residue triturated with ether and acetone, suction filtered and dried.
Yield: 200 mg (86 0 of theory), C26H31Ns04S x HCl (509.64/546.1) Mass spectrum: (M+H)' - 510 4-[(5-phenylsulphonyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride a . 4 -b n . n ~ ~ 1 phon~rl -p h~nyl_amine Prepared analogously to Example lc from 4-nitrodiphenylsulphone and hydrogen/palladium on activated charcoal in methylene chlo-ride/methanol.
Yield: 99 % of theory, Rf value: 0.6 (silica gel; methylene chloride/ethanol - 19:1) b. N- (4-benzenesLlz honyl -phen~rl ~-m han ~ ~lmhonami~3P
Prepared analogously to Example ld from 4-benzenesulphonyl-phenylamine and methanesulphonic acid chloride in pyridine.
Yield: 81 % of theory, Rf value: 0.45 (silica gel; methylene chloride/ethanol = 19:1) c . N- ( a -b n . ~ ~ l mhon~rl- 2 -n i ro-ohen~rl) -m han ~ l r~honami de Prepared analogously to Example 189b from N-(4-benzenesul-phonyl-phenyl)-methanesulphonamide and fuming nitric acid.
Yield: 90 0 of theory, Rf value: 0.62 (silica gel; methylene chloride/ethanol = 19:1) '- 25 d. N-(4-benzenesulphonyl-2-nitro-phenyl)-N-methyl-methanesul-nhonamide Prepared analogously to Example 204a from N-(4-benzenesul-phonyl-2-nitro-phenyl)-methanesulphonamide, methyl iodide and sodium hydride in dimethylformamide.
Yield: 50 0 of theory, Rf value: 0.63 (silica gel; ethyl acetate) a . ( 4 -b -n . n ~m l on~,l - -ni ro-~~rl 1 -N-m hurl ami ne 7.2 g (19.4 mmol) of N-(4-benzenesulphonyl-2-nitro-phenyl)-N
methyl-methanesulphonamide are heated to 130'C in 70 ml conc.
sulphuric acid for 15 minutes. Then the mixture is poured onto ice water, the precipitate formed is suction filtered, washed with water and dried.
Yield: 5.5 g (97 % of theory), Rf value: 0.73 (silica gel; ethyl acetate/petroleum ether =
3:1) f . (4-benzenesLl~~rl -~-ami no-~yl ) -N-meth~rl am; nP
Prepared analogously to Example lc from (4-benzenesulphonyl-2-nitro-phenyl)-methyl-amine and palladium on activated char-coal/hydrogen in methylene chloride/methanol.
Yield: 100 0 of theory, g. 4-(5-benzenesulphonyl-1-methyl-1H-benzimidazol-2-ylmethyl)-ben2onitri1e Prepared analogously to Example 24f from (4-benzenesulphonyl-2-amino-phenyl)-methyl-amine, 4-cyanophenylacetic acid and N,N'-carbonyldiimidazole in tetrahydrofuran/glacial acetic acid.
Yield: 80 0 of theory, Rf value: 0.54 (silica gel; methylene chloride/ethanol = 19:1) h. 4-(5-benzenesulphonyl-1-methyl-1H-benzimidazol-2-ylmethyl)-Prepared analogously to Example le from 4-(5-benzenesulphonyl-1-methyl-1H-benzimidazol-2-ylmethyl)-benzonitrile and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 57 0 of theory, C22HzoN402S x HCl (404.5/441.0) Mass spectrum: (M+H)' - 405 4-[(5-(N-cyclopentyl-N-(2-ethoxycarbonyl-ethylsulphonyl)-amino-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydro-chloride a. ~~~~.Lo~ ent~rl_- (4-fl Toro-'~-ni ro-nhen~rl) -amine 6.7 g (0.08 mol) of cyclopentanone, 12.5 g (0.08 mol) of 4-fluoro-3-nitro-aniline and 30 ml titanium-IV-isopropoxide (0.1 mol) are stirred for 30 minutes at 40~C and for one hour at ambient temperature. After the addition of 150 ml ethanol the reaction mixture is stirred for 30 minutes and then com-bined batchwise with 2.4 g (0.066 mol) of sodium borohydride.
After 4 hours the reaction mixture is poured onto ice water and combined with ethyl acetate. After filtration the organic phase is separated off, dried and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with petro-leum ether/ethyl acetate (9:1). The desired fractions are com-bined and concentrated by evaporation.
Yield: 8.8 g (49 % of theory), Rf value: 0.68 (silica gel; petroleum ether/ethyl acetate =
4:1) b. s~_rcl o p~p~~rl - (4-m ~rlami no- -ni ro-phen~r) 1 -ami nP
Prepared analogously to Example 168a from cyclopentyl-(4-flu-oro-3-nitrophenyl)-amine and methylamine solution.
Yield: 100% of theory, Rf value: 0.44 (silica gel; methylene chloride) c. Methyl 3-[cyclopentyl-(4-methylamino-3-nitro-phenyl)-sulph-Prepared analogously to Example ld from cyclopentyl-(4-methyl-amino-2-nitro-phenyl)-amine and methyl chlorosulphonyl-propio-nate in pyridine.
Yield: 36 0 of theory, Rf value: 0.45 (silica gel; methylene chloride/ethanol 50:1) d. Methyl 3-[cyclopentyl-(3-amino-4-methylamino-phenyl)-sulph-~,~rl ]-prot~i onate Prepared analogously to Example lc from methyl 3-[cyclopentyl-(4-methylamino-3-nitro-phenyl)-sulphamoyl]-propionate and palladium on activated charcoal/hydrogen in methylene chlo-ride/methanol.
Yield: 100 0 of theory, Rf value: 0.52 (silica gel; methylene chloride/ethanol 50:1) e. 4-[(5-(N-cyclopentyl-N-(2-ethoxycarbonyl-ethylsulphonyl)-Prepared analogously to Example 24f from methyl 3-[(3-amino-4-methylamino-phenyl)-cyclopentyl-sulphamoyl]-propionate, 4-cyanophenylacetic acid and N,N'-carbonyldiimidazole in tetrahydrofuran/glacial acetic acid.
Yield: 72 % of theory, Rf value: 0.41 (silica gel; methylene chloride/ethanol - 50:1) f. 4-[(5-(N-cyclopentyl-N-(2-ethoxycarbonyl-ethylsulphonyl)-amino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-h_~rdrochloride Prepared analogously to Example le from 4-[(5-(N-cyclopentyl-N-(2-ethoxycarbonyl-ethylsulphonyl)-amino)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammo-_ 25 nium carbonate in ethanol.
Yield: 76 % of theory, Cz6H33N5O4S x HC1 ( 511 . 66/548 . 12 ) Mass spectrum: (M+H)+ - 512 3 0 _F.~mry 4-[(5-(1-methoxycarbonylmethyl-4-isobutyl-imidazol-5-yl)-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride 35 a. L ( hl o onhPnyl ) -4-meth~rl -z n an-~ -on To a suspension of 66.7 g (0.5 mol) of aluminium chloride in 300 ml chlorobenzene is added a solution of 56 g (0.42 mol) of isocaproic acid chloride in 20 ml chlorobenzene dropwise. The solution is stirred for 3 hours at 50'C and then concentrated by evaporation. The residue is carefully poured onto ice water, acidified with hydrochloric acid and extracted with ethyl ace-s tate. The organic phases are washed with water, dried, concen-trated by evaporation and the residue obtained is chromato-graphed on silica gel with petroleum ether/methylene chloride (2:8) .
Yield: 72.5 g (83 % of theory), Rf value: 0.6 (silica gel; methylene chloride) b. 2-Bromo-l - (4- _hl oro-r~he_n_~1 ) -4-m . hurl -z Pntan-1 -on 55 g (0.344 mol) of bromine are added dropwise to a solution of 72.5 g (0.344 mol) of 1-(4-chloro-phenyl)-4-methyl-pentan-1-one in 300 ml dioxan and 300 ml methylene chloride until deco lorisation is just starting. After 10 minutes at ambient tempe-rature the solvent is evaporated off.
Yield: 99 g (100 0 of theory), Rf value: 0.76 (silica gel; methylene chloride) c. r-~- (4-Chloro-mhen~rl ) -4-i yob yrl-~ _u_-imi da .ol P
38 g (0.43 mol) of 2-bromo-1-(4-chloro-phenyl)-4-methyl-pentan-1-one are heated to 160°C in 400 ml formamide for 10 hours.
After 12 hours at ambient temperature the mixture is diluted with water and combined with ammonia. The precipitate formed is filtered off, washed with water and ether.
Yield: 19 g (66 0 of theory), Rf value: 0.5 (silica gel; methylene chloride/methanol - 9:1) d. E~h~rl [S- ! hl oro-~ hPn~rl~i sob ~ yl -i mi da .ol -'1 -~rl1 -a . a 19 g (0.085 mol) of 5-(4-chloro-phenyl)-4-isobutyl-1H-imidazole are dissolved in 500 ml acetone and after the addition of 41.5 g (0.3 mol) of potassium carbonate and 16.7 g (0.13 mol) of ethyl bromoacetate the mixture is refluxed for 16 hours.
Then it is filtered to remove the insoluble matter and the mother liquor is concentrated by evaporation. The residue is chromatographed on silica gel and eluted with methylene chlo-ride/methanol (80:1). The desired fractions are combined and concentrated by evaporation.
Yield: 5.4 g (200 of theory), Rf value: 0.54 (silica gel; methylene chloride/methanol = 9:1) e. f5- (4-chloro-~ hPn~rl_) -4-i yob ~ girl-imi da .ol -'1 -girl l -a i a i d 4.8 g (0.015 mol) of ethyl [5-(4-chloro-phenyl)-4-isobutyl-imi-dazol-1-yl]-acetate are dissolved in 15 ml ethanol and 40 ml water and after the addition of 2.0 g (0.05 mol) of sodium hy-droxide stirred for 2 hours at ambient temperature. The alcohol is distilled off, the residue diluted with water and adjusted to pH 5 with hydrochloric acid. The precipitate formed is fil-tered off, washed with water and dried.
Yield: 3.9 g (89 0 of theory), Rf value: 0.38 (silica gel; methylene chloride/methanol = 5:1) f. [5-(4-chloro-3-nitro-phenyl)-4-isobutyl-imidazol-1-yl]-ace-Prepared analogously to Example 189b from [5-(4-chloro-phenyl)-4-isobutyl-imidazol-1-yl]-acetic acid and fuming nitric acid.
Yield: 75 % of theory, Rf value: 0.4 (silica gel; methylene chloride/methanol - 5:1) g. [4-isobutyl-5-(4-methylamino-3-nitro-phenyl)-imidazol-1-yl-a . . i . a .i d Prepared analogously to Example 7b from [5-(4-chloro-3-nitro-phenyl)-4-isobutyl-imidazol-1-yl]-acetic acid and methylamine solution (40 0 ) .
Yield: 99 a of theory, Rf value: 0.42 (Reversed phase, RP 18, methanol/5o sodium chloride solution = 6:4) h. ethyl [4-isobutyl-5-(4-methylamino-3-nitro-phenyl)-imidazol-1-~rll -ar_etate 100 ml absolute ethanol is saturated with hydrochloric acid gas and after the addition of 3.6 g (0.011 mol) of [4-isobutyl-5-(4-methylamino-3-nitro-phenyl)-imidazol-1-yl]-acetic acid stir-red for 3 hours at ambient temperature. The solution is concen-trated in vacuo by evaporation, the residue is dissolved in wa-ter, made basic with ammonia and extracted with ethyl acetate.
The combined organic extracts are dried and concentrated by evaporation.
Yield: 2.9 g (73 0 of theory), Rf value: 0.64 (silica gel; methylene chloride/methanol = 9:1) i. 4-[(5-(1-methoxycarbonylmethyl-4-isobutyl-imidazol-5-yl)-1-me~h~rl-1 H-b n .i mi da .ol - -~rl~~rl 1 -l~Pn~nni tri 1 a Prepared analogously to Example 24f from [4-isobutyl-5-(4-me-thylamino-3-nitro-phenyl)-imidazol-1-yl]-acetic acid, N,N'-car-bonyldiimidazole and 4-cyanophenylacetic acid in tetrahydrofu-ran/glacial acetic acid.
Yield: 37 0 of theory, Rf value: 0.67 (silica gel; methylene chloride/methanol = 9:1) k. 4-[(5-(1-methoxycarbonylmethyl-4-isobutyl-imidazol-5-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydro-chlo_r,'de Prepared analogously to Example le from 4-[(5-(1-methoxycar-bonylmethyl-4-isobutyl-imidazol-5-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium car-,w... bonate in methanol.
Yield: 29 0 of theory, C26H30N6O2 x HC1 (458.57/495.038) Mass spectrum: (M+H)' - 459 (M+2H)" - 230 3 0 F,xamz 1 a ~ ~ n 4-[(5-(N-cyclopentyl-tetrazol-5-yl-methylcarbonylamino)-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-cyclopentyl-tetrazol-5-yl-methylcarbonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 63 % of theory, C24Hz.,N90 x HCl (457.55/494.01) Mass spectrum: (M+H)+ - 458 4-[(5-(N-cyclohexyl-methanesulphonylamino)-1-methyl-1H-benzimi-dazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-cyclohexyl-methanesulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 89 % of theory, C23HZ9NSOzS x HCl (439.59/476.06) Mass spectrum: (M+H)' - 440 2 0 F,xam=
4-[(5-(N-cyclopentyl-3-carboxypropionylamino)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride '~ 25 Prepared analogously to Example 13 from 4-[(5-(N-cyclopentyl-3-ethoxycarbonylpropionylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in etha-nol.
Yield: 52 % of theory, 30 CZSH29Ns0 x HC1 (447.55/484.02) Mass spectrum: (M+H)' - 448 (M+Na)' - 470 ( M+H+Na ) " - 2 3 5 . 6 4-[(5-(N-phenyl-methylaminocarbonyl)-1,7-dimethyl-1H-benzimi-dazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-phenyl-methyl-aminocarbonyl)-1,7-dimethyl-1H-benzimidazol-2-yl)-methyl]-ben-zonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 56 0 of theory, C25HzsNsO x HCl (411.5/448.0) Mass spectrum: M+ - 411 4-[(5-(N-cyclopentyl-ethoxycarbonylmethyloxyacetylamino)-1-me-thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-cyclopentyl-ethoxycarbonylmethyloxyacetylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium car-bonate in ethanol.
Yield: 68 0 of theory, Cz.,H33N504 x HC 1 ( 4 91 . 6 0 / 5 2 8 . 0 7 ) Mass spectrum: M+ - 492 (M+2H)'~ - 246.6 (M+H+Na)'+ - 235.6 4-[(5-(N-cyclopentyl-carboxymethyloxyacetylamino)-1-methyl 1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-cyclopentyl-ethoxycarbonylmethyloxyacetylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol.

