NZ337323A - Disubstituted bicyclic heterocycles with thrombin inhibiting effect against related serine proteases - Google Patents

Disubstituted bicyclic heterocycles with thrombin inhibiting effect against related serine proteases

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Publication number
NZ337323A
NZ337323A NZ337323A NZ33732398A NZ337323A NZ 337323 A NZ337323 A NZ 337323A NZ 337323 A NZ337323 A NZ 337323A NZ 33732398 A NZ33732398 A NZ 33732398A NZ 337323 A NZ337323 A NZ 337323A
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New Zealand
Prior art keywords
group
methyl
denotes
amide
benzimidazol
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NZ337323A
Inventor
Norbert Hauel
Uwe Ries
Henning Priepke
Wolfgang Wienen
Jean-Marie Stassen
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Boehringer Ingelheim Pharma
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Priority claimed from DE19706229A external-priority patent/DE19706229A1/en
Priority claimed from DE1997151939 external-priority patent/DE19751939A1/en
Application filed by Boehringer Ingelheim Pharma filed Critical Boehringer Ingelheim Pharma
Publication of NZ337323A publication Critical patent/NZ337323A/en

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Abstract

Disubstituted bicyclic heterocycles of the Formula (I) in particular for inhibiting thrombin and prolonging thrombin time. The disclosed compounds relates to the tautomers, stereoisomers, mixtures, and salts, which have valuable properties. The compounds of the above general formula (I), in which E is a cyano group, 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 RbNH-C(=NH)-group, have valuable pharmacological properties. Wherein; A denotes a carbonyl or sulphonyl group linked to benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno moiety of the group Het. B denotes an ethylene group, in which a methylene group, linked to 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 C1-5alkyl group; E denotes an RbNH-C(=NH)-group wherein Rb denotes a hydrogen atom, hydroxy group, C1-3alkyl or C1-3alkoxy group; Ar denotes a phenylene group optionally substituted by fluorine, chlorine or bromine atom or by trifluoromethyl, C1-3alkyl or C1-3alkoxy group; a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted by C1-3alkyl group; Het denotes a bicyclic heterocycle of the formula (II), (III), (IV), (V), (VI), (VII) or (VIII); Ra denotes C1-6alkyl group, C3-7cycloalkyl group optionally substituted by C1-3alkyl group. Ra is further described as disclosed.

Description

<div class="application article clearfix" id="description"> <p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number 337323 <br><br> f <br><br> Intellectual Property Office of New Zealand IP Summary Report <br><br> Page: 2 of 2 Date: 25 March 2003 Time: 09:57:42 (iprip02 3.00.07) <br><br> (11) NZ Patent number: 337323 <br><br> (57) Abstract: <br><br> Patent 337323 <br><br> Disubstituted bicyclic heterocycles of the Formula (I) in particular for inhibiting thrombin and prolonging thrombin time. The disclosed compounds relates to the tautomers, stereoisomers, mixtures, and salts, which have valuable properties. The compounds of the above general formula (I), in which E is a cyano group, 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 RbNH-C(=NH)-group, have valuable pharmacological properties. <br><br> A denotes a carbonyl or sulphonyl group linked to benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno moiety of the group Het. <br><br> B denotes an ethylene group, in which a methylene group, linked to either to the group Het or Ar, may be replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl, carbonyl or -NRr group, wherein rt denotes a hydrogen atom or C^alkyl group; <br><br> E denotes an RbNH-C(=NH)-group wherein <br><br> Rb denotes a hydrogen atom, hydroxy group, Ci.3alkyl or Ci_3alkoxy group; <br><br> Ar denotes a phenylene group optionally substituted by fluorine, chlorine or bromine atom or by trifluoromethyl, C^alkyl or Ci.3alkoxy group; a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted by Chalky! <br><br> group; <br><br> Het denotes a bicyclic heterocycle of the formula (II), (III), (IV), (V), (VI), (VII) or (VIII); <br><br> Ra denotes Ci.6alkyl group, C3.7cycloalkyl group optionally substituted by Ci_3alkyl group. Ra is further described as disclosed. <br><br> Wherein; <br><br> Drawing: <br><br> &lt;Ii <br><br> (vin) <br><br> ** End of report ** <br><br> NOW AMENDED <br><br> * <br><br> - 1 - <br><br> *55 732 <br><br> 70656001.900 <br><br> WO 98/37075 <br><br> PCT/EP98/0 0 8 65 <br><br> 5 Disubstituted bicyclic heterocyclee, /the preparation and the use thereof as pharmaceutical compositions <br><br> The present invention relates tp i/ew disubstituted bicyclic 10 heterocycles of general formuli <br><br> Ra - A <br><br> Het - <br><br> Ar - E <br><br> , (I) <br><br> the tautomers, stereoisoraors/and mixtures thereof and the 15 salts thereof, particulatfly/the physiologically acceptable salts thereof with organric/or inorganic acids or bases which have valuable pr&lt;/p^rties. <br><br> The compounds of gene^rafr formula I above wherein E denotes 2 0 a cyano group are valuable intermediates for preparing the other compounds of/general formula I, and the compounds of general formula i/abtove wherein E denotes an R^NH-C(=NH)- <br><br> group, and the tautzomers and stereoisomers thereof have useful pharmacological properties, particularly a thrombin-25 inhibiting actyiv/ty and the effect of extending thrombin time. <br><br> 30 <br><br> The present/ application thus relates to the new compounds of general/ formula I above and the preparation thereof, pharmaceutical compositions containing the pharmacologically active compounds and the use thereof. <br><br> In the <br><br> )ove general formula <br><br> 3 5 A denotes a carbonyl or sulphonyl group linked to the benza, pyrido, pyrimido, pyrazino, pyridazino or thieno <br><br> !m ' actual property office of n.z. <br><br> 1 1 MAY 2000 RECEIVED <br><br> NOW AMENDED * <br><br> J 2 <br><br> 10 <br><br> - 2 <br><br> 323 <br><br> 15 <br><br> moiety of the group Het, whilst moreover/tl/e abovementioned moieties may not contain an Rx group, <br><br> B denotes an ethylene group, in whicly a/methylene group, linked either to the group Het or At/, may be replaced by an oxygen or sulphur atom or by a sul^ni^iyl, sulphonyl, carbonyl or -NRX- group, wherein <br><br> Rx denotes a hydrogen atom or/a C^-alkyl group, <br><br> E denotes an RbNH-C(=NH)- groi^p ^herein <br><br> Rb denotes a hydrogen a/tom, a hydroxy group, a C^-alkyl group or a grotip which may be cleaved in vivo, <br><br> 20 <br><br> Ar denotes a phenylene /jr®up optionally substituted by a fluorine, chlorine or iircmine atom or by a trifluoromethyl, C^j-alkyl or C^-alkojcy ^jroup, <br><br> a thienylene, thiaafol^lene, pyridinylene, pyrimidinylene, pyrazinylene or pyriyaazinylene group optionally substituted in the carbon skgrlq/con by a C1_3-alkyl group, <br><br> 25 Het denotes a hjioyclic heterocycle of formula <br><br> , wherein <br><br> 30 <br><br> 35 <br><br> X is si nitrogen atom and <br><br> Y/is/ an oxygen or sulphur atom or a nitrogen atom 5pt/ionally substituted by a C^g-alkyl or 'cV7-cycloalkyl group, whilst additionally one or two <br><br> /on-angular methyne groups in the phenyl moiety of the /above-mentioned bicyclic heterocycle may each be replaced by a nitrogen atom, <br><br> intellectual property office of n.z. <br><br> 1 I MAY <br><br> ocrciucn <br><br> NOW AMENDED <br><br> J <br><br> , /wherein <br><br> R, is as hereinbefore defi/ne/9, <br><br> Z denotes an oxygen or eul/phur atom, <br><br> 10 <br><br> one of the groups D cJr (&amp; denotes a nitrogen atom and the other group D orj G/denotes a methyne group, <br><br> 15 <br><br> and Ra denotes a C^-alKy!/ group, a C3_7-cycloalkyl group optionally substituted by a C1_3-alkyl group, wherein the C-L.j-alkyl group may ^adationally be substituted by a carboxyl group or by sf group which may be converted in vivo into a carboxy groiflp. <br><br> or a R2NR3- groujy wnerein <br><br> 20 <br><br> 25 <br><br> R2 denote^ s/ C^-alkyl group, which may be substituted by a camoxy, C1_6-alkyloxycarbonyl, benzyloxycarbonyl, C^-alkyl/ulphonylaminocarbonyl, <br><br> phenyl/su/phonylaminocarbonyl, trif luorosulphonylamino, trifMiorosulphonylaminocarbonyl or 1H-tetrazolyl groi <br><br> 30 <br><br> a/C2/-alkyl group substituted by a hydroxy, phenyl- <br><br> /-alkoxy, carboxy-C^-alkylamino, C1_3-'a^coxycarbonyl-C1.3-alkylamino, N- (C^-alkyl) -carboxy- <br><br> i^.j-alkylamino or N- (C1_3-alkyl) -C1.3-alkoxycarbonyl-C1.3-^alkylamino group, whilst in the abovementioned groups intellectual property office of n.z. <br><br> ' I MAY 2000 <br><br> RECEIVED <br><br> NOW AMENDED <br><br> - 5 - <br><br> 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 5 C-L.j-alkyl group and / / <br><br> R3 denotes a hydrogen atom, a/C-,/6-alkyl group, a C3_7-cycloalkyl group optionally substituted by a C^-alkyl group, a C3.6-alkenyV or alkynyl group, 10 wherein the unsaturated pa/rt/may not be linked directly to the nitrogen/atom of the R2NR3- group, <br><br> a phenyl group optionally substituted by a fluorine, chlorine or bromine at^on/ or by a C^.-j-alkyl or 15 C^j-alkoxy group, a hseneyl, oxazolyl, isoxazolyl, <br><br> thiazolyl, isothiazclyl, pyrazolyl, pyrrolyl, thienyl, pyridinyl, pyrimid/nyl, pyrazinyl, pyridazinyl, <br><br> 2 0 R2 and R3 together/with the nitrogen atom between them denote a 5- tcV 7/membered cycloalkyleneimino group, <br><br> C^-alkoxycarbfflnyl group, onto which a phenyl ring may additionally pe. fused, particularly those compounds 25 wherein / / <br><br> Het denotes one of the abovementioned benzimidazolylene, benzothiazolylerie, benzoxazolylene, indolylene, <br><br> imidazo[4 ,/-y]pyridinylene, imidazo[1,2-a]pyridinylene, <br><br> 3 0 thiazolo [t&gt;, 4r-b] pyridinylene or thieno [2, 3-d] imidazolylene intellectual property office of n.z. <br><br> 1 1 MAY 2000 RECEIVED <br><br> NOW AMENDED <br><br> - 6 - <br><br> The compounds of the above general formula /i which contain a group capable of being cleaved in vivp are thus prodrugs and compounds of general formula I which/contain two groups capable of being cleaved in vivo are iso/called double <br><br> 5 prodrugs. / / <br><br> The phrase "a group which may be converted in vivo into a carboxy group" denotes, for example/ a hydroxymethyl group, a carboxy group esterified with /ary alcohol, in which the 10 alcoholic moiety is preferably /a yC1.6-alkanol, a phenyl-C1_3-alkanol, a C3.9-cyclioalkanol, wherein a C5_8-cycloalkanol may addition/al/y be substituted by one or two C^.-j-alkyl groups, a C5_8-/:ycloalkanol, in which a methylene group in the 3- ®r A-position is replaced by an 15 oxygen atom or by an imin© tfroup optionally substituted by a C^.j-alkyl, phenyl-Cx.3-alky 1 / phenyl -C^-alkoxycarbonyl or C2_s-alkanoyl group, and/the cycloalkanol moiety may additionally be substituted by one or two C^-alkyl groups, a C4.7-cycloalkenol, a/CX-alkenol, a phenyl-C3_5-alkenol, a 20 C3_5-alkynol or phenyZ-O^-alkynol, with the proviso that no bond to the oxygen fitp emanates from a carbon atom which <br><br> C3.8-cycloalkyl-C1/-alkanol, a bicycloalkanol having a total of 8 to 10 carbon atoms, which may additionally be 25 substituted in /the bicycloalkyl moiety by one or two <br><br> C-^-alkyl groups/ a 1,3-dihydro-3-oxo-1-isobenzofuranol or <br><br> 30 / / <br><br> R4 oeiiotes a C^.g-alkyl, Cs_7-cycloalkyl, phenyl or 35 /rvdenotes a hydrogen atom, a C^-alkyl, C5_7-cycloalkyl intellectual property office of n.z. <br><br> 1 1 MAY 2000 RECEIVED <br><br> NOW AMENDED <br><br> - 7 - <br><br> R6 denotes a hydrogen atom or a yaLfcyl group, <br><br> 10 <br><br> 15 <br><br> 20 <br><br> 25 <br><br> or the phrase "a group which may be c]^a/ed in vivo from an imino or amino group" denotes for example a hydroxy group, <br><br> an acyl group such as a benzoyl- or /pwidinoyl group or a C1_1g-alkanoyl group such as the fornjyl-, acetyl- <br><br> propionyl-, butanoyl-, pentanoyl-/oy hexanoyl group, an allyloxycarbonyl group, a C]__3_g-^fll^oxycarbonyl group such as the methoxycarbonyl - , ethoxyc£a:tfbonyl-, propoxycarbonyl - , isopropoxycarbonyl - , butoxycarloorfyl - , <br><br> tert. -butoxycarbonyl - , pentoxycafrbonyl -, hexoxycarbonyl - , octyloxycarbonyl-, nonyloxycaroonyl-, decyloxycarbonyl-, undecyloxycarbonyl-, dodecyioxycarbonyl- or hexadecyloxycarbonyl group/ f phenyl-C^_6-alkoxycarbonyl group such as the benzyloxycarbonyl-, phenylethoxycarbonyl-or phenylpropoxycarbonyl/group, a C]_ _3-alkylsulphonyl- <br><br> C2-4"alkoxycarbonyl-&lt;-2 - 4 ~ koxyc arbony1 -R4 to Rg are as here: <br><br> Examples of prefer^/ec include a C]__g-al} <br><br> , -alkoxy-C2-4-alkoxy-^CO-O-(RgCRg)-O-CO-group, wherein lbj^fore defined. <br><br> prodrug groups for a carboxy group rcarbonyl group such as the methoxycarbonyl,/etfaoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarjporwl, n-butyloxycarbonyl, n-pentyloxycarmortyl, n-hexyloxycarbonyl or cyc-lohexyloxycar^Doi^yl group or phenyl-Ci-3-alkoxycarbonyl group such tfhe benzyloxycarbonyl group and for an imiilo /or amino group a C]__g-alkoxycarbonyl group 3 0 such as the/methoxycarbonyl, ethoxycarbonyl, n-propyLoxycarbonyl, isopropyloxycarbonyl, n-butylyoxycarbonyl, n-pentyloxycarbonyl, <br><br> n-hexyioxycarbonyl, cyclohexyloxycarbonyl, n-heracyioxycarbonyl, n-octyloxycarbonyl or 3 5 n-no/Ly/oxycarbonyl group, a phenyl-Ci_3-alkoxycarbonyl gro(ip/such as the benzyloxycarbonyl group, a phenylcarbonyl group optionally substituted by a C]__3~alkyl group such as intellectual property office of n.z. <br><br> 1 1 MAY 2000 <br><br> NOW AMENDED <br><br> - 8 - <br><br> the benzoyl or 4-ethyl-benzoyl group, a/pwidinoyl group such as the nicotinoyl group, a C]_ _ 3 - aMcm sulphonyl - <br><br> n-C2-3-alkoxycarbonyl or C]__3-alkoxy-Q^-/3-alkoxy- <br><br> C2_4-alkoxycarbonyl group such as t <br><br> 5 2-methylsulphonylethoxycarbonyl or ^-/2-ethoxy)- <br><br> ethoxycarbonyl group. <br><br> Moreover, the saturated alkyl anfl aflkoxy moieties containing more than 2 carbon acorns as well as alkanoyl and 10 unsaturated alkyl moieties containing more than 3 carbon atoms as mentioned in the foregoing definitions also include the branched isomers' tnereof such as for example the isopropyl, tert. -butyl /anp. isobutyl group, etc. <br><br> 15 Particularly preferred c/rngounds of general formula I above are those wherein <br><br> 20 <br><br> A denotes a carbonyl ®r Sulphonyl group linked to the benzo, pyrido, pyrim/dor, pyrazino, pyridazino or thieno moiety of the group/Hart, whilst moreover the abovement ioned moieties may not contain an Rx group, <br><br> B denotes an eth/lafne group in which the methylene group linked to the group Ar may be replaced by an oxygen or 2 5 sulphur atom or ay an -NRX- group, wherein r-l denotes/ a hydrogen atom or a -alkyl group, <br><br> 30 <br><br> 35 <br><br> E denotes ,an/RbNH-C (=NH) - group wherein <br><br> Rb denotes a hydrogen atom, a hydroxy, C]__/-atlkoxycarbonyl, cyclohexyloxycarbonyl, phenyl- <br><br> C1/3/alkoxycarbonyl, benzoyl, p-Ci_3-alkyl-benzoyl or ridinoyl group, whilst the ethoxy moiety in the -position of the abovement ioned Cj__g-alkoxycarbonyl group may additionally be substituted by a C^__3-alkyl-ulfonyl or 2-(Ci_3-alkoxy)-ethyl group, <br><br> (TME NEXT PAGE IS PAGE 13) <br><br> intellectual property office of n.z. <br><br> 1 1 MAY 2000 <br><br> RECEIVED <br><br> NOW AMENDED <br><br> - 9 - <br><br> X is a nitrogen atom and <br><br> 10 <br><br> Y is an oxygen or sulphur aeon/ or a nitrogen atom optionally substituted by a C^_s-alkyl or C3_7-cycloalkyl group, whiYsty additionally one or two non-angular methyne groups/in the phenyl moiety of the above-mentioned bicyclic neterocycle may each be replaced by a nitrogeiy atom, <br><br> 15 <br><br> or X denotes a methwie/group optionally substituted by the group Rlf where/n^ is as hereinbefore defined, <br><br> and <br><br> Y denotes a niti/og4n atom optionally substituted by a C^-alkyl or C^-jcycloalkyl group, <br><br> 20 <br><br> or Het denotes a group of the formulae <br><br> N" <br><br> /Rl <br><br> N <br><br> 25 <br><br> R <br><br> 1 <br><br> I <br><br> N^O <br><br> N <br><br> NOW AMENDED <br><br> - 10 R-, <br><br> .N, <br><br> ll <br><br> ■N <br><br> 'G <br><br> R-. <br><br> or <br><br> 10 <br><br> 15 <br><br> N <br><br> • ^ N \ <br><br> R-. <br><br> , wherein <br><br> Rx is as hereinbefore defined, <br><br> Z denotes/an oxygen or sulphur atom, <br><br> one of fch.&lt;k groups D or G denotes a nitrogen atom and the otfixe/ group D or G denotes a methyne group, <br><br> and Ra deAotfes a C1.6-alkyl group, a C3_7-cycloalkyl group 20 optiona/1y/ substituted by a C^.-j-alkyl group, wherein the Ci.j-alky1/group may additionally be substituted by a carbojcy]/ group or by a group which may be converted in vivo into/ a/carboxy group, <br><br> 25 o» a/R2NR3- group wherein <br><br> NOW AMENDED <br><br> 11 - <br><br> m^y be substituted jenzyloxycarbonyl, <br><br> R2 denotes a C^-alkyl group, whicl by a carboxy, C1.6-alkyloxycarbony^ C1-3—alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, tftrifluorosulphonylamino, trifluorosulphonylaminocarbonm pr lH-tetrazolyl group, <br><br> 10 <br><br> 15 <br><br> a C2_4-alkyl group substituted/by a hydroxy, phenyl-C1.3-alkoxy, carboxy-Ci_3-aLKyZamino, Ci_3-alkoxycarbonyl-Cj^.j-alkylamino, N- (C^-alkyl) -carboxy-C1.3-alkylamino or N-(C^Z-alkyl)-Ci_3-alkoxycarbonyl-Ci_3-alkylamino group, whilst /in the abovementioned groups the carbon atom in tli/fe (/-position relative to the adjacent nitrogen atabm/may not be substituted, or a piperidinyl groi C1-3 — alky 1 group ip /optionally substituted by a <br><br> 20 <br><br> far/&gt;gen atom, a Ci_6-alkyl group, a oup optionally substituted by a a C3_6-alkenyl or alkynyl group, wherein the/unsaturated part may not be linked directly to the nitrogen atom of the R2NR3- group, <br><br> R3 denotes a h^ C3_7-cycloalky] •alkyl gr©ur <br><br> -1-3 <br><br> 25 <br><br> 30 <br><br> 35 <br><br> a phenyl/ group optionally substituted by a fluorine, chlorirj(e pr bromine atom or by a Ci_3-alkyl or Cx.3-a]jkoJty group, a benzyl, oxazolyl, isoxazolyl, thia/olyl, isothiazolyl, pyrazolyl, pyrrolyl, thienyl, pyr^dinyl, pyrimidinyl, pyrazinyl, pyridazinyl, lmXd^zolyl or piperidinyl group or ind R3 together with the nitrogen atom between them 'denote a 5- to 7-membered cycloalkyleneimino group, <br><br> lionally substituted by a carboxy or 'Ci.4-alkoxycarbonyl group, onto which a phenyl ring may additionally be fused, particularly those compounds wherein <br><br> NOW AMENDED <br><br> 15 <br><br> 20 <br><br> 25 <br><br> Het denotes one of the abovementioned ttan&amp;imidazolylene, benzothiazolylene, benzoxazolylene, ind^lylene, quinazolinylene, quinoxazolinonylene, <br><br> imidazo [4 , 5-b] pyridinylene, imidazo/1 '2-a] pyridinylene, thiazolo [5 , 4-b] pyridinylene or thijeng 2 , 3-d] imidazolylene groups, <br><br> 10 the tautomers, the prodrugs, stereoisomers and the salts /t] <br><br> Particularly preferred cop are those wherein double prodrugs, the reof. <br><br> nds of general formula I above <br><br> A denotes a carbonyl op sulphonyl group linked to the benzo, pyrido, pyrimino/ pyrazino, pyridazino or thieno moiety of the group flep, whilst moreover the abovementioned moieties may not contain an Rx group, <br><br> 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 -NR^ group, wherein <br><br> Rx denotes/a hydrogen atom or a C^-alkyl group, <br><br> E denotes an/RbNH-C (=NH) - group wherein <br><br> Rb denotes a hydrogen atom, a hydroxy, C^-A-alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C-/-alkoxycarbonyl, benzoyl, p-Ci_3-alkyl-benzoyl or y^Ldinoyl group, whilst the ethoxy moiety in the osition of the abovementioned 9-alkoxycarbonyl roup may additionally be substituted by a Ci_3-alkyl- <br><br> sulfonyl or 2-(Ci_3-alkoxy)-ethyl group, <br><br> NOW AMENDED <br><br> 10 <br><br> - 13 - <br><br> 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, <br><br> Het denotes a 1-(Ci_3~alkyl)-2,5-benzamidazolylene, 1-cyclopropyl-2,5-benzimidazolylene/ 2,5-benzothiazolylene, 1- (Ci_3 -alkyl) -2 , 5-indolylene, 1/ ($?l-3 -alkyl) -2 , 5-imidazo [4 , 5-b] pyridinylene,/ 3/ (C]__3-alkyl) -2 , 7-imidazo [1, 2-a] pyridinylen/oy 1- (C^.3 - alkyl) -2 , 5-thieno [2 , 3 -d] imidazolylene /group and <br><br> Ra denotes an R2NR3- group wherein <br><br> 15 <br><br> R2 is a C^-alkyl grduw substituted by a carboxy, Ci _ g - alkyloxycarbonfyl/ benzyloxycarbonyl, Ci_3-alkylsulphonylaminocarbonyl or lH-tetrazol-5-yl group, <br><br> 20 <br><br> 25 <br><br> 30 <br><br> a C2-4-alkyl gfcojdp substituted by a hydroxy, benzyloxy, carboxy-_ 3 /aykylamino, Ci_ 3 -alkoxycarbonyl-C]__3-alkylai^info, N- (Ci-3-alkyl) -carboxy-Ci_3-alkylamino or N- (C]__3/a2kyl) -Ci_3-alkoxycarbonyl-Ci_3-alkylamino group, wtp-ipt in the abovement ioned groups the carbon atom in fthjk a-position to the adjacent nitrogen atom may no^? substituted, <br><br> R3 denotes a C3_7-cycloalkyl group, a propargyl group, where/n the unsaturated part may not be linked directly tcy tile nitrogen atom of the R2NR3 group, a phenyl group it/onally substituted by a fluorine or chlorine atom, /or/by a methyl or methoxy group, a pyrazolyl, py-mdazolyl or pyridinyl group optionally substituted by methyl group or <br><br> NOW AMENDED <br><br> - 14 - <br><br> R2 and R3 together with the nitrogeri 3/tom between them denote a 5- to 7-membered cycloalkylefaeimino group, optionally substituted by a carboxy /or C1_4-alk- <br><br> oxycarbonyl group, to which a pfyenyl ring may 5 additionally be fused, <br><br> the tautomers, the stereoisomers/ano the salts thereof. <br><br> Most particularly preferred copnp&lt;/unds of the above general 10 formula I are those wherein <br><br> 15 <br><br> A denotes a carbonyl or sulphonyl group linked to the benzo, pyrido or thieno mcAety of the group Het, whilst moreover the abovementioi^ed/moieties may not contain an Ra group, <br><br> 20 <br><br> 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/-KRi- group, wherein <br><br> Rx denotes a/hyarogen atom or a methyl group, <br><br> E denotes an RbNH/C(=NH)- group, wherein <br><br> 25 <br><br> 30 <br><br> Rb denotes/a hydrogen atom or a hydroxy, Cx.9 -alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-Ci_3-alkyl-benzoyl or nicojcirfoyl group, whilst the ethoxy moiety in the 2-positj/on of the abovement ioned C^-alkoxycarbonyl gryoup may additionally be substituted by a C^.j-'lsulphonyl or 2- (C^-alkoxy) -ethyl group, <br><br> 35 <br><br> Ar gTery6tes a 1,4-phenylene group optionally substituted by a &lt;#il/6rine atom or by a methyl, ethyl or methoxy group, or dfenotes a 2,5-thienylene group, <br><br> NOW AMENDED <br><br> - 15 - <br><br> Het denotes a 1-methyl-2,5-benzimidazo cyclopropyl-2,5-benzimidazolylene, 2, 1-methyl-2,5-indolylene, 1-methyl-2,5- imidazo [4 , 5 -b] pyridinylene, 3 -mefch/Vi -2,7-imidazo[1,2-a]pyridinylene or /-mfethyl-2 , 5-thieno [2 , 3-d] imidazolylene gr©UT7 and ne, 1-nzothiazolylene, <br><br> Ra denotes a R2NR3- group wherein. <br><br> 10 <br><br> R2 denotes a C^_3-alkyl gfcojdp which may be substituted by a carboxy, C^.g-alkyl/ox^carbonyl, benzyloxycarbonyl, methylsulphonylaminocarboTiyl or lH-tetrazol-5-yl group, <br><br> 15 <br><br> 20 <br><br> a C2-3-alkyl group substituted by a hydroxy, benzyloxy, carboxy- Ci _ 3 - alkyl ^miiio, _ 3 - alkoxycarbonyl -Ci_3-alkylamino, ]tf- (£1-3-alkyl)-carboxy-Ci_3-alkylamino or N- (Ci_3-alkyl/-C?i_3-alkoxycarbonyl-Ci_3-alkylamino group, whilst in tzhe abovement ioned groups the carbon atom in the a-position to the adjacent nitrogen atom may not be substituted, and <br><br> 25 <br><br> R3 denotes /a propargyl group, wherein the unsaturated moiety maV not be linked directly to the nitrogen atom of the R/W3 group, a phenyl group optionally substituted by a fluorine or chlorine atom, or by a me thy]/ ojt methoxy group, or denotes a pyridinyl group, <br><br> particul/arly those wherein <br><br> 30 A denote® a carbonyl group linked to the benzo or thieno moietzy/&gt;f the group Het, <br><br> B denotes an ethylene group wherein the methylene group :tffched to the group Ar may be replaced by an -NR^ group, <br><br> 35 ywhjferem <br><br> NOW AMENDED <br><br> - 16 <br><br> Rl denotes a hydrogen atom or a methyl group, <br><br> E denotes an R^NH-C(=NH)- group wheneii <br><br> 10 <br><br> Rk is a hydrogen atom, a hydrcW _9-alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-Ci-3-alkyl-benzoyl or nicotimoyl group, whilst the ethoxy moiety in the 2-posA.t/on of the abovement ioned C]__9-alkoxycarbonyl groujy m^y additionally be substituted by a methylfml^onyl or 2-ethoxy-ethyl group, <br><br> Ar denotes a 1,4-phenyleme /group optionally substituted by 15 a methoxy group, or denpters a 2, 5-thienylene group, <br><br> Het denotes a l-methyl-z,5-benzimidazolylene, 2 , 5-benzothiazolylenye,/l-methyl-2 , 5-indolylene or 1-methyl-2 , 5-thieno [2 , 3-d] iimdazolylene group and <br><br> 20 <br><br> Ra denotes an R2NK3/ group wherein <br><br> 25 <br><br> R2 denotes /a £i_3-alkyl group which may be substituted by a carb©xy, C^.g-alkyloxycarbonyl, benzyloxycarbonyl, methylsu^f^nylaminocarbonyl or lH-tetrazol-5-yl group, <br><br> 30 <br><br> a C2-3Aalkyl group substituted by a hydroxy, benzyloxy, carbdxyAC1_3- alkylamino, C]__3 - alkoxycarbonyl-C-L_/-alkylamino, N- (Ci-3-alkyl) -carboxy-Ci_3-alkylamino or/N7(Ci_ 3 -alkyl)-_ 3 -alkoxycarbonyl-_ 3 -alkylamino rojdp, whilst in the abovement ioned groups the carbon it(6m in the a-position to the adjacent nitrogen atom ly not be substituted, and <br><br> NOW AMENDED <br><br> - 17 - / / <br><br> R3 denotes a phenyl group optionally ^substituted by fluorine atom, or denotes a 2-pyrSainyl group, <br><br> the tautomers, stereoisomers and the aalts thereof. <br><br> The following are mentioned as eKamples of particularly preferred compounds: / / <br><br> 10 (a) 2-[N-(4-amidinophenyl)-arainomethyl]-benzthiazole-5-carboxylic adid-N-phenyl-N- (A-carboxyethyl)-amide, <br><br> (b) 2-[N-(4-midinophenyl)/N^roethyl-aminomethyl]-benzthiazol-5-yl-carboxyiia: acid-N-phenyl-N- (2- <br><br> 15 hydroxycarbonylethyl)-amide, <br><br> (c) l-Methyl-2-[N-(4Tamidinophenyl)-aminomethyl]-benzimidazol-5-yl-cafrhoxylic acid-N-phenyl-N- (2-hydroxycarbonyle thyl)/- amide, <br><br> 20 / / <br><br> (d) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-v\Vcarboxylic acid-N-phenyl- <br><br> N- (3 -hydroxycarbconylpropyl) - amide, <br><br> 25 (e) 1-Methyl^-2/ [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-y5-yl-carboxylic acid-N- (2-pyridyl) -N- (hydroxycairbonylmethyl) -amide, <br><br> (f) l-M^thyl-2-[2-(2-amidinothiophen-5-yl)ethyl]- <br><br> 30 benzim/dateol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxyc/arbonylethyl) -amide, <br><br> (g)/ l/Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benz/midazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- <br><br> 3 5 hydroxycarbonylethyl)-amide, <br><br> NOW AMENDED <br><br> - 18 - / / <br><br> (h) l-Methyl-2-[2-(4-amidinophenyl)ethyl]/benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2y / hydroxycarbonylethyl)-amide, / / <br><br> 5 (i) l-Methyl-2-[2-(4-amidinophenylVetnyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-h(yda:oxycarbonylethyl) -amide, / / <br><br> (j) l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-10 yl-carboxylic acid-N-phenyl-N/ [3r- (lH-tetrazol-5-yl) ethyl] amide, / / <br><br> (k) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxvliic acid-N-phenyl-N- [2- (1H-15 tetrazol-5-yl) ethyl] -ami/ue/ <br><br> (1) l-Methyl-2-[N-(4-Smiainophenyl)-N-methyl-aminomethyl] benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl) yamide, <br><br> 20 / / <br><br> (m) l-Methyl-2-[NA(d- amidinophenyl)-N-methyl-aminomethyl] benzimidazol-5-yl-carboxylic acid-N- (3-pyridyl) -N- (2-hydroxycarbonyletnyl)-amide, <br><br> 25 (n) l-Methyl/2 -AN-(4-amidinophenyl)-N-methyl-aminomethyl] benzimidazo]/-5Ayl-carboxylic acid-N-phenyl-N- (2-hydroxycarBonylethyl)-amide, <br><br> (o) l-Me/h.yi-2- [N- (4-amidinophenyl) -aminomethyl] -30 benzimidayol-5-yl-carboxylic acid-N-phenyl-N-[(N- <br><br> hydroxycafrbonylethyl-N-methyl) -2-aminoethyl] -amide, <br><br> (p) A-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benreimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2 3 5 hytLr/oxycarbonylethyl) - amide, <br><br> NOW AMENDED <br><br> - 19 - / / <br><br> (q) l-Methyl-2-[N-(4-amidinophenyl)-am/nomethyl]-benzimidazol-5-yl-carboxylic acid-N-(/-muorophenyl)-N-(2-hydroxycarbonylethyl)-amide, / / <br><br> 5 (r) l-Methyl-2-[N-(4-amidino-2-metnoxy-phenyl)- <br><br> aminomethyl]-benzimidazol-5-yl-carb©xylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, / / <br><br> (s) l-Methyl-2- [N- (4-amidino-^-myethoxy-phenyl) -10 aminomethyl] -benzimidazol-5-yl-ycarboxylic acid-N- (2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, <br><br> (t) l-Methyl-2 - [N-(4-amidrnophenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl/NV(2-methoxycarbonylethyl)-amide 15 and / / <br><br> (u) l-Methyl-2-[N-(4-amidinophenyl)aminomethyl]-thieno [2 . 3-d] imidazod.-^-yl-carboxylic acid-N-phenyl-N- (2-hydroxycarbonylethyl)/amide, <br><br> 20 / / <br><br> the tautomers, prodrugs, double prodrugs, stereoisomers and the salts thereof/ <br><br> 2 5 The new compounds may be prepared by methods known per se, for exampl^by the following methods: <br><br> a. In order/to prepare a compound of general formula I, wherein ydenotes an RbNH-C(=NH)- group, wherein Rb is a 30 hydrogen Atom, a hydroxy or C^-alkyl group: <br><br> By reacting a compound of general formula <br><br> 35 <br><br> / / Ra - A - Het - B - Ar - C(=NH) - Z± •ptionally formed in the reaction mixture, <br><br> , (II) <br><br> NOW AMENDED <br><br> 10 <br><br> - 20 - <br><br> wherein <br><br> A, B, Ar, Het and Ra are as hereinbefore lefined and <br><br> Z1 denotes an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or beriey/oxy group or an alkylthio or aralkylthio group sucly as the methylthio, ethylthio, n-propylthio or benzyl t^aiip group, with an amine of general formula <br><br> H2N - Rb <br><br> ,(III) <br><br> wherein <br><br> Rb 1 denotes a hydrogen atom/o^ a hydroxy or C^.j-alkyl group. <br><br> 15 The reaction is conveniently carried out in a solvent such as methanol, ethanol, n-nropanol, water, methanol/water, tetrahydrofuran or dioxane at temperatures between 0 and 150°C, preferably at temperatures between 20 and 120°C, <br><br> with a compound of fleneral formula III or with a <br><br> 20 corresponding acicy addition salt such as ammonium carbonate, for es^ample. <br><br> A compound of g'eneral formula II may be obtained, for example, by rsaoting a compound of general formula I 25 wherein E demobes a cyano group, with a corresponding alcohol sucM ars methanol, ethanol, n-propanol, isopropanol or benzyl aldohol in the presence of an acid such as <br><br> :±a acid or by reacting a corresponding amide with a trialk^lfflxonium salt such as triethyloxonium-3 0 tetraf 1/uoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 50°C,/b\at preferably at 20°C, or a corresponding nitrile witM hydrogen sulphide, appropriately in a solvent such as ^idlne or dimethylformamide and in the presence of a base 3 5 sp.cn as triethylamine and subsequent alkylation of the ressulting thioamide with a corresponding alkyl or aralkyl halide. <br><br> NOW AMENDED <br><br> - 21 - / / <br><br> b. In order to prepare a compound of /general formula I wherein the Ra-A- group and E are as/h^reinbefore defined, with the proviso that the Ra-A- group /contains a carboxy 5 group and E as hereinbefore definera or that the Ra-A- group is as hereinbefore defined and E/denotes an NH2-C(=NH)-group, or that the Ra-A- group contains a carboxy group and E denotes an NH2-C(=NH)- group/ / <br><br> 10 Converting a compound of general formula <br><br> Ra* - A - Het - B/- Ar - C - E' ,(IV) <br><br> wherein J / <br><br> A, B, Ar and Het are as/hQreinbefore defined and 15 the Ra'-A- group and e/ have the meanings given for the <br><br> Ra-A- group and E hereinbefore, with the proviso that the Ra'-A- group contain^ dgroup which may be converted into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis ^r/hydrogenolysis and E is as 20 hereinbefore defi/neya or E1 denotes a group which may be converted into mi JSH2-C(=NH)- group by hydrolysis, <br><br> treatment with/an/acid or base, thermolysis or hydrogenolysi^ and the Ra'-A- group has the meanings given for the Ra-Ay group hereinbefore or the Ra 1 -A- group 25 contains a grdup which may be converted into a carboxyl group by hydrolysis, treatment with an acid or base, thermolys/s/or hydrogenolysis and E1 denotes a group which may be converted into an NH2-C(=NH)- group by hydrolysis, treatment/with an acid or base, thermolysis or 3 0 hydrogenolysis, <br><br> is yoiwerted 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 3 5 aer4inbefore defined, with the proviso that the Ra-A- group /contains a carboxy group and E is as hereinbefore defined / Gfr the Ra-A- group has the meanings given above and E <br><br> NOW AMENDED <br><br> - 22 <br><br> denotes an NH2-C(=NH)- group or the R&amp;-P/-carboxy group and E denotes an NH2-C(=I <br><br> jroup contains a group. <br><br> Examples of groups which may be concerted into a carboxy 5 group include a carboxyl group protected by a protecting group and the functional derivatiye^thereof, e.g. the unsubstituted or substituted amicjes/, esters, thioesters, trimethylsilylesters, orthoesters /)r iminoesters which may conveniently be converted into/a /carboxyl group by 10 hydrolysis, / / <br><br> the esters thereof with tertiary alcohols, e.g. the tert.butylester, which am conveniently converted into a carboxyl group by treatment/with an acid or by thermolysis, 15 and / / <br><br> the esters thereof wit/n Aralkanols, e.g. the benzylester, which are conveniently Converted into a carboxyl group by <br><br> 20 / / <br><br> The hydrolysis is/expediently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric: acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence 25 of a base suon as lithium hydroxide, sodium hydroxide or potassium hytlroxide in a suitable solvent such as water, water/methSnol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane at temperatiards between -10 and 120°C, e.g. at temperatures 30 between/room temperature and the boiling temperature of the <br><br> If the/Ra'-A- group and/or E1 in a compound of formula IV conca/ns the tert.-butyl or tert.-butyloxycarbonyl group, 35 for- example, these may also be cleaved by treating with an afcxa. such as trifluoroacetic acid, formic acid, p-AioAuenesulphonic acid, sulphuric acid, hydrochloric acid, <br><br> NOW AMENDED <br><br> ~ 23 ~ / / <br><br> phosphoric acid or polyphosphoric acid1 dptionally in an inert solvent such as methylene chlorL&amp;a, chloroform, benzene, toluene, diethylether, tetrahydrofuran or dioxane, preferably at temperatures between AlJo and 12 0°C, e.g. at 5 temperatures between 0 and 60°C, or t:hermally optionally in an inert solvent such as methylene ^rhloride, chloroform, benzene, toluene, tetrahydrofuran /or dioxane and preferably in the presence of a catalytic/qyantity of an acid such as p-toluenesulphonic acid, sulpjruric acid, phosphoric acid or 10 polyphosphoric acid, preferafcly at the boiling temperature of the solvent - used, e.g. a/c Itemperatures between 4 0 and 120°C. / / <br><br> If the Ra'-A- group and/or/E1 in a compound of formula IV 15 contains the benzyloxy/oy benzyloxycarbonyl group, for example, these may alio/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, 20 dioxane or dimethyl/ormamide, preferably at temperatures between 0 and 50^c/ e.g. at room temperature, under a hydrogen pressyr^of 1 to 5 bar. <br><br> c. In order tto Prepare a compound of general formula I 25 wherein the/R.&gt;A- group contains one of the ester groups mentioned In /the definition of the Ra-A- group hereinbefore: <br><br> Reaction ©f a compound of general formula <br><br> 30 / / <br><br> / / Ra" - A - Het - B - Ar - E ,(V) <br><br> wherein b/ h, Ar and Het are as hereinbefore defined and 35 Ra"-A- group has the meanings given for the Ra-A- group <br><br> /hereinbefore, with the proviso that the Ra"-A- group <br><br> NOW AMENDED <br><br> - 24 - <br><br> contains a carboxyl group or a group wl; into a corresponding ester group by with an alcohol of general formula <br><br> :icjti may be converted of an alcohol, <br><br> 10 <br><br> HO - R7 / / , (VI) <br><br> wherein <br><br> R7 is the alkyl moiety of one of/thfe above-mentioned groups which may be cleaved in vivo, with the exception of the <br><br> R6-C0-0- (RsCR6) - group for a c^orbpxyl group, or with the formamide acetals thereof. <br><br> or with a compound of general/ formula <br><br> 15 <br><br> 20 <br><br> Z2 - Rg wherein <br><br> , (VII) <br><br> R8 denotes the alkyl moiety of one of the above-mentioned groups which may be/cl4aved in vivo, with the exception of the R6-C0-0- (RsCR6) / gfcoup for a carboxyl group and Z2 denotes a leaving'group such as a halogen atom, e.g. a chlorine or bromine atom. <br><br> The reaction witp. an alcohol of general formula VI is conveniently Carried out in a solvent or mixture of 25 solvents sucfti As methylene chloride, benzene, toluene, <br><br> chlorobenz^ne/ tetrahydrofuran, benzene/tetrahydrofuran or dioxane, auxJ preferably in an alcohol of general formula VI, optian^Lly in the presence of an acid such as hydroch/oyic acid or in the presence of a dehydrating 3 0 agent,/e/g. in the presence of isobutylchloroformate, <br><br> thionyl /chloride, trimethylchlorosilane, hydrochloric acid, sulpyhuric acid, methanesulphonic acid, p-toluenesulphonic acLa,/phosphorus trichloride, phosphorus pentoxide, N,N'-;:Lcy&lt;clohexylcarbodiimide, N,N' -dicyclohexylcarbodiimide/N-35 l&gt;ydroxysuccinimide, N,N'-carbonyldiimidazole or N,N'- <br><br> lonyldiimidazole, triphenylphosphine/carbon tetrachloride ofc triphenylphosphine/diethylazodicarboxylate, optionally <br><br> NOW AMENDED <br><br> - 25 <br><br> in the presence of a base such as pota^s/um carbonate, N-ethyl-diisopropylamine or N,N-dimethmamino-pyridine, conveniently at temperatures betweenr o/and 150°C, <br><br> preferably at temperatures between/0 And 80°C. <br><br> 5 / / <br><br> With a compound of general formula/vil the reaction is usefully carried out in a solvent/such as methylene chloride, tetrahydrofuran, dioKaiie, dimethylsulphoxide, dimethylformamide or acetone,/optionally in the presence of 10 a reaction accelerator such /as/sodium or potassium iodide and preferably - in the presanae of a base such as sodium carbonate or potassium capDonate or in the presence of a tertiary organic base suah As N-ethyl-diisopropylamine or N-methyl-morpholine, whxchr may act as solvent at the same 15 time, or optionally in/tne presence of silver carbonate or silver oxide at temperatures between -30 and 100°C, but preferably at tempe»kt/ires between -10 and 80°C. <br><br> d. In order to prepare a compound of general formula I 20 wherein Rb denot^4 p. group which may be cleaved in vivo: <br><br> Reacting a com£&gt;oy(nd of general formula <br><br> 25 <br><br> Ra - # -/Het - B - Ar - C(=NH) - NH. <br><br> ,(VIII) <br><br> wherein <br><br> Ra, A, H^t,/B and Ar are as hereinbefore defined, with a compound, ©f general formula <br><br> 30 <br><br> z2 " R5 <br><br> , (IX) <br><br> 35 <br><br> wh^sre <br><br> R/ denotes a group which may be cleaved in vivo and <br><br> J2 /denotes a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom. <br><br> NOW AMENDED <br><br> - 26 - <br><br> The reaction is preferably carried ouy in a solvent such as methanol, ethanol, methylene chlorid^, tetrahydrofuran, toluene, dioxane, dimethylsulphoxid^ or dimethylformamide, 5 optionally in the presence of an iaocganic or tertiary organic base, preferably at temperat/ures between 2 0°C and <br><br> With a compound of general foEmu/a IX, wherein Z2 denotes a 10 nucleofugic leaving group, the reaction is preferably carried out in a solvent sudn iks methylene chloride, acetonitrile, tetrahydrofu/an/ toluene, dimethylformamide or dimethylsulphoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium 15 tert.-butoxide or N-ethyl/diisopropylarnine at temperatures e. In order to prep^:^a compound of general formula I wherein B denotes an /ethylene group, in which a methylene 20 group is replaced/by a sulphinyl or sulphonyl group: <br><br> EL, / A - Het - B' - Ar - E , (X) <br><br> 25 / / <br><br> A, E, Ar,/ne/t and Ra are as hereinbefore defined and B1 denotes /an ethylene group, wherein a methylene group is <br><br> 30 / / <br><br> The oxidation is preferably carried out in a solvent or mixfrurie of solvents, e.g. in water, water/pyridine, <br><br> acetone, methylene chloride, glacial acetic acid, glacial adetic acid/acetic anhydride, dilute sulphuric acid or 3 5 tfrlfluoroacetic acid, and depending on the oxidising agent <br><br> NOW AMENDED <br><br> - 27 <br><br> In order to prepare a corresponding sj/lpninyl compound of general formula I oxidation is conveniOTitly carried out with one equivalent of the oxidising agent used, e.g. with hydrogen peroxide in glacial acetic flcid, trifluoroacetic acid or formic acid at 0 to 20°C pr /in acetone at 0 to 60°C, with a peracid such as pei}£o/mic acid in glacial acetic acid or trifluoroacetic/ac/id at 0 to 50°C or with m-chloroperbenzoic acid in methyl^ne chloride, chloroform or 10 dioxane at -20 to 80°C, with/sgoium metaperiodate in aqueous methanol or ethanol/ ajL -15 to 25°C, with bromine in glacial acetic acid or aqueo(is acetic acid, optionally in the presence of a weak bas&amp; such as sodium acetate, with N-bromosuccinimide in ethanaG., with tert.-butylhypochlorite 15 in methanol at -80 to f 3CrC, with iodobenzodichloride in aqueous pyridine at d tp 50°C, with nitric acid in glacial acetic acid at 0 to/2Q^C, with chromic acid in glacial acetic acid or in acetone at 0 to 2 0°C and with sulphuryl chloride in methylene chloride at -70°C, the resulting 20 thioether chlorin^/complex is conveniently hydrolysed with aqueous ethanol. <br><br> In order to prepare a sulphonyl compound of general formula I, oxidation is carried out starting from a corresponding 25 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 hydrocfery peroxide in glacial acetic acid/acetic anhydride, 30 trifluoroacetic acid or in formic acid at 20 to 100°C or in ^e at 0 to 60°C, with a peracid such as performic acid ox/w/th m-chloroperbenzoic acid in glacial acetic acid, <br><br> iluoroacetic acid, methylene chloride or chloroform at riperatures between 0 and 60°C, with nitric acid in 35 / glacial acetic acid at 0 to 20°C, with chromic acid or <br><br> AMENDED <br><br> - 28 - / / <br><br> potassium permanganate in glacial acetic Acid, water/sulphuric acid or in acetone at/0 fto 20°C. Thus, by-carrying out oxidation, for example,/st/arting from a corresponding sulphenyl compound, preferably in methylene 5 chloride, by treating with a corresponding amount of m- <br><br> chloroperbenzoic acid at temperatyuries between 20°C and the reflux temperature of the reacti/oiy mixture, a corresonding sulphonyl compound of general formula I is obtained which may still contain a small amount^ of the corresponding 10 sulphinyl compound. / / <br><br> 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 15 is replaced by an oxygen pr sulphur atom or by a sulphinyl, sulphonyl, carbonyl or -NRi.- group: <br><br> Reacting a compound /ofjgeneral formula <br><br> EL / A - Het - U , (XI) <br><br> 20 /a/ <br><br> with a compouncy ol general formula <br><br> / / V - Ar - CN ,(XII) <br><br> 25 / / <br><br> wherein / / <br><br> Ra, A, Ar Anp Het are as hereinbefore defined, <br><br> one of tjae Aroups U or V denotes an H0-, HS-, H0S0-, H0S"02-or HNR1-/ group and the other group denotes a Z3CH2- group, 30 wherein is as hereinbefore defined and Z3 denotes a nuclepfugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom. <br><br> The reaction is preferably carried out in a solvent such as 35 methanol, ethanol, methylene chloride, tetrahydrofuran, <br><br> fcoLuene, dioxane, dimethylsulphoxide or dimethylformamide, 'optionally in the presence of an inorganic or a tertiary <br><br> NOW AMENDED <br><br> - 29 - <br><br> organic base, preferably at temperaturfes/between 20°C and the boiling temperature of the solvenrt used. <br><br> g. In order to prepare a compound c/f General formula I, 5 wherein E is a cyano group and Ra yaenotes an R2NR3- group <br><br> Reacting a compound of general formula <br><br> 10 <br><br> H - A <br><br> Het <br><br> B <br><br> \.r/ - CN <br><br> ,(XIII) <br><br> wherein A, B, Het and Ar are as he of general formula re/nbefore defined, with an amine <br><br> 15 <br><br> H - N, <br><br> , (XIV) <br><br> 'R- <br><br> wherein <br><br> R2 and R3 are as hereinbefore defined, or with the reactive derivatives there/of/ <br><br> 20 The reaction of afa acid of general formula XIII is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, ch/oyobenzene, tetrahydrofuran, <br><br> benzene/tetrahydrofuran or dioxane or in a corresponding 25 amine of -general formula III, optionally in the presence of a dehydrating agent, e.g. in the presence of isobutyl-chloroformate, tetraethylorthocarbonate, trimethylortho-acetate,/2,2-dimethoxypropane, tetramethoxysilane, thionyl chlorade, trimethylchlorosilane, phosphorus trichloride, 30 phosphorus pentoxide, N,N' -dicyclohexylcarbodiimide, N,N'-dioyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-d^fcyclohexylcarbodiimide/l-hydroxy-benzotriazole, 2-(1H-*enfeotriazol-l-yl)-1,1,3,3-tetramethyluronium-/tafcrafluoroborate, 2- (lH-benzotriazol-l-yl)-1,1,3,3-35 / t^tramethyluronium-tetrafluoroborate/1-hydroxy- <br><br> NOW AMENDED <br><br> - 30 - <br><br> benzotriazole, N,N'-carbonyldiimidazole/o] <br><br> triphenylphosphine/carbon tetrachloride and optionally with the addition of a base such as pyridine/ 4-dimethylamino-pyridine, N-methyl-morpholine or triy^tjaylamine, <br><br> conveniently at temperatures betweefi p and 150°C, <br><br> preferably at temperatures between 0/ and 100°C. <br><br> The reaction of a corresponding/reactive compound of general formula XIII such as tlie /esters, imidazolides or 10 halides thereof with an amine/oy general formula XIV is preferably carried out in a jtoi/responding 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-15 diisopropylamine or N-methyl-morpholine at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C. <br><br> h. In order to prep^.rd a benzimidazolyl, benzothiazolyl or 20 benzoxazolyl compound of general formula I wherein B denotes an ethylene/group: <br><br> Reacting a compound of general formula <br><br> 25 <br><br> - A <br><br> NH. <br><br> YH <br><br> , (XV) <br><br> wherein Ra, A ai genera] <br><br> are as hereinbefore defined, with a compound of formula <br><br> 30 <br><br> HO-CO - CH2CH2 - Ar - E <br><br> , (XVI) <br><br> wherein <br><br> Ay and E are as hereinbefore defined, or with the reactive ier/vatives thereof. <br><br> NOW AMENDED <br><br> 31 <br><br> The reaction is conveniently carried fxiXJ in a solvent or mixture of solvents such as methylene onloride, dimethylformamide, benzene, toluene/ c/nlorobenzene, 5 tetrahydrofuran, benzene/tetrahydrpfyran or dioxane, <br><br> optionally in the presence of a dehydrating agent, e.g. in the presence of isobutylchloroformate, tetraethylortho-carbonate, trimethylorthoacetatye, 1, 2 -dimethoxypropane, tetramethoxysilane, thionyl cMoride, trimethylchloro-10 silane, phosphorus trichloride,/phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,M1/dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N' -di/cyclohexylcarbodiimide/l-hydroxy-benzotriazole, 2-/lH^benzotriazol-l-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(lH-benzotriazol-1-15 yl)-1,1, 3 , 3-tetramethyluroaiium tetraf luoroborate/l-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base siflcht as pyridine, 4-dimethylamino-pyridine, N-methyl-moi/pholine or triethylamine, 20 appropriately at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C. <br><br> The reaction of af corresponding reactive compound of general formula Avi such as the esters, imidazolides or 25 halides thereoy with an amine of general formula XV is preferably parried out in a solvent such as methylene chloride, etl/er or tetrahydrofuran and preferably in the presence of /a tertiary organic base such as triethylamine, N-ethyl-yai/sopropylamine or N-methyl-morpholine, which may 3 0 simultaneously be used as solvents, at temperatures between 0 and h.5p°C, preferably at temperatures between 50 and i./Ii/ order to prepare a quinoxalin-2-one compound of the 3 5 general formula: <br><br> NOW AMENDED <br><br> - 32 <br><br> Reacting a compound of general formula/ <br><br> NH- <br><br> ,(xvii; <br><br> NR^H <br><br> wherein <br><br> Ra, Ri and A are as hereinbefor^ Refined, with a compound of general formula <br><br> HO-CO - COCH2 - /Ar/ - E <br><br> ,(XVIII) <br><br> wherein <br><br> 10 Ar and E are as hereinbef/6r^ defined, or with the reactive derivatives thereof. <br><br> The reaction is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, 15 dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, bdnzene/tetrahydrofuran, ethanol or dioxan, optionally in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate,/tyimethyl orthoacetate, 20 2, 2-dimethoxyproprane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N/-dicyclohexylcarbodiimide, <br><br> N, N1 -dicyc Lohexylcarbodi imide/N-hydroxysucc inimide, N,N' -dicyololiexylcarbodiimide/l-hydroxy-benzotriazole, 25 2- (lH-beiyzoltriazol-l-yl) -1,1,3, 3-tetramethyluronium-tetrafluory6borate, 2- (lH-benzotriazol-l-yl) -1,1,3,3-tetramo'fchw'luronium-tetraf luoroborate/l-hydroxy-benzot/rl^zole, N,N'-carbonyldiimidazole or triphfenylphosphine/carbon tetrachloride, and optionally 3 0 witl/ trie addition of a base such as pyridine, <br><br> 4-dimfethylaminopyridine, N-methyl-morpholine or triethylamine, appropriately at temperatures of between 0 150°C, preferably at temperatures of between 0 and <br><br> 'icyooc. <br><br> NOW AMENDED <br><br> 33 - <br><br> 10 <br><br> However, it is particularly preferred/tcy carry out the reaction with a corresponding reactive Compound of general formula XVIII such as the esters, imidfazolides or halides thereof with an amine of general fornmla XVII in a solvent such as methylene chloride, ether/ ^thanol or tetrahydrofuran and optionally in /he presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine, which may simultaneously serve as solvent/ at temperatures of between 0 and 150°C, preferably at ^Btrjperatures of between 50 and 100°C. <br><br> j . In order to prepare a/cotnpound of general formula I 15 wherein R2 denotes a C^/^./alkyl group substituted by an alkylsulphonylaminocarfcomyl group: <br><br> Reacting a compound /of/general formula <br><br> 20 <br><br> 25 <br><br> R- <br><br> R- <br><br> \ / <br><br> N, <br><br> - Het - B - Ar - E <br><br> ,(IXX) <br><br> wherein <br><br> R3, A, B, E,/arya Het are as hereinbefore defined and R2' denotes/a/Ci_4-alkyl group substituted by a carboxy group, or /tYie. reactive derivatives thereof, with a salt of a compound yof general formula <br><br> C]_ _ 3 - Alkyl - S02-NH2 <br><br> (XX) . <br><br> The re/ction is preferably carried out with a corresponding 3 0 reactive compound of general formula IXX such as the <br><br> ;e/s, imidazolides or halides thereof with a salt of a impound of general formula XX, preferably with an alkali ne/al salt thereof such as a sodium salt, in a solvent such methylene chloride, ether, ethanol, tetrahydrofuran or <br><br> NOW AMENDED <br><br> - 34 - / / <br><br> dimethylformamide at temperatures between/0 and 150°C, preferably at temperatures of between Mo/and 100°C. <br><br> In the reactions described hereinbe/ore, any reactive 5 groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected duying the reaction by means of conventional protecting/gi/oups which are removed by cleaving after the reaction./ / <br><br> 10 For example, the protecting groidp for a hydroxy group may be the trimethylsilyl, acetyl,/benzoyl, tert.butyl, trityl, benzyl or tetrahydropyranyy group, <br><br> the protecting group for/a ycarboxyl group may be the 15 trimethylsilyl, methyl, /etnyl, tert.butyl, benzyl or tetrahydropyranyl group, And the protecting group/fdr an amino, alkylamino or imino group may be the acetyl, trifluoroacetyl, benzoyl, 20 ethoxycarbonyl, tert/-butoxycarbonyl, benzyloxycarbonyl, <br><br> benzyl, methoxybeAzyl or 2,4-dimethoxybenzyl group and for the amino group /the phthalyl group may also be considered. <br><br> The optional subsequent cleaving of a protecting group may, 25 for example, yce/carried out hydrolytically in an aqueous solvent, e.g. Ln water, isopropanol/water, tetrahydro-furan/watey or dioxane/water, in the presence of an acid such as tyifiauoroacetic acid, hydrochloric acid or sulphuriaf acid or in the presence of an alkali metal base 30 such as/lythium hydroxide, sodium hydroxide or potassium hydrox/de' 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. <br><br> 3 5 HgWever, a benzyl, methoxybenzyl or benzyloxycarbonyl group for example be cleaved hydrogenolytically, e.g. using Irogen in the presence of a catalyst such as <br><br> NOW AMENDED <br><br> - 35 - / / <br><br> palladium/charcoal in a solvent such as/ methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally w/thr the addition of an acid such as hydrochloric acid, at cen/peratures between 0 5 and 50°C, but preferably at room temperature, under a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar. <br><br> A