CA2277949C - Disubstituted bicyclic heterocycles, the preparation and the use thereof as pharmaceutical compositions - Google Patents

Disubstituted bicyclic heterocycles, the preparation and the use thereof as pharmaceutical compositions Download PDF

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CA2277949C
CA2277949C CA002277949A CA2277949A CA2277949C CA 2277949 C CA2277949 C CA 2277949C CA 002277949 A CA002277949 A CA 002277949A CA 2277949 A CA2277949 A CA 2277949A CA 2277949 C CA2277949 C CA 2277949C
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methyl
amide
carboxylic acid
phenyl
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CA2277949A1 (en
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Norbert Hauel
Uwe Ries
Henning Priepke
Wolfgang Wienen
Jean-Marie Stassen
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Boehringer Ingelheim Pharma GmbH and Co KG
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    • C07D513/04—Ortho-condensed systems

Abstract

The invention relates to new disubstituted bicyclic heterocycles of the general formula (I): R a-A-Het-B-Ar-E, in which A, B, Ar, Het and R a are defined as in claim 1. The invention also relates to their tautomers, their stereoisomers, their mixtures, and their salts, which have valuable properties. The compounds of the above general formula (I), in which E is a cyano group, thus represent valuable intermediate products for the production of the other compounds of the general formula (I). Furthermore, the compounds of the above general formula (I), in which E stands for a R b NH-C(=NH)-group, have valuable pharmacological properties, in particular in inhibiting thrombin and prolonging thrombin time.

Description

S017002pct.200 Disubstituted bicyclic hete:rocycles, the preparation and the use thereof as pharmaceutical compositions The present invention relates. to new disubstituted bicyclic heterocycles of general formula --~ Ra - A - Het - H. - Ar - E , ( I ) the tautomers, stereoisomers and mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases which have valuable properties.
The compounds of general fortr~ula I above wherein E denotes a cyano group are valuable intermediates for preparing the other compounds of general formula I, and the compounds of general formula I above wherein E denotes an RbNH-C(=NH)-group, and the tautomers and stereoisomers thereof have -- useful pharmacological properties, particularly a thrombin-inhibiting activity and the effect of extending thrombin time.
The present application thus relates to the new compounds of general formula I above and the preparation thereof, pharmaceutical compositions containing the pharmacologically active comF~ounds and the use thereof.
In the above general formula A denotes a carbonyl or sulph.onyl group linked to the benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno moiety of the group Het, whilst moreover the abovementioned moieties may not contain an R., group, B denotes an ethylene group, wherein a methylene group, linked either to the group Het or Ar, may be replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl, carbonyl or -NR1 group, wherein R1 denotes a hydrogen atom or a C1_6-alkyl group, E denotes a cyano or RbNH-C(=NH)- group wherein Rb denotes a hydrogen atom, a hydroxy group, a Cl_3-alkyl group or a group which may be cleaved in vi vo, Ar denotes a phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom or by a trifluoromethyl, Cl_3-alkyl or Cl_3-alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C1_3-alkyl group, Het denotes a bicyclic heterocycle of formula X
Y Il , , wherein X is a nitrogen atom and Y is an oxygen or sulphur atom or a nitrogen atom optionally substituted by a Cl_6-alkyl or C3_,-cycloalkyl group, whilst additionally one or two non-angular methyne groups in the phenyl moiety of the above-mentioned bicyclic heterocycle may each be replaced by a nitrogen atom, or X denotes a methyne group optionally substituted by the group R1, wherein R1 is as hereinbefore defined, and Y denotes a nitrogen atom optionally substituted by a C,_6-alkyl or C,_,-cycloal~:yl group, or Het denotes a group of the formula 'N I
\ ~ i N

Nw O
I ~ , N

N
,~- s I , rr \ Z
D
G or w ~~ N
wherein N

R1 is as hereinbefore defined, Z denotes an oxygen or ~~ulphur atom, one of the groups D or C~ denotes a nitrogen atom and the other group D or G denotes a methyne group, and Ra denotes a Cl_6-alkyl group, a C3_.,-cycloalkyl group optionally substituted by a C'1_3-alkyl group, wherein the Cl_3-alkyl group may additionally be substituted by a carboxyl group or by a group which may be converted in vivo into a carboxy group, or an R2NR3- group wherein R2 denotes a C1_4-alkyl group, which may be substituted by a carboxy, C1_6-alkylo~cycarbonyl, benzyloxycarbonyl, C1_3-alkylsulphonylaminocarbonyl , phenylsulphonylaminocarbonyl, trifluorosulphonylamino, trifluorosulphonylaminocarbonyl or 1H-tetrazolyl group, a CZ_q-alkyl group substituted by a hydroxy, phenyl-Cl_3-alkoxy, carboxy-Cl_3-alkyl amino, Cl_3-alkoxycarbonyl-Cl_3-alkylamino, N- (Cl_3-alkyl) -carboxy-Cl_3-alkyl amino or N- (Cl_3-alkyl) -Cl_3-alkoxycarbonyl-Cl_3' alkylamino group, whilst in the abovementioned groups the carbon atom in the a-position relative to the adjacent nitrogen atom may not be substituted, or a piperidinyl group optionally substituted by a CI_3-alkyl group and R3 denotes a hydrogen atom, a C1-6-alkyl group, a C3_~-cycloalkyl group optionally substituted by a C1-3-alkyl group, a C3-6-alkenyl or alkynyl group, wherein the unsaturated part may not be linked directly to the nitrogen atom of the RzNR3- group, a phenyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C1_3-alkyl or C1_3-alkoxy group, a benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl or imidazolyl group or RZ and R3 together with the nitrogen atom between them denote a 5- to 7-membered cycloalkyleneimino group, optionally substituted by a carboxy or C1-4-alkoxycarbonyl group, onto which a phenyl ring may additionally be fused.
According to one aspect of the present invention, there is provided a disubstituted bicyclic heterocycle of general formula Ra - A - Het - B - Ar - E, ( I ) wherein A denotes a carbonyl or sulphonyl group linked to the benzo, pyrido or thieno moiety of the group Het, -5a-B denotes an ethylene group in which the methylene group linked to the group Ar is optionally replaced by an oxygen or sulphur atom or by an -NR1- group, wherein R1 denotes a hydrogen atom or a C1-4-alkyl group, E denotes an RbNH-C (=NH) -group wherein Rb denotes a hydrogen atom, a hydroxy, C1_9-alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C1-3-alkoxycarbonyl, benzoyl, p-C1-3-alkyl-benzoyl or pyridinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C1_9-alkoxycarbonyl group is optionally substituted by a C1-3-alkyl-sulphonyl or 2- (C1-3-alkoxy) -ethyl group, Ar denotes a 1,4-phenylene group optionally substituted by a chlorine atom or by a methyl, ethyl or methoxy group or Ar denotes a 2,5-thienylene group, Het denotes a 1-(C1-3-alkyl)-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-(C1-3-alkyl) -2, 5-indolylene, 1- (C1-3-alkyl) -2, 5-imidazo [4, 5-b]pyridinylene, 3-(C1-3-alkyl)-2,7-imidazo[1,2-a]pyridinylene or 1-(C1-3-alkyl)-2,5-thieno[2,3-d]imidazolylene group and Ra denotes an R2NR3- group wherein R2 is a C1-4-alkyl group optionally substituted by a carboxy, C1-6-alkyloxycarbonyl, benzyloxycarbonyl, C1_3-alkylsulphonylaminocarbonyl or 1H-tetrazol-5-yl group, or a C2_4-alkyl group substituted by a hydroxy, benzyloxy, carboxy-C1_3-alkylamino, C1-3-alkoxycarbonyl-Cl-3-alkylamino, N- (C1-3-alkyl) -carboxy-C1-3-alkylamino or N- (C1_3-alkyl) -C1-3-alkoxycarbonyl-C1_3-alkylamino group, whilst in the abovementionied groups the carbon atom in the a-position to the adjacent nitrogen atom is not substituted, R3 denotes a C3_~-cycloalkyl group; a propargyl group, wherein the unsaturated part is not linked directly to the nitrogen atom of the R2NR3 group; a phenyl group optionally substituted by a fluorine or chlorine atom, or by a methyl o~ methoxy group, a pyrazoyl, pyridazolyl or pyridinyl group optionally substituted by a methyl group or RZ and R3 together with the nitrogen atom between them denote 274C0-188(S) -5b-a 5- to 7-membered cycloalkyleneimino group, optionally substituted by a carboxy or C1-9-alkoxycarbonyl group, to which a phenyl ring is optionally fused, or a tautomer, stereoisomer or salt thereof.
According to another aspect of the present invention, there is provided a disubstituted bicyclic heterocycle of general formula I or tautomer, stereoisomer or salt thereof as described herein, wherein R1 denotes a hydrogen atom or a methyl group, Rb denotes a hydrogen atom;
a hydroxy, C1_9-alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C1_3-alkylbenzoyl or nicotinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C1-9-alkoxycarbonyl group is optionally substituted by a C1_3-alkylsulphonyl or 2- (C1_3-alkoxy) -ethyl group, Het denotes a 1-methyl-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene, 1-methyl-2,5-imidazo[4,5-b]pyridinylene,3-methyl-2,7-imidazo[1,2-a]pyridinylene or 1-methyl-2,5-thieno[2,3-d]imidazolylene group, R2 denotes a C1_3-alkyl group optionally substituted by a carboxy, C1_6-alkoxycarbonyl, benzyloxycarbonyl, methylsulphonylaminocarbonyl or 1H-tetrazol-5-yl group, a CZ-3-alkyl group substituted by a hydroxy, benzyloxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl-C1_3-alkylamino, N- (C1-3-alkyl) -carboxy-C1-3-alkylamino or N- (C1-3-alkyl) -C1-3-alkoxycarbonyl-C1-3-alkylamino group, whilst in the abovementioned groups the carbon atom in the a-position to the adjacent nitrogen atom is not substituted, and R3 denotes a propargyl group, wherein the unsaturated moiety is not linked directly to the nitrogen atom of the R2NR3 group, a phenyl group optionally substituted by a fluorine or chlorine atom, or by a methyl or methoxy group, or R3 denotes a py:ridinyl group.

27400-188(S) -5c-According to still another aspect of the present invention, there is provided a disubstituted bicyclic heterocycle of general formula I or tautomer, stereoisomer or salt thereof as described herein, wherein A denotes a car~~onyl group linked to the benzo or thieno moiety of the group Het, R1 denotes a hydrogen atom or a methyl group, Rb is a hydrogen atom, a hydroxy, C1-9-alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-Cl._3-alkyl-benzoyl or nicotinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C1_9-alkoxycarbonyl group is optionally substituted by a methylsulphonyl or 2-ethoxy-ethyl group, Ar denotes a 1,4-phenylene group optionally substituted by a methoxy group or Ar denotes a 2,5-thienylene group, Het denotes a 1-methyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene or 1-methyl-2,5-thieno[2,3-d]imidazolylene group and R2 denotes a C1-3-alkyl group optionally substituted by a carboxy, C1_6-alkyloxycarbonyl, benzyloxycarbonyl, methylsulphonylaminocarbonyl or 1H-tetrazol-5-yl group, or a C2_3-alkyl group substituted by a hydroxy, benzyloxy, carboxy-C1_3-alkylamino, C1_3-alkoxycarbonyl-Cl_3-alkylamino, N- (C1_3-alkyl) -carboxy-C1_3-alkylamino or N- (C1_3-alkyl ) -C1_3-alkoxycarbonyl-C1_3-alkylamino group, whilst in the abovementioned groups the carbon atom in the a-position to the adjacent nitrogen atom is not substituted, and R3 denotes a phenyl group optionally substituted by a fluorine atom, or R3 denotes a 2-pyridinyl group.
The compounds of the above general formula I which contain a group capable of being cleaved in vivo are thus prodrugs and compounds of general formula I which contain two groups capable of being cleaved in vivo are so-called double prodrugs.

274C0-188(S) -5d-The phrase ~~a group which may be converted in vivo intc a carboxy group" denotes, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol, in which the alcoholic moiety is preferably a C1-6-alkanol, a phenyl-s C1-3-alkanol, a C3_9-cycloalkanol, wherein a CS_8-cycloalkanol may additionally be substituted by one or two Cl_,-alkyl groups, a CS_e-cycloalkanol, in which a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by a Cl_3-alkyl, phenyl-Cl_,-alkyl, phenyl-Cl_3-alkoxycarbonyl or C2_6-alkanoyl group, and the cycloalkanol moiety may additionally be substituted by one or two C1_3-alkyl groups, a C,_.,-cycloalkenol, a C3_5-alkenol, a phenyl-C3_5-alkenol, a C3_5-alkynol or phenyl-C,_5-alk~~nol, with the proviso that nc bond to the oxygen atom emanates from a carbon atom which carries a double or triple bond, a C3_8-cycloalkyl-X1_3-alkanol, a bicycloalkanol having a total of 8 to 10 carbon atoms, which may additionally be substituted in the bicycloalkyl moiety by one or two C1_3-alkyl groups, a 1,3-dihyd:ro-3-oxo-1-isobenzofuranol or an alcohol of formula R4-CO-O-(:R5CR6)-OH, wherein R4 denotes a Cl_e-alkyl, CS_.,-cycloalkyl, phenyl or phenyl-Cl_3-alkyl group, RS denotes a hydrogen atom, a Cl_3-alkyl, CS_.,-cycloalkyl or phenyl group and R6 denotes a hydrogen atom or a C1_3-alkyl group, or the phrase "a group which may be cleaved in vivo from an imino or amino group" denotes for example a hydroxy group, an acyl group such as a benzoyl- or pyridinoyl group or a C1-16-alkanoyl group such as t:he formyl-, acetyl-, propionyl-, butanoyl-, pentanoyl- or hexanoyl group, an allyloxycarbonyl group, a C1-1.6-alkoxycarbonyl group such as the methoxycarbonyl-, etho~s:ycarbonyl-, propoxycarbonyl-, isopropoxycarbonyl-, butoxycarbonyl-, tert.-butoxycarbonyl-, pentox~~carbonyl-, hexoxycarbonyl-, octyloxycarbonyl-, nonyloxycarbonyl-, decyloxycarbonyl-, _ 7 -undecyloxycarbonyl-, dodecyloxycarbonyl- or hexadecyloxycarbonyl group, a. phenyl-C1_6-alkoxycarbonyl group such as the benzyloxyca.rbonyl-, phenylethoxycarbonyl-or phenylpropoxycarbonyl group, a C1_3-alkylsulphonyl-C2_4-alkoxycarbonyl-, C1-3-alkoxy-C2_4-alkoxy-C2-4-alkoxycarbonyl- or R4C0-O-(R5CR6)-O-CO-group, wherein R4 to R6 are as hereinbefore defined.
Examples of preferred prodrug groups for a carboxy group include a C1_6-alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, ,,....
isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexylo:xycarbonyl or cyc-lohexyloxycarbonyl group or phenyl-C1_3-alkoxycarbonyl group such as the benzyloxyca:rbonyl group and for an imino or amino group a C1-g-alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropy:Loxycarbonyl, n-butyloxycarbonyl, n-pentyloacycarbonyl, n-hexyloxycarbonyl, cyclohexy:Loxycarbonyl, n-heptyloxycarbonyl, n-octyloaycarbonyl or n-nonyloxycarbonyl group, a phenyl-C1_3-alkoxycarbonyl -.
group such as the benzyloxycarbonyl group, a phenylcarbonyl group optionally substituted by a C1_3-alkyl group such as the benzoyl or 4-ethyl-benzoyl group, a pyridinoyl group such as the nicotinoyl group, a C1_3-alkylsulphonyl-n-C2_3-alkoxycarbonyl or C1_3--alkoxy-C2_3-alkoxy-C2_4-alkoxycarbonyl group such as the 2-methylsulphonylethoxycarbonyl or 2-(2-ethoxy)-ethoxycarbonyl group.
Moreover, the saturated alkyl and alkoxy moieties containing more than 2 carbon atoms as well as alkanoyl and unsaturated alkyl moieties containing more than 3 carbon .. g -atoms as mentioned in the foregoing definitions also include the branched isomers thereof such as for example the isopropyl, tert.-butyl and isobutyl group, etc.
Preferred compounds of the above general formula I, however, are those wherein A denotes a carbonyl or sulphonyl group linked to the benzo, pyrido, pyrimido, pyra.zino, pyridazino or thieno moiety of the group Het, whilst moreover the abovementioned moieties may not contain an R.1 group, B denotes an ethylene group, in which a methylene group, linked either to the group Het or Ar, may be replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl, carbonyl or -NR1- group, wheresin Rl denotes a hydrogen atom or a Cl_5-alkyl group, E denotes an RbNH-C(=NH)- group wherein Rb denotes a hydrogen atc>m, a hydroxy group, a Cl_3-alkyl group or a group which may be cleaved in vi vo, Ar denotes a phenylene group optionally substituted by a fluorine, chlorine or bromine atom or by a trifluoromethyl, Cl_3-alkyl or Cl_3-alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C,_3-alkyl group, Het denotes a bicyclic heterocycle of formula _ g _ / X
Y~' , wherein X is a nitrogen atom and Y is an oxygen or sulphur atom or a nitrogen atom optionally substituted b;y a Cl_6-alkyl or C3_,-cycloalkyl group, wh~~lst additionally one or two non-angular methyne groups in the phenyl moiety of the above-mentioned bicyclic heterocycle may each be replaced by a nitrogen ai:om, ,...
or X denotes a methyne group optionally substituted by the group R1, wherein R1 :is as hereinbefore defined, and Y denotes a nitrogen atom optionally substituted by a Cl_6-alkyl or C3_,-cycloalkyl group, or Het denotes a group of the formulae ".." / ~ N
N
Rl N ~O
i ~ , N

R1.
N ,' S ~ ~~
-N

~ ~ , ' Z
D
G
or ~~N
. wherein N
R:L
Rl is as hereinbefore de:Eined, Z denotes an oxygen or sulphur atom, one of the groups D or G denotes a nitrogen atom and the other group D or G denotes a methyne group, and R8 denotes a Cl_6-alkyl grc>up, a C3_.,-cycloalkyl group optionally substituted by a C1_3-alkyl group, wherein the Cl_3-alkyl group may additiona:Lly be substituted by a carboxyl group or by a group 'which may be converted in vivo into a carboxy group, or a RZNR3- group wherein - :L 1 -R2 denotes a C,_,-alkyl group, which may be substituted by a carboxy, C,_6-alkylo:~cycarbonyl, benzyloxycarbonyl, C1_3-alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, trifluorosulphonylamino, trifluorosulphonylaminocarbonyl or 1H-tetrazolyl group, a CZ_,-alkyl group substituted by a hydroxy, phenyl-Cl_,-alkoxy, carboxy-Cl_3-alkylamino, Cl_3-alkoxycarbonyl-Cl_3-alkylamino, N- (Cl_3-alkyl) -carboxy-C,_3-alkyl amino or N- (Cl_3-alkyl) -Cl_3-alkoxycarbonyl-Cl_3-,"", alkylamino group, whilst in the abovementioned groups the carbon atom in the a--position relative to the adjacent nitrogen atom may not be substituted, or a piperidinyl group optic>nally substituted by a Cl_3-alkyl group and R3 denotes a hydrogen atom, a Cl_6-alkyl group, a C3_,-cycloalkyl group optionally substituted by a Cl_3-alkyl group, a C3_6-alkenyl or alkynyl group, wherein the unsaturated part may not be linked directly to the nitrogen atom of the RZNR3- group, a phenyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C1_3-alkyl or Cl_3-alkoxy group, a benzy:L, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, :pyrazolyl, pyrrolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl or piperidinyl group or Rz and R3 together with the nitrogen atom between them denote a 5- to 7-membered cycloalkyleneimino group, optionally substituted by a carboxy or C1_,-alkoxycarbonyl group, onto which a phenyl ring may additionally be fused, particularly those compounds wherein Het denotes one of the abovementioned benzimidazolylene, benzothiazolylene, benzoxazo].ylene, indolylene, quinazolinylene, quinoxazolinonylene, imidazo[4,5-b]pyridinylene, imidazo[1,2-a]pyridinylene, thiazolo [5, 4-b] pyridinylene c>r thieno [2, 3-d] imidazolylene groups, the tautomers, the prodrugs, the double prodrugs, the stereoisomers and the salts thereof.
Particularly preferred compounds of general formula I above are those wherein A denotes a carbonyl or sulphonyl group linked to the benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno moiety of the group Het, whilst moreover the abovementioned moieties may not contain an R1 group, B denotes an ethylene group in which the methylene group linked to the group Ar may be replaced by an oxygen or sulphur atom or by an -NRl- group, wherein R1 denotes a hydrogen atom or a Cl_4-alkyl group, E denotes an RbNH-C(=NH)- group wherein Rb denotes a hydrogen atom, a hydroxy, C1_9-alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C1_3-alkoxycarbonyl, benzoyl, p-C1_3-alkyl-benzoyl or pyridinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C1_9-alkoxycarbonyl group may additionally be substituted by a C1_3-alkyl-sulfonyl or 2-(C1_3-alkoxy)-ethyl group, - :L 3 -Ar denotes a 1,4-phenylene group optionally substituted by a chlorine atom or by a methyl, ethyl or methoxy group or it denotes a 2,5-thienylene group, Het denotes a 1-(C1_3-alkyl)-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-(C1_3-alkyl)-2,5-indolylene, 1-(C1_3-alkyl)-2, 5-imidazo [4, 5-b] pyridinylen~e, 3- (C1_3-alkyl) -2,7-imidazo[1,2-a]pyridinylen or 1-(Cl_3-alkyl)-2,5-thieno[2,3-d]imidazolylene group and Ra denotes an RZNR3- group wherein Rz is a Cl_4-alkyl group substituted by a carboxy, C1_6-alkyloxycarbonyl, benzyloxycarbonyl, C1_3-alkylsulphonylaminocarbonyl or 1H-tetrazol-5-yl group, a C2_4-alkyl group substituted by a hydroxy, benzyloxy, carboxy-C1_3-alkylamino, C'1_3-alkoxycarbonyl-C1_3-alkylamino, N-(C1_3-alkyl)-carboxy-C1_3-alkylamino or N-(C1_3-alkyl)-C1_3-alk:oxycarbonyl-Cl_3-alkylamino "-.. group, whilst in the above:mentioned groups the carbon atom in the a-position to the adjacent nitrogen atom may not be substituted, R3 denotes a C3_7-cycloalkyl group, a propargyl group, wherein the unsaturated part may not be linked directly to the nitrogen atom of the R2NR3 group, a phenyl group optionally substituted by a fluorine or chlorine atom, or by a methyl or methoxy group, a pyrazolyl, py-ridazolyl or pyridinyl group optionally substituted by a methyl group or R2 and R3 together with the nitrogen atom between them denote a 5- to 7-membered. cycloalkyleneimino group, optionally substituted by a carboxy or C1-4-alk-oxycarbonyl group, to which a phenyl ring may additionally be fused, the tautomers, the stereoisomers and the salts thereof.
Most particularly preferred compounds of the above general formula I are those wherein '" A denotes a carbonyl or sulphonyl group linked to the benzo, pyrido or thieno moiety of the group Het, whilst moreover the abovementioned moieties may not contain an R1 group, B denotes an ethylene group in which the methylene group linked to the group Ar may be replaced by an oxygen or sulphur atom or by an -NR1- group, wherein R1 denotes a hydrogen atom or a methyl group, E denotes an RbNH-C(=NH)- group, wherein Rb denotes a hydrogen atom or a hydroxy, Cl_9-alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C1-3-alkyl-benzoyl or nicotinoyl group, whilst the ethoxy moiety in the 2-position of the abovement.ioned C,_9-alkoxycarbonyl group may additionally be: substituted by a Cl_3-alkylsulphonyl or 2- (Cl_3-alkoxy) -ethyl group, Ar denotes a 1,4-phenylene group optionally substituted by a chlorine atom or by a methyl, ethyl or methoxy group, or it denotes a 2,5-thienylene group, - :L 5 -Het denotes a 1-methyl-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene, 1-methyl-2,5-imidazo[4,5-b]pyridinylene, 3-methyl-2,7-imidazo[1,2-a]pyridinylene or 1-methyl 2,5-thieno[2,3-d]imidazolylene group and Ra denotes a R2NR3- group wherein R2 denotes a C1_3-alkyl group which may be substituted by a carboxy, Cl_6-alkyloxycarbonyl, benzyloxycarbonyl, '~ methylsulphonylaminocarbonyl or 1H-tetrazol-5-yl group, a C2_3-alkyl group substituted by a hydroxy, benzyloxy, carboxy-C1_3-alkylamino, C1_3-alkoxycarbonyl-C1_3-alkylamino, N-(C1_3-alkyl)-carboxy-C1_3-alkylamino or N-(Cl_3-alkyl)-C1_3-alkoxycarbonyl-C1_3-alkylamino group, whilst in the above:mentioned groups the carbon atom in the a-position to the adjacent nitrogen atom may not be substituted, and R3 denotes a propargyl group, wherein the unsaturated moiety may not be linked directly to the nitrogen atom of the R2NR3 group, a phenyl group optionally substituted by a fluorine or chlorine atom, or by a methyl or methoxy group, or denotes a pyridinyl group, particularly those wherein A denotes a carbonyl group linked to the benzo or thieno moiety of the group Het, B denotes an ethylene group wherein the methylene group attached to the group Ar may be replaced by an -NR1 group, wherein R1 denotes a hydrogen atom or a methyl group, E denotes an RbNH-C(=NH)- group wherein Rb is a hydrogen atom, a hydroxy, C1_9-alkoxycarbonyl, cyclohexyloxycarbonyl, besnzyloxycarbonyl, benzoyl, p-C1_3-alkyl-benzoyl or nicotinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C1_g-alkoxycarbonyl group may additionally be substituted by a methylsulfonyl or 2-ethoxy-ethyl group, Ar denotes a 1,4-phenylene group optionally substituted by a methoxy group, or denotes a 2,5-thienylene group, Het denotes a 1-methyl-2,5-be:nzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene or 1-methyl-2,5-thieno[2,3-d]imidazolylene group and Ra denotes an R2NR3- group wherein R2 denotes a C1_3-alkyl group which may be substituted by a carboxy, C1_6-alkylo:xycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl group, a C2_3-alkyl group substituted by a hydroxy, benzyloxy, carboxy-C1_3-alkylamino, C1_3-alkoxycarbonyl-C1_3-alkylamino, N-(C1_3-alkyl)-carboxy-C1_3-alkylamino or N-(C1_3-alkyl)-C1_3-alkoxycarbonyl-C1_3-alkylamino group, whilst in the abovE~mentioned groups the carbon atom in the a-position to the adjacent nitrogen atom may not be substituted, and - :L7 -R3 denotes a phenyl group optionally substituted by a fluorine atom, or denotes a 2-pyridinyl group, the tautomers, stereoisomers and the salts thereof.
The following are mentioned ass examples of particularly preferred compounds:
(a) 2-[N-(4-amidinophenyl)-am:inomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)-amide, (b) 2- [N- (4-midinophenyl) -N-methyl-aminomethyl] -benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (c) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (d) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl)-amide, (e) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide, (f) 1-Methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (g) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (h) 1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (i) 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5 yl-carboxylic acid-N-phenyl-l~f-(2-hydroxycarbonylethyl) amide, (j) 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide, -(k) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide, (1) 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (m) 1-Methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (n) 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (o) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-hydroxycarbonylethyl-N-methyl)-2-aminoethyl]-amide, (p) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide, (q) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide, (r) 1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (s) 1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (t) 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl)-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide and (u) 1-Methyl-2- [N- (4-amidinophenyl) aminomethyl] -thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, the tautomers, prodrugs, doub7_e prodrugs, stereoisomers and the salts thereof.
The new compounds may be prepared by methods known per se, for example by the following methods:
a. In order to prepare a compound of general formula I, wherein E denotes an RbNH-C (=N13) - group, wherein Rb is a hydrogen atom, a hydroxy or C1..3-alkyl group:
By reacting a compound of general formula Ra - A - He t - B - Ar -~ C ( =NH ) - Z 1 , ( I I ) optionally formed in the reaction mixture, wherein A, B, Ar, Het and Ra are as lzereinbefore defined and Z1 denotes an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthio group such as the methylthio, ethylthio, n-propylthio or benzylthio group, with an amine of general formula H2N - Rb~ ,(III) wherein ''-' Rb ~ denotes a hydrogen atom or a hydroxy or Cl_3-alkyl group.
The reaction is conveniently carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol/water, tetrahydrofuran or dioxane at: temperatures between 0 and 150°C, preferably at temperatures between 20 and 120°C, with a compound of general formula III or with a corresponding acid addition salt such as ammonium carbonate, for example.
A compound of general formula. II may be obtained, for ,... example, by reacting a compound of general formula I
wherein E denotes a cyano group, with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a trialkyloxonium salt such as triethyloxonium-tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 50°C, but preferably at 20°C, or a corresponding nitrile with hydrogen sulphide, appropriately in a solvent such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and subsequent alkylation of the resulting thioamide with a corresponding alkyl or aralkyl halide.