Yield: 98 % of theory, CasHa9Ns04 x HCl (463.55/500.02) Mass spectrum: (M+H)' - 464 (M+2H)+' - 232.7 ( M+H+Na ) '+ - 2 4 3 . 7 4-[(5-(2,3-dihydroindol-1-yl-sulphonyl)-1-methyl-1H-benzimida-zol-2-yl)-methyl]-benzamidine-hydrochloride ~~ Prepared analogously to Example le from 4-[(5-(2,3-dihydro-indol-1-yl-sulphonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 32 % of theory, C24H23NSOZS x HCl (445.545/ 482.00) Mass spectrum: (M+H)+ - 446 2 0 F,xam=
4-[(5-(1,3-dihydro-isoindol-2-yl-sulphonyl)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-hydrochloride y z5 Prepared analogously to Example le from 4-[(5-(1,3-dihydro-isoindol-2-yl-sulphonyl)-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 32 0 of theory, 30 C24H23N5025 x HCl (445.545/482.00) Mass spectrum: (M+H)+ - 446 4-[[5-(1-(N-ethoxycarbonylmethyl-methylaminocarbonyl)-cyclo propan-1-yl)-1-methyl-1H-benzimidazol-2-yl]-methyl]-benzami dine-hydrochloride a. Di eth~rl -a girl ami no- - ( Drano-benz~rl 1 -m 1 onat-3 g sodium are dissolved in 100 ml ethanol and then combined with a solution of 27.7 g (0.127 mol) of diethyl acetamidomalo-nate and 6.4 g (0.04 mol) of potassium iodide in 200 ml dioxan.
Then a solution of 25 g (0.127 mol) of 4-cyanobenzylbromide in 200 ml dioxan is added dropwise and the reaction mixture is re-fluxed for 3 hours. After 12 hours at ambient temperature it is filtered, the filtrate is concentrated by evaporation, the re-sidue is crystallised with petroleum ether and suction filte-red.
Yield: 41.1 g (97 % of theory), Rf value: 0.62 (silica gel; methylethylketone/xylene = 1:1) Melting point: 177-178'C
b. -ami no-'~- ( Drano-phen~,l ) -z roni_onic acid 40 g (0.12 mol) of diethyl 2-acetylamino-2-(4-cyano-benzyl)-malonate are dissolved in 110 ml glacial acetic acid, 50 ml concentrated hydrochloric acid and 135 ml water and refluxed ~~25 for 8 hours. The solution is concentrated by evaporation in vacuo, the residue is crystallised with isopropanol/ether, suc-tion filtered and dried.
Yield: 18.6 g (68 % of theory), Rf value: 0.37 (silica gel; methylethylketone/xylene = 1:1) c. 4-(5-oxo-2-trifluoromethyl-4,5-dihydro-oxazol-4-yl)methyl-benzonitrile 5.7 g (2.5 mmol) of 2-amino-3-(4-cyano-phenyl)-propionic acid are dissolved in 26.3 g (12.5 mmol) of trifluoracetic anhydride and refluxed for 24 hours. Then the solution is concentrated by evaporation in vacuo, the residue is chromatographed on silica gel and eluted with methylene chloride. The desired fractions are combined and concentrated by evaporation.
Yield: 3.6 g (53 0 of theory), Rf value: 0.71 (silica gel; methylethylketone/xylene = 1:1) d. ~- (~-oxo-z ror~i oni c- a _i d) -b n oni firi 1 P
3.5 g (0.013 mol) of 4-(5-oxo-2-trifluoromethyl-4,5-dihydro-oxazol-4-ylmethyl)-benzonitrile are dissolved in 20 ml of 70a trifluoracetic acid and stirred for 24 hours at ambient tempe-rature. The solid formed is suction filtered, washed with water and dried.
Yield: 1.8 g (75 0 of theory), Rf value: 0.2 (silica gel; methylene chloride/ethanol = 9:1) e.
350 ml fuming nitric acid are combined batchwise at -25 to -30°C with 50.0 g (0.21 mol) of 1-(4-chloro-phenyl)-cyclopro-panecarboxylic acid. After it has all been added the mixture is stirred for a further 15 minutes at -25°C and then poured onto ice. The substance precipitated is suction filtered, washed with water and dried.
Yield: 58.5 g (95 % of theory), Rf value: 0.43 (silica gel; methylene chloride/methanol =
9.5:0.5) f.
20.0 g (0.083 mol) of 1-(4-chloro-3-nitro-phenyl)-cyclopropane-,, carboxylic acid are heated to 180°C with 100 ml methylamine so-lution (400) in a glass bomb for 5 hours. The solution is con-centrated by evaporation in vacuo, the residue is taken up in water and acidified with glacial acetic acid. The substance precipitated is suction filtered, washed with water and dried.
Yield: 16.9 g (93 % of theory), Rf value: 0.59 (silica gel; methylene chloride/methanol - 9:1) g.
3.2 g (13.5 mmol) of 1-(4-methylamino-3-nitro-phenyl)-cyclopro-panecarboxylic acid are dissolved in 120 ml ethanol and after the addition of 0.5 g palladium on activated charcoal hydroge-nated with hydrogen for 90 minutes. The catalyst is filtered off, the solution is evaporated down.
Yield: 2.8 g (100 0 of theory), Rf value: 0.41 (silica gel; methylene chloride/methanol = 9:1) h. 4-[(5-(1-carboxy-cyclopropan-1-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and 4-[(6-(1-carboxy-cyclopropan-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-methyl]-ben2onitrilP
2.6 g (13.5 mmol) of 4-(2-oxo-propionic acid)-benzonitrile and 2.8 g (13.5 mmol) of 1-(3-amino-4-methylamino-phenyl)-cyclopro-panecarboxylic acid are placed in 100 ml ethanol and refluxed for 5 hours under a nitrogen current. The reaction mixture is stirred for 72 hours at ambient temperature and then half the solvent is distilled off. The substance precipitated is suction filtered and dried.
Yield: 1.3 g (28 0 of theory) of 4-[(5-(1-carboxy-cyclopropan-1-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile, Rf value: 0.43 (silica gel; methylene chloride/ethanol = 9:1) C2oH1.,N302 ( 3 31 . 3 8 ) -~°" 25 Mass spectrum: M+ - 331 The filtrate is evaporated down and combined with ether. The precipitate formed is suction filtered and dried.
Yield: 1.0 g (21 0 of theory), 4-[(6-(1-carboxy-cyclopropan-1-yl)-1-methyl-2-oxo-1.2-dihydroquinoxalin-3-yl)-methyl]-benzonitrile.
Rf value: 0.50 (silica gel; methylene chloride/ethanol = 9:1) CzlH1,N30a ( 3 5 9 . 3 8 ) Mass spectrum: M' - 359 i. 4-[[5-(1-(N-ethoxycarbonylmethyl-methylaminocarbonyl)-cyclopropan-1-yl)-1-methyl-1H-benzimidazol-2-yl]-methyl]-benzoni ril 0.5 g (1.5 mmol) of 4-[(5-(1-carboxy-cyclopropyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile are dissolved in 5 ml dimethylformamide and after the addition of 0.48 g (1.5 mmol) of O-(benzotriazol-1-yl)-N,N,N'N'-tetramethyluroniumtetra-fluoroborate, 0.46 ml N-methylmorpholine and 0.3 g sarcosine ethylester hydrochloride the mixture is stirred for 20 hours at ambient temperature. The suspension is diluted with water and extracted with ethyl acetate. The combined organic extracts are ~. washed with sodium hydrogen carbonate solution and sodium chlo-ride solution, dried and concentrated by evaporation. The resi due is chromatographed on silica gel and eluted with ethyl ace tate/lo ammonia. The desired fractions are combined and concen trated by evaporation.
Yield: 370 mg (58 % of theory), Rf value: 0.61 (silica gel; methylene chloride/ethanol - 9:1) k. 4-[[5-(1-(N-ethoxycarbonylmethyl-methylaminocarbonyl)-cyclo-propan-1-yl)-1-methyl-1H-benzimidazol-2-yl]-methyl]-benzami-dine-h~rdro hl on d Prepared analogously to Example le from 4-[[5-(1-(N-ethoxy-carbonylmethyl-methylaminocarbonyl)-cyclopropan-1-yl)-1-methyl-1H-benzimidazol-2-yl]-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 93 0 of theory, CasHa9NsOa x HC1 (447.55/484.02) Mass spectrum: (M+H)+ - 448 4-[(5-(1-(pyrrolidin-1-yl-carbonyl)-cyclopropan-1-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(1-(pyrrolidin-1-yl-carbonyl)-cyclopropan-1-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbo-nate in ethanol.
Yield: 96 0 of theory, C24Hz.,N50 x HC1 (401.52/437.99) Mass spectrum: (M+H)+ - 402 4-[(5-(1-(N-carboxymethyl-methylaminocarbonyl)-cyclopropan-1-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(1-(N-ethoxycar-bonylmethyl-methylaminocarbonyl)-cyclopropan-1-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide solution in ethanol.
Yield: 86 0 of theory, Ca3HzsNsOa x HCl (419.49/455.96) Mass spectrum: (M+H)' - 420 (M+Na)+ - 442 4-[(5-(pyrrolidin-1-yl-carbonyl-(ethoxycarbonylmethyl)-methy-lene)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride a. 2- (4-c-.hl ors-z hPn~rl ) -1 -~~rrrnl i rli n-'I -girl -PthancmP
Prepared analogously to Example 2301 from p-chlorophenylacetic acid, pyrrolidine, O-(benzotriazol-1-yl)-N,N,N~N~-tetramethyl-uronium tetrafluoroborate and N-methylmorpholine in dimethyl-formamide.
Yield: 75 0 of theory, Rf value: 0.5 (silica gel; methylene chloride/ethanol 19:1) b. eth~ 1 '~- (4-c~hl oro-~ hP_n_~sl 1 -4-oxo-4-~~rrol i r7i n 1 girl bm ~rrat-P
16.8 g (0.075 mol) of 2-(4-chloro-phenyl)-1-pyrrolidin-1-yl-ethanone are dissolved in 175 ml dimethylsulphoxide and after the addition of 8.9 g (0.08 mol) of potassium tert.butoxide stirred for 15 minutes at ambient temperature. After the addi-tion of 18.1 ml (0.085 mol) of ethyl iodoacetate the reaction mixture is stirred for 45 hours at ambient temperature. The solution is poured onto ice water and extracted with ethyl acetate. The combined organic extracts are washed with sodium chloride solution, dried and concentrated by evaporation. The residue is chromatographed on silica gel, initially eluting with petroleum ether and later with petroleum ether/ethyl ace-tate (8:2 and 1:1). The desired fractions are combined and con-centrated by evaporation.
Yield: 11.0 g (48 % of theory), Rf value: 0.73 (silica gel; ethyl acetate/petroleum ether =
7:3) c. Ethyl 3-(4-chloro-3-nitro-phenyl)-4-oxo-4-pyrrolidin-1-yl butyrate and ethyl 3-(4-chloro-2-nitro-phenyl)-4-oxo-4-pyrro 1 i di n-l -girl -bu ~rrat-P
To 40 ml fuming nitric acid, 7.8 g (0.025 mol) of ethyl 3-(4-chloro-phenyl)-4-oxo-4-pyrrolidin-1-yl-butyrate are added batchwise at -30'C. The solution is stirred for 15 minutes at "-25 -30~C and then poured onto ice water. The supernatant water is decanted off, the residue is taken up in ethyl acetate and so-dium hydrogen carbonate solution and extracted. The combined organic extracts are dried and concentrated by evaporation.
Yield: 7.9 g (89 0 of theory), ethyl 3-(4-chloro-3-nitro-phenyl)-4-oxo-4-pyrrolidin-1-yl-buty-rate and ethyl 3-(4-chloro-2-nitro-phenyl)-4-oxo-4-pyrrolidin-1-yl-butyrate as a mixture of isomers in the ratio 1:9.
Rf value: 0.68 (silica gel; methylene chloride/ethanol - 19:1) d. Ethyl 3-(4-methylamino-3-nitro-phenyl)-4-oxo-4-pyrrolidin-1-yl-b ~ yratP
7.9 g (23 mmol) of ethyl 3-(4-chloro-3-nitro-phenyl)-4-oxo-4-pyrrolidin-1-yl-butyrate and ethyl 3-(4-chloro-2-nitro-phenyl)-4-oxo-4-pyrrolidin-1-yl-butyrate (isomer mixture) are dissolved in 65 ml ethanol and after the addition of 5 ml me-thylamine the mixture is heated to 80°C for 1 hour in a pres-sure vessel. After cooling to ambient temperature and the addi-tion of 5 g silica gel the mixture is evaporated to dryness.
The residue is chromatographed on silica gel, eluting initially with petroleum ether and later with petroleum ether/ethyl ace-~_ tata ( 9 : 1 ) .
Yield: 330 mg (3.6 % of theory), Rf value: 0.58 (silica gel; methylene chloride/ethanol = 19:1) C1.,H23N305 ( 3 4 9 . 4 ) Mass spectrum: M' - 349 e. Ethyl 3-(4-methylamino-3-amino-phenyl)-4-oxo-4-pyrrolidin-1-yl -~b y~ratP
300 mg (8.6 mmol) of ethyl 3-(4-methylamino-3-nitro-phenyl)-4-oxo-4-pyrrolidin-1-yl-butyrate are dissolved in 60 ml ethyl acetate and 10 ml methanol and after the addition of 600 mg Raney nickel the mixture is hydrogenated with hydrogen for 2.5 hours at ambient temperature. The catalyst is filtered off and w-' 25 the filtrate is evaporated down.
Yield: 260 mg (94 0 of theory), Rf value: 0.28 (silica gel; methylene chloride/ethanol = 19:1) f. 4-((5-(pyrrolidin-1-yl-carbonyl-(ethoxycarbonylmethyl)-me-thylene)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and 4-[(5-(pyrrolidin-1-yl-carbonyl-(ethoxycarbonylmethyl)-methy-lene)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-methyl]-260 mg (0.81 mmol) of ethyl 3-(3-amino-4-methylamino-phenyl)-4-cyclopentyl-4-oxo-butyrate and 189 mg (1.0 mmol) of 3-(4-cyano-phenyl)-2-oxo-propionic acid are refluxed in 10 ml ethanol for 1 hour. The reaction solution is combined with 5 g silica gel and evaporated to dryness. The residue is chromato-graphed on silica gel, eluting initially with petroleum ether and later with petroleum ether/ethyl acetate 9:1 and 8:2. The desired fractions are combined and concentrated by evaporation.
Yield: 100 mg (28 0 of theory), 4-[(5-(pyrrolidin-1-yl-carbon-yl-(ethoxycarbonylmethyl)methylene)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile:
Rf value: 0.28 (silica gel; methylene chloride/ethanol = 19:1) lO CZ6HZgN4O3 (444.5) Mass spectrum: M+ - 444 and 200 mg (52 % of theory) 4-[(5-(pyrrolidin-1-yl-carbonyl-(ethoxycarbonylmethyl)methylene)-1-methyl-2-oxo-1,2-dihydro-quinoxalin-3-yl)-methyl]-benzonitrile, CZ.,HZeN404 ( 4 72 . 5 ) Mass spectrum: M+ - 472 g. 4-[(5-(pyrrolidin-1-yl-carbonyl-(ethoxycarbonylmethyl)-me-thylene)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hvdrochlo_ride Prepared analogously to Example le from ethyl 3-[3-(4-cyano-benzyl)-1-methyl-2-oxo-1,2-dihydro-quinoxalin-6-yl]-4-cyclo-pentyl-4-oxo-butyrate and hydrochloric acid/ammonium carbonate in ethanol.