methoxybenzyl group may also /oejcleaved in the presence of an oxidising agent such as Cerium(IV)ammonium nitrate in 10 a solvent such as methylene dnLoride, acetonitrile or acetonitrile/water at tempe/ayures between 0 and 50°C, but preferably at room temperajtuye. <br><br> However, a 2,4-dimethoxyc&gt;eazyl group is preferably cleaved 15 in trif luoroacetic acid/ in the presence of anisole. <br><br> A tert.butyl or tertyDutyloxycarbonyl group is preferably cleaved by treatment^ with an acid such as trifluoroacetic acid or hydrochloric Acid, optionally using a solvent such 20 as methylene chloride, dioxane, or ether. <br><br> A phthalyl group i/s preferably cleaved in the presence of hydrazine or a/pyimary amine such as methylamine, <br><br> ethylamine oiy n/butylamine in a solvent such as methanol, 25 ethanol, isoprfflpanol, toluene/water or dioxane, at temperatures between 20 and 50°C. <br><br> An allylasx^carbonyl group is cleaved by treating with a catalytic Amount of tetrakis-(triphenylphosphine)-3 0 pallad/un/(0) , preferably in a solvent such as tetranydfcofuran and preferably in the presence of an excess of a/ba/se 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 35 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- <br><br> NOW AMENDED <br><br> - 36 - / / <br><br> diazabicyclo[2.2.2]octane, at temperatures between 20 and 70°C. / / <br><br> The compounds of general formulae if fo XX used as starting 5 materials, some of which are knowiy from the literature, may be obtained by methods known frony tfe literature and moreover their production is described in the - Examples. <br><br> Thus, for example, a compoundptfgeneral formula II is 10 obtained by reacting a corresponding nitrile which in turn is conveniently obtained by Processes f to h, with a corresponding thio or alcohfoy in the presence of hydrogen chloride or bromide. / / <br><br> 15 A compound of general formulae IV, V, VIII, X and IXX used as starting material i.p conveniently obtained according to a process of the present/ invention. <br><br> A starting compouncy of general formula XI in which U 20 denotes a halomettoyl/group is conveniently obtained by cyclisation of a Corresponding ester which is substituted in the o-position py a suitable halogen atom and a methoxyacetamicfo ygroup, to form a corresponding bicyclic 2-alkoxymethyl yompound, optionally subsequent hydrolysis and 25 optionally subsequent amidation of a resulting carboxylic acid with a/carresponding amine, converting the alkoxymethyl /compound thus obtained into the corresponding halomethyl: yompound, which can if necessary be subsequently converted. j/nto the desired compound by means of a suitable 30 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, meroapto or amino group. <br><br> 35 A/starting compound of general formula XIII is obtained by .isation of a corresponding o-disubstituted ester, .lowed by saponification of the resulting ester and <br><br> NOW AMENDED <br><br> - 37 - <br><br> subsequent amidation of the carboxylic/ac/id thus obtained with a corresponding amine. <br><br> 10 <br><br> 15 <br><br> Furthermore, an imidazopyridine substi/tuted in the 5-position by a methyl group and obtained by cyclisation can be converted, via the corresponding/N-oxide, into the corresponding hydroxymethyl compyoumd which is- converted by oxidation into the desired carboxylic acid of general formula XIII. <br><br> The compounds Of general foi/muiae 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-pos/ti/on by an optionally substituted amino group and a nitro/group, and optionally subsequent cyclisation of the resulting o-diamino compound with a corresponding carboxylie acid. <br><br> Furthermore, the compounds of general formula I obtained 20 may be separated ^ntyo their enantiomers and/or diastereomers. <br><br> 25 <br><br> 30 <br><br> 35 <br><br> Thus, for example/, the compounds of general formula I obtained whicji occur in racemate form may be separated by methods know# ]per se (see Allinger N. L. and Eliel E. L. in <br><br> "Topics in ^Stereochemistry", Vol. 6, Wiley Interscience, 1971) into&lt; their optical antipodes, and compounds of general fiormula I having at least 2 asymmetric carbon atoms may be Separated on the basis of their physical-chemical snoes using known methods, e.g. by chromatography and/o/ firactional crystallisation, into the diastereomers <br><br> ', which, if they occur in racemic form, may subsequently be separated into the enantiomers as mentioned ab&gt;/t <br><br> The separation of enantiomers is preferably effected by column separation on chiral phases or by recrystallisation <br><br> NOW AMENDED <br><br> - 38 - / / <br><br> from an optically active solvent or by Reacting with an optically active substance, especially aicids and the activated derivatives thereof or alcaftiols, which forms salts or derivatives such as e.g. enters or amides with the 5 racemic compound, and separation of trie diastereomeric salt mixture or derivative thus obtained/e .g. on the basis of their different solubilities, wh/lyt the free - antipodes may be released from the pure diastyereomeric salts or derivatives by the action of auilcable agents. Particularly 10 common, optically active acids are, for example, the D- and L-forms of tartaric acid, ana dibenzoyltartaric acid, di-o-tolyl tartaric acid, malic/acA-d, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid and quinaldic acid. Example^ or optically active alcohols 15 include for example (+)/ Qt (-)-menthol and examples of optically active acyl &lt;grdups in amides include, for example, ( + ) - or (-)-meiithyloxycarbonyl. <br><br> Moreover, the compounds of formula I obtained may be 20 converted into ther salts thereof, particularly for pharmaceutical use Znto the physiologically acceptable salts thereof wi/tly inorganic or organic acids. Examples of suitable acids/include for example hydrochloric acid, hydrobromic a/idr, sulphuric acid, phosphoric acid, fumaric 25 acid, succin/c Acid, lactic acid, citric acid, tartaric acid or maleid acid. <br><br> In addition/ the new compounds of formula I thus obtained, if they ^contain a carboxyl group, may subsequently, if 3 0 desired/, pe 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, 3 5 e/hafaolamine, diethanolamine and triethanolamine. <br><br> NOW AMENDED <br><br> 39 - <br><br> 10 <br><br> 15 <br><br> As already mentioned, the new compounds pi/general formula I and the salts thereof have valuable properties. Thus, the compounds of general formula I wherain 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 tautom^ri^/, the stereoisomers and the physiologically acceptable shits 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 Vila, factor Xa, factor IX, factor XI and factzor XII, whilst a few compounds such as for example the compound of Example 16 simultaneously also have/a/slight inhibitory effect on thrombocyte aggregation/. <br><br> For example, the foil/owing compounds: <br><br> 20 A = 2- [N- (4-amidiraoprienyl) -aminomethyl] -benzthiazole- <br><br> 5-carboxylic/ac/id-N-phenyl-N- (2-car boxy ethyl) -amide, <br><br> 25 <br><br> B = l-methyl-2/[1-(4-amidinophenyl)ethyl]-benzimidazol -5-yl-carb6x/lic acid-N-phenyl-N-(3-hydroxycarbonyl-propyl) -Amide, <br><br> C = l-metttyl/-2-[ (4-amidinophenyl) oxymethyl] -benzimidazol-5-yl/carboxylic acid -N-phenyl-N-(hydroxycarbonyl-metny]/) -amide, <br><br> D = y-m/thyl-2-[N-(4-amidinophenyl)-aminomethyl]- <br><br> benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-^droxycarbonylethyl)-amide, <br><br> l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl) N-(hydroxycarbonylmethyl)-amide, <br><br> NOW AMENDED <br><br> - 40 - <br><br> F = l-methyl-2-[2-(4-amidinophenyl) ethyl/]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2/ (/H-tetrazol-5-yl)ethyl]-amide and <br><br> 5 <br><br> G = 1-methyl-2-[N-(4-amidinophenyl)/aminomethyl] - <br><br> benzimidazol-5-yl-carboxyli&lt;/ ^cid-N-(2-pyridyl)-N-(2 hydroxycarbonylethyl)-amide <br><br> 10 were investigated as follows their effects on thrombin time: <br><br> 15 <br><br> Materials plasma, from human citrated blood. <br><br> Test thrombin /bovine), 3 0U/ml, Behring Werke, Marburg <br><br> DiethylbaEDiturate acetate buffer, ORWH 60/61, Behring Wei:ke, Marburg Biomaticr Ba.0 coagulometer, Sarstedt <br><br> 2 0 Method: <br><br> The thrombin tir coagulometer me <br><br> ?as determined using a Biomatic BIO 'by Messrs. Sarstedt. <br><br> 25 As the test s*uh£tance, 0.1 ml of human citrated plasma and 0.1 ml dietttylfoarbiturate buffer (DBA buffer) were added to the test st/rip prescribed by the manufacturer. The mixture was incubatera. for one minute at 37°C. The clotting reaction/was started by the addition of 0.3 U test thrombin 30 in 0.1 /ml/DBA buffer. The time is measured using the apparatus from the addition of the thrombin up to the clotying of the mixture. Mixtures to which 0.1 ml of DBA buf fier/were added were used as the controls. <br><br> 35 According to the definition, a dosage-activity curve was ise'cl to determine the effective concentration of the <br><br> NOW AMENDED <br><br> - 41 - <br><br> substance, i.e. the concentration time is double compared with at whyci the control the thrombin <br><br> The Table which follows contains the/rersults found: <br><br> Substance <br><br> Throrefbin time <br><br> CED/QO in MM) - <br><br> A <br><br> / / 0.04 <br><br> B <br><br> / / 0.06 <br><br> C <br><br> / / 0.15 <br><br> D / <br><br> / 0. 03 <br><br> E / <br><br> / 0.09 <br><br> f 1 <br><br> 0 . 03 <br><br> G / / <br><br> 0 . 03 <br><br> By way of example, no §(cu/fce toxic side effects were observed when compounds IK, D, E and G were administered to rats in doses of up Jto/10 mg/kg i.v. The compounds are thus well tolerated. <br><br> irmacological properties the new Physiologically acceptable salts thereof prevention and treatment of venous and iiseases, such as for example the j vein thrombosis, for preventing sr bypass operations or angioplasty :lusion in peripheral arterial diseases r embolism, disseminated intravascular preventing coronary thrombosis, stroke and shunts or stents. In addition, the .ng to the invention are suitable for jmbotic support in thrombolytic treatment, such as with rt-PA or streptokinase, for preventing ^stenosis after PT(C)A, for preventing md the growth of clot-dependent tumours and inflammatory processes. <br><br> NOW AMENDED <br><br> " 42 " / / <br><br> The dosage required to achieve such an Affect is appropriately 0.1 to 3 0 mg/kg, preferably 0.3 to 10 mg/kg by intravenous route, and 0.1 to 50 n*g/Ag, preferably 0.3 to 3 0 mg/kg by oral route, in each da.sk administered 1 to 4 5 times a day. For this purpose, the? compounds of formula I prepared according to the invention Anay be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucosse, microcrystalline 10 cellulose, magnesium stearat&amp;, polyvinylpyrrolidone, citric acid, tartaric acid, water, ywafcer/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearyl alcohol, carWoxymethylcellulose or fatty substances such as hard jbXJ or suitable mixtures thereof, 15 to produce conventional/galenic preparations such as plain or coated tablets, caps3u2/es, powders, suspensions or suppositories. / / <br><br> The Examples which ^o/low are intended to illustrate the 20 invention: / / <br><br> NOW AMENDED <br><br> - 43 - / / <br><br> Preliminary remarks / / <br><br> Unless otherwise specified, the Rf valuers were always determined using polygram silica gel/ plates produced by 5 Messrs. E. Merck of Darmstadt. / / <br><br> The EKA mass spectra (electrospray mass spectra of cations) are described, for example, in /Cftemie unserer Zeit 6., 308-316 (1991). / / <br><br> 10 / / <br><br> Example 1 / / <br><br> 3-Methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b]-pyridine-6-carboxylic ac/d AN-phenyl-N-(2-15 ethoxycarbonylethyl)-amxd&amp; <br><br> a) Methyl 6-methvlamino/5-nitro-nicotinate <br><br> 1.6 g (7.4 mMol) of lnet/hyl 6-chloro-5-nitro-nicotinate (see Bernie et al. in J./cMem. Soc. 1951, 2590) were stirred in 20 20 ml of 40% aqueous/methylamine solution at room temperature for 3/u Minutes. The reaction mixture was then diluted with ice/ water, the yellow precipitate formed was filtered off arid Aried. <br><br> Yield: 1.2 g /q&lt;j % of theory), <br><br> 25 Rf value: 0 .(56/(silica gel; ethyl acetate/ethanol/glacial <br><br> / / acetic acid = 90:5:5) <br><br> b) Methyl/ 5/amino-6-methvlamino-nicotinate <br><br> To a solmt/on of 3.1 g (15 mMol) of methyl 6-methylamino-30 5-nitre/-nacotinate in 100 ml of ethanol/dichloromethane <br><br> (3:1)/was added 1 g of palladium on charcoal (10%) and the resulLti/ng suspension was hydrogenated at room temperature under/5 bar of hydrogen pressure for 1.5 hours. The ca/a^yst was then filtered off and the solvent was 35 d^st/illed off in vacuo. The crude oily product obtained <br><br> Xvas further reacted directly. <br><br> /meld: 2.4 g (92 % of theory), <br><br> NOW AMENDED <br><br> - 44 - <br><br> Rf value: 0.44 (silica gel; ethyl acetate/ethanol/ammonia <br><br> 90:10:1) <br><br> c) Methyl 5- \2-(4-cvanophenvl)ethvlcftrtyonvlaminol 5 6-methvlamino-nicotinate <br><br> A solution of 2.6 g (15 mMol) of 3/ (4f-cyanophenyl) propionic acid in 25 ml of absolute tetrahyarsfuran was.mixed with 2.4 g (15 mMol) of N,N1-carbonyLai/midazole and stirred for 20 minutes at room temperature./ Then the imidazolide was 10 mixed with a solution of 2.3 q {a.3 mMol) of methyl 5-amino-6-methylamino-nicotinate in 2'S 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 organL6 phase was washed with water and 15 after drying over sodiun/ sidlphate it was again freed from solvent. The residue attained was purified by flash chromatography (silicar gel; gradient: dichloromethane to dichloromethane/ethanoy = 19:1) . <br><br> Yield: 2.1 g (50 % af theory) of beige solid 20 Rf value: 0.54 (siZida. gel; ethyl acetate/ethanol/ammonia = <br><br> 90/ 10:1) <br><br> 25 <br><br> 30 <br><br> d) Methvlvl 3-mfetftvl-2-T2-(4-cvanophenvl)ethyl 1 -imidazo \4. S-b'l/jvg'idine-e-carboxvlate A solution of 2j.0g (5.9 mMol) of methyl 5-[2-(4-cyanophenyl/et^iylcarbonylamino] -6-methylamino-nicotinate in 50 ml glac/al/ acetic acid was heated to 100°C for one hour. After removal of the solvent the residue was taken up in dichlorometmane, washed with sodium hydrogen carbonate solution,/dried with sodium sulphate and the solvent was distil/Lejd off again. <br><br> Yielc^: jL.l g brown solid (89 % of theory) , <br><br> Rf ya]/ie: 0.50 (silica gel; ethyl acetate/ethanol/ammonia = <br><br> 90:10:1) <br><br> NOW AMENDED <br><br> - 45 - <br><br> 10 <br><br> 15 <br><br> e) 3-Methyl-2-\2-(4-cvanophenvl)ethyl 1 imidazo T4.5-blpyridine-6-carboxylic acic <br><br> A solution of 3.2 g (10 mMol) of metliy]/ 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 distillerd &gt;6ff and the aqueous phase was washed with ethyl acetate/ After acidification with dilute hydrochloric acid the/mi/xture was extracted several times with dichloromethane/meynanol (9:1), the organic phase was dried with sodiujn ^ulphate and the solvent was distilled off. <br><br> Yield: 2.1 g beige solid/(i0 % of theory), <br><br> Rf value: 0.3 8 (silica /je/; ethyl acetate/ethanol/ammonia <br><br> = 50:45:E) <br><br> f) 3-Methyl-2- f2- (4/cyanophenyl) ethvll -imidazo T4 . 5-bl -pyridine-6-carboxviicr acid-N-phenvl-N- (2-ethoxvcarbonvl-20 ethyl)-amide <br><br> A solution of 2.j % (6.5 mMol) of 3-methyl-2-[2-(4-cyanophenyl)/4tnyl] - imidazo [4 , 5-b] pyridine-6-carboxylic acid in 100 mlI dichloromethane was mixed with 20 ml thionyl chloride and/ref luxed for 2 hours. After the liquid 25 components Macy been distilled off the crude product was taken up twiae more in dichloromethane and the solvent was distilled/ofir each time. The crude acid chloride thus obtained/{2 g) was suspended in 100 ml of tetrahydrofuran and mixfed/with 1.2 g (6.5 mMol) of N-(2-ethoxycarbonyl-3 0 ethyl)ya.n/line. Then within 5 minutes 0.73 g (7.2 mMol) of triet/nylamine were added dropwise. After 1 hour's stirring the /Solvent was distilled off in vacuo, the residue was cei/ up in ethyl acetate, the organic phase was washed 'th[ water and dried with sodium sulphate. After 3 5 /di/tillation of the solvent and flash chromatography <br><br> (silica gel; dichloromethane to dichloromethane/ethanol = [9:1) the desired compound was isolated as a brownish oil. <br><br> NOW AMENDED <br><br> - 46 - <br><br> Yield: 1.9 g (65 % of theory), <br><br> Rf value: 0.44 (silica gel; ethyl acetate/ethanol/ammonia <br><br> 90:10:1) <br><br> 5 g) 3-Methvl-2- f2- (4-amidinophenyl) etihy£] -imidazo [4 . 5-bl -pyridine-6-carboxylic acid-N-phenyl-N- (2-ethoxvcarbonvlethvl)-amide <br><br> 1.8 g (3.7 mMol) of 3-methyl -2- [2- j/4 -cyanophenyl) ethyl] imidazo [4 , 5-b] pyridine-6-carboxyli/c acid-N-phenyl-N- (2-10 ethoxycarbonylethyl) -amide werje gstirred into 100 1 of ethanol saturated with hydrogen/chloride for 16 hours first at 0°C and then at room temp&amp;er^ture until no more starting material could be detected hy/thin layer chromatography. Then the solvent was disti/llyfed off, the oily residue was 15 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 vf.cxfo, the crude product obtained was purified by flash chromatography (silica gel; gradient dichloromethane/etha^o/ 19:1 to 4:1) and evaporated down 20 again. <br><br> Yield: 1.6 g of bexgie solid (80 % of theory), <br><br> Rf value: 0.30 (silica gel; ethyl acetate/ethanol/ammonia = <br><br> 5) <br><br> 25 Example 2 <br><br> 30 <br><br> 35 <br><br> 3-Methyl-2-/2y(4-amidinophenyl)ethyl]-imidazo[4,5-b]-pyridine-6Acarboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide <br><br> A solution of 535 mg (1.0 mMol) of 3-methyl-2-[2-(4-amidinfopAenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-^-phenyl-N-(2-ethoxycarbonylethyl)-amide in 10 ml eth^nql was mixed with 5 ml of 2N sodium hydroxide solution anal gtirred for 2 hours at room temperature. Then the mxxt/ure was diluted with 10 ml water, the alcohol was ll§/tilled off, the aqueous phase was washed with 20 ml <br><br> NOW AMENDED <br><br> - 47 - <br><br> ethyl acetate and acidified with concei acid, whereupon the desired compound the form of white crystals. <br><br> Yield: 375 mg (74 % of theory), <br><br> ited hydrochloric 'precipitated in <br><br> 5 Rf value: 0.23 (silica gel; ethyl ^ce/ate/ethanol/ammonia = <br><br> 90:5:5) <br><br> C26H26N603 (470.54) <br><br> Mass spectrum: (M+H)+ = 471 <br><br> 10 Example 3 <br><br> 15 <br><br> 20 <br><br> 25 <br><br> 3-Methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b] pyridin-6-yl-carboxylic/ aycid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amac^-hydrochloride <br><br> Prepared analogously tzo Example 1 from 3-methyl-2-[2-(4-cyanophenyl) ethyl] -imidazo [4 , 5-b] pyridin-6-yl-carboxylic acid-N- (2-pyridyl) -»-y2-methoxycarbonylethyl) -amide, methanolic hydroch/oyic acid, methanol and ammonium carbonate. <br><br> Yield: 75 % of ttfie0ry, <br><br> C26H27N7°3 (48^.5j£) <br><br> ilica gel; ethyl acetate/ethanol/ammonia = 50:45:5) <br><br> EKA mass spyfec/rum: (M+H) + = 486 <br><br> Rf value: 0.3 <br><br> Example <br><br> 3-MethVl-;2- [2- (4-amidinophenyl) ethyl] -imidazo[4,5-30 b]pyr/din-6-yl-carboxylic acid-N-phenyl-N-ethojcyc^arbonylme thyl - amide -hydrochloride <br><br> 35 <br><br> Pryepared analogously to Example 1 from 3-methyl-2-[2-(4-ramophenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic ic/d-N-phenyl-N-ethoxycarbonylmethyl-amide, ethanolic rdrochloric acid, ethanol and ammonium carbonate. <br><br> NOW AMENDED <br><br> - 48 - <br><br> Yield: 84 % of theory, J / <br><br> C27H28N603 (484.56) / / <br><br> Rf value: 0.44 (silica gel; ethyl acet&amp;te/ethanol/ammonia <br><br> = 50:45:5) / / <br><br> 5 EKA mass spectrum: (M+H)+ = 485 / / <br><br> Example 5 / / <br><br> 3-Methyl-2- [2- (4-amidinophenylyemyl]-imidazo[4,5-10 b] pyridin-6-yl-carboxylic acid-N'-phenyl-N-hydroxycarbonylme thyl - amide - liycrrochlor ide <br><br> Prepared analogously to Example 2 from 3-methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic 15 acid-N-phenyl-N-ethoxycarbonylmethyl-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 85 % of theory/ / <br><br> C25H24Ng03 (456.51) j j <br><br> Rf value: 0.19 (sili/c^gel; ethyl acetate/ethanol/ammonia 20 = sj-.fS-.S) <br><br> EKA mass spectrum: AM+H)+ = 457 <br><br> Example 6 / / <br><br> 25 2-[2-(4-amid/naphenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl-2, 3 -dihydroA.ndol-1-yl-carbonyl) -imidazo [4, 5-b] pyridine-hydrochloride <br><br> Prepared analogously to Example 1 from 2-[2-(4-3 0 cyanophfenyl) ethyl] - 3-methyl-6- (2-methoxycarbonyl.- <br><br> 2 , 3-dimwroindol-l-yl-carbonyl) - imidazo [4 , 5-b] pyridine, methanolic hydrochloric acid, methanol and ammonium carjporfate. <br><br> Yidla: 20 % of theory, <br><br> 35 ^27^26^6^3 (482.54) <br><br> /RjX/'alue: 0.30 (silica gel; ethyl acetate/ethanol/ammonia <br><br> NOW AMENDED <br><br> - 49 <br><br> = 50 :45:5) EKA mass spectrum: (M+H)+ = 483 <br><br> Example 7 <br><br> 2-[2-(4-amidinophenyl)ethyl] -3-met 2,3-dihydroindol-l-yl-carbonyl)-ymj hydrochloride <br><br> .-6-(2-carboxy-lazo [4 , 5-b] pyridine- <br><br> 10 <br><br> 15 <br><br> 20 <br><br> Prepared analogously to Example II from 2 — [2— (4-amidinophenyl)ethyl]-3-methyl-S-(2-methoxycarbonyl- <br><br> y~t) - imidazo[4,5-b]pyridine-droxide solution. <br><br> 2,3- dihydroindol -1 -yl - carbo/ <br><br> hydrochloride and sodium Yield: 90 % of theory, <br><br> C26H24N603 (468.52) <br><br> Rf value: 0.24 {silica./geL; ethyl acetate/ethanol/ammonia <br><br> = 50:4,5:/) <br><br> EKA mass spectrum: CM+H)+ = 469 <br><br> (ty+Na)+ = 491 <br><br> Example 8 <br><br> 25 <br><br> l-Methyl-2 - [ (-imidazo [4,5 (2-ethoxyca: <br><br> -amidinophenyl)oxymethyl]- <br><br> ^ridin-5-yl-carboxylic acid-N-(2-pyridyl)-N-iylethyl)-amide a) 2 -Amin/- ^-methylamino-6-methyl-pyridine <br><br> 8.35 g (/o /nMol) of 2-Methyl-5-methylamino-6-nitro-pyridine (Hetero/y/les 38, 529 (1994)) were dissolved in 300 1 ethyl 30 acetate /and hydrogenated with 1.5 g Raney nickel for 3.5 hours/at room temperature. Then the catalyst was filtered off AnA the filtrate was evaporated down. After crystallisation of the resulting residue from petroleum etznoo:, 5.75 g (84 % of theory) were obtained as olive-green 35 Gfrvffetals. <br><br> C^11N3 (137.20) <br><br> NOW AMENDED <br><br> - 50 - / / <br><br> Melting point: 112-113°C / / <br><br> b) 1.5-Dimethyl-2-f(4-cvanophenvl)oxvTrfetAvll-imidazo f4.5-bl -pyridine J / <br><br> 5 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 /nMol) of <br><br> N,N'-carbonyldiimidazole. After/1^ minutes at 60°C, 5.70 g (41.5 mMol) of 2-amino-3-methyLam/no-6-methyl-pyridine were 10 added. After 2 hours at 60°C solvent was distilled off and the crystalline residue was/mixed with water, washed with water and dried. Aftey crystallisation from ethanol 9.95 g (91 % of theory) weye &gt;obtained in the form of white crystals. / / <br><br> 15 C16H14N40 (278.32) / / <br><br> Mass spectrum: M+ = 27w / <br><br> c) 1,5-Dimethvl-2-T(d-cyanophenyl)oxvmethvll-imidazo l"4 . 5-bl pvridjm-^-N-oxide <br><br> 20 2.62 g (10 mMol) o/ V, 5-dimethyl-2-[(4-cyanophenyl)- <br><br> oxymethyl]-imidaziD[V, 5-b] pyridine were suspended in 125 ml dichloromethane and mixed with 2.62 g (12.7 mMol) of m-chloroperbenzjoit acid, whereupon a clear solution was obtained. After/2 hours at room temperature the solvent 25 was distilled/ ott and the residue obtained was mixed with a sodium hydrogen carbonate solution. After 3 0 minutes the white crystalline product obtained was suction filtered, washed wit/h water and dried at 40°C. <br><br> Yield: 2/4^g (83 % of theory), <br><br> 3 0 Ci6H14N/O/ (294.30) <br><br> Mass speyctrum: M+ =294 <br><br> d) l/-Methvl-2- f (4-cvanophenvl) oxvmethvll - 5-hvdroxymethyl-im/dareo \A . 5 -bl pyridine <br><br> 35 2/40/g (8.2 mMol) of 1, 5-dimethyl-2 - [ (4-cyanophenyl) - <br><br> /xyTnethyl]-imidazo [4 , 5-b] pyridin-4-N-oxide were suspended /ini 75 ml dichloromethane and mixed with 2.4 ml of <br><br> NOW AMENDED <br><br> - 51 - / / <br><br> trifluoroacetic acid anhydride (16.9 mMol)/ whereupon a clear solution was obtained. After 16 monrs at room temperature the solvent was distilled /oik, the viscous residue obtained was taken up in 50 ml dichloromethane and 5 covered with 50 ml of 2M sodium hydrogen carbonate solution. After 3 hours' vigorous/syirring the precipitate formed was suction filtered, washed/with water and dried at 40°C. / / <br><br> Yield: 1.85 g white powder (78 k pi theory), <br><br> 10 c16h14n4°2 (294.30) / / <br><br> Melting point: '172°C / / <br><br> e) l-Methvl-2- f (4-cyanopheny]/) oxymethvll - imidazo [4 . 5-b] -pyridine-5-carbaldehvde / / <br><br> 15 3.65 g (12.5 mMol) of 1 -mej/hyl-2 -[ (4-cyanophenyl) - <br><br> oxymethyl] -5-hydroxymetry/-imidazo [4, 5-b] pyridine were dissolved in 500 ml di/chloromethane and mixed with 15.0 g of manganese dioxide/ After 96 hours at room temperature the mixture was filt/e»ed through kieselgur and the solvent 20 was distilled off. / "Pne filtrate obtained was evaporated down, the crystal/irfe precipitate was triturated with ether, suction f/ltzered and dried. <br><br> Yield: 3.05 g wnit/e powder (84 % of theory), <br><br> Ci6Hi2N402 (29/2.20) <br><br> 25 Melting point/: ^31-234°C <br><br> f) l-Methyli-a*- \ (4-cyanophenyl) oxvmethvll -5-carboxv-imidazo-[4.5-blpyridine <br><br> 1.25 g (A-/ mMol) of l-methyl-2-[(4-cyanophenyl)oxymethyl]-30 imidazcVi4/5-b] pyridine-5-carbaldehyde were dissolved in 10 ml formiic acid and mixed at 0°C with 1.0 ml hydrogen peroxxde (33% strength). After 12 hours at 4°C the white precn.pa.tate formed was suction filtered, washed with water and dried at 40°C. <br><br> 35 Yieyd: 0.81 g (61 % of theory), <br><br> /l#*12N403 (308.7) <br><br> NOW AMENDED <br><br> - 52 - <br><br> g) 1-Methyl-2-f(4-cyanophenyl)oxvmethvll imidazo f4 . 5-bl pyridin-5-vl-carboxvlic/ac/id-N- (2-pvridvl) -N-(2-methoxvcarbonvlethvl)-amide <br><br> 3 08 mg (1.0 mMol) of 1-methyl-2-[(4/cVanophenyl)oxymethyl]-5-carboxy-imidazo [4.5-b]pyridine were suspended in 5 ml of dimethylformamide and mixed with SO3 mg (3.0 mMol) of N-methyl-morpholine and 321 mg mMol) of <br><br> O- (benzotriazol-l-yl) -N,N,N1 , N'/teetramethyl-uronium tetraf luoroborate. After 10 rqanjates at room temperature a 10 solution of 215 mg (1.2 mMol)/of methyl N-(2-pyridyl)- <br><br> 3-amino-propionate in 2 ml af climethyl formamide was added, whereupon a clear solution A/as obtained. After 12 hours at room temperature the reaction solution was stirred into ice-water. After extracting 3 times with ethyl acetate the 15 combined organic extracts Are re washed with a saline solution, dried over sodium sulphate and evaporated down. The residue obtained toad chromatographed on silica gel with dichloromethane/ethano/ (90:1 to 25:1). <br><br> Yield: 165 mg of viyitp powder (35 % of theory) , 20 C25H12N604 (407.5&lt; <br><br> Melting point: 12&gt;9-/L40°C <br><br> h) l-Methvl-2-/(f-amidinophenyl)oxvmethvll -imidazof4.5-bl-pyridin-5-vl-caAoxvlic acid-N- (2-pvridvl) -N- (2-25 ethoxvcarboiwl/ethvl) -amide <br><br> Prepared b^reacting 140 mg (0.3 mMol) of 1-methyl-2-[(4-cyanophenyl)oxymethyl] -imidazo[4,5-b]pyridin-5-yl-carboxyli/c Acid-N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide wj/tly ethanol saturated by hydrogen chloride and with 3 0 ammonium yfcarbonate/ethanol analogously to Example lg. The result/ing product was purified by chromatography over silica Ael with dichloromethane/ethanol (19:1 to 4:1) . Yie/d/ 48 mg of white powder (3 6 % of theory) , <br><br> c2y6H/7N7°4 (501.57) <br><br> 35 I^&amp;s/£ spectrum: (M+H) + = 502 <br><br> NOW AMENDED <br><br> - 53 - <br><br> Example 9 / / <br><br> 2- [N- (4-amidinophenyl) -aminomethyl] -benyothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxw:arbonylethyl)-amide a) Ethvl 4-fluoro-3-methoxvacetam j/ao/benzoate <br><br> A solution of 2.8 g (15.3 mMol) off &gt;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 10 methoxyacetylchloride in 50 md. dhlorobenzene was stirred for 1 hour at 50°C and then re/luxed for 15 minutes. Then the solvent was distilled okf/in vacuo and the crude product obtained was purifiaaa by flash chromatography (silica gel; dichlorometl/ana/ethanol = 100:1). The desired 15 compound, initially oily, Solidified within a few days. Yield: 3.8 g (98 % of /herory) , <br><br> Rf value: 0.38 (silica; gel; dichloromethane/ethanol = 19:1) <br><br> b) Ethvl-2-methoxvmetMvl-benzothiazole-5-carboxvlate 20 A mixture of 3.0 g/ ({.1.1 mMol) of 4-fluoro-3- <br><br> methoxyacetamido-TPe/izoic acid and 2.1 g (5.2 mMol) of Lawesson's reagerity was refluxed for 6 hours in 90 ml toluene, mixed/tfiyth 1.0 g Lawesson's reagent and heated to 120°C for another 6 hours. After the solvent was replaced 25 with xylene /her mixture was heated to 180°C for a further 8 hours in a pre/ssurised vessel. Then the solvent was distilled off in vacuo, the crude product obtained was purifiedflash chromatography (silica gel; ethyl acetate/petroleum ether = 5:95) and evaporated down again. 30 Yield: g of yellow crystals (72 % of theory) , <br><br> Rf val/ue/ 0.55 (silica gel; ethyl acetate/petroleum ether = / / 3:7) <br><br> 35 <br><br> NOW AMENDED <br><br> - 54 - <br><br> hour at room temperature. Then the alcqfioX was distilled off, the crude product was taken up in^O/ml water, washed with 50 ml diethylether and the aqueous phase was acidified with concentrated hydrochloric acid WhMst being cooled with ice. The pinkish-beige compoundthereby precipitated was suction filtered, washed with watyer and dried. <br><br> Yield: 1.6 g (86 % of theory), <br><br> Rf value: 0.12 (silica gel; dich^oiyomethane/ethanol = 29:1) <br><br> 10 d) 2-Methoxvmethvl-benzothiazoflLe/5-carboxylic acid-N-phenvl-N-(2-ethoxycarbonylethyl/-amide A suspension of 1.6 g (7.2 raMoi) of 2-methoxymethyl-benzothiazole-5-carboxylic /aoo.d in 60 ml dichloromethane was mixed with 1.6 ml (22/mMol) of thionyl chloride and 15 refluxed for 1 hour. Thj£ gfclid 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 Aiptilled off. The crude acid chloride thus obtained/was taken up in 50 ml of 20 tetrahydrofuran, addeifl dropwise to a mixture of 1.4 g (7.2 mMol) of N-(2-ethdxycarbonylethyl)aniline and 3.0 ml (21 mMol) of triethy/amine in 50 ml of tetrahydrofuran and stirred overnight At room temperature. Then the solvent was distilled pffi in vacuo, the residue was taken up in 3 0 <br><br> 25 ml of dichloE6mSthane, this solution was washed with water and dried wiA:h/sodium sulphate. After distillation of the solvent and f/Lash chromatography (silica gel; gradient: dichloromoithane/ethanol 98.5:1.5 to 80:20) the desired compound/was isolated as a brownish oil. <br><br> 30 Yield: /. Qr5 (72 % of theory), <br><br> 0.40 (silica gel; ethyl acetate/petroleum ether = 1:1) <br><br> Rf value: <br><br> e) fe. — aN-(4-Cvanophenvl)-aminomethvll -benzothiazole-35 5-Carboxylic acid-N-phenvl-N-(2-ethoxycarbonylethyl)-amide Lxture of 2.05 g (5.14 mMol) of 2-methoxymethyl-izothiazole-5-carboxylic acid-N-phenyl-N-(2- <br><br> NOW AMENDED <br><br> - 55 - <br><br> ethoxycarbonylethyl)-amide and 5.7 ml (#."/ mMol) of a 1M solution of boron tribromide in dichlofonfethane was dissolved in a further 60 ml of dichlprc/methane and stirred for 16 hours at room temperature. Tfaefi the mixture was 5 washed with 4 0 ml of saturated sodium/hydrogen carbonate solution, the organic phase was dyiea with sodium sulphate and the solvent was distilled ofS. / The crude 2-bromomethyl-benzothiazole-5-carb6xylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide tonus obtained (2.4 g) was 10 taken up in 5.0 ml of N, N-diijsopropyl-ethylamine and mixed with 0.64 g (5.4 mMol) of 4-amtno-benzonitrile. After 1 hour's heating to 130°C th^solvent was distilled off in vacuo and the crude product obtained was purified by flash chromatography (silica gel / gradient: ethyl 15 acetate/petroleum ether/=/l: 3 to 1:1), whilst an orange foam was obtained whery tme eluates were evaporated down. Yield: 1.1 g (44 % oy tileory) , <br><br> Rf value: 0.35 (silipa/jel; ethyl acetate/petroleum ether = 7:3) <br><br> 20 <br><br> f) 2- l"N- (4-amidiiaopnenvl) - aminomethyl 1 -benzothiazole-5-carboxvlic ac/d-rfj-phenvl-N-(2-ethoxycarbonylethyl)-amide 1.1 g (2.27 mMol)/ of 2-[N-(4-cyanophenyl)-aminomethyl]-benzothiazole/5Vcarboxylic acid-N-phenyl-N-(2-25 ethoxycarbonylethyl)-amide was stirred in 100 ml of ethanol saturated witn hydrogen chloride for 5 hours first at 0°C and then at room temperature until no more starting material Cioiuld be detected by thin layer chromatography. Then thd solvent was distilled off at a maximum bath 30 temperatyte of 3 0°C and the oily residue was taken up in 100 m~L at absolute ethanol and mixed with 1.6 g (22 mMol) of atoafnium carbonate. After 18 hours stirring at room teir\pe/ature the solvent was distilled off in vacuo and the product was purified by flash chromatography (silica /el/; gradient: water/methanol = 19:1 to 4:1) . When the /eluates are evaporated down the desired compound is )tained as a white foam. <br><br> NOW AMENDED <br><br> - 56 - / / <br><br> Yield: 0.77 g (63 % of theory), / / <br><br> Rf value: 0.19 (silica gel; dichlorometthane/ethanol = 3:7) <br><br> C27H27N5O3S (501.60) j j <br><br> Mass spectrum: (M+H)+ = 502 / / <br><br> Example 10 / / <br><br> 2-[N-(4-amidinophenyl)-aminometnyl]-benzothiazole-5-carboxylic acid-N-phenyl-N- (yS-^ar boxy ethyl) -amide <br><br> 10 / / <br><br> 0.4 5 g (0.84 mMol) of 2-[N-(A-amidinophenyl)-aminomethyl]-benzothiazole-5-carboxylic yac/d-N-phenyl-N-(2-ethoxycarbonylethyl) -amidar were dissolved in 15 ml of ethanol, mixed with 2 ml /oy 2N-sodium hydroxide solution 15 and stirred for 4 hours/ay room temperature. Then the mixture was acidified with 3 ml of 2N hydrochloric acid and the solvent was distilLLea off. The crude product obtained was taken up in 5 ml/dichloromethane/ethanol (2:1) and filtered to remove the insoluble sodium chloride. After 20 the distillation of tzhe solvent the desired compound was obtained as a yellow foam. <br><br> Yield: 0.26 g (6/7 4 of theory), <br><br> Rf value: 0.47 /si/lica gel; methanol/5 % aqueous sodium chloride = 6:&lt;0 / <br><br> 25 C25H23N503S JAIR.55) <br><br> Mass spectrum/ (M+H)+ = 474 Example 1A J <br><br> 30 2-[N-(^Zamidinophenyl)-aminomethyl]benzothiazol-5-yl- <br><br> carboxyl/c acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide/- (^hydrochloride <br><br> Pr^pa^ed analogously to Example 9 from 2-[N-(4-35 cyanophenyl) -aminomethyl] benzothiazol-5-yl-carboxylic acid-N-C^-pyridyl)-N-(2-methoxycarbonylethyl) -amide, methanolic /h\?arochloric acid, methanol and ammonium carbonate. <br><br> NOW AMENDED <br><br> - 57 - <br><br> Yield: 68 % of theory, / / <br><br> c25h24n6°3s (488.57) / / <br><br> Rf value: 0.13 (silica gel; methylene/chloride/ethanol = <br><br> 4:1 +a few drops of acetic acid) 5 EKA mass spectrum : (M+H)+ = 489 / / <br><br> Example 12 / / <br><br> 2-[2-(4-amidinophenyl)ethyl]-benzothiazol-5-yl-carboxylic 10 acid-N-(2-pyridyl)-N-(ethoxyoarponylmethyl)-amide-dihydrochloride / / <br><br> Prepared analogously to Example 9 from 2- [2- (4-cyanophenyl)ethyl]-benzothiazol-5-yl-carboxylic acid-N-(2-15 pyridyl)-N-(ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid, ethanoQ. and ammonium carbonate. <br><br> Yield: 95 % of theory/ / <br><br> C26H25N5°3S (487.58)/ / <br><br> Rf value: 0.20 (sil/ca: gel; methylene chloride/ethanol = 20 4:3/ +/a few drops of acetic acid) <br><br> EKA mass spectrum: /(M+H)+ = 488 <br><br> Example 13 j J <br><br> 25 2-[N-(4-amidanophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic Ac/d-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrpchloride <br><br> Prepared analogously to Example 9 from 2-[N-(4- <br><br> 30 cyanophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-/2-pyridyl)-N-(ethoxycarbonylmethyl)-amide, <br><br> ethano/ic hydrochloric acid, ethanol and ammonium caEoonate. <br><br> Yield: 68 % of theory, <br><br> 35 925^24N603S (488.57) <br><br> /Rf/value: 0.14 (silica gel; methylene chloride/ethanol = <br><br> NOW AMENDED <br><br> 10 <br><br> 15 <br><br> 20 <br><br> - 58 - <br><br> 4:1 + a few drops of acetzicy acid) EKA mass spectrum: (M+H)+ = 489 <br><br> Example 14 <br><br> 2-[N-(4-amidinophenyl)-aminomethyV] -benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N- jfti^roxycarbonylmethyl) amide-dihydrochloride <br><br> Examp <br><br> Prepared analogously to amidinophenyl)-aminomethyl] -acid-N-(2-pyridyl)-N-(etho dihydrochloride and sodiu Yield: 90 % of theory, C23H20N6°3S (460.52) <br><br> e/10 from 2-[N-(4- <br><br> 'zothiazol-5-yl-carboxylic rbonylmethyl)-amide-hydroxide solution. <br><br> Rf value: <br><br> EKA mass spectrum: (] <br><br> hH/+ l+$a) + <br><br> = 461 = 483 <br><br> (Wh2Na) <br><br> ++ _ <br><br> = 253 <br><br> Example 15 <br><br> 2-[N-(4-amidinopMenyl)-N-methyl-aminomethyl]-benzothiazol-5-yl-carboxyLac/acid-N-phenyl-N-(2-ethoxycarbonylethyl)-25 amide-hydrognlpride a) 2-fN-(ff-Qvanophenvl)-N-methvl-aminomethvll -benzothiazol-5-vl-car}poyvlic acid-N-phenvl-N- (2-ethoxycarbonylethyl) -amide <br><br> 3 0 Prepared/analogously to Example 9e from 4-cyano-N-methyl-aniline /and 2-methoxymethyl-benzothiazole-5-carboxylic acic^-N/phenyl-N- (2-ethoxycarbonylethyl) -amide. <br><br> YioQ.d/ 57 % of theory, <br><br> ilue: 0.46 (silica gel; dichloromethane/ethanol = <br><br> 35 <br><br> NOW AMENDED <br><br> 59 <br><br> 10 <br><br> b) 2-fN-(4-amidinophenyl)-N-methvl-amirtbmi£thvl1 benzothiazol-5-vl-carboxvlic acid-N-pHeryyl-N- (2-ethoxycarbonylethyl)-amide-hydrochlori' <br><br> Prepared analogously to Example 9 froxd 2-[N-(4-cyanophenyl) -N-methyl-aminomethyl] /befnzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethpxycarbonylethyl) -amide, ethanolic hydrochloric acid, eth^n^l and ammonium carbonate. <br><br> Yield: 73 % of theory, <br><br> C28H29N5O3S (515.64) <br><br> Rf value: 0.2 9 (,'silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid)/ <br><br> EKA mass spectrum: (M+H)+/=/516 <br><br> 15 Example 16 <br><br> 20 <br><br> 25 <br><br> 30 <br><br> 2- [N- (4-amidinophenyl) -^-methyl-aminomethyl] -benzothiazol-5-yl-carboxylic acifi-lf-phenyl-N- (2-hydroxycarbonylethyl) -amide-hydrochloride <br><br> Prepared analogously to Example 10 from 2-[N-(4-amidinophenyl) -methyl-aminomethyl] -benzothiazol-5-yl-carboxylic acLa-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochlorider and sodium hydroxide solution. <br><br> Yield: 96 %/of/theory, <br><br> C26H25N5O3/ 0^87.58) <br><br> '0./48 (Merck RP-8, methanol/5% NaCl solution = <br><br> 6:4) <br><br> EKA mage Spectrum: (M+H)+ = 488 <br><br> (M+2Na)++ = 266.5 <br><br> NOW AMENDED <br><br> - 60 - <br><br> Example 17 <br><br> 2- [ (4-amidinophenyl) thiomethyl] -benzoychYazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 10 <br><br> 15 <br><br> Prepared analogously to Example Sf f£om 2-[(4-cyanophenyl)thiomethyl]-benzoth^aaol-S-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonyletny]/) -amide, ethanolic hydrochloric acid, ethanol ana Ammonium carbonate. <br><br> Yield: 61 % of theory, <br><br> C27H26N4°3S2 (518.66) <br><br> R£ value: 0.27 (silica ge\J-, vfiethylene chloride/ethanol = 4:1 + a few drops of ace/ic/ acid) <br><br> EKA mass spectrum: (M+IV)+/= 519 <br><br> Example 18 <br><br> 2- [ (4-amidinophenyl) raiiomethyl] -benzothiazol-5-yl-20 carboxylic acid-N/phenyl-N-(2-hydroxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 10 from 2 — [ (4 -amidinophenyl)thiomethyl]-benzothiazol-5-yl-carboxylic <br><br> 25 acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium/hyuroxide solution. <br><br> Yield: 95/%/of theory, <br><br> C25H22N^03/2 (490.61) <br><br> 0.25 (Merck RP-8, methanol/5% NaCl solution = <br><br> 30 6:4) <br><br> EKA j/na^ss spectrum: (M+H)+ = 491 <br><br> (M+Na)+ = 513 <br><br> NOW AMENDED <br><br> 61 - <br><br> Example 19 <br><br> 2-[N-(4-amidinophenyl)-aminomethyl]-bfeneothiazol-5-yl-carboxylic acid-N-phenyl-N- (ethoxyca/rbonylmethyl) -amide-hydrochloride <br><br> Prepared analogously to Example f fifcom 2-[N-(4-cyanophenyl) -aminomethyl] -benzothi/azol-5-yl-carboxylic acid-N-phenyl-N- (ethoxycarbony/merthyl) -amide, ethanolic <br><br> 10 hydrochloric acid, ethanol an/a. Ammonium carbonate. <br><br> Yield: 82 % of theory, <br><br> C26h25N503S (487.58) <br><br> Rf value: 0.21 (silica geLI-, ^ethylene chloride/ethanol = <br><br> 4:1 + a few drops of acet/ic/ acid) <br><br> 15 EKA mass spectrum: (M+h/+/= 488 <br><br> Example 20 <br><br> 2- [N- (4-amidinophei 20 carboxylic acid-N-hydrochloride rll-aminomethyl]-benzothiazol-5-yl-;nyl-N-(hydroxycarbonylmethyl)-amide- <br><br> 25 <br><br> 30 <br><br> Prepared analogously to Example 10 from 2-[N-(4-amidinophenylZ-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-pheny/-N-(ethoxycarbonylmethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 75 / pf theory, <br><br> c24h21n59W (459 . 53) <br><br> value/: 0.14 (silica gel; methylene chloride/ethanol = 4:1 + ?( fifew drops of acetic acid) <br><br> EKA m&gt;£s^ spectrum: (M+H) + = 460 <br><br> (M+Na)+ = 482 <br><br> NOW AMENDED <br><br> - 62 - <br><br> Example 21 <br><br> 2- [2- (4-amidinophenyl) ethyl] -benzothiyazafl-S-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethjyl/-amide-hydrochloride <br><br> 10 <br><br> 15 <br><br> Prepared analogously to Example 9 ftr/&gt;m 2 - [2 - (4-cyanophenyl) ethyl] -benzothiazol-y-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyly-amide, ethanolic hydrochloric acid, ethanol and/anjmonium carbonate. <br><br> Yield: 80 % of theory, <br><br> C28H28N4°3S (500.62) <br><br> Rf value: 0.30 (silica gel;/methylene chloride/ethanol = 4:1 + a few drops of acetic £cid) <br><br> EKA mass spectrum: (M+H) / =f 501 <br><br> Example 22 <br><br> 2- [2- (4-amidinophenyl) a thy].] -benzothiazol-5-yl-carboxylic acid-N-phenyl-N- (2-yhyjaroxycarbonylethyl) -amide-20 hydrochloride <br><br> Prepared analogously to Example 10 from 2-[2-(4-amidinophenyl)ftlwl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl)-amide-hydrochloride and <br><br> 25 sodium hydroxide solution. <br><br> Yield: 77 Voir theory, <br><br> C26H24N4°3^ /472.57) <br><br> Rf value:/o/l8 (silica gel; methylene chloride/ethanol = <br><br> 4:1 + a/few drops of acetic acid) <br><br> 30 EKA ma^s/spectrum: (M+H)+ = 473 <br><br> (M+Na)+ = 495 (M+H+Na)++ = 259 <br><br> NOW AMENDED <br><br> " 63 ~ / / <br><br> Example 23 / / <br><br> 2-[N-(4-amidinophenyl)-aminomethyl]-ben/othiazol- 5-yl-carboxylic acid-N-(n-propyl)-N-(2-ebnoxycarbonylethyl)-5 amide-hydrochloride / / <br><br> Prepared analogously to Example 9 firom 2-[N-(4-cyanophenyl)-aminomethyl]-benzotmi4zol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide, 10 ethanolic hydrochloric acid, etnanol and ammonium carbonate. / / <br><br> Yield: 83 % of theory, / / <br><br> C24H29N5°3 (467.59) / / <br><br> Rf value: 0.31 (silica gal;/methylene chloride/ethanol = 15 4:1 + a few drops of acetic acid) <br><br> EKA mass spectrum: (M^Hy+ = 468 <br><br> ^M/H)* = 935 <br><br> Example 24 / / <br><br> 20 / / <br><br> 2- [N- (4-amidinopMertyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid/N7(n-propyl)-N-(2-hydroxycarbonylethyl)-amide-hydrochloride <br><br> 25 Prepared analogously to Example 10 from 2-[N-(4- <br><br> amidinopheiwl/-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N- (n-Tpropyl) -N- (2-ethoxycarbonylethyl) -amide- <br><br> hydrochlorLae and sodium hydroxide solution. <br><br> Yield: 75 k of theory, <br><br> 30 ^--22^25^503^ (439.54) <br><br> Rf val/ueA 0.14 (silica gel; methylene chloride/ethanol = <br><br> 4:1 if. few drops of acetic acid) <br><br> EKW mass spectrum: (M+H)+ = 440 <br><br> / / (M+H+Na)++ = 231.6 <br><br> 35 <br><br> NOW AMENDED <br><br> - 64 - / / <br><br> Example 25 / / <br><br> l-Methyl-2- [N- (4-amidinophenyl) -aminromethyl] -benzimidazol-5 5-yl-carboxylic acid-N-phenyl-N- (2/Ethoxycarbonylethyl) -amide-hydrochloride / / <br><br> a) 4-Methvlamino-3-nitro-benzoic arcid-N-phenvl-N- (2-ethoxv-carbonvlethvl)-amide / / <br><br> 10 To a solution of 24.7 g (O.llyE mol) of 4-methylamino-3-nitro-benzoic acid chloride Ana. 22.3 g (0.115 mol) of N-(2-ethoxy-carbonylethyl)-An/line in 300 ml of tetrahydrofuran, 13.1 g ((/-1/ mol) of triethylamine were added dropwise in 15 minutes, with stirring, at room 15 temperature. After 2 hdure stirring the solvent was distilled off in a watarr-Vjet vacuum and the residue was mixed with 700 ml of water with stirring. The mixture was extracted 3 times witzh £200 ml of dichloromethane, the organic extract was washed twice with 200 ml of 2N 2 0 hydrochloric acid s.na twice with 300 ml of water and dried over sodium sulphate/. The solvent was then distilled off and the oily pro/auat thus obtained was purified by column chromatography /(I/kg silica gel; eluant: petroleum ether/ethyl acetate = 2:1) . <br><br> 25 Yield: 35.0 q {t&gt;2 % of theory), <br><br> Rf value: 0.28/(silica gel; dichloromethane/ethanol = 50:1) <br><br> b) 3-Aminc/-4/methvlamino-benzoic acid-N-phenvl-N- (2-ethoxv-carbonviethvl) -amide <br><br> 30 12 .1 g /o70326 mol) of 4-methylamino-3-nitro-benzoic acid-N-phenyl yN-(2-ethoxycarbonylethyl)-amide were hydrogenated in 30(0 nu. ethanol and 150 ml dichloromethane after the addi/ioin of about 4 g of palladium/charcoal (10%) at room temperature and under a hydrogen pressure of 5 bar. Then 35 the catalyst was filtered off and the filtrate was evaporated down. The crude product thus obtained was reacted without further purification. <br><br> NOW AMENDED <br><br> 65 - <br><br> Yield: 10.6 g (95 % of theory), <br><br> R£ value: 0.19 (silica gel; dichloromet^h&lt; <br><br> le/ethanol = 50:1) <br><br> c) l-Methvl-2- TN- (4-cvanophenvl) -amffiotfiethvll -benzimidazol-5 5-vl-carboxylic acid-N-phenvl-N- (2yetjioxvcarbonvlethvl) -amide <br><br> 6.17 g (0.035 mol) of N-(4-cyanophenyl)glycine and 5.68 g (0.035 mol) of N,N1-carbonyldiimidazole were refluxed in 300 ml of tetrahydrofuran for 2S0 Xninutes, then 10.6 g 10 (0.032 mol) of 3-amino-4-methylamino-benzoic acid-N-phenyl -N-(2-ethoxycarbonylethyl)-anyL.de were added and the mixture was refluxed for a further /five hours. Then the solvent was distilled off in vacua, the residue was dissolved in 150 ml of glacial acetic/aoad and refluxed for one hour. 15 Then the glacial acetic/ac/id was distilled off in vacuo, <br><br> the residue was dissolved in about 3 00 ml of dichloromethane, the ^o/ution was washed twice with about 150 ml water and then dried over sodium sulphate. After evaporation of the /solvent the crude product thus obtained 20 was purified by column chromatography (800 g silica gel; eluant: dichlorounetmane with 1-2 % ethanol) . <br><br> Yield: 8.5 g (5# ^ of theory), <br><br> Rf value: 0.51/(syalica gel; dichloromethane/ethanol = 19:1) <br><br> 25 d) 1-Methvl-/2-/n- (4-amidinophenyl) -aminomethyl] -benzimidazod-E-vl-carboxvlic acid-N-phenvl-N-(2-ethoxvcarboiwlethvl)-amide-hydrochloride 1.2 g (2 A9/mMol) of 1-methyl-2 -[N-(4-cyanophenyl)-aminometzhm] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N-30 (2-eth©xVcarbonylethyl)-amide were stirred in 100 ml of satur#te!a ethanolic hydrochloric acid for 6 hours at room temperature. Then the mixture was evaporated to dryness in vaguo/, the residue was dissolved in 100 ml of ethanol, <br><br> mixetl with 2.5 g (26 mMol) of ammonium carbonate and 35 ssti/rred overnight at room temperature. After distillation oy the solvent the crude product thus obtained was purified column chromatography (100 g silica gel; eluant: <br><br> NOW AMENDED <br><br> 10 <br><br> - 66 - <br><br> dichloromethane/ethanol = 4:1). By conc/nt/rating the eluates the desired compound was obtadyne^a as a white, amorphous solid. <br><br> Yield: 1.10 g (83 % of theory), <br><br> Rf value: 0.18 (silica gel; dichloiy6m^thane/ethanol = 4:1) C28H30N6°3 x hc1 (498.6) <br><br> EKA mass spectrum: (M+H)+ =/4#9 <br><br> (M+2H) ++ /= £50 (M+H+Na) +7 =/ 261 <br><br> Example 26 <br><br> 15 <br><br> l-Methyl-2 - [N- (4-amidinopy 5-yl-carboxylic acid-N-j amide emyl)-aminomethyl]-benzimidazol-eilyl-N- (2-hydroxycarbonylethyl) - <br><br> A mixture of 300 mg J[0 y56 mMol) of l-methyl-2-[N-(4-amidinophenyl)-aminamethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2/etfnoxycarbonylethyl) -amide-2 0 hydrochloride, 15/m]/ of ethanol, 4 ml of water and 12 0 mg <br><br> (3.0 mMol) of soaij/m hydroxide was stirred for two hours at room temperature./ Then the mixture was diluted with about 20 ml of watey and made weakly alkaline with glacial acetic acid. The product which crystallised out was suction 25 filtered, wstshed with water and dried at 60°C in vacuo. <br><br> Yield: 25o/mc/ (95 % of theory) , <br><br> C26H26N6O/ /470.5) <br><br> EKA mass/1 spectrum: (M+H)+ = 471 <br><br> (M+H+Na)++ = 247 30 II (M+2Na)++ = 258 <br><br> NOW AMENDED <br><br> - 67 - <br><br> Example 27 <br><br> l-Methyl-2- [ (4-amidinophenyl) thiomethfylfl -benzimidazol-5-yl-carboxylic acid-N- (n-propyl) -N- (2-ejzhgxycarbonylethyl) -5 amide-hydrochloride a) 4-Methvlamino-3-chloracetamid/-t/enzoic acid-N- (n-propvl) -N- (2-ethoxvcarbonvlethyjL) /amide <br><br> A solution of 1.8 g (5.9 mMol)/oj. 3-amino-4-methylamino-10 benzoic acid-N-(n-propyl)-N- yl-ethoxycarbonylethyl)-amide <br><br> [prepared analogously to 3-amino-4-ethylamino-benzoic acid-N-phenyl-N- (2-ethoxycarbonyleychyl) -amide] , 1. lg (6.8 mMol) of N,N1-carbonyldiimidazoYe And 0.65 g (6.9 mMol) of chloroacetic acid in 75 ml tetrahydrofuran was stirred for 15 1 hour at room temperature/. Then the solvent was distilled off in vacuo, and the prude product was purified by flash chromatography (siligk. jgel; methylene chloride/ethanol = 49 :1) . <br><br> Yield: 1.7 g (77% off ^heory) yellow oil, <br><br> 20 Rf value: 0.58 (silica gel; ethyl acetate/ethanol/ammonia <br><br> = /9Qr: 10 :1) <br><br> b) 2-Chiorometftvl-l-methvl-benzimidazol-5-vl-carboxvli c acid-N-(n-nropvl)-N-(2-ethoxycarbonylethyl)-amide 25 1.6 g (4.3 mMo/) of 4-methylamino-3-chloracetamido-benzoic <br><br> &gt;yl)-N-(2-ethoxycarbonylethyl)-amide were °C in 25 ml of acetic acid for 30 minutes. <br><br> vent was distilled off, the crude product was 40 ml methylene chloride/ethanol (9:1) and 3 0 washed/wi/th 20 ml saturated sodium hydrogen carbonate solut/oi/. The organic phase was dried with sodium sulphate and ^vg^porated down. <br><br> Yie£d/ 1.5 g (100% of theory) of brown oil, <br><br> Rf/value: 0.63 (silica gel; ethyl acetate/ethanol/ammonia 35 / / = 90:10:1) <br><br> acid-N-(n-heated to Then the/s taken u <br><br> NOW AMENDED <br><br> 68 - <br><br> c) 1-Methyl-2-T(4-cvanophenvl)thiomethvAl /benzimidazol-5-vl-carboxvlic acid-N-(n-propyl)-N-(2-Qchftxvcarbonvlethvl) amide <br><br> A mixture of 1.5 g (4.1 mMol) of 2-olil/iromethyl-1 -methyl-benzimidazol-5-yl-carboxylic acid-Kr- (n-propyl) -N-(2-ethoxycarbonylethyl) -amide and/0./65 g (4.8 mMol) of p-cyanothiophenol was heated in 10/my of dimethylformamide and 10 ml of diisopropylethylamxne' for 1 hour to 100°C. The solvent was distilled off /n/vacuo, the crude product was dissolved in 3 0 ml ethyl Acetate, washed with 3 0 ml water, and after concentration/purified by flash chromatography (silica gel •,/ n^ethylene chloride/ethanol (49:1 to 19 :1) . <br><br> Yield: 1.5 g (79% of theo/ry'; of brown oil, <br><br> Rf value: 0.65 (silica gel/ ethyl acetate/ethanol/ammonia <br><br> = 90:lo/l ] <br><br> 10 <br><br> 15 <br><br> d) l-Methvl-2- f (4-aroa.dxnoph.envl) thiomethvll -benzimidazol-5-yl-carboxvlic acid-^W-/n-propyl) -N- (2-ethoxycarbonylethyl) 20 amide-hydrochloric <br><br> 1.4 g (3.01 mMol)/ of 1 -methyl-2-[ (4-cyanophenyl) -thiomethyl]-benaamidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarooiwlethyl)-amide were stirred in 50 ml of ethanol saturated with hydrogen chloride for 5 hours first 25 at 0°C, later aft room temperature, until no more starting material covildf 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 3 0 carbonate/ After 18 hours the solvent was distilled off in vacuo/an/a. the crude product was purified by flash chrot^atifcigraphy (silica gel; methylene chloride/ethanol = 19:2L t/o 4:1) . <br><br> Yield: 1.3 g (83% of theory) as a light beige solid, 35 r/ "\4?alue: 0.29 (silica gel; ethyl acetate/ethanol/ammonia <br><br> = 50:45:5) <br><br> NOW AMENDED <br><br> - 69 - <br><br> ^-25^31^6^3^ (481.62) <br><br> EKA mass spectrum: (M+H)+ = 482 <br><br> Example 28 <br><br> l-Methyl-2-[ (4-amidinophenyl) thiortieti'hyl] -benzimidazol-5-yl -carboxylic acid-N- (n-propyl) -N- (^-l/ydroxycarbonylethyl) amide-hydrochloride <br><br> 10 0.52 g (1.0 mMol) of l-Methyl/-2/[ (4-amidinophenyl) - <br><br> thiomethyl]-benzimidazol-5-yl-/arboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amine-hydrochloride was dissolved in 15 ml ethanol, mixed witly 5 ml of 2N sodium hydroxide solution and stirred for/2 /hours at room temperature. Then 15 5 ml of water were added, Ahe alcohol was distilled off, and it was acidified w/tl/ concentrated hydrochloric acid. The water was distilLed/off in vacuo, and the crude product was taken up in 5 my o£ ethanol and filtered to remove the insoluble sodium chloride. After the solvent had been 20 distilled off the /tiytle compound was obtained as a white solid. <br><br> Yield: 0.43 g ($8%/ of theory), <br><br> s/lica gel; ethyl acetate/ethanol/ammonia 50:45:5) <br><br> 25 Co^HpvNqOoS /4^3 .57) <br><br> Rf value: 0.19 <br><br> C23H27N5O3S EKA mass si <br><br> ;rum: (M+H)+ =454 (M+Na)+ = 476 <br><br> 30 <br><br> Example/2&lt; <br><br> l-Met^iy/-2- [ (4-amidinophenyl) thiomethyl] -benzimidazol-5-yl-carbOxylic acid-N- (2-methylpropyl) -N- (2-ett/ox^carbonylethyl) -amide-hydrochloride <br><br> 35 <br><br> NOW AMENDED <br><br> - 70 - <br><br> ethanolic hydrochloric acid, ethanol arva jmmonium carbonate. <br><br> Yield: 83 % of theory, <br><br> c25h31n6°3S (495.65) <br><br> R£ value: 0.3 0 (silica gel; ethyl ^ce/ate/ethanol/ammonia <br><br> = 50:45:5) : <br><br> EKA mass spectrum: (M+H)+ = 496 <br><br> 10 <br><br> Example 3 0 <br><br> l-Methyl-2-[(4-amidinophenyY) thiomethyl]-benzimidazol-5-yl■ carboxylic acid-N-phenyl-N/(^-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 15 <br><br> 20 <br><br> 25 <br><br> Prepared analogously t cyanophenyl)thiomethy N-phenyl-N- (2-ethoxy hydrochloric acid, Yield: 90 % of theoCr^/, C28H29N503S (515./4) Rf value:0.24 (s 50:45:5) <br><br> EKA mass spectyru/i <br><br> Example 27 from l-methyl-2-[(4 -benzimidazol-5-yl-carboxylic acid-Sonylethyl)-amide, and ethanolic mol and ammonium carbonate. <br><br> a gel; ethyl acetate/ethanol/ammonia = <br><br> (M+H)+ = 516 <br><br> (M+H+Na)++ = 269.7 <br><br> Example 31/ <br><br> 30 <br><br> l-Methy]/-2/ [ (4-amidinophenyl) thiomethyl] -benzimidazol-5-yl-carboxvlip acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide-hydrogfalpride <br><br> Pretfarifed analogously to Example 28 from l-methyl-2-[(4-amZdii/nophenyl) thiomethyl-benzimidazol-5-yl-carboxylic acid-N/ptyenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and <br><br> 35 podium hydroxide solution, /eld: 76 % of theory, <br><br> NOW AMENDED <br><br> - 71 - / / <br><br> c26h25N503S (487.58) / / <br><br> Rf value: 0.31 (silica gel; ethyl acet/ate/ethanol/ammonia <br><br> = 50:45:5) / / <br><br> EKA mass spectrum: (M+H)+ = 488 / / 5 (M+Na)+ = 510 / / <br><br> Example 3 2 / / <br><br> l-Methyl-2- [ (4-amidinophenyl)Oxymethyl] -benzimidazol-5-yl-10 sulphonic acid-:N- (1-methyl-paperidin-4-yl) -N-methyl-amide-hydrochloride / / <br><br> a) 4-Chloro-3-nitrobenzemesoilphonic acid-N- (1-methyl-pjperidin-4-vl)-N-methvI-amide <br><br> 15 To a solution of 2.2 ml /l5 mMol) of l-methyl-4- <br><br> methylamino-piperidine /n 60 ml pyridine, 3.8 g (15 mMol) of 4-chloro-3-nitro-oemzenesulphonic acid chloride were added, in batches, -whilst cooling with ice. The mixture was then stirred for two/hours with cooling, then evaporated to 20 dryness, the resi/uu/e was mixed with about 50 ml of water and made alkalinre ywith concentrated ammonia whilst stirring vigorously. The; oorude product precipitated was suction filtered and purified by column chromatography (250 g silica gel, elTiant: dichloromethane with 1.5% ethanol). 