27400-188(S) b. In order~to prepare a compound of general formula I
wherein the Ra-A- group and E are as hereinbefore defined, with the proviso that the R8-A- group contains a carboxy group and E as hereinbefore defined or that the Ra-A- group is as hereinbefore defined and E denotes an NHZ-C(=NH)-group, or that the Ra=A- group contains a carboxy group and E denotes an NHZ-C(=NH)- group:
Converting a compound of general formula Ra' - A - Het - B - Ar - - E' , ( IV) wherein A, B, Ar and Het are as hereinbefore defined and the Ra'-A- group and E' have the meanings given for the Ra-A- group and E hereinbefore, with the proviso that the Ra'-A- group contains a group which may be converted into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and E is as hereinbefore defined or E' denotes a group which may be converted into an NHZ-C(=NH)- group by~hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and the Ra'-A- group has the meanings given for the Ra-A- group hereinbefore or the Ra'-A- group contains a group which may be converted into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and E' denotes a group which may be converted into an NH2-C(=NH)- group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis, is converted by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into a compound of general formula I, wherein the Ra-A- group and E are as hereinbefore defined, with the proviso that the Ra-A- group contains a carboxy group and E is as hereinbefore defined or the Ra-A- group has the meanings given above and E

denotes an NHZ-C(=NH)- group or the Ra-A- group contains a carboxy group and E denotes am NH2-C(=NH)- group.
Examples of groups which may be converted into a carboxy group include a carboxyl group protected by a protecting group and the functional derivatives thereof, e.g. the unsubstituted or substituted amides, esters, thioesters, trimethylsilylesters, orthoesters or iminoesters which may conveniently be converted into a carboxyl group by hydrolysis, ... the esters thereof with tertiary alcohols, e.g. the tert.butylester, which are conveniently converted into a carboxyl group by treatment with an acid or by thermolysis, and the esters thereof with aralkanols, e.g. the benzylester, which are conveniently converted into a carboxyl group by hydrogenolysis.
The hydrolysis is expediently carried out either in the presence of an acid such as h:Ydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence '""' 25 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/tetrahydrofuran or water/dioxane at temperatures between -10 and L20°C, e.g. at temperatures between room temperature and t:he boiling temperature of the reaction mixture.
If the Re'-A- group and/or E' in a compound of formula IV
contains the tert.-butyl or te:rt.-butyloxycarbonyl group, for example, these may also be: cleaved by treating with an acid such as trifluoroacetic acid, formic acid, p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, , ' - 23 -phosphoric acid or polyphosphoric acid, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethylether, tetrahydrofuran or dioxane, preferably at temperatures bEStween -10 and 120°C, e.g. at temperatures between 0 and 60°C, or thermally optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydroi:uran or dioxane and preferably in the presence of a catalytic quantity of an acid such as p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40 and 120°C.
If the Ra'-A- group and/or E' in a compound of formula IV
contains the benzyloxy or ben.zyloxycarbonyl group, for example, these may also be cleaved by hydrogenolysis in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50°C, e.g. at room temperature, under a hydrogen pressure of 1 to 5 bar.
c. In order to prepare a compound of general formula I
wherein the R8-A- group contains one of the ester groups mentioned in the definition o:f the Ra-A- group hereinbefore:
Reaction of a compound of general formula Ra" - A - Het - B - Ar - E , (V) wherein B, E, Ar and Het are as hereinbefore defined and the Ra"-A- group has the meanings given for the Ra-A- group hereinbefore, with the proviso that the Ra"-A- group contains a carboxyl group or a group which may be converted into a corresponding ester group by means of an alcohol, with an alcohol of general formula HO - R~ ,(VI) wherein R, is the alkyl moiety of one of the above-mentioned groups which may be cleaved in vivo, with the exception of the R6-CO-O- (RSCR6) - group for a carboxyl group, or with the formamide acetals thereof.
'"'~' or with a compound of general formula Z2 - Rg . (VII) ..
wherein RB denotes the alkyl moiety o:E one of the above-mentioned groups which may be cleaved in vivo, with the exception of the R6-CO-O- (RSCR6) - group for a carboxyl group and Zz denotes a leaving group such as a halogen atom, e.g. a chlorine or bromine atom.
The reaction with an alcohol of general formula VI is .~-~ conveniently carried out in a solvent or mixture of solvents such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, but preferably in an alcohol of general formula VI, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, e.g. in the presence o:E isobutylchloroformate, thionyl chloride, trimethylch:Lorosilane, hydrochloric acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole, triphenylphosphine/carbon tetrachloride or triphenylphosphine/diethylazodicarboxylate, optionally 27400-188(S) n the presence of a base such as potassium carbo~late, 1s~-ethyl-diisopropylamine or N,N-dimethylamino-pyridine, conveniently at temperatures between 0 and 150°C, preferably at temperatures between 0 and 80°C.
R7ith a compound of general formula VII the reaction ~s usefully carried out in a solvent such as meth~Tlene chloride, tetrahydrofuran, dio~~ane, dimethylsulphoxide, 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 tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which may act as solvent at the same time, 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.
d. In order to prepare a compound of general formula I
wherein Rb denotes a group which may be cleaved in vivo:
Reacting a compound of general formula Ra - A - Het - B - Ar - C(=NH) - NH2 ,(VIII) LJhere 1n Ra, A, Het , B and Ar are as hereini~efore def fined, wi th a compound of general formula 3 D z3 - R5 , ( IX) wherein RS denotes a group which may be cleaved in Yi vo and Z3 denotes a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom.

27400-188(S) The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dio}:ane, dimethylsulphoxide or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base, preferably at temperatures between 20°C and the boiling temperature of the solvent used.
With a compound of general formula IX, wherein Z3 denotes a nucleofugic leaving group, the reaction is preferably carried out in,'a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylfor-mamide or dimethylsulphoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium tart.-buto~:ide or N-ethyl-diisopropylamine at temperatures between 0 and 60°C.
e_ In order to prepare a compound of general formula I
wherein B denotes an ethylene group, in which a methylene group is replaced by a sulphinyl or sulphonyl group:
Oxidation of a compound of general formula Ra - A - Het - B' - Ar - E , (X) wherein A, E, Ar, Het and Ra are as hereinbefore defined and B' denotes an ethylene group, wherein a methylene group is replaced by a sulphenyl or sulphinyl group.
The oxidation is preferably carried out in a solvent or mixture of solvents, e.g. in water, water/pyridine, acetone, methylene chloride, glacial acetic acid, glacial acetic acid/acetic anhydride, dilute sulphuric acid or trifluoroacetic acid, and depending on the o}>idising agent used, at temperatures between -80 and 100°C.

In order to prepare a corresponding sulphinyl compound of general formula I oxidation is conveniently carried out with one equivalent of the oxidising agent used, e.g. with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20°C or in acetone at 0 to 60°C, with a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50°C or with m-chloroperbenzoic acid in methylene chloride, chloroform or dioxane at -20 to 80°C, with sodium metaperiodate in aqueous methanol or ethanol at -15 to 25°C, with bromine in glacial acetic acid or aqueous acetic acid, optionally in the presence of a weak base such as sodium acetate, with N-bromosuccinimide in ethanol, with tert.-butylhypochlorite in methanol at -80 to -30°C, with iodobenzodichloride in aqueous pyridine at 0 to 50°C, with nitric acid in glacial acetic acid at 0 to 20°C, witra chromic acid in glacial acetic acid or in acetone at 0 to 20°C and with sulphuryl chloride in methylene chloride' at -70°C, the resulting thioether chlorine complex is conveniently hydrolysed with aqueous ethanol.
In order to prepare a sulphonyl compound of general formula I, oxidation is carried out starting from a corresponding sulphinyl compound, conveniently with one or more equivalents of the oxidising agent used, or starting from a corresponding sulphenyl compound, conveniently with two or more equivalents of the oxidising agent used, e.g. with hydrogen peroxide in glacial acetic acid/acetic anhydride, trifluoroacetic acid or in formic acid at 20 to 100°C or in acetone at 0 to 60°C, with a peracid such as performic acid or with m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 60°C, with nitric acid in glacial acetic acid at 0 to 20°C, with chromic acid or potassium permanganate in glacial acetic acid, water/sulphuric acid or in acetone at 0 to 20°C. Thus, by carrying out oxidation, for example, starting from a corresponding sulphenyl compound, preferably in methylene chloride, by treating with a corresponding amount of m-chloroperbenzoic acid at temperatures between 20°C and the reflux temperature of the reaction mixture, a corresonding sulphonyl compound of genera7_ formula I is obtained which may still contain a small amount of the corresponding sulphinyl compound.
-.
f. In order to prepare a compound of general formula I
wherein E is a cyano group and B is an ethylene group in which a methylene group linked either to group Het or to Ar is replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl, carbonyl or -NR1- group:
Reacting a compound of general formula Ra - A - Het - U , (XI) with a compound of general formula ''~ V - Ar - C1V , (XI I ) wherein R8, A, Ar and Het are as herei.nbefore defined, one of the groups U or V denotes an HO-, HS-, HOSO-, HOSOZ-or HNR1- group and the other group denotes a Z3CH2- group, wherein R1 is as hereinbefore defined and Z3 denotes a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom.
The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulphoxide or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base, preferably at i:emperatures between 20°C and the boiling temperature of the solvent used.
g. In order to prepare a compound of general formula I, wherein E is a cyano group and Ra denotes an RZNR3- group:
Reacting a compound of generail formula H - A - Het - B - Ar - CN , (XI I I ) wherein A, B, Het and Ar are as hereinbefore defined, with an amine of general formula ~R2 H - N , (XIV) \R

wherein RZ and R3 are as hereinbefore defined, or with the reactive derivatives thereof.
The reaction of an acid of general formula XIII is optionally carried out in a solvent or mixture of solvents such as methylene chloride, d:imethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane or in a corresponding amine of general formula III, optionally in the presence of a dehydrating agent, e.g. in t:he presence of isobutyl-chloroformate, tetraethylorthocarbonate, trimethylortho-acetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, 30- phosphorus pentoxide, N,N'-dic:yclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-dicyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tet:ramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride and optionally with the addition of a base such ais pyridine, 4-dimethylamino-pyridine, N-methyl-morpholine: or triethylamine, conveniently 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 XIII such as the esters, imidazolides or halides thereof with an amine of general formula XIV is preferably carried out in a corresponding amine as solvent, '"~ optionally in the presence of another 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-methyl-morpholine at temperatures between 0 and 150°C, preferab:Ly at temperatures between 50 and 100°C.
h. In order to prepare a benzimidazolyl, benzothiazolyl or benzoxazolyl compound of general formula I wherein B
denotes an ethylene group:
Reacting a compound of genera:L formula ~2 Ra - A ~ . (XV) wherein Ra, A and Y are as hereinbefore defined, with a compound of general formula HO-CO - CH2CH2 - .Ar - E ,(XVI) wherein Ar and E are as hereinbefore defined, or with the reactive derivatives thereof.

The reaction is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, optionally in the presence of a dehydrating agent, e.g. in the presence of isobutylchloroformate, tetraethylortho-carbonate, trimethylorthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchloro-silane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-,.~. hydroxysuccinimide, N,N'-dicyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-:benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxy-benzotriazole, N,N'-carbonyld:iimidazole or triphenyl-phosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylamino-pyridine, 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 XVI such as the esters, imidazolides or halides thereof with an amine of general formula XV is preferably carried out in a solvent such as methylene chloride, ether or tetrahydrofuran and preferably in the presence of a tertiary organic' base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine, which may simultaneously be used as solvents, at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.
i. In order to prepare a quinoxalin-2-one compound of the general formula:

Reacting a compound of general formula ~2 Ra A ( , (XVI I ) wherein Ra, R1 and A are as hereinbefore defined, with a compound of general formula HO-CO - COCH2 - i~r - E , (XVI II ) wherein Ar and E are as hereinbefore defined, or with the reactive derivatives thereof.
The reaction is conveniently carried out in a solvent or mixture of solvents such as nnethylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, ethanol or dioxan, optionally in the preaence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl ort:hoacetate, 2,2-dimethoxypropane, tetrameahoxysilane, thionyl chloride, "., trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide:/N-hydroxysuccinimide, N,N'-dicyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,N'-carbonyldiimidazole 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 of between 0 and 150°C, preferably at temperatures of between 0 and 100°C.

- :33 -However, it is particularly preferred to carry out the reaction with a corresponding reactive compound of general formula XVIII such as the esters, imidazolides or halides thereof with an amine of general formula XVII in a solvent such as methylene chloride, ether, ethanol or tetrahydrofuran and optionally in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-onorpholine, which may simultaneously serve as solvent, at temperatures of between 0 and 150°C, preferably at temperatures of between 50 and ,.-. 100°C.
j. In order to prepare a compound of general formula I
wherein R2 denotes a C1_4-alk~rl group substituted by an alkylsulphonylaminocarbonyl group:
Reacting a compound of genera7_ formula R ' N - A - Het - B - Ar - E , ( IXX) wherein R3, A, B, E, and Het are as he:reinbefore defined and R2' denotes a C1-4-alkyl group substituted by a carboxy group, or the reactive derivatives thereof, with a salt of a compound of general formula Cl_3-Alkyl-S02-NH2 (XX) .
The reaction is preferably carried out with a corresponding reactive compound of general formula IXX such as the esters, imidazolides or halides thereof with a salt of a compound of general formula XX, preferably with an alkali metal salt thereof such as a stadium salt, in a solvent such as methylene chloride, ether, ethanol, tetrahydrofuran or dimethylformamide at temperatures between 0 and 150°C, preferably at temperatures of: between 50 and 100°C.
In the reactions described he:reinbefore, any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by means of conventional protecting groups which are removed by cleaving after the reaction.
For example, the protecting group for a hydroxy group may be the trimethxlsilyl, acetyl, benzoyl, tert.butyl, trityl, -- benzyl or tetrahydropyranyl group, the protecting group for a carboxyl group may be the trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group, and the protecting group for an amino, alkylamino or imino group may be the acetyl, trif:Luoroacetyl, benzoyl, ethoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group the phthalyl group may also be considered.
The optional subsequent cleaving of a protecting group may, for example, be carried out hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydro-furan/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether cleaving', e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group may for example be cleaved hydrogenolytically, e.g. using 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 hydrochloric acid, at temperatures between 0 and 50°C, but preferably at room temperature, under a hydrogen pressure of 1 to 7 b,ar, preferably 3 to 5 bar.
A methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cerium(IV)ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures between 0 and 50°C, but '"' preferably at room temperature.
However, a 2,4-dimethoxybenzy:l group is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane~, or ether.
A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine :such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, .-.
ethanol, isopropanol, toluenefwater or dioxane, at temperatures between 20 and 5G°C.
An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis-(triphenylphosphine)-palladium(O), preferably 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 room temperature and under inert gas, or by treating with a catalytic amount of tris-(triphenylphosphine)-rhodium(I)-chloride, in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-~ - 36 -diazabicyclo[2.2.2)octane, a.t temperatures between 20 and 70°C.
The compounds of general formulae II to XX used as starting materials, some of which are known from the literature, may be obtained by methods known from the literature and moreover their production is described in the Examples.
Thus, for example, a compound of general formula II is obtained by reacting a corresponding nitrile which in turn is convenientl~r obtained by processes f to h, with a ~-~ corresponding thio or alcohol in the presence of hydrogen chloride or bromide.
A compound of general formulae IV, V, VIII, X and IXX used as starting material is conveniently obtained according to a process of the present invention.
A starting compound of general formula XI in which U
denotes a halomethyl group i:~ conveniently obtained by cyclisation of a corresponding ester which is substituted in the o-position by a suitable halogen atom and a methoxyacetamido group, to farm a corresponding bicyclic 2-alkoxymethyl compound, optionally subsequent hydrolysis and optionally subsequent amidation of a resulting carboxylic acid with a corresponding amine, converting the alkoxymethyl compound thus obtained into the corresponding halomethyl compound, which can if necessary be subsequently converted into the desired compound by means of a suitable compound. If the cyclisation is carried out with a suitable carbonic acid derivative, a starting compound of general formula XI is obtained wherein U denotes a hydroxy, mercapto or amino group.
A starting compound of general formula XIII is obtained by cyclisation of a corresponding o-disubstituted ester, followed by saponification of the resulting ester and _ 37 _ subsequent amidation of the carboxylic acid thus obtained with a corresponding amine.
Furthermore, an imidazopyridi.ne substituted in the 5-position by a methyl group and obtained by cyclisation can be converted, via the corresponding N-oxide, into the corresponding hydroxymethyl compound which is converted by oxidation into the desired carboxylic acid of general formula XIII.
The compounds of general formulae III, VI, VII, IX and XII
-- used as starting materials are obtained by conventional methods, for example by reducing an aromatic ester substituted in the o-position by an optionally substituted amino group and a nitro group, and optionally subsequent cyclisation of the resulting o-diamino compound with a corresponding carboxylic acid.
Furthermore, the compounds of general formula I obtained may be separated into their enantiomers and/or diastereomers.
Thus, for example, the compounds of general formula I
obtained which occur in racemate form may be separated by "~ 25 methods known per se (see Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes, and compounds of general formula I having at least 2 asymmetric carbon atoms may be separated on the basis of their physical-chemical differences using known methods, e.g. by chromatography and/or fractional crystallisation, into the diastereomers thereof, which, if they occur in racemic form, may subsequently be separated into the enantiomers as mentioned above.
The separation of enantiomers is preferably effected by column separation on chiral pr~ases or by recrystallisation from an optically active solvent or by reacting with an optically active substance, e=specially acids and the activated derivatives thereof= or alcohols, which forms salts or derivatives such as e.g. esters or amides with the racemic compound, and separation of the diastereomeric salt mixture or derivative thus obtained, e.g. on the basis of their different solubilities, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids are, for example, the D- and L-forms of tartaric acid, and dibenzoyltartaric acid, di-o °~ tolyl tartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid and quinaldic acid. Examples of optically active alcohols include for example (+)- or (-)-menthol and examples of optically active acyl groups in amides include, for example, (+)- or (-)-menthyloxycarbonyl.
Moreover, the compounds of formula I obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Examples of suitable acids include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or malefic acid.
In addition, the new compounds of formula I thus obtained, if they contain a carboxyl group, may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, more particularly, for pharmaceutical use, into the physiologically acceptable salts thereof.
Examples of suitable bases include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine .and triethanolamine.

As already mentioned, the new compounds of general formula I and the salts thereof have valuable properties. Thus, the compounds of general forcr~ula I wherein E denotes a cyano group are valuable intermediate products for preparing the other compounds of general formula I and the compounds of general formula I wherein E denotes an RbNH-C(=NH)- group and the tautomers, the stereoisomers and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly a thrombin-inhibiting effect, an effect of prolonging the thrombin time and an inhibitory effect on related serine proteases ",~ such as e.g. trypsin, urokinase factor VIIa, factor Xa, factor IX, factor XI and factor XII, whilst a few compounds such as for example the compound of Example 16 simultaneously also have a slight inhibitory effect on thrombocyte aggregation.
For example, the following compounds:
A = 2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)-amide, B = 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol 5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonyl propyl)-amide, C = 1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid -N-F~henyl-N-(hydroxycarbonyl-methyl)-amide, D = 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, E = 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide, 27400-188(S) F = 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide and G = 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide were investigated as follows for their effects on thrombin time:
Materials: plasma, from human citrated blood.
Test thrombin (bovine), 30U/ml, Behring Werke, Marburg Diethylbarbiturate acetate buffer, ORWH 60/61, Behring Werke, Marburg TM
Biomatic B10 coagulometer, Sarstedt Method:
The thrombin time was determined using a Biomatic B10 coagulometer made by Messrs. Sarstedt.
As the test substance, 0.1 ml of human citrated plasma and 0.1 ml diethylbarbiturate buffer (DBA buffer) were added to the test strip prescribed by the manufacturer. The mixture was incubated for one minute at 37°C. The clotting reaction was started by the addition of 0.3 U test thrombin in 0.1 ml DBA buffer. The time is measured using the apparatus from the addition of the thrombin up to the cloy ting of the mixture. Mixtures to which o.1 ml of DBA
buffer were added were used as the controls.
According to the definition, a dosage-activity curve was used to determine the effective concentration of the substance, i.e. the concentration at which the thrombin time is double compared with the control.
The Table which follows contains the results found:
Substance Thrombin time (ED200 in ~M) 0.04 B 0.06 C 0.15 D 0.03 '~ E 0.09 0.03 G 0.03 By way of example, no acute toxic side effects were observed when compounds A, D, E and G were administered to rats in doses of up to 10 mg/k:g i.v. The compounds are thus well tolerated.
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 thrombotic diseases, such as for example the treatment of deep leg vein thrombosis, for preventing reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, for preventing coronary thrombosis, stroke and the occlusion of shunts or stents. In addition, the compounds according to the invention are suitable for antithrombotic support in thrombolytic treatment, such as for example with rt-PA or streptokinase, for preventing long-term restenosis after PT(C')A, for preventing metastasis and the growth of clot-dependent tumours and fibrin-dependent inflammatory processes.

The dosage required to achieve such an effect 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 30 mg/kg by oral route, in each case administered 1 to 4 times a day. For this purpose, the compounds of formula I
prepared according to the invention may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g.
with corn starch, lactose, glucose, microcrystalline l0 cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric,~acid, water, water/ethanol, water/glycerol, .-- water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearyl alcohol, carbox;rmethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The Examples which follow are: intended to illustrate the invention:

- ~4 3 -Preliminary remarks Unless otherwise specified, the Rf values were always determined using polygram silica gel plates produced by Messrs. E. Merck of Darmstadt.
The EKA mass spectra (electrospray mass spectra of cations) are described, for example, in ~~Chemie unserer Zeit 6, 308-316 (1991) .
Example 1 3-Methyl-2- (2- (4-amidinopheny:L) ethyl] -imidazo [4, 5-b] -pyridine-6-carboxylic acid -N~-phenyl-N-(2-ethoxycarbonylethyl)-amide a) Methyl 6-methylamino-5-nitr_o-nicotinate 1.6 g (7.4 mMol) of methyl 6-c:hloro-5-vitro-nicotinate (see Bernie et al. in J. Chem. Soc.. 1951, 2590) were stirred in 20 ml of 40% aqueous methylamine solution at room temperature for 30 minutes. The reaction mixture was then diluted with ice water, the yellow precipitate formed was filtered off and dried.
Yield: 1.2 g (80 % of theory), .-- 25 Rf value: 0.66 (silica gel; ethyl acetate/ethanol/glacial acetic acid = 90:5:5) b) Methyl 5-amino-6-methylamino-nicotinate To a solution of 3.1 g (15 mMol) of methyl 6-methylamino-5-vitro-nicotinate in 100 ml of ethanol/dichloromethane (3:1) was added 1 g of palladium on charcoal (10%) and the resulting suspension was hydrogenated at. room temperature under 5 bar of hydrogen pressure for 1.5 hours. The catalyst was then filtered off and the solvent was distilled off in vacuo. The crude oily product obtained was further reacted directly.
Yield: 2.4 g (92 % of theory), ' - 44 -Rf value: 0.44 (silica gel; ethyl acetate/ethanol/ammonia =
90:10:1) c) Methyl 5-f2-(4-cyanophenvl~ethylcarbonvlaminol-6-methvlamino-nicotinate A solution of 2.6 g (15 mMol) of 3-(4-cyanophenyl)propionic acid in 25 ml of absolute tetrahydrofuran was mixed with 2.4 g (15 mMol) of N,N'-carbonyldiimidazole and stirred for 20 minutes at room temperature. Then the imidazolide was mixed with a solution of 2.3 g (13 mMol) of methyl 5-amino-6-methylamino-nicotinate in :..>5 ml of dimethylformamide and .-..
heated for 3 hours to 100°C. After the removal of the solvent in vacuo the crude product obtained was taken up in ethyl acetate, the organic phase was washed with water and after drying over sodium sulphate it was again freed from solvent. The residue obtained was purified by flash chromatography (silica gel; gradient: dichloromethane to dichloromethane/ethanol = 19:1).
Yield: 2.1 g (50 0 of theory) of beige solid Rf value: 0.54 (silica gel; ethyl acetate/ethanol/ammonia =
90:10:1) d) Methylyl 3-methyl-2- 2-(4-cvanophenvl)ethyl imidazo f4 5-blp~~ridine-6-carboxyl ate A solution of 2 . 0 g (5 . 9 mMol l of methyl 5- [2- (4-cyanophenyl)ethylcarbonylamino]-6-methylamino-nicotinate in 50 ml glacial acetic acid was heated to 100°C for one hour.
After removal of the solvent t:he residue was taken up in dichloromethane, washed with rhodium hydrogen carbonate solution, dried with sodium sulphate and the solvent was distilled off again.
Yield: 1.7 g brown solid (89 ~c of theory), Rf value: 0.50 (silica gel; ethyl acetate/ethanol/ammonia =
90:10:1) e) 3-Methyl-2- f2- (4-cvanophenyl) ethvll imidazof4,5-b]pvridine-6-carboxylic acid A solution of 3 .2 g (10 mMol;l of methyl 3-methyl-2- [2- (4-cyanophenyl)ethyl]-imidazo[4.5-b]pyridine-6-carboxylate in 150 ml methanol was mixed with a solution of 1.5 g lithium hydroxide in 20 ml water and stirred for 24 hours at room temperature. Then the mixture was diluted with 50 ml of water, the alcohol was disti7.led off and the aqueous phase was washed with ethyl acetate:. After acidification with dilute hydrochloric acid the mixture was extracted several times with dichloromethane/me~thanol (9:1), the organic "~. phase was dried with sodium ~;ulphate and the solvent was distilled off.
Yield: 2.1 g beige solid (70 °s of theory), Rf value: 0.38 (silica gel; ethyl acetate/ethanol/ammonia - 50:45:5) f) 3-Methyl-2-f2-(4-cyanophenyl)ethyl]-imidazof4 5-bl-pvridine-6-carboxylic acid-N-phenyl-N-(2-ethoxvcarbonvl-ethyl)-amide A solution of 2.0 g (6.5 mMo1) of 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid in 100 ml dichloromethane was mixed with 20 ml thionyl chloride and refluxed for 2 hours. After the liquid components had been distilled off the crude product was taken up twice more in dichloromethane and the solvent was distilled off each time. The crude acid chloride thus obtained (2 g) was suspended in 100 ml of tetrahydrofuran and mixed with 1.2 g (6.5 mMo~.) of N-(2-ethoxycarbonyl-ethyl)aniline. Then within 5 minutes 0.73 g (7.2 mMol) of triethylamine were added dropwise. After 1 hour's stirring the solvent was distilled off in vacuo, the residue was taken up in ethyl acetate, the' organic phase was washed with water and dried with sodium sulphate. After distillation of the solvent and flash chromatography (silica gel; dichloromethane t.o dichloromethane/ethanol =
49:1) the desired compound was isolated as a brownish oil.

Yield: 1.9 g (65 % of theory), Rf value: 0.44 (silica gel; ~'thyl acetate/ethanol/ammonia =
90:10:1) g) 3-Methyl-2-f2-l4-amidinophenvl)ethvll-imidazof4 5-bl-pvridine-6-carboxylic acid-N-phenyl-N-(2-ethoxvcarbonyleth~rl)-amide 1.8 g (3.7 mMol) of 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were stirred into 100 1 of ethanol saturated with hydrogen chloride for 16 hours first at 0°C and then at room temperature until no more starting r.
material could be detected by thin layer chromatography.
Then the solvent was distillESd off, the oily residue was taken up in 50 ml of absolutE~ ethanol and mixed with 3.6 g (37 mMol) of ammonium carbonate. After 4 hours the solvent was distilled off in vacuo, t:he crude product obtained was purified by flash chromatography (silica gel; gradient:
dichloromethane/ethanol 19:1 to 4:1) and evaporated down again.
Yield: 1.6 g of beige solid (80 % of theory), Rf value: 0.30 (silica gel; ethyl acetate/ethanol/ammonia =
90:5:5) Example 2 3-Methyl-2- [2- (4-amidinophenyl) ethyl] -imidazo [4, 5-b] -pyridine-6-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide A solution of 535 mg (1.0 mMol) of 3-methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide in 10 ml ethanol was mixed with 5 ml of 2N sodium hydroxide solution and stirred for 2 hours at room temperature. Then the mixture was diluted with 10 m:1 water, the alcohol was distilled off, the aqueous phase was washed with 20 ml , ' _ 47 -ethyl acetate and acidified with concentrated hydrochloric acid, whereupon the desired compound was precipitated in the form of white crystals.
Yield: 375 mg (74 % of theory), Rf value: 0.23 (silica gel; ethyl acetate/ethanol/ammonia =
90:5:5) C26H26N6~3 (470.54) Mass spectrum: (M+H)+ = 471 Example 3 """"' 3-Methyl-2- [2- (4-amidinopheny.l) ethyl] -imidazo [4, 5-b]pyridin-6-yl-carboxylic acid-N- (2-pyridyl) -N- (2-methoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl) ethyl] -imidazo [4, 5-b] pyridin-6-yl-carboxylic acid-N- (2-pyridyl) -N- (2-metho:~cycarbonylethyl) -amide, methanolic hydrochloric acid, methanol and ammonium carbonate.
Yield: 75 % of theory, C26H27N7~3 (485.55) Rf value: 0.31 (silica gel; ethyl acetate/ethanol/ammonia 50:45:5) EKA mass spectrum: (M+H)+ = 486 Example 4 3-Methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acif.-N-phenyl-N-ethoxycarbonylmethyl-amide-hydrochloride Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-ethoxycarbonylmethyl-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Yield: 84 % of theory, C27H28N603 (484.56) Rf value: 0.44 (silica gel; a_thyl acetate/ethanol/ammonia - 50:45:5) EKA mass spectrum: (M+H)+ = 485 Example 5 3-Methyl-2- [2- (4-amidinophenyl) ethyl] -imidazo [4, 5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-hydroxycarbonylmethyl-amide-:hydrochloride Prepared analogously to Example 2 from 3-methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-ethoxycarbom,rlmethyl-amide-hydrochloride and sodium hydroxide solution.
Yield: 85 % of theory, C25H24N6~3 (456.51) Rf value: 0.19 (silica gel; ethyl acetate/ethanol/ammonia - 50:45:5) EKA mass spectrum: (M+H) + = 9:57 Example 6 2-[2-(4-amidinophenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl-2,3-dihydroindol-1-yl-carbonyl)-imidazo[4,5-b)pyridine-hydrochloride Prepared analogously to Example 1 from 2-[2-(4-cyanophenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl-2,3-dihydroindol-1-yl-carbonyl)-imidazo[4,5-b]pyridine, methanolic hydrochloric acid, methanol and ammonium carbonate.
Yield: 20 % of theory, C27H26N603 (482.54) Rf value: 0.30 (silica gel; ethyl acetate/ethanol/ammonia - ~49 -- 50:45:5) EKA mass spectrum: (M+H)+ = 483 Example 7 2-[2-(4-amidinophenyl)ethyl]-3-methyl-6-(2-carboxy-2,3-dihydroindol-1-yl-carbonyl)-imidazo[4,5-b]pyridine-hydrochloride Prepared analogously to Example 2 from 2-[2-(4-amidinophenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl-2,3-dihydroindol-1-yl-carbony:L)-imidazo[4,5-b]pyridine-hydrochloride and sodium hydroxide solution.
Yield: 90 % of theory, C26H24N6~3 (468.52) Rf value: 0.24 (silica gel; ethyl acetate/ethanol/ammonia - 50:45:5) EKA mass spectrum: (M+H)+ - x:69 ( M+Na ) + = 9: 91 Example 8 1-Methyl-2-[(4-amidinophenyl)oxymethyl]-"... imidazo[4,5-b]pyridin-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide a) 2-Amino-3-methylamino-6-methyl-pyridine 8.35 g (50 mMol) of 2-Methyl-5-methylamino-6-nitro-pyridine (Heterocycles 38, 529 (1994)) were dissolved in 300 1 ethyl acetate and hydrogenated with 1.5 g Raney nickel for 3.5 hours at room temperature. Then the catalyst was filtered off and the filtrate was evaporated down. After crystallisation of the result ing residue from petroleum ether, 5.75 g (84 % of theory) were obtained as olive-green crystals.
C7H11N3 (137.20) Melting point: 112-113°C
b) 1.5-Dimethvl-2-f(4-cvanophenyl)oxymethvll imidazof4,5-bl-pyridine 11.4 g (63 mMol) of 4-cyano-;phenoxyacetic acid were dissolved in 200 ml of absolute tetrahydrofuran and mixed at room temperature with 10.:2 g (63 mMol) of N,N'-carbonyldiimidazole. After 15 minutes at 60°C, 5.70 g (41.5 mMol) of 2-amino-3-metlzylamino-6-methyl-pyridine were added. After 2 hours at 60°C the solvent was distilled off and the crystalline residue was mixed with water, washed with water and~dried. After crystallisation from ethanol 9.95 g (91 % of theory) were obtained in the form of white crystals.
C16H14N40 (278.32) Mass spectrum: M+ = 278 c) 1, 5-Dimethyl-2- f (4-cyanophenvl) oxvmeth~rll -imidazo 4,5-blgyridin-4-N-oxide 2.62 g (10 mMol) of 1,5-dimethyl-2-[(4-cyanophenyl)-oxymethyl]-imidazo[4,5-b]pyridine were suspended in 125 ml dichloromethane and mixed with 2.62 g (12.7 mMol) of m-chloroperbenzoic acid, whereupon a clear solution was obtained. After 2 hours at room temperature the solvent "~' 25 was distilled off and the residue obtained was mixed with a sodium hydrogen carbonate solution. After 30 minutes the white crystalline product obtained was suction filtered, washed with water and dried a~~ 40°C.
Yield: 2.45 g (83 % of theory;l, C16H14N402 (294.30) Mass spectrum: M+ - 294 d) 1-Methyl-2-f(4-cyano~henyl)oxymethyll-5-hvdroxvmethvl-imidazof4,5-blpyridine 2.40 g (8.2 mMol) of 1,5-dimet:hyl-2-[(4-cyanophenyl)-oxymethyl]-imidazo[4,5-b]pyridin-4-N-oxide were suspended in 75 ml dichloromethane and mixed with 2.4 ml of trifluoroacetic acid anhydride (16.9 mMol), whereupon a clear solution was obtained. After 16 hours at room temperature the solvent was distilled off, the viscous residue obtained was taken up in 50 ml dichloromethane and covered with 50 ml of 2M sodium hydrogen carbonate solution. After 3 hours' vigorous stirring the precipitate formed was suction filtered, washed with water and dried at 40°C.
Yield: 1.85 g white powder (78 % of theory), C16H14N402 (294.30) Melting point: 172°C
e) 1-Methyl-2-f(4-cvanophenyl)oxvmethyll-imidazo 4 5-bl-pyridine-5-carbaldehyde 3.65 g (12.5 mMol) of 1-methyl-2-[(4-cyanophenyl)-oxymethyl]-5-hydroxymethyl-imidazo[4,5-b]pyridine were dissolved in 500 ml dichloromethane and mixed with 15.0 g of manganese dioxide. After :~6 hours at room temperature the mixture was filtered through kieselgur and the solvent was distilled off. The filtrate obtained was evaporated down, the crystalline precipit=ate was triturated with ether, suction filtered and dried.
Yield: 3.05 g white powder (8~6 % of theory), C16H12N4~2 (292.30) Melting point: 231-234°C
f) 1-Methyl-2-f(4-cyanophenyl)oxvmethyll-5-carboxy-imidazo-[4 . 5-b~ pvridine 1 .25 g (4.3 mMol) of 1-methyl-2- [ (4-cyanophenyl) oxymethyl] -imidazo[4,5-b]pyridine-5-carba.ldehyde were dissolved in 10 ml formic acid and mixed at 0°C with 1.0 ml hydrogen peroxide (33% strength). After 12 hours at 4°C the white precipitate formed was suction filtered, washed with water and dried at 40°C.
Yield: 0.81 g (61 % of theory) , C16H12N4~3 (308.7) ' , - 52 -g) 1-Methyl-2-f(4-cyanophenyl)oxymethyll-imidazof4 5-blpyridin-5-yl-c:arboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonvlethyl)-amide 308 mg (1.0 mMol) of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-5-carboxy-imidazo(4.5-b]pyri.dine were suspended in 5 ml of dimethylformamide and mixed with 303 mg (3.0 mMol) of N-methyl-morpholine and 321 mg (1.0 mMol) of O-(benzotriazol-1-yl)-N,N,N~,N~-tetramethyl-uronium tetrafluoroborate. After 10 minutes at room temperature a solution of 215 mg (1.2 mMol) of methyl N-(2-pyridyl)-3-amino-propionate in 2 ml of dimethylformamide was added, ,.... whereupon a clear solution was obtained. After 12 hours at room temperature the reaction solution was stirred into ice-water. After extracting 3 times with ethyl acetate the combined organic extracts were washed with a saline solution, dried over sodium aulphate and evaporated down.
The residue obtained was chromatographed on silica gel with dichloromethane/ethanol (90::1 to 25:1).
Yield: 165 mg of white powder (35 % of theory), C25H12N604 (407.50) Melting point: 139-140°C
h) 1-Methyl-2-f(4-amidinopheryl)oxymethyll-imidazo 4 5 b1 pvridin-5-yl-carboxylic acid--N- (2-pyridyl) -N- (2-ethoxycarbonyl-ethyl)-amide Prepared by reacting 140 mg 1;0.3 mMol) of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-imidazo[4,5-b]pyridin-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide with ethanol saturated by hydrogen chloride and with ammonium carbonate/ethanol analogously to Example 1g. The resulting product was purified by chromatography over silica gel with dichloromethane/ethanol (19:1 to 4:1).
Yield: 48 mg of white powder (36 % of theory), C26H27N704 (501.57) Mass spectrum: (M+H)+ = 502 Example 9 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide a) Ethvl 4-fluoro-3-methoxyacetamido-benzoate A solution of 2.8 g (15.3 mMol) of ethyl 3-amino-4-fluoro-benzoate (cf. L.S. Fosdick, A.F. Dodds in J. Amer. Chem.
Soc. 65, 2305 (1943)) and 1.56 ml (1.85 g = 17.0 mMol) of methoxyacetylchloride in 50 m:1 chlorobenzene was stirred for 1 hour at 50°C and then refluxed for 15 minutes. Then the solvent was distilled off in vacuo and the crude product obtained was purified by flash chromatography (silica gel; dichloromethane/e~thanol = 100:1). The desired compound, initially oily, solidified within a few days.
Yield: 3.8 g (98 % of theory),, Rf value: 0.38 (silica gel; dichloromethane/ethanol = 19:1) b) Ethyl-2-methox~rmethvl-benzothiazole-5-carboxylate A mixture of 3.0 g (11.7 mMol) of 4-fluoro-3-methoxyacetamido-benzoic acid and 2.1 g (5.2 mMol) of Lawesson's reagent was refluxe:d for 6 hours in 90 ml toluene, mixed with 1.0 g Laweason's reagent and heated to 120°C for another 6 hours. After the solvent was replaced with xylene the mixture was heated to 180°C for a further 8 hours in a pressurised vessel. Then the solvent was distilled off in vacuo, the crude product obtained was purified by flash chromatography (silica gel; ethyl acetate/petroleum ether = 5:95) and evaporated down again.
Yield: 2.1 g of yellow crystals (72 % of theory), Rf value: 0.55 (silica gel; ethyl acetate/petroleum ether =
3:7) c) 2-Methoxymethyl-benzothiazo:le-5-carboxylic acid A mixture of 2.1 g (8.36 mMol) of ethyl 2-methoxymethyl-benzothiazole-5-carboxylate and 16 ml of 2N sodium hydroxide solution was stirred into 60 ml ethanol for 1 CA 02277949 1999-07-14 .''- ~-.'~