°°~' 25 Yield: 21 0 of theory, C26H31N503 x HC1 (461.6/498.05) Mass spectrum: (M+H)+ - 462 4-[(5-(1-(pyridine-2-yl-carbonyl)-cyclopropan-1-yl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride a.
To a solution of 19.6 g (0.124 mol) of 2-bromopyridine in 200 ml tetrahydrofuran, a solution of 85 ml (0.141 mol) of n-butyl-lithium (15a in hexane) is added dropwise at -45'C. After 1 hour at -45~C a solution of 21.2 g (0.119 mol) of 1-(4-chloro-phenyl)-1-cyclopropanecarbonitrile in 50 ml tetrahydrofuran is added dropwise. After heating to ambient temperature the mix-ture is poured onto ice water, adjusted to pH 5 with formic acid and extracted with ethyl acetate. The organic extracts are washed with sodium chloride solution, dried and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (19:1). The desired fractions are combined and concentrated by evaporation.
Yield: 7.2 g (23 0 of theory), Rf value: 0.71 (silica gel; methylene chloride/ethanol = 19:1) b. [1-(4-chloro-3-nitro-phenyl)-cyclopropan-1-yl]-pyridin-2-yl-mPt-hanP
Prepared analogously to Example 231c from [1-(4-chloro-phenyl)-cyclopropan-1-yl]-pyridin-2-yl-methanone and fuming nitric acid.
Yield: 28 0 of theory), Rf value: 0.73 (silica gel; petroleum ether/ethyl acetate =
1:1) c. [1-(4-methylamino-3-nitro-phenyl)-cyclopropan-1-yl]-pyridin-Prepared analogously to Example 231d from [1-(4-chloro-3-nitro-'°°'25 phenyl)-cyclopropan-1-yl]-pyridin-2-yl-methanone and methyl-amine in isopropanol.
Yield: 60 0 of theory.
d. 4-[5-(1-(hydroxy-pyridin-2-yl-methyl)-cyclopropan-1-yl)-1-merl-wl -1 H-bPn i mi r3a~n1 - -girl ) mPth~rl ] -b n oni tri 1 P
Prepared analogously to Example 231f and Example lc from [1-(4-methylamino-3-nitro-phenyl)-cyclopropan-1-yl]-pyridin-2-yl-methanone, hydrogen/palladium on activated charcoal and 3-(4-cyano-phenyl)-2-oxo-propionic acid in ethanol.
Yield: 10 % of theory, CasHzzN40 ( 3 94 . 5 ) Mass spectrum: M' - 394 e. 4-[5-(1-(pyridin-2-yl-carbonyl)-cyclopropan-1-yl)-1-methyl-1H-bPn .i mi da .ol - -girl ) mc~t-h~rl ] -h n nni tri l a 415 mg (1.0 mmol) of 4-[5-(1-(hydroxy-pyridin-2-yl-methyl)-cyclopropan-1-yl]-1-methyl-1H-benzimidazol-2-yl)methyl]-benzo-nitrile are dissolved in 50 ml methylene chloride and after the addition of 2.5 g manganese dioxide stirred for 16 hours at am-bient temperature. The precipitate is filtered off and the mother liquor is concentrated by evaporation. The residue is chromatographed on silica gel, eluting initially with methylene chloride and later with methylene chloride/ethanol (50:1 and ..... 25:1). The desired fractions are combined and concentrated by evaporation.
Yield: 285 mg (69 a of theory), Rf value: 0.63 (silica gel; methylene chloride/ethanol = 19:1) f. 4-[(5-(1-(pyridin-2-yl-carbonyl)cyclopropan-1-yl-1-methyl-1H-h i mi da .ol - -yl ) -mPrh~rl 1 -bPn ami r7 i nP h~rdrocr~ err; ~o Prepared analogously to Example le from 4-[5-(1-(pyridin-2-yl-carbonyl)-cyclopropan-1-yl)-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 41 % of theory, C2sH2aNs0 (409.5/445.96) "- 25 Mass spectrum: (M+H)+ - 410 4-[(5-benzenesulphonylamino-benzoxazol-2-yl)-methyl]-benzami-dine-hydrochloride a. 4-b n . nc~~W hon~rl ami no-2-ni t-r iphPnr,l Prepared analogously to Example ld from 4-hydroxy-3-nitro-aniline and benzenesulphonic acid chloride in pyridine.
Yield: 45 % of theory, Rf value: 0.47 (silica gel; methylene chloride/ethanol = 19:1) b . ~h - n ~ ~ 1 on~rl ami no-2 -ami no-z hPnr,l Prepared analogously to Example lc from 4-benzenesulphonyl-amino-2-nitrophenol, palladium on activated charcoal in metha-nol and hydrogen.
Yield: 80 % of theory, Rf value: 0.26 (silica gel; methylene chloride/ethanol = 19:1) c. 4-[(5-benzenesulphonylamino-benzoxazol-2-yl)-methyl]-benzo-Prepared analogously to Example 24f from 4-benzenesulphonyl-amino-2-amino-phenol, N,N~-carbonyldiimidazole in tetrahydro-_.. furan and sulpholane.
Yield: 9.8 % of theory, Rf value: 0.38 (silica gel; methylene chloride/ethanol = 19:1) d. 4-[(5-benzenesulphonylamino-benzoxazol-2-yl)-methyl]-benz-amid; n -h~rdrochl on dP
Prepared analogously to Example le from 4-[(5-benzenesulphon-ylamino-benzoxazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 56 0 of theory, C21H18N40jS x HC1 (406.5/442.9) Mass spectrum: (M+H)' - 407 ( M+Na ) ' - 4 3 9 "..°~° 25 (2 M+H)' - 813 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-benzothiazol-2-yl)-methyl]-benzamidine-hydrochloride a.
7.0 g (44.8 mmol) of 4-cyanophenylacetic acid are dissolved in 200 ml methylene chloride and 4 drops of dimethylformamide and after the addition of 14 ml thionylchloride the mixture is re-fluxed for 30 minutes. The solvent is evaporated to dryness in vacuo,.the residue is dissolved in 20 ml chlorobenzene and re-fluxed for 15 minutes with 7.0 g (44.8 mmol) of 2-fluoro-5-ni-tro-aniline. The solution is cooled, the precipitated substance is suction filtered and dried.
Yield: 10.9 g (81.5 % of theory), Rf value: 0.18 (silica gel; ethyl acetate/petroleum ether =
3:7) b. 4- (5-ni ro-b -n .o -hi a .ol - -~rl~~,l -b oni ri 1 10.9 g (36.5 mmol) of 4-nitro-2-(4-cyanophenyl-methylcarbonyl-amino)-fluorobenzene, 7.6 g 2,4-bis-(4-methoxyphenyl)-1,3-di-thio-2,4-diphosphetan-2,4-disulphide and 300 ml toluene are re-fluxed for 18 hours. The solvent is distilled off, the residue is chromatographed on silica gel and extracted with methylene chloride. The desired fractions are combined and concentrated by evaporation.
Yield: 8.2 g (76 0 of theory), Rf value: 0.44 (silica gel; ethyl acetate/petroleum ether =
3:7) c . ~ -ami no-b -n .othi a .ol - -~rl~yl -b .o i ri 1 8.8 g (29.8 mmol) of 4-(5-nitro-benzothiazol-2-ylmethyl)-benzo-nitrile are dissolved in 300 ml pyridine, combined with 15.4 g sodium dithionite and 60 ml water at 50'C and heated to 95~C
for 1 hour. The pyridine is distilled off, the residue is com-bined with ice water, the precipitated product is suction fil-tered and dried.
Yield: 6.9 g (87 % of theory), Melting point: 178-180'C
Rf value: 0.2 (silica gel; ethyl acetate/petroleum ether = 1:1) d. 4-[(5-(quinolin-8-yl-sulphonylamino)-benzothiazol-2-yl)-me-th~rl] -benzonitrile Prepared analogously to Example ld from 4-(5-amino-benzothia-zol-2-yl)-methyl-benzonitrile and quinolin-8-sulphonylchloride in pyridine.

Yield: 77 0 of theory, Rf value: 0.25 (silica gel; ethyl acetate/petroleum ether/ammo-nia = 1:1:0.01) e. 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-be_n_2thi .ol - -~rl~~rl 1 -b n oni firi 1 a h~dro hl on d 3.8 g (8.3 mmol) of 4-[(5-(quinolin-8-yl-sulphonylamino)-benzo-thiazol-2-yl)-methyl]-benzonitrile, 5.7 g (41.6 mmol) of potas-slum carbonate, 2.3 ml (20.8 mmol) of ethyl bromoacetate and 1.4 ml (9.2 mmol) of 1,8-diazabicyclo(5.4.0)undec-7-ene are dissolved in 200 ml acetone and refluxed for 1 hour. The inso-.- luble matter is filtered off and the mother liquor is concen-trated by evaporation. The residue is chromatographed on silica gel and eluted with ethyl acetate/petroleum ether (1:9, 2:8 and 3:7). The desired fractions are combined and concentrated by evaporation.
Yield: 1.3 g (29 % of theory), Rf value: 0.45 (silica gel; ethyl acetate/petroleum ether/ammo-nia = 1:1:0.01) f. 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino) Prepared analogously to Example le from 4-[(5-(N-ethoxycarbo-nylmethyl-quinolin-8-yl-sulphonylamino)-benzthiazol-2-yl)-me-W'~25 thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 59 v of theory, CZeH25N504S2 x HC1 (559.67/596.13) Mass spectrum: (M+H)' - 560 4-[(5-(N-carboxymethy-quinolin-8-yl-sulphonylamino)-benzothia-zol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-ethoxycar-bonylmethyl-quinolin-8-yl-sulphonylamino)-benzothiazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide solution in ethanol.
Yield: 88 % of theory.
CasHziNs~as x HC1 (531.62/568.08) Mass spectrum: (M+H)' - 532 (M+Na)' - 554 4-[(5-(2-methylphenyl)-benzothiazol-2-yl)-methyl]-benzamidine-hydrochloride a. 4-[(5-(2-methylphenyl)-benzothiazol-2-yl)-methyl]-benzo-nitri1 P
Under a nitrogen atmosphere 1.3 g (3.95 mmol) of 4-[(5-bromo-benzothiazol-2-yl)-methyl]-benzonitrile and 1.3 g (1.1 mmol) of bis(triphenylphosphine)-palladium(II)-chloride are stirred into 40 ml toluene for 15 minutes at 40°C. Then 1.3 g (12.3 mmol) of sodium carbonate in 5.6 ml water and 0.84 g (6.1 mmol) of o-to-lylboric acid in 5 ml methanol are added. The reaction mixture is refluxed for 10 hours. After cooling the reaction solution is diluted with ethyl acetate and extracted with water. The combined organic extracts are washed with sodium chloride so-lution and dried. The residue is chromatographed on silica gel and eluted with ethyl acetate/petroleum ether 5:95, 10:95 and 15:85. The desired fractions are combined and concentrated by evaporation.
Yield: 0.55 g (41 0 of theory), Rf value: 0.51 (silica gel; ethyl acetate/petroleum ether =
3:7) b. 4-[(5-(2-methylphenyl)-benzothiazol-2-yl)-methyl]-benzami-dine-hydrc~o~_h_1 nri r7P
Prepared analogously to Example le from 4-[(5-(2-methylphenyl) benzothiazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/
ammonium carbonate in ethanol.

Yield: 58 a of theory, Cz2H19N3S x HC1 357.48/393.94) Mass spectrum: (M+H)' - 358 Exami l P ~'~ 7 4-[(5-(Quinolin-8-yl-sulphonylamino)-indol-2-yl)-methyl]-benzamidine-hydrochloride a 1-mPth~rl- rib~t~rlt-in-1H-in n1P
To a solution of 10.0 g (76.2 mmol) of N-methylindole in 100 ml -- tetrahydrofuran 30.5 ml (75 mmol) of n-butyllithium (2.5 molar in hexane) are added dropwise at 0 to 5 °C under a nitrogen atmosphere. After two hours at 0°C the reaction mixture is coo-led to -60°C, and 24.4 g (75 mmol) of tributyltin chloride are added dropwise. The reaction mixture is heated overnight to am-bient temperature and extracted with ethyl acetate/sodium chlo-ride solution. The combined organic extracts are dried and con-centrated by evaporation. The residue is distilled in vacuo at 9 mbar and 196 to 200°C.
Yield: 20.9 g (65.3 0 of theory), Rf value: 0.48 (aluminium oxide, petroleum ether) CZ1H35NSn ( 4 2 0 . 219 ) Mass spectrum: M+ - 417/19/21 (Sn) ~' 2 5 b . 4- ( 1 -meth~rl -'1 H- i dol - -~rl~yl -bPnzon i t ri 1 P
12.9 g (30.7 mmol) of 1-methyl-2-tributyltin-1H-indole, 5.7 g (29.2 mmol) of 4-(bromomethyl)-benzonitrile and 0.34 g bis-(triphenylphosphine)-palladium-dichloride are refluxed in 90 ml tetrahydrofuran for 2 hours under a nitrogen atmosphere. After cooling the mixture is diluted with ethyl acetate and 15% po-tassium fluoride solution and stirred overnight at ambient tem-perature. The precipitate formed is suction filtered and washed with ethyl acetate. The organic phase is washed with sodium chloride solution, dried and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with ethyl acetate/petroleum ether (5:95). The desired fractions are com-bined and concentrated by evaporation.
Yield: 5.9 g (81.4 0 of theory), Rf value: 0.41 (silica gel; ethyl acetate/petroleum ether =
3:7) C. 4- (1-metl_'yrl -5-ni tro-l H-i ndol - -girl ) -mp hurl -bPn nni t-ri l P
6.9 g (28 mmol) of 4-(1-methyl-1H-indol-2-yl)-methyl-benzo-nitrile are placed in 50 ml conc. sulphuric acid. At 2°C 2.9 g (28 mmol) of potassium nitrate are added batchwise, whereupon the temperature rises to 10°C. After 30 minutes at 2°C the --- mixture is poured onto ice and the product precipitated is suction filtered, washed with ice water, dried and recrystal-lised from acetone.
Yield: 5.2 g (63.7 % of theory), Rf value: 0.17 (silica gel; ethyl acetate/petroleum ether =
3:7) d. 4- (1 -mPth~rl -5-amino-l H-i ndol -~-girl ) -~~rl -bPn oni t-ri 1 P
Prepared analogously to Example lc from 4-(1-methyl-5-nitro-1H-indol-2-yl)-methyl-benzonitrile, palladium on activated char-coal in methylene chloride/methanol and hydrogen.
Yield: 90 0 of theory, Rf value: 0.34 (silica gel; ethyl acetate/petroleum ether =
~'25 5:5) e. 4-[(5-(Quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-Prepared analogously to Example ld from 4-(1-methyl-5-amino-1H-indol-2-yl)-methyl-benzonitrile and quinolin-8-sulphonic acid chloride.