25 Yield: 1.6 s v31% of theory), <br><br> Ci3Hi8ClN3l64s/ (347.8) <br><br> Rf value :/o/l9 (silica gel; dichloromethane/ethanol = 19:1) <br><br> b) 4-Mefthylamino-3-nitrobenzenesulphonic acid-N-methyl-N-3 0 (l-metmylpiperidin-4-vl) -amide <br><br> 1.6 g Ja.S mMol) of 4-chloro-3-nitrobenzenesulphonic acid-N-m^thyl-N-(l-methyl-piperidin-4-yl)-amide was mixed with 3 0/m]/ of 4 0% methylamine solution and stirred in a sealed fla^k for four hours at room temperature. Then the mixture 3 5 jwa/ diluted with about 40 ml of water, the product <br><br> /precipitated was suction filtered, washed with water and ' dried. <br><br> NOW AMENDED <br><br> - 72 - / / <br><br> Yield: 1.5 g (95% of theory), / / <br><br> c14h22n4°4s (343.4) / / <br><br> Rf value: 0.45 (silica gel; dichlorometMane/ethanol = 4:1) <br><br> 5 c) 3-Amino-4-methvlaminobenzenesulphonic acid-N-methyl-N-(l-methvlpjperidin-4-vl)-amide / / <br><br> 1.5 g (4.4 mMol) of 4-methylaminiD-3'-nitrobenzenesulphonic acid-N-methyl-N- (1-methyl-piper/ditn-4-yl) -amide were dissolved in 100 ml methanol and/catalytically hydrogenated 10 at room temperature and undey 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 reacterd /without any purification. <br><br> Yield: 1.4 g (100% of thafoioy) , <br><br> 15 C14H24N402S (312.4) / / <br><br> Rf value: 0.33 (silica/gel; dichloromethane/ethanol = 4:1) <br><br> d) l-Methvl-2- f (4-cyanipphenvl) oxvmethvll -benzimidazol-5-vl-sulfonic acid-N-metmyA-N-(l-methvl-piperidin-4-vl)-amide 20 532 mg (3.0 mMol) /ofJ 4-cyanophenyloxyacetic acid and 486 mg (3.0 mMol) of 1, "i' -/carbonyldiimidazole were dissolved in 40 ml of tetrahydrofuran and refluxed for 15 minutes. Then 700 mg (2.24 mjlol') of 3-amino-4-methylaminobenzenesulphonic acid-N-methyl/N/(l-methyl-piperidin-4-yl)-amide were added 25 and boiling ywass continued for a further eight hours. Then the mixtury was evaporated down and the resulting oily residue w^s refluxed in 3 0 ml of glacial acetic acid for one hour/ The glacial acetic acid was distilled off, the residue A/as mixed with about 30 ml of water and made 3 0 alkaline /with concentrated ammonia, and the solution was extrasctera three times with about 20 ml of dichloromethane. The org/anic phases were dried and evaporated down. The resulting product was further reacted without any purification. <br><br> 35 me/d: 400 mg (39% of theory) , <br><br> /:2/3h27n5°3s (453.6) <br><br> / l/ value: 0.37 (silica gel; dichloromethane/ethanol = 4:1) <br><br> NOW AMENDED <br><br> - 73 <br><br> 10 <br><br> e) 1-Methyl-2-1"(4-amidinophenyl)oxvmeEhyil -benzimidazol-5-vl-sulphonic acid-N-methvl-N- (l-methylpiperidin-4-vl) amide-hydrochloride <br><br> Prepared analogously to Example 25yd from 4 00 mg of 1-methyl-2-[(4 -cyanophenyl)oxymethyl]/benzimidazol-5-yl-sulphonic acid-N-methyl-N-(l-metonyIpiperidin-4-yl)-amide with ethanolic hydrochloric acjra jknd ammonium carbonate. Yield: 370 mg (83% of theory) <br><br> C-23H3 QNg03S (470.6) <br><br> EKA mass spectrum: (M+H)+ /=/471 <br><br> (M+2H) y+ /= 236 <br><br> Example 3 3 <br><br> 15 <br><br> l-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-N-metnyl-N-phenyl-amide-hydrochloride <br><br> Prepared analogously/to Example 32 from l-methyl-2-[(4-20 cyanophenyl)-oxymetliyl]-benzimidazol-5-yl-sulphonic acid-N-meth.yl-N-phenyl73.1mde and ethanolic hydrochloric acid, ethanol and ami/onA-um carbonate. <br><br> Yield: 46 % otf ttieory, <br><br> C23H23N5O3S &gt;(4^9 . 5) <br><br> 25 EKA mass spec/rum: (M+H)+ = 450 <br><br> (M+H+Methanol)+ = 482 (M+2H)++ = 223 <br><br> 30 <br><br> Example <br><br> '■1-2- [ (4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-jnic acid-N-(3-ethoxycarbonyl-n-propyl)-N-phenyl-!-hydrochloride <br><br> 35 <br><br> NOW AMENDED <br><br> - 74 - <br><br> (3-ethoxycarbonyl-n-propyl)-N-phenyl-ar hydrochloric acid, ethanol and ammonia Yield: 57 % of theory, <br><br> c28h31n5°5s (549.7) <br><br> EKA mass spectrum: (M+H)+ = 550 <br><br> Ld«£, ethanolic farbonate. <br><br> Example 3 5 <br><br> 10 <br><br> l-Methyl-2-[(3-amidinophenyl)o&amp;yjtfethyl]-benzimidazol-5-yl-sulphonic acid-pyrrolidide-hydrochloride <br><br> Prepared analogously to Ex&lt; cyanophenyl)oxymethyl]-be pyrrolidide, ethanolic 15 ammonium carbonate. <br><br> Yield: 71 % of theory, C20H23N5°3S (413.5) EKA mass spectrum: (/M+JS) + <br><br> apie 32 from l-methyl-2-[ (3-lidazol-5-yl-sulphonic acid-chloric acid, ethanol and <br><br> = 414 <br><br> 20 Example 36 <br><br> 25 <br><br> 30 <br><br> l-Methyl-2- [2- (4f-a/fnidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid-N'-phenyl-N- (3-methoxycarbonylpropyl) -amide-dihydrochloride <br><br> 35 <br><br> Prepared analogously to Example 25d from l-methyl-2- [2- (4- <br><br> .)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl -N-/( 3 /tert . butyloxycarbonylpropyl) -amide and methanolac/hydrochloric acid, methanol and ammonium carbona/te/ <br><br> Yield/ 8yS.5 % of theory, <br><br> R£ va/Lue: 0.17 (silica gel; dichloromethane/ethanol = 4:1) ^29/3^503 (497.6) <br><br> EKA i/ass spectrum: (M+H) + = 498 <br><br> (M+H+Na)++ = 260.7 <br><br> NOW AMENDED <br><br> - 75 - <br><br> Example 3 7 <br><br> l-Methyl-2- [2- (4-amidinophenyl) ethyl/ -carboxylic acid-N-phenyl-N-(3-hydr hydrochloride tz imidazol - 5 -yl -:y&lt;£arbonylpropyl) -amide - <br><br> 10 <br><br> 15 <br><br> Prepared analogously to Example/26/from l-methyl-2-[(4-amidinophenyl) aminomethyl] -ben/imadazol-5-yl-carboxylic acid-N-phenyl-N- (3-methoxycarftonylpropyl) -amide-dihydrochloride and sodium h/dyoxide solution. <br><br> Yield: 92 % of,theory, <br><br> Rf value: 0.09 (silica gel/ dichloromethane/ethanol = 4:1) <br><br> C28H29N5O3 (483.6) EKA mass spectrum: <br><br> = 484 <br><br> (M+Jtay+ = 506 (*y+H/Na)++ = 253.7 <br><br> Example 3 8 <br><br> 20 l-Methyl-2-[N-(4/arafidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic/acrid-N-phenyl-N- (3-ethoxycarbonylpropyl) -ami de - d i hydrocnl qsr i de a) l-Methvl-/2-/N- (4-cvanophenvl) -aminomethvll -benzimidazol-25 5-vl-carboxvl/c acid-N-phenvl-N-(3-tert.butvloxv-carbonvlpDQPV'l) -amide <br><br> Prepared Analogously to Example 25c from N-(4-cyanophenyl)■ glycine/ana 3-amino-4-methylamino-benzoic acid-N-phenyl-N- (3 - tert/. butyloxycarbonylpropyl) - amide. <br><br> 30 Yield/ 6*5 % of theory, <br><br> Rf vafruife: 0.17 (silica gel; dichloromethane/methanol = <br><br> 19 :1) <br><br> -Methvl-2-fN-(4-amidinophenyl)-aminomethvll -35 benzimidazol-5-vl-carboxylic acid-N-phenvl- <br><br> (3-ethoxvcarbonvlpropvl)-amide-dihydrochloride <br><br> NOW AMENDED <br><br> - 76 <br><br> l/methyl-2- [N- (4-'■1-carboxylic jropyl)-amide and ammonium <br><br> 10 <br><br> Prepared analogously to Example 25d frot] cyanophenyl)-aminomethyl]-benzimidazol; acid-N-phenyl-N-(3-tert.butyloxycarbor ethanolic hydrochloric acid, ethanol/ar carbonate. <br><br> Yield: 68 % of theory, <br><br> Rf value: 0.12 (silica gel; dichl^rc^methane/ethanol = 4:1) C29H32N6°3 (512.6) <br><br> EKA mass spectrum: (M+H)+ 4 513 <br><br> (M+H+Na) ++/ = /2 68 <br><br> Example 3 9 <br><br> l-Methyl-2- [N- (4-amidinopfrie/iyl) -aminomethyl] -benzimidazol-15 5-yl-carboxylic acid-N-ph^nyl-N-(3-hydroxycarbonylpropyl) amide-hydrochloride <br><br> 20 <br><br> 25 <br><br> Prepared analogously/td Example 26 from l-methyl-2-[N-(4-amidinophenyl) -aminiomesthyl] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3Aethoxycarbonylpropyl)-amide-dihydrochloride ^nd/sodium hydroxide solution. <br><br> Yield: 73.5 %• otJ t/ieory, <br><br> C27H28N6°3 (48 <br><br> EKA mass spectrum: <br><br> (M+H)+ = 485 <br><br> (M+2H)++ = 243 (M+H+Na)++ =254 <br><br> Example 40 <br><br> 30 l-Meth^l/2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxy/ic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydtfo chloride <br><br> 35 <br><br> reared analogously to Example 25d from l-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N- <br><br> NOW AMENDED <br><br> 10 <br><br> 15 <br><br> 20 <br><br> - 77 - <br><br> phenyl-N-(ethoxycarbonylmethyl)-amide afc\d/ethanolic hydrochloric acid, ethanol and ammoniyffo Carbonate. <br><br> Yield: 73 % of theory, <br><br> Rf value: 0.15 (silica gel; dichlorc^ne/hane/ethanol = 4:1) C28H29N5O3 (483.6) <br><br> EKA mass spectrum: (M+H)+ = 4/64 <br><br> (M+H+Na)++ =/25&gt;S.7 <br><br> Example 41 <br><br> l-Methyl-2- [2-(4-amidinopheliy]/) ethyl] -benzimidazol-5-yl carboxylic acid-N-phenyl-N/(Mydroxycarbonylmethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 26 from l-methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (ethoxycarbonylmethyl)-amide-hydrochloride and sodium hydroxide so/ut/ion. <br><br> Yield: 97 % of the? <br><br> C26H25N5O3 (455.! <br><br> EKA mass spectri/m:/ (M+H) + <br><br> (M+Na) + <br><br> = 456 = 478 <br><br> (M+2Na)++ = 250.6 <br><br> 25 Example 42 <br><br> 30 <br><br> 35 <br><br> 1-Methyl72-7[ (4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxy]/iy acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydro c jfrl qfr i de id analogously to Example 25d from l-methyl-2-[(4-cya/iocfhenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid-N-pnenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic rdrochloric acid, ethanol and ammonium carbonate. <br><br> ri£ld: 76 % of theory, <br><br> value: 0.17 (silica gel; dichloromethane/ethanol = 4:1) <br><br> NOW AMENDED <br><br> - 78 - <br><br> C27H27N5O4 (485.6) <br><br> EKA mass spectrum: (M+H)+ = 486 <br><br> (M+H+Na)++ = 254 <br><br> 5 Example 43 <br><br> l-Methyl-2-[(4-amidinophenyl)ox} carboxylic acid-N-phenyl-N-(hyc hydrochloride <br><br> 10 <br><br> 15 <br><br> 20 <br><br> lepnyl]-benzimidazol-5-yl-dycarbonylmethyl)-amide- <br><br> Prepared analogously to Exam£&gt;L£ 26 from l-methyl-2-[ (4-amidinophenyl) oxymethyl] -baoizylmidazol-5-yl-carboxylic acid-N-phenyl-N- (ethoxycarbony/mq/chyl) -amide-hydrochloride and sodium hydroxide solutioji. <br><br> Yield: 58 % of theory, <br><br> C25H23N5O4 (457.5) <br><br> EKA mass spectrum: (M+H/ + = 458 <br><br> ?M+&amp;a)+ = 480 (M+2Na)++ = 251.6 <br><br> Example 44 <br><br> l-Methyl-2-[Ny( 4/amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxyl/ic/acid-N-phenyl-N- (ethoxycarbonylmethyl) -25 amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophe(nyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic 30 hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield/: 14 % of theory, <br><br> Rf valiie: 0.12 (silica gel; dichloromethane/ethanol = 4:1) C27«2/eN603 (484.6) <br><br> EJtA/faass spectrum: (M+H) + = 485 <br><br> 35 / / (M+H+Na)++ = 254 <br><br> NOW AMENDED <br><br> - II <br><br> - 79 - / / <br><br> Example 4 5 / / <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminamathyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (hydroxycarbonylmethyl) -5 amide-hydrochloride / / <br><br> Prepared analogously to Example p.6/from l-methyl-2-[N-(4-amidinophenyl) -aminomethyl] -beneimidazol-5-yl-carboxylic acid-N-phenyl-N- (ethoxycarbonmmethyl) -amide-hydrochloride 10 and sodium hydroxide solution?. / <br><br> Yield: 84 % of theory, / / <br><br> C25H24N603 (456.5) / / <br><br> EKA mass spectrum: (M+H)+/ / = 457 <br><br> (M+Na^y = 4 79 15 (M+2lNa/(++ = 251 <br><br> Example 4 6 / / <br><br> l-Methyl-2- [ (4-amiainophenyl) oxymethyl] -benzimidazol-5-yl-20 carboxylic acid-N1^ (&lt;i-pyrimidyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[ (4-cyanophenyLO oxymethyl] -benzimidazol-5-yl-carboxylic 25 acid-N- (4-pyri/midyl) -N- (2-ethoxycarbonylethyl) -amide and ethanolic nydxochloric acid, ethanol and ammonium carbonate/ / <br><br> Yield: 1/4 4 of theory, <br><br> c26h271^70/ (501.6) <br><br> 30 Mass/spectrum: (M+H) + = 502 <br><br> NOW AMENDED <br><br> - 80 - <br><br> Example 4 7 <br><br> l-Methyl-2-[(4-amidinophenyl)oxymethyl]/benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (eti/oxycarbonylmethyl) 5 amide-dihydrochloride <br><br> 10 <br><br> 15 <br><br> Prepared analogously to Example tSdf from l-methyl-2 [ (4-cyanophenyl) oxymethyl] -benz/mi/dazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, /tj^anol and ammonium carbonate. <br><br> Yield: 44 % of theory, <br><br> Rf value: 0.12 (silica gel/ dichloromethane/ethanol = 4:1) C26h26N604 (486.5) <br><br> EKA mass spectrum: (M+H/+/ = 487 <br><br> &gt;H/++ = 244 (M+H^Na)++ = 255 <br><br> 20 <br><br> Example 4 8 <br><br> l-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid/N/(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide-hydrochLor/de <br><br> 25 Prepared analogously to Example 26 from l-methyl-2-[ (4- <br><br> amidinophenyl/oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridy]/ -N-(ethoxycarbonylmethyl)-amide-dihydrocnloride and sodium hydroxide solution. <br><br> Yield: 05 A of theory, <br><br> 30 (458.5) <br><br> spectrum: (M+H)+ = 459 (M+Na)+ = 481 (M+2Na)++ = 252 <br><br> c24h22 EKA <br><br> NOW AMENDED <br><br> - 81 - / / <br><br> Example 4 9 / / <br><br> l-Methyl-2-[N-(4-amidinophenyl)-amin®methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)- / 5 N-(ethoxycarbonylmethyl)-amide-dihydrochloride a) l-Methvl-2- TN- (4-cvanophenvl)/-aminomethvll -benzimidazol-5-vl-carboxylic acid-N-(2-pyrid/yl/-N-ethoxvcarbonvlmethvl- <br><br> 10 Prepared analogously to Example/25c from N-(4-cyanophenyl)-glycine and 3-amino-4-methyl/ama.no-benzoic acid- <br><br> Rf value: 0.56 (silica gel;/dichloromethane/methanol = 4:1) <br><br> 15 / / <br><br> b) l-Methvl-2- TN- (4-am/dj/nophenvl) -aminomethvll -benzimidazol-5-vl-carboxylic acid-N-(2-pvridvl)-N- (ethoxvcarbonvlmetAvj:) -amide-dihydrochloride <br><br> Prepared analogously Jto Example 25d from l-methyl-2- [N- (4-20 cyanophenyl) -aminomeythyl] -benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl/) -Jn- (ethoxycarbonylmethyl) -amide and ethanolic hydroc/hLoric acid, ethanol and ammonium <br><br> 25 Rf value: 0.2/b Asilica gel; dichloromethane/ethanol = 4:1) <br><br> NOW AMENDED <br><br> - 82 - / / <br><br> Example 50 / / <br><br> l-Methyl-2- [N- (4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-/ / 5 N-(hydroxycarbonylmethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 26/from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-beneimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-10 dihydrochloride and sodium hyar©xide solution. <br><br> Yield: 91 % of theory, / / <br><br> C24H23N7O3 (457.5) / / <br><br> EKA mass spectrum: (M+H)+/ / = 458 <br><br> (M+Na/+/ = 480 15 (M+2Na/++ = 251.7 <br><br> Example 51 / / <br><br> l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-20 carboxylic acid-N/(2^-pyridyl)-N-(ethoxycarbonylmethyl) -amide -dihydrochlor i/de <br><br> Prepared analogously to Example 25d from l-methyl-2-[2-(4-cyanophenyl)echyl]-benzimidazol-5-yl-carboxylic acid-N-(2-25 pyridyl)-N-Ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 90 A yof theory, <br><br> Rf value:/o/l7 (silica gel; dichloromethane/ethanol = 4:1) C27H28NXV (484.6) <br><br> 30 EKA mass/spectrum: (M+H)+ = 485 <br><br> / / (M+2H)++ = 243 <br><br> / / (M+H+Na)++ = 254 <br><br> NOW AMENDED <br><br> - 83 - / / <br><br> Example 52 / / <br><br> l-Methyl-2 - [2- (4-amidinophenyl) ethyly-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (hydfroKycarbonylmethyl) -5 amide-hydrochloride / / <br><br> Prepared analogously to Example 26/from l-methyl-2-[2-(4-amidinophenyl) ethyl] -benzimidazol75-yl-carboxylic acid-N-(2-pyridyl) -N- (ethoxycarbonylmetMyl) -amide-dihydrochloride 10 and sodium hydroxide solution/. / <br><br> Yield: 89 % of theory, / / <br><br> C25H24N6O3 (456.5) / / <br><br> EKA mass spectrum: (M+H)+/ / = 457 <br><br> (M+Na/+/ = 479 <br><br> 15 / / <br><br> Example 53 / / <br><br> l-Methyl-2- [N- (4 - amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic ac/dyil-phenyl-N- (2-methoxyarbonylethyl) -20 amide-hydrochloride / <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl/-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-phenylAN/(2-ethoxycarbonylethyl)-amide and 25 methanolic hydrochloric acid, methanol and ammonium carbonate. / / <br><br> Yield: 87/4 pi theory, <br><br> Rf value:/o/ll (silica gel; dichloromethane/ethanol = 4:1) C27H28IVO3/ (484.6) <br><br> 30 EKA mass/spectrum: (M+H)+ = 485 <br><br> / / (M+2H)++ = 243 <br><br> / / (M+H+Na)++ = 254 <br><br> NOW AMENDED <br><br> - 84 <br><br> Example 54 <br><br> l-Methyl-2 - [ (4-amidinophenyl)oxymeth) carboxylic acid-N-phenyl-N-(2-ethox} hydrochloride <br><br> .]/benzimidazol-5-yl-rbonylethyl)-amide- <br><br> 10 <br><br> 15 <br><br> Prepared analogously to Example from l-methyl-2- <br><br> [ (4-cyanophenyl) oxymethyl] -benzimi/dazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbcmy/ethyl)-amide and ethanolic hydrochloric acid, ethanol arva Ammonium carbonate. <br><br> Yield: 79.5 % of theory, <br><br> C28H29N5O4 (499.6) Rf value: 0.15 (silica gel <br><br> EKA mass spectrum: <br><br> (M+H), (M+I <br><br> lichloromethane/ethanol = 4:1) = 500.0 l)++ = 261.7 <br><br> 20 <br><br> Example 55 <br><br> l-Methyl-2-[(4-amiainophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N/phenyl-N-(2-hydroxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogoj/sly to Example 26 from l-methyl-2-[ (4-amidinophenyLOoxymethyl]-benzimidazol-5-yl-carboxylic acid-25 N-phenyl-N- yl-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydyoxAde solution. <br><br> Yield: 82/% bf theory, <br><br> C26h25n5?4 /(471.5) <br><br> R, valugr: £.11 (silica gel; dichloromethane/ethanol = 4:1) 30 EKA ra^s/spectrum: (M+H) + = 472 <br><br> (M+H+Na)++ = 24 7.6 (M+Na)+ =4 94 (M+2Na)++ = 258.6 <br><br> 35 <br><br> NOW AMENDED <br><br> - 85 - / / <br><br> Example 56 / / <br><br> l-Methyl-2-[2-(2-amidinothiophen-5-ylyethyl]-benzimidazol-5 5-yl-carboxylic acid-N-(2-pyridyl) AN/(2-ethoxycarbonylethyl)-amide-hydrochloride a) l-Methvl-2-\2-(2-cvanothiophen/5-vl)-ethvll-benzimidazol-5-vl-carboxvlic a^cLa-N- (2-pvridvl) -N- (2- <br><br> 10 ethoxycarbonylethyl)-amide / / <br><br> Prepared analogously to Example 25c from 3-(2-cyanothiophen-5-yl)-propionic/ acid and 3-amino-4-methylamino-benzoic acid-Kr- (2-pyridyl) -N-(2-ethoxycarbonylethyl/amide. <br><br> 15 Yield: 18 % of theory, / / <br><br> Rf value: 0.66 (silica/gea; dichloromethane/methanol = 9:1) <br><br> b) l-Methvl-2-\2-(2^m/dinothiophen-5-vl)ethvll-benzimidazol-5-vl-dar£&gt;oxvlic acid-N- (2-pyridvl) -N- (2- <br><br> 20 ethoxycarbonylethyl)/-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[2-(2-cyanothiophen-5/yl/) ethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyrioyY)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium <br><br> 25 carbonate. / / <br><br> Yield: 53 "J of. theory, <br><br> C26H28N60J* A 504.6) <br><br> Rf value/0/22 (silica gel; dichloromethane/methanol = 5:1) EKA masiS ^pectrum: (M+H)+ = 505 <br><br> 30 / / (M+H+Na)++ = 264 <br><br> NOW AMENDED <br><br> - 86 - / / <br><br> Example 57 / / <br><br> l-Methyl-2-[2-(2-amidinothiophen-5-yY)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-M-y2-5 hydroxycarbonylethyl)-amide / / <br><br> Prepared analogously to Example ,26/from l-methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-berazimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-10 hydrochloride and sodium hydroxide solution. <br><br> Yield: 98 % of theory, / / <br><br> C24H24N6O3S (476-6) / / <br><br> EKA mass spectrum: (M+H)y /= 477 <br><br> (M+Na^+/ = 4 99 15 (M+2?H)A+ = 239 <br><br> Example 58 / / <br><br> l-Methyl-2- [N- (4-amicainophenyl) -aminomethyl] -benzimidazol-20 5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylebnyZ)-amide-hydrochloride a) 1-Methvl-2/iNA (4-cvanophenvl)-aminomethvll -benzimidazol-5-vl-carboxylic/ acid-N-(2-pvridvl)-N-(2- <br><br> 25 ethoxvcarbop/3/ethvl) -amide <br><br> Prepared anal/ogously to Example 25c from N- (4 - cyanophenyl) -glycine and/3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)/N/(2-ethoxycarbonylethyl)-amide. <br><br> Yield: y€l/% of theory, <br><br> 30 Rf value/ 0.62 (silica'gel; dichloromethane/methanol = 19:1)/ / <br><br> b) /l-yMethvl-2- fN- (4-amidinophenyl) -aminomethyl] -beinzamidazol-5-vl-carboxylic acid-N- (2-pvridvl) -N- (2- <br><br> 35 ethoxycarbonylethyl)-amide-hydrochloride <br><br> /Prepared analogously to Example 25d from l-methyl-2-[N-(4-/ dyanoPhenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic <br><br> NOW AMENDED <br><br> 10 <br><br> - 87 <br><br> acid-N- (2-pyridyl) -N- (2-ethoxycarbonyl4tl/yl) -amide and ethanolic hydrochloric acid, ethanol ^anja ammonium carbonate. <br><br> Yield: 71 % of theory, <br><br> C27H29N703 (499.6) <br><br> Rf value: 0.28 (silica gel; dich]/or;6methane/methanol = 5:1) EKA mass spectrum: (M+H) + =/500 <br><br> (M+H+Na) ++ /= ^61.8 (M+2H) ++ / =/ 250 . 8 <br><br> Example 5 9 <br><br> 15 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-Ny(2/pyridyl)-N-(2-hydroxycarbonyl ethyl) -Vam/de <br><br> 20 <br><br> 25 <br><br> Prepared analogously t6 Example 26 from l-methyl-2 - [N- (4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridylZ-N1- (2-ethoxycarbonylethyl) -amide-hydrochloride ana srodium hydroxide solution. <br><br> Yield: 91 % of ith^ory, <br><br> c2 5h2 5n7°3 (47/.?) <br><br> EKA mass speaftrum: <br><br> (M+H)+ = 472 (M+H+Na)++ = 247.6 <br><br> (M+2H)++ = 236.7 <br><br> (M+2Na)++ = 258.6 <br><br> Example <br><br> 30 l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-anvfl.de-hydrochloride <br><br> 35 <br><br> pyridvl) <br><br> NOW AMENDED <br><br> - 88 - / / <br><br> Prepared analogously to Example 149a from/3-(4-cyanophenyl)-propionic acid and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide. Yield: 22 % of theory, / / <br><br> 5 Rf value: 0.68 (silica gel; dichloromethane/methanol = 19:1) / / <br><br> b) l-Methvl-2- \2-(4-amidinophenylVethvll-benzimidazol-5-vl-carboxvlic acid-N-(2-pvridvl)-N-/2-ethoxycarbonylethyl)-10 amide-hydrochloride / / <br><br> Prepared analogously to Example 25d from l-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. 15 Yield: 85 % of theory, / / <br><br> C28H30N6O3 (498.6) / / <br><br> Rf value: 0.30 (silica gel; dichloromethane/methanol = 5:1) EKA mass spectrum: Gm+H) + = 499 <br><br> j (M+H+Na)++ = 261 <br><br> 20 / / <br><br> Example 61 / / <br><br> l-Methyl-2-[2-A4/amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic aaad/N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-25 amide / / <br><br> Prepared analogously to Example 26 from l-methyl-2-[2-(4-amidinophferwl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridlyLO -N- (2-ethoxycarbonylethyl) -amide-hydrochloride <br><br> 3 0 and sodium hydroxide solution. <br><br> Yield1 97 % of theory, <br><br> (470.5) <br><br> EKA/mass spectrum: (M+H)+ = 471 <br><br> / / (M+H+Na)++ = 247 <br><br> 35 / / (M+Na)+ = 493 <br><br> NOW AMENDED <br><br> - 89 - <br><br> 10 <br><br> 15 <br><br> Example 62 <br><br> l-Methyl-2-[2-(4-amidinophenyl)ethyf]^enzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Exampl^ 2&amp;d from l-methyl-2-[2-(4-cyanophenyl) ethyl] -benzimidazol-£-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl/-amide and ethanolic hydrochloric acid, ethanol Yield: 86 % of theory, C29H31N5°3 (497.6) <br><br> Rf value: 0.11 (silica g^l, EKA mass spectrum: (M+H)+/ <br><br> tnd/ammonium carbonate. <br><br> dichloromethane/ethanol = 4:1) = 498 <br><br> (M/2H0++ = 249.8 <br><br> Example 63 <br><br> 20 l-Methyl-2-[2-(4-carboxylic acid-hydrochloride <br><br> Ldinophenyl)ethyl]-benzimidazol-5-yl-Dhenyl-N-(2-hydroxycarbonylethyl)-amide- <br><br> 25 <br><br> 30 <br><br> Prepared analogously to Example 26 from l-methyl-2-[2-(4-amidinophenylVethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (^-etthoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: In. ft of theory, <br><br> C27H27l^o/ (469.6) <br><br> EKA massr spectrum: (M+H) <br><br> = 470 <br><br> (M+H+Na)++ = 24 6.6 <br><br> (M+Na)+ (M+2H)++ <br><br> = 492 = 235.6 <br><br> NOW AMENDED <br><br> - 9° - / / <br><br> Example 64 / / <br><br> l-Methyl-2-[N-(4-amidinophenyl)-amindmechyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N- / 5 (methoxycarbonylmethyl) -amide-dihycjrachloride <br><br> Prepared analogously to Example 25a from l-methyl-2-[N-(4-cyanophenyl) -aminomethyl] -benzimiafazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (methoxycyarlponylmethyl) -amide and 10 methanolic hydrochloric acid,/methanol and ammonium <br><br> Rf value: 0.12 (silica gea;/dichloromethane/ethanol = 4:1) 15 EKA mass spectrum: (M+H/+/ = 472 <br><br> 20 l-Methyl-2-[N-(4-amiainophenyl)-aminomethyl]-benzimidazol- <br><br> Prepared anaLogously to Example 25d from l-methyl-2-[N-(4-25 cyanophenyl)/aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyri.dyl) -N- (2-methoxycarbonylethyl) -amide and methanolic/ hydrochloric acid, methanol and ammonium <br><br> 30 ^26^27^703 (485.6) <br><br> Rf val/uef 0.31 (silica gel; dichloromethane/methanol = 5:1) <br><br> NOW AMENDED <br><br> 91 <br><br> Example 6 6 <br><br> l-Methyl-2-[2 -(4-amidinophenyl)ethyl/-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- [2- (lH-tietirazol-5-yl) ethyl] 5 amide-hydrochloride a) l-Methvl-2 - \2- (4-cvanophenvl)/4tlWll -benzimidazol-5-vl-carboxvlic acid-N-phenvl-N-T2-ylI^tetrazol-5-vl) ethvll -amide <br><br> 10 Prepared analogously to Example/ 25c from 3-(4-cyanophenyl) propionic acid and 3-amino-4-ra(ethylamino-benzoic acid-N-phenyl-N- [2-(lH-tetrazol/5/yl)ethyl]-amide. <br><br> Yield: 67 % of theory, <br><br> IR Mass spectrum (KBr): Characteristic bands at 15 / 3A39.5 cm-1 (N-H); 2235.5 cm-1 <br><br> :=N) ; <br><br> 1631.6 cm-1 (C=Q) <br><br> b) l-Methvl-2-f2-(A-amidinophenyl)ethvll -benzimidazol-5-vl-20 carboxylic acid-N^-pjaenvl-N- \2 - (lH-tetrazol-5-vl) ethvl] amide-hvdrochloyic Prepared analogously to Example 25d from l-methyl-2-[2-(4-cyanophenyl) et/hw.] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N- [2-/l^-tetrazol-5-yl) ethyl] -amide and ethanolic 25 hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 92 Is di theory, <br><br> C27H27N9O/ (/93.6) <br><br> EKA masgf g/bectrum: (M+H) + = 494 <br><br> (M+Na)+ = 516 30 / / (M+2H)++ = 258.7 <br><br> NOW AMENDED <br><br> - 92 - / / <br><br> Example 67 / J <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminome/hyl] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-frlH/tetrazol-5-5 yl)ethyl]-amide-hydrochloride / / <br><br> Prepared analogously to Example Z5dr from l-methyl-2-[N-(4-cyanophenyl) -aminomethyl] -benzimidfazol-5-yl-carboxylic acid-N-phenyl-N- [2- (lH-tetrazoZ-9'-yl) ethyl] -amide and 10 ethanolic hydrochloric acid, yetManol and ammonium carbonate. / / <br><br> Yield: 29 % of theory, / / <br><br> C26H26Nl0O (494.6) / / <br><br> EKA mass spectrum: (M+H)/ 4 495 <br><br> 15 / / <br><br> Example 68 / / <br><br> l-Methyl-2-[N-(4-amiainophenyl)-aminomethyl] -benzimidazol-5-yl-carboxylic acia-N-(2-pyridyl)-N-(2-n-20 hexyloxycarbonyletfnyfl.)-amide-hydrochloride <br><br> 0.60 g (1.1 mMol) /of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] -benarimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2/eyhoxycarbonylethyl) -amide-hydrochloride were 25 added to abojut/30 ml of n-hexanol saturated with hydrogen chloride ana tfhe mixture was stirred for 19 hours at room temperature./ Then the hexanol was distilled off in vacuo, <br><br> the residue/was mixed with about 5 ml of IN ammonia solution With stirring and evaporated down once more. The <br><br> 3 0 crude product thus obtained was purified by column chromatography (silica gel, dichloromethane/methanol = 5:1)/ / <br><br> YieldI 53 % of theory, <br><br> &lt;-3Q.H/7N703 (555.7) <br><br> 35 Wt yalue: 0.36 (silica gel; dichloromethane/methanol / / = 5:1 ) <br><br> NOW AMENDED <br><br> - 93 - / / <br><br> EKA mass spectrum: (M+H)+ = 556 / / <br><br> Example 69 / / <br><br> 5 l-Methyl-2-[N-(4-amidinophenyl)-N/mathyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-Mr- (2-pyridyl) -N- (2-ethoxycarbonylethyl) - amide - hydrochloride a) l-Methyl-2-[N-(4-cyanopherwl/-N-methyl-aminomethyl]-10 benzimidazol-5-yl-carboxylic/ acid-N-(2-pyridyl)-N-(2- <br><br> ethoxvcarbonvlethvl)-amide / / <br><br> Prepared analogously to Example 25c from N-(4-cyanophenyl)-N-methylglycine and 3-am/nc^-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycam)onylethyl)-amide. <br><br> 15 Yield: 71 % of theory,/ / <br><br> Rf value: 0.66 (silica: gel,• dichloromethane/methanol = <br><br> 19:1)/ / <br><br> b) l-Methyl-2-[N--amidinophenyl)-N-methyl-aminomethyl]-20 benzimidazol-5-ylAC/arboxylic acid-N- (2-pyridyl) -N- (2- <br><br> ethoxvcarbonvletfnvA)-amide-hvdrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl) -M-mfethyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-25 amide and eythafnolic hydrochloric acid, ethanol and ammonium carbonate./ / <br><br> Yield: 111%/of theory, <br><br> C28H31N7°3/ (513.6) <br><br> EKA mass Spectrum: (M+H)+ = 514 <br><br> 30 / / (M+H+Na)++ = 268.7 <br><br> NOW AMENDED <br><br> - 94 - / / <br><br> Example 70 / / <br><br> l-Methyl-2-[N-(4-amidinophenyl)-N-mettnyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N/(2Apyridyl)-N-(2-5 hydroxycarbonylethyl)-amide / / <br><br> Prepared analogously to Example 26/from l-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl) -fi-Li-ethoxycarbonylethyl)-10 amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 66 % of theory, / / <br><br> 026^27^7^3 (485.6) / / <br><br> EKA mass spectrum: (M+H)4"/ / = 486 <br><br> (M+Natf+/ = 508 15 (M+2Na/++ = 265.6 <br><br> Example 71 J j l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-20 carboxylic acid-N/cyclopentyl-N-(2-ethoxycarbonylethyl)-amide-hydrochlomde <br><br> Prepared analogously to Example 25d from l-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-25 cyclopentyl7N-/(2-ethoxycarbonylethyl) -amide and ethanolic hydrochloric Acid, ethanol and ammonium carbonate. <br><br> Yield: 65 /% jot theory, <br><br> *-28^3 5^5^3 /(489 . 6) <br><br> EKA mass ispectrum: (M+H)+ = 490 <br><br> NOW AMENDED <br><br> " 95 * / / <br><br> Example 72 / / <br><br> l-Methyl-2 - [2- (4-amidinophenyl) ethyLl -joenzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N- (2-7nyaroxycarbonylethyl) - <br><br> v / / <br><br> 5 amide / / <br><br> Prepared analogously to Example/26/ from l-methyl-2-[2-(4-amidinophenyl) ethyl] -benzimidafol/-5-yl-carboxylic acid-N-cyclopentyl-N- (2-ethoxycarbonylefthyl) -amide-hydrochloride 10 and sodium hydroxide solution./ <br><br> Yield: 8 9 % of theory, / / <br><br> C26H31N5O3 (461.6) / / <br><br> EKA mass spectrum: (M+H)/ / = 462 <br><br> (M+H/N/)++ = 242.6 15 (Mj/Na/+ = 484 <br><br> (Nl+2fi)++ = 231.6 <br><br> Example 73 / / <br><br> 20 l-Methyl-2-[N-(d- amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic/ aicid-N-cyclopentyl-N- (2-e t hoxycarbonyl/e tnyl) - amide - hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2- [N- (4-25 cyanopheny/) ^aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-cy/laipentyl-N- (2-ethoxycarbonylethyl) -amide and ethanoliyc hydrochloric acid, ethanol and ammonium carbonate/ <br><br> Yield j 610 % of theory, <br><br> 30 C27HV4N/03 (490.6) <br><br> EKA/ma/ss spectrum: (M+H)+ = 491 <br><br> NOW AMENDED <br><br> - 96 - / / <br><br> Example 74 / / <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminome/hyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N1- (2-5 hydroxycarbonylethyl)-amide / / <br><br> Prepared analogously to Example 26 /from l-methyl-2-[N-(4-amidinophenyl) -aminomethyl] -ben35iniidazol-5-yl-carboxylic acid-N-cyclopentyl-N- (2-ethoxyeai/oonylethyl) -amide-10 hydrochloride and sodium hydrox/de solution. <br><br> Yield: 45 % of theory, / / <br><br> C25H30N3O4 (462.6) / / <br><br> EKA mass spectrum: (M+H)+/ / = 463 <br><br> (M+H+Na /++ = 243 <br><br> 15 (M+N4)/ = 485 <br><br> (M/2N4)++ = 254 <br><br> Example 75 / / <br><br> 20 l-Methyl-2- [N- (4-amj/dinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-hydrochloride <br><br> Prepared anal/bgpusly to Example 25d from l-methyl-2 - [N- (4-25 cyanophenylV-N^methyl-aminomethyl]-benzimidazol-5-yl- <br><br> carboxylic/aoid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and/etinanolic hydrochloric acid, ethanol and ammonium carbonate. / <br><br> Yield: pA /% of theory, <br><br> 3 0 C27H2 ^^7^3 (499.6) <br><br> EKA mass spectrum: (M+H)+ = 500 / / (M+2H )++ = 250.7 <br><br> NOW AMENDED <br><br> - 97 - <br><br> Example 76 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl] benzimidazol-5-yl-carboxylic acid-N^- (^-pyridyl) -N-(hydroxycarbonylmethyl)-amide <br><br> 10 <br><br> 15 <br><br> Prepared analogously to Example^y from l-methyl-2-[N-(4 amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)/Ny(ethoxycarbonylmethyl)-amide-hydrochloride and sodi/mhydroxide solution. <br><br> Yield: 68 % of theory, <br><br> C25H25N7°3 (471.5) EKA. mass spectrum: <br><br> (M+H) (M+NA) <br><br> = 472 = 494 <br><br> (M-t^NA)++ = 258.6 <br><br> Example 77 <br><br> l-Methyl-2- [2- (4-§tm: 20 carboxylic acid-M-amide-hydrochloric <br><br> Linophenyl)-ethyl]-benzimidazol-5-yl--pyridyl)-N-(2-ethoxycarbonylethyl)- <br><br> 25 <br><br> 30 <br><br> Prepared analogously to Example 25d from l-methyl-2-[2-(4-cyanophenyl)/etuiyl] -benzimidazol-5-yl-carboxylic acid-N- (3-pyridyl)-Ny(2/ethoxycarbonylethyl)-amide and ethanolic hydrochloric/acid, ethanol and ammonium carbonate. <br><br> Yield: 9l/ %/of theory, <br><br> c28h30n/°:/ (498.6) <br><br> Rf vali/e:/o.l9 (silica gel; dichloromethane/ethanol = 4:1) <br><br> EKA <br><br> iss spectrum: (M+H)+ = 499 <br><br> NOW AMENDED <br><br> - 98 - <br><br> Example 78 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-amine 5-yl-carboxylic acid-N-(3-pyridyl) 5 ethoxycarbonylethyl) -amide-dihydroafh] <br><br> ae/hyl] -benzimidazol- <br><br> &gt;ride <br><br> Prepared analogously to Example from l-methyl-2-[N-(4- <br><br> cyanophenyl)-aminomethyl]-benzimiaazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and 10 ethanolic hydrochloric acid, /ethanol and ammonium carbonate. <br><br> Yield: 86 % of theory, <br><br> C27H29N7O3 (499.6) <br><br> Rf value: 0.09 (silica gei//dichloromethane/ethanol =4:1 ) <br><br> 15 EKA mass spectrum: (M+H/+/= 500 <br><br> Example 79 <br><br> l-Methyl-2- [N- (4-ar 20 5-yl-carboxylic ac hydroxycarbonylel <br><br> Lnophenyl)-aminomethyl]-benzimidazol--N-(3-pyridyl)-N-(2-.) -amide <br><br> 25 <br><br> 30 <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4-amidinophenyl/-^minomethyl] -benzimidazol-5- yl-carboxylic acid-N-(3 dihydrochl Yield: 85 C25H25N70/ <br><br> py^Kjtyl) -N- (2-ethoxycarbonylethyl) -amide-iae and sodium hydroxide solution. <br><br> f theory, <br><br> 471.5) <br><br> EKA mass spectrum: <br><br> (M+H)+ = 472 (M+2H)++ = 236.6 (M+2Na)++ = 258.6 <br><br> NOW AMENDED <br><br> 10 <br><br> 15 <br><br> 20 <br><br> 25 <br><br> Example 80 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-N-me£h^l-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N^- (25-pyridyl) -N- (2 ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 5$. from l-Methyl-2- [N- (4-cyanophenyl)-N-methyl-aminomett 1-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)fl 2-ethoxycarbonylethyl)-amide and ethanolic hydrochljor^ acid, ethanol and ammonium carbonate. <br><br> Yield: 64 % of theory, <br><br> (-28^31^7^&gt;3 (513.6) <br><br> EKA mass spectrum: (M+H/+ = 514 <br><br> Example 81 <br><br> l-Methyl-2- [N- (4-ama.dinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-ycarboxylic acid-N- (3-pyridyl) -N- (2-hydroxycarbonylet^ny/) -amide <br><br> Prepared analogously to Example 26 from l-Methyl-2-[N-(4-amidinophenyl )/-W- me thyl - aminomethyl ] -benz imidazol - 5 -yl -carboxylic ac/id^N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 70 / q/r theory, <br><br> P485.6) spectrum: <br><br> (M+H)+ (M+Na)+ <br><br> = 486 = 508 <br><br> (M+2Na)++ = 265.6 <br><br> NOW AMENDED <br><br> - 100 - / / <br><br> Example 82 / / <br><br> l-Methyl-2-[N-(4-amidinophenyl)-N-metmm-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N/ph4nyl-N-(2-5 ethoxycarbonylethyl)-amide-hydrochloride a) l-Methvl-2-fN-(4-cvanophenvl)/N7methvl-aminomethvll -benzimidazol-5-vl-carboxvlic ac/d/N-phenvl-N-(2-pvridvl)-N-(2-ethoxycarbonylethyl)-amide / / <br><br> 10 Prepared analogously to Exampxe/25c from N-(4-cyanophenyl)-N-methylglycine and 3-amino-^-methylamino-benzoic acid-N-phenyl-N- (2-ethoxycarbonylethyl)-amide. <br><br> Yield: 71 % of theory, / / <br><br> Rf value: 0.38 (silica gea;/dichloromethane/methanol = 15 19:1) / / <br><br> b) l-Methvl-2- fN- (4-amiainophenvl) -N-methvl-aminomethvll -benzimidazol-5-vl-carboxylic acid-N-phenvl-N-(2-ethoxvcarbonvlethvlA -amide-hydrochloride <br><br> 20 Prepared analogous4y/to Example 25d from l-methyl-2-[N-(4-cyanophenyl) -N-mefthyl-aminomethyl] -benzimidazol-5-yl-carboxylic acidVN-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic Hydrochloric acid, ethanol and ammonium carbonate. / / <br><br> 25 Yield: 74 % (of theory, <br><br> C29H32N603 IsA.S) <br><br> EKA mass s^pactrum: (M+H)+ = 513 <br><br> / / (M+H+Na)++ = 268 <br><br> / / (M+2H)++ = 257 <br><br> NOW AMENDED <br><br> - 101 - <br><br> Example 83 <br><br> l-Methyl-2- [N- (4-amidinophenyl) -N-met/hyl-aminomethyl] benzimidazol-5-yl-carboxylic acid-N/pl/enyl-N- (2-5 hydroxycarbonylethyl)-amide <br><br> Prepared analogously to Example ll6/from l-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2/etiioxycarbonylethyl) -amide-10 hydrochloride and sodium hydyo3Qa.de solution. <br><br> Yield: 80 % of/theory, <br><br> C27H28N603 (484.6) <br><br> EKA mass spectrum: (M+H) y / = 485 <br><br> (M+HVNc^++ = 254 15 (M+^a)/+ = 507 <br><br> (M4-2tfa)+ = 265 <br><br> Example 84 <br><br> 20 1-ethyl-2- [N- (4-amyainophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic accidr-N- (2-pyridyl) -N- (2-etho3cycarbonylethyl) ■ amide-hydrochlori/de <br><br> Prepared analogously to Example 25d from l-ethyl-2-[N-(4-25 cyanophenyl^ -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N- (2-vpyridyl) -N- (2-etho3cycarbonylethyl) -amide and ethanolic/ hydrochloric acid, ethanol and ammonium carbonatfe .&gt; <br><br> Yield:fas/% of theory, <br><br> C28H3/N7^3 (513.6) <br><br> R, vg£Ln&amp;: 0.21 (silica gel; dichloromethane/methanol = 5:1) EKty raj^ss spectrum: (M+H)+ = 514 <br><br> (M+H+Na)++ = 268.6 (M+2H)++ = 257.7 <br><br> NOW AMENDED <br><br> - 102 <br><br> Example 85 <br><br> l-ethyl-2-[N-(4-amidinophenyl)-amino yl-carboxylic acid-N-(2-pyridyl)~N/(: hydroxycarbonylethyl)-amide <br><br> /thyl] -benzimidazol-5- <br><br> Prepared analogously to Example/20 from l-ethyl-2-[N-(4-amidinophenyl)-aminomethyl]-benz/midazol-5-yl-carboxylic 10 acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and 2N sodium /lyjaroxide solution. <br><br> Yield: 49 % of theory, <br><br> C26H27N7O3 (485.6) <br><br> EKA mass spectrum: (M+H)/ / = 486 15 (M+H4-Ni)++ = 254.6 <br><br> (Mh/2H/++ = 243.6 (M+2faa)++ = 265.7 <br><br> 20 <br><br> Example 86 <br><br> l-Methyl-2 - [N- (4/anfidinophenyl) - aminomethyl] -benzimidazol -5-yl-carboxylic/aeid-N-(2-fluorophenyl)-N-(2-ethoxycarbonyLetnyl)-amide-hydrochloride <br><br> 25 <br><br> 30 <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanopheny^O -/aminomethyl] -benzimidazol-5-yl-carboxylic orophenyl)-N-(2-ethoxycarbonylethyl)-amide and drochloric acid, ethanol and ammonium acid-N- (2-/f ethanoli carbonate Yield:/8 <br><br> C28H2, <br><br> R <br><br> E <br><br> 35 <br><br> of theory, <br><br> '603 (516.6) <br><br> li/e: 0.08 (silica gel; dichloromethane/ethanol = 4:1) ss spectrum: (M+H)+ = 517 <br><br> (M+H+Na)++ = 270 (M+2H)++ = 259 <br><br> NOW AMENDED <br><br> - 103 - <br><br> Example 87 / / <br><br> 5 l-Methyl-2- [N- (4-amidinophenyl) -an/inomethyl] -benzimidazol-5-yl-carboxylic acid-N- (2-fluoropshenyl) -N- (2-hydroxycarbonylethyl)-amide / / <br><br> Prepared analogously to Example/26 from l-methyl-2-[N-(4-10 amidinophenyl) -aminomethyl] -oemzimidazol-5-yl-carboxylic acid-N- (2-fluorophenyl) -N- Ul -pthoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 45 % of theory, / / <br><br> C26H25FN6°3 (488.5) / / <br><br> 15 Rf value: 0.05 (silicaygel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (m£h/+ = 489 <br><br> CM+H+Na)++ = 267 /(M4-2H)++ = 256 <br><br> 20 Example 88 / / <br><br> l-Methyl-2- [N-/( 4/amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylo.c/acid-N- (3-methylphenyl) -N- (2-e thoxycarboxwl/s t hyl) - amide - hydrochloride <br><br> 25 / <br><br> Prepared a/nalogously to Example 25d from l-methyl-2-[N-(4-cyanopherfyLO -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N- 13 -Xethylphenyl) -N- (2-ethoxycarbonylethyl) -amide and ethano/ic/ hydrochloric acid, ethanol and ammonium 3 0 carbonate. <br><br> Yield: /l9 % of theory, <br><br> C29/3/N6O3 (512.6) <br><br> Rf/vaG.ue: 0.10 (silica gel; dichloromethane/ethanol = 4:1) Hka/mass spectrum: (M+H)+ = 513 <br><br> 35 / / (M+H+Na)++ = 268 <br><br> NOW AMENDED <br><br> - 104 - <br><br> Example 8 9 <br><br> l-Methyl-2- [N- (4-amidinophenyl) -amina&lt;me£hyl] -benzimidazol-5-yl-carboxylic acid-N- (3-methylphei/y]/ -N- (2-5 hydroxycarbonylethyl)-amide <br><br> 10 <br><br> 15 <br><br> Prepared analogously to Example ^6/from l-methyl-2-[N-(4 amidinophenyl)-aminomethyl]-benEimidazol-5-yl-carboxylic acid-N- (3-methylphenyl) -N- (2-eychoxycarbonylethyl) -amide-hydrochloride and sodium hydrox/de solution. <br><br> Yield: 62 % of theory, <br><br> C27H28N6°3 (484.6) <br><br> EKA mass spectrum: (M+H)+/ / = 485 <br><br> (M+H+fray++ = 254 (M+Ijfa)/" = 507 (M/2$a)++ = 265 <br><br> Example 90 <br><br> 20 l-Methyl-2- [N- [4-/(N/n-hexyloxycarbonylamidino) phenyl] - <br><br> aminomethyl]-beneimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarboryylpthyl) -amide <br><br> 1.1 g (2.06 nftool) of l-methyl-2-[N-(4-amidinophenyl) -25 aminomethylV-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride was dissolved in a mixtiaror of 4 0 ml of tetrahydrofuran and 10 ml of water, tnen 570 mg (4.12 mMol) of potassium carbonate and 362 mg A2/2 mMol) of n-hexyl chloroformate were added and 30 stirred for two hours at room temperature. The solvent was then/listilled off, the residue was mixed with about 50 ml of ^atnrated saline solution and the resulting solution was extracted three times with 20 ml of dichloromethane. The e^ti/acts were dried over sodium sulphate and evaporated 3 5 gtowh. The crude product thus obtained was purified by <br><br> .umn chromatography (100 g silica gel; dichloromethane + ethanol). <br><br> NOW AMENDED <br><br> - 105 - / / <br><br> Yield: 78 % of theory, / / <br><br> ^-3 5^42^6^5 (626.8) J j <br><br> Rf value: 0.49 (silica gel; dichlorametchane/ethanol = 19:1) EKA mass spectrum: (M+H)+ = 627 J <br><br> 5 (M+H+Na)++ = 3/25/ <br><br> (M+2H) ++ =/3l&gt;4 <br><br> Example 91 J / <br><br> 10 l-Methyl-2-[N-[4-(N-methoxycaroonylamidino)phenyl]-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide / <br><br> Prepared analogously "cd Example 90 from l-methyl-2-[N-(4-15 amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-eftnoKycarbonylethyl) -amide-hydrochloride and methyl chlorofoDiuace. <br><br> Yield: 41 % of theory, <br><br> C30H32N6O5 (556.6/ / <br><br> 20 Rf value: 0.85 (s/ila.ca gel; dichloromethane/ethanol = 4:1) EKA mass spectrum/ (M+H)+ = 557 <br><br> / / (M+H+Na)++ = 290 / / (M+Na)+ = 579 <br><br> 25 Example 92/ / <br><br> l-Methy]&gt;-2/[N- [4- (N-ethoxycarbonylamidino) phenyl] -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-meb4ioKycarbonylethyl) -amide <br><br> 3 0 / / <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-am/di/nophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acidf-N-phenyl-N- (2-methoxycarbonylethyl) -amide-nyarochloride and ethyl chloroformate. <br><br> 35 jYiield: 62 % of theory, <br><br> / /30h32N6O5 (556.6) <br><br> NOW AMENDED <br><br> - 106 - <br><br> R£ value: 0.51 (silica gel; dichlorometyna/e/ethanol = 19:1) EKA mass spectrum: (M+H)+ = 557 <br><br> (M+H+Na)++ = 290 (M+2H) ++ = 27J <br><br> Example 93 <br><br> 10 <br><br> l-Methyl-2- [N- [4- (N-cyclohexyl&lt;6xVcarbonylamidino) phenyl] -aminomethyl]-benzimidazol-5-yl-parboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl) -amd/ley <br><br> 15 <br><br> 20 <br><br> Prepared analogously to E: amidinophenyl)-aminometh} acid-N-phenyl-N-(2-meth^ hydrochloride and cycl$ Yield: 25 % of theory; C34H38N6°5 (610.7) <br><br> ile 90 from l-methyl-2 - [N-(4-]/■ benzimidazol- 5-yl-carboxylic larbonylethyl) - amide-'1 chlorof ormate. <br><br> Rf value: 0.44 (silica/ gel; dichloromethane/ethanol = 19:1) <br><br> EKA mass spectrum: <br><br> 1+H) + = 611 /(M+2H) ++ = 306 <br><br> Example 94 <br><br> l-Methyl-2-25 amidino]phe/ acid-N-pheny] <br><br> f4-[N-[2-(methylsulphonyl)ethyloxycarbonyl]-(] -aminomethyl] -benzimidazol-5-yl-carboxylic -N-(2-ethoxycarbonylethyl)-amide <br><br> Preparecy analogously to Example 90 from l-methyl-2-[N-(4-amidinophjenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic 30 acid-t/-p/ienyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and 3^- (/hethyl sulphonyl) -ethyl chlorof ormate . <br><br> Yie3/d:/ 66 % of theory, <br><br> c3/Hy6N6°7s (648.8) <br><br> R/ vAlue: 0.44 (silica gel; dichloromethane/ethanol = 19:1) 35 y£K?L mass spectrum: (M+H) + = 649 <br><br> (M+H+Na)++ = 336 <br><br> NOW AMENDED <br><br> 107 - <br><br> (M+2H) <br><br> + + <br><br> = 325 <br><br> 10 <br><br> 15 <br><br> Example 95 <br><br> l-Methyl-2- [N-[4-(N-n-octyloxycarbbn^lamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide <br><br> Prepared analogously to Examp/e/90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarponylethyl)-amide-hydrochloride and n-octyl ^hjoroformate, <br><br> Yield: 41 % of theory, <br><br> C36H44N6°5 (640.8) <br><br> 0.43 (silica EKA mass spectrum: (M/-H/+ <br><br> Rf value dichloromethane/ethanol = 19:1) = 641 <br><br> 1+Na) + = 663 <br><br> 20 <br><br> Example 96 <br><br> l-Methyl-2- [N- [d- (^J-hydroxylamidino) phenyl] -aminomethyl] benzimidazol-5/yl/-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylet/hyl) -amide <br><br> 25 1.44 g (3.0/mMol) of l-methyl-2-[N-(4-cyanophenyl)- <br><br> aminomethm]/benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, 0.625 g (9.0 mMol) of hydroxyl/ama.ne hydrochloride and 0.425 g (4.0 mMol) of sodium/carbonate were dissolved in 80 ml of ethanol and 30 refluxed/for 7 hours. Then a further 210 mg of hydr^xmamine hydrochloride and 170 mg of sodium carbonate wer# ^aded, the mixture was boiled for a further 5 hours an0. tyhen evaporated down in vacuo. The residue was <br><br> Solved in about 3 0 ml of dichloromethane, the solution 35 &gt;6bt£ained was washed with 20 ml of water, the organic phase is dried and evaporated down. The crude product thus <br><br> NOW AMENDED <br><br> - 108 - / / <br><br> obtained was purified by column chromatography (200 g silica gel, dichloromethane + 4% ethano]:) . <br><br> Yield: 39 % of theory, / j <br><br> C28h30N6O4 (514.6) / / <br><br> 5 Rf value: 0.15 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H) + =5155 / <br><br> (M+Na)+ = sfl/ <br><br> (2M+H) + = risks (2M+Na) + f 3/051 <br><br> 10 / / <br><br> Example 97 / / <br><br> l-Methyl-2-[N-[4-(N-n-heptyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol/5-yl-carboxylic acid-N-phenyl-N-15 (2-methoxycarbonylethyl)/amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl) -amiiaomethyl] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (21-methoxycarbonylethyl) -amide-20 hydrochloride anA nf-heptyl chlorof ormate . <br><br> Yield: 43 % of ithefory, <br><br> C35H42N6O5 (62fe.&amp;) <br><br> Rf value: 0.4y0 /silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ = 627 <br><br> 25 / / (M+H+Na)++ = 325 <br><br> / / (M+Na)+ = 649 <br><br> Example! 9/8 <br><br> 30 l-Me^hyl-2- [N- [4-(N-benzoylamidino)phenyl]-aminomethyl]-ben/iniidazol-5-yl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-35 /amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic <br><br> NOW AMENDED <br><br> - 109 - / / <br><br> acid-N-phenyl-N-(2-methoxycarbonylethyl)/amide-hydrochloride and benzoyl chloride. / / <br><br> Yield: 88 % of theory, / / <br><br> c34h32n6°4 (588.7) / / <br><br> 5 R£ value: 0.37 (silica gel; dichldromethane/ethanol = 19:1) l-H-NMR spectrum (Dg-DMSO) : 2.61 At/2H) , 3.54 (s,3H), 3.76 <br><br> (s,3H), 4.10 (t,2H), 4.61 (d,2rf) ,/6.83 (d,2H), 7.05 to 7.55 (m, 12H) ,8.03 (d,2H), 8.25 (ddAw , 8.98 (s,lH), 10.48 (s, 1H) / / <br><br> 10 / / <br><br> Example 9 9 / / <br><br> l-Methyl-2-[N-[4-(N-n-hexyl/oxycarbonylamidino) phenyl]-aminomethyl] -benzimidazyol/5-yl-carboxylic acid-N-phenyl-N-15 (2-methoxycarbonylethwj/amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N- (4-amidinophenyl)-amirtomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-20 hydrochloride and n/-hexyl chlorof ormate . <br><br> Yield: 54 % of ^heory, <br><br> C34H40N6O5 (61£ -p <br><br> Rf value: 0.455 ^silica gel; dichloromethane/ethanol = 19:1) EKA mass speotrum: (M+H)+ = 613 <br><br> 25 / / <br><br> Example 1(70 / <br><br> l-Methyl-2/- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-3 0 (2-n-prdpyloxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amadlnophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-n-propyloxycarbonylethyl)-amide-3 5 hydrochloride and n-hexyl chloroformate. <br><br> / Yield: 31 % of theory, <br><br> NOW AMENDED <br><br> - 110 - / / <br><br> C36H44N6O5 (640.8) j J <br><br> Rf value: 0.42 (silica gel; dichloromathane/ethanol = 19:1) EKA mass spectrum: (M+H)+ = 641 / / <br><br> (M+H+Na)++ = 332/ / 5 (M+Na) + = 660 / <br><br> Example 101 / J <br><br> l-Methyl-2- [N- [4- (N-ethoxycarjoortylamidino) phenyl] -10 aminomethyl]-benzimidazol-5-yl/carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarboiwl/thyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminometftyLj -benzimidazol-5-yl-carboxylic 15 acid-N-(2-pyridyl)-N-(Sj-methoxycarbonylethyl)-amide-hydrochloride and ethyl Chloroformate. <br><br> Yield: 72 % of theory,/ <br><br> C29H31N7°5 (557.6) / / <br><br> Rf value: 0.58 (sili/ca gel; dichloromethane/methanol = 20 9:1) / / <br><br> EKA mass spectrum:/(M+H)+ = 558 <br><br> / / (M+H+Na)++ = 290.8 / / (M+Na)+ = 580 <br><br> 25 Example 102/ / <br><br> 1-Methyl72-AN-[4-(N-n-octyloxycarbonylamidino)phenyl]-aminometinyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridy]/) -jk~ (2-methoxycarbonylethyl) -amide <br><br> 3 0 / / <br><br> Prepares analogously to Example 90 from l-methyl-2-[N-(4-amiainrophenyl) - aminomethyl] -benzimidazol-5-yl-carboxylic ac/d/N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate. <br><br> 35 Kipld: 57 % of theory, <br><br> /C/5h43n705 (641.8) <br><br> NOW AMENDED <br><br> - 112 - <br><br> Example 103 <br><br> l-Methyl-2- [N- [4- (N-methoxycarbonylamidrino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxylic atcid-N- (2-pyridyl) 5 N-(2-ethoxycarbonylethyl)-amide <br><br> Prepared analogously to Example .dO/from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-10 hydrochloride and methyl chl^roytormate. <br><br> Yield: 48 % of theory, <br><br> C29H31N7O5 (557.6) <br><br> Rf value: 0.62 (silica gey; /Qichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)A / = 558 15 (M+^+lp)++ = 290.7 <br><br> (M/NgO+ = 580 <br><br> Example 104 <br><br> 20 l-Methyl-2 - [N- [4-/(N/n-octyloxycarbonylamidino) phenyl] -aminomethyl) -ber/zimidazol-5-yl-carboxylic acid-N- (2-pyridyl)-N-(2-ttyc^oxycarbonylethyl)-amide <br><br> 0.7 g (1.1 mMol/) of l-methyl-2-[N-[4-(N-n-25 octyloxycaroorfylamidino)-phenyl]-aminomethyl]-benzimidazol-5-yl-carboKy3/ic acid-N- (2-pyridyl) -N- (2- <br><br> methoxycarb©nylethyl)-amide was stirred in a mixture of 0.12 g 0./ mMol) of sodium hydroxide, 5 ml of water and 10 ml or methanol for one hour at room temperature. Then 3 0 the miActyUre was diluted with 20 ml of water and adjusted to pH 6 /wi/ch glacial acetic acid. Then about 5 ml of die/hi^l ether were added and the mixture was vigourously st^rrfed for one hour. The product thus precipitated was si&amp;ccrion filtered, washed with a little water, then with 35 jfiieTthylether and dried. <br><br> Yjeld: 80 % of theory, <br><br> NOW AMENDED <br><br> c34h41n7o5 (627.8) <br><br> EKA mass spectrum: (M+H)+ = 628 <br><br> (M+H+Na)++ = 325/7 (M+Na) + = 65/ 5 (M+2Na)++ = 3/37/7 <br><br> Example 105 <br><br> l-Methyl-2- [N- [4- [N- (2-methy/siilphonyl-10 ethyloxycarbonyl)amidino]-phenyl]-aminomethyl]-benzimidazol-5-yl-carboxyl/c /acid-N-(2-pyridyl) N-(2-ethoxycarbonylethyl)/amide <br><br> 15 <br><br> 20 <br><br> 25 <br><br> Prepared analogously td Example 90 from l-methyl-2-[n-(4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-n- (2-pyridyl) -n/(2/-ethoxycarbonylethyl) -amide-hydrochloride and 2/(rp(ethylsulphonyl) -ethyl chloroformate Yield: 65 % of th? <br><br> c31h35n7°7s (649.3^) <br><br> value: 0.54 (sil/ica gel; dichloromethane/methanol = 9:1 <br><br> EKA mass spect] <br><br> (M+H)+ = 650 <br><br> (M+H+Na)++ = 336.6 <br><br> (M+Na)+ = 672 <br><br> (M+2Na)++ = 347.6 <br><br> Example 106/ <br><br> 30 <br><br> 1-Methyl-/2- [N- [4- (N-n-butyloxycarbonylamidino) phenyl] aminojfietjrnyl] -benzimidazol-5-yl-carboxylic acid-N- (2-pynifty/)-N-(2-methoxycarbonylethyl)-amide <br><br> 35 <br><br> NOW AMENDED <br><br> - 114 - / / <br><br> Yield: 30 % of theory, / / <br><br> c31h35n7°5 (585.7) / / <br><br> Rf value: 0.62 (silica gel; dichlororaetliane/methanol = 9:1) EKA mass spectrum: (M+H) + = 586/ / <br><br> 5 (M+H+Na)++ = 3o4 .77 <br><br> (M+2H)++ = lsy.l <br><br> Example 10 7 / / <br><br> 10 l-Methyl-2 - [N- [4- (N-n-hexyloKyaarbonylamidino)phenyl] -aminomethyl] -benzimidazol-Sl-yi.