hour at room temperature. Then the alcohol was distilled off, the crude product was taken up in 20 ml water, washed with 50 ml diethylether and the aqueous phase was acidified with concentrated hydrochloric acid whilst being cooled with ice. The pinkish-beige compound thereby precipitated was suction filtered, washed with water and dried.
Yield: 1.6 g (86 % of theory), Rf value: 0.12 (silica gel; dichloromethane/ethanol = 29:1) d) 2-Methoxymethyl-benzothia2:ole-5-carboxylic acid-N-phenvl-N-(2-ethoxycarbonylethyl)-amide .-.. A suspension of 1.6 g (7.2 mr!fol) of 2-methoxymethyl-benzothiazole-5-carboxylic acid in 60 ml dichloromethane was mixed with 1.6 ml (22 mMol) of thionyl chloride and refluxed for 1 hour. The solid dissolved after 20 minutes.
After distillation of the liquid components the crude product was taken up in dichloromethane twice more and each time the solvent was distilled off. The crude acid chloride thus obtained was taken up in 50 ml of tetrahydrofuran, added dropwise to a mixture of 1.4 g (7.2 mMol) of N-(2-ethoxycarbonylethyl)aniline and 3.0 ml (21 mMol) of triethylamine in 50 vml of tetrahydrofuran and stirred overnight at room temperature. Then the solvent was distilled off in vacuo, t:he residue was taken up in 30 ml of dichloromethane, this solution was washed with water and dried with sodium sulphates. After distillation of the solvent and flash chromatography (silica gel; gradient:
dichloromethane/ethanol 98.5::L.5 to 80:20) the desired compound was isolated as a brownish oil.
Yield: 2.05 (72 % of theory), Rf value: 0.40 (silica gel; ethyl acetate/petroleum ether =
1:1) e) 2- fN- (4-Cyanophe~l) -aminomethyll -benzothiazole-5-carboxylic acid-N=phenyl-N-(2-ethoxycarbonylethyl)-amide A mixture of 2.05 g (5.14 mMol.) of 2-methoxymethyl-benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and 5.7 ml (5.7 mMol) of a 1M
solution of boron tribromide in dichloromethane was dissolved in a further 60 ml of dichloromethane and stirred for 16 hours at room temperat=ure. Then the mixture was washed with 40 ml of saturated sodium hydrogen carbonate solution, the organic phase was dried with sodium sulphate and the solvent was distilled off. The crude 2-bromomethyl-benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide thus obtained (2.4 g) was taken up in 5.0 ml of N,N-diisopropyl-ethylamine and mixed with 0.64 g (5.4 mMol) of 4-amino-benzonitrile. After 1 hour's heating to 130°C the solvent was distilled off in vacuo and the crude product obtained was purified by flash chromatography (silica gel; gradient: ethyl acetate/petroleum ether = 1:3 to 1:1), whilst an orange foam was obtained when the eluates were evaporated down.
Yield: 1.1 g (44 % of theory), Rf value: 0.35 (silica gel; ethyl acetate/petroleum ether =
7:3) f) 2-fN-(4-amidinophe ~1)-aminomethyll-benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbon~rlethyl)-amide 1.1 g (2.27 mMol) of 2- [N- (4-cyanophenyl) -aminomethyl] -benzothiazole-5-carboxylic ac_~d-N-phenyl-N-(2-ethoxycarbonylethyl)-amide wa,~ stirred in 100 ml of ethanol saturated with hydrogen chloride for 5 hours first at 0°C
and then at room temperature until no more starting material could be detected by thin layer chromatography.
Then the solvent was distilled off at a maximum bath temperature of 30°C and the oily residue was taken up in 100 ml of absolute ethanol and mixed with 1.6 g (22 mMol) of ammonium carbonate. After 18 hours stirring at room temperature the solvent was distilled off in vacuo and the crude product was purified by flash chromatography (silica gel; gradient: water/methanol = 19:1 to 4:1). When the eluates are evaporated down th.e desired compound is obtained as a white foam.

Yield : 0 . 77 g ( 63 % of theory) , Rf value: 0.19 (silica gel; dichloromethane/ethanol = 3:7) C27H27N503S (501.60) Mass spectrum: (M+H)+ = 502 Example 10 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazole-5-carboxylic acid-N-phenyl-N-~(2-carboxyethyl)-amide 0.45 g (0.84 mMol) of 2-[N-(9:-amidinophenyl)-aminomethyl]-''~' benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were dissolved in 15 ml of ethanol, mixed with 2 ml of 2N sodium hydroxide solution and stirred for 4 hours at room temperature. Then the mixture was acidified with 3 ml of 2N hydrochloric acid and the solvent was distilled off. The crude product obtained was taken up in 5 ml dichloromethane/ethanol (2:1) and filtered to remove the insoluble sodium chloride. After the distillation of the solvent the desired compound was obtained as a yellow foam.
Yield: 0.26 g (67 % of theory), Rf value: 0.47 (silica gel; meahanol/5 % aqueous sodium chloride = 6:4) ,......
C25H23N5~3S (473.55) Mass spectrum: (M+H)+ = 474 Example 11 2- [N- (4-amidinophenyl) -aminomethyl]benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)--N-(2-methoxycarbonylethyl)-amide-dihydrochloride Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)-aminomethyl]benzc>thiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide, methanolic hydrochloric acid, methanol anal ammonium carbonate.

_ 57 _ Yield: 68 % of theory, C25H24N6~3S (488.57) Rf value: 0.13 (silica gel; methylene chloride/ethanol -4:1 +a few drops of acetic acid) EKA mass spectrum . (M+H)+ = 489 Example 12 2-[2-(4-amidinophenyl)ethyl]-benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride Prepared analogously to Example 9 from 2-(2-(4-cyanophenyl)ethyl]-benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 95 % of theory, C26H25N5~3S (487.58) Rf value: 0.20 (silica gel; meahylene chloride/ethanol =
4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H) + = 4E38 Example 13 2-[N-(4-amidinophenyl)-aminomeahyl]-benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)--N-(ethoxycarbonylmethyl)-amide-dihydrochloride Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)-aminomethyl)-benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxyca.rbonylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 68 % of theory, C25H24N6~3S (488.57) Rf value: 0.14 (silica gel; met:hylene chloride/ethanol =

4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)+ = 489 Example 14 2-(N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide-dihydrochloride Prepared analogously to ExamF~le 10 from 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic "" acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride and sodium hydroxide solution.
Yield: 90 % of theory, C23H20N603S (460.52) Rf value EKA mass spectrum: (M+H)+ - 461 (M+Na)+ - 483 (M+2Na)++ = 253 Example 15 2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzothiazol-''" 5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) 2-fN-(4-Cyanophenyl)-N-methyl-aminomethyll-benzothiazol-5-yl-carboxylic acid-N-phenyl--N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Examp7_e 9e from 4-cyano-N-methyl-aniline and 2-methoxymethyl-be:nzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide.
Yield: 57 % of theory, Rf value: 0.46 (silica gel; dichloromethane/ethanol =
19:1) .

' - .'59 -b) 2-fN-(4-amidinophenyl)-N-methyl-aminomethvl benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxvcarbonylethvl)-amide-h~rdrochloride Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 73 % of theory, C28H29N503S (515.64) Rf value:0.29 (silica gel; met:hylene chloride/ethanol = 4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H) + = 5:L6 Example 16 2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzothiazol-5-yl-carboxyli:c acid-N-phenyl-~N-(2-hydroxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 10 from 2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 96 % of theory, C26H25N5~3S (487.58) Rf value: 0.48 (Merck RP-8, mei_hanol/5% NaCl solution =
6:4) EKA mass spectrum: (M+H)+ - 488 (M+2Na)++ = 266.5 27400-188(S) Example 17 2-[(4-amidinophenyl)thiomethyl]-benzothiazol-5-yl-.
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 9 from 2-[(4-cyanophenyl)thiomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hyd:~-ochloric acid, ethanol and ammonium carbonate.
Yield: 61 % of ,'theory, C27~~26N403S2 (518.66) Rf value: 0_27 (silica gel; methylene chloride/ethanol =
4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)+ = 519 Example 18 2-[(4-amidinophenyl)thiomethyl]-benzothiazol-5-yl-car)r~oxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 10 from 2-[(4-amidinophenyl)thio-48- [sic] methyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 95 % of theory, C25H22N4~3S2 (490.61) TM
Rf value: 0.25 (Merck RP-8, methanol/5% NaCl solution =
6:4) EKA mass spectrum: (M+H)+ - 491 (M+Na)+ = 513 ' - 61 -Examt~le 19 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride Prepared analogously to ExamF~le 9 from 2- [N- (4-cyanophenyl)-aminomethyl]-ben.zothiazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbon.ylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 82 0 of theory, C26H25N5~3S (487.58) Rf value: 0.21 (silica gel; methylene chloride/ethanol =
4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)+ = 488 Example 20 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)-amide-hydrochloride Prepared analogously to Example 10 from 2-[N-(4-amidinophenyl)-aminomethyl]-be;nzothiazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 75 % of theory, C24H21N5~3S (459.53) Rf value: 0.14 (silica gel; methylene chloride/ethanol =
4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)+ - 460 (M+Na)+ = 482 ' ~ - 62 -Example 21 2-[2-(4-amidinophenyl)ethyl]--benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 9 from 2-[2-(4-cyanophenyl)ethyl]-benzothiaz;ol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol anal ammonium carbonate.
Yield: 80 % of theory, C28H28N403S (500.62) Rf value: 0.30 (silica gel; methylene chloride/ethanol =
4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)+ = 501 Example 22 2- [2- (4-amidinophenyl) ethyl] -lbenzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 10 from 2-[2-(4-amidinophenyl)ethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and ,,....
sodium hydroxide solution.
Yield: 77 % of theory, C26H24N4~3S (472.57) Rf value: 0.18 (silica gel; methylene chloride/ethanol =
4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)+ - 473 (M+Na)+ - 495 (M+H+Na)++ = 259 Example 23 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 9 from 2-(N-(4-cyanophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
,,.,., Yield: 83 % of theory, C24H29N5~3 (467.59) Rf value: 0.31 (silica gel; meahylene chloride/ethanol -4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)+ - 468 (2M+H)+ = 935 Example 24 2-[N-(4-amidinophenyl)-aminomeahyl]-benzothiazol-5-yl-carboxylic acid-N-(n-propyl)-td-(2-hydroxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 10 from 2-[N-(4-amidinophenyl)-aminomethyl]-be:nzothiazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 75 % of theory, C22H25N5~3S (439.54) Rf value: 0.14 (silica gel; methylene chloride/ethanol =
4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)+ - 440 (M+H+Na)++ = 231.6 Example 25 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-pheny].-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) 4-Methylamino-3-nitro-benzoic acid-N-phenyl-N-(2-ethoxv-carbonylethyl ) -amide To a solution of 24.7 g (0.115 mol) of 4-methylamino-3-nitro-benzoic acid chloride and 22.3 g (0.115 mol) of ,"~," N-(2-ethoxy-carbonylethyl)-aniline in 300 ml of tetrahydrofuran, 13.1 g (0.13 mol) of triethylamine were added dropwise in 15 minutes, with stirring, at room temperature. After 2 hours stirring the solvent was distilled off in a water-jet vacuum and the residue was mixed with 700 ml of water with stirring. The mixture was extracted 3 times with 200 ml of dichloromethane, the or-ganic extract was washed twice with 200 ml of 2N
hydrochloric acid and twice with 300 ml of water and dried over sodium sulphate. The solvent was then distilled off and the oily product thus obt<~ined was purified by column chromatography (1 kg silica gE~l; eluant: petroleum ether/ethyl acetate = 2:1).
Yield: 35.0 g (82 % of theory), Rf value: 0.28 (silica gel; dichloromethane/ethanol = 50:1) b) 3-Amino-4-methylamino-benzoic acid-N-phenyl-N-(2-ethoxv-carbonyleth~rl ) -amide 12.1 g (0.0326 mol) of 4-methylamino-3-nitro-benzoic acid-N-phenyl-N-(2-ethoxycarbonylet:hyl)-amide were hydrogenated in 300 ml ethanol and 150 ml cLichloromethane after the addition of about 4 g of palla~dium/charcoal (10%) at room temperature and under a hydrogen pressure of 5 bar. Then the catalyst was filtered off and the filtrate was evaporated down. The crude product thus obtained was reacted without further purification.

Yield: 10.6 g (95 % of theor~~) , Rf value: 0.19 (silica gel; dichloromethane/ethanol = 50:1) c) 1-Methyl-2-fN-(4-cyanophenyl)-aminomethyll-benzimidazol-5-vl-carboxylic acid-N-phenyl-N-(2-ethoxvcarbonvlethyl)-amide 6.17 g (0.035 mol) of N-(4-cyanophenyl)glycine and 5.68 g (0.035 mol) of N,N'-carbonyld.iimidazole were refluxed in 300 ml of tetrahydrofuran for 30 minutes, then 10.6 g (0.032 mol) of 3-amino-4-methylamino-benzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were added and the mixture ..- was refluxed for a further five hours. Then the solvent was distilled off in vacuo, the residue was dissolved in 150 ml of glacial acetic acid and refluxed for one hour.
Then the glacial acetic acid was distilled off in vacuo, the residue was dissolved in .about 300 ml of dichloromethane, the solution was washed twice with about 150 ml water and then dried over sodium sulphate. After evaporation of the solvent the, crude product thus obtained was purified by column chromai:ography (800 g silica gel;
eluant: dichloromethane with .l-2 o ethanol).
Yield: 8.5 g (57 0 of theory),.
Rf value: 0.51 (silica gel; dichloromethane/ethanol = 19:1) d) 1-Methyl-2- N- (4-amidinot~hEnvl) -aminomethvl benzimidazol-5-yl-carboxylic skid-N phenyl-N-(2-ethoxycarbonylet ~1 ) -amide-hydrochloride 1.2 g (2.49 mMol) of 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl.-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were stirred in 100 ml of saturated ethanolic hydrochloric acid for 6 hours at room temperature. Then the mixture was evaporated to dryness in vacuo, the residue was dissolved in 100 ml of ethanol, mixed with 2.5 g (26 mMol) of ammonium carbonate and stirred overnight at room temperature. After distillation of the solvent the crude product thus obtained was purified by column chromatography (100 g silica gel; eluant:

' - 66 -dichloromethane/ethanol = 4:1). By concentrating the eluates the desired compound was obtained as a white, amorphous solid.
Yield: 1 .10 g (83 % of theory) , Rf value: 0.18 (silica gel; dichloromethane/ethanol = 4:1) C28H3pN603 x HC1 (498.6) EKA mass spectrum: (M+H)+ - 499 (M+2H)++ - 250 ( M+H+Na ) -~+ = 2 61 Example 26 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl.-N-(2-hydroxycarbonylethyl)-amide A mixture of 300 mg (0.56 mMol) of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride, 15 ml of ethanol, 4 ml of water and 120 mg (3.0 mMol) of sodium hydroxide was stirred for two hours at room temperature. Then the mixture was diluted with about 20 ml of water and made weakly alkaline with glacial acetic -- acid. The product which crystallised out was suction filtered, washed with water a:nd dried at 60°C in vacuo.
Yield: 250 mg (95 % of theory), C26H26N6~3 (470.5) EKA mass spectrum: (M+H)+ - 471 ( M+H+Na ) +~~ = 2 4 7 (M+2Na)++ - 258 Example 27 1-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-~N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) 4-Methylamino-3-chloracetamido-benzoic acid-N-(n-propvl)-N-(2-ethoxycarbonylet.hyl)-amide A solution of 1.8 g (5.9 mMol) of 3-amino-4-methylamino-- 10 benzoic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide [prepared analogously to 3-amino-4-ethylamino-benzoic acid-..... N-phenyl-N-(2-ethoxycarbonylethyl)-amide], 1.1g (6.8 mMol) of N,N'-carbonyldiimidazole and 0.65 g (6.9 mMol) of chloroacetic acid in 75 ml tetrahydrofuran was stirred for 1 hour at room temperature. Then the solvent was distilled off in vacuo, and the crude product was purified by flash chromatography (silica gel; m~ethylene chloride/ethanol =
49:1) .
Yield: 1.7 g (77% of theory) yellow oil, Rf value: 0.58 (silica gel; ethyl acetate/ethanol/ammonia - 90:10:1) b) 2-Chloromethyl-1-methyl-benzimidazol-5-yl-carboxylic acid-N- !n-propyl) -N- (2-ethoxyc.arbonylethyl) -amide ,.-.
1.6 g (4.3 mMol) of 4-methylamino-3-chloracetamido-benzoic acid-N-(n-propyl)-N-(2-ethoxyc:arbonylethyl)-amide were heated to 100°C in 25 ml of acetic acid for 30 minutes.
Then the solvent was distilled off, the crude product was taken up in 40 ml methylene chloride/ethanol (9:1) and washed with 20 ml saturated sodium hydrogen carbonate solution. The organic phase was dried with sodium sulphate and evaporated down.
Yield: 1.5 g (100% of theory) of brown oil, Rf value: 0.63 (silica gel; ethyl acetate/ethanol/ammonia - 90:10:1) c) 1-Methyl-2- f (4-c~rano~heny'L~ thiomethyll -benzimidazol-5-yl-carboxylic acid-N- (n-prop~,~l) -N- (2-ethoxycarbonylethyl) amide A mixture of 1.5 g (4.1 mMol) of 2-chloromethyl-1-methyl-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide and 0.65 g (4.8 mMol) of p-cyanothiophenol was heated in 10 ml of dimethylformamide and 10 ml of diisopropylethyl.amine for 1 hour to 100°C.
The solvent was distilled off in vacuo, the crude product was dissolved in 30 ml ethyl acetate, washed with 30 ml water, and after concentration purified by flash chromatography (silica gel; m.ethylene chloride/ethanol (49:1 to 19:1) .
Yield: 1.5 g (79% of theory) of brown oil, Rf value: 0.65 (silica gel; et:.hyl acetate/ethanol/ammonia - 90:10:1) d) 1-Methyl-2-f(4-amidinophenyrl)thiomethyll-benzimidazol-5--carboxylic acid-N- (n =propel) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride 1.4 g (3. 01 mMol) of 1-methyl-2- [ (4-cyanophenyl) -thiomethyl]-benzimidazol-5-yl~-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide were stirred in 50 ml of ethanol saturated with hydrogesn chloride for 5 hours first at 0°C, later at room temperature, until no more starting material could be detected by thin layer chromatography.
Then the solvent was distilled off at a maximum bath temperature of 30°C, the oily residue was taken up in 40 ml of absolute ethanol and mixed with 2.8 g of ammonium carbonate. After 18 hours the solvent was distilled off in vacuo and the crude product ways purified by flash chromatography (silica gel; meahylene chloride/ethanol =
19:1 to 4:1).
Yield: 1.3 g (83% of theory) as a light beige solid, Rf value: 0.29 (silica gel; ethyl acetate/ethanol/ammonia - 50:45:5) C25H31N603S (481.62) EKA mass spectrum: (M+H)+ = 482 Example 28 1-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-hydroxycarbonylethyl)-amide-hydrochloride 0.52 g (1.0 mMol) of 1-Methyl-2-[(4-amidinophenyl)-thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-""r' N-(2-ethoxycarbonylethyl)-amide-hydrochloride was dissolved in 15 ml ethanol, mixed with 5 ml of 2N sodium hydroxide solution and stirred for 2 hours at room temperature. Then 5 ml of water were added, the alcohol was distilled off, and it was acidified with concentrated hydrochloric acid.
The water was distilled off in vacuo, and the crude product was taken up in 5 ml of ethanol and filtered to remove the insoluble sodium chloride. After the solvent had been distilled off the title compound was obtained as a white solid.
Yield: 0.43 g (88% of theory), Rf value: 0.19 (silica gel; ethyl acetate/ethanol/ammonia - 50:45:5) C23H27N503S (453.57) EKA mass spectrum: (M+H)+ - 454 ( M+Na ) + = 4 7 6 Example 29 1-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-methylpro:pyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 27 from 1-methyl-2-[(4-cyanophenyl)thiomethyl]-benzim:idazol-5-yl-carboxylic acid-(N-(2-methylpropyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 83 % of theory, C25H31N603S (495.65) Rt value: 0.30 (silica gel; ethyl acetate/ethanol/ammonia - 50:45:5) .
EKA mass spectrum: (M+H) + = 496 Example 30 1-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to ExamF>le 27 from 1-methyl-2-[(4-cyanophenyl)thiomethyl]-benzi.midazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyleahyl)-amide, and ethanolic hydrochloric acid, ethanol anal ammonium carbonate.
Yield: 90 % of theory, C28H29N503S (515.64) Rf value:0.24 (silica gel; ethyl acetate/ethanol/ammonia =
50:45:5) EI~A mass spectrum: (M+H) + - 516 (M+H+Na)++ = 269.7 Example 31 1-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2~-hydroxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 28 from 1-methyl-2-[(4-amidinophenyl)thiomethyl-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylet:hyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 76 % of theory, - 71 _ C26H25N5~3S (487.58) Rf value: 0.31 (silica gel; ethyl acetate/ethanol/ammonia - 50:45:5) EKA mass spectrum: (M+H)+ - 488 ( M+Na ) + _ 510 Example 32 1-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl sulphonic acid-N-(1-methyl-piperidin-4-yl)-N-methyl-amide hydrochloride ,,....
a) 4-Chloro-3-nitrobenzenesulphonic acid-N-(1-methyl-piperidin-4-yl)-N-methyl-amide To a solution of 2.2 ml (15 mbiol) of 1-methyl-4-methylamino-piperidine in 60 ml pyridine, 3.8 g (15 mMol) of 4-chloro-3-vitro-benzenesul.phonic acid chloride were added, in batches, whilst cooling with ice. The mixture was then stirred for two hours with cooling, then evaporated to dryness, the residue was mixef. with about 50 ml of water and made alkaline with concentrated ammonia whilst stirring vigorously. The crude product precipitated was suction filtered and purified by column chromatography (250 g ..-- silica gel, eluant: dichloromethane with 1.5% ethanol).
Yield: 1.6 g (31% of theory), C13H18C1N304S (347.8) Rf value: 0.19 (silica gel; dichloromethane/ethanol = 19:1) b) 4-Methylamino-3-nitrobenzenesulphonic acid-N-methyl-N-(1-methylpiperidin-4-yl)-amide 1.6 g (4.6 mMol) of 4-chloro-3-nitrobenzenesulphonic acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide was mixed with 30 ml of 40% methylamine solution and stirred in a sealed flask for four hours at room temperature. Then the mixture was diluted with about 40 ml of water, the product precipitated was suction filtered, washed with water and dried.