Yield: 51 % of theory Rf value: 0.49 (silica gel; methylene chloride/ethanol - 19:1) f. 4-[(5-(Quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-me-thyl1 -benzami chi nP-h~rdroc~hl nri r7a Prepared analogously to Example le from 4-[(5-(quinolin-8-yl sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 30 0 of theory, Rf value: 0.24 (silica gel; methylene chloride/ethanol/glacial acetic acid = 4:1:0.01) Cz6H23N4O2S x HC1 (469 . 57/506 . 03 ) Mass spectrum: (M+H)+ - 470 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-ethoxycar-bonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 71 0 of theory, Rf value: 0.26 (silica gel; methylene chloride/ethanol/glacial acetic acid = 4:1:0.01) C3oHz9N5O4S x HC1 (555.66/592.12) ' ~ 25 Mass spectrum: (M+H)' - 556 (M+2H)'+ - 278.8 (M+Na+H)" - 289.8 4-[(5-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-ethoxycar-bonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol.

Yield: 23 a of theory, Rf value: 0.14 (silica gel; methylene chloride/ethanol/glacial acetic acid = 4:1:0.01) CzaH2sNs04s x HC1 (527.61/564.07) Mass spectrum: (M+H)' - 528 (M+Na)' - 550 4-[(5-benzenesulphonylamino-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-benzenesulphonyl-amino-1-methyl-indol-2-yl)-methyl]-benzonitrile and hydrochlo-ric acid/ammonium carbonate in ethanol.
Yield: 20 0 of theory, Rf value: 0.26 (silica gel; methylene chloride/ethanol/glacial acetic acid = 4:1:0.01) C23H22N402S x HCl (418.52/454.98) Mass spectrum: (M+H)' - 419 4-[(5-(N-(ethoxycarbonylmethylaminocarbonylmethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-(ethoxycarbon-ylmethylaminocarbonylmethyl)-quinolin-8-yl-sulphonylamino-1-methyl-indol-2-yl)-methyl]-benzonitrile and hydrochloric acid/-ammonium carbonate in ethanol.
Yield: 52 0 of theory, Rf value: 0.22 (silica gel; methylene chloride/ethanol = 4:1) C32H32N6OSS x HC1 ( 612 . 71 / 64 9 . 17 ) Mass spectrum: (M+H)' - 613 4-[(5-n-propanesulphonylamino-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-n-propanesulphon-ylamino-1-methyl-indol-2-yl)-methyl]-benzonitrile and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 71 0 of theory, Rf value: 0.21 (silica gel; methylene chloride/ethanol = 4:1) CzaH24N4O2S x HCl (384.51/420.97) ~._ Mass spectrum: (M+H)' - 385 4-[(5-(N-ethoxycarbonylmethyl-n-propanesulphonylamino)-1-me-thyl-indol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(N-ethoxycarbo-nylmethyl-n-propanesulphonylamino)-1-methyl-indol-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 66 0 of theory, Rf value: 0.52 (silica gel; methylene chloride/ethanol - 4:1) °" 25 Cz4H3oN404S x HC1 (470.60/507.06) Mass spectrum: (M+H)' - 471 4-[(5-(N-carboxymethylaminocarbonylmethyl-quinolin-8-yl-sulpho-nylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochlo-ride Prepared analogously to Example 13 from 4-[(5-(N-ethoxycar-bonylmethylaminocarbonylmethyl-quinolin-8-yl-sulphonylamino-1-methyl-indol-2-yl)-methyl]-benzamidine hydrochloride and sodium hydroxide in ethanol.

Yield: 93 0 of theory, C3oH28N6O5S x HCl (584.66/621.12) Mass spectrum: (M+H)+ - 585 Exams 1 _ 4 5 4-[(5-(N-carboxymethyl-n-propanesulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-ethoxycar-bonylmethyl-n-propanesulphonylamino)-1-methyl-indol-2-yl)-me-thyl]-benzamidine-hydrochloride and sodium hydroxide in etha-nol.
Yield: 86 % of theory, Rf value: 0.17 (silica gel; methylene chloride/ethanol = 4:1) Cz2Hz6N404S x HCl (442.54/479.60) Mass spectrum: (M+H)+ - 443 ( M+Na ) + - 4 6 5 Examr~le 246 4-[(5-(N-ethoxycarbonylmethyl-n-butanesulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride ,°'~25 Prepared analogously to Example le from 4-[(5-(N-ethoxycar-bonylmethyl-n-butanesulphonylamino)-1-methyl-indol-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 71 a of theory, Rf value: 0.25 (silica gel; methylene chloride/ethanol - 4:1) Cz5H32N4O4S x HCl (484.62/521.08) Mass spectrum: (M+H)' - 485 4-[(5-(N-carboxymethyl-n-butanesulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(N-ethoxycar-bonylmethyl-n-butanesulphonylamino)-1-methyl-indol-2-yl)-me-thyl]-benzamidine-hydrochloride and sodium hydroxide in etha-nol.
Yield: 68 % of theory, Rf value: 0.25 (silica gel; methylene chloride/ethanol= 4:1) C23H28N4O4'-S x HCl (456 . 57/493 . 03 ) Mass spectrum: (M+H)' - 457 (M+Na)+ - 479 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino) 1-methyl-indol-2-yl)-methyl]-N'-(methoxycarbonyl)benzamidine Prepared analogously to Example 97 from 4-[(5-(N-ethoxycar-bonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride, methyl chloroformate and potassium carbonate in tetrahydrofuran.
"~" 25 Yield: 85 0 of theory, C32H31NSO6S ( 613 . 70 ) Mass spectrum: (M+H)' - 614 (M+Na)+ - 636 Examnl 4A
4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-N'-(2-methanesulphonyl-ethyloxy-carbonyl)benzamidine 300 mg (0.5 mmol) of 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride, 170 mg (0.6 mmol) of 2-(methylsulphonyl)-ethyl-4-nitrophenylcarbonate and 210 mg (1.5 mmol) of potassium car-bonate are stirred in 30 ml tetrahydrofuran for 5 hours at am-bient temperature. Then the reaction mixture is filtered and the mother liquor is concentrated by evaporation. The residue is taken up in methylene chloride and washed with sodium hydro-gen carbonate solution. The combined organic extracts are dried and concentrated by evaporation. The residue is chroma-tographed on aluminium oxide and eluted with methylene chlo-ride/ethanol (99:1).
Yield: 150 mg (43 % of theory), ,.n..". C34H35N5~8'S2 ( 705 . 81 ) Mass spectrum: (M+H)' - 706 (M+Na)' - 728 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino-1-methyl-indol-2-yl)-methyl]-N,N-dimethylbenzamidine 450 mg (0.76 mmol) of 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine are suspended in 15 ml tetrahydrofuran and at 5°C combined with 0.11 ml (1.0 mmol) of 2-bromoethyl chloroformate. After 10 mi-~25 nutes the mixture is extracted with ethyl acetate and sodium chloride solution, and the combined organic extracts are dried and concentrated by evaporation. The residue is taken up in 10 ml tetrahydrofuran and stirred with 5 ml dimethylamine for 18 hours at ambient temperature. After evaporation of the solvent the residue is chromatographed on aluminium oxide, eluting with methylene chloride + 1-2% ethyl acetate.
Yield: 150 mg (34 0 of theory), C32H33N5~4S (583 .71) Mass spectrum: (M+H)' - 584 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-(methylcarbonyloxy-(methyl)methy-leneoxycarbonyl)-benzamidine a . arhon i c~ a i d- ( l - 1 ornPfi her 4 n i t rnz h~n~rl ) ~ Pr To a solution of 12.6 g (90 mmol) of p-nitrophenol in 300 ml methylene chloride and 7.2 g (91 mmol) of pyridine, 14.2 g (99 mmol) of 1-chloroethyl chloroformate are added dropwise at -10°C. The solution is stirred for 72 hours at ambient tempe-rature and then extracted with water and 0.5% sodium hydroxide solution. The combined organic extracts are dried and concen-trated by evaporation. The residue is chromatographed on alumi-nium oxide and eluted with methylene chloride. The combined fractions are concentrated by evaporation, triturated with pe-troleum ether and suction filtered.
Yield: 7.3 g (33 a of theory), Rf value: 0.58 (silica gel; ethyl acetate/petroleum ether =
3:7) b. 1- (4-ni ro-z h nox~rc-~arhon~~~r~~rl rare 7.2 g (29.3 mmol) of carbonic acid-(1-chloroethyl-4-nitrophen-yl)-ester and 10.9 g (34.2 mmol) of mercury(II)-acetate are '°"~25 stirred in 200 ml glacial acetic acid for 16 hours at ambient temperature. Then the mixture is evaporated to dryness, the residue chromatographed on silica gel and extracted with methy-lene chloride.
Yield: 4.2 g (53 % of theory), Rf value: 0.48 (silica gel; methylene chloride) c. 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl)-sulphonylami-no)-1-methyl-indol-2-yl)-methyl]-N-(methylcarbonyloxy-(methyl)-300 mg (0.5 mmol) of 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl)-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride, 25 ml methylene chloride, 150 mg (0.55 mmol) of 1-(4-nitro-phenoxycarbonyloxy)-ethyl acetate and 0.18 ml (1 mmol) of N-ethyldiisopropylamine are stirred for 18 hours at ambient temperature. The solvent is distilled off, the residue chromatographed on aluminium oxide and eluted with methylene chloride/ethanol (99:1). The desired fractions are combined and concentrated by evaporation.
Yield: 220 mg (65 0 of theory), C35H35N5~8'S (685.76) Mass spectrum: (M+H)+ - 686 (M+Na)' - 708 4-((5-(N-hydroxyaminocarbonylmethyl-quinolin-8-yl-sulphonyl-amino)-1-methyl-indol-2-yl)-methyl]-N-hydroxybenzamidine 540 mg (1 mmol) of 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl)-sulphonylamino-1-methyl-indol-2-yl)-methyl]-benzonitrile are refluxed for 5 hours with 278 mg (4 mmol) of hydroxylamine hydrochloride, 205 mg (4 mmol) of sodium carbonate, 14 ml me-thanol and 2 ml water. The solvent is distilled off, the resi-due chromatographed on silica gel and eluted with methylene chloride/1 to 5o ethanol. The desired fractions are combined and concentrated by evaporation.
Yield: 250 mg (44.6 0 of theory), C2aHasNs~ss ( S S 8 . 61 ) Mass spectrum: (M+H)' - 559 (M+Na)+ - 581 3 0 ~z 4-((5-(N-isopropyloxycarbonylmethyl-quinolin-8-yl-sulphonyl amino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride 420 mg (0.75 mmol) of 4-[(5-(N-carboxymethyl-quinolin-8-yl)-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydro-chloride are dissolved in 10 ml isopropanol and refluxed. Then hydrogen chloride gas is introduced for 30 minutes. The reac-tion mixture is concentrated by evaporation, the residue is triturated with ether and washed with acetone.
Yield: 450 mg (100 % of theory), C31H31Ns04S x HC1 (569.70/606.16) Mass spectrum: (M+H)' - 570 4-[(5-(N-(2-hydroxyethyloxycarbonylmethyl)-quinolin-8-yl)-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 253 from 4-[(5-(N-carboxyme-thylquinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride, ethylene glycol monobenzylether and hydrogen chloride gas.
Yield: 11 0 of theory, C30H29NSOSs x HCl (571.66/608.12) Mass spectrum: (M+H)' - 572 4-[(5-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-N-hydroxybenzamidine 260 mg (0.5 mmol) of 4-[(5-(N-carboxymethyl-quinolin-8-yl-sulphonylamino-1-methyl-indol-2-yl)-methyl]-benzonitrile are refluxed for 24 hours together with 14 ml methanol, 139 mg hydroxylamine hydrochloride, 105 mg sodium carbonate and 1 ml water. The solvent is distilled off, the residue is mixed with water and acidified with hydrochloric acid. The precipitated substance is suction filtered and dried. The crude product is chromatographed on silica gel and eluted with methylene chlo-ride/6 to 30% ethanol. The desired fractions are combined and concentrated by evaporation.

Yield: 180 mg (67 % of theory), CzsHzsNsOsS ( 543 . 61 ) Mass spectrum: (M+H)' - 544 (M+Na)' - 566 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino-1-methyl-indol-2-yl)-methyl]-N,N-bis-(n-octyloxycarbonyl)-benzamidine Prepared analogously to Example 97 from 4-[(5-(N-ethoxycar-bonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride, n-octyl chloroformate and potassium carbonate in tetrahydrofuran.
Yield: 19 % of theory, C4aHsiNs~as (868.11) Mass spectrum: (M)' - 868 Example 257 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-N-(n-octyloxycarbonyl)-benzamidine Prepared analogously to Example 97 from 4-[(5-(N-ethoxycar-bonylmethyl-quinolin-8-yl-sulphonylamino-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride, n-octyl chloroformate and potassium carbonate in tetrahydrofuran.
Yield: 16 0 of theory, 3 0 C39H4sNsOsS ( 711 . 8 9 ) Mass spectrum: (M+H)' - 712 (M+H+Na)" - 367.7 ' - 193 -Example 258 4-[(5-(methoxycarbonylmethyloxymethyl)carbonyl-N-cyclopentyl-amino-1-methyl-indol-2-y1)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(methoxycarbo-nylmethyloxymethyl)carbonyl-N-cyclopentylamino-1-methyl-indol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in methanol.
Yield: 49 0 of theory, C2~H3zN404 x HC1 (476.58/513.04) Mass spectrum: (M+H)+ - 477 (M+2H)++ - 239 (M+H+Na)++ - 250 Example 259 4-[(5-(ethoxycarbonylmethylamino)carbonyl-N-cyclopentylamino-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(ethoxycarbo-nylmethylamino)carbonyl-N-cyclopentylamino-1-methyl-indol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 79 0 of theory, C27H33N5~3 X HC1 ( 4 7 5 . 6 / 512 . 0 6 ) Mass spectrum: (M+H)+ - 476 (M+H+Na) ++ - 250 Example 260 4-[(5-(carboxymethylamino)carbonyl-N-cyclopentylamino-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(ethoxycarbonyl-methylamino)carbonyl-N-cyclopentylamino-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol.
Yield: 79 % of theory, CZSH29N503 x HCl (447.54/484.0) Mass spectrum: (M+H)+ - 448 (M+Na)+ - 470 (M+H+Na)++ - 235.6 Example 261 4-[(5-(carboxymethyloxymethyl)carbonyl-N-cyclopentylamino-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(ethoxycarbonyl-methyloxymethyl)carbonyl-N-cyclopentylamino-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol.
Yield: 43 a of theory, C26H3oN4O4 X HC1 (462.55/499.01) Mass spectrum: (M+H)+ - 463 (M+2H)++ - 232 (M+H+Na) ++ - 243 Example 262 4-[(6-(Quinolin-8-yl)-sulphonylamino-3-methyl-benzofuran-2-yl)-methyl]-benzamidine-hydrochloride a. 3-methyl-2-tributyltin-benzofuran Prepared analogously to Example 237a from 3-methylbenzofuran, n-butyllithium in tetrahydrofuran and tributyltin chloride.