-carboxylic acid-N- (2-pyridyl)-N-(2-methoxycarbonylethyl)-amide <br><br> Prepared analogously to^xample 90 from l-methyl-2-[N-(4-15 amidinophenyl) -aminoraepm] -benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N-^-yraethoxycarbonylethyl) -amide-hydrochloride and n-Mewl chlorof ormate. <br><br> Yield: 51 % of theo/yy c33h39n7o5 (613.7)/ / <br><br> 20 Rf value: 0.56 (s/ll/ca gel; dichloromethane/methanol = 9:1) EKA mass spectrmri:/ (M+H) + = 614 <br><br> / / (M+H+Na)++ = 318.7 / / (M+2H)++ = 307.6 <br><br> 25 Example 10 a/ / <br><br> 1-Methyl/2-AN- [4- (N-n-heptyloxycarbonylamidino) -phenyl] -aminometfnw]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridy]/) -fa- (2-methoxycarbonylethyl) -amide <br><br> 3 0 / / <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic ac/d/N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide-hydrochloride and n-heptyl chloroformate. <br><br> 3 5 Kipld: 21 % of theory, <br><br> / Q84H43.N7O5 (627.8) <br><br> NOW AMENDED <br><br> - 115 - <br><br> Rf value: 0.60 (silica gel; dichloromet^ia/e/methanol = 9:1) EKA mass spectrum: (M+H)+ = 628 <br><br> (M+H+Na)++ = 325./ <br><br> (M+2H) ++ = 31#. 7/ <br><br> Example 109 <br><br> 10 <br><br> l-Methyl-2-[N-[4-(N-n-pentylo: aminomethyl]-benzimidazol-5 pyridyl)-N-(2-methoxycarbonvtf irbonylamidino)-phenyl]-Carboxylic acid-N-(2-^hyl)-amide <br><br> 15 <br><br> 20 <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl) - aminomethyl ]/-benz imidazol - 5 -yl - carboxy 1 ic acid-N-(2-pyridyl)-N-(2/mathoxycarbonylethyl)-amide-hydrochloride and n-pejityl chloroformate. <br><br> Yield: 66 % of theori c32h37n7o5 (599.7) <br><br> Rf value: 0.58 (sil/c^ gel; dichloromethane/methanol = 9:1) EKA mass spectrum/ CM+H) + = 600 <br><br> (M+H+Na)++ = 311.7 (M+Na)+ = 622 <br><br> Example 110 <br><br> 25 1 -Methyl-2f[w- [4- (n-n-nonyloxycarbonylamidino) phenyl] -aminomethyl ]/-benzimidazol-5-yl-carboxylic acid-n- (2-pyridyl)/n-/(2-methoxycarbonylethyl) -amide <br><br> Prepared/analogously to Example 90 from l-methyl-2-[N-(4 -30 amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid/-N/ (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide-hydfro/:hloride and n-nonyl chloroformate. <br><br> Yi/etljk: 60 % of theory, <br><br> £3&amp;^45^7^5 (655.8) <br><br> 35 /Rf/value: 0.48 (silica gel; dichloromethane/methanol = 9:1) SKA mass spectrum: (M+H)+ = 656 <br><br> NOW AMENDED <br><br> - 117 <br><br> Example 111 <br><br> l-Methyl-2-[N-[4-(N-benzoylamidino) benzimidazol-5-yl-carboxylic acid-^-methoxycarbonylethyl)-amide lyl]-aminomethyl] !-pyridyl) -N- (2- <br><br> 10 <br><br> 15 <br><br> Prepared analogously to Example/9u from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benz/midazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoKycarbonylethyl)-amide-hydrochloride and benzoyl cfylo/ide Yield: 62 % of,'theory, <br><br> c33h31n7°4 (589.7) <br><br> Rf value: 0.50 (silica ge/L;/dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H/ + / = 590 <br><br> (M^a/ + = 612 <br><br> Example 112 <br><br> l-Methyl-2- [N- [4-/nTricotinoylamidino)phenyl]aminomethyl]-20 benzimidazol-5-y3.-cferboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonyletWyl)-amide <br><br> 25 <br><br> 30 <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)/aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloyide and nicotinic acid chloride. <br><br> Yield: 4u % of theory, <br><br> c32h30n/°/ (590.7) <br><br> Rf valye:/0.47 (silica gel; dichloromethane/methanol = 9:1) EKA nyasjs spectrum: (M+H)+ = 591 <br><br> (M+H+Na)++ =3 07 (M+Na)+ = 613 <br><br> NOW AMENDED <br><br> - 118 <br><br> Example 113 <br><br> l-Methyl-2 - [N- [4- (N-n-hexyloxycarbonj| aminomethyl]-benzimidazol-5-yl-carb/ pyridyl) -N- (2-ethoxycarbonylethyl)/-ag jrcnidino) phenyl] -^lic acid-N- (2-[ide <br><br> 10 <br><br> 15 <br><br> Prepared analogously to Exampley^O/from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-beireiiriidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-hexyl chyoxpiormate. <br><br> Yield: 51 % of theory, <br><br> c34h41n7°5 (627.8) Rf value: 0.53 (silica ge^ EKA mass spectrum: (M+H)/ <br><br> (M+I <br><br> lichloromethane/methanol = 9:1) = 628 l)++ = 325.7 <br><br> (M/2H)++ = 314.7 <br><br> Example 114 <br><br> 20 l-Methyl-2- [N- [4-/(N/n-octyloxycarbonylamidino) phenyl] -aminomethyl] -benc:imidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-9a:hpxycarbonylethyl) -amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4 25 amidinophenyl)/-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyEadyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate. <br><br> Yield: 5/ y of theory, <br><br> c36h45^°S( (655.8) <br><br> 3 0 Rf valifle/ 0.46 (silica gel; dichloromethane/methanol <br><br> = 9:1 ) <br><br> EKA/mafes spectrum: (M+H)+ = 656 <br><br> (M+H+Na)++ = 339.7 (M+2H)++ = 328.7 <br><br> NOW AMENDED <br><br> - 119 - / / <br><br> Example 115 / / <br><br> l-Methyl-2-[N-[4-[N-(2-methylsulphonylj ethyloxycarbonyl)amidino]-phenyl]-amiraomethyl] -5 benzimidazol-5-yl-carboxylic acid-/l-/2-pyridyl) -N-ethoxycarbonylmethyl-amide / / <br><br> Prepared analogously to Example 9/6 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzamidazol-5-yl-carboxylic 10 acid-N- (2-pyridyl) -N-ethoxycarbonylmethyl-amide- <br><br> hydrochloride and 2-(methyleu3/phonyl)-ethyl chloroformate. Yield: 72 % of theory, / / <br><br> C3oH33N707S (635.7) / / <br><br> Rf value: 0.23 (silica gjel/ dichloromethane/ethanol = 19:1) 15 EKA mass spectrum: (M+H)y = 636 <br><br> (M/HVNa)++ = 329.8 <br><br> Example 116 / J <br><br> 20 l-Methyl-2- [N- [4-7(N/cyclohexyloxycarbonylamidino) - <br><br> phenyl] aminomethyl/-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl)-N-methoxycarbonylmethyl-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-25 amidinophenyl)/-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N- (2-pyyidyl) -N-methoxycarbonylmethyl-amide-hydrochloriae and cyclohexyl chloroformate. <br><br> Yield: 4j0 y of theory, <br><br> C32H35N/70/ (597.7) <br><br> 30 Rf value/ 0.26 (silica gel; dichloromethane/ethanol = 19:1) EKA n/ase spectrum: (M+H) + = 598 / / (M+Na)+ = 620 <br><br> NOW AMENDED <br><br> - 120 - <br><br> Example 117 <br><br> l-Methyl-2- [N- [4- (N-methoxycarbonylamiftiilo) -phenyl] -aminomethyl]-benzimidazol-5-yl-carboxyl/c acid-N-(2-5 pyridyl) -N-ethoxycarbonylmethyl-amicre <br><br> 10 <br><br> 15 <br><br> Prepared analogously to Example 9&amp; fifcom 1-methyl-2- [N-(4-amidinophenyl) -aminomethyl] -benziimi/uazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonyimethyl-amide-hydrochloride and methyl chloryof^ <br><br> Yield: 62 % of theory, <br><br> C28H29N7O5 (543.6) <br><br> Rf value: 0.19 (silica gel;/ d/chloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+/ / = 544 <br><br> (M+H+^a/++ = 283.8 (M+Na)/" = 566 <br><br> Example 118 <br><br> 20 l-Methyl-2- [N- [4- (N-efthoxycarbonylamidino) -phenyl] -aminomethyl] -benzimidazo/-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylnjetjayl-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-25 amidinophenyl/) -&gt;aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyritiyl)-N-methoxycarbonylmethyl-amide-hydrochloriLder and ethyl chloroformate. <br><br> Yield: 42/% /of theory, <br><br> C28H29^7P5/(543.6) <br><br> 30 Rf valu«£:/0.20 (silica gel; dichloromethane/ethanol = 19:1) EKA mgtsq/ spectrum: (M+H) + = 544 <br><br> NOW AMENDED <br><br> - 121 - <br><br> Example 119 <br><br> l-Methyl-2- [N- [4- (N-n-octyloxycarbon^l/amidino) -phenyl] aminomethyl] -benzimidazol-5-X^l/carboxylic acid-N- (3 5 pyridyl) -N- (2-ethoxycarbonylethyl)/-amide <br><br> 10 <br><br> Prepared analogously to Example/9 0/from l-methyl-2-[N-(4-amidinophenyl) -aminomethyl] -benrzlmidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-octyl ch/oijof ormate . <br><br> Yield: 35 % of theory, <br><br> C36H45N705 (655.8) <br><br> R <br><br> EKA mass spectrum: <br><br> f value: 0.28 (silica gey <br><br> 15 <br><br> /iichloromethane/ethanol = 19:1) (M+H)/+ / = 656 tmr+ = 328.7 <br><br> Example 12 0 <br><br> l-Methyl-2- [N- [4- QST-ii-hexyloxycarbonylamidino) -phenyl] -20 N-methyl-aminometny3.] -benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N-/(2/ethoxycarbonylethyl) -amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyY) -^N-methyl-aminomethyl] -benzimidazol-5-yl-25 carboxylic aicitl-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and n-hexyl chloroformate. <br><br> Yield: 58/% /of theory, <br><br> C35H43N7^5 /(641. 2) <br><br> Rf valu^: /o .42 (silica gel; dichloromethane/ethanol = 19:1) 30 EKA m^/ss/spectrum: (M+H) + = 642 <br><br> (M+H+Na)++ = 332.7 <br><br> NOW AMENDED <br><br> - 122 - <br><br> Example 121 <br><br> l-Methyl-2-[N-[4-(N-n-octyloxycarbon^limidino)-phenyl] N-methyl-aminomethyl] -benzimidazol-,S-/l-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> 10 <br><br> Prepared analogously to Example /9Qj from l-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl) -M~K2-ethoxycarbonylethyl) amide-hydrochloride and n-oct/yl/chloroformate . <br><br> Yield: 36 % of theory, <br><br> c37h47n7o5 (669.8) EKA mass spectrum: <br><br> 15 <br><br> (M+H) +/ (M+HH <br><br> (M+ZHV <br><br> = 670 ++ = 346.8 + = 335.6 <br><br> Example 122 <br><br> l-Methyl-2- [N- [4- (ft-rf-butyloxycarbonylamidino) -phenyl] 20 N-methyl-aminomethy]:] -benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N-/(2/ethoxycarbonylethyl) -amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl/) -N-methyl-aminomethyl] -benzimidazol-5-yl-25 carboxylic acia-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and n-butyl chloroformate. <br><br> Yield: 34/% /ot theory, <br><br> C33H39N705/(613. 7) <br><br> EKA mai^s /spectrum: (M+H)+ = 614 <br><br> 30 / / (M+H+Na)++ = 318.7 <br><br> (M+Na)+ = 636 <br><br> NOW AMENDED <br><br> 123 - <br><br> Example 123 <br><br> l-Methyl-2-[N-[4-(N-benzoylamidino)pherfyl] -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl) 5 N-(2-ethoxycarbonylethyl)-amide <br><br> 10 <br><br> Prepared analogously to Example/90/from l-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) 7^-/(2-ethoxycarbonylethyl) -amide-hydrochloride and benzg/yl/chloride . <br><br> Yield: 63 % of theory, <br><br> c35h35n7o4 (617.7) <br><br> EKA mass spectrum: (M+H) <br><br> 15 <br><br> Example 124 <br><br> l-Methyl-2- [ (4-amiy&amp;ii^ophenyl) oxymethyl] -benzimidazol-5-yl-2 0 (1-ethoxycarbonylmethyl-cyclohex-l-yl)-ketone-hydrochloride <br><br> 25 <br><br> 30 <br><br> 35 <br><br> a) 4-Chlorophe ketone <br><br> 8.4 g (40 mMi dissolved i of sodium My added in Ka r\f (1-hydroxycarbonylmethyl-cvclohex-l-vl)- <br><br> )/of 3-(4-chlorobenzoyl)-propionic acid were )0 ml of tetrahydrofuran and 5.8 g (120 mMol) :ide (50-60% suspension in paraffin oil) were 'ches. Then the mixture was refluxed for 1.5 hours wi^h/stirring, after which 8.9 ml (60 mMol) of 1,5-diiodoppntfane were added dropwise and boiling was continued for a /uyther 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 wagf a/ridified with 2N hydrochloric acid and extracted three tjftnefe with 150 ml of dichloromethane. The organic phase ta.s/ dried and evaporated down, the crude product thus 'obtained was purified by column chromatography (500 g /ilica gel; eluant: dichloromethane with 1-2% ethanol). <br><br> NOW AMENDED <br><br> - 124 - / / <br><br> Yield: 6.2 g (55% of theory) of oily p/oduct, <br><br> c15h17c103 (280.8) / / <br><br> Rf value: 0.56 (silica gel; dichlorocneynane/ethanol = 19:1) <br><br> 5 b) 4-Chloro-3-nitrophenvl-(1-hydroxycarbonylmethyl-cvclohex-l-vl)-ketone j / <br><br> 7.0 g (25 mMol) of 4-chlorophenyiy(l-hydroxycarbonyl-methylcyclohex-l-yl)-ketone were Added in batches, with stirring, at -5 to -10°C, to 550 /nl of fuming nitric acid. 10 The solution was then stirrer fior a further 10 minutes, <br><br> then stirred into 200 ml of/icre-water, the precipitated product was then washed wiyth/water and dried. <br><br> Yield: 7.8 g (96% of theory/, <br><br> c15h16c1no5 (325.8) / / <br><br> 15 Rf value: 0.41 (silicayye/; petroleum ether/ethyl acetate <br><br> 4:6) / / <br><br> c) 4-Methvlamino-3-nitoxophenvl-(1-hydroxycarbonylmethyl-cvclohex-l-yl) -ketone; <br><br> 20 7.8 g ( 23.9 mMol/ di 4-chloro-3-nitrophenyl-(1- <br><br> hydroxycarbonylmetMyl-cyclohex-l-yl)-ketone were stirred in 100 ml of a 40y agueous methylamine solution at room temperature for ±4 hours, then diluted with about 150 ml of water and made yslightly acidic with glacial acetic acid. 25 The precipitiatyed product was suction filtered, washed with water and cfried. <br><br> Yield: 7.j g/(93% of theory), <br><br> Ci6H20N2y5 7(320.4) <br><br> Rf valuer: ^.34 (silica gel; dichloromethane/ethanol = 19:1) <br><br> 30 / / <br><br> d) 4 -Meehvlamino-3-nitrophenvl-(1-methoxvcarbonylmethvl- <br><br> cvcLoh^x-l-vl) -ketone <br><br> 4.9/ gJ(15 mMol) of 4-methylamino-3-nitrophenyl-(l-hyarpxycarbonylmethyl-cyclohex-1-yl)-ketone were dissolved <br><br> 35 i/n /00 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 <br><br> NOW AMENDED <br><br> - 125 <br><br> off, 3 0 ml of methanol were added and boiled for three hours with stirring, had been distilled off the crude prodfuc mixture was iter the methanol thus obtained was purified by column chromatography (2!5(J g silica gel, <br><br> eluant: dichloromethane with 1 to Yield: 2.4 g (48% of theory), *-•17^22^2^5 (334.4) <br><br> /ethanol) . <br><br> Rf value <br><br> 0.76 (silica gel; dicnlafromethane/ethanol = 19:1) <br><br> 10 <br><br> 15 <br><br> 20 <br><br> 25 <br><br> 30 <br><br> e) 3 -Amino-4 -methvlaminophenyl-/(l-methoxvcarbonvlmethvl-cvclohex-l-vl)-ketone <br><br> 2.4 g (7.2 mMol) of 4-methyia/nino-3-nitrophenyl-time thoxycarbonylme thyl-cyc/ottex-l-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. <br><br> Yield: 2.1 g (96% ofJtlieory) , <br><br> Rf value: 0.34 (sil/c^r gel; dichloromethane/ethanol = 19:1) <br><br> f) 3- (4-Cvanophei (1-methoxvcarboi axvacetvlamino)-4-methylaminophenvl-lethvl-cvclohex-l-vl)-ketone <br><br> 620 mg (3.5 mMal)/of 4-cyanophenyloxyacetic acid and 570 mg (3.5 mMol) of/l, A 1-carbonyl-diimidazole were refluxed in 50 ml of tetrahydrofuran for 15 minutes. Then 1.0 g (3.28 mMol) of 3-amimo-4-methylaminophenyl-(1-methoxycarbonylmethyl-cyclonex-l-yl) -ketone were added and the mixture was boiled for a further 4 hours. Then the solvent was evaporated/off and the crude product thus obtained was purifieA toy column chromatography (150 g silica gel; <br><br> eluant/ #ichloromethane with 0 to 2% ethanol) . <br><br> Yield/: X-4 g (93% of theory), <br><br> c26^29^3°5 (463.5) <br><br> Rf/ra/ue: 0.44 (silica gel; dichloromethane/ethanol = 19:1) <br><br> 35 <br><br> NOW AMENDED <br><br> - 126 - <br><br> 10 <br><br> 15 <br><br> 20 <br><br> 25 <br><br> g) l-Methvl-2 - f (4-cvanophenvl) oxvmethvll -&gt;penzimidazol-5-vl- <br><br> (1-methoxvcarbonvlmethvl-cvclohex-1-vx) -Ketone <br><br> 1.4 g (3.02 mMol) of 3 - (4-cyanopheny/owacetylamino) -4 -methylaminophenyl-(1-methoxycarbony/methyl-cyclohex-l-yl)-ketone were refluxed in 50 ml of g/aorial acetic acid for one hour. Then the glacial acetic acid was distilled off, the residue was mixed with 20 ml/oj 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: dichloronvethane with 0 to 2% ethanol) . Yield: 700 mg (52% of thegor^ <br><br> c26h27n3°4 (445.5) <br><br> h) l-Methvl-2- F (4-amid/n' vl - (1-ethoxvcarbonvlmi* <br><br> phenyl)oxvmethvll-benzimidazol-5-t#vl-cvclohex-1-vl)-ketone- <br><br> analogousl hydrochloride Prepared of l-methyl-2-(4-(1 - me t hoxyc arbon^lmj ethanolic hydro Yield: 390 mg o Example 25d from 700 mg (1.57 mMol) aiiophenyloxymethyl) -benzimidazol-5-yl- <br><br> thyl-cyclohex-l-yl)-ketone with ric acid and ammonium carbonate. of theory), <br><br> C27H32N4O4 (4Y6./6) <br><br> EKA mass specti/um: (M+H) + = 477 <br><br> 1H-NMR speccrrfm (dg-DMSO): 1.10 (t,3H); 1.0-2.15 (m,10H); <br><br> 3.36 (s,3 HO;/3.90 (s,2H); 3.94 (q,2H); 5.60 (s,2H); 7 . 25-7 . 4c/ Wh,3H); 7.56-7.75 (m,2H); 7.90 (d, 2H) ; 9.20 (broad 9, 4fil) ppm. <br><br> NOW AMENDED <br><br> - 127 - / / <br><br> Example 125 / / <br><br> l-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-tert.butyl-ketone-hydrochloride / <br><br> 5 / / <br><br> Prepared analogously to Example 2:5d/from l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benziraidazol-5-yl-tert.butyl-ketone, ethanolic hydrochloric/aoad, ethanol and ammonium carbonate. / / <br><br> 10 Yield: 59 % of theory, / / <br><br> C21H25N5O (363:5) / / <br><br> EKA mass spectrum: (M+H)+ = B64 Example 12 6 / / <br><br> 15 / / <br><br> l-Methyl-2- [N- (4-amidicngphenyl) -aminomethyl] -benzimidazol-5-yl- (l-methylcyclopent/-l-yl) -ketone-hydrochloride <br><br> Prepared analogously/to Example 25d from l-methyl-2-[N-(4-20 cyanophenyl) -aminpmssthyl] -benzimidazol-5-yl- (1- <br><br> methylcyclopent-i-yl)-ketone, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 63.5 % &gt;of/theory, <br><br> C23H27N5O (3 &amp;0./) <br><br> 25 EKA mass spectrum: (M+H)+ = 390 <br><br> NOW AMENDED <br><br> - 128 - / / <br><br> Example 12 7 / / <br><br> 2-[(4-amidinophenyl)sulphinylmethyl]ytenzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-5 hydrochloride / / <br><br> A solution of 0.15 g (0.27 mMol)/o£ 2-[(4-amidinophenyl)thiomethyl]-benzoch/azol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbony/ethyl) -amide-hydrochloride 10 in 10 ml of acetic acid was max^d with 0.09 ml (about 0.81 mMol) of 30% hydrogen peroxi/a^solution and stirred at room temperature. After 4 days/a further 0.18 ml of hydrogen peroxide solution was addesd And the resulting mixture was stirred for a further tw© dfays. After removal of the 15 solvent in vacuo the crude product obtained was purified by flash chromatography Osi/ica gel; methylene chloride/ethanol = loAl/to 4:1). <br><br> Yield: 58 % of theory,/ <br><br> C27H26N4O4S2 (534 .jsj 20 Rf value: 0.24 (silica gel; methylene chloride/ethanol f- a few drops of acetic acid) <br><br> EKA mass specyrujri: (M+H)+ = 535 <br><br> 25 Example 12 8 / / <br><br> 1 -Methyl-T- /(4-amidinophenyl)sulphonylmethyl] -benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarraonylethyl)-amide-hydrochloride <br><br> 3 0 / / <br><br> A soLut/on of 0.40 g (0.70 mMol) of l-methyl-2-[(4-amidanpphenyl) thiomethyl] -benzimidazol-5-yl-carboxylic aci/u-N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride in 10 ml of formic acid was mixed with 2 ml 3 5 of /3 0% hydrogen peroxide solution and the mixture was <br><br> /starred for 16 hours at room temperature. Then the solvent / Was distilled off in vacuo, whereupon the desired compound <br><br> NOW AMENDED <br><br> 129 - <br><br> 10 <br><br> was obtained as a beige solid (contaminated with some l-methyl-2-[(4-amidinophenyl)sulfinyWne/hyl]-benzimidazol -5-yl-carboxylic acid-N-(n-propyl)-Ny(2/ ethoxycarbonylethyl)-amide-hydrochyor/de). <br><br> Yield: 95 %'of theory, <br><br> c25h31n6°5s (513.62) <br><br> Rf value: 0.50 (silica gel; eth^lyfecetate/ethanol/lN hydrochloric acid <br><br> = 50:45:5) <br><br> EKA mass spectrum: (M+H) + =/51/ <br><br> Example 12 9 <br><br> 2-[N-(4-amidinophenyl)-^mVnomethyl]-thiazolo[5,4-b]pyridin-15 6-yl-carboxylic acid-N/pl/enyl-N-(2-ethoxycarbonylethyl) -amide-hydrochloride a) Methyl 5-amino-6/-ctlloro-nicotinate <br><br> A solution of 1.0&amp; g/ (5.00 mMol) of methyl 6-chloro-5-20 nitro-nicotinate /(see A.H. Berrie, G.T. Newbold, F.S. <br><br> Spring in J. Ch^m./Soc., 2590, 1951) in 25 ml of absolute ethanol was mi^ecV successively with 0.53 ml (29 mMol) of water, 3.2 g 151/ mMol) of iron powder and 0.030 ml of concentrated/hydrochloric acid and heated to boiling for 25 one hour. Tjaei/ equal quantities of water, iron powder and hydrochlor/c/acid were added and the mixture was heated to boiling fy6r/30 minutes. The precipitate formed on cooling was tilt/fered off and washed with ethanol and the solvent was dig^i/led off in vacuo. <br><br> 30 Yield/ 0/. 75 g (81% of theory) of greenish-yellow solid, <br><br> Rf va/Lufi: 0.31 (silica gel;ethyl acetate/petroleum ether = <br><br> 35 <br><br> LN202 (186.60) <br><br> Mass spectrum: M+ = 186 and 188 (chlorine isotopes) <br><br> AMENDED <br><br> - 130 <br><br> 10 <br><br> b) Methyl 6 -chloro- 5 - me thoxvacetamido/no/cot inate A solution of 0.75 g (4.02 mMol) of metinyl 5-amino-6-chloro-nicotinate and 0.43 g = 0.35/m]/ (4.5 mMol) of methoxyacetylchloride in 2 0 ml of chlorobenzene was stirred for one hour at 110°C. After th^solvent had been removed in vacuo the crude product obtained was purified by flash chromatography (silica gel; methylene chloride/ethanol = 100:1) , evaporated down again/iiy vacuo and then digested with petroleum ether. <br><br> Yield: 0.55 g (53% of theor/) /light yellow amorphous solid, Rf value: 0.33 (silica gel/ e/chyl acetate/petroleum ether = 1:4) <br><br> 15 <br><br> 20 <br><br> 25 <br><br> c) Methyl 2-methoxymetl carboxvlate <br><br> rl/thiazolo T5 . 4 -bl pyridin-6-vl- <br><br> A mixture of 0.53 g methoxyacetamido-ni Lawessons reagent xylene. After th&lt; <br><br> crude product ob (silica gel; me/h; evaporated dow. <br><br> Yield: 0.33 g/ ( <br><br> 5 mMol) of methyl 6-chloro-5-/otAnate and 0.42 g (1.0 mMol) of refluxed for 16 hours in 25 ml of S/Olvent had been removed in vacuo the ed was purified by flash chromatography ene chloride/ethanol = 100:1) and in vacuo. <br><br> gain <br><br> Rf value <br><br> 7% of theory) of yellow amorphous solid, 0.82/(silica gel; ethyl acetate/petroleum ether = <br><br> 1:4) <br><br> d) 2-Metl/offinriethyl-thiazolo T5 . 4-bl pvridin-6-vl-carboxvlic acid <br><br> 30 A mixture/ of 1.1 g (4.62 mMol) of methyl 2-methoxymethyl-thiaz0lc/[5 , 4-b] pyridine-6-carboxylate and 9.2 ml of 2N sodiidm/hydroxide solution were stirred into 50 ml of eth,an&lt;/l for one hour at room temperature. Then 9.2 ml of 'hydrochloric acid were added, the alcohol was distilled 35 °/^f/ an&lt;^ it was diluted with 20 ml of water. The aqueous )hase was acidified with concentrated hydrochloric acid <br><br> NOW AMENDED <br><br> - 131 - / / <br><br> whilst cooling with ice, the beige precipitate formed was filtered off, then washed with water knd. dried. <br><br> Yield: 1.03 g (100% of theory), / j <br><br> Rf value: 0.10 (silica gel; ethyl a^eyate/petroleum ether = <br><br> 5 3:7) // <br><br> e) 2-Methoxymethyl-thiazolo f5.4 Volpyridin-6-vl-carboxvlic acid-N-phenvl-N- (2-ethoxvcarbonjvLethvl) - amide <br><br> A suspension of 1.03 g (4.62 vmoL) of 2-methoxymethyl-10 thiazolo [5 , 4-b] pyridin-6-yl-afarooxylic acid in 40 ml of methylene chloride was mixed with 1.6 g = 1.0 ml (13.5 mMol) of thionyl chloride d.n&amp; refluxed for 90 minutes, during which time the sol/dGradually dissolved. After the liquid components had be«en /iistilled off the crude product 15 was taken up twice more/in methylene chloride and concentrated again. Tne/resulting crude acid chloride (1.2 g) was taken up /n/4 0 ml of tetrahydrofuran, added dropwise to a mixtur/e ©f 0.94 g (4.86 mMol) of N- (2-ethoxycarbonylethyl) aniline/and 2.1 ml (13.8 mMol) of 2 0 triethylamine in 3\p ml of tetrahydrofuran and stirred for 2 hours at room temperature. Then it was diluted with 2 00 ml of ethyl acetate', washed with 100 ml of 14% saline solution and the organic' phase was dried with sodium sulphate. <br><br> After the solvent had been removed in vacuo the crude <br><br> 25 product obta/nea was purified by flash chromatography (silica gel/ methylene chloride/ethanol = 100:1). <br><br> Yield: 1.5/ q (87% of theory)of yellow oil, <br><br> Rf value: fa ,E5 (silica gel; methylene chloride/ethanol = 19:1) / / <br><br> 30 / / <br><br> f) 2-fN-lA-Cvanophenvl)-aminomethvll -thiazoloT5.4-bl -pvridan/6-vl-carboxylic acid-N-phenvl-N-(2-ethOKyearbonvlethvl)-amide <br><br> 35 <br><br> NOW AMENDED <br><br> - 132 - / / <br><br> was dissolved in a further 3 0 ml of methylene chloride and stirred for 5 hours at room temperature./ Then the mixture was washed with 40 ml of saturated soainm hydrogen carbonate solution, the organic phase ywas dried with sodium 5 sulphate and the solvent was distil/lea off. The crude product (1.9 g) was taken up in 1 fml of N,N-diisopropyl-ethylamine, mixed with 0.50 g (4/2/nMol) of 4-aminobenzonitrile and heated tofoiling for one hour. <br><br> Then the solvent was distilled/o/f in vacuo, the crude <br><br> 10 product was taken up in 100 iyi of methylene chloride, the organic phase was washed wiftn 2.00 ml of water and dried with sodium sulphate. Afterr yche solvent had been removed in vacuo the crude productz obtained was purified by flash chromatography (silica gyel / ethyl acetate/petroleum ether = 15 35:65 to 1:1) and evaporat/ed down again in vacuo. <br><br> Yield: 0.45 g (24% of theory) of yellow amorphous solid, Rf value: 0.34 (silica, gel; ethyl acetate/petroleum ether = <br><br> 1:1) f <br><br> 20 g) 2-TN- (4-amidin(/phenvl) -aminomethvll -thiazoloT5,4-bl -pyridin-6-vl-carteoffvlic acid-N-phenvl-N-(2-ethoxvcarbonvlefchyl)-amide-hydrochloride <br><br> 0.3 9 g (0.803 mMol) of 2- [N- (4-cyanophenyl) -aminomethyl] -thiazolo [5,4-y£&gt;] pyridin-6-yl-carboxylic acid-N-phenyl-N- (2-25 ethoxycarbonylfethyl)-amide were stirred in 40 ml of ethanol saturated yitli hydrogen chloride for 5 hours first at 0°C and then art room temperature, until no more starting material/could be detected by thin layer chromatography. Then thd solvent was distilled off at a maximum bath 30 temper^tufre of 30°C, the oily residue was taken up in 40 ml of abso2mte ethanol and mixed with 0.5 g ammonium carbonate. After 18 hours the solvent was removed in vacuo an&lt;y tne crude product obtained was purified by flash chromatography (silica gel; methylene chloride/ethanol = 35 ?:yto 4:1). <br><br> /Yield: 78 % of theory of yellow foam, <br><br> NOW AMENDED <br><br> - 133 - <br><br> c26h26N603S (502.60) <br><br> Rf value: 0.19 (silica gel; methylen^chloride/ethanol <br><br> = 4:1 <br><br> + a few drops of ac^t^c acid) <br><br> 5 EKA mass spectrum: (M+H)+ = 503 <br><br> Example 13 0 <br><br> l-Methyl-2- [ (4-amidinophenyl)/friey6hylthio] -benzimidazol-5-yl-10 carboxylic acid-N-phenyl-N-y2-ethoxycarbonylethyl)-amide-hydrochloride a) 1-Methyl-2-mercapto-banzamidazol-5-vl-carboxylic acid-N-phenvl-N- (2-ethoxvcarbomv3/ethvl) -amide 15 A solution of 6.5 g iplol) of 3-amino-4-methylamino- <br><br> benzoic acid-N-phenyl/N-/(2-ethoxycarbonylethyl)-amide and 4.5 g (22.8 mMol) of/N/N1-thiocarbonyldiimidazole were dissolved in 100 ml/of tetrahydrofuran under a nitrogen atmsphere, the solution was heated to 90°C for 4 hours and 20 left to stand iox/1p hours at room temperature. After removal of the qolyent in vacuo the crude product obtained was purified bV filash chromatography (silica gel; petroleum ether/ethyl aaJerate = 100:0 to 65:35). <br><br> Yield: 6.8 g/(9tt % of theory) of beige crystalline solid, 25 Rf value: 0y65/ (silica gel; ethyl acetate) <br><br> b) l-Methyl/2-T(4-cvanophenvl)methvlthiol -benzimidazol-5-vl-carboKv/ic acid-N-phenvl-N-(2-ethoxycarbonylethyl)-amide A solut/om of 1.30 g (3.4 mMol) of l-methyl-2-mercapto-30 benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2- <br><br> etho^ycarbonylethyl)-amide, 0.52 g (3.74 mMol) of potassium carbton&amp;te and 0.66 g (3.4 mMol) of 4-bromo-met/ny/Lbenzonitrile were dissolved in 40 ml of absolute et/na^ol, stirred for 4 hours at 60°C and 16 hours at room 35 t/enyfoerature. Then the solvent was distilled off in vacuo, <br><br> {e crude product was taken up in 30 ml of methylene lloride, washed with 4 0 ml of water and dried with sodium <br><br> NOW AMENDED <br><br> - 134 - <br><br> sulphate. After filtration and distill4t/on of the solvent the desired compound was obtained as a/ b/ige-white solid. Yield: 1.8 g (100 % of theory), <br><br> Rf value: 0.64 (silica gel; ethyl acy^tafte) <br><br> 5 / / <br><br> c) l-Methvl-2- T (4-amidinophenyl) mefth/vlthiol -benzimidazol-5-yl-carboxylic acid-N-phenvl-N- (2Vet/hoxvcarbonvlethvl) -amide-hydrochloride <br><br> 1.5 g (3.0 mMol) of l-methyl-2/[ (^4-cyanophenyl) methylthio] 10 benzimidazol-5-yl-carboxylic acia-N-phenyl-N-(2- <br><br> ethoxycarbonylethyl)-amide were stirred in 80 ml of ethanol saturated with hydrogen chlyor/de for 6.5 hours first at 0°C, then at room temperature, until no more starting material could be detected Joy thin layer chromatography. 15 Then the solvent was digti/led off at a maximum bath temperature of 30°C, th&amp; ©ily residue taken up in 80 ml of absolute ethanol and mixed with 1.0 g (10.5 mMol) of ammonium carbonate. /A^ter 18 hours the solvent was distilled off in va£uc/ and the crude product obtained was <br><br> 20 purified by flash y6h^omatography (silica gel; methylene chloride/ethanol / 3:9:1 to 10:1) . <br><br> Yield: 78 % of t/ne©ry of light beige solid, <br><br> C28H29N5°3S (52^.p3) <br><br> Rf value: 0.19/ (^ilica gel; methylene chloride/ethanol = 25 4:1) <br><br> EKA mass sp^c0rum: (M+H)+ = 516 <br><br> (M+H+Na)++ = 269.7 (M+2H)++ = 258.7 <br><br> 30 Example <br><br> 35 <br><br> l-Met/hvl-2- [ (4-amidinophenyl) methylthio] -benzimidazol-5-yl-carJj5o&gt;?ylic acid-N-phenyl-N- (2-hydroxycarbonylethyl) -amide-hydrc/chloride <br><br> NOW AMENDED <br><br> - 135 - <br><br> 10 <br><br> Prepared analogously to Example 10 frotd 2/-methyl-2-[ (4-amidinophenyl)methylthio]-benzimidazoZ-y-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl/-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 57 % of theory, <br><br> C26H25N5°3S (487.58) <br><br> Rf value: 0.23 (Reversed Phase s/l/ca gel RP-8; Methanol/5' <br><br> saline solution =y6:4) <br><br> EKA mass spectrum: (M+H) + /= /488 <br><br> (M+Na)+ / 4 510 (M+Na+H)/+/= 255.6 <br><br> Example 132 <br><br> 15 l-Methyl-2-[N-(4-amidirtbn&amp;enyl)-aminomethyl] -benzimidazol-5-yl-carboxylic acid-Nr-j^ropargyl-N- (2-ethoxycarbonylethyl) amide-hydrochloride <br><br> 20 <br><br> 25 <br><br> Prepared analogously k.o Example 25d from l-methyl-2- [N- (4-cyanophenyl)-amin/methyl]-benzimidazol-5-yl-carboxylic acid-N-propargyl/Ny(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid/ ethanol and ammonium carbonate. <br><br> Yield: 81 % of/tbfeory, <br><br> C25H28n6°3 (4/0/6) <br><br> 0.094/ (silica gel; dichloromethane/ethanol = 4:1) EKA mass st/ecjfcrum: (M+H)+ = 461 <br><br> (M+H+Na)++ = 242 (M+2H)++ = 231 <br><br> Rf value <br><br> 3 0 Example y3 3 <br><br> 35 <br><br> l-Meyfch/1-2- [2- [4- (N-n- <br><br> hes^l^xycarbonylamidino)phenyl]ethyl]-benzimidazol-5-yl-catb^xylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) • ;i&lt;ae <br><br> NOW AMENDED <br><br> 10 <br><br> - 136 - <br><br> Prepared analogously to Example 90 fron/ l/methyl-2-[2-(4 amidinophenyl) ethyl] -benzimidazol-5-yl/-carboxylic acid-N-(2-pyridyl) -N- (2-ethoxycarbonylethyl)/-^mide-hydrochloride and n-hexyl chloroformate. <br><br> Yield: 72 % of theory, <br><br> C35H42N6°5 (626.8) <br><br> Rf value: 0.54 (silica gel; dich^oiy6methane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 6; <br><br> (M+Na) + = ^4! <br><br> Example 134 <br><br> 15 <br><br> l-Methyl-2- [2- [4- (N-benzoylc benzimidazol-5-yl-carboxyl: ethoxycarbonylethyl) -am4-d§ <br><br> lidino) phenyl] ethyl] -acid-N-(2-pyridyl)-N-(2- <br><br> Prepared analogously £o/Example 90 from l-methyl-2-[2-(4-amidinophenyl) ethyl]/-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl) -N- (2-et^ioycycarbonylethyl) -amide-hydrochloride 20 and benzoyl chlorj <br><br> Yield: 79 % of theory, <br><br> c35h34n6°4 (602 Jl), <br><br> Rf value: 0.52/(s/lica gel; dichloromethane/methanol = 9:1] EKA mass spec/:ry(m: (M+H)+ = 603 25 / / (M+Na)+ = 625 <br><br> Example 1^5 <br><br> 1-Methy f-2J- [2- [4- (N-nicotinoylamidino) phenyl] ethyl] -30 benzim?da/zol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-etnoxy-cgfrbonylethyl) -amide <br><br> 35 <br><br> red analogously to Example 90 from l-methyl-2-[2-(4-amid/nophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(/2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride nicotinic acid chloride. <br><br> NOW AMENDED <br><br> - 137 - <br><br> Yield: 56 % of theory, <br><br> C34h33n7°4 (603.7) <br><br> Rf value: 0.52 (silica gel; dichloro/\e/hane/methanol EKA mass spectrum: (M+H)+ = 604 <br><br> (M+Na)+ = 626 <br><br> = 9:1) <br><br> Example 136 <br><br> 10 l-Cyclopropyl-2-[N-(4-amidi: benzimidazol- 5-yl-carboxyl: ethoxycarbonylethyl)-amide lenyl)-aminomethyl] icid-N-phenyl-N-(2-/■drochloride <br><br> Prepared analogously to/Example 25d from l-Cyclopropyl-2-15 [N- (4-cyanophenyl) - ami norafe thyl] -benzimidazol-5-yl- <br><br> carboxylic acid-N-pheny¥-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric/acid, ethanol and ammonium carbonate. <br><br> Yield: 31 % of thq6r2 20 C3oH33N603 (524 <br><br> Rf value: 0.40 Csi/ica gel; dichloromethane/methanol = 5:1) <br><br> 25 <br><br> EKA mass spectrun <br><br> (M+H)+ (M+H+Na) (M+2H) <br><br> = 525 <br><br> ++ . <br><br> ++ <br><br> = 274 <br><br> = 263 <br><br> Example II <br><br> 30 <br><br> l-Cyclopropyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzim/dgrcol-5-yl-carboxylic acid-N-phenyl-N- (2-hydro^yt/arbonylethyl) -amide <br><br> 35 <br><br> NOW AMENDED <br><br> - 138 - <br><br> C28H28N603 (496.6) <br><br> EKA mass spectrum: (M+H)+ = 497 <br><br> (M+H+Na)++ = 260 (M+Na) + =51 5 (M+2Na)++ = 2 <br><br> NOW AMENDED <br><br> - 139 - <br><br> Example 13 8 <br><br> l-Methyl-2- [N-(4-amidinophenyl)-N-(nVbutyl)-aminomethyl] benzimidazol-5-yl-carboxylic acid-N/phenyl-N-(2 5 ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example i5d from l-methyl-2-[N- (4-cyanophenyl) -N- (n-butyl) -aminorryetayl] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-etMoxycarbonylethyl) -amide, 10 ethanolic hydrochloric acid, yetjaanol and ammonium carbonate. <br><br> Yield: 62 % of theory, <br><br> C32H38N6O3 (554.7) <br><br> EKA mass spectrum: (M+H)/ / = 555 15 (M+H4-Ni)++ = 289 <br><br> (MH^H/++ = 278 <br><br> Example 13 9 <br><br> 20 l-Methyl-2- [N- (4-afmydino-2-chloro-phenyl) -aminomethyl] -benzimidazol-5-yI-aarboxylic acid-N-phenyl-N-(2-ethoxycarbonylerhyl)-amide-hydrochloride <br><br> 25 <br><br> 30 <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4 • cyano-2-chl9ro/phenyl)-aminomethyl]-benzimidazol-5-yl- <br><br> c/d-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, rochloric acid, ethanol and ammonium carboxylic ethanolic carbonat Yield: <br><br> C28H29 <br><br> EKA rtv&amp;sg spectrum: <br><br> of theory, (533.1) <br><br> (M+H)+ = 533/5 <br><br> (M+H+Na)++ = 278/9 <br><br> NOW AMENDED <br><br> - 140 - <br><br> Example 140 <br><br> l-Methyl-2-[N-[4-(n-octyloxycarbonyLam/dino)phenyl] -aminomethyl] -benzimidazol-5-yl-cari^oxyiic acid-N-phenyl-N-5 (2-ethoxycarbonylethyl)-amide <br><br> Prepared analogously to Examplepojfrom l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-beiVz imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyiethyl)-amide-hydrochloride 10 and n-octyl chloroformate Yield: 34 % of theory, <br><br> (-3 7^46^6(-)5 (654.8) <br><br> Rf value: 0.15 (silica ge EKA mass spectrum: (M+H) <br><br> 15 (M+: <br><br> (M-i/r=,/+ <br><br> ichloromethane/ethanol = 19:1) = 655 )++ = 339 = 677 <br><br> Example 141 <br><br> 20 l-Methyl-2 - [N- (4-^mi/dino-2-ethyl-phenyl) -aminomethyl] -benzimidazol-5-y/-aarboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4- <br><br> 25 cyano-2-e carboxylic ethanolic carbonat Yield: 01 30 C30H34u6 <br><br> EKA m^ss spectrum: <br><br> -phenyl)-aminomethyl]-benzimidazol-5-yl-cid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, yarochloric acid, ethanol and ammonium of theory (526.6) <br><br> (M+H)+ = 527 <br><br> (M+H+Na)++ = 275 (M+2H)++ = 264 <br><br> NOW AMENDED <br><br> - 141 - / / <br><br> Example 142 / / <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminromethyl]-benzimidazol-5-yl-carboxylic acid-benzylamide-hydrochloride <br><br> 5 / / <br><br> Prepared analogously to Example Z5d? from l-methyl-2-[N- (4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-benzylamide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. / / <br><br> 10 Yield: 63 % of theory, / / <br><br> C24H24N6O (412,5) / / <br><br> Rf value: 0.76 (silica gel/ aichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)f d 413 <br><br> 15 Example 143 / / <br><br> l-Methyl-2- [N- [4- (N-/2/(2-ethoxyethoxy) ethyloxy) -carbonylamidino)-phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-/(2/pyridyl) -N- (2-ethoxycarbonylethyl) -2 0 amide / / <br><br> Prepared analogbucly to Example 90 from l-methyl-2-[N-(4-amidinophenyl)/-aminomethyl ] -benzimidazol - 5 -yl - carboxyl ic acid-N-(2-pyyicwl)-N-(2-ethoxycarbonylethyl)-amide-25 hydrochloride /and diethyleneglycolmonoethylether chloroformate. <br><br> Yield: 43/% /of theory, <br><br> ^■34^41^7^7 /(659 . 8) <br><br> Rf value: /o.56 (silica gel; dichloromethane/methanol = 9:1) 30 EKA mass/spectrum: (M+H)+ = 660 <br><br> / / (M+H+Na)++ = 341.7 <br><br> NOW AMENDED <br><br> - 142 - <br><br> Example 144 <br><br> l-Methyl-2- [N- (4-amidinophenyl) -aminc^me'thyl] -benzimidazol-5-yl-carboxylic acid-N-(l-methylpyrazdl-4-yl)-N-(2-5 ethoxycarbonylethyl)-amide-hydrochloride <br><br> 10 <br><br> 15 <br><br> Prepared analogously to Example /£5d from l-methyl-2-[N-(4 cyanophenyl) -aminomethyl] -benzimiaazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycayrbonylethyl) -amide, ethanolic hydrochloric acid, ^tjianol and ammonium carbonate. <br><br> Yield: 60 % of theory, C26H30N8O3 (502.6) Rf value: 0.13 (silica EKA mass spectrum: (M+I <br><br> (Mh dichloromethane/ethanol = 4:1) = 503 [+/Ta) ++ = 263 :)++ = 252 <br><br> 20 <br><br> Example 145 <br><br> 3-Methyl-2-[(4 pyridin-6-yl-c; ethoxycarbony! <br><br> n^linophenyl) - thiomethyl] - imidazo [4, 5-b] :b&lt;6xylic acid-N-phenyl-N-(2-itjiyl) -amide-hydrochloride <br><br> 25 Prepared analogously to Example 1 from 3-methyl-2-[(4-cyanophenyl/) thiomethyl] - imidazo [4, 5-b] pyridin-6-yl-carboxylicf acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide, ethanoliq! hydrochloric acid, ethanol and ammonium carbonate J 30 Yield:/88/ % of theory, <br><br> C27H2^N^3S (516.63) <br><br> Rf valuA: 0.23 (silica gel; ethyl acetate/ethanol/ammonia <br><br> 50:45:5) <br><br> EI$A /hass spectrum: (M+H) + = 517 <br><br> 35 / / (M+H+Na)++ = 270 <br><br> NOW AMENDED <br><br> - 143 - <br><br> Example 14 6 / / <br><br> 3-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-5 imidazo[4,5-b]pyridin-6-yl-carboxy/ia acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example/1/from 3-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-imidazo[4,5-b]pyridin-6-yl-10 carboxylic acid-N-phenyl-N-(2Amethoxycarbonylethyl)-amide, ethanolic hydrochloric acid,/ ethanol and ammonium carbonate. / / <br><br> Yield: 82 % of theory, / / <br><br> C27H29N7O3 (499.58) / / <br><br> 15 Rf value: 0.20 (silica QeU; ethyl acetate/ethanol/ammonia = <br><br> 50:45:s/ / <br><br> EKA mass spectrum: (M+H/ + = 500 <br><br> /M+H+Na)++ = 261.7 <br><br> 20 Example 147 / J <br><br> 3-Methyl-2- [ (4-iim/dinophenyl) - thiomethyl] - <br><br> imidazo[4,5-bLpyridin-6-yl-carboxylic acid-N-phenyl-N- <br><br> (2-hydroxyca:doonylethyl) -amide-hydrochloride <br><br> 25 / / <br><br> Prepared analogously to Example 2 from 3-methyl-2-[(4-amidinophaurwl) -thiomethyl] -imidazo[4,5-b]pyridin-6-yl-carboxylic Acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydro ch/omde and sodium hydroxide solution. 30 Yield:/% of theory, <br><br> C25E2A®/°3S (488.56) <br><br> Rf vaLLue: 0.21 (silica gel; ethyl acetate/ethanol/ammonia = <br><br> / / 50:45:5) <br><br> EKA /mass spectrum: (M+H)+ = 489 35 / / (M+Na)+ = 511 <br><br> NOW AMENDED <br><br> - 144 <br><br> Example 14 8 <br><br> 3-Methyl-2-[N-(4-amidinophenyl)-am imidazo[4,5-b]pyridin-6-yl-carbox (2-hydroxycarbonylethyl) -amide-hVdr&gt; <br><br> o/nethyl] -ijC acid-N-phenyl-N-chloride <br><br> 10 <br><br> 15 <br><br> 20 <br><br> from 3-methyl-2-[N-(4-licj&amp;zo [4 , 5-b] pyridin-6-yl-:hoxycarbonylethyl)-amide-:ide solution. <br><br> Prepared analogously to Example amidinophenyl)-aminomethyl]-ir carboxylic acid-N-phenyl-N-(j hydrochloride and sodium hy^ <br><br> Yield: 80 % of theory, <br><br> C25H25N7°3 (471.52) <br><br> Rf value: 0.19 (silica gfil/ ethyl acetate/ethanol/ammonia = <br><br> 50:45:5)/ <br><br> eka mass spectrum: (mVh)/*" = 472 <br><br> (M+Na) + =4 94 <br><br> ++ _ <br><br> = 258.6 <br><br> Example 14 9 <br><br> l-Methyl-2 - [N- 0^4-Amidinophenyl) -aminomethyl] - benz imidazol-5-yl-sulphonicr acid-N-phenyl-N-(2-ethoxycarbonylethyl)-25 amide-hydrochloride a) 1-Methyl-^fN-(4-cvanophenvl)-aminomethvll -benzimidazol-5-vl-sulpftoi/ic acid-N-phenvl-N- (2-ethoxycarbonylethyl) <br><br> amide <br><br> 30 2.54 g /6/2 mMol) of 3-nitro-4-methylamino-benzenesulphonic acid-N/pMenyl-N-(2-ethoxycarbonylethyl)-amide were hydrc^ejaated at room temperature under 5 bar hydrogen sufe over palladium/charcoal (10%) in a mixture of 75 /nl/of ethanol and 75 ml of dichloromethane. The 35 r^su/ting crude 3-amino-4-methylamino-benzenesulphonic yci/l-N-phenyl-N- (2-ethoxycarbonylethyl) -amide was taken up /in/30 ml of phosphorus oxychloride, without purification, <br><br> NOW AMENDED <br><br> - 145 - j then 1.1 g (6,2 mMol) of N-(4-cyanophenyl/-glycine were added and the mixture was refluxed foy two hours. After cooling to room temperature the reacferion mixture was added to about 70 ml of water with cooling and in this way the 5 excess phosphorus oxychloride was destroyed. The resulting solution was neutralised with sol/d/sodium carbonate and extracted three times with 3 0 ml/o/ ethyl acetate. After evaporation of the solvent the ycri/de product was purified by column chromatography (100 « ssilica gel; eluant: 10 cyclohexane/ethyl acetate = 2/: 3J . <br><br> Yield: 860 mg (26.8 % of therory), <br><br> Melting point: 188-191°C / / <br><br> C27H27N5O3S (517.6) j j <br><br> Rf value: 0.52 (silica gorl;/dichloromethane/methanol = 9:1) 15 EKA mass spectrum: (M+HO+/ = 518 <br><br> (MVNa/5 + = 540 <br><br> b) l-Methvl-2- fN- (4/artidinophenvl) -aminomethvll -benzimidazol - 5 -vl -fiu]/phonic acid-N-phenvl -N-20 (2-ethoxvcarbonvLetMvl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-sulphonic acid-N-phenyl-N- (2-T4t2ioxycarbonylethyl) -amide, ethanolic hydrochloric/a.aLd, ethanol and ammonium carbonate. 25 Yield: 87 %/ofJtheory, <br><br> C27H3 0N6O4/^534. 6) <br><br> R£ value: /o .A3 (silica gel; dichloromethane/ethanol = 9:1) EKA mass/spectrum: (M+H)+ = 535 <br><br> / / (M+H+Na)++ = 279 <br><br> 30 / / <br><br> Example? 150 <br><br> l-Me/hyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-s/y/-sulphonic acid-N-(l-methylpyrazol-4-yl)-35 yN-/2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> NOW AMENDED <br><br> - 146 - / / <br><br> Prepared analogously to Example 25d from A-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazo/-y-yl-sulphonic acid-N- (l-methylpyrazol-4-yl) -N- (2-ethoxyeayoonylethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium 5 carbonate. / / <br><br> Yield: 38 % of theory, / / <br><br> C25H30N8°4S (538.6) / / <br><br> Rf value: 0.0 9 (silica gel; dicnlaromethane/ethanol = 9:1) EKA mass spectrum: (M+H) + = 53f9 / <br><br> 10 / / <br><br> Example 151 / / <br><br> l-Methyl-2 - [N- (4-amidinonnemyl) -aminomethyl] -5- (2 .3-dihydroindol-l-ylA-sulphonyl) -benzimidazole-15 hydrochloride / / <br><br> Prepared analogously/tcV Example 25d from l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-5- (2.3-dihydroindol-l-yl-sulphonyl)-benzimiaazole and ethanolic hydrochloric acid, 20 ethanol and ammoniura carbonate. <br><br> Yield: 15 % of tjaeoiry, <br><br> Rf value: 0.36 /silica gel; dichloromethane/methanol = 4:1) <br><br> C24H24N6O2S ido/s) <br><br> EKA mass spe^tPum: (M+H)+ = 461 25 / / <br><br> NOW AMENDED <br><br> - 147 - / / <br><br> Example 152 / / <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl] -benzimidazole-5-yl-sulphonic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-5 amide / / <br><br> Prepared analogously to Example/26^ from 1-methyl-2-[N-(4-amidinophenyl)-aminome/hyi]-benzimidazol-5-yl-sulphonic acid-N-phenyl-N- (2-ethfoxy carbonyl ethyl) -amide-10 hydrochloride and sodium hydroxide solution. <br><br> Yield: 24 % of theory, / / <br><br> Rf value: 0.55 (Reverse-Phas«e RP-18 silica gel; methanol/5% <br><br> saline soj/utyion = 3:2) <br><br> C25H26N6°4S (506.6) / / <br><br> 15 EKA mass spectrum: (M+H)/ = 507 <br><br> GM+Na)+ =52 9 /(M4-2Na)++ = 276 <br><br> Examt3le 153 / / <br><br> 20 / / <br><br> 1-Methyl-2- [N- (/4-amidinophenyl) -aminomethyl] -5- (isoindolin- <br><br> 2-yl-sulphonyl/-Benzimidazol-hydrochloride <br><br> Prepared analogously to Example 25d from 1-methyl-25 2-[N-(4-cyamophenyl)-aminomethyl]-5-(isoindolin-2-yl- <br><br> sulphonyiy-benzimidazole and ethanolic hydrochloric acid, ethanol /nd/ ammonium carbonate. <br><br> Yield: 13 A of theory, <br><br> Rf valiae/ 0.32 (silica gel; dichloromethane/methanol = 4:1) 30 C24H24N/O2S (460.6) <br><br> EKA/mass spectrum: (M+H)+ = 461 <br><br> NOW AMENDED <br><br> - 148 - <br><br> Example 154 <br><br> 2- [2- (4-Amidinophenyl) -ethyl] -quinazoliri-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl/-amide-hydrochloride <br><br> 5 <br><br> a. Ethvl 4-methyl-3-nitro-benzoate To a solution of 3 ml of concentrat/fed hydrochloric acid and 4 ml of concentrated sulphuric aci/a, 4.9 g (0.03 mol) of ethyl p-tolylate were added drcpyise with stirring at 5°C 10 and stirred for 1 hour whilst/casoling 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. <br><br> 15 Yield: 5.7 g (90 % of theory), <br><br> Rf value: 0.81 (silica/gel, ethyl acetate/cyclohexane = <br><br> 1:1) <br><br> 20 <br><br> 25 <br><br> b. Methvl 4-(2-dimefchylaminovinvl)-3-nitro-benzoate 1.0 g (4.8 mmol) at ^thyl 4-methyl-3-nitro-benzoate, 0.74 g (6.2 mmol) of dimethylformamide dimethylacetal and 2 ml of dimethylformamicjfe /ere heated to 14 0°C with stirring for 3 <br><br> hours. Then product thus purification Yield: 1.2 Rf value: 1:1) <br><br> thV s/&gt;lvent was distilled off and the crude lined was reacted without any further <br><br> ^100 % of theory) , <br><br> f4 (silica gel, ethyl acetate/cyclohexane = <br><br> 3 0 c. Methyl/4-formvl-3-nitro-benzoate <br><br> 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 (l/.y mmol) of sodium metaperiodate the mixture was 35 s/iyred for 20 hours at ambient temperature. The suspension then diluted with water and methylene chloride and £tracted with methylene chloride. The combined organic <br><br> NOW AMENDED <br><br> 149 - <br><br> extracts were washed with sodium hydrogen/carbonate le/residue was :ejfl with ethyl solution, dried and evaporated down. <br><br> chromatographed on silica gel and el\ acetate/cyclohexane (1:3). <br><br> Yield: 0.6 g (63 % of theory), <br><br> Rf value: 0.63 (silica gel, ethyl /acetate/cyclohexane 1:1) <br><br> d. Methyl 3-Amino-4-formvl-benzoate 10 To a solution of 25 ml of ethanol/glacial acetic acid/water (2:2:1) were added 0.6 g (2mmol) of methyl 4-formyl-3-nitro-benzoate, 1.2 g (21.y mmol) of iron powder and 0.01 ml of concentrated hydrochloric acid and the mixture was refluxed with stirrir?g &gt;for 15 minutes. Then the iron 15 was separated off, the sfol&amp;tion was diluted with water and extracted with methylene Chloride. The combined organic extracts were washed witn water, dried and evaporated down. <br><br> Yield: 0.3 g (58 % it 20 Rf value: 0.74 (si/i^a gel, methylene chloride/methanol = <br><br> 9.5:0.5) <br><br> e. Methyl 3- [3-/(4/cyanophenyl) -propionylamino] -4-formyl-benzoate <br><br> 25 1.0 g (5.6 xndol/} of methyl 3-amino-4-formyl-benzoate and 1.1 g (5.6 mmol) of 4-cyanophenylpropionic acid chloride were dissojivoa in 50 ml of methylene chloride and after the addition /f/o .7 g (5.6 mmol) of N-ethyl-diisopropylamine the mixture was stirred for 24 hours at ambient 3 0 temperajtuye. Then it was extracted with sodium hydrogen t^ solution, the combined organic extracts were dried/acid evaporated down. The residue was chromatographed on s/Llica gel and eluted with ethyl acetate/cyclohexane (l:/3), <br><br> 35 Yi^ld: 0.6 g (32 % of theory), <br><br> ralue: 0.60 (silica gel, ethyl acetate/cyclohexane = <br><br> fl-jL) <br><br> NOW AMENDED <br><br> - 150 - / / <br><br> f. Methyl 2-[2-(4-cyanophenyl)-ethyl]yxmanazoline-7-carboxvlate / / <br><br> 5 0.6 g (1.8 mmol) of ethyl 3 -[3 -(4-/yamophenyl)- <br><br> propionylamino]-4-formyl-benzoate/ar/d 10 ml of methanolic ammonia solution were agitated in a pressure vessel for 3 6 hours. Then the solvent was disyti/led off, the residue was chromatographed on silica gel &gt;an&lt;a eluted with methylene 10 chloride containing 0 to 1 % methanol. <br><br> Yield: 0.35 g (62 % of theory)/ <br><br> Rf value: 0.3 8 (silica gel,/ethyl acetate/cyclohexane = <br><br> 1:1) / / <br><br> 15 g. 2- f2 — (4-Cvanophenvl)/etmyll -cruinazolin-7-carboxylic acid 0.3 g (0.94 mmol) of methyl 2-[2-(4-cyanophenyl)-ethyl]-quinazoline-7-carboxy/aye were dissolved in 4.7 ml of IN lithium hydroxide so/utfion and 4 ml of tetrahydrofuran and stirred for 3 hours/atz ambient temperature. Then 4.7 ml of 20 IN hydrochloric acad/were added and the mixture was stirred for 3 0 minutes. The/product precipitated was suction filtered, washed/w/th water and dried. <br><br> Yield: 0.30 g % °f theory), <br><br> Rf value: 0.l/(s/lica gel, ethyl acetate/cyclohexane = 1:1) <br><br> 25 / / <br><br> h. 2-[2-(4-Cyanophenyl)-ethyl]-quinazolin-7-yl-carboxylic acid-N-phenvy-N-(2-methoxvcarbonvlethvl)-amide <br><br> 0.4 g (1/3/nmol) of 2-[2-(4-cyanophenyl)-ethyl]-3 0 quinazolime-7-carboxylic acid and 5 ml of thionyl chloride were scirred for 60 minutes at 50°C. Then the thionyl chloradiE was distilled off, the residue was dissolved in methylene chloride, mixed with 0.24 g (1.3 mmol) of methyl 3 -tN-phenylamino)-propionate and 0.22 ml of (1.3 mmol) of 3 5 NVetnyldiisopropylamine and stirred for 18 hours at ambient temperature. After evaporation of the solvent in vacuo the <br><br> NOW AMENDED <br><br> - 151 - <br><br> residue was chromatographed on silica g/l /and eluted with methylene chloride containing 1 % meth/an&lt;/l. <br><br> Yield: 230 mg (37 % of theory), <br><br> Rf value: 0.64 (silica gel, methyler^ ^hloride/methanol = 5 9:1) <br><br> i. 2- [2- (4-Amidinophenyl) -ethyl} /qu/inazolin-7-yl-carboxylic acid-N-phenvl-N- (2-ethoxvcarbonylerthvl) -amide-hydrochloride <br><br> 10 230 mg (0.5 mmol) of 2-[2-(4/cyanophenyl)-ethyl] -quinazolin-7-yl-carboxylic acid-N-phenyl- <br><br> N- (2-methoxycarbonylethyl) -&gt;am/de were stirred in 30 ml of saturated ethanolic hydrogfolj6ric acid for 8 hours at ambient temperature. Then the mixture was evaporated to 15 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 stirrecy overnight at ambient temperature. After evaporation of/ ttie solvent the crude product was chromatographed on Ai/ica gel and eluted with methylene 20 chloride/ethanol (A:/) . <br><br> Yield: 100 mg (3y yof theory), <br><br> Rf value: 0.5 (silaca gel, methylene chloride/ethanol = <br><br> 4:1) <br><br> c29h29n5o3 (4^5/59) <br><br> 25 Mass spectn/m:/ (M+H) + = 496 <br><br> Example la5 <br><br> 1-MethyA-7-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-30 5-yl-snltfShonic acid-N- (l-methylpyrazol-4-yl) -N- (2-hydrq^y/arbonylethyl)-amide <br><br> 35 <br><br> NOW AMENDED <br><br> - 152 - / / <br><br> Yield: 95 % of theory, / / <br><br> C23H26n804S (510.6) / / <br><br> Rf value: 0.53 (Reversed Phase silica/ g/l RP-18, methanol + 5% saline solution) / / <br><br> 5 EKA mass spectrum: (M+H) + = 511/ / <br><br> (M+Na) + = 5G 3/ <br><br> (M+2Na)++ = Ilk <br><br> Example 156 / / <br><br> 10 / / <br><br> l-Methyl-2-[N-(3-amidino-pyriain-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxyLa.c/acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl)/-amide-hydrochloride <br><br> 15 / / <br><br> a) 3-[(N-tert.Butoxycarbonyl-amino)acetylamino]- <br><br> 4-methylamino-benzoic acid-N-(2-pyridyl)- <br><br> N-(2-ethoxycarbonylethyl)-amide <br><br> 20 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 /)-}oenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 11.0 g of triethylamine/ and 34.2 g (0.10 mol) of 3-amino-4-methyl-25 amino-benzo/c Acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ssti/rred for 2.5 hours at ambient temperature. <br><br> Then the reaction solution was mixed with 5 1 of ice water and stirrea for 2 hours. The grey precipitate formed was filtered off, washed with water, dried and recrystallised 30 from achyl acetate with the addition of activated charcoal. Yield/: 2s 9.85 g (80 % of theory), <br><br> c25933^5°6 (499.6) <br><br> Rf/value: 0.55 (silica gel; methylene chloride/ethanol = <br><br> l/:/) <br><br> 35 / / <br><br> NOW AMENDED <br><br> - 153 - <br><br> b) l-Methvl-2- (N-tert . butoxvcarbonvl-ami.nqfmethvl) benzimidazol-5-vl-carboxylic acid-N-(2/pyridvl)-N-(2-ethoxycarbonylethyl)-amide <br><br> 10.0 g (0.02 mol) of 3-[ (N-tert. butL6x^carbonyl-5 amino)acetylamino]-4-methylamino-benzoic acid- <br><br> 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 ctis/cilled off, the residue was mixed with ice water and adjusted to pH 8 by the 10 addition of 2N ammonia. After/ej^traction three times with ethyl acetate the combined o/gahic phases were washed with saline solution and dried o/ey sodium sulphate. After evaporation of the solvent/tye crude product was chromatographed on silica/gal, eluting first with methylene 15 chloride, then with methylene chloride/ethanol (50:1) and (25:1). The desired fr^ct/ons were combined and evaporated down. <br><br> Yield: 5.85 g (61 % cfi. ^heory) , <br><br> C25H31N5°5 (481.6) <br><br> 20 Rf value: 0.70 (si/io&amp; gel; methylene chloride/ethanol = 9:1) <br><br> c) 1-Methyl-2-aminomethyl-benzimidazol-5 -vl-carboxylic acid-N-(2-pvri^y/)-N-(2-ethoxycarbonylethyl)-amide-25 trifluoracet; <br><br> 4.81 g (0.1&lt;/mi6l) of l-methyl-2-(N-tert .but oxycarbonyl-aminomethy]/) -fcenzimidazol-5-yl-carboxylic acid-N-(2-pyriayy) -N-(2-ethoxycarbonylethyl)-amide were dissolve^ i/n 25 ml of methylene chloride, mixed with 5 ml 3 0 of trif/uc/roacetic acid and stirred for 5 hours at ambient itiire. 