Yield: 1.5 g (95% of theory), C14H22N4~4S (343.4) Rf value: 0.45 (silica gel; dichloromethane/ethanol - 4:1) c) 3-Amino-4-methylaminobenze:nesulphonic acid-N-methyl-N-(1-methylpi~eridin-4-yl) -amide 1.5 g (4.4 mMol) of 4-methylamino-3-nitrobenzenesulphonic acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide were dissolved in 100 ml methanol and catalytically hydrogenated at room temperature and under 5 bar hydrogen pressure (10%
palladium on charcoal). Then the catalyst was filtered off '"' and the filtrate was evaporated down. The resulting oily product was further reacted without any purification.
Yield: 1.4 g (100% of theory), C14H24N4~2S (312.4) Rf value: 0.33 (silica gel; dichloromethane/ethanol = 4:1) d) 1-Methyl-2-f(4-cyanophenyl)oxymethyll-benzimidazol-5-vl-sulfonic acid-N-methyl-N-(1-m~~thvl-piperidin-4-vl)-amide 532 mg (3.0 mMol) of 4-cyanop:henyloxyacetic acid and 486 mg (3.0 mMol) of 1,1'-carbonyldi:imidazole were dissolved in 40 ml of tetrahydrofuran and _refluxed for 15 minutes. Then 700 mg (2.24 mMol) of 3-amino-4-methylaminobenzenesulphonic ,"" acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide were added and boiling was continued for a further eight hours. Then the mixture was evaporated down and the resulting oily residue was refluxed in 30 ml of glacial acetic acid for one hour. The glacial acetic acid was distilled off, the residue was mixed with about 30 ml of water and made alkaline with concentrated amrnonia, and the solution was extracted three times with about 20 ml of dichloromethane.
The organic phases were dried and evaporated down. The resulting product was further reacted without any purification.
Yield: 400 mg (39% of theory).
C23H27N5~3S (453.6) Rf value: 0.37 (silica gel; dichloromethane/ethanol - 4:1) - '73 -e) 1-Methyl-2-((4-amidinophenyl)oxymethyll-benzimidazol-5-yl-sulphonic acid-N-methyl-N-~1-methyl~iperidin-4-yl)-amide-hydrochloride Prepared analogously to Example 25d from 400 mg of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-N-methyl-N-(1-vmethylpiperidin-4-yl)-amide with ethanolic hydrochloric acid and ammonium carbonate.
Yield: 370 mg (83's of theory) .
C23H30N6~3S (470.6) EKA mass spectrum: (M+H)+ - 471 ,~-~
(M+2H) ++ = 236 Example 33 1-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-N-methyl-N-phenyl-amide-hydrochloride Prepared analogously to Examp'.Le 32 from 1-methyl-2-((4-cyanophenyl)-oxymethyl]-benzinnidazol-5-yl-sulphonic acid-N-methyl-N-phenyl-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate:.
Yield: 46 0 of theory, C23H23N5~3S (449.5) EKA mass spectrum: (M+H)+ - 450 (M+H+Methanol)+ = 482 (M+2H)++ - 223 Example 34 1-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-N-(3-ethoxycarbonyl-n-propyl)-N-phenyl-amide-hydrochloride Prepared analogously to Example 32 from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-N-(3-ethoxycarbonyl-n-propyl)-rf-phenyl-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 57 % of theory, C28H31N5~5S (549.7) EKA mass spectrum: (M+H)+ = 550 Example 35 1-Methyl-2-[(3-amidinophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-pyrrolidide-hydrochloride Prepared analogously to Example 32 from 1-methyl-2-[(3-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-pyrrolidide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 71 % of theory, C20H23N5~3S (413.5) EKA mass spectrum: (M+H)+ = 4:14 Example 36 1-Methyl-2- [2- (4-amidinopheny:l) ethyl] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3~-methoxycarbonylpropyl)-amide-., dihydrochloride Prepared analogously to Examp:Le 25d from 1-methyl-2- [2- (4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert.butyloxycarbonylpropyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate.
Yield: 83.5 % of theory, Rf value: 0.17 (silica gel; dichloromethane/ethanol = 4:1) C29H31N5~3 (497.6) EKA mass spectrum: (M+H)+ - 498 (M+H+Na)++ = 260.7 - ;~ 5 _ Example 37 1-Methyl-2- [2- (4-amidinopheny:l) ethyl] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl)-amide-hydrochloride Prepared analogously to Examp:Le 26 from 1-methyl-2-((4-amidinophenyl)aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-methoxycarbonylpropyl)-amide-dihydrochloride and sodium hydroxide solution.
Yield: 92 % of theory, .- Rf value: 0.09 (silica gel; dichloromethane/ethanol = 4:1) C28H29N5~3 (483.6) EKA mass spectrum: (M+H)+ - 484 (M+Na) + - 506 ( M+H+Na ) ++ = 2 5 3 . 7 Example 38 1-Methyl-2-[N-(4-amidinophenyl.)-aminomethylJ-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-ethoxycarbonylpropyl)-amide-dihydrochloride -.. a) 1-Methyl-2- fN- (4-cyanoQhenvlL-aminomethyll -benzimidazol-5-vl-carboxylic acid-N-phenyl-N-(3-tert.butyloxy-carbonylpropyl)-amide Prepared analogously to Example 25c from N-(4-cyanophenyl)-glycine and 3-amino-4-methylam.ino-benzoic acid-N-phenyl-N-(3-tert.butyloxycarbonylpropyl)-amide.
Yield: 65 % of theory, Rf value: 0.17 (silica gel; dichloromethane/methanol =
19:1) b) 1-Methyl-2- (N- (4-amidinophenyl) -aminomethyl~ -benzimidazol-5-yl-carboxylic acid-N-phenyl-N-~3-ethoxycarbonyl,propel)-amide-dihydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert.buty] _oxycarbonylpropyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 68 % of theory, Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1) C29H32N6~3 (512.6) EKA mass spectrum: (M+H)+ - 513 ( M+H+Na ) ++' - 2 6 8 ''~ Example 39 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol 5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl) amide-hydrochloride Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-ethoxycarbonylpropyl)-amide-dihydrochloride and sodium hydroxide solution.
Yield: 73.5 % of theory, C27H28N6~3 (484.6) EKA mass spectrum: (M+H)+ - 485 (M+2H) ++ - 243 ( M+H+Na ) ++ = 2 5 4 Example 40 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-- '7 7 -phenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol anal ammonium carbonate.
Yield: 73 % of theory, Rf value: 0.15 (silica gel; d:ichloromethane/ethanol = 4:1) C2gH29N5~3 (483.6) EKA mass spectrum: (M+H)+ - 484 (M+H+Na)++ = 253.7 Example 41 1-Methyl-2-[2-(4-amidinopheny:l)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(h;ydroxycarbonylmethyl)-amide-hydrochloride Prepared analogously to Example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]benzimida:~ol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethy:L)-amide-hydrochloride and sodium hydroxide solution.
Yield: 97 % of theory, C26H25N5~3 (455.5) EKA mass spectrum: (M+H)+ -- 456 (M+Na) + -- 478 (M+2Na) ++ _- 250 . 6 Example 42 1-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(et.hoxycarbonylmethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 76 % of theory, Rf value: 0.17 (silica gel; dichloromethane/ethanol = 4:1) c27H27N5~4 (485.6) EKA mass spectrum: (M+H)+ - 486 ( M+H+Na ) +~~ - 2 5 4 . 7 Example 43 1-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)-amide-hydrochloride Prepared analogously to Example 26 from 1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 58 % of theory, C25H23N5~4 (457.5) EKA mass spectrum: (M+H)+ - 458 (M+Na) + - 480 (M+2Na) ++ = 251 . 6 Example 44 1-Methyl-2-[N-(4-amidinopheny:L)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 74 % of theory, Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1) C27H28N603 (484.6) EKA mass spectrum: (M+H)+ - 485 3 5 ( M+H+Na ) ++ = 2 5 4 - '19 -Example 45 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)-amide-hydrochloride Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-b~enzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbon~ylmethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 84 % of theory, .- C25H24N6~3 (456.5) EKA mass spectrum: (M+H)+ .- 457 (M+Na) + .- 479 (M+2Na) ++ :- 251 Example 46 1-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl carboxylic acid-N-(4-pyrimidy:L)-N-(2-ethoxycarbonylethyl) amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-,..- [(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-pyrimidyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, eahanol and ammonium carbonate.
Yield: 14 % of theory, C26H27N7~4 (501.6) Mass spectrum: (M+H)+ = 502 Example 47 1-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride Prepared analogously to Example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
"~,. Yield : 44 0 of theory, Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1) C26H26N6~4 (486.5) EKA mass spectrum: (M+H)+ - 487 (M+2H)++ - 244 ( M+H+Na ) ++ = 2 5 5 Exam-ple 48 1-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)--N-(hydroxycarbonylmethyl)-amide-hydrochloride Prepared analogously to Example 26 from 1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride and sodium hydroxide solution.
Yield: 85 % of theory, C24H22N604 (458.5) EKA mass spectrum: (M+H)+ -. 459 (M+Na)+ - 481 (M+2Na)++ = 252 Example 49 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride a) 1-Methyl-2- fN- (4-cyanophen~Yl) -aminomethyll -benzimidazol-5-vl-carboxylic acid-N-(2-pyr:idyl)-N-ethoxycarbonvlmethyl-amide Prepared analogously to Examp:Le 25c from N-(4-cyanophenyl)-glycine and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-ethoxycarbony:Lmethyl-amide.
Yield: 24 % of theory, Rf value: 0.56 (silica gel; dichloromethane/methanol = 4:1) b) 1-Methvl-2- fN- (4-amidinophenyl) -aminomethyll -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmet ~l ) -amide'-dihydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-ben2:imidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 70 % of theory, Rf value: 0.16 (silica gel; di~~hloromethane/ethanol = 4:1) C26H27N7~3 (485.6) EKA mass spectrum: (M+H)+ - 486 (M+2H)++ - 243.7 (M+H-Na)++ = 254.6 _.__~__.__. _________~___.._. ._______..~____._.... ..

Example 50 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide-hydrochloride Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxyc:arbonylmethyl)-amide-dihydrochloride and sodium hydroxide solution.
Yield: 91 0 of,'theory, C24H23N7~3 (457.5) EKA mass spectrum: (M+H)+ - 458 (M+Na) + - 480 (M+2Na)++ = 251.7 Example 51 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride Prepared analogously to Example 25d from 1-methyl-2-(2-(4 .-- cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2 pyridyl)-N-(ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 90 % of theory, Rf value: 0.17 (silica gel; dichloromethane/ethanol = 4:1) C27H28N6~3 (484.6) EKA mass spectrum: (M+H)+ - 485 (M+2H)++ - 243 (M+H+Na)++ = 254 Example 52 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl) amide-hydrochloride Prepared analogously to Example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride and sodium hydroxide solution.
Yield: 89 % of theory, C25H24N6~3 (456.5) EKA mass spectrum: (M+H)+ .- 457 (M+Na) + -- 479 Example 53 1-Methyl-2-[N-(4-amidinopheny:L)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl--N-(2-methoxyarbonylethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate.
Yield: 87 % of theory, Rf value: 0.11 (silica gel; dichloromethane/ethanol = 4:1) C27H28N6~3 (484.6) EKA mass spectrum: (M+H) + - 485 (M+2H)++ - 243 ( M+H+Na ) ++ = 2 5 4 Example 54 1-Methyl-2-[(4-amidinophenyl)oxymethyl)-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2,-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl)-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 79.5 % of theory, ~~ C28H29N5~4 (499.6) Rf value: 0.15 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ - 500.0 ( M+H+Na ) ++ - 2 61. 7 Example 55 1-Methyl-2-[(4-amidinophenyl)oxymethyl)-benzimidazol-5-yl carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide hydrochloride Prepared analogously to Examp:Le 26 from 1-methyl-2-[(4-amidinophenyl)oxymethyl)-benz:imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 82 % of theory, C26H25N5~4 (471.5) Rf value: 0.11 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ - 472 (M+H+Na)++ = 247.6 (M+Na)+ - 494 (M+2Na) ++ - 258 . 6 - ;B 5 -Example 56 1-Methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) 1-Methyl-2- f2- (2-cvanothiophen-5 girl) -ethyll -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxvcarbonylethyl)-amide Prepared analogously to Example 25c from 3-(2-~- cyanothiophen-5-yl)-propionic acid and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amid~e.
Yield: 18 % of theory, Rf value: 0.66 (silica gel; dichloromethane/methanol = 9:1) b) 1-Methyl-2-f2-(2-amidinothiophen-5-vl)ethvl benzimidazol-5-yl-carboxylic acid-N- (2 pyridyl) -N- (2-ethoxycarbonyleth~rl) -amide-hydrochloride Prepared analogously to Examp:Le 25d from 1-methyl-2-[2-(2-cyanothiophen-5-yl)ethyl]-ben:aimidazol-5-yl-carboxylic acid-N- ( 2 -pyridyl ) -N- ( 2 -ethox!~carbonylethyl ) -amide and ethanolic hydrochloric acid, ethanol and ammonium ,.-.
carbonate.
Yield: 53 % of theory, C26H28N6~3S (504.6) Rf value: 0.22 (silica gel; dichloromethane/methanol = 5:1) EKA mass spectrum: (M+H)+ - 505 3 0 ( M+H+Na ) ++ = 2 6 4 Example 57 1-Methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to ExamF~le 26 from 1-methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethox:ycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 98 % of ,'theory, '~" C24H24N6~3S (476 . 6 ) EKA mass spectrum: (M+H)+ - 477 (M+Na) + - 499 (M+2H) ++ = 239 Example 58 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) 1-Methyl-2- (N- (4-cyano~henyl) -aminomethyll -benzimidazol-?~ 5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarboMethyl)-amide Prepared analogously to Example 25c from N-(4-cyanophenyl)-glycine and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide.
Yield: 61 0 of theory, Rf value: 0.62 (silica gel; dichloromethane/methanol =
19:1) b) 1-Methyl-2- fN- (4-amidinophenyl) -aminomethyll -benzimidazol-5-vl-carboxvlic acid-N-(2-pvridvl)-N-(2-ethoxycarbonvlethyl)-amide-hydrochloride Prepared analogously to Examp:Le 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic - Ei7 -acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 71 % of theory, C27H29N7~3 (499.6) Rf value: 0.28 (silica gel; di.chloromethane/methanol = 5:1) EKA mass spectrum: (M+H)+ - 500 ( M+H+Na ) ++ = 2 61. 8 (M+2H)++ - 250.8 Example 59 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Examp7_e 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-be~nzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 91 % of theory, C25H25N7~3 (471.5) EKA mass spectrum: (M+H)+ - 472 (M+H+Na)++ = 247.6 (M+2H)++ - 236.7 (M+2Na)++ - 258.6 Example 60 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) 1-Methyl-2- [2- (4-cyanophenyl) -ethyll -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide ___ ___~___..__._... _____~ CA 02277949 1999-07-14 "~~....
.___._____...____._..

Prepared analogously to Example 149a from 3-(4-cyanophenyl)-propionic acid wind 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-~(2-ethoxycarbonylethyl)-amide.
Yield: 22 % of theory, Rf value: 0.68 (silica gel; dichloromethane/methanol =
19:1) b) 1-Methyl-2-f2-(4-amidinophenvl)ethvll-benzimidazol-5-vl-carboxylic acid-N- ( 2 -Qvrid~rl ) -N- ( 2 -ethoxycarbonylethvl ) -amide-hvdrochloride Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 85 0 of theory, C28H30N6~3 (498.6) Rf value: 0.30 (silica gel; dichloromethane/methanol = 5:1) EKA mass spectrum: (M+H)+ - 499 ( M+H+Na ) ++ = 2 61 Example 61 1-Methyl-2- [2- (4-amidinopheny:l) ethyl] -benzimidazol-5-yl-~~ carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Examp:Le 26 from 1-methyl-2-[2-(4 amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N
(2-pyridyl)-N-(2-ethoxycarbon~tlethyl)-amide-hydrochloride and sodium hydroxide solution..
Yield: 97 % of theory, C26H26N6~3 (470.5) EKA mass spectrum: (M+H)+ - 471 ( M+H+Na ) ++ = 2 4 7 (M+Na)+ - 493 Example 62 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
,,~. Yield: 86 % of theory, C29H31N5~3 (497.6) Rf value: 0.11 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ - 498 (M+2H)++ = 249.8 Example 63 1-Methyl-2-[2-(4-amidinopheny:L)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2~-hydroxycarbonylethyl)-amide-hydrochloride ",_", Prepared analogously to Example 26 from 1-methyl-2- [2- (4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 71 % of theory, C27H27N5~3 (469.6) EKA mass spectrum: (M+H)+ - 470 (M+H+Na)++ = 246.6 (M+Na) + - 492 (M+2H)++ - 235.6 _____..... _._. CA 02277949 1999-07-14 ~_. . . ..........___.._.
- :90 -Example 64 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(methoxycarbonylmethyl)-amide-dihydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(methoxycarbonylmethyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate.
.- Yield: 73 % of theory, C25H25N7~3 (471.5) Rt value: 0.12 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ - 472 (M+H+Na)++ = 247.8 Example 65 1-Methyl-2-[N-(4-amidinopheny:L)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyr:idyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride ,,... Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-metho~cycarbonylethyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate.
Yield: 78 % of theory, C26H27N703 (485.6) Rf value: 0.31 (silica gel; dichloromethane/methanol = 5:1) EKA mass spectrum: (M+H)+ - 486 (M+H+Na)++ = 254.8 _ cal _ Example 66 1-Methyl-2- [2- (4-amidinopheny:l) ethyl] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide-hydrochloride a) 1-Methyl-2-f2-(4-cyanophemrl)ethyll-benzimidazol-5-yl-carboxylic acid-N=phenyl-N-f2~-(1H-tetrazol-5-vl)ethyll-amide Prepared analogously to Example 25c from 3-(4-cyanophenyl) propionic acid and 3-amino-4-cnethylamino-benzoic acid ,~ N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -amide.
Yield: 67 % of theory, IR Mass spectrum (KBr): characaeristic bands at 3439.5 cm-1 (N-H); 2235.5 cm-1 C=N ) ;
1631.E~ cm-1 (C=O) b) 1-Methyl-2-f2-(4-amidinophEnvl)ethyl]-benzimidazol-5-vl-carboxylic acid-N-phenyl-N-f2-(1H-tetrazol-5-yl)ethyll-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide and ethanolic -, hydrochloric acid, ethanol and. ammonium carbonate.
Yield: 92 % of theory, C27H27N90 (493.6) EKA mass spectrum: (M+H)+ - 494 (M+Na)+ - 516 (M+2H) ++ = 258 . 7 Example 67 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl.-N-[2-(1H-tetrazol-5-yl)ethyl)-amide-hydrochloride:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetraz;ol-5-yl)ethyl]-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
,,,.~ Yield: 29 % of theory, C26H26N10~ (494.6) EKA mass spectrum: (M+H}+ = 495 Example 68 1-Methyl-2-[N-(4-amidinophenyl}-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-n-hexyloxycarbonylethyl)-amide-hydrochloride 0.60 g (1.1 mMol) of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride were added to about 30 ml of n-hexanol saturated with hydrogen chloride and the mixture was stirred for 19 hours at room temperature. Then the hexano:l was distilled off in vacuo, the residue was mixed with about 5 ml of 1N ammonia solution with stirring and evaporated down once more. The crude product thus obtained w;as purified by column chromatography (silica gel, d:ichloromethane/methanol =
5:1) .
Yield: 53 0 of theory, C31H37N7~3 (555.7) Rf value: 0.36 (silica gel; di.chloromethane/methanol - 5:1 ) i _ c~3 _ EKA mass spectrum: (M+H)+ = 556 Example 69 1-Methyl-2- [N- (4-amidinopheny:l) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) 1-Methyl-2- [N- (4-cyanophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Examp:Le 25c from N-(4-cyanophenyl)-N-methylglycine and 3-amino-4--methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide.
Yield: 71 % of theory, Rf value: 0.66 (silica gel; dichloromethane/methanol =
19:1) b) 1-Methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonvlethYl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomet.hyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-,,~..
amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 77 % of theory, C28H31N7~3 (513.6) EKA mass spectrum: (M+H)+ - 514 (M+H+Na)++ = 268.7 Example 70 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 66 % of~theory, C26H27N7~3 (485.6) EKA mass spectrum: (M+H)+ - 486 (M+Na) + - 508 (M+2Na)++ = 265.6 Example 71 1-Methyl-2- [2- (4-amidinopheny:l) ethyl] -benzimidazol-5-yl carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl) amide-hydrochloride Prepared analogously to Examp:Le 25d from 1-methyl-2-[2-(4-.-- cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 65 % of theory, C28H35N503 (489.6) EKA mass spectrum: (M+H)+ = 490 Example 72 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-methyl-2-[2-(4 amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N
cyclopentyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 89 0 of theory, "' C26H31N5~3 (461. 6 ) EKA mass spectrum: (M+H)+ - 462 ( M+H+Na ) ++ = 2 4 2 . 6 (M+Na)+ - 484 (M+2H)++ - 231.6 Example 73 1-Methyl-2-[N-(4-amidinopheny:L)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride ''"' Prepared analogously to Examp:Le 25d from 1-methyl-2- [N- (4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethox;rcarbonylethyl)-amide and ethanolic hydrochloric acid, eahanol and ammonium carbonate.
Yield: 60 % of theory, C27H34N6~3 (490.6) EKA mass spectrum: (M+H)+ = 491 Examt~le 74 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-b~enzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 45 % of ,'theory, C25H30N3~4 (462.6) EKA mass spectrum: (M+H)+ - 463 (M+H+Na)++ = 243 (M+Na) + - 485 (M+2Na) ++ - 254 Example 75 1-Methyl-2-[N-(4-amidinopheny7:)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-hydrochloride Prepared analogously to Examp7.e 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomet:hyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-~N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 54 % of theory, C27H2gN703 (499.6) EKA mass spectrum: (M+H) + -. 500 (M+2H )++ _- 250.7 Example 76 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 68 % of theory, ~~ C25H25N703 (471.5) EKA mass spectrum: (M+H)+ -- 472 (M+Na) + -- 494 (M+2Na) ++ _- 258 . 6 Example 77 1-Methyl-2-[2-(4-amidinopheny7_)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)--N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Exampl-a 25d from 1-methyl-2- [2- (4-.- cyanophenyl)-ethyl]-benzimida2:o1-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylet:hyl)-amide and ethanolic hydrochloric acid, ethanol anct ammonium carbonate.
Yield: 91 % of theory, C28H30N6~3 (498.6) Rf value: 0.19 (silica gel; di~~hloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ - 499 ___._______._____... ____________CA-02277949 1999-07-14 --________. _ .

Example 78 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-dihydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. ,' Yield: 86 % of theory, C27H29N7~3 (499.6) Rf value: 0.09 (silica gel; dichloromethane/ethanol = 4:1 ) EKA mass spectrum: (M+H)+ = 500 Example 79 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-methyl-2-[N-(4--. amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-dihydrochloride and sodium hydroxide solution.
Yield: 85 % of theory, C25H25N7~3 (471.5) EKA mass spectrum: (M+H)+ - 472 (M+2H)++ - 236.6 (M+2Na)++ = 258.6 _ c~9 _ Example 80 1-Methyl-2- [N- (4-amidinopheny:l) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Examp:Le 25d from 1-Methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomei=hyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)~-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 64 % of theory, C28H31N7~3 (513.6) EKA mass spectrum: (M+H) + = 57_4 Example 81 1-Methyl-2-[N-(4-amidinophenyl_)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-'~ 25 amide-hydrochloride and sodium hydroxide solution.
Yield: 70 % of theory, C26H27N703 (485.6) EKA mass spectrum: (M+H)+ - 486 (M+Na)+ - 508 (M+2Na)++ = 265.6 - :L00 -Example 82 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-h~~drochloride a) 1-Methyl-2-fN-(4-cyanopherwl)-N-methyl-aminomethyll-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-pvridvl)-N-(2-ethoxycarbonylethyl) -amide:
Prepared analogously to Example 25c from N-(4-cyanophenyl) N-methylglycine and 3-amino-4-methylamino-benzoic acid ,~ N-phenyl-N-(2-ethoxycarbonylethyl)-amide.
Yield: 71 °s of theory, Rf value: 0.38 (silica gel; d:ichloromethane/methanol =
19 :1 ) b) 1-Methyl-2-fN-(4-amidinophenvl)-N-methyl-aminomethvl benzimidazol-5-vl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethvl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 74 % of theory, C29H32N6~3 (512.6) EKA mass spectrum: (M+H)+ - 513 ( M+H+Na ) ++ = 2 6 8 (M+2H) ++ - 257 Example 83 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 80 % of theory, C27H28N6~3 (484.6) EKA mass spectrum: (M+H)+ - 485 (M+H+Na) ++ = 254 (M+Na) + - 507 (M+2Na) + - 265 Example 84 1-ethyl-2-[N-(4-amidinophenyl;I-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyrid~girl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-ethyl-2-[N-(4-cyanophenyl)-aminomethyl]-ben::imidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, eahanol and ammonium carbonate.
Yield: 85 % of theory, C28H31N703 (513.6) Rf value: 0.21 (silica gel; dichloromethane/methanol = 5:1) EKA mass spectrum: (M+H)+ - 514 (M+H+Na)++ = 268.6 (M+2H)++ - 257.7 - :L02 -Example 85 1-ethyl-2-[N-(4-amidinopheny7_)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-ethyl-2-[N-(4 amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-etho~sycarbonylethyl)-amide hydrochloride end 2N sodium hydroxide solution.
.....~. Yield: 49 % of theory, C26H27N703 (485.6) EKA mass spectrum: (M+H)+ - 486 (M+H+Na)++ = 254.6 (M+2H) ++ - 243 . 6 (M+2Na) ++ - 265 . 7 Example 86 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-~ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ~=thanol and ammonium carbonate.
Yield: 88 % of theory, C28H2gFN603 (516.6) Rf value: 0.08 (silica gel; di.chloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ - 517 ( M+H+Na ) ++ = 2 7 0 (M+2H) ++ - 259 Example 87 1-Methyl-2-[N-(4-amidinopheny:l)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Examp:Le 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-be~nzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-eahoxycarbonylethyl)-amide-..-. hydrochloride and sodium hydroxide solution.
Yield: 45 % of theory, C26H25F'N6~3 (488.5) Rf value: 0.05 (silica gel; dichloromethane/ethanol = 4:1;
EKA mass spectrum: (M+H)+ - 489 ( M+H+Na ) ++ = 2 6 7 (M+2H)++ - 256 Example 88 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-meth.ylphenyl)-N-(2-.~- ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 79 % of theory, C29H32N603 (512.6) Rf value: 0.10 (silica gel; dic:hloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ - 513 3 5 ( M+H+Na ) ++ :- 2 6 8 CA 02277949 1999-07-1.4' - :L04 -Example 89 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (3-met:hylphenyl) -N- (2-hydroxycarbonylethyl)-amide Prepared analogously to Exams>le 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 62 % of theory, ,.~.,. C27H28N6~3 (484.6) EKA mass spectrum: (M+H)+ - 485 ( M+H+Na ) ++ = 2 5 4 (M+Na) + - 507 (M+2Na)++ - 265 Example 90 1-Methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] -aminomethyl]-benzimidazol-5-y:l-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide -- 1.1 g (2. 06 mMol) of 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl]-benzimidazol-5-y:L-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride was dissolved in a mixture of 40 ml of tetrahydrofuran and 10 ml of water, then 570 mg (4.12 mMol) of potassium carbonate and 362 mg (2.2 mMol) of n-hexyl chloroformate were added and stirred for two hours at room temperature. The solvent was then distilled off, the residue was mixed with about 50 ml of saturated saline solution and the resulting solution was extracted three times with 20 ml of dichloromethane. The extracts were dried over sodium sulphate and evaporated down. The crude product thus obtained was purified by column chromatography (100 g silica gel; dichloromethane +
5% ethanol).

- T_05 -Yield: 78 % of theory, C35H42N6~5 (626.8) Rf value: 0.49 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ - 627 (M+H+Na) +~~ - 325 (M+2H)++ - 314 Example 91 1-Methyl-2-[N-[4-(N-methoxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and methyl chloroformate.
Yield: 41 % of theory, C30H32N6~5 (556.6) Rf value: 0.85 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ - 557 ( M+H+Na ) ++ = 2 9 0 ... (M+Na) + - 579 Example 92 1-Methyl-2- [N- [4- (N-ethoxycarbonylamidino) phenyl] -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide Prepared analogously to Examp7Le 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and ethyl chloroformate.
Yield: 62 % of theory, C30H32N6~5 (556.6) .~ ~."-CA 02277949 1999-07-14 ~ -- 7_06 -Rf value: 0.51 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ - 557 ( M+H+Na ) +~~ - 2 9 0 (M+2H)++ - 279 Example 93 1-Methyl-2-[N-[4-(N-cyclohexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and cyclohexyl chloroformate.
Yield: 25 % of theory, C34H38N6~5 (610.7) Rf value: 0.44 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ - 611 (M+2H)++ = 306 Example 94 1-Methyl-2- [N- [4- [N- [2- (methy:Lsulphonyl) ethyloxycarbonyl] -amidino]phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Examp:Le 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and 2-(methylsulphonyl)-ethyl chloroformate.
Yield: 66 % of theory, C32H36N607S (648.8) Rf value: 0.44 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ - 649 ( M+H+Na ) ++ = 3 3 6 (M+2H) ++ - 325 Example 95 1-Methyl-2-[N-[4-(N-n-octyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate.
Yield: 41 % of theory, C36H44N6~5 (640.8) Rf value: 0.43 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ - 641 ( M+Na ) + _ ~6 6 3 Example 96 1-Methyl-2- [N- [4- (N-hydroxylamidino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxylic <~cid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide 1.44 g (3. 0 mMol) of 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide,, 0.625 g (9.0 mMol) of hydroxylamine hydrochloride and 0.425 g (4.0 mMol) of sodium carbonate were dissolve=d in 80 ml of ethanol and refluxed for 7 hours. Then a further 210 mg of hydroxylamine hydrochloride and 170 mg of sodium carbonate were added, the mixture was boiled for a further 5 hours and then evaporated down in v~acuo. The residue was dissolved in about 30 ml of dichloromethane, the solution obtained was washed with 20 m7_ of water, the organic phase was dried and evaporated down. The crude product thus _______... ... .. __________,___ CA 02277949 1999-07-14 .- __...
- 7_08 -obtained was purified by column chromatography (200 g silica gel, dichloromethane -~- 4% ethanol).
Yield: 39 % of theory, C28H30N6~4 (514.6) Rf value: 0.15 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ -. 515 (M+Na)+ -. 537 (2M+H)+ - 1029 (2M+Na) + = 1051 .--. Exampl a 9 7 1-Methyl-2-[N-[4-(N-n-heptyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-heptyl chloroformate.
Yield: 43 % of theory, C35H42N6~5 (626.8) Rf value: 0.40 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ - 627 2 5 ( M+H+Na ) ++ = 3 2 5 (M+Na)+ - 649 Example 98 1-Methyl-2- [N- [4- (N-benzoylam:idino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-be_nzimidazol-5-yl-carboxylic - 7_09 -acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and benzoyl chloride.
Yield: 88 % of theory, C34H32N604 (588.7) Rf value: 0.37 (silica gel; dichloromethane/ethanol = 19:1) 1H-NMR spectrum (D6-DMSO): 2.61 (t,2H), 3.54 (s,3H), 3.76 (s,3H), 4.10 (t,2H), 4.61 (d,2H), 6.83 (d,2H), 7.05 to 7.55 (m,l2H),8.03 (d,2H), 8.25 (dd.,2H), 8.98 (s,lH), 10.48 (s, 1H) Example 99 1-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-b~~nzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycar7nonylethyl)-amide-hydrochloride and n-hexyl chloroformate.
Yield: 54 % of theory, C34H40N605 (612.7) Rf value: 0.45 (silica gel; dichloromethane/ethanol = 19:1) .~..
EKA mass spectrum: (M+H)+ - 613 Example 100 1-Methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] -aminomethyl]-benzimidazol-5-y7.-carboxylic acid-N-phenyl-N-(2-n-propyloxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-n-propyloxycarbonylethyl)-amide-hydrochloride and n-hexyl chlc>roformate.
Yield: 31 % of theory, CA 02277949 1999-07-14 ~ -- :L 10 -C36H44N6~5 (640.8) Rf value: 0.42 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ - 641 (M+H+Na) +i- - 332 (M+Na) + - 663 Example 101 1-Methyl-2- [N- [4- (N-ethoxycarbonylamidino) phenyl] -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and ethyl chloroformate.
Yield: 72 % of theory, C29H31N7~5 (557.6) Rf value: 0.58 (silica gel; dichloromethane/methanol =
9:1) EKA mass spectrum: (M+H)+ - 558 (M+H+Na)++ = 290.8 (M+Na) + - 580 Example 102 1-Methyl-2- [N- [4- (N-n-octylox;rcarbonylamidino) phenyl] -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide Prepared analogously to Examp]_e 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-metho~:ycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate.
Yield: 57 % of theory, C35H43N705 (641.8) - 1:11 -Rf value: 0.60 (silica gel; di.chloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ - 642 (M+H+Na)++ = 332.8 (M+Na) + - 664 _._ .._____.___. . ... _._._______CA.O2277949 1999-07-14 ''-w°_.______ ._____.__.__._____..
- :L 12 -Example 103 1-Methyl-2- [N- [4- (N-methoxycarbonylamidino) phenyl] -amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and methyl chloroformate.
Yield: 48 0 of,'theory, ~ C29H31N705 (557.6) Rf value: 0.62 (silica gel; d:ichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ - 558 (M+H+Na)++ = 290.7 (M+Na) + - 580 Example 104 1-Methyl-2-[N-[4-(N-n-octyloxycarbonylamidino)phenyl]-aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide 0.7 g (1.l mMol) of 1-methyl-2- [N- [4- (N-n-octyloxycarbonylamidino)-phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide was stirred in a mixture of 0.12 g (3.0 mMol) of sodium hydroxide, 5 ml of water and 10 ml of methanol for one hour at room temperature. Then the mixture was diluted with 20 ml of water and adjusted to pH 6 with glacial acetic acid. Then about 5 ml of diethylether were added and tlhe mixture was vigourously stirred for one hour. The product thus precipitated was suction filtered, washed with a little water, then with diethylether and dried.
Yield: 80 0 of theory, C34H41N7~5 (627.8) EKA mass spectrum: (M+H)+ - 628 (M+H+Na)++ = 325.7 (M+Na)+ - 650 (M+2Na) ++ - 337 . 7 Example 105 1-Methyl-2- [N- [4- [N- (2-methyl;~ulphonyl-ethyloxycarbonyl)amidino]-phenyl]-aminomethyl]-,~-- benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and 2-(methylsul.phonyl)-ethyl chloroformate.
Yield: 65 % of theory, C31H35N707S (649.7) Rf value: 0.54 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ - 650 ( M+H+Na ) ++ = 3 3 6 . 6 ~~ (M+Na)+ - 672 (M+2Na) ++ - 347 . 6 Example 106 1-Methyl-2-[N-[4-(N-n-butyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-be:nzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-butyl chlo:roformate.