Yield: 100 0 of theory, Rf value: 0.73 (silica gel; petroleum ether) CZ1H340Sn ( 421 . 19 ) Mass spectrum: M+ - 422 b. 4- (3-meth~rl -b n .of Aran- -yl ) methyl -b n .oni ri 1 Prepared analogously to Example 237b from 3-methyl-2-tributyl-tin-benzofuran, 4-(bromomethyl)-benzonitrile and bis(triphen-ylphosphine)-palladium(II)-chloride in tetrahydrofuran.
Yield: 49 0 of theory, Rf value: 0.57 (silica gel; petroleum ether/ethyl acetate =
4:1) c. 4~3-meth~rl -6-nit_ro-ben2ofLran-2-yl )~meth~rl -b .o i ri 1 P
4.3 g (17.4 mmol) of 4-(3-methyl-benzofuran-2-yl)methyl-benzo-nitrile are dissolved in 50 ml methylene chloride and at -50°C
mixed within 30 minutes with a solution of 9.0 g (34.8 mmol) of tin(IV)chloride in 22 g (34.8 mmol) of fuming nitric acid.
After 2 hours at -50°C the mixture is extracted with methylene chloride and water. The combined organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluted with methylene chloride, the desired frac-tions are combined and concentrated by evaporation.
Yield: 2.5 g (49 0 of theory), Rf value: 0.79 (silica gel; methylene chloride) d. ~3-meth~rl -6-ami no-b n .o Aran- . ~1 ) m~th~rl -b n .oni ri 1 Prepared analogously to Example 189d from 4-(3-methyl-6-nitro-benzofuran-2-yl)methyl-benzonitrile and Raney nickel/hydrogen in methanol/methylene chloride.
Yield: 64 0 of theory, Rf value: 0.25 (silica gel; methylene chloride) e. 4-[(6-(Quinolin-8-yl-sulphonylamino)-3-methyl-benzofuran-7-vl) -methvl1 -ben2onitri1e__.
Prepared analogously to Example ld from 4-(3-methyl-6-amino-benzofuran-2-yl)methyl-benzonitrile and quinoline-8-sulphonic acid chloride in pyridine.
Yield: 17 a of theory, Rf value: 0.66 (silica gel; methylene chloride/ethanol = 95:5) f. 4-[(6-(Quinolin-8-yl-sulphonylamino)-3-methyl-benzofuran-~-yl ) -mPth~rl_1 -b n .ami r3i nP-h~rdro hl c~ri r3P
Prepared analogously to Example le from 4-[(6-(quinolin-8-yl-sulphonylamino)-3-methyl-benzofuran-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 59 0 of theory, C26H22N4O3S x HC1 (470 . 56/507. 03 ) Mass spectrum: (M+H)+ - 471 F,xamnl~6'~
4-[(6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-3-methyl-benzofuran-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(6-(N-ethoxycar-bonylmethyl-quinolin-8-yl-sulphonylamino)-3-methyl-benzofuran-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 41 0 of theory, C3aH28N405S x HCl (556.65/593.12) Mass spectrum: (M+H)' - 557 (M+2H)" - 279 ( M+H+Na ) '+ - 2 9 0 2 5 Fxamt~
4-[(6-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-3-methyl-benzofuran-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(6-(N-ethoxycarbon-ylmethyl-quinolin-8-yl-sulphonylamino-3-methyl-benzofuran-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol.
Yield: 83 % of theory, Cz8H24N405S x HCl (528.6/565.06) Mass spectrum: (M+H)' - 529 (M+Na)' - 551 (M+H+Na)" - 276 Fxamnl .6 4-[(6-(Quinolin-8-yl-sulphonylamino)-3-bromo-benzofuran-2-yl)-methyl]-benzamidine-hydrochloride a. 4= (b n .ofura -yl m t- yl -han~n"; rr; ~ o 10.4 g (77.3 mmol) of 2-coumaranone are dissolved in 200 ml xylene and after the addition of 32 g (77.3 mmol) of 4-cyano-benzyl-triphenylphosphonium chloride and 8.7 g (77.3 mmol) of potassium-tert.butoxide the mixture is refluxed for 3 hours under a nitrogen atmosphere. The solvent is distilled off, the residue is taken up in ethyl acetate, combined with silica gel and concentrated by evaporation. Then it is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (8:2).
The desired fractions are combined and concentrated by evapo-ration.
Yield: 17.0 g (94 0 of theory), R~ value: 0.5 (silica gel; petroleum ether/ethyl acetate = 4:1) b. ~- (3-Bromo-hPn .nf»ran-7-girl )~~~1 -han~nn; r,.~; ~ o '. 25 To a solution of 1.2 g (5 mmol) of 4-(benzofuran-2-yl)methyl-benzonitrile in 25 ml methylene chloride, a solution of 0.8 g (5 mmol) of bromine in 5 ml carbon tetrachloride is added drop-wise at 2°C. The solution is stirred for 90 minutes at 2°C, the precipitate formed is suction filtered, washed with a little methylene chloride and dried.
Yield: 1.1 g (70 % of theory), Rf value: 0.57 (silica gel; petroleum ether/ethyl acetate =
4:1) C. 4- (3-B_romo-6-ni tro-b n ofmran- -girl ) mPt-h~l -hPn~~n; r,.-; ~ o Prepared analogously to Example 262c from 4-(3-bromo-benzofu-ran-2-yl)-methyl-benzonitrile and tin(IV)chloride/fuming nitric acid in methylene chloride.
Yield: 30 0 of theory, Rf value: 0.71 (silica gel; methylene chloride) d. 4=(6-ami o-~-bromo-bPn~nfmran- -~r1 ) mPt-hyl -bPn oni 1-ri 1 P
Prepared analogously to Example 189d from 4-(3-bromo-6-nitro-benzofuran-2-yl)methyl-benzonitrile and Raney nickel/hydrogen in methylene chloride/methanol.
Yield: 59 0 of theory, Rf value: 0.25 (silica gel; methylene chloride) e. 4-[(6-(Quinolin-8-yl-sulphonylamino)-3-bromo-benzofuran-Prepared analogously to Example ld from 4-(6-amino-3-bromo-benzofuran-2-yl)methyl-benzonitrile and quinolin-8-sulphonic acid chloride in pyridine.
Yield: 93 a of theory, Rf value: 0.7 (silica gel; methylene chloride/ethanol - 95:5) f. 4-[(6-(Quinolin-8-yl-sulphonylamino)-3-bromo-benzofuran-~-girl) -mPth~rl1 -benzamidine-h~rdrorhl Sri r~P
Prepared analogously to Example le from 4-[(6-(quinolin-8-yl-sulphonylamino)-3-bromo-benzofuran-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 42 0 of theory, CZSHI9BrN403S x HC1 ( 53 5 . 44 /571 . 9 ) Mass spectrum: (M+H)' - 535/7 (Cl) 4-[(6-(1,2,3,4-tetrahydroquinolin-8-yl-sulphonylamino)-3-bromo-benzofuran-2-yl)-methyl]-benzamidine and 4-[(6-(1,2,3,4-tetra-hydroquinolin-8-yl-sulphonylamino)-benzofuran-2-yl)-methyl]-benzamidine 0.18 g (0.336 mmol) of 4-[(6-(quinolin-8-yl-sulphonylamino)-3-bromo-benzofuran-2-yl)-methyl]-benzamidine-hydrochloride are dissolved in 10 ml methanol and after the addition of 200 mg palladium on activated charcoal hydrogenated with hydrogen for 60 minutes. The catalyst is filtered off, the solvent concen-trated by evaporation. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol/glacial acetic acid 95:5:0.1 and 90:10:0.1. The desired fractions are combined and concentrated by evaporation.
Yield: 30 mg (18 a of theory) CzsHa3Bz'N403S ( 53 9 . 4 7 ) Mass spectrum: (M2+H)' - 539/41 (Br) C25H24N403S (460.57) Mass spectrum: (M1+H)~ - 461 as a mixture in the ratio 1:1.
4-[(6-(N-ethoxycarbonylmethyl-quinolin-8-yl)-sulphonylamino)-3-bromo-benzofuran-2-yl)-methyl]-benzamidine-hydrochloride a. 4-[(6-(N-ethoxycarbonylmethyl-quinolin-8-yl)-sulphonyl-amino-3-bromo-h n .of Aran- -girl 1 -me hurl 1 -ben oni tri 1 P
1.0 g (2 mmol) of 4-[(6-(quinolin-8-yl-sulphonylamino)-3-bromo-benzofuran-2-yl)-methyl]-benzonitrile are dissolved in 20 ml absolute tetrahydrofuran and after the addition of 100 mg (2 mmol) of sodium hydride (50a in oil) stirred for 20 minutes at ambient temperature. Then 0.22 ml (2 mmol) of ethyl bromo-acetate are added under a nitrogen atmosphere. The reaction mixture is refluxed for 6 hours, cooled, diluted with ethyl acetate and washed with sodium chloride solution. The combined organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with petro-leum ether/ethyl acetate (90:10 and 75:25). The desired frac-tions are combined and concentrated by evaporation.
Yield: 420 mg (35 0 of theory), Rf value: 0.55 (silica gel; petroleum ether/ethyl acetate =
l:l) b. 4-[(6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino) - Prepared analogously to Example le from 4-[(6-(N-ethoxycarbon-ylmethyl-quinolin-8-yl-sulphonylamino)-3-bromo-benzofuran-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium car-bonate in ethanol.
Yield: 43 % of theory, C29H25BrN405S x HCl (621.53/658.0) Mass spectrum: (M+H)' - 621/23 (Br) 2 0 F~xamy 4-[(6-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-3-ethoxy-benzofuran-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(6-(N-ethoxycarbon-ylmethyl-quinolin-8-yl-sulphonylamino)-3-bromo-benzofuran-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol.
Yield: 90 % of theory, 3O C29HzsN4OsS x HC1 (558.63/595.09) Mass spectrum: (M+H)' - 559 (M+Na)' - 5816 4-[(5-(2-ethoxycarbonyl-ethyl-benzimidazol-1-yl)methyl-1-me thyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride a. Fth~rl_ 3- (1 H-b n .i mi da~nl - -girl ) -proz i c~nafiP
hydrogen chloride gas is introduced into a suspension of 10 g (52.5 mmol) of 2-benzimidazole-propionic acid refluxing in 250 ml absolute ethanol over 1 hour. Then the mixture is concentra-ted by evaporation, the residue is dissolved in water and made alkaline with concentrated ammonia. Then it is extracted with ethyl acetate, the combined organic extracts are washed with water, dried and concentrated by evaporation.
Yield: 10.2 g (89 a of theory).
b. Ethyl 3-[1-(4-chloro-3-vitro-benzyl)-1H-benzimidazol-2-yl]-Prepared analogously to Example 231b from ethyl 3-(1H-benz-midazol-2-yl)-propionate, 4-chloro-3-vitro-benzylester methane-sulphonate and potassium-tert.butoxide in dimethylsulphoxide.
Yield: 75 % of theory, Rf value: 0.54 (silica gel; methylene chloride/ethanol - 19:1) c. N-methyl-3-[1-(4-methylamino-3-vitro-benzyl)-1H-benzimida-zQl--~-yl 1 -r~rot~i onami d Prepared analogously to Example 7b from ethyl 3-[1-(4-chloro-3-nitro-benzyl)-1H-benzimidazol-2-yl]-propionate and methylamine solution at 80°C.
Yield: 99 % of theory, Rf value: 0.21 (silica gel; methylene chloride/ethanol - 19:1) d. 3-[1-(4-methylamino-3-vitro-benzyl)-1H-benzimidazol-2-yl]-mror~ioni a i d 4.5 g (12.2 mmol) of N-methyl-3-[1-(4-methylamino-3-vitro-ben-zyl)-1H-benzimidazol-2-yl]-propionamide are stirred in 100 ml semiconc. hydrochloric acid for 3 hours at 100°C. Then the mix-ture is cooled, the precipitated product is suction filtered, washed with water and dried.
Yield: 4.1 g (95 % of theory), Rf value: 0.12 (silica gel; methylene chloride/ethanol = 19:1) e. Ethyl 3-[1-(4-methylamino-3-nitrobenzyl)-1H-benzimidazol-2-Prepared from 3-[1-(4-methylamino-3-nitro-benzyl)-1H-benzi-midazol-2-yl]-propionic acid and hydrochloric acid gas in ethanol.
Yield: 93 0 of theory, Rf value: 0.33 (silica gel; methylene chloride/ethanol = 19:1) f. Ethyl 3-[1-(3-amino-4-methylamino-benzyl)-1H-benzimidazol-2-~rll- rot~ionate Prepared analogously to Example lc from ethyl 3-[1-(4-methyl-amino-3-nitro-benzyl)-1H-benzimidazol-2-yl]-propionate and palladium on activated charcoal in methanol/methylene chloride.
Yield: 100 a of theory, g. 4-[(5-(2-ethoxycarbonyl-ethyl-benzimidazol-1-yl)methyl-1-meth~rl_-1H-benzimi o3azc~1 - -girl ) -m thyl ] -b n oni tri 1 P
Prepared analogously to Example 24f from ethyl 3-[1-(3-amino-4-methylamino-benzyl)-1H-benzimidazol-2-yl]-propionate, 4-cyano-~-25 phenylacetic acid and N,N'-carbonyldiimidazole in tetrahydrofu-ran, glacial acetic acid.
Yield: 100 0 of theory.
h. 4-[(5-(2-ethoxycarbonyl-ethyl-benzimidazol-1-yl)methyl-1-me-~htzl-1H-benzi mi c3azol -7-vl 1 -mPth~rl l -hAn~am; ~; "A-h~rr~rnr~hl !".-;
r7o Prepared analogously to Example le from 4-[(5-(2-ethoxycarbon-yl-ethyl-benzimidazol-1-yl)methyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbo-nate in ethanol.
Yield: 58 0 of theory, C29H30N6~2 x HC1 ( 4 94 . 6 / 5 31 . 0 7 ) Mass spectrum: (M+H)' - 495 (M+2H)" - 248 (2M+H)+ - 989 F~x~mpl_e 270 4-[(5-(2-carboxy-ethyl-benzimidazol-1-yl)methyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride Prepared analogously to Example 13 from 4-[(5-(2-ethoxycarbon-yl- ethyl-benzimidazol-1-yl)methyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol.
Yield: 78 % of theory, Cz.,H26N60z x HC1 ( 4 6 6 . 5 5 / 5 0 3 . 01 ) Mass spectrum: (M+H)' - 467 (M+Na) + - 489 4-[(5-(imidazol-1-yl-methyl)-1-methyl-1H-benzimidazol-2-yl)-me-thyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[(5-(imidazol-1-yl-methyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 52 a of theory, C20H20N6 x HC1 (344 .4/380.9) Mass spectrum: (M+H)' - 345 (M+2H) " - 173 4-[(5-(2-ethyl-4-methyl-imidazol-1-yl-methyl)-1-methyl-1H-benz-imidazol-2-yl)-methyl]-benzamidine-dihydrochloride Prepared analogously to Example le from 4-[(5-(2-ethyl-4-me-thyl-imidazol-1-yl-methyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 30 % of theory, C2aHzsNs x 2 HCl (386.5/459.42) Mass spectrum: (M+H)+ - 387 (M+2H)" - 194 ~= 1 7 ~
4-[[5-(1-methyl-pyrazol-5-yl-carbonyl-cyclopropan-1-yl)-1-me-thyl-1H-benzimidazol-2-yl]-methyl]-benzamidine-hydrochloride Prepared analogously to Example le from 4-[[5-(1-methyl-pyra-zol-5-yl-carbonyl-cyclopropan-1-yl)-1-methyl-1H-benzimidazol-2-yl]-methyl]-benzonitrile and hydrochloric acid/ammonium car-bonate in ethanol.