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. <br><br> Yield/ 3.15 g (68 % of theory), <br><br> 3 5 C2/6H/3N5O3 (381.4) <br><br> •if //-alue: 0.18 (silica gel; methylene chloride/ethanol = f9:A) <br><br> NOW AMENDED <br><br> - 154 - <br><br> d) l-Methvl-2-fN-(3-cvano-pvridin-6-vl/ -aminomethvll-benzimidazol-5-vl-carboxvlic acid-N-GQ-pvridvl)- <br><br> N-(2-ethoxycarbonylethyl)-amide / / <br><br> 1.5 g (3.25 mmol) of l-methyl-2-3(m:ynomethyl-benzimidazol-5-yl-carboxylic acid-N-(2-pyridy/)- <br><br> N-(2-ethoxycarbonylethyl)-amide/tyifluoracetate were stirred into 10 ml of N-ethyl-aii/sopropylamine and heated 10 to 100°C for 15 minutes. Afteyr t/ne addition of 720 mg (5.25 mmol) of. 2-chloro-5-cyaEio-pyridine the reaction mixture was heated to 125°c/f®r 2 hours. After cooling to ambient temperature and starring with about 20 ml of water, the pH was adjusted to 4 ®y/the addition of IN hydrochloric 15 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 s/ilaca gel, eluting first with methylene 20 chloride, later wit/h/nethylene chloride/ethanol (25:1) and (19:1) . The desired/fractions were combined and evaporated down. / / <br><br> Yield: 1.05 g jljh of theory), <br><br> C26H25N7O (483A6/ <br><br> 25 Mass spectrum: /(M+H) + = 484 <br><br> e) l-MethvA-2-fN-(3-amidino-pvridin-6-vl)-aminomethvll-benzimidazo]/-5-vl-carboxvlic acid-N- (2-pvridvl) - <br><br> N-(2-ethoxycarbonylethyl)-amide-hydrochloride 30 Prepared analogously to Example 25d from l-Methyl-2-[N-(3-cyano-Tpyridin-6-yl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide &gt;and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> 35 Y/elo: 38 % of theory, <br><br> /28^28N8°3 (500.6) <br><br> NOW AMENDED <br><br> - 155 - / / <br><br> Mass spectrum: (M+H)+ = 501 / / <br><br> Example 157 / / <br><br> 5 l-Methyl-2 - [N- (4-amidinophenyl) aminyomerthyl] -indol-5-yl- <br><br> carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide-hydro iodide / / <br><br> a) 4-Nitro-benzoic acid-N-phenyl-tf- (2-10 methoxycarbonylethvl)amide / j <br><br> 16.7 g (0.1 mol) of 4-nitrobfeiyzoic acid were refluxed in 50 ml of thionyl chloride and h drops of dimethylformamide for 1 hour. After the solvent/ had been distilled off in vacuo the crude product was/dissolved in 150 ml of <br><br> 15 tetrahydrofuran and addetl nropwise to a solution of 18 g (0.1 mol) of N-(2-methfoxycarbonylethyl)aniline in 250 ml of tetrahydrofuran anca 4/2 ml 0.3 mol) of triethylamine. After being stirred toy one hour at ambient temperature the reaction mixture was diluted with 250 ml of ethyl acetate 20 and washed 2x witJy 2(?0 ml of 14% saline solution. After the solvent had been Ai^stilled off and the residue chromatographed/(sl.lica gel; methylene chloride) a yellow oil was obtained which slowly solidified. <br><br> Yield: 32.6 g/(3Jj0 % of theory), <br><br> 25 Rf value: 0.31 /(silica gel; methylene chloride/methanol = <br><br> 50:1) / / <br><br> b) 4-Amino-Benzoic acid-N-phenvl-N-(2-methoxvcarponvlethvl)amide <br><br> 30 22 g (&amp;7 mmol) of 4-nitro-benzoic acid-N-phenyl-N-(2- <br><br> metho^ycarbonylethyl)-amide were hydrogenated in 500 ml of methsmoa. with 2 g of 10% palladium on charcoal at 3 bar hydrogen pressure for 3 hours. After filtration and dis/ti/llation of the solvent the reaction mixture was washed 35 w/th: 100 ml of ether and the white crystalline product was fuyther reacted directly. <br><br> NOW AMENDED <br><br> - 156 - / / <br><br> Yield: 18.6 g (94 % of theory), / / <br><br> Rf value: 0.70 (silica gel; methylene (Chloride/ethanol = <br><br> 19:1) / / <br><br> 5 c) 2-Methyl-3-thiomethyl-indol-5-yV-carboxylic acid-N- <br><br> phenvl-N- (2-methoxycarbonylethyl) /amgde <br><br> 26.8 g (91 mmol) of 4-amino-ben/oiA acid-N-phenyl-N-(2-methoxycarbonylethyl) amide were/di/ssolved in 500 ml of methylene chloride, cooled to /7c/°c and mixed within 3 0 10 minutes with freshly preparecy t^rt .butylhypochlorite (M. J. Mintz et al., Organic Synthesi^, Coll. Vol. 5, page 184). The mixture was stirred foy 2/hours at -70°C, then 9.46 g (91 mmol) of me thyl thioac/e tone in 40 ml of methylene chloride were added dropwis4 within 10 minutes and stirring 15 was continued for a fur/heo: 1.5 hours. Then 12.7 ml (9.1 g, 91 mmol) of triethylam/nor in 25 ml of methylene chloride . were added. The mixtvyreA/as left for 30 minutes at -78°C and then slowly warmed/to ambient temperature overnight. After washing twic^w/th 50 ml of water the organic phase 20 was separated off/anA dried with sodium sulphate. After removal of the sc/lvent in vacuo a white amorphous substance is obtained aft&lt;ferAurification by chromatography (silica gel; ethyl acejcatze/petroleum ether = 2:8 to 3:7) . <br><br> Yield: 24.1 w (69 % of theory), <br><br> 25 Rf value: 0/58/(silica gel; ethyl acetate/petroleum ether = <br><br> 1:1) / / <br><br> C21H22N2°/S /(382.49) <br><br> Mass spect/um: (M)+ = 382 <br><br> NOW AMENDED <br><br> 157 - <br><br> d) 1-1ert-Butoxvcarbonvl-2-methvl-indol /s -/rl -carboxvlic acid-N-phenvl-N-(2-methoxycarbonylethyl) -Amide 8.9 g (23 mmol) of 2-Methyl-3-thiomejzhm-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide <br><br> 5 were dissolved in 600 ml of ethanol/ mixed with about <br><br> 150 mg of Raney nickel and stirred/far 2 hours at ambient temperature (analogously to P.G. yGassman et al. , Organic Synthesis Coll. Vol. 6, page 601/./Then the mixture was filtered and the solvent eliminAty£d in vacuo. The crude <br><br> 10 product thus obtained (8 g) was Alissolved 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 toy 2.5 hours at 50°C. Then the solvent was distilled off/im vacuo and the crude product <br><br> 15 was purified by chromatography (silica gel, ethyl acetate/petroleum ether =/l:4). <br><br> Yield: 10.0 g (98 % off theory), <br><br> Rf value: 0.40 (silica Ajel; ethyl acetate/petroleum ether =3 :7) <br><br> 20 <br><br> e) 2-TN-(4-Cvanophenvl)aminomethvll-indol-5-vl-carboxylic acid-N-phenvl-N-/(2/methoxvcarbonvlethvl) -amide <br><br> 3.5 g (8 mmol) /of/ 1-tert.butoxycarbonyl-2-methyl-indol-5-yl-carboxylic /agad-N-phenyl-N-(2-methoxycarbonylethyl)-25 amide were dissolved in 80 ml of carbon tetrachloride, <br><br> mixed with 1.3 g (8.4 mmol) of N-bromo-succinimide and 20 mg of azob/si/sobutyronitrile and refluxed for 2.5 hours. Then the jktill warm solution was filtered, the filtrate obtainecy was washed with saturated sodium hydrogen 3 0 carbonate/solution and dried with sodium sulphate. After distilAarion of the solvent the crude product was dissolved in 3(/ ml of N-ethyl-diisopropylamine, mixed with 1.0 g (8 n(mgl) of 4-aminobenzonitrile and refluxed for 2.5 hours. The solvent was distilled off in vacuo and the residue <br><br> 35 obtained was purified by chromatography (silica gel; ethyl icetate/petroleum ether = 1:4 to 1:1). <br><br> NOW AMENDED <br><br> - 158 - / / <br><br> Yield: 1.1 g (30 % of theory), j / <br><br> Rf value: 0.21 (silica gel; ethyl acetate/petroleum ether = <br><br> 1:1) // <br><br> 5 f . l-Methvl-2 - TN- (4-thiocarbamovl-phenyl) aminomethvll -indol-5-vl-carboxvlic acid-N-phenylVN-(2-methoxvcarbonvlethvl)-amide / / <br><br> 1.5 g (3.3 mmol) of 2-[N-(4-cyanophenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl -A3-/2-methoxycarbonylethyl) -10 amide were dissolved in 6 0 my ok xylene, mixed with 0.4 5 g (3.3 mmol) of potassium caponate and 0.5 ml of (3.3 mmol) of methyl p-toluenesulphonaite/ and refluxed for 4 hours. <br><br> Then the same amounts of potassium carbonate and methyl toluenesulphonate were a4dad a second time and the mixture 15 was refluxed overnight./It/ was filtered and washed with acetone. After concentration of the filtrate thus obtained, the residue obtained X^as 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 20 theory) was disso/vea in 20 ml of pyridine and mixed with 0.67 ml (1.37 mmpl)/ of triethylamine. Then hydrogen sulphide gas wae introduced into the solution thus obtained. After z.5 days nitrogen was passed through the reaction solution for 30 minutes, the solvent was distilled 25 off and the /residue obtained was purified by chromatography (silica gel/; methylene chloride/ethanol 99:1 to 98:2). Yield: 0-fOh (43 % of theory), <br><br> C28H28N4/3J (500.62) <br><br> EKA mass yspectrum: (M+H) + = 501 30 / / (M+Na)+ = 523 <br><br> 35 <br><br> g) x-Methvl-2-TN-(4-amidinophenyl)aminomethvll-indol-5-yl-carbqtxvlic acid-N-phenvl-N- (2-methoxycarbonylethyl) -amide-fdroiodide f0 g (0.60 mmol) of l-methyl-2-[N-(4-thiocarbamoyl)-phenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-f-(2-methoxycarbonylethyl)-amide were dissolved in 20 ml of <br><br> NOW AMENDED <br><br> - 159 - <br><br> 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/lours at 40°C. The solvent was distilled off in vacuo/ar/d the residue obtained was purified by chromatography (s/l/ca gel; methylene chloride/ethanol = 9:1 to 4:1) <br><br> Yield: 55 % of theory, <br><br> 10 C28H29N5O3 (483.58) <br><br> Rf value: 0.20 (silica gel; 4:1+1 drop of acetic acic EKA mass spectrum: (M+H) +/= <br><br> (etnylene chloride/ethanol = <br><br> : 8 4 <br><br> 15 Example 158 <br><br> 20 <br><br> 25 <br><br> 30 <br><br> l-Methyl-2-[N-(4-amidfnofchenyl)aminomethyl]-thieno[2.3-d]imidazo/-H-yl-carboxylic acid-N-phenyl-N-(2- <br><br> -amide-hydrochloride a) Iminoethvl metAo^vacetate hydrochloride A solution of 35/5/g (0.50 mol) of methoxyacetonitrile in 29 ml (23 g, 0y£&gt;0/mol) of ethanol and 30 ml of absolute diethylether was/cooled to 0°C and over 1 hour 22.5 g (0.62 mol) oS hydrogen chloride gas was introduced, whilst towards the/erya of the introduction of gas the reaction product crV-st/allised out. To complete the precipitation 130 ml of diejthylether were added and the colourless needles were filtered off Yield: /o&amp;/4 g (86 % of theory) , <br><br> Melting /oint: 117-118°C. <br><br> b) y~Iwdroxvmethvl-2-methoxymethyl- imidazole A rtfijgfcure of 30.6 g (0.20 mol) of iminoethyl 35 m^tbfoxyacetate-hydrochloride, 18 g (0.20 mol) of 1.3- <br><br> myydroxyacetone and 2 00 ml of liquid ammonia was heated to '6^°C for 3 hours in a stirred autoclave at a pressure of 27 <br><br> NOW AMENDED <br><br> - 160 - <br><br> 10 <br><br> bar (analogously to: P. Dziuron et al 1974, p.470). Then the ammonia was el methylene chloride were added. The was filtered off and washed with m filtrate was evaporated down and t purified by chromatography (alumi chloride/ethanol = 90:10 to 85:1 Yield: 26.7 g (94 % of theory), Rf value: 0.43 (silica gel; me 9 :1) <br><br> c6h10n2°2 (142.20) <br><br> Mass spectrum: (M)+ = 142 <br><br> Pharm. 3 07, uryated and 20 0 ml of precipitate formed (ene chloride. The 'esidue obtained was oxide; methylene ene chloride/ethanol = <br><br> 15 <br><br> 20 <br><br> 25 <br><br> 30 <br><br> c) 4 -Hvdroxvmethvl -2 -metKo&gt;zVmethvl - 1-methvl - imidazole as a 1:1 mixture with 5-hvdr/xymethyl -2-methoxymethyl -1 -methyl -imidazole mol) of 4-hydroxymethyl-2-3.0 g (53 mmol) of powdered <br><br> A mixture of 7.1 g (5y methoxymethy1imidaz potassium hydroxide/ and 3.4 ml (0.55 mmol) of methyl iodide was heated to 50°(7 hours (analogously /to <br><br> 100 ml of dimethylformamide for 4 I. Sinclair et al., J. Med. Chem., 29., 1986, 261) ./Thfen the solvent was distilled off in vacuo and the crude j6r^duct purified by column chromatography methylene chloride/ethanol = 99:1 to of theory; 1:1 mixture of the two <br><br> (aluminium o 95:5). <br><br> Yield: 6.1 fa /78 regioisomeors <br><br> Rf value / 0/.32 (silica gel; methylene chloride/ethanol = 19:1) <br><br> d) 5 -jChXoro - 4 -hvdroxymethyl - 2 -methoxymethyl - 1-methvl -lmictftzple <br><br> A l/: l/ mixture of 7.7 g (4 9 mmol) of 4 -hydroxymethyl-2 -/nei:hoxymethyl-l-methyl -imidazole and 5-hydr oxymethyl-35 thoxymethyl-1-methyl-imidazole and 7.3 g (55 mmol) of <br><br> :hloro-succinimide was heated to 50°C in 48 ml of :hylene glycol monoethylether and 70 ml of dioxan for 10 <br><br> NOW AMENDED , <br><br> - 161 - / / <br><br> hours. Then the solvent was distilled ofir An vacuo and the crude product purified by chromatograpMy /(silica gel; methylene chloride/ethanol = 99:1 to jBOyLO) to obtain the isomerically pure title compound. / / <br><br> 5 Yield: 3.4 g (36 % of theory), / / <br><br> Rf value: 0.40 (silica gel; methyLene chloride/ethanol = <br><br> 19:1) / / <br><br> e) 5-chloro-4 -formvl- 2 -methoxvraetAivl- 1-methvl -imidazole 10 3.4 g (18 mmol) of 5-chloro-4/hyaroxymethyl-2- <br><br> methoxymethyl-l-methyl-imida^ol/e were dissolved in 100 ml of methylene chloride and at cwo-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 15 was eliminated and the oruide product obtained was further reacted without any further purification. <br><br> Yield: 3.0 g (89 % of /theory) , <br><br> Rf value: 0.44 (silica /jel; methylene chloride/ethanol = <br><br> 50:1) / / <br><br> 20 / / <br><br> NOW AMENDED <br><br> - 162 - I <br><br> f) Ethyl l-methyl-2-methoxymethyl-thieno) [2/. 3-d] imidazol-5- <br><br> vl-carboxvlate <br><br> To a freshly prepared sodium ethoxide/saQution (from 391 mg, 17 mMol of sodium) in 15 ml yof /ethanol were added 5 dropwise 1.9 ml (2.1 g, 17 mmol) oy e/hyl thioglycolate. After 1 hour stirring at ambient temperature 1.6 g (8.5 mmol) of 5-chloro-4-formyl-y-miethoxymethyl-l-methyl-imidazole in 2 0 ml of absolute e/thanol were added and the mixture was heated to 80°C (analogously to B. Iddon et al., 10 J. Chem. Soc. Perkin Trans. I / 1/987, 1457) . After 5 hours the solvent was distilled of/, /the residue was taken up in 50 ml of methylene chloride/anfd washed with 2 0 ml of water. The aqueous phase was washed/again with 20 ml of methylene chloride and then the combined organic phases were dried 15 with sodium sulphate. Afiter removal of the solvent in vacuo the crude product obta/nea was purified by column chromatography (aluminium oxide; methylene chloride). <br><br> Yield: 1.0 g (46 % of Wneory), <br><br> Rf value: 0.48 (sil/ca gel; methylene chloride/ethanol = 20 50:1) / / <br><br> C11H14N2O3S (254 h&gt;\{ <br><br> EKA mass spectrum/ (M+H)+ = 255 / / (M+Na)+ = 277 <br><br> 25 g) 1-Methyl76-lriethoxymethyl-thieno [2 . 3-d] imidazol-5-yl- <br><br> carboxvlic /acad : <br><br> To a solution of 0.90 g (3.54 mmol) of ethyl l-methyl-2-methoxym^tftyl-thieno[2.3-d]imidazol-5-yl-carboxylate in 30 ml of e/hamol were added dropwise 5 ml of 2 N sodium 3 0 hydrox/dei solution and the mixture was stirred for 2 hours at anpi^nt temperature. Then the solvent was distilled off in vfacjio, the residue was taken up in 5 ml of water and warned with 10 ml of diethylether. The aqueous phase was a/idafied with 6 ml of 2N hydrochloric acid, cooled to 0°C 35 fn&lt;/ the precipitated crystals are filtered off. <br><br> /Yi/eld: 0.50 g (63% of theory) <br><br> NOW AMENDED <br><br> 10 <br><br> 15 <br><br> 20 <br><br> - 163 <br><br> Rf value: 0.21 (silica gel; methylene c]/lq^:ide/ethanol = 9:1 + a few drops of acetic acid) <br><br> C9H10N2°3S (226.26) <br><br> Mass spectrum: (M)+ = 226 <br><br> h) 1 -Methyl-2-methoxymethyl-thien&lt;£ [2^. 3-d] imidazol-5-yl-carboxvlic acid-N-phenvl-N- (2-me/hc/xvcarbonvlethvl) -amide A suspension of 0.50 g (2.2 mmol)/of l-methyl-2-methoxymethyl-thieno[2.3-d]imiaa/ol-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 solia gradually dissolved. After distillation of the liquid oomponents 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 /n/20 ml of tetrahydrofuran and added dropwise to a mixtur^of 0.42 g (2.3 mmol) of yl)aniline and 0.92 ml (6.6 mmol) of of tetrahydrofuran. After 16 hours' solvent was eliminated and the crude purified by chromatography (silica ride/ethanol = 100:1). <br><br> of theory), <br><br> silica gel; methylene chloride/ethanol = <br><br> N-(2-methoxycarbony triethylamine in 3 stirring at 50°C product obtained gel; methylene Yield: 0.66 g Rf value: 0. <br><br> 25 19:1) <br><br> i) l-Methyi-^-(N-4-cvanophenvlaminomethvl)-thieno f2 /3-/al imidazol-5-vl-carboxylic acid-N-phenvl-N- (2-methoxveayponylethvl)-amide 3 0 To a solution of 0.73 g (1.88 mmol) of l-methyl-2- <br><br> metho^ynfethyl - thieno [2 . 3 -d] imidazol-5-yl-carboxylic acid-N-phen^l/N- (2-methoxycarbonylethyl) -amide in 3 0 ml of met/tvy/Lene chloride were added dropwise at 5°C 2.9 ml (2.9 mmol/ of a 1-molar solution of boron tribromide in 35 itfetnylene chloride. After 16 hours' stirring at ambient aperature the mixture was washed with 20 ml of saturated jdium hydrogen carbonate solution, the organic phase was <br><br> NOW AMENDED <br><br> 164 - <br><br> 10 <br><br> separated off, dried with sodium sulphate/and filtered. The filtrate was mixed with 14 ml of N-ethyl/diisopropylamine and 0.43 g (3.64 mmol) of 4-aminobenzyon/trile. Then the methylene chloride was distilled otfj in vacuo, the residue obtained was heated to 50°C for 1 l/our and then the residual solvent was distilled off i/n vacuo. After chromatography (silica gel; methylene chloride/ethanol = 99:1 to 97:3) a yellow oil was pbpained which slowly solidified. <br><br> Yield: 0.37 g (42% of theory)/, <br><br> Rf value: 0.2 9 (silica gel; Jnejthylene chloride/ethanol = 50:1 + a few drops of ammoniV) <br><br> j) l-Methyl-2-[N-(4-amidinophenyl)aminomethyl]-15 thieno [2 . 3-d] imidazol-5/y]/-carboxylic acid-N-phenyl-N-(2- <br><br> ethoxvcarbonvlethvl)-amide-hydrochloride <br><br> 0.3 8 g (0.80 mmol) ofj l/methyl-2- (N-4-cyanophenylaminomethyl/-thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-tfnenyl-N-(2-methoxycarbonylethyl)-amide 20 were stirred in 4C/ ml of ethanol saturated with hydrogen chloride for 5 hasuKs first at 0°C, then later at ambient temperature until Ao more starting material could be detected by thiin Aayer chromatography. Then the solvent was distilled off/at/ a maximum 28°C bath temperature, the oily 25 residue was taken up in 40 ml of absolute ethanol and mixed with 1.1 g of/ammonium carbonate. After 18 hours the solvent wbJs jaistilled off in vacuo and the crude product was punffieo. by chromatography (silica gel; methylene chloride/ethanol = 9:1 to 4:1) . <br><br> 30 Yield / 97 % of theory C26H2/eN/&gt;3s (504.62) <br><br> Rf v&amp;lide: 0.21 (silica gel; methylene chloride/ethanol = 4 :1/ +/a few drops of acetic acid) <br><br> EKA Mass spectrum: (M+H)+ = 505 <br><br> 35 / / (M+H+Na)++ = 264 <br><br> NOW AMENDED <br><br> 10 <br><br> 15 <br><br> - 165 - <br><br> Example 15 9 <br><br> l-Methyl-2-[N-(4-amidinophenyl)aminomfetMyl]-thieno [2 .3-d] imidazol-5-yl-carboxylic .acid-N-phenyl-N- (2-hydroxycarbonylethyl)-amide-hydrocfylo/ ide <br><br> Prepared analogously to Example amidinophenyl)aminomethyl]-thie carboxylic acid-N-phenyl-N-(2-hydrochloride and sodium Yield: 85 % of theory, <br><br> C24H24N6°3S (476.56) <br><br> Rf value: 0.3 6 (Reversed <br><br> + 5 % sal/n EKA mass spectrum: (M+ <br><br> (Mf+Na) + <br><br> :om l-methyl-2-[N-(4-.3-d]imidazol-5-yl-fcxycarbonylethyl)-amide-(de solution. <br><br> e silica gel RP-8; methanol solution) <br><br> = 477 = 499 <br><br> (M-/2Na) ++ = 25 0 <br><br> 20 <br><br> Example 160 <br><br> l-Methyl-3- [N- (4/-amidinophenyl) thiomethyl] -quinoxalin-2-on-6-yl-carboxylia acid-N-phenyl-N-(2-ethoxycarbonylethyl) amide-hydrochloride <br><br> 25 a) 1 -Methyl/3-/fN- (4-cvanophenvl) thiomethvll -cruinoxalin-2-on-6-vl-carboxylic acid-N-phenvl-N-(2-methoxvcarbc/nvlethvl) -amide <br><br> A solution/of 2.5 g (7.6 mmol) of 3-amino-4-methylamino-benzoic/ aa:id-N-phenyl-N- (2-methoxycarbonylethyl) -amide and 30 2.4 g /(9/6 mmol) of ethyl 3-(4-cyanophenyl) thio-2-oxo- <br><br> propi/mate were heated to boiling in 50 ml of ethanol for 3 0 n/injutes. After removal of the solvent the crude product obt/ained was purified by chromatography (silica gel; methylene chloride). <br><br> 35 Xi^ld: 1.6 g (40 % of theory), <br><br> 'R/ value: 0.63 (silica gel; EtOAc/EtOH/ammonia = 90:10:1) <br><br> NOW AMENDED <br><br> - 166 - / / <br><br> b) l-Methyl-3- [N- (4-amidinophenyl) thiometlayl] -quinoxalin-2-on-6-yl-carboxylic acid-N-phenyl-N-(2-^tnoxycarbonylethyl)- <br><br> amide-hydrochloride / / <br><br> 5 Prepared analogously to Example 1 f/on/l-methyl-3-[N-(4-cyanophenyl)thiomethyl]-quinoxalin/2 -hn-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 23 % of theory, / / <br><br> 10 C28H27N5O4S (543.64) / / <br><br> Rf value: 0.25 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5) / / <br><br> EKA mass spectrum: (M+H)+ /=/544 <br><br> (M+NaO +/= 566 <br><br> 15 / / <br><br> Example 161 / / <br><br> 3-Methyl-2- [2- (4-amiainiophenyl) ethyl] - <br><br> imidazo[1.2-a] pyrid/n/7-yl-carboxylic acid-N-phenyl-N-(2-20 ethoxycarbonylethyl)/amide-hydrochloride a) 3-Methvl-2-\2h (4-cvanophenvl)ethvll - <br><br> imidazo fl. 2-al •p^rridin-7-vl-carboxylic acid-N-phenyl-N- (2-ethoxvcarbonvLetnvl)-amide 25 1.4 g (4.6 mmol/ of 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[1.2ya]pyridin-7-yl-carboxylic acid (prepared from - 4-bromo-l-/4-&gt;cyanophenyl) -l-penten-3-one and methyl 2-aminopyridine-4-carboxylate analogously to Y. Katsura et al. Chem/ Dharm. Bull. 1992, 40, 1424-1438) were suspended 3 0 in 15 ml at thionyl chloride and heated to boiling for 1 <br><br> hour unt/l fully dissolved. After the thionyl chloride had been di/tilled off the acid chloride was dissolved in 15 ml of nyr/dine without any further purification and at 0°C mixed/with 1.0 g (5.2 mmol) of N-(2-ethoxycarbonylethyl)-35 arvil/ne. After 1 hour the solvent was distilled off, the ares/due was taken up in 3 0 ml of methylene chloride, washed /wlch 15 ml of IN hydrochloric acid and dried with sodium <br><br> NOW AMENDED <br><br> - 167 - / / <br><br> sulphate. After distillation of the sol/vent and chromatography (silica gel; methylene /ih/oride/ethanol = 0 to 2 %) a brown oil was obtained. / / <br><br> Yield: 1.48 g (64 % of theory), / / <br><br> 5 Rf value: 0.73 (silica gel; ethyl arce/zate/ethanol/ammonia = <br><br> 90:10:1) / / <br><br> b) 3-Methvl-2- f2 - (4-amidinophenyl/ethvll - <br><br> imidazo\1.2-alpyridin-7-vl-carboxylic acid-N-phenvl-N-(2-10 ethoxycarbonylethyl)-amide-hygrpchloride <br><br> Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl) ethyl] - imidazo Da .p.-a] pyridin-7-yl-carboxylic acid-N-phenyl-N- (2-ethoxyaarfoonylethyl)-amide and ethanolic hydrochloric acid, ethanal /and ammonium carbonate. 15 Yield: 62 % of theory, / / <br><br> C29H31N5°3 (497.60) j / <br><br> Rf value: 0.23 (silica gel; ethyl acetate/ethanol/ammonia <br><br> = 50:45:5) / / <br><br> EKA mass spectrum:/(M+H)+ = 4 98 <br><br> 20 / / <br><br> Example 162 / / <br><br> 3-Methyl-2-[2y(4/amidinophenyl)ethyl]- <br><br> imidazo[1.2-aflpyridin-7-yl-carboxylic acid-N-phenyl-N- (2-25 hydroxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 2 from 3-methyl-2-[2-(4-amidinopViertyl) ethyl] -imidazo [1.2-a] pyridin-7-yl-carboxylic acid-N-johenyl-N-(2-ethoxycarbonylethyl) -amide-hydrochloride 3 0 and sodium hydroxide solution. <br><br> Yields 4l % of theory, <br><br> C27^27^503 (469.55) <br><br> / Rf value: 0.19 (silica gel; ethyl / / acetate/ethanol/ammonia = 50:45:5) <br><br> 35 /EKa mass spectrum: (M+H) + = 470 <br><br> / / (M+Na)+ = 492 <br><br> NOW AMENDED <br><br> 5 Example 163 <br><br> - 168 - <br><br> (M+2H)++ = 235.7 (M+H+Na)++ = 246.7/ (M+2Na)++ = 257/7 <br><br> 10 <br><br> 15 <br><br> 20 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-Aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-W- [/N-ethoxycarbonylethyl-N-methyl) -2-aminoethyl] -amide-djjnysarochloride lj£ 25d from l-methyl-2-[N-(4- <br><br> imidazol-5-yl-carboxylic bonylethyl-N-methyl)-2-ic hydrochloric acid, ethanol <br><br> Prepared analogously to Exati cyanophenyl)-aminomethyl]-tfei acid-N-phenyl-N-[(N-ethoxVcj aminoethyl] -amide and etj7iar)(ol and ammonium carbonate. <br><br> Yield: 80 % of theorytj c31h37n7°3 (555.7) <br><br> Rf value: 0.24 (sili6a/gel; dichloromethane/methanol = 4:1) <br><br> EKA mass spectrum:/ (M+H)+ = 556 <br><br> '(M+H+Na)++ = 289.8 (M+2H)++ = 278.8 <br><br> Example 164 <br><br> 25 1-Methyl-2-/N-/(4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxy]/ic acid-N-phenyl-N- [(N-hydroxycarbonylethyl-N-methyl)-2/aminoethyl]-amide-hydrochloride <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4-3 0 amidiryop^enyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-^-phenyl-N-[(N-ethoxycarbonylethyl-N-methyl)-2-amitfoe/thyl] -amide-dihydrochloride and sodium hydroxide soJ^ut/Lon. <br><br> '.ei/d: 79 % of theory, <br><br> 35 029^33^703 (527.6) <br><br> NOW AMENDED <br><br> - 169 - <br><br> Rf value: 0.43 (Reversed Phase sil/cs/ gel RP-18; methanol/5% aqueous saline solutipn/= 6:4) <br><br> EKA mass spectrum: (M+H)+ = 528 <br><br> (M+H+Na)++ = 27JI 5 (M+2H) ++ = 2/64/6 <br><br> Example 165 <br><br> l-Methyl-2-[N-(4-amidinophenyl) y4minomethyl]-benzimidazol-10 5-yl-carboxylic acid-N-pheny/-ly- (3-hydroxy-n-propyl) -amide-hydrochloride <br><br> Prepared from 1-methyl-2-/tN/ (4-amidinophenyl) -aminomethyl] - <br><br> phenyl-N- (3-benzyloxy-rogenation over drogen pressure and at benzimidazol-5-yl-carboxyl/c acic 15 n-propyl)-amide-hydrochloride by palladium/charcoal (1 y%)/at 5 t&gt;ar ambient temperature. <br><br> Yield: 61 % of theory, <br><br> c26h28n6°2 (456.6) <br><br> 20 Rf value: 0.70 (Reversed Phase silica gel RP-18; methanol/5% aqueous saline solution = 9:1) <br><br> EKA mass spectrur <br><br> (M+H)+ (M+H+Na) <br><br> = 457 <br><br> ++ _ <br><br> 240 <br><br> NOW AMENDED <br><br> - 170 - <br><br> Example 166 <br><br> l-Methyl-2 - [N- [4- (N-n-hexyloxycarbonylatmidino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N- (2-5 pyridyl)-N-(2-hydroxycarbonylethyl^-amide <br><br> Prepared analogously to Example ,£6/from l-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxylic arcla-N- (2-pyridyl) -N- (2-10 ethoxycarbonylethyl)-amide apd /sodium hydroxide solution. Yield: 97 % of theory, <br><br> c32h37n7°5 (599.7) <br><br> Rf value: 0.22 (silica gel;/dichloromethane/methanol = 9:1) <br><br> EKA mass spectrum: (M+H)+/ = 600 <br><br> 15 (M/H*Na)++ = 311.7 <br><br> (W+2fH)++ = 300.8 <br><br> /(M/2Na)+ + = 322.8 <br><br> 20 <br><br> Example 167 <br><br> l-Methyl-2- [N- [4r- CN-n-hexyloxycarbonylamidino) phenyl] aminomethyl]-benzamidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxy-n-pr9pyl)-amide <br><br> 25 <br><br> 30 <br><br> Prepared analogously to Example 165 from l-methyl-2-[N- [4-(N-n-hexyloxycarbonylamidino)phenyl] -aminomethyl] -benz imidazo/-5-yl-carboxylic acid-N-phenyl-N- (3-benzyloxy-n-propyl/-amide by catalytic debenzylation. <br><br> Yield: /26/% of theory, <br><br> C-33^40^6^4 (584.7) <br><br> Rf vatlue: 0.3 9 (silica gel; dichloromethane/ethanol = 9:1 ) <br><br> mjiss spectrum: (M+H) + = 585 <br><br> (M+H+Na)++ = 304 (M+Na)+ = 607 <br><br> E <br><br> 35 <br><br> NOW AMENDED <br><br> - 171 - / / <br><br> Example 16 8 / / <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (3-fluorophertyl/ -N- (2-5 ethoxycarbonylethyl) -amide- hydrochYoro.de <br><br> Pethyl-2- [N- (4-carboxylic thyl)-amide and onium nethanol = 5:1) <br><br> -benzimidazol- <br><br> ethyl-2-[N-(4-carboxylic thyl)-amide and onium methanol = 5:1) <br><br> NOW AMENDED <br><br> - 172 <br><br> Example 170 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-amin^ 5-yl-carboxylic acid-N-(3-fluorophej hydroxycarbonylethyl)-amide <br><br> :hyl]-benzimidazol--N-(2- <br><br> 10 <br><br> 15 <br><br> Prepared analogously to Example ^6 /from l-methyl-2-[N-(4-amidinophenyl) -aminomethyl] -benye imidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-e/hcxycarbonylethyl)-amide-hydrochloride and sodium hyd^ox/de solution. <br><br> Yield: 97 % of theory, <br><br> C26H25fN603 (488.5) <br><br> Rf value: 0.13 (silica ge^; /iichloromethane/ethanol = 4:1) <br><br> EKA mass spectrum: (M+H^+/ = 489 <br><br> (MfKa/+ = 511 (M+2fra)++ = 267 <br><br> Example 171 <br><br> 20 l-Methyl-2- [N- (4-^amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic Ac/d-N-(4-fluorophenyl)-N-(2-hydroxycarbonyl/etnyl) - amide <br><br> Prepared ana^ogfously to Example 26 from l-methyl-2-[N-(4-25 amidinophenyl)/-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide- <br><br> ride and sodium hydroxide solution. <br><br> Yield: 8&gt;6 % of theory, <br><br> C26H25^SI6^)3 (488.5) <br><br> 30 Rf va]/u^: 0.15 (silica gel; dichloromethane/ethanol = 4:1) <br><br> EKA jfha^s spectrum: (M+H) + = 489 <br><br> (M+Na)+ = 511 (M+2Na)++ = 267 <br><br> 35 <br><br> NOW AMENDED <br><br> 173 - <br><br> Example 172 <br><br> l-Methyl-2- [N- (4-amidino-2-methoxy-pheny2) -^aminomethyl] -5 benzimidazol-5-yl-carboxylic acid-N-pheny]/-N-(2 ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d^r©m l-methyl-2-[N-(4 cyano-2-methoxy-phenyl) -aminomethyl/] -benzimidazol-5-yl-10 carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide and ethanolic hydrochloric acid, /etynanol and ammonium carbonate. <br><br> Yield: 89 % of theory, <br><br> C29H32N6°4 (528.6) <br><br> 15 Rf value: 0.13 (silica gel; y&amp;i^hloromethane/ethanol = 4:1) <br><br> EKA mass spectrum: (M+H)+/ / = 529 <br><br> (M+H+NaV++ - 276 (M+^H)/+ = 265 <br><br> 20 Example 173 <br><br> 25 <br><br> 30 <br><br> 35 <br><br> l-Methyl-2- [N- [4- (N/4-yethylbenzoylamidino)phenyl] -aminomethyl] -benzimictazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethjpxycarbonylethyl) - amide <br><br> Prepared analog6u^ly to Example 90 from l-methyl-2-[N-(4-amidinophenyl)/- aminomethyl ] -benz imidazol - 5 -yl - carboxyl ic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloriae And 4-ethylbenzoylchloride. <br><br> Yield: 64 4 at theory, <br><br> C36H37N7°i ^631.7) <br><br> Rf value/ Gf. 78 (silica gel; dichloromethane/methanol = 9:1) <br><br> EKA ma^s ^pectrum: (M+H)+ = 632 <br><br> (M+H+Na)++ = 327.8 (M+Na)+ = 654 <br><br> NOW AMENDED <br><br> - 174 - <br><br> Example 174 <br><br> l-Methyl-2- [N- [4- (N-benzyloxycarbony]/ama.dino) phenyl] aminomethyl]-benzimidazol-5-yl-carboxmic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)/amade <br><br> Prepared analogously to Example fi0/from l-methyl-2-[N-(4-amidinophenyl) -aminomethyl] -berLEimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-10 hydrochloride and benzyl chloroformate. <br><br> Yield: 64 % of'theory, <br><br> c35h35n7o5 (633.6) <br><br> Rf value: 0.60 (silica ge/; /iichloromethane/methanol = 9:1) <br><br> EKA mass spectrum: (M+HO +/ = 634 15 (MyH+/la)++ = 328.8 <br><br> i+tia) + = 656 <br><br> Example 175 <br><br> 20 l-Methyl-2- [N- (4-/a.vxf.di.rvo-2-methoxy-phenyl) -aminomethyl] -benzimidazol-5-V-L-Carboxylic acid-N-phenyl-N- (2-hydroxycarbonyl/et/iyl) -amide <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4-25 amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic/aorid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 1JI 4 of theory, <br><br> C27H28%01 (500.6) <br><br> 30 Rf vaYue/: 0.15 (silica gel; dichloromethane/ethanol = 4:1) <br><br> EKA j/nafs spectrum: (M+H) + = 501 <br><br> (M+Na)+ = 523 (M+2Na)+ + = 273 <br><br> NOW AMENDED <br><br> - 175 - <br><br> Example 176 <br><br> l-Methyl-2-[N-(4-amidino-2-methoxy-phfen/1)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-Ny(2/pyridyl)-N-(2-5 ethoxycarbonylethyl)-amide-hydrochlorA.de <br><br> Prepared analogously to Example /5d/from l-methyl-2-[N-(4-cyano-2-methoxy-phenyl) -aminometthyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-M- /2-ethoxycarbonylethyl)-10 amide and ethanolic hydrochlo/ii/ acid, ethanol and ammonium carbonate. <br><br> Yield: 67 % of theory, <br><br> c28h31n7°4 (529.6) Rf value: 0.16 (silica dichloromethane/ethanol = 4:1) <br><br> 15 EKA. mass spectrum: (M+H/ + /= 530 <br><br> NOW AMENDED <br><br> 10 <br><br> 15 <br><br> - 176 - <br><br> Example 177 <br><br> l-Methyl-2- [N- (4-amidino-2-methoxy-pj^en^l) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N/(2/-pyridyl) -N- (2 hydroxycarbonylethyl)-amide <br><br> Prepared analogously to Example fc.6/from l-methyl-2-[N-(4- <br><br> lechyl]-benzimidazol-5-yl• [2-ethoxycarbonylethyl)-iydroxide solution. <br><br> amidino-2-methoxy-phenyl)-amine carboxylic acid-N-(2-pyridyl) <br><br> amide-hydrochloride and sodii Yield: 78 % of .theory, <br><br> C26H27N7°4 (501.6) <br><br> Rf value: 0.12 (silica ge/;/dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)/1" /= 502 <br><br> Example 178 <br><br> 20 <br><br> l-Methyl-2-[N-[4-(N/befazyloxycarbonylamidino)phenyl]-aminomethyl] -benzimidazol75-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbony/etzhyl) -amide <br><br> 25 <br><br> 30 <br><br> Prepared analog6usly to Example 104 from l-methyl-2-[N-[4-(N-benzyloxyca/rbiDnylamidino)phenyl] -aminomethyl] -benzimidazol-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonfyLethyl) -amide and sodium hydroxide solution. Yield: 62 H of theory, <br><br> 7605.7) <br><br> Rf value/ .26 (silica gel; dichloromethane/methanol = 9:1! <br><br> EKA ma^s /spectrum: (M+H)+ = 606 <br><br> (M+Na)+ = 628 (M-H+2Na)+ = 650 (M+2H)++ = 303.8 (M+H+Na)++ = 314.8 (M+2Na)++ = 325.7 <br><br> 35 <br><br> NOW AMENDED <br><br> - 177 <br><br> Example 179 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-pex^yloxy-n-propyl) 5 amide-hydrochloride <br><br> Prepared analogously to Example ^5/from l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-rL^propyl)-amide and ethanolic 10 hydrochloric acid, ethanol arva Ammonium carbonate. <br><br> Yield: 61 % of theory, <br><br> C33H34N6°2 (546.7) <br><br> Rf value: 0.19 (silica ge^; /lichloromethane/ethanol = 4:1) <br><br> EKA. mass spectrum: (M+H$+/ = 547 15 (MfH+jfra) ++ = 285 <br><br> Example 180 <br><br> l-Methyl-2- [N- [4- (N/n-^iexyloxycarbonylamidino) phenyl] aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-2 0 (3-benzyloxy-n-prppyl)-amide <br><br> 25 <br><br> 30 <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-ami di nopheny1)-aminome thy1]-benzimidazol-5-yl-carboxyli c acid-N-phenylA-N/ (3-benzyloxy-n-propyl) -amide-hydrochloride and n-hexyl/chloroformate. <br><br> Yield: 73 <br><br> c40h46n6°; Rf value, <br><br> EKA mag's theory, <br><br> J74 .9) <br><br> '.46 (silica gel; dichloromethane/ethanol = 9:1) <br><br> spectrum: (M+H)+ = 675 (M+H+Na)++ = 349 <br><br> (M+Na)+ = 697 <br><br> (M+K)+ = 713 <br><br> NOW AMENDED <br><br> - 178 <br><br> Example 181 <br><br> 10 <br><br> 15 <br><br> 20 <br><br> 3-Methyl-2-[2-(4-amidinophenyl)ethyli imidazo[1.2-a]pyridin-7-yl-carboxylac/acid-N-(2-pyridyl)-N-(2 - ethoxycarbonylethyl) - amide - hydrochloride <br><br> Prepared analogously to Example h. from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[1.2Va]pyridin-7-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxyoarbonylethyl)-amide-hydrochloride and ethanolic Jayc^rochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 53 % of theory, <br><br> C28H30n6o3 (498.59) <br><br> Rf value: 0.42 (silica gfel/ ethyl acetate/ethanol/ammonia = 50:45:5) <br><br> EKA mass spectrum: m+#)+ = 499 <br><br> /(M/2Na)++ = 272 (M+H+Na)++ = 261 '(M+2H)+ + = 250 <br><br> Example 182 <br><br> 25 <br><br> l-Methyl-2- [1^- (yf-amidino-pyridin-6-yl) -aminomethyl] -benzimidazol/-5/yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide <br><br> Prepared/analogously to Example 2 6 from 1-methyl-2-[N-(3/cyanopyridin-6-yl)-aminomethyl] -benzimidazol-5-yl-carboxyl^ acid-N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -3 0 amide/and sodium hydroxide solution. <br><br> YieLa:/40 % of theory, <br><br> C2^2/N8°3 (472.9) <br><br> R-/ v/lue: 0.67 (Reversed Phase silica gel RP-8; methanol/5' <br><br> saline solution = 1:1) <br><br> 35 / EJ(A mass spectrum: (M+H) + = 473 <br><br> NOW AMENDED <br><br> - 179 - / / <br><br> Example 183 / / <br><br> l-Methyl-2-[N-[4-(N-hydroxylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-/(2/pyridyl) -N- [2-5 (methansulphonylaminocarbonyl)-ethm]/amide a . l-Methvl-2- fN- (4-cvanophenvl) -&gt;^mi.nomethvl1 -benzimidazol- <br><br> 10 2.0 g (4.5 mmol) of l-methyl-2:- Dw-(4-cyanophenyl) -aminomethyl]-benzimidazol-5-ylyciarboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl) -amide and 0.73 g (4.7 mmol) of carbonyldiim/dafzole were dissolved in 80 ml of tetrahydrofuran and 5 pilot dimethylformamide and 15 stirred for 3 0 minutes ac ambient temperature and for 2 hours at 90°C. In paral/el 0.55 g (5.8 mmol) of methansulphonic acid amide and 0.28 g (5.8 mmol) of sodium hydride were suspended pn 15 ml of dimethylformamide and stirred for 2 hours/at/ambient temperature. Then this 20 suspension was added At ambient temperature to the tetrahydrofuran solution. After 12 hours at ambient temperature 50 ml at 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 chloride/ettfianol (40:1)). The desired fractions were combined afndJevaporated down. Yield: 1.05 g (44 % of <br><br> 30 C26H25NyO^S (531.6) <br><br> Rf value/ 0.72 (silica gel; dichloromethane/methanol = 9:1) <br><br> NOW AMENDED <br><br> - 180 - / / <br><br> b. l-Methvl-2 - TN- f4- (N-hvdroxvlamidino)phenyl 1 -aminomethvll -benzimidazol-5-vl-carboxv/ic acid-N- (2-pvridvl) -N- l"2- (methansulphonvl/arn/Lnocarbonvl) -ethvll -5 amide / / <br><br> Prepared analogously to Example S&gt;6 Arom 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]yfcenzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-Y2-(methanesulphonylaminocarbonyi)/ethyl]-amide and 10 hydroxylamine. / / <br><br> Yield: 27% of theory, / / <br><br> C26H28N805S (564.6) / / <br><br> Rf value: 0.75 (silica gel -J dichloromethane/ethanol = 7:3 + 1% glacial acetic acid)/ / <br><br> 15 EKA mass spectrum: (IH+&amp;)/ = 565 <br><br> (M4N/) + = 587 <br><br> Example 184 / / <br><br> 20 l-Methyl-2- [N- (5/amadino-thiazol-2-yl) -aminomethyl] -benzimidazol-5-ylyfcarboxylic acid-N-(2-pyridyl) -N-(2-ethoxycarbonylettiyl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d from 1-methyl-25 2-[N-(5-cyano/thiazol-2-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic/ acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide andr ethanolic hydrochloric acid, ethanol and ammonium carbonatfe./ <br><br> 3 0 Example A85 <br><br> l-MfitMyl-2-[N-(5-amidino-thiazol-2-yl)-aminomethyl]-beAz/midazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-bydroxycarbonylethyl)-amide <br><br> 3 5 / / <br><br> / Prepared analogously to Example 26 from 1-methyl-/ A- [N-(5-amidino-thiazol-2-yl)-aminomethyl]-benzimidazol- <br><br> NOW AMENDED <br><br> - 181 - / / <br><br> 5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- / ethoxycarbonylethyl)-amide-hydrochlor/dor and sodium hydroxide solution. / / <br><br> 5 Example 186 / / <br><br> 1-Methyl-2- [N- (2-amidino-pyrazinr-5Ayl) -aminomethyl] -benzimidazol-5-yl-carboxylic acfid^N- (2-pyridyl) -N- (2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 10 / <br><br> Prepared analogously to Exampl/e 25d from 1-methyl- <br><br> 2-[N-(2-cyano-pyrazin-5-yl/-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyriay1)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrocliloric acid, ethanol and ammonium <br><br> 15 carbonate. / / <br><br> Yield: 19 % of theory, / <br><br> c25h27n9°3 (501.6) / / <br><br> Rf value: 0.28 (sificfa gel; dichloromethane/methanol = 4:1 + 1% glacial acetic acid) <br><br> 20 EKA mass spectrun/: / (M+H)+ = 502 <br><br> / / (M+H+Na)+ = 262.5 <br><br> Example 187 / / <br><br> 25 l-Methyl-2y[N/(2-amidino-pyrazin-5-yl)-aminomethyl]-benzimidazol/5-yl-carboxylic acid-N- (2-pyridyl)-N-(2-hydroxycafrbyonylethyl) -amide <br><br> Prepared Analogously to Example 26 from 1-methyl-30 2-[N-/2/amidino-pyrazin-5-yl)-aminomethyl]-benzimidazol-5-yl/catrboxylic acid-N- (2-pyridyl) -N- (2-ethpxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> me/d: 11 % of theory, <br><br> 35 /C2AH23N9O3 (473.5) <br><br> NOW AMENDED <br><br> - 182 - <br><br> Rf value: 0.55 (Reversed Phase silic^g^l RP-8; 5% saline solution/methanol = 6:4) <br><br> EKA mass spectrum: (M+H)+ = 474, <br><br> (M+H+Na)+ = 4! <br><br> Example 188 <br><br> 10 <br><br> l-Methyl-2-[2-[4-(N-n-hexylox^ ethyl]-benzimidazol-5-yl-carl (lH-tetrazol-5-yl)-ethyl]-amic rbonylamidino)phenyl]-'■lie acid-N-phenyl-N- [2- <br><br> 15 <br><br> Prepared analogously to Exarafele 90 from l-methyl-2-[2-(4 amidinophenyl) -ethyl] -benzi/midazol-5-yl-carboxylic acid-N-phenyl-N- [2-(lH-tetraEoY-5-yl)-ethyl]-amide and n-hexyl chloroformate. <br><br> Example 18 9 <br><br> l-Methyl-2 - [N- (2-t 2 0 phenyl)-aminomet} phenyl-N-(2-etho ioxy-4-n-pentoxycarbonylamidino--benzimidazol-5-yl-carboxylic acid-N-:arbonylethyl)-amide <br><br> 25 <br><br> 30 <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic Ac/d-N-phenyl-N-(2-ethoxycarbonylethyl)-amide- <br><br> Lde and n-pentyl chloroformate. <br><br> Yield: 53/ %/of theory, <br><br> C35H42N066/(642.7) <br><br> Rf value:/ 0.54 (silica gel; dichloromethane/ethanol = 9:1 ) <br><br> EKA <br><br> spectrum: <br><br> (M+H)+ = 643 <br><br> (M+H+Na)++ = 333.4 <br><br> NOW AMENDED <br><br> - 183 - <br><br> Example 190 <br><br> l-Methyl-2-[N-(4-n-heptyloxycarbonyL&amp;mfdino-2-methoxy -phenyl)-aminomethyl]-benzimidazol-^-y/-carboxylic acid-N-5 phenyl-N- (2-ethoxycarbonylethyl) -#mi£ie <br><br> Prepared analogously to Example/9Q/ from l-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-amin®methyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2/ethoxycarbonylethyl)-amide-10 hydrochloride and n-heptyl chloroformate. <br><br> Yield: 68 % of theory, <br><br> C37H46N606 (670.8) <br><br> Rf value: 0.56 (silica g^Q.;/dichloromethane/ethanol = 9:1 ) EKA mass spectrum: (M+J&amp;) J = 671 <br><br> 15 (I^+H/Na)++ = 347.4 <br><br> Example 191 <br><br> l-Methyl-2-[N-(4-etftoxycarbonylamidino-2-methoxy-phenyl) 20 aminomethyl]-ben^eimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidino-2-m^ch/oxy-phenyl) -aminomethyl] -benzimidazol-5-yl-25 carboxylic /acad-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydroonloride and ethyl chloroformate. <br><br> Yield: 4/ V of theory, <br><br> JOd (601.7) <br><br> Rf valy&amp;e/ 0.44 (silica gel; dichloromethane/ethanol = 9:1) <br><br> 30 EKA xyfa^fe spectrum: (M+H) + = 602 <br><br> (M+H+Na)++ = 312.8 <br><br> NOW AMENDED <br><br> - 184 - / / <br><br> Example 192 / / <br><br> l-Methyl-2- [N- (2-methoxy-4-n-pentoxycarbonylamidino-phenyl)-aminomethyl]-benzimidazol-yl-carboxylic acid-N-5 (2-pyridyl) -N- (2-ethoxycarbonylethfylfl -amide <br><br> Prepared analogously to Example/9(y from l-methyl-2-[N-(4-amidino-2-methoxy-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)/n/(2-ethoxycarbonylethyl)-10 amide-hydrochloride and n-pentyl chloroformate. <br><br> Yield: 72 % of theory, / / <br><br> C34H41N7°6 (643.7) / / <br><br> Rf value: 0.49 (silica gel;/ dichloromethane/ethanol = 9:1) EKA mass spectrum: (M+H)/ = 644 <br><br> 15 (M+H/Na)++ = 333.9 <br><br> Example 193 / / <br><br> l-Methyl-2- [N- (2-meraioxy-4-n-heptyloxycarbonylamidino-20 phenyl) -aminometliyl/j -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidino-2-methoxy-phenyl) -aminomethyl] -benzimidazol-5-yl-25 carboxylic Ac/d-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-heptyl chloroformate. <br><br> Yield: 55^ y of theory, <br><br> C36H45N/O0' (671.8) <br><br> Rf valiae/ 0.54 (silica gel; dichloromethane/ethanol = 9:1) <br><br> 30 EKA mass spectrum: (M+H)+ = 672 <br><br> / / (M+H+Na)++ = 347.9 <br><br> NOW AMENDED <br><br> Example 194 <br><br> Dry ampoule containing 75 mg of actiys &gt;substance per 10 ml <br><br> Composition: <br><br> Active substance Mannitol 10 water for injections <br><br> 75.0 mg 50.0 mg ad 10.0 ml <br><br> 15 <br><br> Preparation: <br><br> Active substance and manni l are dissolved in water. <br><br> After packaging the solutzi is freeze-dried. To produce the solution ready for yis^ ;he product is dissolved in water for injections <br><br> NOW AMENDED <br><br> - 186 <br><br> Example 195 <br><br> Dry ampoule containing 3 5 mg of active/substance per 2 ml <br><br> Composition: <br><br> Active substance Mannitol 10 water for injections <br><br> 3 5.0 mg 100.0 mg ad 2.0 ml <br><br> 15 <br><br> Preparation: <br><br> Active substance and manr/it&gt;6l are dissolved in water. After packaging, the solutionJi.sJ freeze-dried. <br><br> To produce the solution/ready for use, the product is dissolved in water for/injections. <br><br> 20 Example 196 <br><br> Tablet containimc/ 50 mg of active substance <br><br> 25 Composition/ <br><br> 30 <br><br> Active <br><br> (1) <br><br> (2) Lac <br><br> (3) Ma <br><br> (4) Pgfl <br><br> (5) yia substance ze/ starch inylpyrrolidone esium stearate <br><br> 50.0 mg 98.0 mg 50.0 mg 15.0 mg 2 .0 mg <br><br> 215.0 mg <br><br> 35 <br><br> NOW AMENDED <br><br> - 187 - <br><br> biplanar, faceted on both sides and wit} on one side. <br><br> Diameter of the tablets: 9 mm. <br><br> dividing notch <br><br> 5 Example 197 <br><br> Tablet containing 3 50 mg of active substance <br><br> 10 Preparation: <br><br> 15 <br><br> (1) Active substance <br><br> (2) Lactose <br><br> (3) Maize starch <br><br> (4) Polyvinylpyrrolidone <br><br> (5) Magnesium stearate <br><br> 350.0 mg <br><br> 136.0 mg <br><br> 80.0 mg <br><br> 3 0.0 mg <br><br> 4 .0 mg <br><br> 600.0 mg <br><br> 20 <br><br> 25 <br><br> (1) , (2) and (3) ard md_xed together and granulated with an aqueous solution of &lt;A) . (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. <br><br> Diameter of the tablets: 12 mm. <br><br> Example 198 <br><br> Capsules ctorycaining 50 mg of active substance <br><br> 3 0 Compos i/ic <br><br> 35 <br><br> (1) Aj6t^ve substance <br><br> (2) £&gt;rjfed maize starch <br><br> (3)/Powdered lactose {4/i Magnesium stearate <br><br> 50.0 mg <br><br> 58.0 mg <br><br> 50.0 mg <br><br> 2. 0 mg <br><br> 160.0 mg <br><br> NOW AMENDED <br><br> - 188 <br><br> Preparation: <br><br> (1) is triturated with (3) . This tritAir&amp;tion is added to the mixture of (2) and (4) with vigorous mixing. <br><br> 5 This powder mixture is packed into/size 3 hard gelatin capsules in a capsule filling macyhij^e. <br><br> Example 19 9 <br><br> 10 Capsules containing 350 mg of active substance <br><br> Composition: <br><br> 15 <br><br> 20 <br><br> (1) Active substance <br><br> (2) Dried maize starcl <br><br> (3) Powdered lactose <br><br> (4) Magnesium stearate/ <br><br> 350.0 mg <br><br> 46.0 mg <br><br> 30.0 mg <br><br> 4 . 0 mg <br><br> 43 0.0 mg <br><br> Preparation: <br><br> (1) is triturated with (3). This trituration is added to the mixture of K2) and (4) with vigorous mixing. <br><br> 25 <br><br> This powder m/xtzure is packed into size 0 hard gelatin capsules in /k papsule filling machine. <br><br> Example 2 0/ <br><br> 30 <br><br> Suppositiora.es containing 100 mg of active substance <br><br> 35 <br><br> 1 suppository contains: <br><br> Actyve substance ?o/yethyleneglycol (M.W. 1500) P^lyethyleneglycol (M.W. 6000) Polyethylenesorbitan monostearate <br><br> 10 0.0 mg 60 0.0 mg 460.0 mg 840.0 mg 2,000.0 mg <br><br> m <br><br> - 189 - <br><br> Patent Claims <br><br> 1. Disubstituted bicyclic heterocycles of general: formula wherein <br><br> 10 <br><br> A denotes a carbonyl or sulphonyl group Linked to/the benzo, pyrido, pyrimido, pyrazino, pyrdjaazino oy thieno moiety of the group Het, whilst moreoyer the Movementioned moieties may not contain an Rx group/ <br><br> 15 <br><br> B denotes an ethylene group, in Jifhich 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 -NRj- group, wherein <br><br> Rx denotes a hydrogen atom pr a G^-alkyl group, <br><br> 20 E denotes an RhNH-CC/nh)- group wherein <br><br> 25 <br><br> Rb denotes ar hydrogarf atom, a hydroxy group, a C1_3-alkylygroup or/a group which may be cleaved in vivo, <br><br> Ar denotes a phenylene group optionally substituted by a fluorirjfe, chlorine or bromine atom or by a trifluoromethyl, <br><br> C^-aZkyl or <br><br> -alkoxy group, <br><br> 3 0 a/thienylene, thiazolylene, pyridinylene, pyrimidinylene, <br><br> jyrazinyZene or pyridazinylene group optionally substituted in the/carbon skeleton by a C1_3~alkyl group, <br><br> Key denotes a bicyclic heterocycle of formula <br><br> 35 <br><br> I INTELLECTUAL"PROPERTY OFFICE! | OF N.Z. j j 1 1 MAY 2000 RECEIVED <br><br> - 189- <br><br> Patent Claims <br><br> 1. Disubstituted bicyclic heterocy/les of general formula <br><br> Ra - A - Het - B - Ar <br><br> , (I) <br><br> wherein <br><br> A denotes a carbonyl or sulpho/ 10 benzo, pyrido or thieno moietjj group linked to the the group Het, <br><br> 15 <br><br> 20 <br><br> 25 <br><br> B denotes an ethylene group/ im which the methylene group linked to the group Ar maw be replaced by an oxygen or sulphur atom or by an -NI54-/group, wherein <br><br> Ri denotes a hydrpgsn atom or a Ci-4-alkyl group, <br><br> E denotes an RbNH-C(^NM)- group wherein <br><br> Rb denotes a iiyarogen atom, a hydroxy, Ci-g-alkoxycarhonyl, cyclohexyloxycarbonyl, phenyl-Ci-3-alkoxy/acfcionyl, benzoyl, p-Ci-3-alkyl-benzoyl or pyridinoy/ cproup, whilst the ethoxy moiety in the 2-positi®n/of the abovementioned Ci-g-alkoxycarbonyl group may /additionally be substituted by a Ci_3-alkyl-sulfonjpl /or 2- (Ci-3-alkoxy) -ethyl group, <br><br> 30. <br><br> Ar donates a 1,4-phenylene group optionally substituted by a chlorine atom or by a methyl, ethyl or/m/thoxy group or it denotes a 2,5-thienylene group, <br><br> 35 <br><br> 40/ <br><br> ielf denotes a 1-{Ci_3-alkyl) -2, 5-benzimidazolylene, 1- <br><br> c/clopropyl-2,5-benzimidazolylene, 2,5- <br><br> 'enzothiazolylene, 1- (Ci_3-alkyl) -2, 5-indolylene, <br><br> '1- (Ci_3-alkyl) -2, 5-imidazo{ 4, 5-b) pyridinylene, 3- (C1-3- <br><br> alkyl)-2, 7-imidazo{1, 2-a] pyridinylene or 1-(Ci-3- <br><br> alkyl)-2, 5-thieno{2,3-d]imidazolylene group and ffN'FELLEGTU/-u. r£l. OFFICE OF SM.Z <br><br> R4 denotes an R2NR3- group wherein <br><br> P F <br><br> NOV 2008 v i <br><br> NOW AMENI <br><br> - 190 <br><br> , wherein <br><br> X is a nitrogen atom and <br><br> 10 <br><br> Y is an oxygen or sulphur atom or / nitrogen atom optionally substituted by a C^-alkyl or C3^7-cycloalkyl group, whilst additionally ofae or two non-angular methyne groups in/the phenylymoiety of the above-mentioned bicyclic hejrerocycle ma# each be replaced by a nitrogen ate <br><br> 15 <br><br> or X denotes a methyne/group optionally substituted by the group Rlf wherein/R^ is as hereinbefore defined, <br><br> and <br><br> Y denotes a nitrogen atom optionally substituted by a C-L.g-alkyl or Cy^-cycloalky^ group, <br><br> 20 <br><br> or Het denotes a/group of thUe formulae <br><br> N- <br><br> N <br><br> Ri <br><br> R, <br><br> 25 <br><br> s—rr <br><br> *2 <br><br> -N <br><br> -N <br><br> ,*JT!„LL£CTUAL PROPERTY OFFICE OF N.Z <br><br> j I i'iAt 2C0u <br><br> RECEIVED <br><br> NOW AMENDED <br><br> R2 is a Ci-4-alkyl group substiti Ci-6-alkyloxycarbonyl, benzylc Ci-3-alkylsulphonylaminocarbon^ group, <br><br> ejfl by a carboxy, <br><br> bonyl, 'or lH-tetrazol-5-yl a C2-4-alkyl group substituted by a hydroxy, benzyloxy, carboxy-Ci-3-alkylamino, c/-3/alkoxycarbonyl-Ci-3-alkylamino, N- (Ci-3-aikyl) -carboxy-Cx-3-alkylamino or N- (Ci-3-alkyl) -Ci^3-aLkoxycarbonyl-Ci-3-alkylamino group, whilst in the afeo/ementioned groups the carbon atom in the a-positiofo po the adjacent nitrogen atom may be not substitutive <br><br> R3 denotes a C3-7-aycjtoalkyl 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, pVritlazolyl or pyridinyl group optionally substituted/bv a methyl group or <br><br> R2 and R3 yfcoj^ether with the nitrogen atom between them denote a/5-/ to 7-membered cycloalkyleneimino group, optiona/lV substituted by a carboxy or Ci-4-alk-oxycarKoriyl group, to which a phenyl ring may addit/opally be fused. <br><br> the tautyom/rs, the stereoisomers and the salts thereof. <br><br> .substituted bicyclic heterocycles of general formula )rsling to claim 1, wherein <br><br> A dferuotes a carbonyl or sulphonyl group linked to the bofazjo, pyrido or thieno moiety of the group Het, <br><br> ienotes an ethylene group in which the methylene group .nked to the group Ar may be replaced by an oxygen or sulphur atom or by an —NR3.