.__......_........ ..__...~~CA 02277949 1999-07-14 ___. _.__... ..

Yield: 30 % of theory, C31H35N705 (585.7) Rf value: 0.62 (silica gel; d:ichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ - 586 ( M+H+Na ) ++ = 3 0 4 . 7 (M+2H) ++ - 293 . 7 Example 107 1-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-b~enzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-metho:xycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate.
Yield: 51 % of theory, c33H39N7~5 (613.7) Rf value: 0.56 (silica gel; di.chloromethane/methanol - 9:1) EKA mass spectrum: (M+H)+ - 614 (M+H+Na)++ = 318.7 (M+2H) ++ - 307. 6 Example 108 1-Methyl-2- [N- [4- (N-n-heptylo:~ycarbonylamidino) -phenyl] -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylesthyl)-amide Prepared analogously to Examp~~'_e 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-heptyl ch7_oroformate.
Yield: 21 0 of theory, C34H41N7~5 (627.8) - :L15 -Rf value: 0.60 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ - 628 ( M+H+Na ) +i- - 3 2 5 . 7 (M+2H)++ - 314.7 Example 109 1-Methyl-2-(N-[4-(N-n-pentyloxycarbonylamidino)-phenyl]-aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide ,~
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl)-b~enzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-pentyl chloroformate.
Yield: 66 % of theory, C32H37N7~5 (599.7) Rf value: 0.58 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ - 600 (M+H+Na)++ = 311.7 (M+Na)+ - 622 Example 110 1-Methyl-2- [N- [4- (N-n-nonyloxycarbonylamidino) phenyl) -aminomethyl]-benzimidazol-5-y:l-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide Prepared analogously to Examp:Le 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoacycarbonylethyl)-amide-hydrochloride and n-nonyl chloroformate.
Yield: 60 0 of theory, C36H45N7~5 (655.8) Rf value: 0.48 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ - 656 Example 111 1-Methyl-2-[N-[4-(N-benzoylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and benzoyl chloride.
Yield: 62 % of theory, C33H31N7~4 (589.7) Rf value: 0.50 (silica gel; d:ichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ - 590 (M+Na)+ = 612 Example 112 1-Methyl-2-[N-[4-(N-nicotinoylamidino)phenyl]aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-metho:xycarbonylethyl)-amide-hydrochloride and nicotinic acid chloride.
Yield: 40 % of theory, C32H30N8~4 (590.7) Rf value: 0.47 (silica gel; di.chloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ - 591 ( M+H+Na ) ++ = 3 0 7 ( M+Na ) + - 613 '~ ~'~ CA 02277949 1999-07-14 Example 113 1-Methyl-2- [N- [4- (N-n-hexylo:xycarbonylamidino)phenyl] -aminomethyl]-benzimidazol-5-:yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-etho~cycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate.
Yield: 51 % of,theory, C34H41N7~5 (627.8) Rf value: 0.53 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ - 628 ( M+H+Na ) + ~- - 3 2 5 . 7 (M+2H) ++ - 314 . 7 Example 114 1-Methyl-2-[N-[4-(N-n-octyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate.
Yield: 57 % of theory, C36H45N7~5 (655.8) Rf value: 0.46 (silica gel; dichloromethane/methanol - 9:1 ) EKA mass spectrum: (M+H)+ - 656 (M+H+Na)++ = 339.7 (M+2H)++ - 328.7 Example 115 1-Methyl-2- (N- [4- [N- (2-methylsulphonyl-ethyloxycarbonyl)amidino]-phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-b~enzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxyca:rbonylmethyl-amide-hydrochloride and 2-(methylsu:lphonyl)-ethyl chloroformate.
'" Yield: 72 % of theory, C30H33N707S (635.7) Rf value: 0.23 (silica gel; di.chloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ - 636 (M+H+Na)++ = 329.8 Example 116 1-Methyl-2- (N- [4- (N-cyclohexy7_oxycarbonylamidino) -phenyl]aminomethyl]-benzimida::ol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide Prepared analogously to Examp].e 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-be~nzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide-hydrochloride and cyclohexyl chloroformate.
Yield: 40 % of theory, C32H35N7~5 (597.7) Rf value: 0.26 (silica gel; di~~hloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ - 598 (M+Na)+ = 620 CA 02277949 1999-07-14~
-1~'.0-Example 117 1-Methyl-2-[N-[4-(N-methoxycarbonylamidino)-phenyl]
aminomethyl]-benzimidazol-5-y7.-carboxylic acid-N-(2 pyridyl)-N-ethoxycarbonylmethyl-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-be:nzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide-hydrochloride and methyl chloroformate.
Yield: 62 % of theory, C2gH29N7~5 (543.6) Rf value: 0.19 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ - 544 (M+H+Na)++ = 283.8 (M+Na) + - 566 Example 118 1-Methyl-2- [N- [4- (N-ethoxycarbonylamidino) -phenyl] -amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-be;nzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide-hydrochloride and ethyl chloroformate.
Yield: 42 % of theory, C28H29N7~5 (543.6) Rf value: 0.20 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ = 544 - 1.21 -Example 119 1-Methyl-2- [N- [4- (N-n-octylox:ycarbonyl-amidino) -phenyl]aminomethyl)-benzimida.zol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate.
Yield: 35 % of theory, C36H45N7~5 (655.8) Rf value: 0.28 (silica gel; d_Lchloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ - 656 (M+2H)++ = 328.7 Example 120 1-Methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) -phenyl] -N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-., amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)~-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-hex~~l chloroformate.
Yield: 58 % of theory, C35H43N7~5 (641.2) Rf value: 0.42 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ - 642 (M+H+Na)++ = 332.7 - :L22 -Example 121 1-Methyl-2- [N- [4- (N-n-octylo}ycarbonylamidino) -phenyl] -N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-s N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate.
Yield: 36 0 of,~theory, C37H47N7~5 (669.8) EKA mass spectrum: (M+H)+ - 670 (M+H+Na)++ = 346.8 (M+2H)++ - 335.6 Example 122 1-Methyl-2-[N-[4-(N-n-butyloxycarbonylamidino)-phenyl]-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Examp:Le 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)~-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-but~~l chloroformate.
Yield: 34 % of theory, C33H39N7~5 (613.7) EKA mass spectrum: (M+H)+ - 614 (M+H+Na)++ = 318.7 (M+Na)+ - 636 Example 123 1-Methyl-2- [N- [4- (N-benzoylam:idino) phenyl] -N-methyl-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Examp:Le 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)~-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and benzo;rl chloride.
Yield: 63 % of theory, C35H35N704 (617.7) EKA mass spectrum: (M+H)+ - 618 ~,;. ,~,: , ..:.- . ( M+H+Na ) ++ = 3 2 0 . 7 °' . . (M+Na) + - 640 Example 124 1-Methyl-2-[(4-amidinophenyl)c>xymethyl]-benzimidazol-5-yl-(1-ethoxycarbonylmethyl-cyclohex-1-yl)-ketone-hydrochloride a) 4-Chloro~henyl-(1-hydroxyca.rbonvlmethyl-cyclohex-1-yl)-ketone "~' 8.4 g (40 mMol) of 3-(4-chlorobenzoyl)-propionic acid were dissolved in 300 ml of tetrahydrofuran and 5.8 g (120 mMol) of sodium hydride (50-60% suspension in paraffin oil) were added in batches. Then the mixture was refluxed for 1.5 hours with stirring, after which 8.9 ml (60 mMol) of 1,5-diiodopentane were added dropwise and boiling was continued for a further three hours. After cooling the solution was stirred into 200 ml of ice-water, then the tetrahydrofuran was distilled off -in vacuo, the resulting aqueous solution was acidified with 2N hydrochloric acid and extracted three times with 150 ml of dichloromethane. The organic phase was dried and evaporated down, the crude product thus obtained was purified by column chromatography (500 g silica gel; eluant: dichloromethane with 1-2% ethanol).

....__ _ ......CA.-U2277949 1999-07-14-~___._.___ __...________.....

Yield: 6.2 g (55°s of theory) of oily product, C15H17C103 (280.8) Rf value: 0.56 (silica gel; dichloromethane/ethanol - 19:1) b) 4-Chloro-3-nitrophenyl-(1-~hydroxycarbonvlmethyl-cyclohex-1-yl)-ketone 7.0 g (25 mMol) of 4-chlorophenyl-(1-hydroxycarbonyl-methylcyclohex-1-yl)-ketone were added in batches, with stirring, at -5 to -10°C, to 80 ml of fuming nitric acid.
The solution was then stirred for a further 10 minutes, then stirred into 200 ml of i.ce-water, the precipitated product was then washed with water and dried.
Yield: 7.8 g (96% of theory), C15H16C1N05 (325.8) Rf value: 0.41 (silica gel; petroleum ether/ethyl acetate 4:6) c) 4-Methylamino-3-nitrophenyl-(1-hydroxycarbonylmethyl-cyclohex-1-yl)-ketone 7.8 g ( 23.9 mMol) of 4-chloro-3-nitrophenyl-(1-hydroxycarbonylmethyl-cyclohex-1-yl)-ketone were stirred in 100 ml of a 40% aqueous methylamine solution at room temperature for 14 hours, then diluted with about 150 ml of - water and made slightly acidic with glacial acetic acid.
The precipitated product was suction filtered, washed with water and dried.
Yield: 7.1 g (93% of theory), C16H20N205 (320.4) Rf value: 0.34 (silica gel; dichloromethane/ethanol = 19:1) d) 4-Methylamino-3-nitrophenyl-(1-methoxycarbonylmethyl-cvclohex-1-yl)-ketone 4.9 g (15 mMol) of 4-methylamino-3-nitrophenyl-(1-hydroxycarbonylmethyl-cyclohe:x-1-yl)-ketone were dissolved in 100 ml of tetrahydrofuran, 2.4 g (15 mMol) of 1,1'-carbonyl-diimidazole were added and the mixture was refluxed for 15 minutes. Then the solvent was evaporated - 7.25 -off, 30 ml of methanol were added and the mixture was boiled for three hours with stirring. After the methanol had been distilled off the crude product thus obtained was purified by column chromatography (250 g silica gel, eluant: dichloromethane with 1 to S% ethanol).
Yield: 2.4 g (48% of theory), C17H22N2~5 (334.4) Rf value: 0.76 (silica gel; d:ichloromethane/ethanol = 19:1) e) 3-Amino-4-methylaminophenyl-(1-methoxycarbonylmethyl-cyclohex-1-y1) -ketone 2.4 g (7.2 mMol) of 4-methylamino-3-nitrophenyl-(1-methoxycarbonylmethyl-cyclohe:x-1-yl)-ketone were catalytically hydrogenated in 100 ml of methanol at room temperature under 5 bar hydrogen pressure (10% palladium on charcoal). The crude product thus obtained was further reacted without purification.
Yield: 2.1 g (96% of theory), Rf value: 0.34 (silica gel; di.chloromethane/ethanol = 19:1) f) 3- (4-C'vanophenyloxyacetylarnino) -4-methylaminophenyl-~1-methoxycarbo ~lmethyl-cyclohex-1-yl)-ketone 620 mg (3.5 mMol) of 4-cyanophenyloxyacetic acid and 570 mg ,~ (3.5 mMol) of 1,1'-carbonyl-diimidazole were refluxed in 50 ml of tetrahydrofuran for 7_5 minutes. Then 1.0 g (3.28 mMol) of 3-amino-4-methylaminophenyl-(1-methoxycarbonylme-thyl-cyclohex-1-yl)-ketone wex-a added and the mixture was boiled for a further 4 hours. Then the solvent was evaporated off and the crude product thus obtained was purified by column chromatography (150 g silica gel;
eluant: dichloromethane with 0 to 2% ethanol).
Yield: 1.4 g (93% of theory), C26H29N3~5 (463.5) Rf value: 0.44 (silica gel; di~~hloromethane/ethanol = 19:1) . .~CA 02277949 1999-07-14 g) 1-Methyl-2-f(4-cyanophenyT)oxymethyll-benzimidazol-5 y1 (1-methoxycarbonylmethyl-cvc7_ohex-1-yl)-ketone 1.4 g (3.02 mMol) of 3-(4-cyanophenyloxyacetylamino)-4-methylaminophenyl-(1-methoxyc:arbonylmethyl-cyclohex-1-yl)-ketone were refluxed in 50 ml. of glacial acetic acid for one hour. Then the glacial acetic acid was distilled off, the residue was mixed with 20 ml of water and made alkaline with concentrated ammonia. 'This solution was extracted three times with 20 ml of dichloromethane, the organic extracts were dried and evaporated down. The crude product thus obtained was purified by column chromatography (100 g silica gel; eluant: dichlorom.ethane with 0 to 2% ethanol).
Yield: 700 mg (52% of theory), C26H27N304 (445.5) h) 1-Methyl-2-f(4-amidinophenyl)oxymethyll-benzimidazol-5-yl-(1-ethoxycarbonylmethyl-cyclohex-1-yl)-ketone-hydrochloride Prepared analogously to Example 25d from 700 mg (1.57 mMol) of 1-methyl-2-(4-cyanophenylo:xymethyl)-benzimidazol-5-yl-(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone with ethanolic hydrochloric acid and ammonium carbonate.
Yield: 390 mg (50% of theory), ,..-.. C27H32N404 (476.6) EKA mass spectrum: (M+H) + = 4'77 1H-NMR spectrum(d6-DMSO): 1.:L0 (t,3H); 1.0-2.15 (m,lOH);
3.36 (s,3H); 3.90 (s,2H); 3.94 (q,2H); 5.60 (s,2H);
7.25-7.40 (m,3H); 7.56-7.75 (rn,2H); 7.90 (d,2H); 9.20 (broad s,4H) ppm.

- :L27 -Example 125 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl)-benzimidazol-5-yl-tert.butyl-ketone-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-tert.butyl-ketone, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 59 % of theory, C21H25N5~ (363.5) EKA mass spectrum: (M+H)+ = 364 Example 126 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-(1-methylcyclopent-1-yl)-ketone-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-(1-methylcyclopent-1-yl)-ketone, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 63.5 % of theory, C23H27N5~ (389.5) EKA mass spectrum: (M+H)+ = 390 ____..... _.______________CA-U2277949 1999-07-14 -__. _ __..__..._.
- 7_28 -Example 127 2-[(4-amidinophenyl)sulphinyl.methyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2;-ethoxycarbonylethyl)-amide-hydrochloride A solution of 0.15 g (0.27 mN~ol) of 2-[(4-amidinophenyl)thiomethyl]-ben.zothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarb~onylethyl)-amide-hydrochloride in 10 ml of acetic acid was mixed with 0. [sic] ml (about 0.81 mMol) of 30o hydrogen peroxide solution and stirred at '~ room temperature. After 4 days a further 0.18 ml of hydrogen peroxide solution was added and the resulting mixture was stirred for a further two days. After removal of the solvent in vacuo the crude product obtained was purified by flash chromatography (silica gel; methylene chloride/ethanol = 10:1 to 4:1).
Yield: 58 % of theory, C27H26N4~4S2 (534.66) Rf value: 0.24 (silica gel; methylene chloride/ethanol - 4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H) + = 5:35 Example 128 1-Methyl-2-[(4-amidinophenyl):aulphonylmethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride A solution of 0.40 g (0.70 mMol) of 1-methyl-2- [ (4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride in 10 ml of forrnic acid was mixed with 2 ml of 30% hydrogen peroxide solut=ion and the mixture was stirred for 16 hours at room temperature. Then the solvent was distilled off in vacuo, whereupon the desired compound was obtained as a beige solid (contaminated with some 1-methyl-2-[(4-amidinophenyl)sulfinylmethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride).
Yield: 95 % of theory, C25H31N605S (513.62) Rf value: 0.50 (silica gel; ethyl acetate/ethanol/1N
hydrochloric acid - 50:45:5) EKA mass spectrum: (M+H)+ = 514 Example 129 2- [N- (4-amidinophenyl) -aminomethyl] -thiazolo [5, 4-b] pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) Methyl 5-amino-6-chloro-nicotinate A solution of 1.08 g (5.00 mMol) of methyl 6-chloro-5-nitro-nicotinate (see A.H. Be:rrie, G.T. Newbold, F.S.
Spring in J. Chem. Soc., 2590, 1951) in [sic] ml of absolute ethanol was mixed successively with 0.53 ml (29 mMol) of water, 3.2 g (57 mMo:1) of iron powder and 0.030 ml ,,,..,, of concentrated hydrochloric <acid and heated to boiling for one hour. Then equal quantities of water, iron powder and hydrochloric acid were added <~nd the mixture was heated to boiling for 30 minutes. The precipitate formed on cooling was filtered off and washed with ethanol and the solvent was distilled off in vacuo.
Yield: 0.75 g (81% of theory) of greenish-yellow solid, Rf value: 0.31 (silica gel;ethyl acetate/petroleum ether =
1:4) C7H7C1N202 (186.60) YEF- Mass spectrum: M+ = 186 and 188 (chlorine isotopes).

. CA 02277949 1999-07-14 - :13 0 -b) Methyl 6-chloro-5-methoxyacetamido-nicotinate A solution of 0.75 g (4.02 mPdol) of methyl 5-amino-6-chloro-nicotinate and 0.43 g = 0.35 ml (4.5 mMol) of methoxyacetylchloride in 20 rnl of chlorobenzene was stirred for one hour at 110°C. After the solvent had been removed in vacuo the crude product obtained was purified by flash chromatography (silica gel; rnethylene chloride/ethanol =
100:1), evaporated down again in vacuo and then digested with petroleum, ether.
Yield: 0.55 g '(53% of theory) light yellow amorphous solid, Rf value: 0.33 (silica gel; ethyl acetate/petroleum ether =
1:4) c) Methyl 2-methoxymethyl-thiazolof5,4-bhyridin-6-yl-carboxylate A mixture of 0.53 g (2.05 mMc>1) of methyl 6-chloro-5-methoxyacetamido-nicotinate and 0.42 8 (1.0 mMol) of Lawessons reagent was refluxe~d for 16 hours in 25 ml of xylene. After the solvent hard been removed in vacuo the crude product obtained was purified by flash chromatography (silica gel; methylene chlori.de/ethanol = 100:1) and evaporated down again in vacuo.
'""~' Yield: 0.33 g (67% of theory) of yellow amorphous solid, Rf value: 0.52 (silica gel; ethyl acetate/petroleum ether =
1:4) d) 2-Methox~meth~l-thiazolof5,4-blpyridin-6-yl-carboxylic acid A mixture of 1.1 g (4.62 mMol) of methyl 2-methoxymethyl-thiazolo[5,4-b]pyridine-6-carboxylate and 9.2 ml of 2N
sodium hydroxide solution were stirred into 50 ml of ethanol for one hour at room temperature. Then 9.2 ml of 2N hydrochloric acid were added, the alcohol was distilled off, and it was diluted with 20 ml of water. The aqueous phase was acidified with concentrated hydrochloric acid whilst cooling with ice, the beige precipitate formed was filtered off, then washed with water and dried.
Yield: 1.03 g (100% of theory), Rf value: 0.10 (silica gel; ethyl acetate/petroleum ether =
3:7) e) 2-Methoxymeth~rl-thiazolof5~4-b]pyridin-6-yl-carboxylic acid-N-t~henyl-N-(2-ethoxycarbonylethyl)-amide A suspension of 1.03 g (4.62 mMol) of 2-methoxymethyl-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid in 40 ml of methylene chloride was mixed with 1.6 g = 1.0 ml (13.5 ''' mMol) of thionyl chloride and refluxed for 90 minutes, during which time the solid gradually dissolved. After the liquid components had been distilled off the crude product was taken up twice more in methylene chloride and concentrated again. The resulting crude acid chloride (1.2 g) was taken up in 40 ml of tetrahydrofuran, added dropwise to a mixture of 0.94 g (4.86 mMol) of N-(2-ethoxy-carbonylethyl)aniline and 2.1 ml (13.8 mMol) of triethylamine in 30 ml of tet:rahydrofuran and stirred for 2 hours at room temperature. Tlzen it was diluted with 200 ml of ethyl acetate, washed with 100 ml of 14% saline solution and the organic phase was driE:d with sodium sulphate.
After the solvent had been removed in vacuo the crude product obtained was purified by flash chromatography (silica gel; methylene chloride/ethanol = 100:1).
Yield: 1.57 g (87% of theory)of yellow oil, Rf value: 0.55 (silica gel; methylene chloride/ethanol =
19:1) f) 2-~N- (4-Cyanophenyl) -aminomethylJ -thiazolo f5, 4-bl -pyridin-6-yl-carboxylic acid-Dl-phenyl-N-(2-etho~carbonylethyl)-amide A mixture of 1.54 g (3.85 mMol.) of 2-methoxymethyl-thiazolo[5,4-b]pyridin-6-yl-ca.rboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and 4.3 ml (4.3 mMol) of a 1 molar solution of boron tribromide in methylene chloride - 1.32 -was dissolved in a further 30 ml of methylene chloride and stirred for 5 hours at room temperature. Then the mixture was washed with 40 ml of saturated sodium hydrogen carbonate solution, the organic phase was dried with sodium sulphate and the solvent was distilled off. The crude product (1.9 g) was taken up in 15.0 ml of N,N-diisopropyl-ethylamine, mixed with 0.50 g (4.2 mMol) of 4-aminobenzonitrile and heated to boiling for one hour.
Then the solvent was distilled off in vacuo, the crude product was taken up in 100 ml of methylene chloride, the organic phase was washed with 100 ml of water and dried "'~ with sodium sulphate. After the solvent had been removed in vacuo the crude product obtained was purified by flash chromatography (silica gel; ethyl acetate/petroleum ether =
35:65 to 1:1) and evaporated down again in vacuo.
Yield: 0.45 g (24°s of theory) of yellow amorphous solid, Rf value: 0.34 (silica gel; ethyl acetate/petroleum ether =
1:1) g) 2-fN-(4-amidinophenyl)-aminomethyl~-thiazolof5,4-bl-pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride 0 . 3 9 g ( 0 . 8 0 3 mMol ) of 2 - [N- ( 4 - cyanophenyl ) - aminomethyl ] -thiazolo[5,4-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were stirred in 40 ml of ethanol saturated with hydrogen chlor~.de for 5 hours first at 0°C
and then at room temperature, until no more starting material could be detected by thin layer chromatography.
Then the solvent was distilled off at a maximum bath temperature of 30°C, the oily residue was taken up in 40 ml of absolute ethanol and mixed with 0.5 g ammonium carbonate. After 18 hours the' solvent was removed in vacuo and the crude product obtained was purified by flash chromatography (silica gel; meahylene chloride/ethanol =
9:1 to 4:1).
Yield: 78 % of theory of yellc>w foam, C26H26N603S (502.60) Rf value: 0.19 (silica gel; mesthylene chloride/ethanol - 4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)+ = 503 Examt~le 130 1-Methyl-2-[(4-amidinophenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2~-ethoxycarbonylethyl)-amide-hydrochloride a) 1-Methyl-2-mercapto-benzim:idazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyleth~~l)-amide A solution of 6.5 g (19 mMol) of 3-amino-4-methylamino-benzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and 4.5 g (22.8 mMol) of N,N~-thiocarbonyldiimidazole were dissolved in 100 ml of tetrahydrofuran under a nitrogen atmsphere, the solution was heated to 90°C for 4 hours and left to stand for 16 hours at room temperature. After removal of the solvent in vacuo the crude product obtained was purified by flash chromatography (silica gel; petroleum ether/ethyl acetate = 100:0 to 65:35).
."-. Yield: 6.8 g (93 % of theory) of beige crystalline solid, Rf value: 0.55 (silica gel; ethyl acetate) b) 1-Methyl-2-f(4-cyanophenyl)methvlthio~-benzimidazol-5-yl-carboxylic acid-N phenyl-N-(2-ethoxycarbonylethyl)-amide A solution of 1.30 g (3.4 mMol) of 1-methyl-2-mercapto-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, 0.52 g (3.74 mMol) of potassium carbonate and 0.66 g (3.4 mMol) of 4-bromo-methylbenzonitrile were dissolved in 40 ml of absolute ethanol, stirred for 4 hours at 60°C and 16 hours at room temperature. Then the solvent was distilled off in vacuo, the crude product was taken up in 30 ml of methylene chloride, washed with 40 ml of water and dried with sodium sulphate. After filtration wind distillation of the solvent the desired compound was obtained as a beige-white solid.
Yield: 1.8 g (100 % of theory), Rf value: 0.64 (silica gel; ethyl acetate) c) 1-Methyl-2-f(4-amidinopherwl)methylthiol-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride 1.5 g (3.0 mMol) of 1-methyl-2-[(4-cyanophenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were stirred in 80 ml of ethanol '"'w saturated with hydrogen chloride for 6.5 hours first at 0°C, then at room temperature, until no more starting material could be detected by thin layer chromatography.
Then the solvent was distilled off at a maximum bath temperature of 30°C, the oily residue taken up in 80 ml of absolute ethanol and mixed with 1.0 g (10.5 mMol) of ammonium carbonate. After 18 hours the solvent was distilled off in vacuo and the crude product obtained was purified by flash chromatography (silica gel; methylene chloride/ethanol = 19:1 to 10:1).
Yield: 78 % of theory of light beige solid, C28H29N5~3S (515.63) ~~~ Rf value: 0.19 (silica gel; methylene chloride/ethanol =
4:1) EKA mass spectrum: (M+H)+ - 516 (M+H+Na)++ = 269.7 (M+2H)++ - 258.7 Example 131 1-Methyl-2-[(4-amidinophenyl)methylthio~-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2~-hydroxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 10 from 1-methyl-2-[(4-amidinophenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 57 % of theory, C26H25N5~3S (487.58) Rf value: 0.23 (Reversed Phase silica gel RP-8; Methanol/5o saline solution = 6:4) EKA mass spectrum: (M+H)+ - 488 ( M+Na ) + - 510 "~ ( M+Na+H ) ++ = 2 5 5 . 6 Example 132 1-Methyl-2-[N-(4-amidinopheny7!)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-proparc~yl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-ben~:imidazol-5-yl-carboxylic acid-N-propargyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 81 % of theory, C25H28N6~3 (460.6) Rf value: 0.094 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ - 461 (M+H+Na) ++ = 242 (M+2H)++ - 231 Example 133 1-Methyl-2- [2- [4- (N-n-hexyloxycarbonylamidino)phenyl]ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate.
Yield: 72 0 of theory, C35H42N6~5 (626.8) Rf value: 0.54 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H) + - 627 ( M+Na ) + _ ~5 4 9 Example 134 ' 1-Methyl-2- [2- [4- (N-benzoylam:idino) phenyl] ethyl] -benzimidazol-5-yl-carboxylic <~cid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[2-(4 amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N
(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and benzoyl chloride.
Yield: 79 % of theory, C35H34N6~4 (602.7) Rf value: 0.52 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H) + - E>03 2 5 ( M+Na ) + = E. 2 5 Example 135 1-Methyl-2- [2- [4- (N-nicotinoylamidino) phenyl] ethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimida.zol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and nicotinic acid chloride.