Yield: 14 0 of theory, C24H24N6~ x HC1 (412.5/448.96) Mass spectrum: (M+H)+ = 413 4-[[5-(3-Methyl-5-(furan-2-yl)-pyrazol-1-yl)-1-methyl-1H-benz-imidazol-2-yl]-methyl]-benzamidin-hydrochlorid Prepared analogously to Example le from 4-[[5-(3-methyl-5-(furan-2-yl)-pyrazol-1-yl)-1-methyl-1H-benzimidazol-2-yl]-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.

Yield: 84 0 of theory, C24H22rT6C x HCl (410.48/446.94) Mass spectrum: (M+H)+ = 411 F-xar~l E? X75 Dry ampoule containing 75 mg active substance per 10 ml Composition:
active substance 75,0 mg mannitol 50,0 mg water for injections ad 10,0 ml Preparation:
The active substance and mannitol are dissolved in water. After decanting the solution is freeze-dried. The product is dissol-ved with water for injections to prepare the finished solution ready for use.
Dry ampoule containing 35 mg active substance per 2 ml Composition:
active substance 35,0 mg mannitol 100,0 mg water for injections ad 2,0 ml Preparation:
The active substance and mannitol are dissolved in water. After decanting, the solution is freeze-dried. The product is dissol-ved with water for injections to prepare the finished solution ready for use.
Tablet containing 50 mg active substance Composition:
(1) active substance 50,0 mg (2) lactose 98,0 mg (3) maize starch 50,0 mg (4) polyvinylpyrrolidone 15,0 mg (5) magnesium stearate 2,0 mg 215,0 mg Preparation:
(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dry granules.
Tablets are compressed from this mixture, which are biplanar, facetted on both sides and have a dividing notch on one side.
Diameter of tablets: 9 mm.
Tablet containing 350 mg active substance Composition:
(1) active substance 350,0 mg (2) lactose 136,0 mg (3) maize starch 80,0 mg (4) polyvinylpyrrolidone 30,0 mg (5) magnesium stearate 4,0 mg 600,0 mg Preparation:
(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dry granules.
Tablets are compressed from this mixture, which are biplanar, facetted on both sides and have a dividing notch on one side.
Diameter of tablets: 12 mm.
Capsules containing 50 mg active substance Composition:
(1) active substance 50,0 mg (2) dried maize starch 58,0 mg (3) powdered lactose 50,0 mg (4) magnesium stearate 2,0 mg 160,0 mg Preparation:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with thorough blending.
This powdered mixture is packed into size 3 hard gelatine cap-sules in a capsule filling machine.

Capsules containing 350 mg active substance Composition:
(1) active substance 350,0 mg (2) dried maize starch 46,0 mg (3) powdered lactose 30,0 mg (4) magnesium stearate 4,0 mg "" 430, 0 mg Preparation:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with thorough blending.
This powdered mixture is packed into size 0 hard gelatine cap-sules in a capsule filling machine.
Suppositories containing 100 mg active substance 1 suppository contains:
active substance 100,0 mg polyethyleneglycol (M.W. 1500) 600,0 mg polyethyleneglycol (M.W. 6000) 460,0 mg polyethylenesorbitanmonostearate 840,0 mg 2 000,0 mg Preparation:
The polyethyleneglycol is melted together with polyethylensor-bitanmonostearate. At 40°C the ground active substance is homo-geneously dispersed in the melt. It is cooled to 38°C and pou-red into slightly chilled suppository moulds.

Claims (13)

Claims
1. 5-Membered heterocyclic condensed benzoderivatives of general formula wherein A denotes an oxygen or sulphur atom, a carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C1-3-alkyl group or a methylene group optionally mono- or di-substituted by a carboxy-C1-3-alkyl- or C1-3-alkoxy-carbonyl-C1-3-alkyl group, Ar denotes a phenylene or naphthylene group each optionally substituted by a fluorine, chlorine or bromine atom, by a tri-fluoromethyl, C1-3-alkyl- or C1-3-alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group each optionally substituted in the carbon skeleton by a C1-3-alkyl group, X denotes a nitrogen atom or an -R1C= group wherein R1 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a C1-3-alkyl or C1-3-alkoxy group, Y denotes an oxygen or sulphur atom or an -R2N- group, wherein R2 denotes a hydrogen atom or a C1-5-alkyl group, a C1-3-alkyl group, which is substituted by a phenyl group optionally substituted by a carboxy or C1-3-alkoxycarbonyl group, a C1-5-alkyl group, which is substituted by a carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkoxycarbonyl, C1-3-alkoxycarbonyl-C1-3-alkoxycarbonyl, carboxy-C1-3-alkyl-aminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group, or an n-C2-4-alkyl group, which is terminally substituted by a di-(C1-3-alkyl)-amino, pyrrolidino, piperidino, morpholino, piperazino or N-C1-3-alkyl-piperazino group, whilst the abovementioned cyclic groups may additionally be substituted by one or two C1-3-alkyl groups, R a denotes a hydrogen atom or a C1-3-alkyl group, R b denotes a R3-CO-C3-5-cycloalkylene, R3-SO2-NR4, R3-CO-NR4, R5NR6-CO, R5NR6-SO2- or R5NR6-CO-C3-5-cycloalkylene group, wherein R3 denotes a C1-6-alkyl- or C5-7-Cycloalkyl group, a C1-3-alkyl group, which is substituted by a C5-7,-cycloalkyl, phenyl, C1-3-alkylamino, di-(C1-3-alkyl)-amino, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonylamino, phenylsulphonylamino or tetrazolyl group, a C1-3-alkyl group, which is substituted by a carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkoxy or C1-3-alkoxy-carbonyl-C1-3-alkoxy group, a C1-3-alkyl group, which is substituted by an imidazolyl or benzimidazolyl group, whilst the imidazole moiety of the abovementioned groups may be substituted by one or two C1-3-alkyl groups or by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, a phenyl group optionally mono or disubstituted by C1-3-alkyl, C1-3-alkoxy, trifluoromethyl, carboxy or C1-3-alkoxycarbonyl groups, wherein the substituents may be identical or different, a phenyl group substituted by 3 or 4 methyl groups, a naphthyl, pyridinyl, pyrazolyl, quinolyl or isoquinolyl group each optionally substituted by a C1-3-alkyl group, R4 denotes a hydrogen atom, a C1-5-alkyl or C5-7-cycloalkyl group, a C1-5-alkyl group, which is substituted by a carboxy group or by a C1-5-alkoxycarbonyl group wherein the alkoxy moiety in the 2 or 3 position may additionally be substituted by a hydroxy group, a C1-3-alkyl group, which is substituted by an aminocarbonyl, hydroxyaminocarbonyl, C1-3-alkylamino-carbonyl, di-(C1-3-alkyl)-aminocarbonyl or C5-7-alkylene-iminocarbonyl group, whilst the C6-7-alkyleneimino moiety may additionally be substituted in the 4 position by a di-(C1-3-alkyl)-amino group, an optionally phenyl-substituted C1-3-alkyl group, which is substituted in the alkyl moiety by a carboxy-C1-3-alkoxy-carbonyl, C1-3-alkoxycarbonyl-C1-3-alkoxycarbonyl, carboxy-C1-3-alkylaminocarbonyl, N-(C1-3-alkyl)-carboxy-C1-3-alkyl-aminocarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl, N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl, morpholinocarbonyl or 4-(C1-3-alkyl)-piperazinocarbonyl group, a C1-3-alkyl group, which is substituted by a carboxy-C1-3-alkyl-aminocarbonyl, N-(C1-3-alkyl)-carboxy-C1-3-alkyl-aminocarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl or N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino-carbonyl group, which are additionally substituted at a carbon atom of the alkylamino moiety by a carboxy or C1-3-alkoxycarbonyl group, a C1-3-alkyl group, which is substituted by a di-(C1-3-alkyl)-aminocarbonyl group wherein an alkyl moiety may additionally be substituted in the 2 or 3 position by a di-(C1-3-alkyl)-amino group, a C1-3-alkyl group, which is substituted by a 4-(morpholinocar-bonyl-C1-3-alkyl)-piperazinocarbonyl, N-(C1-3-alkyl)-pyrrolidinyl or N-(C1-3-alkyl)-piperidinyl group, or an n-C2-4-alkyl group, which is terminally substituted by a di-(C1-3-alkyl)-amino, C5-7-alkyleneimino or morpholino group, R5 denotes a C1-5-alkyl or C5-7-cycloalkyl group, a phenyl-C1-3-alkyl group, which may be substituted in the alkyl moiety by a carboxy or C1-3-alkoxycarbonyl group, an n-C2-4-alkyl group, which is substituted in the 2, 3 or 4 position by a hydroxy, C1-3-alkyl amino or di-(C1-3-alkyl)-amino group, a phenyl group optionally mono or disubstituted by a C1-3-alkyl, C1-3-alkoxy, trifluoromethyl, carboxy or C1-3-alkoxycarbonyl group, wherein the substituents may be identical or different, a phenyl group substituted by 3 or 4 methyl groups, a naphthyl, pyridinyl, quinolyl or isoquinolyl group, R6 denotes a C1-5-alkyl group optionally substituted by a carboxy or C1-3-alkoxycarbonyl group, a C1-3-alkyl group, which is substituted in the alkyl moiety by a C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkyloxycarbonyl-C1-3-alkyl-aminocarbonyl group, or an n-C2-4-alkyl group, which is substituted in the 2, 3 or 4 position by a hydroxy, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, or one of the groups R5 or R6 denotes a hydrogen atom, whilst the other one of the groups has the meanings given for R5 and R6 hereinbefore, or R5 and R6 together with the nitrogen atom between them denote a pyrrolidino or piperidino group optionally substituted by one or two C1-3-alkyl groups, which may additionally be substituted by a carboxy-C1-3-alkyl or C1-3-alkoxy-C1-3-alkyl group or on to which a benzene ring may be condensed via two adjacent carbon atoms, or R b denotes an amino, C1-3-alkyl amino or C5-7-cycloalkyl-amino group, which may be substituted at the nitrogen atom by a phenylaminocarbonyl, N-phenyl-C1-3-alkylaminocarbonyl, phenylsulphonylamino-C1-3-alkylcarbonyl, C1-3-alkyloxy-carbonyl-C1-3-alkyl, N-(C3-5-cycloalkyl)-C1-3-alkyl amino-carbonyl, N-(hydroxycarbonyl-C1-3-alkyl)-aminocarbonyl, N-(C1-3-alkoxycarbonyl-C1-3-alkyl)-aminocarbonyl-C3-5-cyclo-alkylamino group, a piperidino group substituted in the 4 position by a di-(C1-3-alkyl)-amino group, a piperazino group substituted in the 4 position by a C1-3-alkyl group, a C2-4-alkylsulphonyl group, which is substituted in the 2, 3 or 4 position by a di-(C1-3-alkyl)-amino group, a 4-oxo-3,4-dihydro-phthalazinyl-1-yl or 4-oxo-2,3-diazaspiro [5.5]undec-1-en-1-yl group, a methyl group substituted by a C5-7-cycloalkyleneimino-carbonyl group wherein the methyl group is substituted by a carboxy-C1-3-alkyl or C1-3-alkoxy-C1-3-alkyl group, a carbonyl or methyl group substituted by a C3-5-cycloalkyl or C3-5-alkyl group, whilst the cycloalkyl moiety may additionally be substituted by a C1-3-alkyl, carboxy-C1-3-alkyl or C1-3-alkoxy-carbonyl-C1-3-alkyl group and the methyl moiety is substituted by a C1-3-alkoxy or C1-4-alkylamino group, a C5-7-cycloalkyl-N-(carboxy-C1-3-alkoxy)-iminomethylene or C5-7-cycloalkyl-N-(C1-3-alkoxycarbonyl-C1-3-alkoxy)-iminomethylene group, which may additionally be substituted in the cycloalkyl moiety by a C1-3 alkyl group, a phosphinyl group, which is substituted by a C1-5-alkyl or C5-7-cycloalkyl group and by a hydroxy, C1-3-alkoxy, carboxy-C1-3-alkoxy or C1-3-alkoxycarbonyl-C1-3-alkoxy group, a piperidino group wherein in the 2 position a methylene group is replaced by a carbonyl or sulphonyl group, a tetrazolyl group optionally substituted by a C1-5-alkyl group, a phenyl or phenylsulphonyl group optionally mono or disubstituted by a C1-3-alkyl, C1-3-alkoxy, trifluoromethyl, carboxy or C1-3-alkoxycarbonyl group, wherein the substituents may be identical or different, a sulphimidoyl group, which is substituted at the sulphur atom by a C5-7-cycloalkyl group and may additionally be substituted at the nitrogen atom by a C2-4-alkanoyl, carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl, carboxy-C2-4-alkanoyl or C1-3-alkoxycarbonyl-C2-4-alkanoyl group, an imidazolyl group substituted in the 1 position by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, which may additionally be substituted by a C1-5-alkyl group, a C1-3-alkoxycarbonyl-C1-3-alkyl group, which is substituted in the alkyl moiety by a C5-7-cycloalkylaminocarbonyl group, a C1-3-alkyl group, which is substituted by a 1-imidazolyl group, whilst the imidazolyl moiety may additionally be substituted by one or two C1-3-alkyl groups, or in the 2 position by a 1-benzimidazolyl group substituted by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, or a furanyl-1-pyrazolyl group optionally substituted by a C1-3-al-kyl group, and Rc denotes a cyano group or an amidino group, which may be substituted by a hydroxy group, by one or two C1-3-alkyl groups, by one or two C1-8-alkoxycarbonyl groups or by a group which can be cleaved in vivo, the tautomers, stereoisomers, mixtures thereof and salts thereof.
2. 5-Membered heterocyclic condensed benzoderivatives of general formula I as claimed in claim 1, wherein A, X, Y and R a to R d are with the proviso as defined in claim 1 that Ar represents a 1,4-phenylene group, R3 does not represent a pyrazolyl group or a naphthyl, pyridinyl, pyrazolyl, quinolyl or isoquinolyl group each substituted by a C1-3-alkyl group and R b does not represent a furanyl-1-pyrazolyl group optionally substituted by a C1-3-alkyl group, the tautomers, stereoisomers, mixtures thereof and salts thereof.
3. 5-Membered heterocyclic condensed benzoderivatives of general formula wherein A, X, Y and R a to R c are as hereinbefore defined in claim 1, the tautomers, stereoisomers, mixtures thereof and salts thereof.