- group, wherein sCE OF N.: <br><br> r. o <br><br> L - <br><br> R, is as hereinbefore' defined, <br><br> 2 denotes an oxygjen or sulpKur atom one of the gro/ps, D or G/denotes a nitrogen atom and the other grahp D or G/aenotes a methyne group, <br><br> and Ra denotes A C^-alky,! group, a C3_7~cycloalkyl group optionally substituted py a C-^-alkyl group, wherein the Cx_3-alkyl gi?oup may additionally be substituted by a carboxyl group or' by a group which may be converted in vivo into a carboxy grq£p, <br><br> or a yi£3NR3- group wherein es a C^-alkyl group, which may be substituted by a &lt;/arboxy, C^-alkyloxycarbonyl, benzyloxycarbonyl, <br><br> ilkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, trifluorosulphonylamino, <br><br> :ifluorosulphonylaminocarbonyl or IH-tetrazolyl ''group, <br><br> intellectual of N.Z. <br><br> 1 'MAY <br><br> Qcociwrrv <br><br> NOW AMENDED <br><br> - 191 <br><br> Ri denotes a hydrogen atom or a nfetnyl group, <br><br> E denotes an RbNH-C{=NH)- group, where <br><br> .n <br><br> 10 <br><br> Rb denotes a hydrogen atom oi af hydroxy, Ci-g-alkoxycarbonyl, cycloheKy/oxycarbonyl, benzyloxycarbonyl, benzoyl/ ip-Ci-3-alkylbenzoyl or nicotinoyl group, whilst fihp ethoxy moiety in the 2-position of the abovemeiytioned Ci-9-alkoxycarbonyl group may additionally p&amp;f substituted by a C1-.3-alkylsulphonyl or 2- ((A-3/alkoxy) -ethyl group, <br><br> Ar denotes a 1, 4-phenylenre /jroup optionally substituted by 15 a chlorine atom or by a /methyl, ethyl or methoxy group, or it denotes a 2,5-thienyl^ne group. <br><br> Het denotes a 1-methVl-12., 5-benzimidazolylene, 1-cyclopropyl-2,5-ben/irrtidazolylene, 2,5-benzothiazolylene, 20 l-methyl-2,5-indolylene, 1-methyl- <br><br> 2,5-imidazo[4,5-b/pyridinylene, 3-methyl-2,7-imidazo[1,2-a]dyridinylene or 1-methyl-2, 5-thieno [2, 3-/a] /imidazolylene group and <br><br> 25 <br><br> Ra denotes a K2NR3- group wherein <br><br> R2 den^tefe a Ci_3-alkyl group which may be substituted by a ycarboxy, Ci-e-alkyloxycarbonyl, benzyloxycarbonyl, methA^l/ulphonylaminocarbonyl or lH-Letrazol-5-yl grc/ipy <br><br> C/_3~alkyl group substituted by a hydroxy, benzyloxy, /ca^boxy-Ci-3-alkylamino, C1-3-alkoxycarbonyl -C/-3-alkylamino, N- (Ci_3-alkyl) -carboxy-Ci-3-alkylamino &gt;r N- (Ci_3~alkyl) -Ci-3-alkoxycarbonyl-Ci-3-alkyla:mino group, whilst in the abovementioned groups the carbon atom in the a-position to the adjacent nitrogen atom may not be substituted, and <br><br> R3 denotes a propargyl group, wherein the: unsaturai f * y <br><br> ; 2 U N«J ^ lwo - « <br><br> ■ Q ^ f . a/ f* <br><br> - 192 <br><br> a C2_4-alkyl group substituted by a hydroxy, jjaenyl-C1.3-alkoxy, carboxy-C^-alkylamino, C^. alkoxycarbonyl-C^-alkylamino, N- (C1„3-alkyl) -carboxy^ C-L.3-alkylamino or N- {^^-alkyl) -Cj.j-alkowcarbonyl-alkylamino group, whilst in the abovenysntioned groups the carbon atom in the a-position relative to t^tie adjacent nitrogen atom may not be Substituted/, or <br><br> 10 <br><br> a piperidinyl group optionally /substituted^ by a <br><br> C^3-alkyl group and <br><br> 15 <br><br> R, denotes a hydrogen atorn^ <br><br> a C^g-alJ <br><br> group, a <br><br> C3_7-cycloalkyl group optionally substituted by a C.^3-alkyl group, a C3_6,alkenyi oryalkynyl group, wherein the unsaturated part may not be linked directly to the nitjfogen atom-of the R2NR3- group, <br><br> 20 <br><br> a phenyl group optionally substituted by a fluorine, chlorine or bremine atom/or by a C^-alkyl or C-^-alkoxy gwoup, a benzyl, oxazolyl, isoxazolyl, thiazolyl, XsothiazolVl, pyrazolyl, pyrrolyl, thienyl, pyridinyl/ pyrimidioyl, pyrazinyl, pyridazinyl, imidazojyl or piporidinyl group or <br><br> 25 <br><br> 30 <br><br> r, <br><br> ra R3 together with the nitrogen atom between them derfote a 5- t*6 7-membered cycloalkyleneimino group, <br><br> jtionally .substituted by a carboxymethyl or 'C1.4-alkoxycai'bonyl group, onto which additionally a phenyl rang may be fused, <br><br> the tautoj/ers, the stereoisomers and the salts thereof. <br><br> 35 <br><br> 2. n/substituted bicyclic heterocycles of general formula I according to claim 1, wherein denotes a carbonyl or sulphonyl group linked to the jenzo, pyrido, pyrimido, pyrazino, pyrid„ __ . <br><br> ^ ' intellectual property office of tiz <br><br> 1 f MAY 2000 <br><br> RECEIVED <br><br> NOW AMENDED <br><br> -192- <br><br> moiety may not be linked directly/tcV the nitrogen atom of the R2NR3 group, a phenyl group optionally substituted by a fluorine or chiom.ne atom, or by a methyl or methoxy group or it ^leiyotes a pyridinyl 5 group, <br><br> the tautomers, the stereoisomers/and the salts thereof. <br><br> 3. Disubstituted bicyclic here^/ocycles of general formula 10 I according to claim 1, where/ny <br><br> A denotes a carbonyl group yiij^ked to the benzo or thieno moiety of the group Het. <br><br> 15 B denotes an ethylene qifiufi wherein the methylene group attached to the group Tp: ^iay be replaced by an -NRi group, whilst <br><br> 20 <br><br> Ri denotes a hwar®gen atom or a methyl group, E denotes an RbNH-yC (yNH) - group wherein <br><br> 25 <br><br> 30 <br><br> Rb is a hydrogen atom, a hydroxy, Ci-g-alkoxycarbonyl, cyclohexy/oxiycarbonyl, benzyloxycarbonyl, benzoyl, p-Ci_3-alkyy-benzoyl or nicotinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned Ci-g-allcowcarbonyl group may additionally be subst/tyted by a methylsulfonyl or 2-ethoxy-ethyl groui <br><br> Ar denoresr a 1,4-phenylene group optionally substituted by a methoxy group or it denotes a 2,5-thienylene group, <br><br> Het nemotes a l-methyl-2,5-benzimidazolylene, 35 2, ^-benzothiazolylene, l-methyl-2,5-indolylene or 1-methyl-2,^-^hieno[2,3-d]imidazolylene group and <br><br> /denotes an R2NR3- group wherein <br><br> 40, <br><br> R2 denotes a Ci_3-alkyl group which may be substituted <br><br> 10 <br><br> moiety of the group Het, whilst moreover the aboyementionec moieties may not contain an Rx group, <br><br> B denotes an ethylene group in which the methylene gro/p linked to the group Ar may be replaced by fn oxygen sulphur atom or by an -NR,_- group, whereii <br><br> Ri denotes a hydrogen atom oj a G^-alkyl group, <br><br> E denotes an RbNH-C(=NH)- group wherein <br><br> 15 <br><br> 20 <br><br> Rb denotes a hydrogen Atom, a hydroxy, Ci-9-alkoxycarbonyl, ^cyclohexyloxycarbonyl, phenyl- <br><br> Ci-3-alkoxycarbonyLf benzoyl, p-C^-3-alkyl-benzoyl or pyridinoyl group, A/hi1st the/ethoxy moiety in the 2-position of the abovementioned Ci_g-alkoxycarbonyl group may additionally be/substituted by a C]__3~alkyl-sulfonyl or p.-(C]_„3-alkj/xy) -ethyl group, <br><br> 25 <br><br> Ar denotes ap_, 4-phenylene group optionally substituted by a chlorine ^atom or by af methyl, ethyl or methoxy group or it denote/ a 2, 5-thie^nylene group, <br><br> 30 <br><br> Het demotes a 1--3-alkyl)-2,5-benzimidazolylene, 1-cycl^propyl-2 , 5-lSenzimidazolylene, 2 , 5-benzothiazolylene, 1- OC2._3-alkyl) yl, 5-indolylene, 1- (C;j__3~alkyl) -2A 5-imidazo[y 5-b]pyridinylene, 3-(C^,3-alkyl)-2 , 7-imidazo/[l, 2-a] pyridinylene or 1-(C]__3-alkyl) -2 , 5-thien*5[2 , 3-d] imidazolylene group and <br><br> 35 <br><br> Ra denotes an R2NR3- group wherein <br><br> INTELLECTUAL PROPERTY OFFICE | OF N.Z. <br><br> t 1 MAY 2000 <br><br> RECEIVED <br><br> NOW AMENDED <br><br> 11 <br><br> 193- <br><br> by a carboxy, Ci_6-alkyloxycarbonyY, benzyloxycarbonyl, methylsulfonylaminocarbonyl or lH-t^trazol-5-yl group, <br><br> 10 <br><br> a C2-3-alkyl group substituted jpy fa hydroxy, benzyloxy, carboxy-Ci_3-alkylamino, Ci-3-a/koxycarbonyl- C1-3-alkylamino, N-(Ci^3-alkyl)-ca/ba6cy-Ci-3-alkylamino or N-(Ci-3-alkyl) -Ci-3-alkoxycarboXyy-Ci-3-alkylaiaino group, whilst in the abovementionied /groups the carbon atom in the a-position to the adj^ac/nt nitrogen atom may not be substituted, and <br><br> R3 denotes a phenyl gr®ujy optionally substituted by a fluorine atom, or it yae/otes a 2-pyridinyl group, <br><br> 15 the tautomers, stereoisomers and the salts thereof. <br><br> 4. The following cor inds of general formula I: <br><br> (a) 2- [N- (4-amidino/plyenyl) -aminomethyl] -benzthiazole-5 <br><br> 20 carboxylic acid-N-cmerLyl-N- (2~carboxyethyl) -amide, <br><br> (b) 2- [N- (4-amiGfiri(Ophenyl) -N-methyl-aminomethyl] -benzthiazol-5-yi-TCarboxylic acid-N-phenyl-N- (2-hydroxycarbonyl^thyl)-amide, <br><br> 25 <br><br> (c) l-Methy/-^- [N-(4-amidinophenyl)-aminomethyl] benzimidaz©l-V5-yl-carboxylic acid-N-phenyl-N- (2-hydroxycarbomylethyl)-amide, <br><br> 30 (d) l-M4thfyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzinyLdarzol-5-yl-carboxylic acid-N-phenyl-N- (3-hydroKyaarbonylpropyl)-amide, <br><br> 35 <br><br> (e) / l/Methyl-2-[N-benzimidazol-5-yl-carboxylic acid-N-(2-p^stiayl) -N- (hydroxycarbonylmethyl)-amide, <br><br> :)j l-Methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]- <br><br> ;nzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-iydroxycarbonylethyl)-amide, <br><br> 28 NOV <br><br> . # V <br><br> R2 is a C1_4-alkyl group substituted by a/carboxyy C]_- g -alkyloxycarbonyl, benzyloxycarbom <br><br> C1_3-aXkyXsuXphonyXaminocarbonyi or ^-tetra^fel-S-yl group, <br><br> 10 <br><br> a C2-4-alkyl group substituted by a hydroxy, benzyloxy, carboxy-C]_„ 3 - alkylamino, C1„3-slkoxycaB!bonyl-Ci-s-alkylamino, N- (Ci_3-alkm) -carboKy-Ci_3-alkylamino or N-(Cx-3™alkyl)-Cx_3-alko/ycarborwl-C1_3-alkylamino group, whilst in the aboWmention^a groups the carbon atom in the a-position yfo the adjacent nitrogen atom may not be substituted^ <br><br> 15 <br><br> 20 <br><br> R3 denotes a C3_7-c/cloalky/ group, a propargyl group, wherein the unsaturated paort may not be linked directly to the nitrogen /torn of /he R2NR3 group, a phenyl group optionally subsxitutedyfoy a fluorine or chlorine atom, or by a metftwf or metjioxy group, a pyrazolyl, py-ridazolyl oy pyridi^yl group optionally substituted by a methyl g/oup or <br><br> 25 <br><br> R2 and JX3 together with the nitrogen atom between them denot^/ a 5- t&lt;? 7-membered cycloalkyleneimino group, optionally s/bstituted by a carboxy or Cx-4-alk- <br><br> oxycarJDonyjf group, to which a phenyl ring may Iditiona/ly be fused, <br><br> tautomers, the stereoisomers and the salts thereof. <br><br> 30 /3. Disubstituted bicyclic heterocycles of general formula I according to claim 1, wherein <br><br> A denotes a carbonyl or sulphonyl group linked to the fozo, pyrido or thieno moiety of the group Het, whilst Moreover the abovementioned moieties may not contain an Rx group, <br><br> Intellect of nz <br><br> 1 1 MAY 2000 Qcrcix/cn I <br><br> NOW AMENDED <br><br> - 194- <br><br> (g) l-Methyl-2-[N-(4-amidinophenyl) -ar benzimidazol-5-yl-carboxylic acid-N-j/2-hydroxycarbonylethyl)-amide, <br><br> Smethyl] -jyridyl) -N- (2- <br><br> 5 (h) l-Methyl-2-[2-(4-amidinopheny/)ethyl}-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl)/N-/(2-hydroxycarbonylethyl)-amide, <br><br> (i) l-Methyl-2- [2- (4-amidinopiie]^yl) ethyl] -benzimidazol-5-10 yl-carboxylic acid-N-phenyl-^-/2-hydroxycarbonylethyl)-amide, <br><br> 15 <br><br> (j) l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-ph^riy/-N- [2- (lH-tetrazol-5-yl) ethyl] amide, <br><br> 20 <br><br> (k) l-Methyl-2- [N- (4/amidinophenyl) -aminomethyl] -benzimidazol-5-yl-cao:b/oxylic acid-N-phenyl-N- [2- (1H-tetrazol-5—yl) ethy/] -yamide, <br><br> (1) l-Methyl-2-{tf- (^-amidinophenyl)-N-methyl-aminomethyl] benzimidazol-5-y/-garboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonyletijyl) -amide, <br><br> 25 (m) l-Methyl/2-/[N-(4-amidinophenyl)-N-methyl-aminomethyl] benzimidazol/5-Vyl-carboxylic acid-N- (3-pyridyl) -N- (2-hydroxycarb®nyiethyl)-amide, <br><br> (n) l-Meythyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] 30 benzimidfizal-5-yl-carboxylic acid-N-phenyl-N-(2-hydrox^ca/bonylethyl-amide, <br><br> (o) /L-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzam/dazol-5-yl-carboxylic acid-N-phenyl-N-[(N-hy^/roxycarbonylethyl-N-methyl) -2-aminoethyl] -amide, <br><br> &gt;)/ l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]- <br><br> Lzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-fdroxycarbonylethyl)-amide, <br><br> 20 <br><br> B denotes an ethylene group in which the methylene grdup linked to the group Ar may be replaced by an/oxygen px sulphur atom or by an -NR,- group, wherein <br><br> Rx denotes a hydrogen atom or a methyl grou^, <br><br> E denotes an RbNH-C (=NH) - group, wherein <br><br> 10 <br><br> 15 <br><br> Rb denotes a hydrogen atom or A hydrox Ci.9-alkoxycarbonyl, cyclohe^loxycarfconyl, benzyloxycarbonyl, benzoyl/ p-C^-alkylbenzoyl or nicotinoyl group, whilst ythe ethq?xy moiety in the 2-position of the abovemeytioned alkoxycarbonyl group may additionally/be substituted by a C.^-alkylsulphonyl or 2-^^-alkgxy)-ethyl group, <br><br> Ar denotes a 1,4-phen/lene gr/up optionally substituted by 2 0 a chlorine atom or by a methyl, ethyl or methoxy group, or it denotes a 2,5-tKienylen^ group, <br><br> Het denotes a l/methyl-;/, 5-benzimidazolylene, 1-cyclopropyl-2 -benz iimdazolyl ene, 2 , 5-benzothiazolylene, 25 l-methyl-2 , 5/indolyleft.e, 1-methyl- <br><br> 2, 5-imidazO/f4, 5-b] pyridinylene, 3 -methyl-2,7-imidazo[1,2-alpyridinylene or 1-methyl-2 , 5-thieao[2,3-dyimidazolylene group and <br><br> 3 0 Ra dei?i!otes a W2NR3- group wherein <br><br> 35 <br><br> R2 denotes a C]_~3-alkyl group which may be substituted by aycarboxy, C]__ g-alkyloxycarbonyl, benzyloxycarbonyl, metMylsulphonylaminocarbonyl or lH-tetrazol~5-yl group, <br><br> C2,3-alkyl group substituted by a hydroxy, benzyloxy, <br><br> carboxy-C]_„3-alkylamino, Ci -alkoxycarbonyl- <br><br> intellectual property office] of n.2. <br><br> I f MAY 2000 <br><br> RECEIVED <br><br> -195- <br><br> {q) l-Methyl-2- [N- (4-amidinophenyl) -airtinibmethyl] -benzimidazol-5-yl-carboxylic acid-N-(/-^luorophenyl)-N-(2-hydroxycarbonylethyl)-amide, <br><br> (r) l-Methyl-2-[N-{4-amidino-2-aminomethyl]-benzimidazol-5-yl-ca^ hydroxycarbonylethyl)-amide, <br><br> flipfethoxy-phenyl) -_c acid-N-phenyl-N- <br><br> (s) l-Methyl-2- [N- (4-amidino-^-iAethoxy-phenyl) -10 aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonVLe£hyl)-amide, <br><br> 15 <br><br> (t) l-Methyl-2- [N- {4-amid^iri|6phenyl) aminomethyl] -indol-5-yl-carboxylic acid-N-pher^yl/^N- (2-methoxycarbonylethyl) -amide and <br><br> 20 <br><br> (u) l-Methyl-2- [N- (4/arp.dinophenyl) aminomethyl] -thieno [2 . 3-d] imidazo/-5^-yl-carboxylic acid-N-phenyl-N- (2-hydroxycarbonylethy/)yamide, <br><br> the tautomers, pr/odyugs, double prodrugs, stereoisomers and the salts thereof <br><br> 5. 1-Methyl-£-/n-(4-amidinophenyl)-aminomethyl]-25 benzimidazol-j6-/l-carboxylic acid-N-phenyl-N- (2- <br><br> hydroxycarbo^iy^ethyl)-amide, the prodrugs, double prodrugs and the salts/thereof. <br><br> 6. l-M^hyl-2- [N- (4-amidinophenyl) -aminomethyl] -30 benzimiijfeziol-5-yl-carboxylic acid-N- (2-pyridyl) -N- <br><br> (2-hydrfoxvcarbonylethyl)-amide, the prodrugs, double prodri/gs/and the salts thereof. <br><br> 7. / l/Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-35 am^nqfcethyl]-benzimidazol-5-yl-carboxylic acid-N-(2- <br><br> pyridyl)-N-(2-hydroxycarbonylethyl)-amide, the prodrugs, loLjfole prodrugs and the salts thereof. <br><br> l-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl] <br><br> Aminomethyl]-benzimidazol-5-yl-carboxylic ac id-N- (2- <br><br> 2 <br><br> mm pfr pi i/ <br><br> - 196 - <br><br> Ci„3-alkylamino, N~ (C]_-3-alkyl) - carboxy-C]_ V3-alky l^mmo or N- (Ci_3-alkyl) -C]__3~alkoxycarbonyl-Ciy^-alkyl^fnino group, whilst in the abovementioned groiaps the /arbon atom in the a-position to the adjacent/ nitrogen atom may not be substituted, and <br><br> 10 <br><br> R3 denotes a propargyl group, whe/ein the/unsaturated moiety may not be linked directw to th/ nitrogen atom of the R2NR3 group, a phenyl g^oup optionally substituted by a fluorine or/chlorind atom, or by a methyl or methoxy group or p.t denotes a pyridinyl group, <br><br> 15 <br><br> the tautomers, the stereoisomers amd the salts thereof. <br><br> 4. Disubstituted bicyc/Lic heterocycles of general formula I according to claim 1I where: <br><br> A denotes a carbony/ group jinked to the benzo or thieno 2 0 moiety of the group Het, <br><br> 25 <br><br> B denotes an attached to t whilst ethylene gxoup wherein the methylene group group/Ar may be replaced by an -NRx group, <br><br> R]_ deiiotes a /hydrogen atom or a methyl group, <br><br> E denotes an R^jNH-C (=NH) - group wherein <br><br> 3 0 /Rjg is i hydrogen atom, a hydroxy, g-alkoxycarbonyl, <br><br> eyelohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-c/_3-alkyl-benzoyl or nicotinoyl group, whilst the efefioxy moiety in the 2-position of the abovementioned <br><br> Pi-9-alkoxycarbonyl group may additionally be <br><br> 3 5 / substituted by a methylsulfonyl or 2-ethoxy-ethyl group, h <br><br> INTELLECTUAL PROPERTY OFFICE | OF N.Z. <br><br> 1 1 MAY 2000 <br><br> RECEIVED <br><br> NOW AMENDED <br><br> -196- <br><br> pyridyl) -N- (2-ethoxycarbonylethyl) -ami&lt;/e y&amp;nd the salts thereof. <br><br> 9. A compound of claim 4, which id y-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzim/dareol-5-yl-carboxylic acid-N-(2-pyridyl)-N-{2-hydroxycarbonylethyl)-amide. <br><br> 10 <br><br> 15 <br><br> 20 <br><br> 10. Physiologically acceptable/salts of the compounds according to any one of claims/1 /to 9. <br><br> 11. Pharmaceutical compositions containing a compound according to any one of clailmss 1 to 9, or a salt according to claim 10, optionally tqge^her with one or more inert carriers and/or diluents./ <br><br> 12. Use of a compound &amp;ci^ording to any one of claims 1 to 9, or a salt according to claim 10, for preparing a pharmaceutical composat/on having the effect of prolonging the thrombin time, a/ tlirombin-inhibitxng effect and an inhibiting effect 9*n Related serine protease. <br><br> 25 <br><br> 13. Process f or/pnfeparing a pharmaceutical composition according to claiiy 11, wherein a compound according to any one of claims J tp 9, or a salt according to claim 10, is incorporated fn ^)ne or more inert carriers and/or diluents by a non—chegaiQQl method. <br><br> 30 <br><br> 35 <br><br> 14. Process /for preparing compounds according to any one of claims/1 /to 10, wherein a. m o£dgrr to prepare a compound of general formula I, wherei/i # denotes an RbNH-C(=NH)~ group, wherein Rb is a hydroAerf atom or a hydroxy or Cx_3-alkyl group, a compound of ojknaral formula <br><br> 'ra <br><br> A <br><br> Het <br><br> B <br><br> Ar - C(=NH) - Zi <br><br> (ii) <br><br> :ionally formed in the reaction mixtui^e^ <br><br> lerein <br><br> OFF/Cfr Qf- <br><br> &lt;v: <br><br> 2 0 NOV 2008 <br><br> »?CEIVFr <br><br> (WW AMENDE! <br><br> 33732 <br><br> 197 <br><br> Ar denotes a 1,4-phenylene group optionally ^ubstituj/ed by a methoxy group or it denotes a 2,5-thienylene groi <br><br> 5 Het denotes a l-methyl-2, 5~benzimidazol;wlene, <br><br> 2,5-benzothiazolylene, l-methyl-2,5-inofolyleney6r 1-methyl-2, 5-thieno[2,3-d]imidazolylene group And <br><br> 10 <br><br> 15 <br><br> 20 <br><br> Ra denotes an R2NR3- group whereiny <br><br> R2 denotes a C]__3-alkyl gro/p which/may be substituted by a carboxy, Ci-g-alkyloxycarbonVl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or yi-tetrazol-5-yl group, <br><br> a C2_3~alkyl group substitute/ by a hydroxy, benzyloxy, carboxy-C]_ _ 3 -alkylamino, A -alkoxycarbonyl-Cx_3-alkylamino, M- (Ci_3-adkyl) -carboxy-Cx^-alkylamino or N-(C1_3-alkyl/-Cx.3-a/koxycarbonyl-Cx_3-alkylamino group, whilst /n the abovementioned groups the carbon atom in the cc-position to the adjacent nitrogen atom may not be .substituted, and <br><br> 25 <br><br> r3 denotes a phenyl group optionally substituted by a fluoride atom,far it denotes a 2-pyridinyl group, <br><br> the tautramers, stereoisomers and the salts thereof. <br><br> / / <br><br> The following compounds of general formula I: <br><br> 1) 2- [N/(4-amidinophenyl) - aminomethyl] -benzthiazole-'5-carbojcylic acid-N-phenyl-N- {2-carboxyethyl) -amide. <br><br> (b) /- [N- (4-midinophenyl) -N-methyl-aminomethyl] -35 beijEthiazol-5-yl-carboxylic acid-N-phenyl-N- (2-hydroxycarbonylethyl)-amide, <br><br> 'ellectual propertyoff^ of n.z, <br><br> t 1 MAY <br><br> RECEIVED <br><br> NOW AMENDED <br><br> - 197- <br><br> A, B, Ar, Het and Ra are defined as in yfcl^tims 1 to 9 and <br><br> Zi denotes an alkoxy, aralkoxy, alkyl/thyto or aralkylthio group, is reacted with an amine of general formula <br><br> H2N - Kb' <br><br> wherein <br><br> Rb' denotes a hydrogen atom, a/h^Broxy or Ci_3-alkyl group, or b. in order to prepare a y6oi^pound of general formula I, wherein the Ra-A- group and fit are defined as in claims 1 to 9, with the proviso that Ahp Ra-A- group contains a carboxy group and E is defined a*s /n claims 1 to 9 or the Ra-A-group is defined as in /claims 1 to 9 and E denotes an NH2-C(=NH)- group, or the group contains a carboxy group and E denotes an NH2-jC C^NH) - group, a compound of general formula <br><br> (IV) <br><br> wherein <br><br> A, B, Ar and H^t Are defined as in claims 1 to 9 and the Ra'-A- g^ouj6 and E' have the meanings given for the Ra- <br><br> A- group and in claims 1 to 9, with the proviso that the <br><br> Ra' -A- groiip contains a group which can be converted into a carboxyl CTrGOip by hydrolysis, treatment with an acid or base, therntolysis or hydrogenolysis and E is defined as in claims i t/o 9 or E' denotes a group which may be converted into a/i 1/H?-C{=NH)- group by hydrolysis, treatment with an <br><br> )r/Dase, thermolysis or hydrogenolysis and the Ra'-A- <br><br> fas the meanings given for the Ra-A- group in claims I <br><br> 'or the Ra' -A- group contains a group which may be <br><br> £rted into a carboxyl group by hydrolysis, treatment an acid or base, thermolysis or hydrogenolysis and E' <br><br> lotes a group which may be converted into an NH2-C (=NH)- <br><br> ^oup by hydrolysis, treatment with an acid or base, <br><br> , , , , intellectual hhu <br><br> :hermolysxs or hydrogenolysis, OFFICE OF N <br><br> i: R I- <br><br> t I V L <br><br> 25 <br><br> (c) l-Methyl-2-[N-{4-amidinophenyl}-aminomethyl] benzimidazol-5-yl-carboxylic acid-N-ph^nyl-N-{2j hydroxycarbonylethyl)-amide, <br><br> (d) l-Methyl-2- [N- (4-amidinophenyl)/-aminomethyl] benzimidazol-5-yl-carboxylic acid/N-pheny] N-(3-hydroxycarbonylpropyl)-amic <br><br> 10 (e) l-Methyl-2-[N-(4~amidinounenyl)-araanomethyl] -benzimidazol-5-yl-carboxylic/ acid-N-/2-pyridyl) N-(hydroxycarbonylmethyl)-/mide, <br><br> (f) l-Methyl-2-[2-(2-am/dinothio^hen-5-yl)ethyl] - <br><br> 15 benzimidazol-5-yl-carbpxylic agad-N-(2-pyridyl)-N-(2■ <br><br> hydroxycarbonylethyl]/-amide, <br><br> (g) l-Methyl-2-[N-a4-amidinophenyl)-aminomethyl]-benzimidazol-5-y/-carboxylic acid-N-(2-pyridyl)-N-(2- <br><br> 2 0 hydroxycarbonylethyl) <br><br> (h) 1-Methyl/2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl - carboxy lac acid-KF- (2-pyridyl) -N- (2-hydroxyca/bonylethyl)-amide, <br><br> (i&gt; l-Mfethyl-2-yi-(4-amidinophenyl)ethyl] -benzimidazol-5-yl-ca/boxy1ic jacid-N-phenyl-N-(2-hydroxycarbonylethyl)- <br><br> ami' <br><br> 30 (/) l-Metlryl-2-[2-(4-amidinophenyl) ethyl] -benzimidasol-5-'1-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl] amide, <br><br> (k) l/Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-35 ben/imidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide, <br><br> intellectual property office i <br><br> ! of HI. <br><br> * I MAY 2000 <br><br> NOW AMENDED <br><br> -198- <br><br> is converted, by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis,/i]/to a compound of roup and E are defined 5 as in claims 1 to 9, with the provytsrf that the Ra-A- group contains a carboxy group and E is/dafined as in claims 1 to 9 or the Ra-A- group has the meamings given in claims 1 to 9 and E denotes an NH2-C(=NH)- grpuu or the Ra-A- group contains a carboxy group and £/ d/notes an NH2-C(=NH)- group, <br><br> 10 <br><br> or <br><br> 15 <br><br> c. in order to prepare a compound of general formula I wherein the Ra-A- group contains one of the ester groups mentioned in the definitirary of the Ra-A- group in claims 1 to 9, a compound of genaura/ formula <br><br> Ra <br><br> He <br><br> B - Ar - E <br><br> (V) <br><br> wherein <br><br> 20 B, E, Ar and Het a^e Refined as in claims 1 to 9 and Ra"-A-group has the meanings given for the Ra-A- group in claims 1 to 9, with the piomso that the Ra"-A- group contains a carboxyl group ®r fa. group which may be converted by means of an alcohol %ty\Jo a corresponding ester group, is reacted 25 with an alcohol /of general formula HO A ki , (VI) <br><br> 30 <br><br> wherein <br><br> R7 denote^ ^Ci_6-alkyl or benzyl group or with the formamide acetals thereof or with a compound of general formula <br><br> Z2 - R7, (VII) <br><br> whereii <br><br> 35 R? aenotes a Ci_6-alkyl or benzyl group and Z2/d§m.otes a leaving group, or in order to prepare a compound of general formula I ierein Rb denotes a Ci-g-alkoxycarbonyl, 40/ Cyclohexyloxycarbonyl, phenyl-Ci-3-alkoxycarbonyl, benzoyl, <br><br> (INTELLECTUAL <br><br> OFFICE C! <br><br> 2 0 NOV 2mi <br><br> - 199 - <br><br> (1} l-Methyl-2-[N~(4-amidinophenyl)-N-methy/-aminomethyl] benzimidazol-5-yl-carboxylic acid-N- (2-py^jidyl) -N-/2-hydroxycarbonylethyl)-amide, <br><br> (m) l-Methyl-2 - [N- (4-amidinophenyl) -Nyfiethyl-benzimidazol-5-yl-carboxylic acid-N- jjfe -pyrid^ hydroxycarbonylethyl)-amide, <br><br> linomethyl] -.) -N- (2- <br><br> (n) l-Methyl-2- [N- (4-amidinophenVrl) -N-metfiiyl-aminomethyl] 10 benzimidazol-5-yl-carboxylic ac/d-N-phe^yl-N-(2-hydroxycarbonylethyl)-amide, <br><br> (o) l-Methyl-2-[N-(4-amidinophenyl)/aminomethyl] benzimidazol-5-yl-carboxylac acid^^r-phenyl-N- [ {N-15 hydroxycarbonylethyl-N-methyl}-2/aminoethyl] - amide, <br><br> (p) l-Methyl-2-[N-(4-afaidinop#enyl)-aminomethyl] -benzimidazol-5-yl-ca/boxylic/ acid-N-(3 -fluorophenyl}-N-(2-hydroxycarbonylethal)-amid^ <br><br> 20 <br><br> (q) l-Methyl-2- [itf- (4-amidinophenyl) -aminomethyl] benzimidazol-5-/yl-carbgocylic acid-N- (4-fluorophenyl) -N- (2-hydroxycarbon/lethyl) / amide, <br><br> 25 (r) l-Methyl-2-[N-/4-amidino-2-methoxy-phenyl) <br><br> aminomethyl]-benz/midazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl) -amide, <br><br> (s) l/Methyl-^- [N- (4-amidino-2-methoxy-phenyl) -30 amin,omethyl]/-benzimidazol-5-yl-carboxylic acid-N- (2-pytfidyl)-N/ {2-hydroxycarbonylethyl)-amide, <br><br> 35 <br><br> ytt) l-Methyl-2-[N-(4-amidinophenyl)aminomethyl]-indol-5-yl-rlic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide and <br><br> NOW AMENDED <br><br> Li» Inftik k1*1! <br><br> IfllJ r&amp;ivl !■' <br><br> p-Ci-3-alkyl-benzoyl or pyridinoyl grou/, jfrhilst the ethoxy moiety in the 2-position of the abovenf srycioned C1-9-alkoxycarbonyl group may additionally le substituted by a Ci-3-alkylsulphonyl or 2-(Ci_3-alkoxy/-^/:hyl group, a compound of general formula <br><br> ) -NH2 <br><br> wherein Ra, A, Het, B and Ar aj lefined when as in claims 1 10 to 9, is reacted with a componn/ of general formula <br><br> (VIII) <br><br> wherein <br><br> Re denotes a Ci-g-alkoxyc^trbfonyl, cyclohexyloxycarbonyl, phenyl-Ci_3-alkoxycarborwl/ benzoyl, p-Ci_3-alkyl-benzoyl or pyridinoyl group, whi]^t/the ethoxy moiety in the 2-position of the abovementioned Ci-9-alkoxycarbonyl group may additionally be substituted by a Ci-3-alkylsulphonyl or 2-(Ci-3-alkoxy) -ethyl ^jrpup and Z2 denotes a nucleofugic leaving group, or e. in order tor prepare a benzimidazolyl or benzothiazolyl compound of general formula I, wherein B denotes an ethylene compound of general formula <br><br> NH2 <br><br> Ra - A <br><br> (XV) <br><br> Ra and/A/are defined as in claims 1 to 9 and Y denotes a sulphur/atom, or a nitrogen atom substituted by a Ci~3 alkyl or oyc/opropyl group, is reacted with a compound of general formula <br><br> HO-CO - CH2CH2 - Ar - E <br><br> , (XVI) <br><br> I INTELLECTUAL rhv. <br><br> Lr and E are defined as in claims 1 to 9,(or QfiROE GBeN.2 <br><br> 2 n NOV 2098 <br><br> / / <br><br> (u) l-Methyl-2-[N-(4-amidinophenyl) aminomettiyl] - <br><br> thieno [2 . 3-d] imidazol-5-yl-carboxylic aci^N-phe^yl-N- {2- <br><br> / <br><br> hydroxycarbonylethyl)-amide, <br><br> / <br><br> / <br><br> / <br><br> the tautoraers, prodrugs, double prodrugs, stereoisomers and the salts thereof. / / <br><br> 6. l-Methyl-2-[N-(4~amidinophenyl)-aminomethyl] benzimidazol-5-yl-carboxylic ^acid-N-raoenyl-N-(2-hydroxycarbonylethyl)-amidey^ the prodrugs, double prodrugs and the salts thereof. / <br><br> 7 . l-Methyl-2- [N- (4-sffnidinophtenyl) -aminomethyl] <br><br> J / <br><br> benzimidazol-5-yl-carboxylic yacid-N- (2-pyridyl) - <br><br> N-(hydroxycarbonylmethyl)-apu.de, the prodrugs, double <br><br> / <br><br> prodrugs and the smalts thereof. <br><br> / <br><br> J <br><br> l-Methyl-2^ [N- {4-aynidino-2-methoxy~phenyl) - <br><br> / <br><br> aminomethyl]-bfenzimidasol-5-yl-carboxylic acid-N-(2- <br><br> pyridyl) -N- (^ydroxycsfobonylmethyl) -amide, the prodrugs, / / <br><br> double proclrugs and/ the salts thereof. <br><br> / t <br><br> S <br><br> 9. l-M^thyl-2--m- [4- (N-n-hexyloxycarbonylamidino)phenyl- <br><br> aminome.6h.yl] -beiazimidazol-5-yl-carboxylic acid-N- (2-/ / <br><br> pyridyl) ~N- (etJAoxycarbonylethyl) -amide and the salts therefof <br><br> / <br><br> f / <br><br> 10/ Phy: ^Logically acceptable salts of the compounds <br><br> / f aecordini to any one of claims 1 to 9, wherein E denotes an RbNH-C(-£ i- group. <br><br> / <br><br> 11. Rftarmaceutical compositions containing a compound accoming to any one of claims 1 to 9, wherein E denotes an RbN"H/c (-NH) - group, or a salt according to claim 11, optionally together with one or more inert carriers and/or diluents, <br><br> | INTELLECTUAL PROPERTY I OF N.Z. <br><br> 1 1 NAY 200D RECEIVED <br><br> (u) l-Methyl-2- [N- (4-amidinophenyl) arr&amp;ftdtetetjfey thieno [2 . 3-d] imidazol-5-yl-carboxylic acid-N-j snyl-N-/(2 hydroxycarbonylethyl)-amide, <br><br> the tautomers, prodrugs, double prodrugs/stereoisomers and the salts thereof. <br><br> 6 . 1 -Methyl - 2 - [N- (4 - amidinophenyl^/ aminomethyl ] -benzimidazol-5-yl-carboxylic aci d-W-phenyl t4i- (2-hydroxycarbonylethyl)-amide, theprodrugs/ double prodrugs and the salts thereof. <br><br> 7-;.. l-Methyl-2- [N- (4-amidinophenyl) /aminomethyl] - <br><br> ■f f benzimidazol-5-yl-carboxylic acid-N^ (2-pyridyl) -N- (hydroxycarbonylmethyl)^/amide, jme prodrugs, double prodrugs and the salts tKereof. <br><br> 8 . l-Methyl-2- [N- (4 yamidino/2-methoxy-phenyl) -aminomethyl] -benzimi^azol-5~#l-carboxylic acid-N- (2-pyridyl) -N- (hydroxycarbonyLmethyl)-amide, the prodrugs, <br><br> 9. l-Methyl-2/ [N- [4- (ST-n-hexyloxycarbonylamidino) phenyl- <br><br> aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(2- <br><br> // / <br><br> pyridyl) -N- {ethoxycaybonylethyl) -amide and the salts thereof. // <br><br> // / <br><br> / <br><br> / / <br><br> * * Ji <br><br> 10- A cc^npound of claim 5, which is l-methyl-2-[N-(4- <br><br> amidinqpnenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-!$^( 2-pyri^yl) -N- (2-hydroxycarbonylethyl) - amide. <br><br> ilf PhysioJogfcally acceptable salts of the compounds accordingyto .any one of claims 1 to 9, wherein E denotes an /RtoNH-C (=3^;) - group. <br><br> 12. Pharmaceutical compositions containing a compound according to any one of claims 1 to 9, wherein E denotes an (=NH) - group, or a salt according to claim 11, <br><br> / <br><br> optionally together with one or more inert carriers and/or diluents. <br><br> 10 <br><br> 15 <br><br> ^jsjsS- <br><br> INTELLECTUAL OFFICE <br><br> - 200 - <br><br> (u) l-Methyl-2-[N-(4-amidinophenyl)aminometh^tt^t1 thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N/(2-hydroxycarbonylethyl)-amide, <br><br> the tautomers, prodrugs, double prodrugs, the salts thereof. <br><br> ereoi omers and <br><br> 6. l-Methyl-2-[N-{4-amidinophenyl)-aminoir iyl] <br><br> benzimidazol-5-yl-carboxylic acid-N-pbenyl- (2~ <br><br> hydroxycarbonylethyl)-amide, the prodrugs,/ able prodrugs and the salts thereof. <br><br> 7. l-Methyl-2-[N-(4~amidinophe/yl)-astfinomethyl]-benzimidazol-5-yl-carboxylic aoad-N-G£-pyridyl)-N-(hydroxycarbonylethyl)-amide,/the prodrugs, double prodrugs and the salts thereof. <br><br> 20 <br><br> 8. l-Methyl-2-[N-(4-amidino-2yfeethoxy-phenyl)- <br><br> J / <br><br> aminomethyl]-benzimidazafi.-5-yl/carboxylie acid-N-(2-pyridyl) -N- (hydroxycar&amp;onyletriyl) -amide, the prodrugs, double prodrugs and tme sal^s thereof. <br><br> 25 <br><br> 9. l-Methyl-2- [N/[4- (N^i-hexyloxycarbonylamidino) phenyl-aminomethyl]-benz/midaz/l-5-yl-carboxylic acid-N- (2-pyridyl) -N- (ethg&amp;ycart^nylethyl) -amide and the salts thereof. <br><br> 30 <br><br> 10. A compound of/claim 5, which is l-methyl-2-[N-(4-amidinophei/yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2/pyrid/l)-N-(2-hydroxycarbonylethyl)-amide. <br><br> 11. Physiologically acceptable salts of the compounds according any one of claims 1 to 9, wherein E denotes an RbNIj/c (=nh/- group, <br><br> Pharmaceutical compositions containing a compound /according to any one of claims 1 to 9, wherein E denotes an RbNH-jC (=NH) - group, or a salt according to claim 11, optionally together with one or more inert carriers and/or diluents. <br><br> 10 <br><br> 15 <br><br> 20 <br><br> NOW AMENDED <br><br> - 200 - <br><br> (u) l-Methyl-2-[N-(4-amidinophenyl)aminomethyl/ -thieno[2.3-d]imidazol-5-yl-carboxylic acid-N/phenyl-hydroxycarbonylethyl)-amide, <br><br> the tautomers, prodrugs, double prodrug the salts thereof. <br><br> stereoisomers and <br><br> 6. l-Methyl-2-[N-(4-amidinophenyl/-aminom&amp;thyl]-benzimidazol-5-yl-carboxylic acid/N-phenyl/N-(2-hydroxycarbonylethyl)-amide, th^prodrug^ double prodrugs and the salts thereof. <br><br> 7. l-Methyl-2-[N-(4-amidinophenyl) /aminomethyl]-benzimidazol-5-yl-carboxyllc acid-N/(2-pyridyl)-N-(2-hydroxycarbonylethyl)/amide, tj^e prodrugs, double prodrugs and the salts/thereof. <br><br> 8. l-Methyl-2-[N-/4-amidino^2-methoxy-phenyl) -aminomethyl]-benzimidazol-5/yl-carboxylic acid-N-(2- <br><br> pyridyl)-N-(2-hy^xoxycarbonylethyl)-amide, the prodrugs, double prodrugs^and the ^alts thereof. <br><br> 25 <br><br> 9. l-Methyl-2-[N-[4j (N-n-hexyloxycarbonylamidino)phenyl] aminomethv/]-benzimLaazol-5-yl-carboxylic acid-N-{2-pyridyl)/N-(2-ethoj*ycarbonylethyl)-amide and the salts thereoj <br><br> 10. /A compound of claim 5, which is l-methyl-2-[N-(4-am/dinophenyY) -aminomethyl]-benzimidazol-5-yl-carboxylic <br><br> ;id-N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide. <br><br> / <br><br> 11. Physiologically acceptable salts of the compounds according to any one of claims 1 to 9, wherein E denotes an RbNH-(/(=NH) - group. <br><br> 40 <br><br> 12/ Pharmaceutical compositions containing a compound According to any one of claims 1 to 9, wherein E denotes an rRbNH-C(=NH)- group, or a salt according to claim 11, optionally together with one or more inert carriers and/or diluents. <br><br> NOW AMENDED <br><br> 10 <br><br> 20 <br><br> &lt;nw# fWBMRirtWkf <br><br> -200- <br><br> reactive derivatives thereof and f. in order to prepare a compound of/general formula I wherein R2 denotes a Ci~4-alkyl group g/ubstituted by an alkylsulphonylaminocarbonyl group:/ <br><br> a compound of general formula R2' <br><br> r3 <br><br> \ / <br><br> N - A - Het -/B/- Ar - E <br><br> , Cixx) <br><br> wherein <br><br> Ra, A, B, E, and Het are /iefined as in claims 1 to 9 and R2' 15 denotes a Ci-4-alkyl groiip substituted by a carboxy group, or the reactive derivat/ivyes thereof, <br><br> is reacted with a saltf o/E a compound of general formula <br><br> Ci-3~XlWl-S02-NH2 <br><br> (XX) , <br><br> and, if necessary/ a^ protecting group used during the reactions in ordpr /to protect reactive groups is cleaved and/or <br><br> 25 subsequently,/desired, a compound of general formula I thus obtained i/s resolved into the stereoisomers thereof and/or a compouna df general formula I thus obtained is converted 30 into the/ saflts thereof, more particularly for pharmaceutical use into the physiologically acceptable salts /thereof with an inorganic or organic acid or base. <br><br> 15. / D/substituted bicylic heterocycles of general formula I ^ibjstantially as herein described with reference to any 01/e cf the Examples. <br><br> /l6/ Disubstituted bicylic heterocycles according to any le of claims 1-9, substantially as herein described. <br><br> i !NTELi_£CTU* <br><br> OFFICE Of , <br><br> 2 0^ <br><br> lOVZKfe <br><br> 12. Use of a compound according to any one of/claims A to 9, wherein E denotes an RbNH-C{=NH)- group, or a sail according to claim 10, for preparing a pharmaceutical composition having the effect of prolonging the thrombin <br><br> 5 time, a thrombin-inhibiting effect and anr inhibij/ing effect on related serine proteases, <br><br> 13. Process for preparing a pharmaceutical Composition according to claim 11, wherein a compound according to any <br><br> 10 one of claims 1 to 9, wherein E denotes ar/ RbNH-C (=NH) - <br><br> group, or a salt according to cl/im 10, is incorporated in one or more inert carriers and/or diluents by a non-chemical method. <br><br> 15 14. Process for preparing/compound according to any one of claims 1 to 10, wherei; <br><br> a. in order to prepare/a compound of general formula I, wherein E denotes anJRJSIH-CC <br><br> group, <br><br> wherein Rb is a <br><br> 2 0 hydrogen atom or a of general formula/ <br><br> ^droxy oA <br><br> C^3-alkyl group, a compound <br><br> R_, - A -/Het d <br><br> B/- Ar - C(=NH) <br><br> , (II) <br><br> 25 optionally farmed in/the reaction mixture, <br><br> wherein <br><br> A, B, Ar,/ilet and are defined as in claims 1 to 9 and <br><br> Z-l denotes an aMtoxy, aralkoxy, alkylthio or aralkylthio 30 group/ is reacted with an amine of general formula <br><br> H2N - Rb <br><br> , (HI) <br><br> wherein <br><br> 3 5 Rb 1 derates a hydrogen atom, a hydroxy or C^-alkyl group, or fINTELLECTUAL PROPERTY OFFKEi | OF N.Z. <br><br> 1 1 MAY 2000 <br><br> RECEIVED <br><br> 10 <br><br> JB1F #saF 4 / 4 <br><br> V "V <br><br> - 202 - <br><br> b. in order to prepare a compound of general formulA I, wherein the Ra-A~ group and E are defined ds in claims 1 to 9, with the proviso that the Ra-A- group /ontains/ a carboxy group and E is defined as in claims 1 tor 9 or tjae Ra-A-group is defined as in claims 1 to 9 aad E denotes an NH2-C (=NH) - group, or the Ra-A- group/contain^ a carboxy group and E denotes an NH2~C{=NH)- g^roup, a ^compound of general formula <br><br> R ' - A - Het - B - Ar / C - E1 <br><br> O. <br><br> , (IV} <br><br> wherein <br><br> A, B, Ar and Het are defined hs in claims 1 to 9 and the Ra'-A- group and E1 hayfe the meanings given for the 15 Ra-A- group and E in claims 1 to 9, with the proviso that the Ra'-A- group contains a group which can be converted into a carboxyl group By hydrolysis, treatment with an acid or base, thermolysis jor hydrogenolysis and E is defined as in claims 1 to 9 or yE1 denotes a group which may be 20 converted into an ]£h,-C (=NH/- group by hydrolysis, <br><br> treatment with an/acid or/base, thermolysis or hydrogenolysis and the Rf -A- group has the meanings given for the Ra-A- group in aflaims 1 to 9, or the Ra'-A- group contains a gr©up which/ may be converted into a carboxyl 25 group by hydrolysis, /treatment with an acid or base, <br><br> 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 hydrog^fiolysis, <br><br> 30 <br><br> is converted,/by hydrolysis, treatment with an acid or baSje, thermolysis or hydrogenolysis, into a compound of general formula I, wherein the Ra~A- group and E are fefined ad in claims 1 to 9, with the proviso that the 35 /Ra-A- grgoip contains a carboxy group and E is defined as in claims /I to 9 or the Ra-A- group has the meanings given in claims/ 1 to 9 and E denotes an NH2-C(=NH)- group or the <br><br> 'l^LEBuArmP^'WFiCE'i of n.z. <br><br> I t MAY 2000 RECEIVED <br><br> Ra-A- group contains a carboxy group and E denotes an c. in order to prepare a compound of general formu&amp;a I 5 wherein the Ra-A- group contains one of me ester/groups mentioned in the definition of the Ra-.aA' group Jtn claims 1 <br><br> 10 wherein / / <br><br> B, E, Ar and Het are defined as in claims 1 to 9 and Ra"-A- group has the meanings' given fpr the Ra-A- group in claims 1 to 9, with the proviso that the Ra"-A- group contains a carboxyl grout/or a grj/up which may be converted 15 by means of an alcohol /nto a corresponding ester group, is <br><br> 20 R7 denotes the /ikyl moiety of one of the groups which may be cleaved in/vivo mentioned in claims 1 to 9, with the exception oJt the R6-0O-O- (RsCRe) - group for a carboxyl <br><br> 25 / / <br><br> Re .denote*/ the alkyl moiety of one of the groups which may 3 0 'be clea/ed in vivo mentioned in claims 1 to 9, with the exception of the R6-C0~0- {RSCRS) - group for a carboxyl group and / <br><br> Z2 /denotes a leaving group, or <br><br> ACTUAL PROPERTY OFFICE j GF N.Z. <br><br> 1 1 MAY 2000 <br><br> RECEIVED <br><br> - 204 - <br><br> d. in order to prepare a compound of general formula^I wherein Rb denotes a group which may be clea/ed in yivo, a compound of general formula <br><br> R_ <br><br> A - Het - B - Ar - C(=NH) <br><br> {VIII} <br><br> wherein <br><br> Ra, A, Het, B and Ar are defined as fn claipfe 1 to 9, is reacted with a compound of general/formula <br><br> 10 <br><br> z2 - r5 <br><br> , (12 <br><br> 15 <br><br> 20 <br><br> wherein <br><br> Rs denotes a group which ma^ be cleaved in vivo and Z2 denotes a nucleofugic Reavingy^roup, or e. in order to prepare/a compound of general formula I wherein B denotes an /ethylene group wherein a methylene group is replaced b/ a sulphinyl or sulphonyl group, a compound of genera/1 formula <br><br> R_/- A - Het - B1 - Ar - E <br><br> , (X) <br><br> wherein A, E, Ar, Edt and are defined as in claims 1 to 9 and <br><br> 25 B' denotes an ethylene group, in which a methylene group is replace*! by a ysulphenyl or sulphinyl group, is oxidised or f. in ordeivto prepare a compound of general formula I, wherein E/denotes a cyano group and B is an ethylene group, 30 ii/ which/a methylene group, linked either to the group Het &gt;r Ar, As replaced by an oxygen or sulphur atom or by a sulph/nyl, sulphonyl, carbonyl or -NR.,- group, a compound of general formula <br><br> 35 <br><br> R_ - A - Het - U ,(XI) <br><br> 1 1 NAY 2000 RECEIVED <br><br> - 205 - <br><br> 10 <br><br> 15 <br><br> 20 <br><br> 25 <br><br> is reacted with a compound of general formula <br><br> V - Ar - CN ,(XII) <br><br> wherein <br><br> Ra, A, Ar and Het are defined as in claj/ms 1 '9, <br><br> one of the groups U or V denotes an HOf-, HS- IOSO-, HOSCL, or HNRj.- group and the other group denotes b/ ZH2- group wherein Rx is defined as in claims nucleofugic leaving group, or g. in order to prepare a compoj/nd of general formula I, wherein E is a cyano group ana Ra derates an R2KR3- group, a compound of general formujra. <br><br> to 9 id Z3 denotes a <br><br> B <br><br> ,(XIII) <br><br> H - A - Het wherein <br><br> A, B, Het and Ar are defined s.s in claims 1 to 9, is reacted with an aminp of general formula <br><br> ,(XIV) <br><br> wherein R2 and R3 a reactive defined as in claims 1 to 9, or with the ;iyes thereof, or h. in cyfrder to/prepare a benzimidazolyl, benzothiazolyl or benzoj£azolyl (Compound of general formula I, wherein B denotes an ethylene group, a compound of general formula <br><br> (XV) <br><br> 30 <br><br> wherein <br><br> PROPERTY OFFICE I OF Ni, <br><br> I i <br><br> MM 2000 <br><br> RECEIVED <br><br> 10 <br><br> 15 <br><br> 20 <br><br> - 206 - <br><br> Ra, A and Y are defined as in claims 1 to 9, if reacted with a compound of general formula wherein <br><br> Ar and E are defined as in claims 1 to, 4th the reactive derivatives thereof and i. in order to prepare a quinoxal^ /compound of the general formula: <br><br> a compound of general formula <br><br> Ra - A <br><br> ,(xvii; <br><br> wherein <br><br> Ra, R]_ and A are defied as j&amp;i claims 1 to 9, is reacted with a compound of general formula <br><br> HO-C© - COCH/ - Ar - E <br><br> ,(XVIII) <br><br> wherein <br><br> Ar and E are defined As in claims 1 to 9, or with the reactive desivative/thereof, or j. in order to prepare a compound of general formula I 25 wherein/R2 denotes a C]__4-alkyl group substituted by an alkylsyQlphonylj/minocarbonyl group: <br><br> a compound at general formula <br><br> 30 <br><br> :N - A - Het - B - Ar - E <br><br> wherein <br><br> (IXX) <br><br> ftLLECTUAl PROPERTY OFFICE OF NZ <br><br> I MAY 2000 <br><br> RECEIVED <br><br> - 207 - <br><br> R.3, A, B, E, and Het are defined as in claims l/to 9 anc R2 ' denotes a C]__4-alkyl group substituted by fa. carboxj group, or the reactive derivatives thereof, <br><br> is reacted with a salt of a compound of ge/leral formula <br><br> Ci_ 3-Alkyl-S02-NH2 <br><br> (XX) <br><br> 10 <br><br> and, if necessary, a protecting/group us^ci during the reactions in order to protect yreactive^groups is cleaved and/or <br><br> 15 subsequently, if desired,/a compoup&amp; of general formula I thus obtained is resolvoa into the stereoisomers thereof and/or a compound of gener/l formulj/ I thus obtained is converted <br><br> 2 0 into the salts thereof, more particularly for pharmaceutical u/e into the physiologically acceptable salts thereof With an inorganic or organic acid or base. <br><br> 15. Disubstituted bicyclic heterocycles of general formula 25 I substantially as herein described with reference to any one of the Example^. <br><br> 16. ^substituted bicyclic heterocycles according to any one claims p.-9, substantially as herein described. <br><br> 30 <br><br> 1/. Physiologically acceptable salts according to claim 10 /feubstanLi/lly as herein described. <br><br> 18. Pharmaceutical compositions according to claim 11 <br><br> 3 5 substantially as herein described. <br><br> INTELLECTUAL PROPERTY OFRCEI OF N.Z. | <br><br> 1 1 MAY 2000 <br><br> RECEIVED <br><br> - 208 - <br><br> 19. A use according to claim 12 substa^ herein described. <br><br> 20. A process according to claim /3 or clc m. 14 5 substantially as herein described^ <br><br> Be hringer /fngelheim Pharma KG <br><br> 10 <br><br> 15 <br><br> rtorneys BALDWIN SHELSTON WATERS <br><br> END OF CLAIMS <br><br> iNTElECTUAl PROPERTY QFHCE1 OF N.Z. j i ' Ma/ £uOu s RECEIVED <br><br> AS AMENDED <br><br> 1 <br><br> 5 <br><br> Disubstituted bicyclic heterocycles, the preparation and the use thereof as pharmaceutical compositions <br><br> The present invention relates to new disubstituted bicyclic heterocycles of general formula the tautomers, stereoisomers and mixtures thereof and the salts thereof, particularly the physiologically acceptable 15 salts thereof with organic or inorganic acids or bases which have valuable properties. <br><br> The compounds of general formula I above wherein E denotes a cyano group are valuable intermediates for preparing the 20 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 25 time. <br><br> The present application thus relates to the new compounds of general formula I above and the preparation thereof, pharmaceutical compositions containing the 30 pharmacologically active compounds and the use thereof. <br><br> In the above general formula <br><br> 10 <br><br> R <br><br> a <br><br> A - Het - B - Ar - E <br><br> (I) <br><br> 35 <br><br> A denotes a carbonyl or sulphonyl group linked to the benzo, pyrido, or thieno moiety of the group Het, <br><br> AS AMENDED <br><br> - 2 - <br><br> 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 -NRi- group, wherein <br><br> 5 Ri denotes a hydrogen atom or a Ci_4-alkyl group, <br><br> E denotes an RbNH-C(=NH)- group wherein <br><br> Rb denotes a hydrogen atom, a hydroxy, C1_g-alkoxycarbonyl, 10 cyclohexyloxycarbonyl, phenyl-C -alkoxycarbonyl, benzoyl, p-Ci-3-alkyl-benzoyl or pyridinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C1_ g-alkoxycarbonyl group may additionally be substituted by a Ci-3-alkylsulfonyl or 2-(Ci-3-alkoxy) -ethyl group, <br><br> 15 <br><br> 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, <br><br> 20 Het denotes a 1-(Ci_3-alkyl)-2,5-benzimidazolylene, 1- <br><br> cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1- (Ci-3-alkyl) -2, 5-indolylene, 1- (Ci_3-alkyl) -2, 5-imidazo [4, 5-b]pyridinylene, 3- (Ci-3-alkyl) -2,7-imidazo[1,2-a]pyridinylen or 1-(Ci-3-alkyl) 25 2,5-thieno[2,3-d]imidazolylene group and <br><br> Ra denotes an R2NR3- group wherein <br><br> R2 is a Ci-4-alkyl group substituted by a carboxy, Ci-30 6-alkyloxycarbonyl, benzyloxycarbonyl, Ci- <br><br> 3-alkylsulphonylaminocarbonyl or lH-tetrazol-5-yl group, <br><br> a C2-4-alkyl group substituted by a hydroxy, benzyloxy, 35 carboxy-Ci-3-alkylamino, Ci-3-alkoxycarbonyl-Ci- <br><br> 3-alkylamino, N- (Ci-3-alkyl) -carboxy-Ci_3-alkylamino or N- (Ci-3-alkyl) -Ci-3-alkoxycarbonyl-Ci-3-alkylamino group, <br><br> intellectual property office of m.z. <br><br> -3 AUG 2009 <br><br> RECEIVED <br><br> AS AMENDED ~J~ <br><br> whilst in the abovementioned groups the carbon atom in the a-position to the adjacent nitrogen atom may not be substituted, <br><br> 5 R3 denotes a C3-7-cycloalkyl group, a propargyl group, <br><br> 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-10 ridazolyl or pyridinyl group optionally substituted by a methyl group or <br><br> R2 and R3 together with the nitrogen atom between them denote a 5- to 7-membered cycloalkyleneimino group, 15 optionally substituted by a carboxy or Ci_4-alk- <br><br> oxycarbonyl group, to which a phenyl ring may additionally be fused, <br><br> the tautomers, the stereoisomers and the salts thereof. <br><br> 20 <br><br> Preferred compounds of the above general formula I are those wherein <br><br> A denotes a carbonyl or sulphonyl group linked to the 25 benzo, pyrido or thieno moiety of the group Het, <br><br> 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 -NRj.