Yield: 56 % of theory, C34H33N7~4 (603.7) Rf value: 0.52 (silica gel; dichloromethane/methanol - 9:1) EKA mass spectrum: (M+H)+ - 604 (M+Na) + = 626 Example 136 1-Cyclopropyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic .acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-Cyclopropyl-2-[N-(4-cyanophenyl)-aminomethy:l]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 31 % of theory, C3pH33N6~3 (524.6) Rf value: 0.40 (silica gel; dichloromethane/methanol = 5:1) EKA mass spectrum: (M+H)+ - 525 (M+H+Na)++ = 274 (M+2H)++ - 263 Example 137 1-Cyclopropyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-cyclopropyl-2-(N
(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 64 % of theory, C28H28N6~3 (496.6) EKA mass spectrum: (M+H)+ - 497 (M+H+Na)++ = 260 (M+Na)+ - 519 (M+2Na) ++ - 271 ,r Example 138 1-Methyl-2-[N-(4-amidinopheny:l)-N-(n-butyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Examp:Le 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-(n-butyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2~-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, Eahanol and ammonium carbonate.
.~-~ Yield: 62 % of theory, C32H38N6~3 (554.7) EKA mass spectrum: (M+H)+ - 555 ( M+H+Na ) ++ = 2 8 9 (M+2H)++ - 278 Example 139 1-Methyl-2-[N-(4-amidino-2-chl_oro-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride -°'°~ Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-chloro-phenyl)-aminomeahyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, eahanol and ammonium carbonate.
Yield: 82 % of theory, C28H2gC1N603 (533.1) EKA mass spectrum: (M+H)+ - 533/5 (M+H+Na)++ = 278/9 - :L40 -Example 140 1-Methyl-2- [N- [4- (n-octyloxyc:arbonylamidino) phenyl] -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide' Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarx>onylethyl)-amide-hydrochloride and n-octyl chloroformate.
Yield: 34 % of,'theory, '"~' C37H46N6C5 (654.8) Rf value: 0.15 (silica gel; d:ichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ - 655 ( M+H+Na ) ++ = 3 3 9 (M+Na)+ - 677 Example 141 1-Methyl-2-[N-(4-amidino-2-ethyl-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride °~ Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-ethyl-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 61 % of theory C3pH34N6~3 (526.6) EKA mass spectrum: (M+H)+ - 527 (M+H+Na) ++ = 275 (M+2H) ++ - 264 Example 142 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-benzylam.ide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-ben;aimidazol-5-yl-carboxylic acid-benzylamide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 63 % of theory, C24H24N6~ (412.5) ~''-' Rf value: 0.76 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H) + = 4:L3 Example 143 1-Methyl-2- [N- [4- (N- (2- (2-ethoxyethoxy) ethyloxy) -carbonylamidino)-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-~N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-be~nzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy~carbonylethyl)-amide-hydrochloride and diethyleneglycolmonoethylether chloroformate.
Yield: 43 % of theory, C34H41N7~7 (659.8) Rf value: 0.56 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 660 (M+H+Na)++ = 341.7 - :L42 -Example 144 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(1-met:hylpyrazol-4-yl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-etho~sycarbonylethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
--, Yield: 60 % of theory, C26H30N8~3 (502.6) Rf value: 0.13 (silica gel; d.ichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ - 503 (M+H+Na)++ = 263 (M+2H)++ - 252 Example 145 3-Methyl-2-[(4-amidinophenyl)-thiomethyl]-imidazo[4,5-b]-pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 1 from 3-methyl-2-[(4-cyanophenyl)thiomethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 88 % of theory, C27H28N603S (516.63) Rf value: 0.23 (silica gel; ethyl acetate/ethanol/ammonia =
50:45:5) EKA mass spectrum: (M+H)+ - 517 3 5 ( M+H+Na ) ++ = 2 7 0 - 1.43 -Example 146 3-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 1 from 3-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-imidazo[4,5-b]pyridin-6-y1-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 82 % of theory, C27H29N7~3 (499.58) Rf value: 0.20 (silica gel; ethyl acetate/ethanol/ammonia =
50:45:5) EKA mass spectrum: (M+H)+ - 500 (M+H+Na)++ = 261.7 Example 147 3-Methyl-2-[(4-amidinophenyl)--thiomethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-,,.-. ( 2 -hydroxycarbonylethyl ) -amide.-hydrochloride Prepared analogously to Examp7_e 2 from 3-methyl-2-[(4-amidinophenyl)-thiomethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2--ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 88 % of theory, C25H24N603S (488.56) Rf value: 0.21 (silica gel; ethyl acetate/ethanol/ammonia =
50:45:5) EKA mass spectrum: (M+H)+ - 489 3 5 ( M+Na ) + = 511 - 1.44 -Example 148 3-Methyl-2-[N-(4-amidinophenyl)-aminomethyl)-imidazo[4,5-b)pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 2 from 3-methyl-2-[N-(4-amidinophenyl) -aminomethyl] -imidazo [4, 5-b) pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 80 0 of theory, C25H25N7~3 (471.52) Rf value: 0.19 (silica gel; ethyl acetate/ethanol/ammonia =
50:45:5) EKA mass spectrum: (M+H) + -- 472 ( M+Na ) + -- 4 9 4 (M+2Na) ++ _- 258 . 6 Example 149 1-Methyl-2-[N-(4-amidinophenyl_)-aminomethyl)-benzimidazol-.~ 5-yl-sulphonic acid-N-phenyl-Dl-(2-ethoxycarbonylethyl)-amide-hydrochloride a) 1-Methyl-2fN-(4-cyanophenyl.)-aminomethvll-benzimidazol-5-yl-sulphonic acid-N phenyl-N-(2-ethoxycarbonylethyl)-amide 2.54 g (6,2 mMol) of 3-nitro-4-methylamino-benzenesulphonic acid-N-phenyl-N-(2-ethoxycarbo~nylethyl)-amide were hydrogenated at room temperature under 5 bar hydrogen pressure over palladium/charcoal (10%) in a mixture of 75 ml of ethanol and 75 ml of dichloromethane. The resulting crude 3-amino-4-methylamino-benzenesulphonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide was taken up in 30 ml of phospharus oxychloride, without purification, then 1.1 g (6,2 mMol) of N-(4-cyanophenyl)-glycine were added and the mixture was refluxed for two hours. After cooling to room temperature the reaction mixture was added to about 70 ml of water with cooling and in this way the excess phosphorus oxychloride was destroyed. The resulting solution was neutralised with solid sodium carbonate and extracted three times with 30 ml of ethyl acetate. After evaporation of the solvent th~~ crude product was purified by column chromatography (100 g silica gel; eluant:
cyclohexane/ethyl acetate = 2:3).
Yield: 860 mg (26.8 % of theo:ry), Melting point: 188-191°C
C27H27N5~3S (517.6) Rf value: 0.52 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ - 518 ( M+Na ) + = 5 4 0 b) 1-Methvl-2- [N- (4-amidinophe:nvl) -aminomethvl benzimidazol-5-yl-sulphonic acid-N-phenyl-N-(2-ethoxycarbonvlethyl) -amide--hydrochloride Prepared analogously to Examp7_e 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-ben~:imidazol-5-yl-sulphonic acid-N-phenyl-N-(2-ethoxycarbonylet:hyl)-amide, ethanolic ,.... hydrochloric acid, ethanol and ammonium carbonate.
Yield: 87 % of theory, C27H30N6~4S (534.6) Rf value: 0.13 (silica gel; di~~hloromethane/ethanol = 9:1) EKA mass spectrum: (M+H)+ - 535 ( M+H+Na ) ++ = 2 7 9 Example 150 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-sulphonic acid-N-(1-methylpyrazol-4-yl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-(N-(4-cyanophenyl)-aminomethyl]-be:nzimidazol-5-yl-sulphonic acid-N-(1-methylpyrazol-4-yl)-N-(:2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 38 0 of theory, C25H30N8~4S (538.6) Rf value: 0.09 (silica gel; d.ichloromethane/ethanol - 9:1) EKA mass spectrum: (M+H) + = 539 Example 151 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -5-(2.3-dihydroindol-1-yl-sulphonyl)-benzimidazole-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-5-(2.3-dihydroindol-1-yl-sulphonyl)-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 15 % of theory, Rf value: 0.36 (silica gel; dichloromethane/methanol = 4:1) C24H24N6~2S (460.6) r EKA mass spectrum: (M+H)+ = 461 - :14 7 -Example 152 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazole-5-yl-sulphonic acid-N-phenyl--N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-sulphonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 24 % of theory, .-. Rf value: 0.55 (Reverse-Phase: RP-18 silica gel; methanol/5%
saline solution = 3:2) C25H26N6~4S (506.6) EKA mass spectrum: (M+H)+ - 507 (M+Na) + - 529 (M+2Na) ++ = 276 Example 153 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-5-(isoindolin-2-yl-sulphonyl)-benzimidazol-:hydrochloride ..-Prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminometlhyl] -5- (isoindolin-2-yl-sulphonyl)-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 33 % of theory, Rf value: 0.32 (silica gel; dichloromethane/methanol = 4:1) C24H24N6~2S (460.6) EKA mass spectrum: (M+H) + = 4E>1 - 1.48 -Example 154 2-[2-(4-Amidinophenyl)-ethyl]-quinazolin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a. Ethyl 4-methyl-3-nitro-benzoate To a solution of 3 ml of concentrated hydrochloric acid and 4 ml of concentrated sulphuric acid, 4.9 g (0.03 mol) of ethyl p-tolylate were added dropwise with stirring at 5°C
and stirred for 1 hour whilst cooling in an ice-bath. After heating to ambient temperature the mixture was poured onto ice-water and extracted with ethyl acetate. The organic extracts were washed with sodium hydrogen carbonate solution, dried and evaporated down.
Yield: 5.7 g (90 % of theory), Rf value: 0.81 (silica gel, ethyl acetate/cyclohexane =
1:1) b. Methyl 4-(2-dimethylaminov:inyl)-3-nitro-benzoate 1.0 g (4.8 mmol) of ethyl 4-methyl-3-nitro-benzoate, 0.74 g (6.2 mmol) of dimethylformam:ide dimethylacetal and 2 ml of dimethylformamide were heated to 140°C with stirring for 3 hours. Then the solvent was d_Lstilled off and the crude product thus obtained was reacted without any further '""~ 25 purification.
Yield: 1.2 g (100 % of theory), Rf value: 0.54 (silica gel, ethyl acetate/cyclohexane =
1:1) c. Methyl 4-formyl-3-nitro-benzoate 1.2 g (4.8 mmol) of methyl 4-(2-dimethylaminovinyl)-3-nitro-benzoate were dissolved in 120 ml of tetrahydrofuran/water (1:1) and after the addition of 3.0 g (14.3 mmol) of sodium metaperiodate the mixture was stirred for 20 hours at ambier.~t temperature. The suspension was then diluted with water anal methylene chloride and extracted with methylene chloride. The combined organic extracts were washed with sodium hydrogen carbonate solution, dried and evaporated down. The residue was chromatographed on silica gel and eluted with ethyl acetate/cyclohexane (1:3).
Yield: 0.6 g (63 % of theory), Rf value: 0.63 (silica gel, ethyl acetate/cyclohexane =
1:1) d. Methyl 3-Amino-4-formyl-benzoate To a solution of 25 ml of ethanol/glacial acetic acid/water (2:2:1) were added 0.6 g (2.9 mmol) of methyl 4-formyl-3-,,.... nitro-benzoate, 1.2 g (21.4 mmol) of iron powder and 0.01 ml of concentrated hydrochloric acid and the mixture was refluxed with stirring fo:r 15 minutes. Then the iron was separated off, the solution was diluted with water and extracted with methylene chloride. The combined organic extracts were washed with watE_r, dried and evaporated down.
Yield: 0.3 g (58 % of theory) ,, Rf value: 0.74 (silica gel, me~thylene chloride/methanol =
9.5:0.5) e. Methyl 3-[3-(4-cyanophenyl)-propionylamino]-4-formyl-benzoate 1.0 g (5.6 mmol) of methyl 3-amino-4-formyl-benzoate and 1.1 g (5.6 mmol) of 4-cyanophenylpropionic acid chloride were dissolved in 50 ml of met:hylene chloride and after the addition of 0.7 g (5.6 mmol) of N-ethyl-diisopropylamine the mixture was stirred for 29: hours at ambient temperature. Then it was extracted with sodium hydrogen carbonate solution, the combined organic extracts were dried and evaporated down. The: residue was chromatographed on silica gel and eluted with ethyl acetate/cyclohexane (1:3) .
Yield: 0.6 g (32 % of theory), Rf value: 0.60 (silica gel, ethyl acetate/cyclohexane =
1:1) - 7_50 -f . Methyl 2- [2- (4-cyanophenyl.) -ethyl] -quinazoline-7-carboxylate 0.6 g (1.8 mmol) of ethyl 3-[3-(4-cyanophenyl)-propionylamino]-4-formyl-benzoate and 10 ml of methanolic ammonia solution were agitated in a pressure vessel for 36 hours. Then the solvent was distilled off, the residue was chromatographed on silica gel and eluted with methylene chloride containing 0 to 1 % methanol.
Yield: 0.35 g (62 % of theory), Rf value: 0.38~(silica gel, ethyl acetate/cyclohexane =
.-1:1) g. 2-f2-(4-Cyanophenyl)-ethyl]-auinazolin-7-carboxylic acid 0.3 g (0.94 mmol) of methyl 2- [2- (4-cyanophenyl) -ethyl] -quinazoline-7-carboxylate were dissolved in 4.7 ml of 1N
lithium hydroxide solution and 4 ml of tetrahydrofuran and stirred for 3 hours at ambient temperature. Then 4.7 ml of 1N hydrochloric acid were added and the mixture was stirred for 30 minutes. The product precipitated was suction filtered, washed with water a:nd dried.
Yield: 0.30 g (100 % of theor;y), Rf value: 0.1 (silica gel, ethyl acetate/cyclohexane = 1:1) h. 2-[2-(4-Cyanophenyl)-ethyl:)-quinazolin-7-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide 0.4 g (1.3 mmol) of 2- [2- (4-cyanophenyl) -ethyl] -quinazoline-7-carboxylic acid and 5 ml of thionyl chloride were stirred for 60 minutes a1= 50°C. Then the thionyl chloride was distilled off, the residue was dissolved in methylene chloride, mixed with 0.24 g (1.3 mmol) of methyl 3-(N-phenylamino)-propionate and 0.22 ml of (1.3 mmol) of N-ethyldiisopropylamine and stirred for 18 hours at ambient temperature. After evaporation of the solvent in vacuo the residue was chromatographed o~n silica gel and eluted with methylene chloride containing 1 % methanol.
Yield: 230 mg (37 % of theory), Rf value: 0.64 (silica gel, methylene chloride/methanol -9:1) i. 2-[2-(4-Amidinophenyl)-ethyl]-quinazolin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethvl)-amide-hydrochloride 230 mg (0.5 mmol) of 2-[2-(4-cyanophenyl)-ethyl]-quinazolin-7-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide were stirred in 30 ml of saturated ethanolic hydrochloric acid for 8 hours at ambient temperature. Then the mixture was evaporated to dryness in vacuo, the residue was taken up in 20 ml of ethanol, combined with 0.5 g (5.0 mmol) of ammonium carbonate and stirred overnight at ambient temperature.
After evaporation of the solvent the crude product was chromatographed on silica gel and eluted with methylene chloride/ethanol (4:1).
Yield: 100 mg (39 % of theory;., Rf value: 0.5 (silica gel, met:hylene chloride/ethanol =
4:1) C29H29N503 (495.59) Mass spectrum: (M+H)+ = 496 Example 155 1-Methyl-2-[N-(4-amidinophenyl.)-aminomethyl]-benzimidazol-5-yl-sulphonic acid-N-(1-methylpyrazol-4-yl)-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-be:nzimidazol-5-yl-sulphonic acid-N-(1-methylpyrazol-4-yl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium, hydroxide solution.

' - 152 -Yield: 95 % of theory, C23H26N804S (510.6) Rf value: 0.53 (Reversed Phase silica gel RP-18, methanol +
5% saline solution) EKA mass spectrum: (M+H) + .- 511 (M+Na)+ - 533 (M+2Na) ++ = 278 Example 156 1-Methyl-2-[N-(3-amidino-pyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic <~cid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) 3-[(N-tert.Butoxycarbonyl-amino)acetylamino]-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide 19.2 g (0.11 mol) of N-tert.butyloxycarbonylglycine were dissolved in 175 ml of dimethylformamide, mixed with 35.2 g (0.11 mol) of O-benzotriazol-~1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 11.0 g of ..- triethylamine and 34.2 g (0.10 mol) of 3-amino-4-methyl-amino-benzoic acid-N-(2-pyrid~~1)-N-(2-ethoxycarbonylethyl)-amide and stirred for 2.5 hours at ambient temperature.
Then the reaction solution was. mixed with 5 1 of ice water and stirred for 2 hours. The grey precipitate formed was filtered off, washed with water, dried and recrystallised from ethyl acetate with the addition of activated charcoal.
Yield: 39.85 g (80 % of theory), C25H33N506 (499.6) Rf value: 0.55 (silica gel; meahylene chloride/ethanol =
19:1) - 7.53 -b) 1-Methyl-2-(N-tert.butoxvc:arbonyl-aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-!2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide 10.0 g (0.02 mol) of 3-[(N-tert.butoxycarbonyl-amino)acetylamino]-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide were dissolved in 50 ml of glacial acetic acid and refluxed for one hour. Then the solvent was distilled off, the residue was mixed with ice water and adjusted to pH 8 by the addition of 2N ammonia. After extraction three times with ethyl acetate the combined organic phases were washed with saline solution and dried over sodium sulphate. After evaporation of the solvent the crude product was chromatographed on silica gel, eluting first with methylene chloride, then with methylene chloride/ethanol (50:1) and (25:1). The desired fractions were combined and evaporated down.
Yield: 5.85 g (61 % of theory), C25H31N5~5 (481.6) Rf value: 0.70 (silica gel; methylene chloride/ethanol =
9:1) c) 1-Methyl-2-aminomethyl-benzimidazol-5-vl-carboxylic acid-N-(2-,gyridyl)-N-(2-ethoxycarbonylethyl)-amide-trifluoracetate 4.81 g (0.10 mol) of 1-methy:l-2-(N-tert.butoxycarbonyl-aminomethyl)-benzimidazol-5-y:1-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide were dissolved in 25 ml of methylene chloride, mixed with 5 ml of trifluoroacetic acid and sl.irred for 5 hours at ambient temperature. Then the solvent was evaporated off and the residue was stirred with ether. The crystals thus formed were filtered off, washed with ether and dried.
Yield: 3.15 g (68 % of theory), C2pH23N5~3 (381.4) Rf value: 0.18 (silica gel; me~thylene chloride/ethanol =
9:1) - 1.54 -d) 1-Methyl-2- fN- (3-cyano-pyridin-6-yl) -aminomethyll -benzimidazol-5 girl-carboxylic acid-N-(2-pvridyl)-N-(2-ethoxycarbonylethyl)-amide 1.5 g (3.25 mmol) of 1-methyl-2-aminomethyl-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-trifluoracetate were stirred into 10 ml of N-ethyl-diisopropylamine and heated to 100°C for 15 minutes. After the addition of 720 mg (5.25 mmol) of 2-chloro-5-cyano-pyridine the reaction mixture was heated to 125°C for 2 hours. After cooling to ambient temperature and stirring with about 20 ml of water, the pH was adjusted to 4 by t:he addition of 1N hydrochloric acid and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were washed with saline solution and dried over sodium sulphate. After evaporation of the solvent the crude product was chromatographed on silica gel, eluting first with methylene chloride, later with methylenf~ chloride/ethanol (25:1) and (19:1). The desired fractions were combined and evaporated down.
Yield: 1.05 g (67 % of theory), C26H25N70 (483.6) Mass spectrum: (M+H)+ = 484 e) 1-Methyl-2-fN-(3-amidino-pyridin-6-yl)-aminomethyll-benzimidazol-5-vl-carboxylic acid-N-(2-rwridvl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-Methyl-2-[N-(3-cyano-pyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 38 % of theory, C2gH28N803 (500.6) - 7_55 -Mass spectrum: (M+H)+ = 501 Example 157 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydroiodide a) 4-Nitro-benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide 16.7 g (0.1 moh) of 4-nitrobenzoic acid were refluxed in ,"r", 50 ml of thionyl chloride and 3 drops of dimethylformamide for 1 hour. After the solvent had been distilled off in vacuo the crude product was dissolved in 150 ml of tetrahydrofuran and added dropwise to a solution of 18 g (0.1 mol) of N-(2-methoxycarbonylethyl)aniline in 250 ml of tetrahydrofuran and 42 ml 0.3 mol) of triethylamine.
After being stirred for one hour at ambient temperature the reaction mixture was diluted 'with 250 ml of ethyl acetate and washed 2x with 200 ml of 14% saline solution. After the solvent had been distilled off and the residue chromatographed (silica gel; methylene chloride) a yellow oil was obtained which slowly solidified.
Yield: 32.6 g (100 0 of theor;y), Rf value: 0.37 (silica gel; m~~thylene chloride/methanol =
50:1) b) 4-Amino-benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide 22 g (67 mmol) of 4-nitro-benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide were hydrogenated in 500 ml of methanol with 2 g of 10% palladium on charcoal at 3 bar hydrogen pressure for 3 hours. After filtration and distillation of the solvent the reaction mixture was washed with 100 ml of ether and the white crystalline product was further reacted directly.

- 7_56 -Yield: 18.6 g (94 % of theory), Rf value: 0.70 (silica gel; methylene chloride/ethanol -19:1) c) 2-Methyl-3-thiomethyl-indc~1-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonvlet.hyl)-amide 26.8 g (91 mmol) of 4-amino-benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide were dissolved in 500 ml of methylene chloride, cooled to -70°C and mixed within 30 minutes with freshly prepared. tert.butylhypochlorite (M. J.
Mintz et al., Organic Synthesis, Coll. Vol. 5, page 184).
"~ The mixture was stirred for 2 hours at -70°C, then 9.46 g (91 mmol) of methylthioacetone in 40 ml of methylene chloride were added dropwise within 10 minutes and stirring was continued for a further 1.5 hours. Then 12.7 ml (9.1 g, 91 mmol) of triethylamine in 25 ml of methylene chloride were added. The mixture was left for 30 minutes at -78°C
and then slowly warmed to ambient temperature overnight.
After washing twice with 50 ml of water the organic phase was separated off and dried with sodium sulphate. After removal of the solvent in vacuo a white amorphous substance is obtained after purification by chromatography (silica gel; ethyl acetate/petroleum .ether = 2:8 to 3:7).
Yield: 24.1 g (69 % of theory), ''~ 25 Rf value: 0.58 (silica gel; ethyl acetate/petroleum ether =
1:1) C21H22N203S (382.49) Mass spectrum: (M)+ = 382 - :157 -d) 1-tert-Butoxycarbonvl-2-methyl-indol-5 girl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide 8.9 g (23 mmol) of 2-Methyl--3-thiomethyl-indol-5-yl-carboxylic acid-N-phenyl-N-(a?-methoxycarbonylethyl)-amide were dissolved in 600 ml of ethanol, mixed with about 150 mg of Raney nickel and stirred for 2 hours at ambient temperature (analogously to F>.G. Gassman et al., Organic Synthesis Coll. Vol. 6, page 601). Then the mixture was filtered and the solvent eliminated in vacuo. The crude product thus obtained (8 g) was dissolved in 200 ml of absolute tetrahydrofuran, mixed with 150 mg of ,,... dimethylaminopyridine and 6.84 g (32 mmol) of di-tert.butyl pyrocarbonate and stirred for 2.5 hours at 50°C. Then the solvent was distilled off in vacuo and the crude product was purified by chromatography (silica gel, ethyl acetate/petroleum ether = 1:4).
Yield: 10.0 g (98 % of theory), Rf value: 0.40 (silica gel; ethyl acetate/petroleum ether =3:7) e) 2fN- (4-Cyanophenyl) aminomethyl~ -indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide 3.5 g (8 mmol) of 1-tert.butoxycarbonyl-2-methyl-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide were dissolved in 80 ml of carbon tetrachloride, mixed with 1.5 g (8.4 mmol) of N-bromo-succinimide and 20 mg of azobisisobutyronitrile .and refluxed for 2.5 hours.
Then the still warm solution was filtered, the filtrate obtained was washed with saturated sodium hydrogen carbonate solution and dried with sodium sulphate. After distillation of the solvent the crude product was dissolved in 30 ml of N-ethyl-diisoprop:ylamine, mixed with 1.0 g (8 mmol) of 4-aminobenzonitri:le and refluxed for 2.5 hours.
The solvent was distilled off in vacuo and the residue obtained was purified by chromatography (silica gel; ethyl acetate/petroleum ether = 1:4 to 1:1).

- 1.58 -Yield: 1.1 g (30 % of theory), Rf value: 0.21 (silica gel; a hyl acetate/petroleum ether =
1:1) f. 1-Methyl-2-[N-(4-thiocarbamovl-phenyl)aminomethyll-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide 1. 5 g ( 3 . 3 mmol ) of 2 - [N- ( 4 - cyanophenyl ) aminomethyl ] - indol -5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide were dissolved in 60 ml of xylene, mixed with 0.45 g (3.3 mmol) of potassium carbonate and 0.5 ml of (3.3 mmol) ,,..,, of methyl p-toluenesulphonate and refluxed for 4 hours.

Then the same amounts of potassium carbonate and methyl toluenesulphonate were added a second time and the mixture was refluxed overnight. It was filtered and washed with acetone. After concentration of the filtrate thus obtained, the residue obtained was purified by chromatography (silica gel; ethyl acetate/petroleum ether = 1:4 to 2:3). The N-methylated indole obtained (yield: 0.64 g, 41 % of theory) was dissolved in 20 m:1 of pyridine and mixed with 0.67 ml (1.37 mmol) of trietlzylamine. Then hydrogen sulphide gas was introduced into the solution thus obtained. After 4.5 days nitrogen was passed through the reaction solution for 30 minutes, the solvent was distilled off and the residue obtained was purified by chromatography (silica gel; methylene chloride/ethanol 99:1 to 98:2).