4. 5-Membered heterocyclic condensed benzoderivatives of general formula Ia according to claim 2, wherein A denotes a methylene group optionally substituted by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, or a carbonyl or imino group, X denotes a nitrogen atom or an -R1C= group, wherein R1 denotes a hydrogen, fluorine, chlorine or bromine atom, a C1-3-alkyl or C1-3-alkoxy group, Y denotes an oxygen or sulphur atom or an -R2N- group, wherein R2 denotes a hydrogen atom or a C1-5-alkyl group, a benzyl group, which may be substituted in the phenyl moiety by a carboxy or C1-3-alkoxycarbonyl group, a C1-5-alkyl group, which is substituted by a carboxy or C1-3-alkoxycarbonyl group, a C1-3-alkyl group, which is substituted by a carboxy-C1-3-alk-oxycarbonyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkoxycar-bonyl-C1-3-alkylaminocarbonyl group, or an n-C2-4-alkyl group, which is terminally substituted by a di-(C1-3-alkyl)-amino or morpholino group, R a denotes a hydrogen atom or a methyl group, R b denotes an R3-CO-C3-5-cycloalkylene, R3-SO2-NR4, R3-CO-NR4, R5NR6-CO, R5NR6-SO2 or R5NR6-CO-C3-5-cycloalkylene group, wherein R3 denotes a C1-4-alkyl, cyclopentyl, cyclohexyl or benzyl group, a C1-3-alkyl group, which is substituted by a tetrazolyl, carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkoxy, C1-3-alkoxycar-bonyl-C1-3-alkoxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonylamino group, a phenyl group optionally mono or disubstituted by methyl, methoxy, trifluoromethyl, carboxy or methoxycarbonyl groups, wherein the substituents may be identical or different, a phenyl group substituted by 3 or 4 methyl groups, a 5-pyrazolyl group optionally substituted by a C1-3-alkyl group, a naphthyl, pyridinyl, quinolyl or isoquinolyl group, R4 denotes a hydrogen atom, a C1-5-alkyl or C5-7,-cycloalkyl group, a C1-5-alkyl group, which is substituted by a carboxy group or by a C1-5-alkoxycarbonyl group wherein the alkoxy moiety in the 2 or 3 position may additionally be substituted by a hydroxy group, a C1-3-alkyl group, which is substituted by an aminocarbonyl, hydroxyaminocarbonyl or piperidinocarbonyl group, whilst the piperidino moiety may additionally be substituted in the 4 position by a dimethylamino group, a C1-3-alkyl group, which is substituted by a carboxy-C1-3-alkyl-aminocarbonyl, N-(C1-3-alkyl)-carboxy-C1-3-alkyl-aminocarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl, N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl, morpholinocarbonyl or 4-(C1-3-alkyl)-piperazinocarbonyl group, a C1-3-alkyl group, which is substituted by a carboxy-C1-3-alkyl-aminocarbonyl, N-(C1-3-alkyl)-carboxy-C1-3-alkyl-aminocarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl or N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino-carbonyl group, which are additionally substituted at a carbon atom of the alkylamino moiety by a carboxy or C1-3-alkoxycarbonyl group, a C1-3-alkyl group, which is substituted in the alkyl moiety by a di-(C1-3-alkyl)-aminocarbonyl group wherein an alkyl moiety may additionally be substituted in the 2 or 3 position by a di-(C1-3-alkyl)-amino group, a C1-3-alkyl group, which is substituted in the alkyl moiety by a 4-(morpholinocarbonyl-C1-3-alkyl)-piperazinocarbonyl or N-(C1-3-alkyl)-pyrrolidinyl group, or an n-C2-3-alkyl group, which is terminally substituted by a di-(C1-3-alkyl)-amino, C5-7-alkyleneimino or morpholino group, R5 denotes a C1-5-alkyl or C5-7-cycloalkyl group, a phenyl-C1-3-alkyl group, which may be substituted in the alkyl moiety by a carboxy or C1-3-alkoxycarbonyl group, a phenyl, naphthyl, pyridinyl, quinolyl or isoquinolyl group and R6 denotes a C1-5-alkyl group optionally substituted by a carboxy or C1-3-alkoxycarbonyl group, a C1-3-alkyl group, which is substituted in the alkyl moiety by a C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkyloxycarbonyl-C1-3-alkyl-aminocarbonyl group, an n-C2-3-alkyl group, which is substituted in the 2 or 3 position by a C1-3-alkylamino or di-(C1-3-alkyl)-amino group, or one of the groups R5 or R6 denotes a hydrogen atom, whilst the other one of the groups has the meanings given for R5 and R6 hereinbefore, or R5 and R6 together with the nitrogen atom between them denote a pyrrolidino or piperidino group optionally substituted by a C1-3-alkyl, carboxy-C1-3-alkyl or C1-3-alkoxy-C1-3-alkyl group, onto which a benzene ring may additionally be condensed via two adjacent carbon atoms, or R b denotes an amino, methylamino, cyclopentylamino or cyclohexylamino group, substituted at the nitrogen atom by a phenylaminocarbonyl, N-phenyl-methylaminocarbonyl, phenylsulphonyl-aminomethylcarbonyl, hydroxycarbonylmethyl-aminocarbonyl or C1-3-alkyloxycarbonylmethylaminocarbonyl group, a piperidino group substituted in the 4 position by a di-(C1-3-alkyl)-amino group, a piperazino group substituted in the 4 position by a C1-3-alkyl group, a C2-3-alkylsulphonyl group, which is substituted in the 2 or 3 position by a di-(C1-3-alkyl)-amino group, a 4-oxo-3,4-dihydro-phthalazinyl-1-yl or 4-oxo-2,3-diazaspiro [5.5]undec-1-en-1-yl group, a carbonyl or methyl group substituted by a cyclopentyl, cyclohexyl or C3-5-alkyl group wherein the methyl moiety is substituted by a C1-3-alkoxy or C1-4-alkyl amino group and the cycloalkyl moiety may additionally be substituted by a methyl, carboxymethyl or C1-3-alkoxycarbonylmethyl group, a cyclohexyl-N-(carboxymethoxy)-iminomethylene or cyclohexyl-N-(C1-3-alkoxycarbonylmethoxy)-iminomethylene group, which may additionally be substituted by a methyl group in the cyclohexyl moiety, a phosphinyl group, which is substituted by a C3-6-alkyl group and by a hydroxy, C1-3-alkoxy, carboxymethoxy or C1-3-alkoxy-carbonylmethoxy group, a piperidino group wherein in the 2 position a methylene group is replaced by a carbonyl or sulphonyl group, a tetrazolyl group optionally substituted by a C1-5-alkyl group, a phenyl or phenylsulphonyl group optionally substituted by a methyl group, a sulphimidoyl group, which is substituted at the sulphur atom by a cyclohexyl group and may additionally be substituted at the nitrogen atom by a C2-4-alkanoyl, carboxymethyl, C1-3-alkoxy-carbonylmethyl, carboxy-C2-3-alkanoyl or C1-3-alkoxycarbonyl-C2-3-alkanoyl group, an imidazolyl group substituted in the 1 position by a carboxymethyl or C1-3-alkoxycarbonylmethyl group, which may additionally be substituted by a C1-5-alkyl group, a C1-3-alkoxycarbonyl-C1-3-alkyl group, which is substituted in the alkyl moiety by a C5-7-cycloalkylaminocarbonyl group, a C1-3-alkyl group, which is substituted by a 1-imidazolyl group, whilst the imidazolyl moiety may additionally be substituted by one or two C1-3-alkyl groups, or by a 1-benzimidazolyl group substituted in the 2 position by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, or a 5-furanyl-1-pyrazolyl group optionally substituted by a C1-3-alkyl group and R c denotes a cyano group or an amidino group, which may be substituted by one or two C1-3-alkyl groups, by one or two C1-8-alkoxycarbonyl groups or by a hydroxy group, the tautomers, stereoisomers and salts thereof.
5. 5-Membered heterocyclic condensed benzoderivatives of general formula I according to claim 1, wherein A denotes a methylene or imino group, X denotes a nitrogen atom or an -R1C= group, wherein R1 denotes a hydrogen, fluorine, chlorine or bromine atom or a methyl group, Y denotes an oxygen or sulphur atom or an -R2N- group, wherein R2 denotes a hydrogen atom, a methyl, benzyl, 4-carboxybenzyl or 4-methoxycarbonylbenzyl group, a C1-3-alkyl group, which is substituted by a carboxy or C1-3-alkoxycarbonyl group, a methyl group, which is substituted by a carboxymethylamino-carbonyl or C1-3-alkoxycarbonylmethylaminocarbonyl group or an n-C2-3-alkyl group, which is terminally substituted by a morpholino group, R a denotes a hydrogen atom, R b denotes an R3-CO- (l,1-cyclopropylene) , R3-SO2-NR4, R3-CO-NR4, R5NR6-CO, R5NR6-SO2 or R5NR6-CO-C3-5- (l,1-cyclopropylene) group, wherein R3 denotes a C1-3-alkyl, cyclopentyl or cyclohexyl group, a methyl group, which is substituted by a tetrazolyl, carboxy-methoxy, C1-3-alkoxycarbonylmethoxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonylamino group, a phenyl, naphthyl, pyridinyl, 1-methyl-5-pyrazolyl, quinolyl or isoquinolyl group, R4 denotes a hydrogen atom, a C1-3-alkyl or cyclopentyl group, a C1-5-alkyl group, which is substituted by a carboxy group or by a C1-3-alkoxycarbonyl group, a methyl group, which is substituted by a 4-dimethylamino-pi-peridinocarbonyl, morpholinocarbonyl, 4-methylpiperazino or 4-morpholinocarbonylmethyl-piperazinocarbonyl group, a C1-3-alkyl group, which is substituted by a carboxy-methyl-aminocarbonyl, N-(C1-3-alkyl)-carboxymethylamino-carbonyl, C1-3-alkoxycarbonylmethylaminocarbonyl or N-(C1-3-alkyl)-C1-3-alk-oxycarbonylmethylaminocarbonyl group, a C1-3-alkyl group, which is substituted by a di-(C1-3-alkyl)-aminocarbonyl group wherein an alkyl moiety is additionally substituted in the 2 or 3 position by a di-(C1-3-alkyl)-amino group, a C1-3-alkyl group, which is substituted by a carboxymethyl-aminocarbonyl or C1-3-alkoxycarbonyl-methylaminocarbonyl group wherein the methyl group of the methylamino moiety is additionally substituted by an aminocarbonylmethyl group, an n-C2-3-alkyl group, which is terminally substituted by a di-(C1-3-alkyl)-amino, pyrrolidino or morpholino group, R5 denotes a C1-5-alkyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridinyl, quinolyl or isoquinolyl group, R6 denotes a C1-5-alkyl group optionally substituted by a carboxy or C1-3-alkoxycarbonyl group, a C1-3-alkyl group, which is substituted by a C1-3-alkyl-amino-carbonyl, carboxymethylaminocarbonyl or C1-3-alkyloxy-carbonyl-methylaminocarbonyl group, or R5 and R6 together with the nitrogen atom between them denote a pyrrolidino group substituted by a carboxymethyl or C1-3-alkoxy-methyl group or a pyrrolidino group onto which a benzene ring is additionally condensed via two adjacent carbon atoms, or R b denotes an N-pyrrolidinocarbonyl-methylamino, phenylsulphonyl, 4-oxo-2,3-diaza-spiro[5.5]undec-1-en-1-yl or C3-5-alkyl-tetrazolyl group, a cyclohexylcarbonyl group, which is substituted by a methyl, carboxymethyl or C1-3-alkoxycarbonylmethyl group, a cyclohexyl-N-(carboxymethoxy)-iminomethylene or cyclohexyl-N-(C1-3-alkoxycarbonylmethoxy)-iminomethylene group, which is additionally substituted by a methyl group in the cyclohexyl moiety, a phosphinyl group, which is substituted by a C3-6-alkyl group and by a C1-3-alkoxymethoxy group, a sulphimidoyl group, which is substituted at the sulphur atom by a cyclohexyl group and additionally at the nitrogen atom by a C2-4-alkanoyl group, or a 3-methyl-5-(furan-2-yl)-1-pyrazolyl group, and R c denotes an amidino group, the tautomers, stereoisomers and salts thereof.
6. 5-Membered heterocyclic condensed benzoderivatives of gene-ral formula I according to claim 1, wherein A denotes a methylene group, X denotes a nitrogen atom or an -HC= group, Y denotes an oxygen or sulphur atom or an -R2N- group, wherein R2 denotes a hydrogen atom, a methyl, benzyl or C1-3-alkoxycar-bonylmethyl group, R a denotes a hydrogen atom, R b denotes an R5NR6-SO2, R5NR6-CO, R3-SO2-NR4, R3-CO-NR4 or R5NR6-CO-C3-5-(1,1-cyclopropylene) group, wherein R3 denotes a cyclopentyl, cyclohexyl, phenyl, naphthyl, 1-methyl-parazolyl, quinolyl or isoquinolyl group or a methyl group, which is substituted by a carboxymethylamino, C1-3-alk-oxycarbonyl-methylamino, carboxymethoxy, C1-3-alkoxycar-bonylmethoxy or tetrazolyl group, R4 denotes a hydrogen atom or a methyl group, substituted by a carboxy, C1-3-alkoxycarbonyl, morpholinocarbonyl, 4-dimethyl-amino-piperidinocarbonyl, 4-methyl-piperazinocarbonyl, 4-mor-pholinocarbonylmethyl-piperazinocarbonyl, carboxymethylamino-carbonyl, N-methyl-carboxymethylaminocarbonyl, C1-3-alkoxycar-bonylmethyl-aminocarbonyl, N-methyl-C1-3-alkoxycarbonylmethyl-aminocarbonyl, N-(C1-3-alkyl)-N-(2-dimethylamino-ethyl)-amino-carbonyl, N-(1-carboxy-2-aminocarbonyl-ethyl)-aminocarbonyl or N-(1-C1-3-alkoxycarbonyl-2-aminocarbonyl-ethyl)-aminocarbonyl group, or a cyclopentyl group, R5 denotes a C1-5-alkyl, phenyl or pyridyl group and R6 denotes a C1-5-alkyl group, which may be terminally substi-tuted by a carboxy or C1-3-alkoxycarbonyl group, or a C1-3-alkyl group substituted by a methylaminocarbonyl, carboxymethylamino-carbonyl or C1-3-alkoxycarbonylmethylaminocarbonyl group or sub-stituted in the 2 or 3 position by a dimethylamino group, or R5 together with R6 and the nitrogen atom between them denote a 1-methyl-5-pyrazolyl group, a pyrrolidino group optionally substituted by a C1-3-alkoxycarbonyl group or a pyrrolidino group onto which a benzene ring is condensed via two adjacent carbon atoms, or R b denotes a N-pyrrolidinocarbonyl-methylamino, phenylsul-phonyl, 4-oxo-2,3-diaza-spiro[5.5]undec-1-en-1-yl or C3-5-alkyl-tetrazolyl group, a cyclohexylcarbonyl group, which is substituted in the 1 posi-tion by a methyl, carboxymethyl or C1-3-alkoxycarbonyl-methyl group a cyclohexyl-N-(carboxymethoxy)-iminomethylene or cyclohexyl-N-(C1-3-alkoxycarbonylmethoxy)-iminomethylene group, which is additionally substituted in the cyclohexyl moiety by a methyl group, a phosphinyl group, which is substituted by a C3-6-alkyl group and by a C1-3-alkoxymethoxy group, and R c denotes an amidino group, the tautomers, stereoisomers and salts thereof.