- group, wherein <br><br> 30 Ri denotes a hydrogen atom or a methyl group, <br><br> E denotes an RbNH-C(=NH)- group, wherein <br><br> Rb denotes a hydrogen atom or a hydroxy, 35 Ci-9-alkoxycarbonyl, cyclohexyloxycarbonyl, <br><br> benzyloxycarbonyl, benzoyl, p-Ci-3-alkyl-benzoyl or nicotinoyl group, whilst the ethoxy moiety in the 2- <br><br> AS AMENDED " 41 " <br><br> position of the abovementioned Ci_9-alkoxycarbonyl group may additionally be substituted by a C1-3-alkylsulphonyl or 2-(Ci-3-alkoxy)-ethyl group, <br><br> 5 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, <br><br> Het denotes a l-methyl-2,5-benzimidazolylene, 1-10 cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, l-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 <br><br> 15 <br><br> Ra denotes a R2NR3- group wherein <br><br> R2 denotes a Ci_3-alkyl group which may be substituted by a carboxy, Ci_6-alkyloxycarbonyl, benzyloxycarbonyl, 20 methylsulphonylaminocarbonyl or lH-tetrazol-5-yl group, <br><br> a C2-3-alkyl group substituted by a hydroxy, benzyloxy, carboxy-Ci-3-alkylamino, Ci-3-alkoxycarbonyl-Ci_ 3-alkylamino, N- (Ci-3-alkyl) -carboxy-Ci-3-alkylamino or 25 N-(Ci-3-alkyl)-Ci-3-alkoxycarbonyl-Ci_3-alkylamino group, <br><br> whilst in the abovementioned groups the carbon atom in the a-position to the adjacent nitrogen atom may not be substituted, and <br><br> 30 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, <br><br> 35 <br><br> particularly those wherein <br><br> AS AMENDED ~ 3 ~ <br><br> A denotes a carbonyl group linked to the benzo or thieno moiety of the group Het, <br><br> B denotes an ethylene group wherein the methylene group 5 attached to the group Ar may be replaced by an -NRi group, wherein <br><br> Ri denotes a hydrogen atom or a methyl group, <br><br> 10 E denotes an RbNH-C(=NH)- group wherein <br><br> Rb is a hydrogen atom, a hydroxy, Ci-g-alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-Ci-s-alkyl-benzoyl or nicotinoyl group, whilst the <br><br> 15 ethoxy moiety in the 2-position of the abovementioned <br><br> Ci-g-alkoxycarbonyl group may additionally be substituted by a methylsulfonyl or 2-ethoxy-ethyl group, <br><br> 20 Ar denotes a 1,4-phenylene group optionally substituted by a methoxy group, or denotes a 2,5-thienylene group, <br><br> Het denotes a l-methyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, l-methyl-2,5-indolylene or 1-methyl 25 2,5-thieno[2,3-d]imidazolylene group and <br><br> Ra denotes an R2NR3- group wherein <br><br> R2 denotes a Ci-3-alkyl group which may be substituted 30 by a carboxy, Ci_6-alkyloxycarbonyl, benzyloxycarbonyl, <br><br> methylsulfonylaminocarbonyl or lH-tetrazol-5-yl group, <br><br> a C2-3~alkyl group substituted by a hydroxy, benzyloxy, carboxy-Ci-3-alkylamino, Ci-3-alkoxycarbonyl-Ci-35 3-alkylamino, N- (Ci_3-alkyl) -carboxy-Ci_3-alkylamino or <br><br> N- (Ci-3-alkyl) -Ci_3-alkoxycarbonyl-Ci-3-alkylamino group, whilst in the abovementioned groups the carbon atom in <br><br> AS AMENDED <br><br> - 6 - <br><br> the a-position to the adjacent nitrogen atom may not be substituted, and <br><br> R3 denotes a phenyl group optionally substituted by a 5 fluorine atom, or denotes a 2-pyridinyl group, <br><br> the tautomers, stereoisomers and the salts thereof. <br><br> 10 The following are mentioned as examples of particularly preferred compounds: <br><br> (a) 2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)-amide, <br><br> 15 <br><br> (b) 2-[N-(4-midinophenyl)-N-methyl-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, <br><br> 20 (c) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, <br><br> (d) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-25 benzimidazol-5-yl-carboxylic acid-N-phenyl- <br><br> N-(3-hydroxycarbonylpropyl)-amide, <br><br> (e) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)- <br><br> 30 N-(hydroxycarbonylmethyl)-amide, <br><br> (f) l-Methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, <br><br> 35 <br><br> AS AMENDED <br><br> (g) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, <br><br> 5 (h) l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, <br><br> (i) l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-10 yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, <br><br> (j) l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(lH-tetrazol-5-yl)ethyl]-15 amide, <br><br> (k) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide, <br><br> 20 <br><br> (1) l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, <br><br> 25 (m) l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, <br><br> (n) l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-30 benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, <br><br> (o) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-35 hydroxycarbonylethyl-N-methyl)-2-aminoethyl]-amide, <br><br> AS AMENDED ~B~ <br><br> (p) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide, <br><br> 5 (q) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]- <br><br> benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide, <br><br> (r) l-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-10 aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, <br><br> (s) l-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-15 pyridyl)-N-(2-hydroxycarbonylethyl)-amide, <br><br> (t) l-Methyl-2-[N-(4-amidinophenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide and <br><br> 20 <br><br> (u) l-Methyl-2-[N-(4-amidinophenyl)aminomethyl]- <br><br> thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2- <br><br> hydroxycarbonylethyl)-amide, <br><br> 25 <br><br> the tautomers, prodrugs, double prodrugs, stereoisomers and the salts thereof. <br><br> The new compounds may be prepared by methods known per se, 30 for example by the following methods: <br><br> a. In order to prepare a compound of general formula I, wherein E denotes an RbNH-C(=NH)- group, wherein Rb is a hydrogen atom, a hydroxy or Ci-3-alkyl group: <br><br> 35 <br><br> By reacting a compound of general formula <br><br> AS AMENDED " " " <br><br> Ra - A - Het - B - Ar - C(=NH) - Z]_ , (II) <br><br> optionally formed in the reaction mixture, <br><br> 5 wherein <br><br> A, B, Ar, Het and Ra are as hereinbefore defined and Zi 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, 10 ethylthio, n-propylthio or benzylthio group, with an amine of general formula <br><br> H2N - Rb' , (III) <br><br> wherein <br><br> 15 Rb' denotes a hydrogen atom or a hydroxy or Ci-3-alkyl group. <br><br> The reaction is conveniently carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol/water, 20 tetrahydrofuran or dioxane at temperatures between 0 and 150°C, preferably at temperatures between 20 and 120°C, <br><br> with a compound of general formula III or with a corresponding acid addition salt such as ammonium •carbonate, for example. <br><br> 25 <br><br> 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 30 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 35 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 <br><br> AS AMENDED " 1U " <br><br> such as triethylamine and subsequent alkylation of the resulting thioamide with a corresponding alkyl or aralkyl halide. <br><br> b. In order to prepare a compound of general formula I 5 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 as hereinbefore defined or that the Ra-A- group is as hereinbefore defined and E denotes an NH2-C(=NH)-group, or that the Ra-A- group contains a carboxy group and 10 E denotes an NH2-C(=NH)- group: <br><br> Converting a compound of general formula <br><br> Ra 1 - A - Het - B - Ar - E1 , (IV) <br><br> 15 wherein <br><br> 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 20 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 NH2-C(=NH)- group by hydrolysis, <br><br> treatment with an acid or base, thermolysis or 25 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 30 may be converted into an NH2-C(=NH)- group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis, <br><br> is converted by hydrolysis, treatment with an acid or base, 35 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 <br><br> AS AMENDED " 11 " <br><br> contains a carboxy group and E is as hereinbefore defined or the Ra-A- group has the meanings given above and E denotes an NH2-C(=NH)- group or the Ra-A- group contains a carboxy group and E denotes an NH2-C(=NH)- group. <br><br> 5 <br><br> 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, 10 trimethylsilylesters, orthoesters or iminoesters which may conveniently be converted into a carboxyl group by hydrolysis, <br><br> the esters thereof with tertiary alcohols, e.g. the 15 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, 20 which are conveniently converted into a carboxyl group by hydrogenolysis. <br><br> The hydrolysis is expediently carried out either in the presence of an acid such as hydrochloric acid, sulphuric 25 acid, phosphoric acid, acetic acid, trichloroacetic acid, <br><br> trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, 30 ethanol, water/tetrahydrofuran or water/dioxane at temperatures between -10 and 120°C, e.g. at temperatures between room temperature and the boiling temperature of the reaction mixture. <br><br> 35 <br><br> If the Ra'-A- group and/or E' in a compound of formula IV contains the tert.-butyl or tert.-butyloxycarbonyl group, for example, these may also be cleaved by treating with an <br><br> AS AMENDED " iZ " <br><br> acid such as trifluoroacetic acid, formic acid, p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid, optionally in an inert solvent such as methylene chloride, chloroform, 5 benzene, toluene, diethylether, tetrahydrofuran or dioxane, preferably at temperatures between -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, tetrahydrofuran or dioxane and preferably <br><br> 10 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. <br><br> 15 <br><br> If the Rg'-A- group and/or E' in a compound of formula IV contains the benzyloxy or benzyloxycarbonyl group, for example, these may also be cleaved by hydrogenolysis in the presence of a hydrogenation catalyst such as <br><br> 20 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. <br><br> 25 <br><br> c. In order to prepare a compound of general formula I wherein the Ra-A- group contains one of the ester groups mentioned in the definition of the Ra-A- group hereinbefore: <br><br> 30 <br><br> Reaction of a compound of general formula <br><br> Ra" - A - Het - B - Ar - E , (V) <br><br> 35 <br><br> wherein <br><br> B, E, Ar and Het are as hereinbefore defined and <br><br> AS AMENDED " " ' <br><br> 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, 5 with an alcohol of general formula <br><br> HO - R7 , (VI) <br><br> wherein <br><br> R7 is a Ci-6-alkyl or benzyl groupor with the formamide 10 acetals thereof. <br><br> or with a compound of general formula <br><br> 15 <br><br> 20 <br><br> Z2 - Rv , (VII) <br><br> wherein <br><br> R7 denotes a Ci-6-alkyl or benzyl group and <br><br> Z2 denotes a leaving group such as a halogen atom, e.g. <br><br> chlorine or bromine atom. <br><br> 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 25 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 of isobutylchloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, 30 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 35 or triphenylphosphine/diethylazodicarboxylate, optionally in the presence of a base such as potassium carbonate, N-ethyl-diisopropylamine or N,N-dimethylamino-pyridine, <br><br> AS AMENDED <br><br> conveniently at temperatures between 0 and 150°C, <br><br> preferably at temperatures between 0 and 80°C. <br><br> With a compound of general formula VII the reaction is 5 usefully carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, 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 10 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 15 preferably at temperatures between -10 and 80°C. <br><br> d. In order to prepare a compound of general formula I wherein Rb denotes a group which may be cleaved in vivo: <br><br> 20 Reacting a compound of general formula <br><br> Ra - A - Het - B - Ar - C(=NH) - NH2 ,(VIII) <br><br> wherein <br><br> 25 Ra, A, Het, B and Ar are as hereinbefore defined, with a compound of general formula <br><br> Z2 - Rs , (IX) <br><br> 30 wherein <br><br> Re denotes denotes a Ci-g-alkoxycarbonyl, <br><br> cyclohexyloxycarbonyl, phenyl-Ci_3-alkoxycarbonyl, benzoyl, p-Ci-3-alkyl-benzoyl or pyridinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C1-9-35 alkoxycarbonyl group may additionally be substituted by a Ci-3-alkylsulphonyl or 2-(Ci-3-alkoxy)-ethyl group and Z2 denotes a nucleofugic leaving group. <br><br> AS AMENDED <br><br> - 15 - <br><br> Received at IPONZ on 10 February 2010 <br><br> 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 tertiary 5 organic base, preferably at temperatures between 2 0°C and the boiling temperature of the solvent used. <br><br> With a compound of general formula IX, wherein Z2 denotes a nucleofugic leaving group, the reaction is preferably 10 carried out in a solvent such as methylene chloride, <br><br> acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethylsulphoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium tert.-butoxide or N-ethyl-diisopropylamine at temperatures 15 between 0 and 6 0°C. <br><br> e. Also described in this specification, but not claimed, is a method of preparing a compound of general formula I wherein B denotes an ethylene group, in which a methylene 2 0 group is replaced by a sulphinyl or sulphonyl group: <br><br> Oxidation of a compound of general formula <br><br> R_, - A - Het - B' - Ar - E , (X) <br><br> cL <br><br> 25 <br><br> wherein <br><br> 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. <br><br> 30 <br><br> The oxidation is preferably carried out in a solvent or mixture of solvents, e.g. in water, water/pyridine, <br><br> acetone, methylene chloride, glacial acetic acid, glacial acetic acid/acetic anhydride, dilute sulphuric acid or <br><br> AS AMENDED Received at IPONZ on 10 February 2010 <br><br> trifluoroacetic acid, and depending on the oxidising agent used, at temperatures between -80 and 10 0°C. <br><br> In order to prepare a corresponding sulphinyl compound of 5 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 2 0°C or in acetone at 0 to 60°C, with a peracid such as performic acid in glacial 10 acetic acid or trifluoroacetic acid at 0 to 50°C or with m-chloroperbenzoic acid in methylene chloride, chloroform or dioxane at -2 0 to 8 0°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 15 the presence of a weak base such as sodium acetate, with N-bromosuccinimide in ethanol, with tert.-butylhypochlorite in methanol at -80 to -3 0°C, with iodobenzodichloride in aqueous pyridine at 0 to 50°C, with nitric acid in glacial acetic acid at 0 to 20°C, with chromic acid in glacial 2 0 acetic acid or in acetone at 0 to 2 0°C and with sulphuryl chloride in methylene chloride at -7 0°C, the resulting thioether chlorine complex is conveniently hydrolysed with aqueous ethanol. <br><br> 2 5 In order to prepare a sulphonyl compound of general formula <br><br> 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 <br><br> 3 0 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, <br><br> AS AMENDED <br><br> - 16a - <br><br> Received at IPONZ on 10 February 2010 <br><br> trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 6 0°C, with nitric acid in glacial acetic acid at 0 to 20°C, with chromic acid or potassium permanganate in glacial acetic acid, 5 water/sulphuric acid or in acetone at 0 to 2 0°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 2 0°C and the 10 reflux temperature of the reaction mixture, a corresonding sulphonyl compound of general formula I is obtained which may still contain a small amount of the corresponding sulphinyl compound. <br><br> 15 f. Also described in this specification, but not claimed, is a method of preparing 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, 2 0 sulphonyl, carbonyl or -NRi- group: <br><br> Reacting a compound of general formula <br><br> 25 <br><br> R_, - A - Het - U , (Xi; <br><br> cL <br><br> with a compound of general formula <br><br> V - Ar - CN ,(XIIi <br><br> 3 0 wherein <br><br> Ra, A, Ar and Het are as hereinbefore defined, <br><br> one of the groups U or V denotes an HO-, HS-, HOSO-, H0S02-or HNRx- group and the other group denotes a Z3CH2- group, wherein Rx is as hereinbefore defined and Z3 denotes a <br><br> (followed by page 16b) <br><br> AS AMENDED <br><br> - 16b - <br><br> Received at IPONZ on 10 February 2010 <br><br> nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom. <br><br> The reaction is preferably carried out in a solvent such as 5 methanol, ethanol, methylene chloride, tetrahydrofuran, <br><br> toluene, dioxane, dimethylsulphoxide or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 2 0°C and the boiling temperature of the solvent used. <br><br> 10 <br><br> g. Also described in this specification, but not claimed, is a method of preparing a compound of general formula I, wherein E is a cyano group and Ra denotes an R2NR3- group: <br><br> 15 Reacting a compound of general formula <br><br> H - A - Het - B - Ar - CN ,(XIII) <br><br> wherein <br><br> 2 0 A, B, Het and Ar are as hereinbefore defined, with an amine of general formula <br><br> /-R2 <br><br> H - N ,(XIV) <br><br> wherein <br><br> 25 R2 and R3 are as hereinbefore defined, or with the reactive derivatives thereof. <br><br> The reaction of an acid of general formula XIII is optionally carried out in a solvent or mixture of solvents 3 0 such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, <br><br> benzene/tetrahydrofuran or dioxane or in a corresponding amine of general formula III, optionally in the presence of <br><br> (followed by page 16c) <br><br> AS AMENDED <br><br> - 16c - <br><br> Received at IPONZ on 10 February 2010 <br><br> a dehydrating agent, e.g. in the presence of isobutyl-chloroformate, tetraethylorthocarbonate, trimethylortho-acetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, 5 phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-dicyclohexylcarbodiimide/l-hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3 -tetramethyluronium-tetrafluoroborate, 2-(lH-benzotriazol-l-yl)-1,1,3,3-10 tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride and optionally with the addition of a base such as pyridine, 4-dimethylamino-pyridine, N-methyl-morpholine or triethylamine, 15 conveniently at temperatures between 0 and 150°C, <br><br> preferably at temperatures between 0 and 100°C. <br><br> The reaction of a corresponding reactive compound of general formula XIII such as the esters, imidazolides or 2 0 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- <br><br> 2 5 diisopropylamine or N-methyl-morpholine at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C. <br><br> h. In order to prepare a benzimidazolyl or benzothiazolyl <br><br> 3 0 compound of general formula I wherein B denotes an ethylene group: <br><br> Reacting a compound of general formula <br><br> (followed by page 16d) <br><br> AS AMENDED <br><br> - 16d - <br><br> Received at IPONZ on 10 February 2010 <br><br> R. <br><br> , (XV) <br><br> wherein <br><br> Ra and A are as hereinbefore defined, and Y denotes a sulphur atom or a nitrogen atom substituted by a -alkyl or cyclopropyl group, with a compound of general formula <br><br> HO-CO - CH2CH2 - Ar - E <br><br> ,(XVI) <br><br> wherein <br><br> 10 Ar and E are as hereinbefore defined, or with the reactive derivatives thereof. <br><br> The reaction is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, 15 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, <br><br> 2 0 tetramethoxysilane, thionyl chloride, trimethylchloro- <br><br> silane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-dicyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(lH-benzotriazol-1-yl)-1,1,3,3-25 tetramethyluronium-tetrafluoroborate, 2-(lH-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/l-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylamino- <br><br> 3 0 pyridine, N-methyl-morpholine or triethylamine, <br><br> appropriately at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C. <br><br> (followed by page 16e) <br><br> AS AMENDED <br><br> - 16e - <br><br> Received at IPONZ on 10 February 2010 <br><br> 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 5 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 10 100°C. <br><br> i. Also described in this specification, but not claimed, is a method of preparing a quinoxalin-2-one compound of the general formula: <br><br> 15 <br><br> Reacting a compound of general formula <br><br> NR-lH <br><br> wherein <br><br> 2 0 Ra, R]_ and A are as hereinbefore defined, with a compound of general formula <br><br> HO-CO - COCH2 - Ar - E ,(XVIII) <br><br> wherein <br><br> 25 Ar and E are as hereinbefore defined, or with the reactive derivatives thereof. <br><br> The reaction is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, <br><br> 3 0 dimethylformamide, benzene, toluene, chlorobenzene, <br><br> tetrahydrofuran, benzene/tetrahydrofuran, ethanol or dioxan, optionally in the presence of a dehydrating agent, <br><br> (followed by page 16f) <br><br> AS AMENDED <br><br> - 16 f - <br><br> Received at IPONZ on 10 February 2010 <br><br> e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, <br><br> 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus 5 pentoxide, N,N'-dicyclohexylcarbodiimide, <br><br> N,N'-dicyclohexylcarbodiimide/N-hydroxysuecinimide, N,N'-dicyclohexylcarbodiimide/l-hydroxy-benzotriazole, 2-(lH-benzotriazol-l-yl)-1,1,3,3 -tetramethyluronium-tetraf luoroborate , 2 -(lH-benzotriazol-1-yl)-1,1,3,3-10 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 15 triethylamine, appropriately at temperatures of between 0 and 150°C, preferably at temperatures of between 0 and 100°C. <br><br> However, it is particularly preferred to carry out the <br><br> 2 0 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 25 tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine, which may simultaneously serve as solvent, at temperatures of between 0 and 150°C, preferably at temperatures of between 50 and 100°C. <br><br> 30 <br><br> j. In order to prepare a compound of general formula I wherein R2 denotes a C1_4-alkyl group substituted by an alkylsulphonylaminocarbonyl group: <br><br> 3 5 Reacting a compound of general formula <br><br> (followed by page 17) <br><br> AS AMENDED <br><br> 17 <br><br> \ / <br><br> N - A - Het - B - Ar - E <br><br> (IXX) <br><br> wherein <br><br> R3, A, B, E, and Het are as hereinbefore defined and 5 R21 denotes a C]__4-alkyl group substituted by a carboxy group, or the reactive derivatives thereof, with a salt of a compound of general formula <br><br> 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 <br><br> 15 metal salt thereof such as a sodium 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. <br><br> 20 In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by means of conventional protecting groups which are removed by cleaving after the reaction. <br><br> For example, the protecting group for a hydroxy group may be the trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group, <br><br> 30 the protecting group for a carboxyl group may be the trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group, and <br><br> Ci_3-Alkyl-S02"NH2 <br><br> (XX) . <br><br> 10 <br><br> 25 <br><br> 35 <br><br> the protecting group for an amino, alkylamino or imino group may be the acetyl, trifluoroacetyl, benzoyl, <br><br> AS AMENDED " 1B " <br><br> ethoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group the phthalyl group may also be considered. <br><br> 5 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 10 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. <br><br> 15 <br><br> 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, 20 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 bar, preferably 3 to 5 bar. <br><br> 25 <br><br> 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 30 preferably at room temperature. <br><br> However, a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole. <br><br> 35 <br><br> A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treatment with an acid such as trifluoroacetic <br><br> AS AMENDED " 13 " <br><br> acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane, or ether. <br><br> A phthalyl group is preferably cleaved in the presence of 5 hydrazine or a primary amine such as methylamine, <br><br> ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane, at temperatures between 20 and 50°C. <br><br> 10 An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis-(triphenylphosphine)-palladium(0), 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 15 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 1,4-20 diazabicyclo[2.2.2]octane, at temperatures between 20 and 7 0°C. <br><br> The compounds of general formulae II to XX used as starting materials, some of which are known from the literature, may 25 be obtained by methods known from the literature and moreover their production is described in the Examples. <br><br> Thus, for example, a compound of general formula II is obtained by reacting a corresponding nitrile which in turn 30 is conveniently obtained by processes f to h, with a corresponding thio or alcohol in the presence of hydrogen chloride or bromide. <br><br> 35 <br><br> 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. <br><br> AS AMENDED "" "u ~ <br><br> A starting compound of general formula XI in which U denotes a halomethyl group is conveniently obtained by cyclisation of a corresponding ester which is substituted in the o-position by a suitable halogen atom and a 5 methoxyacetamido group, to form 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 10 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, 15 mercapto or amino group. <br><br> 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 20 subsequent amidation of the carboxylic acid thus obtained with a corresponding amine. <br><br> Furthermore, an imidazopyridine substituted in the 5-position by a methyl group and obtained by cyclisation can 25 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. <br><br> 30 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 35 cyclisation of the resulting o-diamino compound with a corresponding carboxylic acid. <br><br> AS AMENDED " Z1 " <br><br> Furthermore, the compounds of general formula I obtained may be separated into their enantiomers and/or diastereomers. <br><br> 5 Thus, for example, the compounds of general formula I <br><br> obtained which occur in racemate form may be separated by 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 10 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 15 subsequently be separated into the enantiomers as mentioned above. <br><br> The separation of enantiomers is preferably effected by column separation on chiral phases or by recrystallisation 20 from an optically active solvent or by reacting with an optically active substance, especially 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 25 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 30 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 35 optically active acyl groups in amides include, for example, (+)- or (-)-menthyloxycarbonyl. <br><br> AS AMENDED <br><br> 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 5 suitable acids include for example hydrochloric acid, <br><br> hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. <br><br> 10 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. 15 Examples of suitable bases include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine. <br><br> As already mentioned, the new compounds of general formula 20 I and the salts thereof have valuable properties. Thus, the compounds of general formula 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 25 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 30 such as e.g. trypsin, urokinase factor Vila, factor Xa, <br><br> 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. <br><br> 35 <br><br> For example, the following compounds: <br><br> AS AMENDED ~ 23 " <br><br> A = 2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazole- <br><br> 5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)-amide, <br><br> B = l-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5 5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonyl- <br><br> propyl)-amide, <br><br> C = l-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid -N-phenyl-N-(hydroxycarbonyl-10 methyl)-amide, <br><br> D = l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]- <br><br> benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, <br><br> 15 <br><br> E = l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]- <br><br> benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide, <br><br> 20 F = l-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(lH-tetrazol-5-yl)ethyl]-amide and <br><br> G = l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-25 benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- <br><br> hydroxycarbonylethyl)-amide were investigated as follows for their effects on thrombin time: <br><br> 30 <br><br> Materials: plasma, from human citrated blood. <br><br> Test thrombin (bovine), 30U/ml, Behring Werke, Marburg <br><br> Diethylbarbiturate acetate buffer, ORWH 60/61, 35 Behring Werke, Marburg <br><br> Biomatic BIO coagulometer, Sarstedt <br><br> AS AMENDED <br><br> Method: <br><br> - 24 - <br><br> The thrombin time was determined using a Biomatic BIO coagulometer made by Messrs. Sarstedt. <br><br> 5 <br><br> 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 10 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 clotting of the mixture. Mixtures to which 0.1 ml of DBA buffer were added were used as the controls. <br><br> 15 <br><br> 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. <br><br> 20 <br><br> The Table which follows contains the results found: <br><br> Substance <br><br> Thrombin time <br><br> (ED200 in PM) <br><br> A <br><br> 0. 04 <br><br> B <br><br> 0.06 <br><br> C <br><br> 0.15 <br><br> D <br><br> 0.03 <br><br> E <br><br> 0.09 <br><br> F <br><br> 0.03 <br><br> G <br><br> 0.03 <br><br> By way of example, no acute toxic side effects were 25 observed when compounds A, D, E and G were administered to rats in doses of up to 10 mg/kg i.v. The compounds are thus well tolerated. <br><br> AS AMENDED ~ ~ <br><br> 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 5 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 10 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 15 metastasis and the growth of clot-dependent tumours and fibrin-dependent inflammatory processes. <br><br> The dosage required to achieve such an effect is appropriately 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg 20 by intravenous route, and 0.1 to 50 mg/kg, preferably 0.3 <br><br> 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 25 or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, 30 cetylstearyl alcohol, carboxymethylcellulose 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. <br><br> 35 <br><br> The Examples which follow are intended to illustrate the invention: <br><br> AS AMENDED <br><br> Preliminary remarks <br><br> - 26 - <br><br> Unless otherwise specified, the Rf values were always determined using polygram silica gel plates produced by 5 Messrs. E. Merck of Darmstadt. <br><br> The EKA mass spectra (electrospray mass spectra of cations) are described, for example, in "Chemie unserer Zeit 6, 308-316 (1991). <br><br> 10 <br><br> Example 1 <br><br> 3-Methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b]-pyridine-6-carboxylic acid -N-phenyl-N-(2-15 ethoxycarbonylethyl)-amide a) Methyl 6-methylamino-5-nitro-nicotinate <br><br> 1.6 g (7.4 mMol) of methyl 6-chloro-5-nitro-nicotinate (see Bernie et al. in J. Chem. Soc. 1951, 2590) were stirred in 20 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. <br><br> Yield: 1.2 g (80 % of theory), <br><br> 25 Rf value: 0.66 (silica gel; ethyl acetate/ethanol/glacial acetic acid = 90:5:5) <br><br> b) Methyl 5-amino-6-methylamino-nicotinate <br><br> To a solution of 3.1 g (15 mMol) of methyl 6-methylamino- <br><br> 30 5-nitro-nicotinate in 100 ml of ethanol/dichloromethane <br><br> (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 <br><br> 35 distilled off in vacuo. The crude oily product obtained was further reacted directly. <br><br> Yield: 2.4 g (92 % of theory), <br><br> AS AMENDED ~ z'~ <br><br> Rf value: 0.44 (silica gel; ethyl acetate/ethanol/ammonia = <br><br> 90:10:1) <br><br> c) Methyl 5-[2-(4-cyanophenyl)ethylcarbonylamino]-5 6-methylamino-nicotinate <br><br> 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 10 mixed with a solution of 2.3 g (13 mMol) of methyl 5-amino-6-methylamino-nicotinate in 25 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 15 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). <br><br> Yield: 2.1 g (50 % of theory) of beige solid 20 Rf value: 0.54 (silica gel; ethyl acetate/ethanol/ammonia = <br><br> 90:10:1) <br><br> d) Methylyl 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylate <br><br> 25 A solution of 2.0 g (5.9 mMol)of methyl 5— [2— (4 — <br><br> cyanophenyl)ethylcarbonylamino]-6-methylamino-nicotinate in <br><br> 50 ml glacial acetic acid was heated to 100°C for one hour. <br><br> After removal of the solvent the residue was taken up in dichloromethane, washed with sodium hydrogen carbonate <br><br> 30 solution, dried with sodium sulphate and the solvent was distilled off again. <br><br> Yield: 1.7 g brown solid (89 % of theory), <br><br> Rf value: 0.50 (silica gel; ethyl acetate/ethanol/ammonia = <br><br> 90:10:1) <br><br> 35 <br><br> AS AMENDED "/8 " <br><br> e) 3-Methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid <br><br> A solution of 3.2 g (10 mMol) of methyl 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4.5-b]pyridine-6-carboxylate in 5 150 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 distilled off and the aqueous phase was washed with ethyl acetate. After acidification with 10 dilute hydrochloric acid the mixture was extracted several times with dichloromethane/methanol (9:1), the organic phase was dried with sodium sulphate and the solvent was distilled off. <br><br> Yield: 2.1 g beige solid (70 % of theory), <br><br> 15 Rf value: 0.38 (silica gel; ethyl acetate/ethanol/ammonia <br><br> = 50:45:5) <br><br> f) 3-Methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]-pyridine-6-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyl-ethyl)-amide <br><br> A solution of 2.0 g (6.5 mMol) 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 mMol) 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 to dichloromethane/ethanol = 49:1) the desired compound was isolated as a brownish oil. <br><br> 20 <br><br> 25 <br><br> 30 <br><br> 35 <br><br> AS AMENDED <br><br> Yield: 1.9 g (65 % of theory), <br><br> Rf value: 0.44 (silica gel; ethyl acetate/ethanol/ammonia = <br><br> 90:10:1) <br><br> 5 g) 3-Methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b]-pyridine-6-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide <br><br> 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-(2-10 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 material could be detected by thin layer chromatography. Then the solvent was distilled off, the oily residue was 15 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, the crude product obtained was purified by flash chromatography (silica gel; gradient: dichloromethane/ethanol 19:1 to 4:1) and evaporated down 20 again. <br><br> Yield: 1.6 g of beige solid (80 % of theory), <br><br> Rf value: 0.30 (silica gel; ethyl acetate/ethanol/ammonia = <br><br> 90:5:5) <br><br> 25 Example 2 <br><br> 3-Methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b]-pyridine-6-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide <br><br> 30 <br><br> A solution of 535 mg (1.0 mMol) of 3-methyl-2-[2-(4- <br><br> 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 <br><br> 35 and stirred for 2 hours at room temperature. Then the mixture was diluted with 10 ml water, the alcohol was distilled off, the aqueous phase was washed with 20 ml <br><br> AS AMENDED " " <br><br> ethyl acetate and acidified with concentrated hydrochloric acid, whereupon the desired compound was precipitated in the form of white crystals. <br><br> Yield: 375 mg (74 % of theory), <br><br> 5 Rf value: 0.23 (silica gel; ethyl acetate/ethanol/ammonia = <br><br> 90:5:5) <br><br> C26H26N603 (470.54) <br><br> Mass spectrum: (M+H)+ = 471 <br><br> 10 Example 3 <br><br> 3-Methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride <br><br> 15 <br><br> 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-methoxycarbonylethyl)-amide, methanolic hydrochloric acid, methanol and ammonium 20 carbonate. <br><br> Yield: 75 % of theory, <br><br> C26H27N7O3 (485.55) <br><br> Rf value: 0.31 (silica gel; ethyl acetate/ethanol/ammonia <br><br> = 50:45:5) <br><br> 25 EKA mass spectrum: (M+H)+ = 486 Example 4 <br><br> 3-Methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5— 30 b]pyridin-6-yl-carboxylic acid-N-phenyl-N-ethoxycarbonylmethyl-amide-hydrochloride <br><br> Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic 35 acid-N-phenyl-N-ethoxycarbonylmethyl-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 84 % of theory, <br><br> AS AMENDED " J1 " <br><br> c27h28n6°3 (484.56) <br><br> Rf value: 0.44 (silica gel; ethyl acetate/ethanol/ammonia <br><br> = 50:45:5) <br><br> EKA mass spectrum: (M+H)+ = 485 <br><br> 5 <br><br> Example 5 <br><br> 3-Methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5— b]pyridin-6-yl-carboxylic acid-N-phenyl-N-10 hydroxycarbonylmethyl-amide-hydrochloride <br><br> 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-ethoxycarbonylmethyl-amide-hydrochloride 15 and sodium hydroxide solution. <br><br> Yield: 85 % of theory, <br><br> C25H24N6O3 (456.51) <br><br> Rf value: 0.19 (silica gel; ethyl acetate/ethanol/ammonia <br><br> = 50:45:5) <br><br> 20 EKA mass spectrum: (M+H)+ = 457 Example 6 <br><br> 2-[2-(4-amidinophenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl-25 2,3-dihydroindol-l-yl-carbonyl)-imidazo[4,5-b]pyridine-hydrochloride <br><br> Prepared analogously to Example 1 from 2—[2—(4— cyanophenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl- <br><br> 30 2,3-dihydroindol-l-yl-carbonyl)-imidazo[4,5-b]pyridine, <br><br> methanolic hydrochloric acid, methanol and ammonium carbonate. <br><br> Yield: 20 % of theory, <br><br> C27H26N6°3 (482.54) <br><br> 35 Rf value: 0.30 (silica gel; ethyl acetate/ethanol/ammonia <br><br> = 50:45:5) <br><br> AS AMENDED <br><br> - 32 - <br><br> EKA mass spectrum: (M+H) + = 483 Example 7 <br><br> 5 2-[2-(4-amidinophenyl)ethyl]-3-methyl-6-(2-carboxy- <br><br> 2,3-dihydroindol-l-yl-carbonyl)-imidazo[4,5-b]pyridine-hydrochloride <br><br> Prepared analogously to Example 2 from 2—[2—(4— 10 amidinophenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl- <br><br> 2,3-dihydroindol-l-yl-carbonyl)-imidazo[4,5-b]pyridine-hydrochloride and sodium hydroxide solution. <br><br> Yield: 90 % of theory, <br><br> C26H24N603 (468.52) <br><br> 15 Rf value: 0.24 (silica gel; ethyl acetate/ethanol/ammonia <br><br> = 50:45:5) <br><br> EKA mass spectrum: (M+H)+ = 469 <br><br> (M+Na)+ = 491 <br><br> 20 Example 8 <br><br> l-Methyl-2-[(4-amidinophenyl)oxymethyl]- <br><br> imidazo[4,5-b]pyridin-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> 25 <br><br> a) 2-Amino-3-methylamino-6-methyl-pyridine <br><br> 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 <br><br> 30 hours at room temperature. Then the catalyst was filtered off and the filtrate was evaporated down. After crystallisation of the resulting residue from petroleum ether, 5.75 g (84 % of theory) were obtained as olive-green crystals. <br><br> 35 C7H11N3 (137.20) <br><br> Melting point: 112-113°C <br><br> AS AMENDED ~ 33 " <br><br> b) 1,5-Dimethyl-2-[(4-cyanophenyl)oxymethyl]-imidazo[4,5-b]-pyridine <br><br> 11.4 g (63 mMol) of 4-cyano-phenoxyacetic acid were dissolved in 200 ml of absolute tetrahydrofuran and mixed 5 at room temperature with 10.2 g (63 mMol) of <br><br> N,N'-carbonyldiimidazole. After 15 minutes at 60°C, 5.70 g (41.5 mMol) of 2-amino-3-methylamino-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 10 with water and dried. After crystallisation from ethanol 9.95 g (91 % of theory) were obtained in the form of white crystals. <br><br> c16h14n4° (278.32) <br><br> Mass spectrum: M+ = 278 <br><br> 15 <br><br> c) 1,5-Dimethyl-2-[(4-cyanophenyl)oxymethyl]-imidazo[4,5-b]pyridin-4-N-oxide <br><br> 2.62 g (10 mMol) of 1,5-dimethyl-2-[(4-cyanophenyl)-oxymethyl]-imidazo[4,5-b]pyridine were suspended in 125 ml <br><br> 20 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 was distilled off and the residue obtained was mixed with a sodium hydrogen carbonate solution. After 30 minutes the <br><br> 25 white crystalline product obtained was suction filtered, <br><br> washed with water and dried at 40°C. <br><br> Yield: 2.45 g (83 % of theory), <br><br> C16H14N4O2 (294.30) <br><br> Mass spectrum: M+ = 294 <br><br> 30 <br><br> d) l-Methyl-2-[(4-cyanophenyl)oxymethyl]-5-hydroxymethyl- <br><br> imidazo[4,5-b]pyridine <br><br> 2.40 g (8.2 mMol) of 1,5-dimethyl-2-[(4-cyanophenyl)- <br><br> oxymethyl]-imidazo[4,5-b]pyridin-4-N-oxide were suspended <br><br> 35 in 7 5 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 <br><br> AS AMENDED " J4 " <br><br> 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 5 formed was suction filtered, washed with water and dried at 40°C. <br><br> Yield: 1.85 g white powder (78 % of theory), <br><br> c16h14n4°2 (294.30) <br><br> Melting point: 172°C <br><br> 10 <br><br> e) l-Methyl-2-[(4-cyanophenyl)oxymethyl]-imidazo[4,5-b]-pyridine-5-carbaldehyde <br><br> 3.65 g (12.5 mMol) of l-methyl-2-[(4-cyanophenyl)-oxymethyl]-5-hydroxymethyl-imidazo[4,5-b]pyridine were 15 dissolved in 500 ml dichloromethane and mixed with 15.0 g of manganese dioxide. After 96 hours at room temperature the mixture was filtered through kieselgur and the solvent was distilled off. The filtrate obtained was evaporated down, the crystalline precipitate was triturated with 20 ether, suction filtered and dried. <br><br> Yield: 3.05 g white powder (84 % of theory), <br><br> Ci6Hi2N402 (292.30) <br><br> Melting point: 231-234°C <br><br> 25 f) l-Methyl-2-[(4-cyanophenyl)oxymethyl]-5-carboxy-imidazo- <br><br> [ 4.5-b]pyridine <br><br> 1.25 g (4.3 mMol) of l-methyl-2-[(4-cyanophenyl)oxymethyl]- <br><br> imidazo[4,5-b]pyridine-5-carbaldehyde were dissolved in 10 <br><br> ml formic acid and mixed at 0°C with 1.0 ml hydrogen <br><br> 30 peroxide (33% strength). After 12 hours at 4°C the white precipitate formed was suction filtered, washed with water and dried at 40°C. <br><br> Yield: 0.81 g (61 % of theory), <br><br> C16H12N4°3 (308.7) <br><br> 35 <br><br> AS AMENDED "" ~ <br><br> g) l-Methyl-2-[(4-cyanophenyl)oxymethyl]- <br><br> imidazo[4, 5-b]pyridin-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide <br><br> 308 mg (1.0 mMol) of l-methyl-2-[(4-cyanophenyl)oxymethyl]-5 5-carboxy-imidazo[4.5-b]pyridine 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 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate. After 10 minutes at room temperature a 10 solution of 215 mg (1.2 mMol) of methyl N-(2-pyridyl)- <br><br> 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 15 combined organic extracts were washed with a saline solution, dried over sodium sulphate and evaporated down. The residue obtained was chromatographed on silica gel with dichloromethane/ethanol (90:1 to 25:1). <br><br> Yield: 165 mg of white powder (35 % of theory), 20 C25H12N6O4 (407.50) <br><br> Melting point: 139-140°C <br><br> h) l-Methyl-2-[(4-amidinophenyl)oxymethyl]-imidazo[4.5-b]-pyridin-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- <br><br> 25 ethoxycarbonyl-ethyl)-amide <br><br> Prepared by reacting 140 mg (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 <br><br> 30 ammonium carbonate/ethanol analogously to Example lg. The resulting product was purified by chromatography over silica gel with dichloromethane/ethanol (19:1 to 4:1). <br><br> Yield: 48 mg of white powder (36 % of theory), <br><br> C26H27N7°4 (501.57) <br><br> 35 Mass spectrum: (M+H)+ = 502 <br><br> AS AMENDED <br><br> Example 9 <br><br> - 36 - <br><br> 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide 5 <br><br> a) Ethyl 4-fluoro-3-methoxyacetamido-benzoate <br><br> 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 10 methoxyacetylchloride in 50 ml 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/ethanol = 100:1). The desired 15 compound, initially oily, solidified within a few days. Yield: 3.8 g (98 % of theory), <br><br> Rf value: 0.38 (silica gel; dichloromethane/ethanol = 19:1) <br><br> b) Ethyl-2-methoxymethyl-benzothiazole-5-carboxylate 20 A mixture of 3.0 g (11.7 mMol) of 4-fluoro-3- <br><br> methoxyacetamido-benzoic acid and 2.1 g (5.2 mMol) of Lawesson's reagent was refluxed for 6 hours in 90 ml toluene, mixed with 1.0 g Lawesson's reagent and heated to 120°C for another 6 hours. After the solvent was replaced 25 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. 30 Yield: 2.1 g of yellow crystals (72 % of theory), <br><br> Rf value: 0.55 (silica gel; ethyl acetate/petroleum ether = <br><br> 3:7) <br><br> c) 2-Methoxymethyl-benzothiazole-5-carboxylic acid <br><br> A mixture of 2.1 g (8.36 mMol) of ethyl 2-methoxymethyl- <br><br> 35 benzothiazole-5-carboxylate and 16 ml of 2N sodium hydroxide solution was stirred into 60 ml ethanol for 1 hour at room temperature. Then the alcohol was distilled <br><br> AS AMENDED " " " <br><br> 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 5 was suction filtered, washed with water and dried. <br><br> Yield: 1.6 g (86 % of theory), <br><br> Rf value: 0.12 (silica gel; dichloromethane/ethanol = 29:1) <br><br> d) 2-Methoxymethyl-benzothiazole-5-carboxylic acid-N-10 phenyl-N-(2-ethoxycarbonylethyl)-amide <br><br> A suspension of 1.6 g (7.2 mMol) 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. 15 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 20 mMol) of N-(2-ethoxycarbonylethyl)aniline and 3.0 ml (21 mMol) of triethylamine in 50 ml of tetrahydrofuran and stirred overnight at room temperature. Then the solvent was distilled off in vacuo, the residue was taken up in 30 ml of dichloromethane, this solution was washed with water 25 and dried with sodium sulphate. After distillation of the solvent and flash chromatography (silica gel; gradient: dichloromethane/ethanol 98.5:1.5 to 80:20) the desired compound was isolated as a brownish oil. <br><br> Yield: 2.05 (72 % of theory), <br><br> 30 Rf value: 0.40 (silica gel; ethyl acetate/petroleum ether = <br><br> 1:1) <br><br> e) 2-[N-(4-Cyanophenyl)-aminomethyl]-benzothiazole- <br><br> 5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide <br><br> 35 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 <br><br> AS AMENDED ~ 38 " <br><br> solution of boron tribromide in dichloromethane was dissolved in a further 60 ml of dichloromethane and stirred for 16 hours at room temperature. Then the mixture was washed with 40 ml of saturated sodium hydrogen carbonate 5 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 10 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 15 foam was obtained when the eluates were evaporated down. Yield: 1.1 g (44 % of theory), <br><br> Rf value: 0.35 (silica gel; ethyl acetate/petroleum ether = 7:3) <br><br> 20 f) 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazole- <br><br> 5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide 1.1 g (2.27 mMol) of 2-[N-(4-cyanophenyl)-aminomethyl]-benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide was stirred in 100 ml of ethanol 25 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 30 100 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 35 eluates are evaporated down the desired compound is obtained as a white foam. <br><br> Yield: 0.77 g (63 % of theory), <br><br> AS AMENDED " " <br><br> Rf value: 0.19 (silica gel; dichloromethane/ethanol = 3:7) <br><br> c27h27n5°3s (501.60) <br><br> Mass spectrum: (M+H)+ = 502 <br><br> 5 Example 10 <br><br> 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazole-5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)-amide <br><br> 10 0.45 g (0.84 mMol) of 2-[N-(4-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 15 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 20 obtained as a yellow foam. <br><br> Yield: 0.26 g (67 % of theory), <br><br> Rf value: 0.47 (silica gel; methanol/5 % aqueous sodium chloride = 6:4) <br><br> C25H23N5O3S (473.55) <br><br> 25 Mass spectrum: (M+H)+ = 474 Example 11 <br><br> 2-[N-(4-amidinophenyl)-aminomethyl]benzothiazol-5-yl-30 carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-dihydrochloride <br><br> Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)-aminomethyl]benzothiazol-5-yl-carboxylic acid- <br><br> 35 N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide, methanolic hydrochloric acid, methanol and ammonium carbonate. <br><br> Yield: 68 % of theory, <br><br> AS AMENDED " ,u " <br><br> c25h24n6°3s (488.57) <br><br> Rf value: 0.13 (silica gel; methylene chloride/ethanol = <br><br> 4:1 +a few drops of acetic acid) <br><br> EKA mass spectrum : (M+H)+ = 489 <br><br> 5 <br><br> Example 12 <br><br> 2-[2-(4-amidinophenyl)ethyl]-benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-10 dihydrochloride <br><br> Prepared analogously to Example 9 from 2— [2— (4 — cyanophenyl)ethyl]-benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide, ethanolic 15 hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 95 % of theory, <br><br> C26H25N5O3S (487.58) <br><br> Rf value: 0.20 (silica gel; methylene chloride/ethanol = <br><br> 4:1 + a few drops of acetic acid) <br><br> 20 EKA mass spectrum: (M+H)+ = 488 Example 13 <br><br> 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-25 carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride <br><br> Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic 30 acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 68 % of theory, <br><br> c25h24n6°3s (488.57) <br><br> 35 Rf value: 0.14 (silica, gel; methylene chloride/ethanol = <br><br> 4:1 + a few drops of acetic acid) <br><br> AS AMENDED " 41 " <br><br> EKA mass spectrum: (M+H) + = 489 Example 14 <br><br> 5 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide-dihydrochloride <br><br> Prepared analogously to Example 10 from 2-[N-(4-10 amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride and sodium hydroxide solution. <br><br> Yield: 90 % of theory, <br><br> c23h20n6°3s (460.52) <br><br> 15 Rf value: <br><br> EKA mass spectrum: (M+H) + = 461 <br><br> (M+Na)+ = 483 (M+2Na)++ = 253 <br><br> 20 Example 15 <br><br> 2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 25 <br><br> a) 2-[N-(4-Cyanophenyl)-N-methyl-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 9e from 4-cyano-N-methyl-30 aniline and 2-methoxymethyl-benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide. <br><br> Yield: 57 % of theory, <br><br> Rf value: 0.46 (silica gel; dichloromethane/ethanol = <br><br> 19:1). <br><br> AS AMENDED " ^ ~ <br><br> b) 2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 9 from 2-[N-(4-5 cyanophenyl)-N-methyl-aminomethyl]-benzothiazol-5-yl- <br><br> carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 73 % of theory, <br><br> 10 C28H29N5O3S (515.64) <br><br> Rf value:0.29 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) <br><br> EKA mass spectrum: (M+H)+ = 516 <br><br> 15 Example 16 <br><br> 2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide-hydrochloride <br><br> 20 <br><br> 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. <br><br> 25 Yield: 96 % of theory, <br><br> c26h25n5°3s (487.58) <br><br> Rf value: 0.48 (Merck RP-8, methanol/5% NaCl solution = <br><br> 6:4) <br><br> EKA mass spectrum: (M+H)+ = 488 30 (M+2Na)++ = 266.5 <br><br> Example 17 <br><br> 2-[(4-amidinophenyl)thiomethyl]-benzothiazol-5-yl-35 carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> AS AMENDED """ <br><br> Prepared analogously to Example 9 from 2-[(4-cyanophenyl)thiomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. 5 Yield: 61 % of theory, <br><br> c27h26n4°3s2 (518.66) <br><br> Rf value: 0.27 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) <br><br> EKA mass spectrum: (M+H)+ = 519 <br><br> 10 <br><br> Example 18 <br><br> 2-[(4-amidinophenyl)thiomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide-15 hydrochloride <br><br> Prepared analogously to Example 10 from 2-[(4-amidinophenyl)thio-48- [sic] methyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-20 hydrochloride and sodium hydroxide solution. <br><br> Yield: 95 % of theory, <br><br> c25h22n4°3s2 (490.61) <br><br> Rf value: 0.25 (Merck RP-8, methanol/5% NaCl solution = 6:4) <br><br> 25 EKA mass spectrum: (M+H)+ = 491 <br><br> (M+Na)+ = 513 <br><br> Example 19 <br><br> 30 <br><br> 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride <br><br> 35 <br><br> Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic <br><br> AS AMENDED <br><br> acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 82 % of theory, <br><br> C26H25N5O3S (487.58) <br><br> 5 Rf value: 0.21 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) <br><br> EKA mass spectrum: (M+H)+ = 488 Example 20 <br><br> 10 <br><br> 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)-amide-hydrochloride <br><br> 15 Prepared analogously to Example 10 from 2-[N-(4- <br><br> amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 75 % of theory, <br><br> 20 C24H21N5O3S (459.53) <br><br> Rf value: 0.14 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) <br><br> EKA mass spectrum: (M+H)+ = 460 <br><br> (M+Na)+ = 482 <br><br> 25 <br><br> Example 21 <br><br> 2-[2-(4-amidinophenyl)ethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 30 <br><br> Prepared analogously to Example 9 from 2-[2-(4-cyanophenyl)ethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. 35 Yield: 80 % of theory, <br><br> C28^28^4&lt;-)3^ (500.62) <br><br> AS AMENDED <br><br> Rf value: 0.30 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) <br><br> EKA mass spectrum: (M+H)+ = 501 5 Example 22 <br><br> 2-[2-(4-amidinophenyl)ethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide-hydrochloride <br><br> 10 <br><br> 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. <br><br> 15 Yield: 77 % of theory, <br><br> c26h24n4°3s (472.57) <br><br> Rf value: 0.18 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) <br><br> EKA mass spectrum: (M+H)+ = 473 <br><br> 20 (M+Na)+ = 495 <br><br> (M+H+Na)++ = 259 <br><br> Example 23 <br><br> 25 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 9 from 2 —[N—(4 — 30 cyanophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 83 % of theory, <br><br> 35 C24H29N5O3 (467.59) <br><br> AS AMENDED " 46 " <br><br> Rf value: 0.31 (silica gel; methylene chloride/ethanol 4:1 + a few drops of acetic acid) <br><br> EKA mass spectrum: (M+H) + = 468 <br><br> (2M+H)+ = 935 <br><br> 5 <br><br> Example 24 <br><br> 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-hydroxycarbonylethyl)-10 amide-hydrochloride <br><br> Prepared analogously to Example 10 from 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-15 hydrochloride and sodium hydroxide solution. <br><br> Yield: 75 % of theory, <br><br> C22H25N5O3S (439.54) <br><br> Rf value: 0.14 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) <br><br> 20 EKA mass spectrum: (M+H)+ = 440 <br><br> (M+H+Na)++ = 231.6 <br><br> Example 25 <br><br> 25 l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) 4-Methylamino-3-nitro-benzoic acid-N-phenyl-N-(2-ethoxy-30 carbonylethyl)-amide <br><br> 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 35 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 <br><br> AS AMENDED " " " <br><br> mixed with 700 ml of water with stirring. The mixture was extracted 3 times with 200 ml of dichloromethane, the organic extract was washed twice with 200 ml of 2N hydrochloric acid and twice with 300 ml of water and dried 5 over sodium sulphate. The solvent was then distilled off and the oily product thus obtained was purified by column chromatography (1 kg silica gel; eluant: petroleum ether/ethyl acetate = 2:1). <br><br> Yield: 35.0 g (82 % of theory), <br><br> 10 Rf value: 0.28 (silica gel; dichloromethane/ethanol = 50:1) <br><br> b) 3-Amino-4-methylamino-benzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl) -amide <br><br> 12.1 g (0.0326 mol) of 4-methylamino-3-nitro-benzoic acid-15 N-phenyl-N-(2-ethoxycarbonylethyl)-amide were hydrogenated in 300 ml ethanol and 150 ml dichloromethane after the addition of about 4 g of palladium/charcoal (10%) at room temperature and under a hydrogen pressure of 5 bar. Then the catalyst was filtered off and the filtrate was 20 evaporated down. The crude product thus obtained was reacted without further purification. <br><br> Yield: 10.6 g (95 % of theory), <br><br> Rf value: 0.19 (silica gel; dichloromethane/ethanol = 50:1) <br><br> 25 c) l-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide <br><br> 6.17 g (0.035 mol) of N-(4-cyanophenyl)glycine and 5.68 g (0.035 mol) of N,N'-carbonyldiimidazole were refluxed in 30 300 ml of tetrahydrofuran for 30 minutes, then 10.6 g <br><br> (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 35 150 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 <br><br> AS AMENDED " " <br><br> 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 chromatography (800 g silica gel; 5 eluant: dichloromethane with 1-2 % ethanol). <br><br> Yield: 8.5 g (57 % of theory), <br><br> Rf value: 0.51 (silica gel; dichloromethane/ethanol = 19:1) <br><br> d) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-10 benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride 1.2 g (2.49 mMol) of l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were stirred in 100 ml of 15 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, <br><br> mixed with 2.5 g (26 mMol) of ammonium carbonate and stirred overnight at room temperature. After distillation 20 of the solvent the crude product thus obtained was purified by column chromatography (100 g silica gel; eluant: dichloromethane/ethanol = 4:1). By concentrating the eluates the desired compound was obtained as a white, amorphous solid. <br><br> 25 Yield: 1.10 g (83 % of theory), <br><br> Rf value: 0.18 (silica gel; dichloromethane/ethanol = 4:1) c28h30n6°3 x hc1 (498.6) <br><br> EKA mass spectrum: (M+H)+ = 499 <br><br> (M+2H)++ = 250 30 (M+H+Na)++ = 261 <br><br> Example 2 6 <br><br> 35 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide <br><br> AS AMENDED <br><br> A mixture of 300 mg (0.56 mMol) of l-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 5 (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 and dried at 60°C in vacuo. 