Yield: 0.30 g (43 0 of theory) , C2gH2gN403S (500.62) EKA mass spectrum: (M+H)+ - 501 (M+Na) + -- 523 g) 1-Methyl-2- [N- (4-amidinophe:nyl) aminomethyll -indol-5-yl-carboxylic acid-N-phenyl-N-(2-~methoxvcarbonylethyl)-amide-hydroiodide 0.30 g (0.60 mmol) of 1-methyl-2-[N-(4-thiocarbamoyl)-phenyl)aminomethyl]-indol-5-yl.-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide were dissolved in 20 ml of acetone together with 0.75 ml (12 mmol) of methyl iodide and stirred for 2 hours at ambient temperature. Then the solvent was distilled off and the crude product was stirred together with 1.0 g of ammonium acetate in 12 ml of ethanol and 5 ml of methylene chloride for 20 hours at 40°C. The solvent was distilled off in vacuo and the residue obtained was purified by chromatography (silica gel; methylene chloride/ethanol = 9:1 to 4::1).
Yield: 55 % of theory, C2gH29N503 (483.58) Rf value: 0.20,'(silica gel; methylene chloride/ethanol =
'~ 4:1 + 1 drop of acetic acid) EKA mass spectrum: (M+H) + = 484 Example 158 1-Methyl-2- [N- (4-amidinophenyl) aminomethyl] -thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) Iminoethyl methoxyacetate hydrochloride A solution of 35.5 g (0.50 me>1) of methoxyacetonitrile in 29 ml (23 g, 0:50 mol) of ethanol and 30 ml of absolute ,.-. diethylether was cooled to 0°C and over 1 hour 22.5 g (0.62 mol) of hydrogen chloride gas was introduced, whilst towards the end of the introduction of gas the reaction product crystallised out. To complete the precipitation 130 ml of diethylether were added and the colourless needles were filtered off.
Yield: 66.4 g (86 % of theory), Melting point: 117-118°C.
b) 4-Hydroxymethyl-2-methoxymethyl-imidazole A mixture of 30.6 g (0.20 mol) of iminoethyl methoxyacetate-hydrochloride, 18 g (0.20 mol) of 1.3-dihydroxyacetone and 200 ml of liquid ammonia was heated to 68°C for 3 hours in a stirred autoclave at a pressure of 27 - 1.60 -bar (analogously to: P. Dziuron et al. Arch. Pharm. 307, 1974, p.470). Then the ammonia was eliminated and 200 ml of methylene chloride were added. The white precipitate formed was filtered off and washed with methylene chloride. The filtrate was evaporated down and the residue obtained was purified by chromatography (aluminium oxide; methylene chloride/ethanol = 90:10 to 85:15).
Yield: 26.7 g (94 0 of theory), Rf value: 0.43 (silica gel; methylene chloride/ethanol -9:1) C6H1pN202 (142.20) '"~ Mass spectrum: (M)+ = 142 c) 4-Hydroxymethyl-2-methox~rm~=_thvl-1-methyl-imidazole as a 1:1 mixture with 5-hydroxymetlzyl-2-methoxymethyl-1-methyl imidazole A mixture of 7.1 g (50 mmol) of 4-hydroxymethyl-2-methoxymethylimidazole, 3.0 g (53 mmol) of powdered potassium hydroxide and 3.4 ml (0.55 mmol) of methyl iodide was heated to 50°C in 100 ml of dimethylformamide for 4 hours (analogously to I. Sinc~~air et al., J. Med. Chem., 29, 1986, 261). Then the solvent was distilled off in vacuo and the crude product purified by column chromatography ,,..,. (aluminium oxide; methylene chloride/ethanol - 99:1 to 95:5).
Yield: 6.1 g (78 % of theory; 1:1 mixture of the two regioisomers) Rf value: 0.32 (silica gel; me:thylene chloride/ethanol =
19:1) d) 5-Chloro-4-hvdroxvmethvl-2-methoxvmethvl-1-methvl imidazole A 1:1 mixture of 7.7 g (49 mmol) of 4-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole and 5-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole and 7.3 g (55 mmol) of N-chloro-succinimide was heated to 50°C in 48 ml of ethylene glycol monoethylether and 70 ml of dioxan for 10 - :L61 -hours. Then the solvent was distilled off in vacuo and the crude product purified by chromatography (silica gel;
methylene chloride/ethanol = 99:1 to 90:10) to obtain the isomerically pure title compound.
Yield: 3.4 g (36 0 of theory), Rf value: 0.40 (silica gel; nnethylene chloride/ethanol =
19:1) e) 5-chloro-4-formyl-2-metho~:ymethyl-1-methyl-imidazole 3.4 g (18 mmol) of 5-chloro-9:-hydroxymethyl-2-methoxymethyl-f-methyl-imida2:ole were dissolved in 100 ml '" of methylene chloride and at two-hour intervals manganese dioxide was added (2 x 6.0 g, a total of 0.14 mol). After 4 hours the inorganic component. was filtered off, the solvent was eliminated and the crude product obtained was further reacted without any further purification.
Yield: 3.0 g (89 0 of theory), Rf value: 0.44 (silica gel; methylene chloride/ethanol =
50:1) f) Ethyl 1-methyl-2-methoxymethyl-thieno[2.3-d]imidazol-5-yl-carboxylate To a freshly prepared sodium ethoxide solution (from 391 mg, 17 mMol of sodium) in 15 ml of ethanol were added dropwise 1.9 ml (2.1 g, 17 mmol) of ethyl thioglycolate.
After 1 hour stirring at ambient temperature 1.6 g (8.5 mmol) of 5-chloro-4-formyl-2-methoxymethyl-1-methyl-imidazole in 20 ml of absolut=a ethanol were added and the mixture was heated to 80°C (analogously to B. Iddon et al., J. Chem. Soc. Perkin Trans. :C, 1987, 1457). After 5 hours the solvent was distilled ofi_, the residue was taken up in 50 ml of methylene chloride and washed with 20 ml of water.
The aqueous phase was washed again with 20 ml of methylene chloride and then the combined organic phases were dried with sodium sulphate. After removal of the solvent in vacuo the crude product obtained was purified by column chromatography (aluminium oxide; methylene chloride).
Yield: 1.0 g (46 0 of theory), Rf value: 0.48 (silica gel; methylene chloride/ethanol =
50:1) C11H14N2~3S (254.31) EKA mass spectrum: (M+H)+ - 255 (M+Na)+ = 277 g) 1-Methyl-2-methoxymethyl-thieno[2.3-d]imidazol-5-yl-carboxylic acid To a solution of 0.90 g (3.54 mmol) of ethyl 1-methyl-2-methoxymethyl-thieno[2.3-d]imidazol-5-yl-carboxylate in 30 ml of ethanol were added dropwise 5 ml of 2 N sodium hydroxide solution and the mi:Kture was stirred for 2 hours at ambient temperature. Then the solvent was distilled off in vacuo, the residue was taken up in 5 ml of water and washed with 10 ml of diethylei:her. The aqueous phase was acidified with 6 ml of 2N hydrochloric acid, cooled to 0°C
and the precipitated crystals are filtered off.
Yield: 0.50 g (630 of theory) - :163 -Rf value: 0.21 (silica gel; rnethylene chloride/ethanol -9:1 + a few drops of acetic acid) CgH1pN203S (226.26) Mass spectrum: (M)+ = 226 h) 1-Methyl-2-methoxymethyl-t:hieno [2 .3-d) imidazol-5-yl-carboxylic acid-N=phenyl-N-(2-methoxycarbonylethyl)-amide A suspension of 0.50 g (2.2 mmol) of 1-methyl-2-methoxymethyl-thieno[2.3-d]imidazol-5-yl-carboxylic acid in 20 ml of methylene chloride was mixed with 2.0 ml (3.2 g, 27 mmol) of thionyl chloride and refluxed for 60 minutes, during which time the solid gradually dissolved. After distillation of the liquid components the crude product was taken up twice more in methylene chloride. After the solvent had been eliminated once more the crude acid chloride was taken up in 20 ml of tetrahydrofuran and added dropwise to a mixture of 0.42 g (2.3 mmol) of N-(2-methoxycarbonylethyl)aniline and 0.92 ml (6.6 mmol) of triethylamine in 30 ml of tetrahydrofuran. After 16 hours' stirring at 50°C the solvent was eliminated and the crude product obtained was purified by chromatography (silica gel; methylene chloride/ethanol = 100:1).
Yield: 0.66 g (770 of theory), Rf value: 0.47 (silica gel; methylene chloride/ethanol -,..-.
19:1) i) 1-Methyl-2-(N-4-cyanopheny:Laminomethyl)-thienoC2.3-dlimidazol-5=yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide To a solution of 0.73 g (1.88 mmol) of 1-methyl-2-methoxymethyl-thieno[2.3-d]im_Ldazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide in 30 ml of methylene chloride were added dropwise at 5°C 2.9 ml (2.9 mmol) of a 1-molar solution of. boron tribromide in methylene chloride. After 16 hours' stirring at ambient temperature the mixture was washed with 20 ml of saturated sodium hydrogen carbonate solution, the organic phase was separated off, dried with sodium sulphate and filtered. The filtrate was mixed with 14 m:1 of N-ethyl-diisopropylamine and 0.43 g (3.64 mmol) of 4-aminobenzonitrile. Then the methylene chloride was distilled off in vacuo, the residue obtained was heated to 50°C :Eor 1 hour and then the residual solvent was distilled off in vacuo. After chromatography (silica gel; rnethylene chloride/ethanol =
99:1 to 97:3) a yellow oil was obtained which slowly solidified.
Yield: 0.37 g (42% of theory), Rf value: 0.29-~(silica gel; methylene chloride/ethanol =
"~ 50:1 + a few drops of ammonia ) j ) 1-Methyl-2- (N- (4-amidinophenyl) aminomethyl] -thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyleth~rl)-amide-hydrochloride 0.38 g (0.80 mmol) of 1-methyl-2-(N-4-cyanophenylaminomethyl)-thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2;-methoxycarbonylethyl)-amide were stirred in 40 ml of ethanol saturated with hydrogen chloride for 5 hours first at 0°C, then later at ambient temperature until no more starting material could be detected by thin layer chromatography. Then the solvent was distilled off at a maximum 28°C bath temperature, the oily residue was taken up in 40 ml of absolute ethanol and mixed with 1.1 g of ammonium carbonate. After 18 hours the solvent was distilled off in vacuo and the crude product was purified by chromatography (silica gel; methylene chloride/ethanol = 9:1 to 4:1).
Yield . 57 % of theory C26H28N603S (504.62) Rf value: 0.21 (silica gel; methylene chloride/ethanol =
4:1 + a few drops of acetic acid) EKA mass spectrum: (M+H)+ - 505 (M+H+Na)++ = 264 - '.L65 -Example 159 1-Methyl-2- [N- (4-amidinophenyl) aminomethyl] -thieno[2.3-d)imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 2 from 1-methyl-2-[N-(4-amidinophenyl) aminomethyl] -th.ieno [2 . 3-d] imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 85 0 of theory, '"' C24H24N603S (476.56) Rf value: 0.36 (Reversed Phase silica gel RP-8; methanol + 5 o saline solution) EKA mass spectrum: (M+H)+ - 477 (M+Na)+ - 499 (M+2Na) ++ = 250 Example 160 1-Methyl-3-[N-(4-amidinopheny:l)thiomethyl]-quinoxalin-2-on-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) 1-Methyl-3-[N-(4-cyanophem~l)thiomethyll-quinoxalin-2-on-6-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonvlethyl)-amide A solution of 2.5 g (7.6 mmol) of 3-amino-4-methylamino-benzoic acid-N-phenyl-N-(2-mei~hoxycarbonylethyl)-amide and 2.4 g (9.6 mmol) of ethyl 3-(4-cyanophenyl)thio-2-oxo-propionate were heated to boiling in 50 ml of ethanol for 30 minutes. After removal of t:he solvent the crude product obtained was purified by chrornatography (silica gel;
methylene chloride).
Yield: 1.6 g (40 0 of theory), Rf value: 0.63 (silica gel; Et:OAc/EtOH/ammonia = 90:10:1) - :L66 -b) 1-Methyl-3-[N-(4-amidinophenyl)thiomethyl]-quinoxalin-2-on-6-yl-carboxylic acid-N-phe:nyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 1 from 1-methyl-3-[N-(4-cyanophenyl)thiomethyl]-quinoxalin-2-on-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol anal ammonium carbonate.
Yield: 23 % of theory, C28H2~N504S (543.64) Rf value: 0.25,~(silica gel; ethyl acetate/ethanol/ammonia ~ - 50:45:5) EKA mass spectrum: (M+H)+ - 544 (M+Na)+ = 566 Example 161 3-Methyl-2- [2- (4-amidinopheny:l) ethyl] -imidazo [1. 2-a] pyridin-7-yl-ca:rboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl)-amide-hydrochloride a) 3-Methyl-2- 2- (4-cvanophen~,rl) ethvll -imidazo 1.2-alpyridin-7-yl-ca~~boxvlic acid-N-phenyl-N-(2-,,,... ethoxycarbonylethyl ) -amide 1 .4 g (4 .6 mmol) of 3-methyl-2- [2- (4-cyanophenyl) ethyl] -imidazo[1.2-a]pyridin-7-yl-carboxylic acid (prepared from 4-bromo-1-(4-cyanophenyl)-1-pe:nten-3-one and methyl 2-aminopyridine-4-carboxylate analogously to Y. Katsura et al. Chem. Pharm. Bull. 1992, 9:0, 1424-1438) were suspended in 15 ml of thionyl chloride amd heated to boiling for 1 hour until fully dissolved. After the thionyl chloride had been distilled off the acid chloride was dissolved in l5 ml of pyridine without any further purification and at 0 mixed with 1.0 g (5.2 mmol) of N-(2-ethoxycarbonylethyl)-aniline. After 1 hour the solvent was distilled off, the residue was taken up in 30 ml of methylene chloride, washed with 15 ml of 1N hydrochloric acid and dried with sodium sulphate. After distillation of the solvent and chromatography (silica gel; methylene chloride/ethanol - 0 to 2 %) a brown oil was obtained.
Yield: 1.48 g (64 0 of theory), Rf value: 0.73 (silica gel; ethyl acetate/ethanol/ammonia =
90:10:1) b) 3-Methyl-2- [2- (4-amidinoph~enyl) ethyll -imidazo[1.2-a]pyridin-7-yl-ca:rboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 1 from 3-methyl-2-[2-(4-a~ cyanophenyl)ethyl]-imidazo[1.:2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 62 % of theory, C29H31N5~3 (497.60) Rf value: 0.23 (silica gel; ei=hyl acetate/ethanol/ammonia - 50:45:5) EKA mass spectrum: (M+H) + = 4!38 Example 162 3-Methyl-2- [2- (4-amidinophenyl) ethyl] -,,...... imidazo [1.2-a] pyridin-7-yl-carboxylic acid-N-phenyl-N- (2-hydroxycarbonylethyl)-amide-hydrochloride Prepared analogously to Examp7_e 2 from 3-methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[7_.2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 92 a of theory, C27H27N5~3 (469.55) Rf value: 0.19 (silica ge:l; ethyl acetate/ethanol/ammonia - 50:45:5) EKA mass spectrum: (M+H)+ - 470 (M+Na) + - 492 - :168 -(M+2H) ++ - 235 . 7 (M+H+Na)-~+ = 246.7 (M+2Na) +-~ - 257 . 7 Example 163 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl.-N-[(N-ethoxycarbonylethyl-N-methyl)-2-aminoethyl]-amide-clihydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-ben.zimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-ethoxycarbonylethyl-N-methyl)-2-aminoethyl]-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 80 % of theory, C31H37N7~3 (555.7) Rf value: 0.24 (silica gel; dichloromethane/methanol = 4:1) EKA mass spectrum: (M+H)+ - 556 2 0 ( M+H+Na ) ++ = 2 8 9 . 8 (M+2H) ++ - 278 . 8 Example 164 1-Methyl-2-[N-(4-amidinopheny:l)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-hydroxycarbonylethyl-N-methyl)-2-aminoethyl]-amide-hydrochloride Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-be~nzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-ethoxycarbonylethyl-N-methyl)-2-aminoethyl]-amide-dihydrochloride and sodium hydroxide solution.
Yield: 79 0 of theory, C2gH33N703 (527.6) - 1.69 -Rf value: 0.43 (Reversed, Phase silica gel RP-18;
methanol/5% aqueous saline solution = 6:4) EKA mass spectrum: (M+H)+ - 528 (M+H+Na)++ = 275.6 (M+2H) ++ - 264 . 6 Example 165 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxy-n-propyl)-amide-hydrochloride Prepared from 1-methyl-2-(N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic .acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide-hydrochloride by hydrogenation over palladium/charcoal (10%) at 5 bar hydrogen pressure and at ambient temperature.
Yield: 61 % of theory, C26H28N602 (456.6) Rf value: 0.70 (Reversed Phass~ silica gel RP-18;
methanol/5% aqueous saline so:Lution = 9:1) EKA mass spectrum: (M+H)+ - 457 ( M+H+Na ) +-~ = 2 4 0 ' - 170 -Example 166 1-Methyl-2- [N- (4- (N-n-hexylo:~cycarbonylamidino)phenyl] -aminomethyl]-benzimidazol-5-girl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-methyl-2-(N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and sodium hydroxide solution.
Yield: 97 % of~theory, ~~ C32H37N7~5 (599.7) Rf value: 0.22 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ - 600 (M+H+Na)+'+ = 311.7 (M+2H)++ - 300.8 (M+2Na)++ - 322.8 Example 167 1-Methyl-2-[N-(4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxy-n-propyl)-amide Prepared analogously to Example 165 from 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino);phenyl] -aminomethyl] -benzimidazol-5-yl-carboxylic .acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide by catalytic debenzylation.
Yield: 26 0 of theory, C33H40N604 (584.7) Rf value: 0.39 (silica gel; d:ichloromethane/ethanol = 9:1 ) EKA mass spectrum: (M+H)+ - 585 (M+H+Na) +~+ = 304 (M+Na) + - 607 - 1.71 -Example 168 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-flu.orophenyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
,.-" Yield: 42 0 of theory, C28H29FN6~3 (516.6) Rf value: 0.31 (silica gel; dichloromethane/methanol = 5:1) EKA mass spectrum: (M+H)+ - 517 ( M+H+Na ) +'+ - 2 7 0 Example 169 1-Methyl-2-[N-(4-amidinopheny:L)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride ~- Prepared analogously to Examp:Le 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-eahoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 90 % of theory, C2gH2gFN603 (516.6) Rf value: 0.29 (silica gel; dichloromethane/methanol = 5:1) EKA mass spectrum: (M+H)+ - 517 (M+H+Na) +~- - 270 - :172 -Example 170 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2--ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 97 % of,theory, ,,... C26H25FN6~3 (488.5) Rf value: 0.13 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ - 489 ( M+Na ) + - 511 (M+2Na) ++' - 267 Example 171 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide ..... Prepared analogously to Example 26 from 1-methyl-2- [N- (4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 89 % of theory, C26H25FN6~3 (488.5) Rf value: 0.15 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ - 489 (M+Na)+ - 511 (M+2Na)++ = 267 Example 172 1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-methoxy-phenyl)-aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, Esthanol and ammonium carbonate.
-,.
Yield: 89 % of theory, C29H32N6~4 (528.6) Rf value: 0.13 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H) + - ~>29 ( M+H+Na ) ++ _ ~: 7 6 (M+2H) ++ - 2 65 Example 173 1-Methyl-2-[N-[4-(N-4-ethylbenzoylamidino)phenyl)-aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-(2-,,-. pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and 4-ethylbenzoylchloride.
Yield: 64 % of theory, C36H37N7~4 (631.7) Rf value: 0.78 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ - 6:32 ( M+H+Na ) ++ = 3 2 7 . 8 (M+Na) + - 654 1-Methyl-2- [N- [4- (N-benzyloxycarbonylamidino) phenyl] -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethox:ycarbonylethyl)-amide-hydrochloride and benzyl chloroformate.
Yield: 64 % of theory, C35H35N7~5 (633.6) Rf value: 0.60 (silica gel; d.ichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ - 634 (M+H+Na)++ = 328.8 (M+Na)+ - 656 1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 71 % of theory, C27H28N604 (500.6) Rf value: 0.15 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ - 501 (M+Na) + - 523 (M+2Na)++ = 273 Example 176 1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 67 % of/theory, C28H31N7~4 (529.6) Rf value: 0.16 (silica gel; dichloromethane/ethanol - 4:1) EKA mass spectrum: (M+H) + _ ~>30 - 1.76 -Example 177 1-Methyl-2-[N-(4-amidino-2-me hoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 78 % of theory, ~- C26H27N7~4 (501.6) Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ = 502 Example 178 1-Methyl-2- [N- [4- (N-benzyloxycarbonylamidino) phenyl] -amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 104 from 1-methyl-2-[N-[4-(N-benzyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and sodium hydroxide solution.
Yield: 62 % of theory, C33H31N7~5 (605.7) Rf value: 0.26 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ - 606 (M+Na) + - 628 (M-H+2Na) ~- - 650 (M+2H)++ - 303.8 (M+H+Na) +~~ - 314 . 8 (M+2Na)++ - 325.7 Example 179 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide-hydrochloride Prepared analogously to Example 25 from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy--n-propyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 61 % of~theory, C33H34N602 (546.7) Rf value: 0.19 (silica gel; clichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ - 547 (M+H+Na)+'+ = 285 Example 180 1-Methyl-2- [N- [4- (N-n-hexylox:ycarbonylamidino)phenyl] -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic ,~-~ acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide-hydrochloride and n-hexyl chloroformate.
Yield: 73 % of theory, C40H46N6~4 (674.9) Rf value: 0.46 (silica gel; dichloromethane/ethanol = 9:1) EKA mass spectrum: (M+H)+ - 675 (M+H+Na)++ = 349 (M+Na) + - 697 (M+K)+ - 713 - :178 -Example 181 3-Methyl-2- [2- (4-amidinophenyl) ethyl] -imidazo[1.2-a]pyridin-7-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide'-hydrochloride Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[1.2-a]pyridin-7-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
,.... Yield : 53 % of theory, C28H30N6~3 (498.59) Rf value: 0.42 (silica gel; ethyl acetate/ethanol/ammonia - 50:45:5) EKA mass spectrum: (M+H)+ - 499 (M+2Na)++ - 272 (M+H+Na)++ = 261 (M+2H)++ - 250 Example 182 1-Methyl-2-[N-(3-amidino-pyridin-6-yl)-aminomethyl]-'"" benzimidazol-5-yl-carboxylic .acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-methyl-2-[N-(3-cyanopyridin-6-yl)-am:inomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide and sodium hydroxide solution.
Yield: 40 % of theory, C24H24N8~3 (472.9) Rf value: 0.67 (Reversed Phase silica gel RP-8; methanol/5%
saline soluti0I1 = 1:1) EKA mass spectrum: (M+H) + = 4'73 - :L79 -Example 183 1-Methyl-2- [N- [4- (N-hydroxylamidino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-(methansulphonylaminocarbonyl)-ethyl]-amide a. 1-Methyl-2-fN-(4-cyanopherwl)-aminomethyll-benzimidazol-5-yl-carbox~rlic acid-N- (2 =pyridyl) -N- f2-(methanesulphonylaminocarbonyl)-ethyl]-amide 2.0 g (4.5 mmol) of 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide and 0.73 g (4.7 mmol) of carbonyldiimida.zole were dissolved in 80 ml of tetrahydrofuran and 5 ml of dimethylformamide and stirred for 30 minutes at ambient temperature and for 2 hours at 90°C. In parallel 0.55 g (5.8 mmol) of methansulphonic acid amide and 0.28 g (5.8 mmol) of sodium hydride were suspended in 15 ml of dimethylformamide and stirred for 2 hours at ambient temperature. Then this suspension was added at ambient temperature to the tetrahydrofuran solution. After 12 hours at ambient temperature 50 ml of water were added and the pH value was adjusted to 6.8. The solution was extracted 4x with methylene chloride, the combined organic phases were dried -- 25 over sodium sulphate and evaporated down. The crude product was chromatographed on silica gel (methylene chloride/ethanol (40:1)). The desired fractions were combined and evaporated down. Yield: 1.05 g (44 0 of theory) , C26H25N7~4S (531.6) Rf value: 0.72 (silica gel; d:ichloromethane/methanol = 9:1) b. 1-Methvl-2-[N-f4-(N-hydroxylamidino)phenyll-aminomethvll-benzimidazol-5-yl-carboxylic acid-N-(2-pvridyl)-N- 2-(methansu'Lphonvlaminocarbonyl)-ethyll-amide Prepared analogously to Example 96 from 1-methyl-2- [N- (4-cyanophenyl) -aminomei:hyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-(methanesulphonylaminocarbonyl)-ethyl]-amide and hydroxylamine.
Yield: 27% of theory, °~~ C26H2gN805S (564.6) Rf value: 0.75 (silica gel; dichloromethane/ethanol = 7:3 +
1% glacial acetic acid) EKA mass spectrum: (M+H)+ - 565 (M+Na)' _ ~~87 Example 184 1-Methyl-2-[N-(5-amidino-thia.zol-2-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride ,,.~ Prepared analogously to Example 25d from 1-methyl-2-[N-(5-cyano-thiazol-2-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Example 185 1-Methyl-2-[N-(5-amidino-thia:zol-2-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-methyl-2-[N-(5-amidino-thiazol-2-yl)--aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Example 186 1-Methyl-2-[N-(2-amidino-pyrazin-5-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 25d from 1-methyl-2-[N-(2-cyano-pyrazin-5-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl>-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 19 0 of theory, C25H27N9~3 (501.6) Rf value: 0.28 (silica gel; dichloromethane/methanol = 4:1 + 1% glacial acetic acid) EKA mass spectrum: (M+H)+ - 502 (M+H+Na)'~ = 262.5 Example 187 1-Methyl-2-[N-(2-amidino-pyrazin-5-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide Prepared analogously to Example 26 from 1-methyl-2-[N-(2-amidino-pyrazin-5-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Yield: 11 % of theory, C23H23N9~3 (473.5) - :L82 -Rf value: 0.55 (Reversed Phase silica gel RP-8; 5% saline solution/methanol = 6:4) EKA mass spectrum: (M+H)+ - 474 ( M+H+Na ) ~- - 4 9 6 . 6 Example 188 1-Methyl-2- [2- [4- (N-n-hexylo~ycarbonylamidino) phenyl] -ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)-ethyl]-amide ,.-Prepared analogously to Example 90 from 1-methyl-2-[2-(4-amidinophenyl)-ethyl]-benzimi.dazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)-ethyl]-amide and n-hexyl chloroformate.
Example 189 1-Methyl-2-[N-(2-methoxy-4-n-pentoxycarbonylamidino phenyl)-aminomethyl]-benzimid.azol-5-yl-carboxylic acid-N
phenyl-N-(2-ethoxycarbonyleth.yl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-~- amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-pentyl chloroformate.
Yield: 53 % of theory, C3 SH42~'T6~6 ( 642 . 7 ) Rf value: 0.54 (silica gel; dichloromethane/ethanol = 9:1 ) EKA mass spectrum: (M+H)+ - 643 (M+H+Na)++ = 333.4 Example 190 1-Methyl-2-[N-(4-n-heptyloxycarbonylamidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyletlzyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4 amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and n-heptyl chloroformate.
Yield: 68 % of,~ theory, '"' C37H46N606 (670.8) Rf value: 0.56 (silica gel; dichloromethane/ethanol = 9:1 ) EKA mass spectrum: (M+H)+ - 671 ( M+H+Na ) 'c-+ = 3 4 7 . 4 Example 191 1-Methyl-2-[N-(4-ethoxycarbor~ylamidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-~~1-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyleahyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-A~ amidino-2-methoxy-phenyl)-ami.nomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and ethyl chloroformate.
Yield: 43 % of theory, C31H35N706 (601.7) Rf value: 0.44 (silica gel; d.ichloromethane/ethanol = 9:1) EKA mass spectrum: (M+H)+ - 602 (M+H+Na)++ = 312.8 - :L 8 4 -Example 192 1-Methyl-2-[N-(2-methoxy-4-n~-pentoxycarbonylamidino-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-pentyl chloroformate.
Yield: 72 % of theory, '""" C34H41N7~6 (643.7) Rf value: 0.49 (silica gel; dichloromethane/ethanol = 9:1) EKA mass spectrum: (M+H)+ - 644 (M+H+Na)+'+ = 333.9 Example 193 1-Methyl-2-[N-(2-methoxy-4-n-heptyloxycarbonylamidino-phenyl)-aminomethyl]-benzimid.azol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-heptyl chloroformate.
Yield: 55 % of theory, C36H45rT7~6 (671.8) Rf value: 0.54 (silica gel; dichloromethane/ethanol = 9:1) EKA mass spectrum: (M+H)+ - 672 ( M+H+Na ) ++ = 3 4 7 . 9 Example 194 Dry ampoule containing 75 mg of active substance per 10 ml Composition:
Active substance 75.0 mg Mannitol 50.0 mg water for injections ad 10.0 ml .~-~ Preparation Active substance and mannito7_ are dissolved in water.
After packaging the solution is freeze-dried. To produce the solution ready for use, t:he product is dissolved in water for injections.

Example 195 Dry ampoule containing 35 mg of active substance per 2 ml Composition:
Active substance 35.0 mg Mannitol 100.0 mg water for injections ad 2.0 ml Preparation:
Active substance and mannito7_ are dissolved in water. After packaging, the solution is freeze-dried.
To produce the solution ready for use, the product is dissolved in water for injections.
Example 196 Tablet containing 50 mg of 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 mq 215.0 mg Preparation:
(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.
Diameter of the tablets: 9 mm.
Example 197 Tablet containing 350 mg of active substance Preparation:
(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.O mct 600.0 mg (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.
Diameter of the tablets: 12 mm.
~'~ 2 5 Example 198 Capsules containing 50 mg of 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 ma 160.0 mg Preparation:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into size 3 hard gelatin capsules in a capsule filling machine.
Example 199 Capsules containing 350 mg of 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 mct 430.0 mg Preparation:
(1) is triturated with (3). This trituration is added to the mixture of ( 2 ) and ( 4 ) with vigorous mixing .
This powder mixture is packed into size 0 hard gelatin ""~ 25 capsules in a capsule filling machine.
Example 200 Suppositories containing 100 mg of active substance 1 suppository contains:
Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitan monostearate 840.0 ma 2,000.0 mg

Claims (39)

CLAIMS:
1. A disubstituted bicyclic heterocycle of general formula R a - A - Het - B - Ar - E, (I) wherein A denotes a carbonyl or sulphonyl group linked to the benzo, pyrido or thieno moiety of the group Het, B denotes an ethylene group in which the methylene group linked to the group Ar is optionally replaced by an oxygen or sulphur atom or by an -NR1- group, wherein R1 denotes a hydrogen atom or a C1-4-alkyl group, E denotes an Rb NH-C(=NH)- group wherein Rb denotes a hydrogen atom, a hydroxy, C1-9-alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C1-3-alkoxycarbonyl, benzoyl, p-C1-3-alkyl-benzoyl or pyridinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C1-9-alkoxycarbonyl group is optionally substituted by a C1-3-alkyl-sulphonyl or 2-(C1-3-alkoxy)-ethyl group, Ar denotes a 1,4-phenylene group optionally substituted by a chlorine atom or by a methyl, ethyl or methoxy group or Ar denotes a 2,5-thienylene group, Het denotes a 1-(C1-3-alkyl)-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-(C1-3-alkyl) -2,5-indolylene, 1-(C1-3-alkyl)-2,5-imidazo[4,5-b]pyridinylene, 3-(C1-3-alkyl)-2,7-imidazo[1,2-a]pyridinylene or 1-(C1-3-alkyl)-2,5-thieno[2,3-d]imidazolylene group and Ra denotes an R2NR3- group wherein R2 is a C1-4-alkyl group optionally substituted by a carboxy, C1-6-alkyloxycarbonyl, benzyloxycarbonyl, C1-3-alkylsulphonylaminocarbonyl or 1H-tetrazol-5-yl group, or a C2-9-alkyl group substituted by a hydroxy, benzyloxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl-C1-3-alkylamino, N-(C1-3-alkyl)-carboxy-C1-3-alkylamino or N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino group, whilst in the abovementioned groups the carbon atom in the .alpha.-position to the adjacent nitrogen atom is not substituted, R3 denotes a C3-7-cycloalkyl group; a propargyl group, wherein the unsaturated part is not linked directly to the nitrogen atom of the R2NR3 group; a phenyl group optionally substituted by a fluorine or chlorine atom, or by a methyl or methoxy group; a pyrazoyl, pyridazolyl or pyridinyl group optionally substituted by a methyl group or R2 and R3 together with the nitrogen atom between them denote a 5- to 7-membered cycloalkyleneimino group, optionally substituted by a carboxy or C1-4-alkoxycarbonyl group, to which a phenyl ring is optionally fused, or a tautomer, stereoisomer or salt thereof.
2. A disubstituted bicyclic heterocycle of general formula I or tautomer, stereoisomer or salt thereof according to claim 1, wherein R1 denotes a hydrogen atom or a methyl group, Rb denotes a hydrogen atom, a hydroxy, C1-9-alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C1-3-alkylbenzoyl or nicotinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C1-9-alkoxycarbonyl group is optionally substituted by a C1-3-alkylsulphonyl or 2-(C1-3-alkoxy)-ethyl group, Het denotes a 1-methyl-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene, 1-methyl-2,5-imidazo[4,5-b]pyridinylene,3-methyl-2,7-imidazo[1,2-a]pyridinylene or 1-methyl-2,5-thieno[2,3-d]imidazolylene group, R2 denotes a C1-3-alkyl group optionally substituted by a carboxy, C1-6-alkoxycarbonyl, benzyloxycarbonyl, methylsulphonylaminocarbonyl or 1H-tetrazol-5-yl group, a C2-3-alkyl group substituted by a hydroxy, benzyloxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl-C1-3-alkylamino, N-(C1-3-alkyl)-carboxy-C1-3-alkylamino or N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino group, whilst in the abovementioned groups the carbon atom in the .alpha.-position to the adjacent nitrogen atom is not substituted, and R3 denotes a propargyl group, wherein the unsaturated moiety is not linked directly to the nitrogen atom of the R2NR3 group, a phenyl group optionally substituted by a fluorine or chlorine atom, or by a methyl or methoxy group, or R3 denotes a pyridinyl group.
3. A disubstituted bicyclic heterocycle of general formula I or tautomer, stereoisomer or salt thereof according to claim 1, wherein A denotes a carbonyl group linked to the benzo or thieno moiety of the group Het, R1 denotes a hydrogen atom or a methyl group, Rb is a hydrogen atom, a hydroxy, C1-9-alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C1-3-alkyl-benzoyl or nicotinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C1-9-alkoxycarbonyl group is optionally substituted by a methylsulphonyl or 2-ethoxy-ethyl group, Ar denotes a 1,4-phenylene group optionally substituted by a methoxy group or Ar denotes a 2,5-thienylene group, Het denotes a 1-methyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene or 1-methyl-2,5-thieno[2,3-d]imidazolylene group and R2 denotes a C1-3-alkyl group optionally substituted by a carboxy, C1-6-alkyloxycarbonyl, benzyloxycarbonyl, methylsulphonylaminocarbonyl or 1H-tetrazol-5-yl group, or a C2-3-alkyl group substituted by a hydroxy, benzyloxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl-C1-3-alkylamino, N-(C1-3-alkyl)-carboxy-C1-3-alkylamino or N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino group, whilst in the abovementioned groups the carbon atom in the .alpha.-position to the adjacent nitrogen atom is not substituted, and R3 denotes a phenyl group optionally substituted by a fluorine atom, or R3 denotes a 2-pyridinyl group.
4. 2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)-amide, or a tautomer, stereoisomer or salt thereof.
5. 2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benz~hiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, or a tautomer, stereoisomer or salt thereof.
6. 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, or a tautomer, stereoisomer or salt thereof.
7. 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl)-amide, or a tautomer, stereoisomer or salt thereof.
8. 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide, or a tautomer, stereoisomer or salt thereof.
9. 1-Methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, or a tautomer, stereoisomer or salt thereof.
10. 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, or a tautomer, stereoisomer or salt thereof.
11. 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, or a tautomer, stereoisomer or salt thereof.
12. 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, or a tautomer, stereoisomer or salt thereof.
13. 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide, a tautomer, stereoisomer or salt thereof.
14. 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide, a tautomer, stereoisomer or salt thereof.
15. 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, a tautomer, stereoisomer or salt thereof.
16. 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, a tautomer, stereoisomer or salt thereof.
17. 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, a tautomer, stereoisomer or salt thereof.
18. 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-hydroxycarbonylethyl-N-methyl)-2-aminoethyl]-amide, a tautomer, stereoisomer or salt thereof.
19. 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide, a tautomer, stereoisomer or salt thereof.
20. 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide, a tautomer, stereoisomer or salt thereof.
21. 1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, a tautomer, stereoisomer or salt thereof.
22. 1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, a tautomer, stereoisomer or salt thereof.
23. 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide, a tautomer, stereoisomer or salt thereof.
24. 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]-thieno[2,3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, a tautomer, stereoisomer or salt thereof.
25. 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, or a salt thereof.
26. 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, or a salt thereof.
27. 1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, or a salt thereof.
28. 1-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide, or a salt thereof.
29. A physiologically acceptable salt of a compound according to any one of claims 1 to 28.
30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28 or a salt according to claim 29 and a pharmaceutically acceptable diluent or carrier.
31. A pharmaceutical composition according to claim 30 for prolonging thrombin time, a thrombin-inhibiting effect or an inhibiting effect on a related serine protease.
32. A use of a compound according to any one of claims 1 to 28 or a salt according to claim 29, in preparing a pharmaceutical composition for prolonging thrombin time, a thrombin-inhibiting effect or an inhibiting effect on a related serine protease.
33. A use of a compound according to any one of claims 1 to 28 or a salt according to claim 29, for prolonging thrombin time, a thrombin-inhibiting effect or an inhibiting effect on a related serine protease.
34. A compound according to any one of claims 1 to 28 or a salt according to claim 29, for prolonging thrombin time, a thrombin-inhibiting effect or an inhibiting effect on a related serine protease.
35. A process for preparing a pharmaceutical composition according to claim 30, wherein a compound according to any one of claims 1 to 28, or a salt according to claim 29, is admixed with a pharmaceutically acceptable carrier or diluent.
36. A process for preparing a compound according to claim 1, wherein a. in order to prepare a compound of general formula I, wherein E denotes an R b NH-C(=NH)- group, wherein R b is a hydrogen atom or a hydroxy group, a compound of general formula R a - A - Het - B - Ar - C (=NH) - Z1 (II) wherein A, B, Ar, Het and R a are defined as in claim 1 and Z1 denotes an alkoxy, aralkoxy, alkylthio or aralkylthio group, is reacted with an amine of general formula H2N-R b', (III) wherein R b' denotes a hydrogen atom or a hydroxy group, or b. in order to prepare a compound of general formula I, wherein the R a -A-group and E are defined in claim 1 with the proviso that the R a -A-group contains a carboxy group and E is defined as in claim 1 or the R a -A-group is defined as in claim 1 and E denotes an NH2-C(=NH)- group, or the R a -A-group contains a carboxy group and E denotes an NH2-C(=NH)- group, a compound of general formula R a' - A - Het - B - Ar - E', (IV) wherein B, Ar and Het are defined in claim 1 and the R a' -A- group and E' have the meanings given for the R a -A- group and E in claim 1, with the proviso that the R a' -A- group contains a group which is convertible into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and E is defined as in claim 1 or E' denotes a group which is convertible into an NH2-C (=NH)- group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and the R a' -A- group has the meanings given for the R a -A- group in claim 1, or the R a' -A- group contains a group which is convertible into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and E' denotes a group which is convertible into an NH2-C(=NH)- group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis, is converted, by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis, into a compound of general formula I, wherein the R a -A- group and E are defined as in claim 1, with the proviso that the R a -A- group contains a carboxy group and E is defined as in claim 1 or the R a -A- group has the meanings given in claim 1 and E
denotes an NH2-C(=NH)- group or the R a -A- group contains a carboxy group and E denotes an NH2-C(=NH)- group, or c. in order to prepare a compound of general formula I wherein the R a -A- group contains one of the ester groups mentioned in the definition of the R a -A- group in claim 1, a compound of general formula R a" - A - Het - B - Ar - E, (V) wherein B, E, Ar and Het are defined as in claim 1 and R a" -A- group has the meanings given for the R a -A- group in claim 1, with the proviso that the R a" -A- group contains a carboxyl group or a group which is convertible by means of an alcohol into a corresponding ester group, is reacted with an alcohol of general formula HO - R7, (VI) wherein R7 denotes a C1-6-alkyl or benzyl group, or with the formamide acetals thereof or with a compound of general formula Z2 - R8 (VII) wherein R8 denotes a C1-6-alkyl or benzyl group and Z2 denotes a leaving group, or d. in order to prepare a compound of general formula I wherein R b denotes a C1-9-alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C1-3-alkoxycarbonyl, benzoyl, p-C1-3-alkyl-benzoyl or pyridinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C1-9-alkoxycarbonyl group is optionally substituted by a C1-3-alkylsulphonyl or 2-(C1-3-alkoxy)-ethyl group, a compound of general formula R a - A - Het - B - Ar - C (=NH) - NH2, (VIII) wherein R a, A, Het, B and Ar are defined as in claim 1, is reacted with a compound of general formula Z3-R5, ~ (IX) wherein R5 denotes a C1-9-alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C1-3-alkoxycarbonyl, benzoyl, p-C1-3-alkyl-benzoyl or pyridinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C1-9-alkoxycarbonyl group is optionally substituted by a C1-3-alkylsulphonyl or 2-(C1-3-alkoxy)-ethyl group, and Z3 denotes a nucleofugic leaving group, or e. in order to prepare a benzimidazolyl or benzothiazolyl compound of general formula I, wherein B
denotes an ethylene group, a compound of general formula wherein R a and A are defined as in claim 1 and Y denotes a sulphur atom, or a nitrogen atom substituted by a C1-3alkyl or cyclopropyl group, is reacted with a compound of general formula HO-CO-CH2CH2-Ar-E, (XVI) wherein Ar and E are defined as in claim 1, or with the reactive derivatives thereof and f. in order to prepare a compound of general formula I wherein R2 denotes a C1-4-alkyl group substituted by an alkylsulphonylaminocarbonyl group:

a compound of general formula wherein R3, A, B, E, Ar and Het are defined as in claim 1 and R2' denotes a C1-4-alkyl group substituted by a carboxy group, or a reactive derivative thereof, is reacted with a salt of a compound of general formula C1-3-Alkyl-SO2-NH2, (XX) , and, optionally, a protecting group used during one of the reactions in order to protect a reactive group is cleaved.
37. A process according to claim 36, wherein, in the reaction set out in paragraph a., the compound of general formula (II) is formed in the reaction mixture in which the compound of general formula I is formed.
38. A process according to any one of claims 36 and 37, wherein a compound of general formula I thus obtained is resolved into stereoisomers thereof.
39. A process according to any one of claims 36 to 38, wherein a compound of general formula I thus obtained is converted into a salt thereof, with an inorganic or organic acid or base.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8981105B2 (en) 2010-07-09 2015-03-17 Esteve Quimica, S.A. Process of preparing a thrombin specific inhibitor