7. 5-Membered heterocyclic condensed benzoderivatives of gene-ral formula I according to claim 1, wherein A denotes a methylene group, X denotes a nitrogen atom or an -HC= group, Y denotes an oxygen or sulphur atom or an -R2N- group, wherein R2 denotes a hydrogen atom, a methyl, benzyl or C1-3-alkoxycar-bonylmethyl group, R a denotes a hydrogen atom, R b denotes a R5 aNR6 a-SOZ group, wherein R5 a denotes a C1-3-alkyl or phenyl group and R6 a denotes a C15-alkyl group, which is terminally substituted by a carboxy or C1-3-alkoxycarbonyl group or is substituted in the 2 or 3 position by a dimethylamino group, or R5 a together with R6 a and the nitrogen atom between them denotes a pyrrolidino group optionally substituted by a C1-3-alkoxycar-bonyl group or a pyrrolidino group onto which a benzene ring is condensed via two adjacent carbon atoms, or an R3 a-SO2-NR4 a group, wherein R3 a denotes a cyclopentyl, cyclohexyl, phenyl, naphthyl, quinolyl or isoquinolyl group and R4 a denotes a hydrogen atom or a methyl group which is substituted by a carboxy, C1-3-alkoxycarbonyl, morpholinocarbonyl, 4-dimethylamino-piperidinocarbonyl, 4-methyl-piperazinocarbonyl, 4-morpholinocarbonylmethyl-piperazinocarbonyl, carboxymethylaminocarbonyl, N-methyl-carboxymethylaminocarbonyl, C1-3-alkoxycarbonylmethyl-aminocarbonyl, N-methyl-C1-3-alkoxycar-bonylmethylamino-carbonyl, N-(C1-3-alkyl)-N-(2-dimethylamino-ethyl)-aminocarbonyl, N-(1-carboxy-2-aminocarbonyl-ethyl)-aminocarbonyl or N-(1-C1-3-alkoxycarbonyl-2-aminocarbonyl-ethyl)-aminocarbonyl group, or an R5 b NR6 b-CO group, wherein R5 b denotes a C3-5-alkyl, phenyl or pyridyl group and R6 b denotes a C1-5-alkyl group or a C1-3-alkyl group, which is substituted by a carboxy, C1-3-alkoxycarbonyl, methylamino-carbonyl, carboxymethylaminocarbonyl or C1-3-alkoxycarbonyl-methylaminocarbonyl group or in the 2 or 3 position is also substituted by a dimethylamino group, or a R3 b-CO-NR4 b group, wherein R3 b denotes a phenyl group and R4 b denotes a C1-3-alkyl group, which is substituted by a carboxy or C1-3-alkoxycarbonyl group, or R3 b denotes a methyl group, which is substituted by a carboxymethylamino, C1-3-alkoxycarbonylmethylamino, carboxymethoxy, C1-3-alkoxycarbonylmethoxy or tetrazolyl group, and R4 b denotes a cyclopentyl group, or a R5 cNR6 c-CO-C3-5-(1,1-cyclopropylene) group, wherein R5 c together with R6 c and the nitrogen atom between them denotes a 1-methyl-5-pyrazolyl group, a pyrrolidino group optionally substituted by a C1-3-alkoxycarbonyl group or a pyrrolidino group onto which a benzene ring is condensed via two adjacent carbon atoms, or R b denotes a N-pyrrolidinocarbonyl-methylamino, phenylsul-phonyl, 4-oxo-2,3-diaza-spiro[5.5]undec-1-en-1-yl or C3-5-alkyl-tetrazolyl group, a cyclohexylcarbonyl group, which is substituted in the 1 posi-tion by a methyl, carboxymethyl or C1-3-alkoxycarbonyl-methyl group a cyclohexyl-N-(carboxymethoxy)-iminomethylene or cyclohexyl-N-(C1-3-alkoxycarbonylmethoxy)-iminomethylene group, which is additionally substituted in the cyclohexyl moiety by a methyl group, a phosphinyl group, which is substituted by a C3-6-alkyl group and by a C1-3-alkoxymethoxy group, and R c denotes an amidino group, the tautomers, the stereoisomers and the salts thereof.
8. The following 5-membered heterocyclic condensed benzoderi-vatives of general formula I according to claim 1:
(a) 4-[(5-(N-Carboxymethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine, (b) 4-[(5-(N-Carboxymethylaminoacetyl-quinolin-8-yl-sulphonyl-amino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine, (c) 4-[(5-(N-(2-Dimethylamino-ethyl)-benzenesulphonylamino)-1-benzyl-1H-benzimidazol-2-yl)-methyl]-benzamidine, (d) 4-[(5-(N-(2-Diethylamino-ethyl)-benzenesulphonylamino)-1-(carboxymethylaminocarbonyl)-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine, (e) 4-[(5-Pyrrolidino-sulphonyl-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine, (f) 4-[(5-(N-Cyclopentyl-methanesulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine, (g) 4-[(5-(N-Cyclopentyl-3-carboxypropionylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine, (h) 4-[(5-Pyrrolidinocarbonylcyclopropyl-1-methyl-1H-benzimid-azol-2-yl)-methyl]-benzamidine and (i) 4-[(5-(N-Carboxymethyl-quinolin-8-yl-sulphonylamino-benzo-thiazol-2-yl)-methyl]-benzamidine and the salts thereof.
9. Physiologically acceptable salts of the compounds according to claims 1 to 8 wherein R c denotes one of the amidino groups mentioned in claims 1 to 8.
10. Pharmaceutical compositions, containing a compound accor-ding to at least one of claims 1 to 8 wherein R c denotes one of the amidino groups mentioned in claims 1 to 8, or a salt accor-ding to claim 9 optionally together with one or more inert car-riers and/or diluents.
11. Use of a compound according to at least one of claims 1 to 8 wherein R c denotes one of the amidino groups mentioned in claims 1 to 8, or a salt according to claim 9 for preparing a pharmaceutical composition with a thrombin time-increasing effect, a thrombin-inhibiting effect and an inhibitory effect on related serine proteases.
12. Process for preparing a pharmaceutical composition accor-ding to claim 10, characterised in that a compound according to at least one of claims 1 to 8 wherein R c denotes one of the amidino groups mentioned in claims 1 to 8, or a salt according to claim 9 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
13. Process for preparing the compounds according to claims 1 to 8, characterised in that a) in order to prepare a compound of general formula I wherein R c denotes a cyano group and X denotes a nitrogen atom, a com-pound of general formula optionally formed in the reaction mixture wherein R a, R b, A, Ar and Y are defined as mentioned in claims 1 to 8, Z1 and Z2, which may be identical or different, denote amino, hydroxy or mercapto groups optionally substituted by alkyl groups having 1 to 8 carbon atoms or Z1 and Z2 together denote an oxygen or sulphur atom, an imino group optionally substituted by an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms, is cyclised, or b) in order to prepare a compound of general formula I wherein R b denotes a R3-SO2-NR4, R3-CO-NR4 or (R5NR6) CO-NR4 group and R c denotes a cyano group, a compound of general formula wherein R a, R4, A, Ar, X and Y are defined as mentioned in claims 1 to 8, is acylated with an acid of general formula R10 - W - OH , (V) wherein R10 has the meanings given for R3 to R6 in claims 1 to 8 and W denotes a carbonyl or sulphonyl group, or with the reactive derivatives thereof, or c) in order to prepare a compound of general formula I wherein R b denotes a R3-SO2-NR4 group and R c denotes a cyano group, a compound of general formula wherein R a, R3, A, Ar, X and Y are defined as mentioned in claims 1 to 8, is reacted with a compound of general formula R4 - Z3 , (VII) wherein R4 is defined as mentioned in claims 1 to 8 and Z3 denotes a nucleofugic leaving group, or d) in order to prepare a compound of general formula I wherein R b denotes one of the groups mentioned for R b in claims 1 to 8 which contains an alkylated phosphinyl and sulphimidoyl group, and R c denotes a cyano group, a compound of general formula wherein R a, R3, A, Ar, X and Y are defined as mentioned in claims 1 to 8 and R b' one of the groups mentioned for R b in claims 1 to 8 which contains a phosphinyl and sulphimidoyl group, is reacted with a compound of general formula Z4 - R22 ,( IX) wherein Z4 denotes a nucleofugic leaving group and R11 denotes one of the alkyl moieties which were mentioned in the definition of the alkylated phosphinyl and sulphimidoyl groups mentioned for the group R b in claims 1 to 8, or e) in order to prepare a compound of general formula I wherein R b denotes one of the groups mentioned for R b in claims 1 to 8, which contains an acylated sulphimidoyl group, a compound of general formula wherein R a, R c, A, Ar, X and Y are defined as mentioned in claims 1 to 8 and R b~ denotes one of the groups mentioned for R b in claims 1 to 8 which contains a sulphimidoyl group, is reacted with a compound of general formula HO - R12 ,(XI ) wherein R12 denotes one of the acyl moieties which were mentioned in the definition of the acylated sulphimidoyl groups given for the group R b in claims 1 to 8, or with the reactive derivatives thereof, or f) in order to prepare a compound of general formula I wherein R b denotes a R5NR6-CO, R5NR6-SO2, R5NR6-CO-C3-5-cycloalkylene or R5NR6-CO-NR4 group and R c denotes a cyano group, a compound of general formula wherein R a, A, Ar, X and Y are defined as mentioned in claims 1 to 8 and U denotes a HO-CO-C3-5-cycloalkylene, HO-CO or HO-SO2, or with the reactive derivatives thereof, is reacted with an amine of general formula (R5NR6) - H ,(XIII) wherein R5 and R6 have the meanings given in claims 1 to 8, or g) in order to prepare a compound of general formula I wherein R b denotes a R3-CO-C3-5-cycloalkylene group and R c denotes a cyano group, a compound of general formula wherein R a, A, Ar, X and Y are defined as mentioned in claims 1 to 8 and R b~ denotes an R3-(HCOH) -C3-5-cycloalkylene group, is oxidised, or h) in order to prepare a compound of general formula I wherein R b denotes one of the groups mentioned for R b in claims 1 to 8, which contains a methyl group linked to the adjacent bicyclic moiety, which is substituted with an optionally substituted amino group, a ketone of general formula wherein R a, R c, A, Ar, X and Y are defined as mentioned in claims 1 to 8 and R b"" denotes one of the groups mentioned for R b in claims 1 to 8, which is linked to the adjacent bicyclic moiety via a car-bonyl group, is reductively aminated with an amine of general formula H - R13 ,(XVI) wherein R13 denotes an optionally substituted amino group, such as those mentioned for R b in claims 1 to 8, if R b is linked with the adjacent bicyclic moiety via a methyl group substituted by an optionally substituted amino group, or i) in order to prepare a compound of general formula I wherein R b denotes one of the optionally substituted phenyl groups men-tioned for R b in claims 1 to 8 and R c denotes a cyano group, a compound of general formula wherein R a, A, Ar, X and Y are defined as mentioned in claims 1 to 8 and V denotes a trifluoromethanesulphonyloxy group, a bromine or iodine atom, is reacted with a compound of general formula R14 - Z5 (XVIII) wherein R14 denotes one of the optionally substituted phenyl groups mentioned for R b in claims 1 to 8 and Z5 denotes a boric acid group or a tri-(C1-3-alkyl)-tin group, or j) in order to prepare a compound of general formula I wherein R c denotes an amidino group, which may be substituted by one or two C1-3-alkyl groups, a compound of general formula optionally formed in the reaction mixture wherein R a, R b, A, Ar, X and Y are defined as mentioned in claims 1 to 8 and Z6 denotes an alkoxy, alkylthio, aralkoxy or aralkylthio group, is reacted with an amine of general formula H - R15NR16 (XX) wherein R15 and R16, which may be identical or different, each denote a hydrogen atom or a C1-3-alkyl group, or with a salt thereof, or k) in order to prepare a compound of general formula I wherein R c denotes an amidino group substituted by a hydroxy group, a nitrile of general formula wherein R a, R b, A, Ar, X and Y are defined as mentioned in claims 1 to 8, is reacted with hydroxylamine or the salts thereof, or 1) in order to prepare a compound of general formula I wherein R b contains a carboxy group and R c is defined as mentioned in claims 1 to 8 or R b is defined as mentioned in claims 1 to 8 and R c denotes an amidino group optionally substituted by a hydroxy group or by one or two C1-3-alkyl groups, a compound of general formula wherein R a, A, Ar, X and Y are defined as mentioned in claims 1 to 8 and R b" " ' and R c' have the meanings given for R b and R c in claims 1 to 8 , with the proviso that R b contains a group which can be converted into a carboxy group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and R c is defined as mentioned in claims 1 to 8 or R c denotes a group which can be converted by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into an amidino group optionally substituted by a hydroxy group or by one or two C1-3-alkyl groups and R b is as defined in claims 1 to 8, is converted by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into a compound of general formula I wherein R b contains a carboxy group and R c is defined as mentioned in claims 1 to 8 or R b is defined as mentioned in claims 1 to 8 and R c denotes an amidino group optionally substituted by a hydroxy group or by one or two C1-3-alkyl groups, or m) in order to prepare a compound of general formula I wherein R c denotes an amidino group, which is substituted by one or two C1-8-alkoxycarbonyl groups or by a group which can be cleaved in vivo, a compound of general formula I

wherein R a, R b, A, Ar, X and Y are defined as mentioned in claims 1 to 8 and R c denotes an amidino group, is reacted with a compound of general formula Z7 - R17 (XXIV) wherein R17 denotes a C1-8-alkoxycarbonyl group or the acyl moiety of one of the groups which can be cleaved in vivo mentioned in claims 1 to 8 and Z7 denotes a nucleofugic leaving group or a nitrophenyl group, and if necessary a protecting group used during the reactions to protective reactive groups is cleaved, and/or subsequently, if desired, a compound of general formula I thus obtained wherein R c denotes an amidino group may be converted, by reacting with a haloacetic acid derivative, by subsequent hydrolysis and decarboxylation, into a corresponding amidino compound substituted by one or two methyl groups, and/or a compound of general formula I thus obtained wherein R c denotes a hydroxyamidino group can be converted by catalytic hydrogenation into a corresponding amidino compound and/or a compound of general formula I thus obtained wherein R b contains a carboxy group can be converted by esterification into a corresponding ester and/or a compound of general formula I thus obtained wherein R b contains an O-alkyl-phosphinyl group can be converted by ether splitting into a corresponding phosphinyl compound and/or a compound of general formula I thus obtained wherein R b contains a halogen atom can be converted by dehalogenation into a corresponding dehalogenated compound and/or a compound of general formula I thus obtained wherein R b contains a quinolyl group may be converted by catalytic hydrogenation into a corresponding tetrahydroquinolyl compound, and/or if desired a compound of general formula I thus obtained is resolved into the stereoisomers thereof and/or a compound of general formula I thus obtained is converted into the salts thereof, particularly, for pharmaceutical use, into the physiologically acceptable salts thereof with an inorganic or organic acid or base.
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