Families Citing this family (170)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU1608399A (en) * 1997-11-26 1999-06-15 Axys Pharmaceuticals, Inc. Substituted amidinoaryl derivatives and their use as anticoagulants
US6114532A (en) * 1998-02-03 2000-09-05 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, the preparation thereof, and their use as pharmaceuticals
CA2319494A1 (en) * 1998-02-03 1999-08-12 Boehringer Ingelheim Pharma Kg 5-membered heterocyclic condensed benzoderivatives, the preparation thereof and their use as pharmaceuticals
JP2002502852A (en) * 1998-02-09 2002-01-29 ３−ディメンショナル ファーマシューティカルズ， インコーポレイテッド Heteroarylamidines, methylamidines and guanidines as protease inhibitors, especially urokinase inhibitors
US6291514B1 (en) 1998-02-09 2001-09-18 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines, preparation thereof, and use thereof as protease inhibitors
TWI248435B (en) * 1998-07-04 2006-02-01 Boehringer Ingelheim Pharma Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions
US6248770B1 (en) 1998-07-09 2001-06-19 Boehringer Ingelheim Pharma Kg Benzimidazoles having antithrombotic activity
CA2362390A1 (en) * 1999-02-09 2000-08-17 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines as protease inhibitors
DE19907813A1 (en) * 1999-02-24 2000-08-31 Boehringer Ingelheim Pharma Substituted bicyclic heterocycles, their preparation and their use as pharmaceuticals
AR023510A1 (en) 1999-04-21 2002-09-04 Astrazeneca Ab A TEAM OF PARTS, PHARMACEUTICAL FORMULATION AND USE OF A THROMBIN INHIBITOR.
US6512000B1 (en) 1999-08-20 2003-01-28 Boehringer Ingelheim Pharma Kg Aminocarbonyl-substituted benzimidazoles having tryptase-inhibitory activity
DE19939463A1 (en) * 1999-08-20 2001-02-22 Boehringer Ingelheim Pharma Tryptase inhibitors useful e.g. for treating inflammatory or allergic disease, arteriosclerosis or neoplasia, comprising new or known 2-phenethyl-benzimidazole-5-carboxamides
DE50001742D1 (en) * 1999-09-24 2003-05-15 Boehringer Ingelheim Pharma ARYLSULFONAMIDE SUBSTITUTED BENZIMIDAZOLE DERIVATIVES AND THEIR USE AS TRYPTASE INHIBITORS
US6413990B1 (en) 1999-09-24 2002-07-02 Boehringer Ingelheim Pharma Kg Arylsulphonamide-substituted benzimidazoles having tryptase-inhibiting activity
DE19945787A1 (en) 1999-09-24 2001-03-29 Boehringer Ingelheim Pharma New 2-(amidino- or aminomethyl-phenethyl)-5-sulfonylamino-benzimidazoles, are tryptase inhibitors useful e.g. for treating inflammatory or allergic disease such as asthma, urticaria or arthritis
DE19945810A1 (en) * 1999-09-24 2001-03-29 Boehringer Ingelheim Pharma Substituted benzimidazole derivatives, process for their preparation and their use as medicaments
US6407130B1 (en) 1999-11-10 2002-06-18 Boehringer Ingelheim Pharma Kg Carboxamide-substituted benzimidazoles having tryptase-inhibiting activity
US6451832B2 (en) 1999-12-23 2002-09-17 Boehringer Ingelheim Pharma Kg Benzimidazoles with antithrombotic activity
US6448281B1 (en) * 2000-07-06 2002-09-10 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
MXPA03009497A (en) 2001-04-19 2004-05-24 Eisai Co Ltd 2-iminopyrrolidine derivatives.
DE10133786A1 (en) * 2001-07-16 2003-02-06 Boehringer Ingelheim Pharma Use of thrombin inhibitors for the treatment of arthritis
PT1870100E (en) * 2002-03-07 2012-04-17 Boehringer Ingelheim Int Ethyl 3-(2-(4-(hexyloxycarbonylamidino)phenylaminomethyl)-1-methyl-1h-benzimidazole-5-carbonyl)-2-pyridylamino)propionate methansulfonate
US20030181488A1 (en) * 2002-03-07 2003-09-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof
DE10235639A1 (en) * 2002-08-02 2004-02-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg New prodrugs of benzimidazole-5-carboxamide derivative thrombin inhibitor, useful for treating or preventing thrombotic diseases, are well tolerated on subcutaneous injection
JP2005535710A (en) 2002-08-09 2005-11-24 トランス　テック　ファーマ，インコーポレイテッド Aryl and heteroaryl compounds and methods for modulating coagulation
PE20040804A1 (en) 2002-12-19 2004-12-31 Boehringer Ingelheim Pharma CARBOXAMID DERIVATIVES AS INHIBITORS OF THE Xa FACTOR
US7429597B2 (en) 2002-12-23 2008-09-30 Boehringer Ingelheim Pharma Gmbh & Co., Kg Substituted nitrogen-containing heterobicycles, the preparation thereof and their use as pharmaceutical compositions
DE10260730A1 (en) * 2002-12-23 2004-07-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel substituted nitrogen-containing heterobicyclene, their preparation and their use as pharmaceuticals
CA2515715C (en) 2003-02-19 2012-05-08 Eisai Co., Ltd. Methods for producing cyclic benzamidine derivatives
DE10310278A1 (en) * 2003-03-10 2004-09-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg New N-(benzazinyl)-(hetero)aralkylamine derivatives, are inhibitors of factor Xa and/or related serine proteases, useful e.g. as antithrombotic agents and intermediates
EP2062580A1 (en) * 2003-04-24 2009-05-27 Boehringer Ingelheim International GmbH Use of dipyridamole or mopidamole for treatment and prevention of thromboembolic diseases and disorders caused by excessive formation of thrombin and/or by elevated expression of trombin receptors
US7208601B2 (en) 2003-08-08 2007-04-24 Mjalli Adnan M M Aryl and heteroaryl compounds, compositions, and methods of use
WO2005014534A1 (en) * 2003-08-08 2005-02-17 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use
US7544699B2 (en) 2003-08-08 2009-06-09 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use
DE10337697A1 (en) * 2003-08-16 2005-03-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tablet containing 3 - [(2 - {[4- (hexyloxycarbonylamino-iminomethyl) -phenyl-amino] -methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] - propionic acid ethyl ester or its salts
DE10339862A1 (en) 2003-08-29 2005-03-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg New crystalline forms of ethyl 3-(N-(2-(4-(hexyloxycarbonylamidino)phenylaminomethyl)-1-methyl-1H-benzimidazole-5-carbonyl)-N-(2-pyridyl)amino)propionate methanesulfonate used for post-operative prophylaxis of deep vein thrombosis
DE10341043A1 (en) * 2003-09-03 2005-03-31 Boehringer Ingelheim Pharma Gmbh & Co. Kg New Oral Dosage Form for 3 - [(2 - {[4-hexyloxycarbonylamino-imino-methyl) -phenyl-amino] -methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] Propionic acid ethyl ester and its salts
EP1609784A1 (en) * 2004-06-25 2005-12-28 Boehringer Ingelheim Pharma GmbH & Co.KG Process for the preparation of 4-(benzimidazolylmethylamino)-benzamidines
US20060222640A1 (en) * 2005-03-29 2006-10-05 Boehringer Ingelheim International Gmbh New pharmaceutical compositions for treatment of thrombosis
DE102005020002A1 (en) * 2005-04-27 2006-11-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg New hexyloxycarbonylamino-imino-methyl-phenylamino-methyl-benzimidazole-pyridine-propionic acid-ethyl ester salts such as hydrochloride useful for the prophylaxis of vein thrombosis and stroke
DE102005025728A1 (en) * 2005-06-04 2006-12-07 Boehringer Ingelheim Pharma Gmbh & Co. Kg Polymorphs of 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenyl-amino] -methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] -propionic acid ethyl ester
US7700620B2 (en) 2005-06-27 2010-04-20 Bristol-Myers Squibb Company C-linked cyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
DE102005061623A1 (en) 2005-12-21 2007-06-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Improved process for the preparation of 4- (benzimidazolylmethylamino) -benzamidines and their salts
DE102005061624A1 (en) * 2005-12-21 2007-06-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Improved process for the preparation of salts of 4- (benzimidazolylmethylamino) -benzamidines
EP1996541B1 (en) 2006-03-09 2014-04-23 Bristol-Myers Squibb Company 2-(aryloxy)acetamide factor viia inhibitors useful as anticoagulants
CN101500993A (en) 2006-06-08 2009-08-05 百时美施贵宝公司 2-aminocarbonylphenylamino-2-phenilacetamides as factor VIIa inhibitors useful as anticoagulants
JP2009543843A (en) * 2006-07-17 2009-12-10 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング New indications for direct thrombin inhibitors
EP2043631A2 (en) * 2006-07-17 2009-04-08 Boehringer Ingelheim International GmbH New indications for direct thrombin inhibitors in the cardiovascular field
EP2074112A1 (en) * 2006-10-10 2009-07-01 Boehringer Ingelheim International GmbH Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester
JP5342450B2 (en) 2006-12-15 2013-11-13 ブリストル−マイヤーズ スクイブ カンパニー Arylpropionamide, arylacrylamide, arylpropinamide, or arylmethylurea analogs as factor XIa inhibitors
PE20081775A1 (en) 2006-12-20 2008-12-18 Bristol Myers Squibb Co MACROCYCLIC COMPOUNDS AS INHIBITORS OF FACTOR VIIA
EP1956018A1 (en) * 2007-02-06 2008-08-13 Boehringer Ingelheim Pharma GmbH & Co. KG Method of preparing a derivative of benzimidazole
BRPI0810462A2 (en) 2007-04-23 2014-10-14 Sanofi Aventis KINOLIN-CARBOXAMIDE DERIVATIVES AS P2Y12 ANTAGONISTS
EP2178849A1 (en) 2007-07-31 2010-04-28 Mallinckrodt Inc. Integrated photoactive agents and uses thereof
JP5504171B2 (en) 2007-12-26 2014-05-28 サノフイ Heterocyclic pyrazole-carboxamides as P2Y12 antagonists
CZ305085B6 (en) * 2008-03-14 2015-04-29 Zentiva, K.S. Process for preparing dabigatran
AR072557A1 (en) * 2008-07-14 2010-09-08 Boehringer Ingelheim Int PROCESS TO PREPARE COMPOSITIONS OF DRUGS CONTAINING DABIGATRAN
JP2012500243A (en) * 2008-08-19 2012-01-05 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Use of dabigatran etexilate for the treatment of patients with pulmonary hypertension
CZ2008669A3 (en) * 2008-10-24 2010-05-05 Zentiva, A. S. Process for preparing dabigatran and intermediates thereof
WO2010086329A1 (en) * 2009-02-02 2010-08-05 Boehringer Ingelheim International Gmbh Lyophilised dabigatran
EP2429520A1 (en) 2009-05-14 2012-03-21 Boehringer Ingelheim International GmbH New combination therapy in treatment of oncological and fibrotic diseases
TW201124143A (en) 2009-08-24 2011-07-16 Boehringer Ingelheim Int Emergency interventions of active charcoal with dabigatran etexilate overdosing
CN102050815B (en) * 2009-11-06 2014-04-02 北京美倍他药物研究有限公司 Dabigatran ester derivatives as prodrug
CN102050814B (en) * 2009-11-06 2014-05-28 北京美倍他药物研究有限公司 Ester derivatives of dabigatran
US8399678B2 (en) * 2009-11-18 2013-03-19 Boehringer Ingelheim International Gmbh Process for the manufacture of dabigatran etexilate
AR079944A1 (en) * 2010-01-20 2012-02-29 Boehringer Ingelheim Int NEUTRALIZING ANTIBODY OF THE ACTIVITY OF AN ANTICOAGULANT
HUP1000069A2 (en) 2010-02-02 2012-05-02 Egis Gyogyszergyar Nyilvanosan M Kod Ruszvunytarsasag New salts for the preparation of pharmaceutical composition
ES2674745T3 (en) 2010-02-11 2018-07-03 Bristol-Myers Squibb Company Macrocycles as inhibitors of factor XIa
ES2509117T3 (en) 2010-03-01 2014-10-17 Ratiopharm Gmbh Oral pharmaceutical composition containing dabigatran etexilate
EP2545044A1 (en) 2010-03-08 2013-01-16 ratiopharm GmbH Dabigatran etexilate-containing pharmaceutical composition
WO2012001156A2 (en) 2010-07-01 2012-01-05 Krka, Tovarna Zdravil, D.D., Novo Mesto Pharmaceutical oral dosage forms comprising dabigatran etexilate and its pharmaceutically acceptable salts
WO2012004397A1 (en) 2010-07-09 2012-01-12 Esteve Química, S.A. Intermediates and process for preparing a thrombin specific inhibitor
WO2012027543A1 (en) 2010-08-25 2012-03-01 Teva Pharmaceuticals Usa, Inc. Solid state forms of dabigatran etexilate, dabigatran etexilate mesylate and processes for preparation thereof
WO2012077136A2 (en) 2010-12-06 2012-06-14 Msn Laboratories Limited Process for the preparation of benzimidazole derivatives and its salts
JP5931752B2 (en) 2011-02-01 2016-06-08 協和発酵キリン株式会社 Fused heterocyclic derivatives
JP2014515740A (en) 2011-03-30 2014-07-03 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Anticoagulant antidote
HUP1100244A2 (en) 2011-05-11 2012-11-28 Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag Pharmaceutical intermediates and process for their production
CN102250099B (en) * 2011-05-16 2013-10-16 中国药科大学 Non-peptide thrombin inhibitors as well as preparation method and medical application thereof
CN102838588B (en) * 2011-06-24 2014-03-19 中国药科大学 Oral thrombin inhibitors, preparation methods and medical uses thereof
PL2550966T3 (en) * 2011-07-25 2017-03-31 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Amidoxime carboxylic acid esters of dabigatran as prodrugs and their use as medicament
TW201311689A (en) 2011-08-05 2013-03-16 必治妥美雅史谷比公司 Novel macrocycles as factor XIa inhibitors
TW201319068A (en) 2011-08-05 2013-05-16 必治妥美雅史谷比公司 Cyclic P1 linkers as factor XIa inhibitors
WO2013024394A1 (en) * 2011-08-12 2013-02-21 Alembic Pharmaceuticals Limited Novel reference markers of dabigatran etexilate
CN102993174A (en) * 2011-09-08 2013-03-27 天津药物研究院 Dabigatran etexilate derivative as a prodrug
CN102993175B (en) * 2011-09-08 2014-08-13 天津药物研究院 Dabigatran derivatives, and preparation method and application thereof
PT2766346T (en) 2011-10-14 2017-05-26 Bristol Myers Squibb Co Substituted tetrahydroisoquinoline compounds as factor xia inhibitors
IN2014CN02805A (en) 2011-10-14 2015-07-03 Bristol Myers Squibb Co
CN103987697B (en) 2011-10-14 2017-04-26 百时美施贵宝公司 Substituted tetrahydroisoquinoline compounds as factor XIA inhibitors
AU2012357956A1 (en) 2011-12-22 2014-05-22 Boehringer Ingelheim International Gmbh Immediate release multi unit pellet system
US9212166B2 (en) 2012-01-20 2015-12-15 Cadila Healthcare Limited Process for the preparation of dabigatran etexilate mesylate and polymorphs of intermediates thereof
EP2806858A1 (en) 2012-01-24 2014-12-03 Boehringer Ingelheim International Gmbh Novel orally administered dabigatran formulation
CN110123774A (en) 2012-02-21 2019-08-16 埃斯蒂维制药有限公司 The combination of oral medication of dabigatran etcxilate
EP2631234A1 (en) 2012-02-23 2013-08-28 Esteve Química, S.A. Solid forms of dabigatran etexilate mesylate and processes for their preparation
WO2013144971A1 (en) 2012-03-27 2013-10-03 Cadila Healthcare Limited New solid forms of dabigatran etexilate bisulfate and mesylate and processes to prepare them
WO2013150545A2 (en) 2012-04-02 2013-10-10 Msn Laboratories Limited Process for the preparation of benzimidazole derivatives and salts thereof
CN103387566B (en) * 2012-05-09 2015-09-09 上海医药工业研究院 Prepare the method for 3-[[[2-[[(4-cyano-phenyl) is amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] ethyl propionate
CN103420980A (en) * 2012-05-22 2013-12-04 北京美倍他药物研究有限公司 Dabigatran derivatives
WO2014001220A1 (en) 2012-06-25 2014-01-03 Boehringer Ingelheim International Gmbh Method for prevention of stroke
WO2014012880A1 (en) 2012-07-16 2014-01-23 Interquim, S.A. Process for the preparation of intermediates for the synthesis of dabigatran etexilate, and crystalline forms of said intermediates
CN102766134B (en) * 2012-07-19 2014-06-25 北京普禄德医药科技有限公司 Dabigatran etexilate derivative and preparation method and application thereof
WO2014021383A1 (en) * 2012-07-31 2014-02-06 協和発酵キリン株式会社 Condensed ring heterocyclic compound
CA2880898A1 (en) 2012-08-03 2014-02-06 Bristol-Myers Squibb Company Dihydropyridone p1 as factor xia inhibitors
CA2880866A1 (en) 2012-08-03 2014-02-06 Bristol-Myers Squibb Company Dihydropyridone p1 as factor xia inhibitors
WO2014041559A2 (en) * 2012-08-27 2014-03-20 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for the preparation of dabigatran etexilate and intermediates thereof
EP2722033A1 (en) 2012-10-19 2014-04-23 Sanovel Ilac Sanayi ve Ticaret A.S. Pharmaceutical Compositions of Dabigatran Free Base
WO2014060561A1 (en) 2012-10-19 2014-04-24 Sanovel Ilac Sanayi Ve Ticaret A.S. Oral pharmaceutical formulations comprising dabigatran
US9399616B2 (en) 2012-10-22 2016-07-26 Boehringer Ingelheim International Gmbh Process for the manufacture of 4-aminobenzoamidine dihydrochloride
WO2014068587A2 (en) * 2012-10-29 2014-05-08 Biophore India Pharmaceuticals Pvt. Ltd. An improved process for the synthesis of dabigatran and its intermediates
US10077251B2 (en) 2012-10-29 2018-09-18 Biophore India Pharmaceuticals Pvt. Ltd. Process for the synthesis of Dabigatran Etexilate and its intermediates
CN102977077A (en) * 2012-11-28 2013-03-20 浙江燎原药业有限公司 Method for preparing dabigatran etexilate intermediate
EP2740471B1 (en) 2012-12-07 2015-05-27 Hexal AG Oral pharmaceutical composition comprising dabigatran etexilate
CN103044404A (en) * 2013-01-14 2013-04-17 中国药科大学 Dabigatran derivatives, and preparation method and application thereof in antithrombosis
ES2712699T3 (en) 2013-03-25 2019-05-14 Bristol Myers Squibb Co Tetrahydroisoquinolines containing substituted azoles as inhibitors of factor XIa
CN103224469A (en) * 2013-05-16 2013-07-31 上海应用技术学院 Pradaxa analogue with fluorine-containing group modified benzene ring as center and synthesis method thereof
UY35592A (en) 2013-06-03 2014-12-31 Bayer Pharma AG BENZOXAZOLES REPLACED
JP2016520110A (en) 2013-06-03 2016-07-11 バイエル ファーマ アクチエンゲゼルシャフト Substituted benzoxazole
CN103288744A (en) * 2013-06-04 2013-09-11 上海应用技术学院 Fluorine group-containing-modified dabigatran etexilate analogue and synthetic method thereof
EP2853260A1 (en) 2013-09-27 2015-04-01 ratiopharm GmbH Pharmaceutical preparation comprising dabigatran etexilate bismesylate
KR20240017118A (en) 2014-01-31 2024-02-06 브리스톨-마이어스 스큅 컴퍼니 Macrocycles with hetrocyclic p2' groups as factor xia inhibitors
NO2760821T3 (en) 2014-01-31 2018-03-10
IN2014MU00675A (en) 2014-02-26 2015-10-23 Megafine Pharma P Ltd
WO2015137680A1 (en) * 2014-03-10 2015-09-17 동아에스티 주식회사 Pharmaceutical composition for treating or preventing stroke and systemic embolism
WO2015145462A1 (en) 2014-03-26 2015-10-01 Cadila Healthcare Limited Pharmaceutical compositions of dabigatran
WO2015155297A1 (en) 2014-04-11 2015-10-15 Sanovel Ilac Sanayi Ve Ticaret A.S. Pharmaceutical combinations of dabigatran and h2-receptor antagonists
EP2933002A1 (en) 2014-04-11 2015-10-21 Sanovel Ilac Sanayi ve Ticaret A.S. Pharmaceutical combinations of dabigatran and proton pump inhibitors
CN104230888A (en) * 2014-06-03 2014-12-24 长春工业大学 Preparation method of benzimidazole compound
CN105218519A (en) * 2014-06-04 2016-01-06 天津药物研究院 A kind of preparation method of dabigatran etexilate intermediate
CN104003977B (en) * 2014-06-05 2016-04-13 雅本化学股份有限公司 The preparation method of N-(2-chloromethyl-1-methyl isophthalic acid H-benzoglyoxaline-5-acyl group)-N-(pyridine-2-base)-3-alanine ethyl ester
DE102014108210A1 (en) 2014-06-11 2015-12-17 Dietrich Gulba rodenticide
CN104045628B (en) * 2014-06-13 2019-04-09 深圳翰宇药业股份有限公司 The purification process of benzimidizole derivatives
CN105315257A (en) * 2014-06-24 2016-02-10 华仁药业股份有限公司 Synthetic and purifying method of dabigatran etexilate
CN106536505A (en) * 2014-08-06 2017-03-22 四川海思科制药有限公司 Dabigatran carboalkoxy derivative, preparation method therefor, and pharmaceutical use thereof
CN107027308A (en) * 2014-08-06 2017-08-08 四川海思科制药有限公司 A kind of dabigatran thioes derivatives and preparation method thereof and purposes pharmaceutically
NO2721243T3 (en) 2014-10-01 2018-10-20
WO2016070696A1 (en) 2014-11-03 2016-05-12 杭州领业医药科技有限公司 Dosing preparation of dabigatran etexilate or a salt thereof and a preparation method thereof
CN104592204B (en) * 2014-12-26 2017-05-17 华润赛科药业有限责任公司 Dabigatran derivatives as well as preparation method and application thereof
CN104650037A (en) * 2014-12-30 2015-05-27 青岛黄海制药有限责任公司 Synthesis method of dabigatran etexilate
TR201502223A2 (en) 2015-02-25 2016-09-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Pharmaceutical combinations of dronedarone and dabigatran
CN104628733A (en) * 2015-03-02 2015-05-20 中国药科大学 Tetrahydrobenzo[4,5] imidazo[1,2-a] pyrazine thrombin inhibitors
JP6742348B2 (en) 2015-06-19 2020-08-19 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Diamide macrocycles as factor XIA inhibitors
CN104987323B (en) * 2015-07-10 2017-08-22 浙江美诺华药物化学有限公司 A kind of preparation method of dabigatran etcxilate
WO2017013106A1 (en) 2015-07-20 2017-01-26 Sanovel Ilac Sanayi Ve Ticaret A.S. Pharmaceutical formulations of dabigatran free base
ES2937156T3 (en) 2015-07-29 2023-03-24 Bristol Myers Squibb Co Macrocyclic factor XIa inhibitors bearing a non-aromatic P2' group
WO2017023992A1 (en) 2015-08-05 2017-02-09 Bristol-Myers Squibb Company Novel substituted glycine derived fxia inhibitors
CN105294651A (en) * 2015-09-23 2016-02-03 烟台东诚药业集团股份有限公司 Method for synthesizing and preparing pradaxa formamidine intermediates
CN106866626A (en) * 2015-12-14 2017-06-20 天津药物研究院有限公司 A kind of preparation method of dabigatran etexilate intermediate
CN105481831B (en) * 2015-12-16 2018-06-12 开封明仁药业有限公司 A kind of method for preparing dabigatran etexilate intermediate
WO2017111637A1 (en) 2015-12-23 2017-06-29 Zaklady Farmaceutyczne Polpharma Sa Pharmaceutical composition comprising dabigatran or a pharmaceutically acceptable salt thereof
CN105566297A (en) * 2015-12-31 2016-05-11 哈药集团技术中心 Preparation method of dabigatran etexilate mesylate
CN109195973A (en) 2016-03-02 2019-01-11 百时美施贵宝公司 Diamides macrocyclic compounds with factor XI, plasma thromboplastin antecedent A inhibitory activity
CN105669651B (en) * 2016-03-07 2018-03-06 山东罗欣药业集团股份有限公司 A kind of preparation technology of dabigatran etexilate methanesulfonate
CN106397400A (en) * 2016-04-14 2017-02-15 江苏康缘药业股份有限公司 Preparation method for dabigatran etexilate
TR201606697A2 (en) 2016-05-20 2017-12-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi NEW ORAL PHARMACEUTICAL FORMULATIONS OF DABIGATRA
CN106349221A (en) * 2016-08-29 2017-01-25 常州市阳光药业有限公司 Preparation method of high-purity dabigatran etexilate
TR201617984A2 (en) 2016-12-07 2018-06-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi PHARMACEUTICAL COMPOSITIONS OF DABIGATRAN
EP3332771A1 (en) 2016-12-07 2018-06-13 Sanovel Ilac Sanayi ve Ticaret A.S. Multilayered tablet compositions of dabigatran
JP2018184375A (en) 2017-04-27 2018-11-22 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Tablet comprising dabigatran etexilate or pharmaceutically acceptable salt thereof and method for producing the same
WO2019004980A2 (en) 2017-05-10 2019-01-03 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Solid oral pharmaceutical compositions of dabigatran etexilate
TR201706848A2 (en) 2017-05-10 2018-11-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi SOLID ORAL PHARMACEUTICAL COMPOSITIONS CONTAINING DABIGATRAN ETEXCLATE
CN109010249A (en) * 2017-06-08 2018-12-18 上海美悦生物科技发展有限公司 Injection dabigatran etcxilate pharmaceutical composition and its preparation method and application
KR20190036857A (en) 2017-09-28 2019-04-05 한미약품 주식회사 Composite capsule formulation comprising dabigatran etexilate
TR201722323A2 (en) 2017-12-27 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Oral pharmaceutical compositions of dabigatran
TR201722186A2 (en) 2017-12-27 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Pharmaceutical compositions of dabigatran
TR201722630A2 (en) 2017-12-28 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
WO2019196111A1 (en) * 2018-04-13 2019-10-17 上海交通大学医学院附属瑞金医院 Anti-tumor multidrug resistance of heteroaryl amide compound, use in treatment of cancers and protein-drug molecular complex
CN108864047A (en) * 2018-07-02 2018-11-23 河南师范大学 A kind of preparation method of non-peptide batroxobin inhibitor dabigatran etcxilate
EP3771465A1 (en) 2019-08-01 2021-02-03 Zaklady Farmaceutyczne Polpharma SA Pharmaceutical composition comprising dabigatran etexilate
CN111606885A (en) * 2020-06-18 2020-09-01 安徽鼎旺医药有限公司 Dabigatran etexilate mesylate and preparation method thereof
CN113929661A (en) * 2020-06-29 2022-01-14 石药集团恩必普药业有限公司 Dabigatran etexilate intermediate and preparation method thereof
EP4070658A1 (en) 2021-04-06 2022-10-12 BIORoxx GmbH Use of anticoagulant active compounds as rodenticide

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4675405A (en) * 1984-09-21 1987-06-23 American Home Products Corporation Quinoline compounds as antiallergic and antithrombotic agents
DE4129603A1 (en) * 1991-09-06 1993-03-11 Thomae Gmbh Dr K CONDENSED 5-LOW HETEROCYCLES, METHOD FOR THE PRODUCTION THEREOF, AND MEDICAMENTS CONTAINING THESE COMPOUNDS
US5416099A (en) * 1991-10-29 1995-05-16 Merck & Co., Inc. Fibrinogen receptor antagonists
ZA928276B (en) * 1991-10-31 1993-05-06 Daiichi Seiyaku Co Aromatic amidine derivates and salts thereof.
CA2134192A1 (en) * 1993-11-12 1995-05-13 Michael L. Denney 5, 6-bicyclic glycoprotein iib/iiia antagonists

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8981105B2 (en) 2010-07-09 2015-03-17 Esteve Quimica, S.A. Process of preparing a thrombin specific inhibitor

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