10 Yield: 250 mg (95 % of theory), <br><br> c26h26n6°3 (470.5) <br><br> EKA mass spectrum: (M+H)+ = 471 <br><br> (M+H+Na)++ = 247 (M+2Na)++ = 258 <br><br> 15 <br><br> Example 27 <br><br> l-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-20 amide-hydrochloride a) 4-Methylamino-3-chloracetamido-benzoic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> A solution of 1.8 g (5.9 mMol) of 3-amino-4-methylamino- <br><br> 25 benzoic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> [prepared analogously to 3-amino-4-ethylamino-benzoic acid- <br><br> N-phenyl-N- (2-ethoxycarbonylethyl) -amide] , l.lg (6.8 mMol) <br><br> of N,N'-carbonyldiimidazole and 0.65 g (6.9 mMol) of chloroacetic acid in 75 ml tetrahydrofuran was stirred for <br><br> 30 1 hour at room temperature. Then the solvent was distilled off in vacuo, and the crude product was purified by flash chromatography (silica gel; methylene chloride/ethanol = <br><br> 49:1). <br><br> Yield: 1.7 g (77% of theory) yellow oil, <br><br> 35 Rf value: 0.58 (silica gel; ethyl acetate/ethanol/ammonia <br><br> = 90:10:1) <br><br> AS AMENDED "" 30 ~ <br><br> b) 2-Chloromethyl-1-methyl-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide 1.6 g (4.3 mMol) of 4-methylamino-3-chloracetamido-benzoic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide were 5 heated to 100°C in 25 ml of acetic acid for 30 minutes. <br><br> 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 10 and evaporated down. <br><br> Yield: 1.5 g (100% of theory) of brown oil, <br><br> Rf value: 0.63 (silica gel; ethyl acetate/ethanol/ammonia <br><br> = 90:10:1) <br><br> 15 c) l-Methyl-2-[(4-cyanophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> A mixture of 1.5 g (4.1 mMol) of 2-chloromethyl-l-methyl-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-20 (2-ethoxycarbonylethyl)-amide and 0.65 g (4.8 mMol) of p-cyanothiophenol was heated in 10 ml of dimethylformamide and 10 ml of diisopropylethylamine 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 25 water, and after concentration purified by flash chromatography (silica gel; methylene chloride/ethanol (49:1 to 19:1). <br><br> Yield: 1.5 g (79% of theory) of brown oil, <br><br> Rf value: 0.65 (silica gel; ethyl acetate/ethanol/ammonia 30 = 90:10:1) <br><br> d) l-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)- <br><br> amide-hydrochloride <br><br> 35 1.4 g (3.01 mMol) of l-methyl-2-[(4-cyanophenyl)- <br><br> thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide were stirred in 50 ml of <br><br> AS AMENDED " 51 " <br><br> ethanol saturated with hydrogen 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 5 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 was purified by flash chromatography (silica gel; methylene chloride/ethanol = 10 19:1 to 4:1). <br><br> Yield: 1.3 g (83% of theory) as a light beige solid, Rf value: 0.29 (silica gel; ethyl acetate/ethanol/ammonia <br><br> = 50:45:5) <br><br> C25H31N6O3S (481.62) <br><br> 15 EKA mass spectrum: (M+H)+ = 482 Example 28 <br><br> l-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-20 carboxylic acid-N-(n-propyl)-N-(2-hydroxycarbonylethyl)-amide-hydrochloride <br><br> 0.52 g (1.0 mMol) of l-Methyl-2-[(4-amidinophenyl)-thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)- <br><br> 25 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 <br><br> 5 ml of water were added, the alcohol was distilled off, <br><br> and it was acidified with concentrated hydrochloric acid. <br><br> 30 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. <br><br> 35 Yield: 0.43 g (88% of theory), <br><br> Rf value: 0.19 (silica gel; ethyl acetate/ethanol/ammonia <br><br> = 50:45:5) <br><br> AS AMENDED ~ ~ <br><br> c23h27n5°3s (453.57) <br><br> EKA mass spectrum: (M+H)+ = 454 <br><br> (M+Na)+ = 476 <br><br> 5 Example 2 9 <br><br> l-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-methylpropyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 10 <br><br> Prepared analogously to Example 27 from l-methyl-2-[(4-cyanophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-(N-(2-methylpropyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium 15 carbonate. <br><br> Yield: 83 % of theory, <br><br> c25h31n6°3s (495.65) <br><br> Rf value: 0.30 (silica gel; ethyl acetate/ethanol/ammonia <br><br> = 50:45:5) : <br><br> 20 EKA mass spectrum: (M+H)+ = 496 Example 30 <br><br> l-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-25 carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 27 from l-methyl-2-[(4-cyanophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-30 N-phenyl-N-(2-ethoxycarbonylethyl)-amide, and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 90 % of theory, <br><br> C28H29N5O3S (515.64) <br><br> Rf value:0.24 (silica gel; ethyl acetate/ethanol/ammonia = 35 50:45:5) <br><br> EKA mass spectrum: (M+H)+ = 516 <br><br> AS AMENDED ~ ~ <br><br> (M+H+Na)++ = 269.7 <br><br> Example 31 <br><br> 5 l-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 28 from l-methyl-2-[(4-10 amidinophenyl)thiomethyl-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 76 % of theory, <br><br> C26H25N5O3S (487.58) <br><br> 15 Rf value: 0.31 (silica gel; ethyl acetate/ethanol/ammonia <br><br> = 50:45:5) <br><br> EKA mass spectrum: (M+H)+ = 488 <br><br> (M+Na)+ = 510 <br><br> 20 Example 32 <br><br> l-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-N-(l-methyl-piperidin-4-yl)-N-methyl-amide-hydrochloride <br><br> 25 <br><br> a) 4-Chloro-3-nitrobenzenesulphonic acid-N-(1-methyl- <br><br> piperidin-4-yl)-N-methyl-amide <br><br> To a solution of 2.2 ml (15 mMol) of l-methyl-4- <br><br> methylamino-piperidine in 60 ml pyridine, 3.8 g (15 mMol) <br><br> 30 of 4-chloro-3-nitro-benzenesulphonic 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 mixed with about 50 ml of water and made alkaline with concentrated ammonia whilst stirring <br><br> 35 vigorously. The crude product precipitated was suction filtered and purified by column chromatography (250 g silica gel, eluant: dichloromethane with 1.5% ethanol). <br><br> AS AMENDED " 54 " <br><br> Yield: 1.6 g (31% of theory), <br><br> c13h18c1n3°4s (347.8) <br><br> Rf value: 0.19 (silica gel; dichloromethane/ethanol = 19:1) <br><br> 5 b) 4-Methylamino-3-nitrobenzenesulphonic acid-N-methyl-N- <br><br> (l-methylpiperidin-4-yl)-amide <br><br> 1.6 g (4.6 mMol) of 4-chloro-3-nitrobenzenesulphonic acid-N-methyl-N-(l-methyl-piperidin-4-yl)-amide was mixed with 30 ml of 40% methylamine solution and stirred in a sealed 10 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. <br><br> Yield: 1.5 g (95% of theory), <br><br> 15 C14H22N4O4S (343.4) <br><br> Rf value: 0.45 (silica gel; dichloromethane/ethanol = 4:1) <br><br> c) 3-Amino-4-methylaminobenzenesulphonic acid-N-methyl-N-(l-methylpiperidin-4-yl)-amide <br><br> 20 1.5 g (4.4 mMol) of 4-methylamino-3-nitrobenzenesulphonic acid-N-methyl-N-(l-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 25 and the filtrate was evaporated down. The resulting oily product was further reacted without any purification. <br><br> Yield: 1.4 g (100% of theory), <br><br> C14H24N4°2S (312.4) <br><br> Rf value: 0.33 (silica gel; dichloromethane/ethanol = 4:1) <br><br> 30 <br><br> d) l-Methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-methyl-N-(l-methyl-piperidin-4-yl)-amide 532 mg (3.0 mMol) of 4-cyanophenyloxyacetic acid and 486 mg (3.0 mMol) of 1,1'-carbonyldiimidazole were dissolved in <br><br> 35 40 ml of tetrahydrofuran and refluxed for 15 minutes. Then 700 mg (2.24 mMol) of 3-amino-4-methylaminobenzenesulphonic acid-N-methyl-N-(l-methyl-piperidin-4-yl)-amide were added <br><br> AS AMENDED """ <br><br> 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 5 residue was mixed with about 30 ml of water and made alkaline with concentrated ammonia, 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 10 purification. <br><br> Yield: 400 mg (39% of theory), <br><br> C23H27N5O3S (453.6) <br><br> Rf value: 0.37 (silica gel; dichloromethane/ethanol = 4:1) <br><br> 15 e) l-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-N-methyl-N-(l-methylpiperidin-4-yl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d from 400 mg of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-20 sulphonic acid-N-methyl-N-(l-methylpiperidin-4-yl)-amide with ethanolic hydrochloric acid and ammonium carbonate. Yield: 370 mg (83% of theory), <br><br> C23H30N6O3S (470.6) <br><br> EKA mass spectrum: (M+H)+ = 471 25 (M+2H)++ = 236 <br><br> Example 33 <br><br> l-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-30 sulphonic acid-N-methyl-N-phenyl-amide-hydrochloride <br><br> Prepared analogously to Example 32 from l-methyl-2-[(4-.cyanophenyl)-oxymethyl]-benzimidazol-5-yl-sulphonic acid-N-methyl-N-phenyl-amide and ethanolic hydrochloric acid, <br><br> 35 ethanol and ammonium carbonate. <br><br> Yield: 46 % of theory, <br><br> C23H23N5O3S (449.5) <br><br> AS AMENDED ~ 36 ~ <br><br> EKA mass spectrum: (M+H)+ = 450 <br><br> (M+H+Methanol)+ = 482 (M+2H)++ = 223 <br><br> 5 Example 34 <br><br> l-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-N-(3-ethoxycarbonyl-n-propyl)-N-phenyl-amide-hydrochloride <br><br> 10 <br><br> Prepared analogously to Example 32 from l-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-N-(3-ethoxycarbonyl-n-propyl)-N-phenyl-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. 15 Yield: 57 % of theory, <br><br> C28H31N5O5S (549.7) <br><br> EKA mass spectrum: (M+H) + = 550 Example 35 <br><br> 20 <br><br> l-Methyl-2-[(3-amidinophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-pyrrolidide-hydrochloride <br><br> Prepared analogously to Example 32 from l-methyl-2-[(3- <br><br> 25 cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid- <br><br> pyrrolidide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 71 % of theory, <br><br> C20H23N5O3S (413.5) <br><br> 30 EKA mass spectrum: (M+H)+ = 414 Example 36 <br><br> 35 <br><br> l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-methoxycarbonylpropyl)-amide-dihydrochloride <br><br> AS AMENDED <br><br> - 57 - <br><br> Prepared analogously to Example 25d from l-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (3-tert.butyloxycarbonylpropyl)-amide and 5 methanolic hydrochloric acid, methanol and ammonium carbonate. <br><br> Yield: 83.5 % of theory, <br><br> Rf value: 0.17 (silica gel; dichloromethane/ethanol = 4:1) C29H31N5°3 (497.6) <br><br> 10 EKA mass spectrum: (M+H)+ = 498 <br><br> (M+H+Na)++ = 260.7 <br><br> Example 37 <br><br> 15 l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl- <br><br> carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl)-amide-hydrochloride <br><br> Prepared analogously to Example 26 from l-methyl-2-[(4- <br><br> 20 amidinophenyl)aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-methoxycarbonylpropyl)-amide- <br><br> dihydrochloride and sodium hydroxide solution. <br><br> Yield: 92 % of theory, <br><br> Rf value: 0.09 (silica gel; dichloromethane/ethanol = 4:1) <br><br> 25 C28H29N5O3 (483.6) <br><br> EKA mass spectrum: (M+H)+ = 484 <br><br> (M+Na)+ = 506 (M+H+Na)++ = 253.7 <br><br> 30 Example 38 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-ethoxycarbonylpropyl)-amide-dihydrochloride <br><br> 35 <br><br> AS AMENDED " 30 " <br><br> a) l-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert.butyloxy-carbonylpropyl)-amide <br><br> Prepared analogously to Example 25c from N-(4-cyanophenyl)-5 glycine and 3-amino-4-methylamino-benzoic acid-N-phenyl-N- (3-tert.butyloxycarbonylpropyl)-amide. <br><br> Yield: 65 % of theory, <br><br> Rf value: 0.17 (silica gel; dichloromethane/methanol = <br><br> 19:1) <br><br> 10 <br><br> b) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl- <br><br> N-(3-ethoxycarbonylpropyl)-amide-dihydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4- <br><br> 15 cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert.butyloxycarbonylpropyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 68 % of theory, <br><br> 20 Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1) C29H32N6O3 (512.6) <br><br> EKA mass spectrum: (M+H)+ = 513 <br><br> (M+H+Na)++ = 268 <br><br> 25 Example 39 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl)-amide-hydrochloride <br><br> 30 <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-ethoxycarbonylpropyl)-amide-dihydrochloride and sodium hydroxide solution. <br><br> 35 Yield: 73.5 % of theory, <br><br> C27h28n6°3 (484.6) <br><br> EKA mass spectrum: (M+H)+ = 485 <br><br> AS AMENDED <br><br> - 59 - <br><br> (M+2H)++ = 243 (M+H+Na)++ = 254 <br><br> Example 40 <br><br> 5 <br><br> l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride <br><br> 10 Prepared analogously to Example 25d from l-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (ethoxycarbonylmethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 73 % of theory, <br><br> 15 Rf value: 0.15 (silica gel; dichloromethane/ethanol = 4:1) C28h29n5°3 (483.6) <br><br> EKA mass spectrum: (M+H)+ = 484 <br><br> (M+H+Na)++ = 253.7 <br><br> 20 Example 41 <br><br> l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)-amide-hydrochloride <br><br> 25 <br><br> Prepared analogously to Example 26 from l-methyl-2-[2-(4- <br><br> amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N- <br><br> phenyl-N- (ethoxycarbonylmethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> 30 Yield: 97 % of theory, <br><br> c26h25n5°3 (455.5) <br><br> EKA mass spectrum: (M+H)+ = 456 <br><br> (M+Na)+ = 478 (M+2Na)++ = 250.6 <br><br> 35 <br><br> Example 42 <br><br> AS AMENDED <br><br> - 60 - <br><br> l-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride <br><br> 5 <br><br> Prepared analogously to Example 25d from l-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (ethoxycarbonylmethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. 10 Yield: 76 % of theory, <br><br> Rf value: 0.17 (silica gel; dichloromethane/ethanol = 4:1) C27H27N5O4 (485.6) <br><br> EKA mass spectrum: (M+H)+ = 486 <br><br> (M+H+Na)++ = 254.7 <br><br> 15 <br><br> Example 4 3 <br><br> l-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)-amide-20 hydrochloride <br><br> Prepared analogously to Example 26 from l-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (ethoxycarbonylmethyl)-amide-hydrochloride and 25 sodium hydroxide solution. <br><br> Yield: 58 % of theory, <br><br> c25h23n5°4 (457.5) <br><br> EKA mass spectrum: (M+H)+ = 458 <br><br> (M+Na)+ = 480 30 (M+2Na)++ = 251.6 <br><br> Example 44 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-35 5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride <br><br> AS AMENDED <br><br> - 61 - <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic 5 hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 74 % of theory, <br><br> Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1) &lt;-'27^28^6&lt;-)3 (484.6) <br><br> EKA mass spectrum: (M+H)+ = 485 <br><br> 10 (M+H+Na)++ = 254 <br><br> Example 4 5 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-15 5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic 20 acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 84 % of theory, <br><br> c25h24n6°3 (456.5) <br><br> EKA mass spectrum: (M+H)4" = 457 25 (M+Na)+ = 479 <br><br> (M+2Na)++ = 251 <br><br> Example 46 <br><br> 30 l-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-pyrimidyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-35 [(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-pyrimidyl)-N-(2-ethoxycarbonylethyl)-amide and <br><br> AS AMENDED " " ~ <br><br> ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 14 % of theory, <br><br> C26H27N7O4 (501.6) <br><br> 5 Mass spectrum: (M+H)+ = 502 Example 47 <br><br> l-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-10 carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic 15 acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 44 % of theory, <br><br> Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1) 20 C26H26N5O4 (486.5) <br><br> EKA mass spectrum: (M+H)+ = 487 <br><br> (M+2H)++ = 244 (M+H+Na)++ = 255 <br><br> 25 Example 4 8 <br><br> l-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide-hydrochloride <br><br> 30 <br><br> Prepared analogously to Example 26 from l-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride and sodium hydroxide solution. <br><br> 35 Yield: 85 % of theory, <br><br> c24h22n6°4 (458.5) <br><br> AS AMENDED " DJ " <br><br> EKA mass spectrum: (M+H)+ = 459 <br><br> (M+Na)+ = 481 (M+2Na)++ = 252 <br><br> 5 Example 4 9 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride <br><br> 10 <br><br> a) l-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide <br><br> Prepared analogously to Example 25c from N-(4-cyanophenyl)-15 glycine and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide. <br><br> Yield: 24 % of theory, <br><br> Rf value: 0.56 (silica gel; dichloromethane/methanol = 4:1) <br><br> 20 b) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic 25 acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 70 % of theory, <br><br> Rf value: 0.16 (silica gel; dichloromethane/ethanol = 4:1) 30 C26H27N7O3 (485.6) <br><br> EKA mass spectrum: (M+H)+ = 486 <br><br> (M+2H)++ = 243.7 (M+H-Na)++ = 254.6 <br><br> AS AMENDED <br><br> Example 50 <br><br> - 64 - <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-5 N-(hydroxycarbonylmethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-10 dihydrochloride and sodium hydroxide solution. <br><br> Yield: 91 % of theory, <br><br> c24h23n7°3 (457.5) <br><br> EKA mass spectrum: (M+H)+ = 458 <br><br> (M+Na)+ = 480 15 (M+2Na)++ = 251.7 <br><br> Example 51 <br><br> l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-20 carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-25 pyridyl)-N-(ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 90 % of theory, <br><br> Rf value: 0.17 (silica gel; dichloromethane/ethanol = 4:1) C27H28N6°3 (484.6) <br><br> 30 EKA mass spectrum: (M+H)+ = 485 <br><br> (M+2H)++ = 243 (M+H+Na)++ = 254 <br><br> AS AMENDED <br><br> Example 52 <br><br> - 65 - <br><br> l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-5 amide-hydrochloride <br><br> Prepared analogously to Example 26 from l-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochroride 10 and sodium hydroxide solution. <br><br> Yield: 89 % of theory, <br><br> c25h24n6°3 (456.5) <br><br> EKA mass spectrum: (M+H) + = 457 <br><br> (M+Na)+ = 4 79 <br><br> 15 <br><br> Example 53 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxyarbonylethyl)-20 amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and 25 methanolic hydrochloric acid, methanol and ammonium carbonate. <br><br> Yield: 87 % of theory, <br><br> Rf value: 0.11 (silica gel; dichloromethane/ethanol = 4:1) c27h28n6°3 (484.6) <br><br> 30 EKA mass spectrum: (M+H)+ = 485 <br><br> (M+2H)++ = 243 (M+H+Na)++ = 254 <br><br> AS AMENDED <br><br> Example 54 <br><br> - 66 - <br><br> l-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-5 hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic 10 hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 79.5 % of theory, <br><br> C28H29N5O4 (499.6) <br><br> Rf value: 0.15 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ = 500.0 <br><br> 15 (M+H+Na)++ = 261.7 <br><br> Example 55 <br><br> l-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-20 carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 26 from l-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-25 N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 82 % of theory, <br><br> c26h25n5°4 (471.5) <br><br> Rf value: 0.11 (silica gel; dichloromethane/ethanol = 4:1) 30 EKA mass spectrum: (M+H)+ = 472 <br><br> (M+H+Na)++ = 247.6 (M+Na)+ = 494 (M+2Na)++ = 258.6 <br><br> 35 <br><br> AS AMENDED <br><br> - 67 - <br><br> Example 56 <br><br> l-Methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-5 5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) l-Methyl-2-[2-(2-cyanothiophen-5-yl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- <br><br> 10 ethoxycarbonylethyl)-amide <br><br> 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)amide. <br><br> 15 Yield: 18 % of theory, <br><br> Rf value: 0.66 (silica gel; dichloromethane/methanol = 9:1) <br><br> b) l-Methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- <br><br> 20 ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[2-(2-cyanothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium 25 carbonate. <br><br> Yield: 53 % of theory, <br><br> C26H28N6°3S (504.6) <br><br> Rf value: 0.22 (silica gel; dichloromethane/methanol = 5:1) EKA mass spectrum: (M+H)+ = 505 <br><br> 30 (M+H+Na)++ = 264 <br><br> Example 57 <br><br> l-Methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-35 5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide <br><br> AS AMENDED <br><br> Prepared analogously to Example 26 from l-methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> 5 Yield: 98 % of theory, <br><br> C24H24N603S (476.6) <br><br> EKA mass spectrum: (M+H)4" = 477 <br><br> (M+Na)4" = 499 (M+2H)4"4" = 239 <br><br> 10 <br><br> Example 58 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-15 ethoxycarbonylethyl)-amide-hydrochloride a) l-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> 20 Prepared analogously to Example 25c from N-(4-cyanophenyl)-glycine and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide. <br><br> Yield: 61 % of theory, <br><br> Rf value: 0.62 (silica gel; dichloromethane/methanol = 25 19:1) <br><br> b) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 30 Prepared analogously to Example 25d from l-methyl-2-[N-(4- <br><br> cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> 35 Yield: 71 % of theory, <br><br> C27H29N7O3 (499.6) <br><br> Rf value: 0.28 (silica gel; dichloromethane/methanol = 5:1) <br><br> AS AMENDED " 63 " <br><br> EKA mass spectrum: (M+H)+ = 500 <br><br> (M+H+Na)++ = 2 61.8 (M+2H)++ = 250.8 <br><br> 5 Example 59 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide <br><br> 10 <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> 15 Yield: 91 % of theory, <br><br> c25h25n7°3 (471.5) <br><br> EKA mass spectrum: (M+H)+ = 472 <br><br> (M+H+Na)++ = 247.6 (M+2H)++ = 236.7 20 (M+2Na)++ = 258.6 <br><br> Example 60 <br><br> l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-25 carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) l-Methyl-2-[2-(4-cyanophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)- <br><br> 30 amide <br><br> Prepared analogously to Example 149a from 3-(4- <br><br> cyanophenyl)-propionic acid and 3-amino-4-methylamino- <br><br> benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide. <br><br> Yield: 22 % of theory, <br><br> 35 Rf value: 0.68 (silica gel; dichloromethane/methanol = <br><br> 19:1) <br><br> AS AMENDED " ,u " <br><br> b) l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride 5 Prepared analogously to Example 25d from l-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. <br><br> Yield: 85 % of theory, <br><br> 10 C28H30N6O3 (498.6) <br><br> Rf value: 0.30 (silica gel; dichloromethane/methanol = 5:1) EKA mass spectrum: (M+H)+ = 499 <br><br> (M+H+Na)++ = 261 <br><br> 15 Example 61 <br><br> l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide <br><br> Prepared analogously to Example 26 from l-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> 25 Yield: 97 % of theory, <br><br> C26H26N6°3 (470.5) <br><br> EKA mass spectrum: (M+H)+ = 471 <br><br> (M+H+Na)++ = 247 <br><br> (M+Na)+ = 493 <br><br> 30 <br><br> Example 62 <br><br> 35 <br><br> l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> AS AMENDED <br><br> - 71 - <br><br> Prepared analogously to Example 25d from l-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide and ethanolic 5 hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 86 % of theory, <br><br> c29h31n5°3 (497.6) <br><br> Rf value: 0.11 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ = 498 10 (M+2H)++ = 249.8 <br><br> Example 63 <br><br> l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-15 carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 26 from l-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-20 phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 71 % of theory, <br><br> C27H27N5O3 (469.6) <br><br> EKA mass spectrum: (M+H)+ = 470 <br><br> 25 (M+H+Na)++ = 246.6 <br><br> (M+Na)+ = 492 (M+2H)++ = 235.6 <br><br> Example 64 <br><br> 30 l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(methoxycarbonylmethyl)-amide-dihydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-35 cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(methoxycarbonylmethyl)-amide and <br><br> AS AMENDED <br><br> methanolic hydrochloric acid, methanol and ammonium carbonate. <br><br> Yield: 73 % of theory, <br><br> C25H25N7°3 (471.5) <br><br> 5 Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ = 472 <br><br> (M+H+Na)++ = 247.8 <br><br> Example 65 <br><br> 10 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride <br><br> 15 Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate. <br><br> 20 Yield: 78 % of theory, <br><br> C26H27N7O3 (485.6) <br><br> Rf value: 0.31 (silica gel; dichloromethane/methanol = 5:1) EKA mass spectrum: (M+H)+ = 486 <br><br> (M+H+Na)++ = 254.8 <br><br> 25 <br><br> Example 66 <br><br> l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(lH-tetrazol-5-yl)ethyl]-30 amide-hydrochloride a) l-Methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(lH-tetrazol-5-yl)ethyl]-amide <br><br> AS AMENDED " J " <br><br> Prepared analogously to Example 25c from 3-(4-cyanophenyl)-propionic acid and 3-amino-4-methylamlno-benzoic acid-N-phenyl-N- [2-(lH-tetrazol-5-yl)ethyl]-amide. <br><br> Yield: 67 % of theory, <br><br> 5 IR Mass spectrum (KBr): characteristic bands at <br><br> 3439.5 cm~l (N-H); 2235.5 cm~l C=N) ; <br><br> 1631.6 cm"1 (c=0) <br><br> 10 b) l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(lH-tetrazol-5-yl)ethyl]-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-15 phenyl-N-[2-(lH-tetrazol-5-yl)ethyl]-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 92 % of theory, <br><br> c27h27n9° (493.6) <br><br> EKA mass spectrum: (M+H)+ = 494 20 (M+Na)+ = 516 <br><br> (M+2H)++ = 258.7 <br><br> Example 67 <br><br> 25 l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(lH-tetrazol-5-yl)ethyl]-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-30 cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(lH-tetrazol-5-yl)ethyl]-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 29 % of theory, <br><br> 35 C26H26N]_qO (494.6) <br><br> EKA mass spectrum: (M+H)+ = 495 <br><br> AS AMENDED <br><br> - 74 - <br><br> Example 68 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5 5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-n-hexyloxycarbonylethyl)-amide-hydrochloride <br><br> 0.60 g (1.1 mMol) of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-10 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 hexanol was distilled off in vacuo, the residue was mixed with about 5 ml of IN ammonia 15 solution with stirring and evaporated down once more. The crude product thus obtained was purified by column chromatography (silica gel, dichloromethane/methanol = <br><br> 5:1) . <br><br> Yield: 53 % of theory, <br><br> 20 C31H37N7O3 (555.7) <br><br> Rf value: 0.36 (silica gel; dichloromethane/methanol <br><br> = 5:1 ) <br><br> EKA mass spectrum: (M+H)+ = 556 <br><br> 25 Example 69 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 30 <br><br> a) l-Methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- <br><br> ethoxycarbonylethyl) -amide <br><br> Prepared analogously to Example 25c from N-(4-cyanophenyl)-35 N-methylglycine and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide. <br><br> Yield: 71 % of theory, <br><br> AS AMENDED " '3 " <br><br> Rf value: 0.66 (silica gel; dichloromethane/methanol = <br><br> 19:1) <br><br> b) l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-5 benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- <br><br> ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-10 amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 77 % of theory, <br><br> c28h31n7°3 (513.6) <br><br> EKA mass spectrum: (M+H) + = 514 <br><br> 15 (M+H+Na)++ = 268.7 <br><br> Example 7 0 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-20 benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-25 carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 66 % of theory, <br><br> c26h27n7°3 (485.6) <br><br> EKA mass spectrum: (M+H)+ = 486 30 (M+Na)+ = 508 <br><br> (M+2Na)++ = 265.6 <br><br> 35 <br><br> AS AMENDED <br><br> Example 71 <br><br> - 76 - <br><br> l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-5 amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide and ethanolic 10 hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 65 % of theory, <br><br> c28h35n5°3 (489.6) <br><br> EKA mass spectrum: (M+H)+ = 490 <br><br> 15 Example 72 <br><br> l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-hydroxycarbonylethyl)-amide <br><br> 20 <br><br> Prepared analogously to Example 26 from l-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N- (2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> 25 Yield: 89 % of theory, <br><br> C26H31N5°3 (461.6) <br><br> EKA mass spectrum: (M+H)+ = 462 <br><br> (M+H+Na)++ = 242.6 (M+Na)+ = 484 30 (M+2H)++ = 231.6 <br><br> Example 73 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-35 5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> AS AMENDED <br><br> - 77 - <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide and 5 ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 60 % of theory, <br><br> C27H34N6O3 (490.6) <br><br> EKA mass spectrum: (M+H)+ = 491 <br><br> 10 <br><br> Example 74 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-15 hydroxycarbonylethyl)-amide <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide-20 hydrochloride and sodium hydroxide solution. <br><br> Yield: 45 % of theory, <br><br> c25h30n3°4 (462.6) <br><br> EKA mass spectrum: (M+H)+ = 463 <br><br> (M+H+Na)++ = 243 25 (M+Na)+ = 485 <br><br> (M+2Na)++ = 254 <br><br> Example 75 <br><br> 30 l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-35 cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl- <br><br> carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)- <br><br> AS AMENDED " '8 " <br><br> amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 54 % of theory, <br><br> C27H29N7O3 (499.6) <br><br> 5 EKA mass spectrum: (M+H)+ = 500 <br><br> (M+2H )++ = 250.7 <br><br> Example 7 6 <br><br> 10 l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4-15 amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 68 % of theory, <br><br> c25h25n7°3 (471.5) <br><br> 20 EKA mass spectrum: (M+H)+ = 472 <br><br> (M+Na)+ = 494 (M+2Na)++ = 258.6 <br><br> Example 77 <br><br> 25 <br><br> l-Methyl-2-[2-(4-amidinophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 30 Prepared analogously to Example 25d from l-methyl-2-[2-(4- <br><br> cyanophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(3- <br><br> pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 91 % of theory, <br><br> 35 C28H30N6O3 (498.6) <br><br> Rf value: 0.19 (silica gel; dichloromethane/ethanol = 4:1) <br><br> AS AMENDED " '3 " <br><br> EKA mass spectrum: (M+H)+ = 499 Example 78 <br><br> 5 l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-dihydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-10 cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 86 % of theory, <br><br> 15 C27H29N7O3 (499.6) <br><br> Rf value: 0.09 (silica gel; dichloromethane/ethanol =4:1 ) EKA mass spectrum: (M+H)+ = 500 <br><br> Example 7 9 <br><br> 20 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-hydroxycarbonylethyl)-amide <br><br> 25 Prepared analogously to Example 26 from l-methyl-2-[N-(4- <br><br> amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide- <br><br> dihydrochloride and sodium hydroxide solution. <br><br> Yield: 85 % of theory, <br><br> 30 C25H25N7O3 (471.5) <br><br> EKA mass spectrum: (M+H)+ = 472 <br><br> (M+2H)++ = 236.6 (M+2Na)++ = 258.6 <br><br> 35 <br><br> AS AMENDED <br><br> Example 80 <br><br> - 80 - <br><br> l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-5 ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-Methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-10 amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 64 % of theory, <br><br> C28H31N7O3 (513.6) <br><br> EKA mass spectrum: (M+H) + = 514 <br><br> 15 <br><br> Example 81 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-20 hydroxycarbonylethyl)-amide <br><br> Prepared analogously to Example 26 from l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)- <br><br> 25 amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 70 % of theory, <br><br> c26h27n7°3 (485.6) <br><br> EKA mass spectrum: (M+H)+ = 486 <br><br> (M+Na)+ = 508 <br><br> 30 (M+2Na)++ = 265.6 <br><br> Example 82 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-35 benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> AS AMENDED <br><br> - 81 - <br><br> a) l-Methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> 5 Prepared analogously to Example 25c from N-(4-cyanophenyl)-N-methylglycine and 3-amino-4-methylamino-benzoic acid-N-phenyl-N- (2-ethoxycarbonylethyl)-amide. <br><br> Yield: 71 % of theory, <br><br> Rf value: 0.38 (silica gel; dichloromethane/methanol = 10 19:1) <br><br> b) l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 15 Prepared analogously to Example 25d from l-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. <br><br> 20 Yield: 74 % of theory, <br><br> c29h32n6°3 (512.6) <br><br> EKA mass spectrum: (M+H)+ = 513 <br><br> (M+H+Na)++ =2 68 (M+2H)++ = 257 <br><br> 25 <br><br> Example 83 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-30 hydroxycarbonylethyl)-amide <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-35 hydrochloride and sodium hydroxide solution. <br><br> Yield: 80 % of theory, <br><br> C27H28N603 (484.6) <br><br> AS AMENDED " ~ <br><br> EKA mass spectrum: (M+H)+ = 485 <br><br> (M+H+Na)++ = 254 (M+Na) + = 507 (M+2Na)+ = 265 <br><br> 5 <br><br> Example 84 <br><br> l-ethyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-10 amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-ethyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and 15 ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 85 % of theory, <br><br> C28H31N7O3 (513.6) <br><br> Rf value: 0.21 (silica gel; dichloromethane/methanol = 5:1) 20 EKA mass spectrum: (M+H)+ = 514 <br><br> (M+H+Na)++ = 268.6 (M+2H)++ = 257.7 <br><br> Example 85 <br><br> 25 <br><br> l-ethyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide <br><br> 30 Prepared analogously to Example 26 from l-ethyl-2-[N-(4- <br><br> amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide- <br><br> hydrochloride and 2N sodium hydroxide solution. <br><br> Yield: 49 % of theory, <br><br> 35 C26H27N7O3 (485.6) <br><br> EKA mass spectrum: (M+H)+ = 486 <br><br> AS AMENDED <br><br> 5 Example 8 6 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 10 <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium 15 carbonate. <br><br> Yield: 88 % of theory, <br><br> C28H29FN6°3 (516.6) <br><br> Rf value: 0.08 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ = 517 <br><br> 20 (M+H+Na)++ = 270 <br><br> (M+2H)++ = 259 <br><br> Example 87 <br><br> 25 l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4-30 amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 45 % of theory, <br><br> C26h25fn6°3 (488.5) <br><br> 35 Rf value: 0.05 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H) + = 489 <br><br> - 83 - <br><br> (M+H+Na)++ = 254.6 (M+2H)++ = 243.6 (M+2Na)++ = 265.7 <br><br> AS AMENDED <br><br> - 84 - <br><br> (M+H+Na)++ = 267 (M+2H)++ = 256 <br><br> Example 88 <br><br> 5 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 10 Prepared analogously to Example 25d from l-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. <br><br> 15 Yield: 79 % of theory, <br><br> C29H32N6°3 (512.6) <br><br> Rf value: 0.10 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ = 513 <br><br> (M+H+Na)++ = 268 <br><br> 20 <br><br> Example 8 9 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-25 hydroxycarbonylethyl)-amide <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-ethoxycarbonylethyl)-amide-30 hydrochloride and sodium hydroxide solution. <br><br> Yield: 62 % of theory, <br><br> c27h28n6°3 (484.6) <br><br> EKA mass spectrum: (M+H)+ = 485 <br><br> (M+H+Na)++ = 254 35 (M+Na)+ = 507 <br><br> (M+2Na)++ = 265 <br><br> AS AMENDED <br><br> - 85 - <br><br> Example 90 <br><br> l-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-5 aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide <br><br> 1.1 g (2.06 mMol) of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-10 (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 15 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 20 column chromatography (100 g silica gel; dichloromethane + 5% ethanol). <br><br> Yield: 78 % of theory, <br><br> c35h42n6°5 (626.8) <br><br> Rf value: 0.49 (silica gel; dichloromethane/ethanol = 19:1) 25 EKA mass spectrum: (M+H)+ = 627 <br><br> (M+H+Na)++ = 325 (M+2H)++ = 314 <br><br> Example 91 <br><br> 30 <br><br> l-Methyl-2-[N-[4-(N-methoxycarbonylamidino)phenyl]-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide <br><br> 35 <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic <br><br> AS AMENDED "• ~ <br><br> acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and methyl chloroformate. <br><br> Yield: 41 % of theory, <br><br> c30h32n6°5 (556.6) <br><br> 5 Rf value: 0.85 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ = 557 <br><br> (M+H+Na)++ = 290 (M+Na)+ = 579 <br><br> 10 Example 92 <br><br> l-Methyl-2-[N-[4-(N-ethoxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide <br><br> 15 <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and ethyl chloroformate. <br><br> 20 Yield: 62 % of theory, <br><br> c30h32n6°5 (556.6) <br><br> Rf value: 0.51 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ = 557 <br><br> (M+H+Na)++ = 290 25 (M+2H)++ = 279 <br><br> Example 93 <br><br> l-Methyl-2-[N-[4-(N-cyclohexyloxycarbonylamidino)phenyl]-30 aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic 35 acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and cyclohexyl chloroformate. <br><br> AS AMENDED " 8'" <br><br> Yield: 25 % of theory, <br><br> C34H38N605 (610.7) <br><br> Rf value: 0.44 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ = 611 5 (M+2H)++ = 306 <br><br> Example 94 <br><br> l-Methyl-2-[N-[4-[N-[2-(methylsulphonyl)ethyloxycarbonyl]-10 amidino]phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic 15 acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and 2-(methylsulphonyl)-ethyl chloroformate. <br><br> Yield: 66 % of theory, <br><br> c32h36n6°7s (648.8) <br><br> Rf value: 0.44 (silica gel; dichloromethane/ethanol = 19:1) 20 EKA mass spectrum: (M+H)+ = 649 <br><br> (M+H+Na)++ = 336 (M+2H)++ = 325 <br><br> Example 95 <br><br> 25 <br><br> l-Methyl-2-[N-[4-(N-n-octyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide <br><br> 30 Prepared analogously to Example 90 from l-methyl-2-[N-(4- <br><br> amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide- <br><br> hydrochloride and n-octyl chloroformate. <br><br> Yield: 41 % of theory, <br><br> 35 C36H44N5O5 (640.8) <br><br> Rf value: 0.43 (silica gel; dichloromethane/ethanol = 19:1) <br><br> AS AMENDED ~ 88 " <br><br> EKA mass spectrum: (M+H)+ = 641 <br><br> (M+Na)+ = 663 <br><br> Example 96 <br><br> 5 <br><br> l-Methyl-2-[N-[4-(N-hydroxylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide <br><br> 10 1.44 g (3.0 mMol) of l-methyl-2-[N-(4-cyanophenyl)- <br><br> aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- <br><br> (2-ethoxycarbonylethyl)-amide, 0.625 g (9.0 mMol) of hydroxylamine hydrochloride and 0.425 g (4.0 mMol) of sodium carbonate were dissolved in 80 ml of ethanol and <br><br> 15 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 vacuo. The residue was dissolved in about 30 ml of dichloromethane, the solution <br><br> 20 obtained was washed with 20 ml of water, the organic phase was dried and evaporated down. The crude product thus obtained was purified by column chromatography (200 g silica gel, dichloromethane + 4% ethanol). <br><br> Yield: 39 % of theory, <br><br> 25 C28H30N6O4 (514.6) <br><br> Rf value: 0.15 (silica gel; dichloromethane/ethanol = 19:1) <br><br> EKA mass spectrum: (M+H)+ = 515 <br><br> (M+Na)+ = 537 <br><br> (2M+H)+ = 1029 <br><br> 30 (2M+Na)+ = 1051 <br><br> Example 97 <br><br> 35 <br><br> l-Methyl-2-[N-[4-(N-n-heptyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide <br><br> AS AMENDED <br><br> - 89 - <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-5 hydrochloride and n-heptyl chloroformate. <br><br> Yield: 43 % of theory, <br><br> C35H42N6°5 (626.8) <br><br> Rf value: 0.40 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H) + = 627 <br><br> 10 (M+H+Na)++ = 325 <br><br> (M+Na)+ = 649 <br><br> Example 98 <br><br> 15 l-Methyl-2-[N-[4-(N-benzoylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4- <br><br> 20 amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide- <br><br> hydrochloride and benzoyl chloride. <br><br> Yield: 88 % of theory, <br><br> C34H32N6°4 (588.7) <br><br> 25 Rf value: 0.37 (silica gel; dichloromethane/ethanol = 19:1) <br><br> 3-H-NMR spectrum (Dg-DMSO) : 2.61 (t,2H), 3.54 (s,3H), 3.76 <br><br> (s,3H), 4.10 (t,2H), 4.61 (d,2H), 6.83 (d,2H), 7.05 to 7.55 <br><br> (m,12H),8.03 (d,2H), 8.25 (dd,2H), 8.98 (s,lH), 10.48 <br><br> (s,lH) <br><br> 30 <br><br> Example 99 <br><br> l-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-35 (2-methoxycarbonylethyl)-amide <br><br> AS AMENDED " yu " <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate. <br><br> 5 Yield: 54 % of theory, <br><br> c34h40n6°5 (612.7) <br><br> Rf value: 0.45 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ = 613 <br><br> 10 Example 100 <br><br> l-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-n-propyloxycarbonylethyl)-amide <br><br> 15 <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-n-propyloxycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate. <br><br> 20 Yield: 31 % of theory, <br><br> C36H44N6°5 (640.8) <br><br> Rf value: 0.42 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ = 641 <br><br> (M+H+Na)++ = 332 25 (M+Na)+ = 663 <br><br> Example 101 <br><br> l-Methyl-2-[N-[4-(N-ethoxycarbonylamidino)phenyl]-30 aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic 35 acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and ethyl chloroformate. <br><br> AS AMENDED " 31 " <br><br> Yield: 72 % of theory, <br><br> C29H31N7O5 (557.6) <br><br> Rf value: 0.58 (silica gel; dichloromethane/methanol = 9:1) <br><br> 5 EKA mass spectrum: (M+H)+ = 558 <br><br> (M+H+Na)++ = 290.8 (M+Na)+ = 580 <br><br> Example 102 <br><br> 10 <br><br> l-Methyl-2-[N-[4-(N-n-octyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide <br><br> 15 Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate. <br><br> Yield: 57 % of theory, <br><br> 20 C35H43N7O5 (641.8) <br><br> Rf value: 0.60 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 642 <br><br> (M+H+Na)++ = 332.8 (M+Na)+ = 664 <br><br> 25 <br><br> Example 103 <br><br> l-Methyl-2-[N-[4-(N-methoxycarbonylamidino)phenyl]-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-30 N-(2-ethoxycarbonylethyl)-amide <br><br> 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-35 hydrochloride and methyl chloroformate. <br><br> Yield: 48 % of theory, <br><br> AS AMENDED <br><br> 92 <br><br> c29h31n7°5 (557.6) <br><br> Rf value: 0.62 (silica gel; dichloromethane/methanol = 9:1) <br><br> Example 104 <br><br> l-Methyl-2-[N-[4-(N-n-octyloxycarbonylamidino)phenyl]-10 aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide <br><br> 0.7 g (1.1 mMol) of l-methyl-2-[N-[4-(N-n- <br><br> octyloxycarbonylamidino) -phenyl]-aminomethyl]-benzimidazol- <br><br> 15 5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- <br><br> methoxycarbonylethyl)-amide was stirred in a mixture of <br><br> 0.12 g (3.0 mMol) of sodium hydroxide, 5 ml of water and <br><br> 10 ml of methanol for one hour at room temperature. Then the mixture was diluted with 20 ml of water and adjusted to <br><br> 20 pH 6 with glacial acetic acid. Then about 5 ml of diethylether were added and the mixture was vigourously stirred for one hour. The product thus precipitated was suction filtered, washed with a little water, then with diethylether and dried. <br><br> 25 Yield: 80 % of theory, <br><br> c34h41n7°5 (627.8) <br><br> EKA mass spectrum: (M+H)+ = 628 <br><br> EKA mass spectrum: (M+H) + <br><br> 558 <br><br> 5 <br><br> (M+H+Na)++ = 290.7 (M+Na)+ = 580 <br><br> 30 <br><br> (M+H+Na)++ = 325.7 (M+Na)+ = 650 (M+2Na)++ = 337.7 <br><br> Example 105 <br><br> 35 <br><br> l-Methyl-2-[N-[4-[N-(2-methylsulphonyl-ethyloxycarbonyl)amidino]-phenyl]-aminomethyl]- <br><br> AS AMENDED " SJ " <br><br> benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-5 amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and 2-(methylsulphonyl)-ethyl chloroformate. Yield: 65 % of theory, <br><br> C31H35N7O7S (649.7) <br><br> 10 Rf value: 0.54 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 650 <br><br> (M+H+Na)++ = 336.6 (M+Na) + = 672 (M+2Na)++ = 347.6 <br><br> 15 <br><br> Example 106 <br><br> l-Methyl-2-[N-[4-(N-n-butyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-20 pyridyl)-N-(2-methoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-25 hydrochloride and n-butyl chloroformate. <br><br> Yield: 30 % of theory, <br><br> C31H35N7°5 (585.7) <br><br> Rf value: 0.62 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 586 <br><br> 30 (M+H+Na)++ = 304.7 <br><br> (M+2H)++ = 293.7 <br><br> Example 107 <br><br> AS AMENDED " 34 " <br><br> l-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide <br><br> 5 Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate. <br><br> Yield: 51 % of theory, <br><br> 10 C33H39N7O5 (613.7) <br><br> Rf value: 0.56 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 614 <br><br> (M+H+Na)++ = 318.7 (M+2H)++ = 307.6 <br><br> 15 <br><br> Example 108 <br><br> l-Methyl-2-[N-[4-(N-n-heptyloxycarbonylamidino)-phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-20 pyridyl)-N-(2-methoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-25 hydrochloride and n-heptyl chloroformate. <br><br> Yield: 21 % of theory, <br><br> C34H41N7O5 (627.8) <br><br> Rf value: 0.60 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 628 <br><br> 30 (M+H+Na)++ = 325.7 <br><br> (M+2H)++ = 314.7 <br><br> 35 <br><br> AS AMENDED <br><br> Example 109 <br><br> - 95 - <br><br> l-Methyl-2-[N-[4-(N-n-pentyloxycarbonylamidino)-phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-5 pyridyl)-N-(2-methoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-10 hydrochloride and n-pentyl chloroformate. <br><br> Yield: 66 % of theory, <br><br> c32h37n7°5 (599.7) <br><br> Rf value: 0.58 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 600 <br><br> 15 (M+H+Na)++ = 311.7 <br><br> (M+Na)+ = 622 <br><br> Example 110 <br><br> 20 l-Methyl-2-[N-[4-(N-n-nonyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-25 amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-nonyl chloroformate. <br><br> Yield: 60 % of theory, <br><br> C36H45N7O5 (655.8) <br><br> 30 Rf value: 0.48 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 656 <br><br> (M+H+Na)++ = 339.8 (M+Na)+ = 678 <br><br> 35 <br><br> Example 111 <br><br> AS AMENDED " " <br><br> l-Methyl-2-[N-[4-(N-benzoylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide <br><br> 5 Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and benzoyl chloride. <br><br> Yield: 62 % of theory, <br><br> 10 C33H31N7O4 (589.7) <br><br> Rf value: 0.50 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 590 <br><br> (M+Na)+ = 612 <br><br> 15 Example 112 <br><br> l-Methyl-2-[N-[4-(N-nicotinoylamidino)phenyl]aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide <br><br> 20 <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and nicotinic acid chloride. <br><br> 25 Yield: 40 % of theory, <br><br> C32H3ON804 (590.7) <br><br> Rf value: 0.47 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 591 <br><br> (M+H+Na)++ = 307 30 (M+Na)+ = 613 <br><br> Example 113 <br><br> 35 <br><br> l-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> AS AMENDED <br><br> - 97 - <br><br> 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-5 hydrochloride and n-hexyl chloroformate. <br><br> Yield: 51 % of theory, <br><br> C34H41N7O5 (627.8) <br><br> Rf value: 0.53 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 628 <br><br> 10 (M+H+Na)++ = 325.7 <br><br> (M+2H)++ = 314.7 <br><br> Example 114 <br><br> 15 l-Methyl-2-[N-[4-(N-n-octyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-20 amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate. <br><br> Yield: 57 % of theory, <br><br> C36H45N7O5 (655.8) <br><br> 25 Rf value: 0.46 (silica gel; dichloromethane/methanol <br><br> = 9:1 ) <br><br> EKA mass spectrum: (M+H)+ = 656 <br><br> (M+H+Na)++ = 339.7 (M+2H)++ = 328.7 <br><br> 30 <br><br> Example 115 <br><br> l-Methyl-2-[N-[4-[N-(2-methylsulphonyl-ethyloxycarbonyl)amidino]-phenyl]-aminomethyl]-35 benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide <br><br> AS AMENDED <br><br> - 98 - <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide-5 hydrochloride and 2-(methylsulphonyl)-ethyl chloroformate. Yield: 72 % of theory, <br><br> c30h33n7°7s (635.7) <br><br> Rf value: 0.23 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ = 636 <br><br> 10 (M+H+Na)++ = 329.8 <br><br> Example 116 <br><br> l-Methyl-2-[N-[4-(N-cyclohexyloxycarbonylamidino)-15 phenyl]aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic 20 acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide-hydrochloride and cyclohexyl chloroformate. <br><br> Yield: 40 % of theory, <br><br> c32h35n7°5 (597.7) <br><br> Rf value: 0.26 (silica gel; dichloromethane/ethanol = 19:1) 25 EKA mass spectrum: (M+H)+ = 598 <br><br> (M+Na)+ = 620 <br><br> Example 117 <br><br> 30 l-Methyl-2-[N-[4-(N-methoxycarbonylamidino)-phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-35 amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic <br><br> AS AMENDED " " <br><br> acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide-hydrochloride and methyl chloroformate. <br><br> Yield: 62 % of theory, <br><br> C28h29n7°5 (543.6) <br><br> 5 Rf value: 0.19 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ = 544 <br><br> (M+H+Na)++ = 283.8 (M+Na)+ = 566 <br><br> 10 Example 118 <br><br> l-Methyl-2-[N-[4-(N-ethoxycarbonylamidino)-phenyl]-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide-hydrochloride and ethyl chloroformate. <br><br> 20 Yield: 42 % of theory, <br><br> C28h29n7°5 (543.6) <br><br> Rf value: 0.20 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ = 544 <br><br> 25 Example 119 <br><br> l-Methyl-2-[N-[4-(N-n-octyloxycarbonyl-amidino)- <br><br> phenyl]aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3- <br><br> pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate. <br><br> 35 Yield: 35 % of theory, <br><br> C36H45N7O5 (655.8) <br><br> AS AMENDED " iUU " <br><br> Rf value: 0.28 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ = 656 <br><br> (M+2H)++ = 328.7 <br><br> 5 Example 120 <br><br> l-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)-phenyl]-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> 10 <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate. <br><br> 15 Yield: 58 % of theory, <br><br> c35h43n7°5 (641.2) <br><br> Rf value: 0.42 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ = 642 <br><br> (M+H+Na)++ = 332.7 <br><br> 20 <br><br> Example 121 <br><br> l-Methyl-2-[N-[4-(N-n-octyloxycarbonylamidino)-phenyl]-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-25 N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-30 amide-hydrochloride and n-octyl chloroformate. <br><br> Yield: 36 % of theory, <br><br> C37H47N7O5 (669.8) <br><br> EKA mass spectrum: (M+H)+ = 670 <br><br> (M+H+Na)++ = 346.8 35 (M+2H)++ = 335.6 <br><br> AS AMENDED <br><br> Example 122 <br><br> - 101 - <br><br> l-Methyl-2-[N-[4-(N-n-butyloxycarbonylamidino)-phenyl]-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-5 N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-10 amide-hydrochloride and n-butyl chloroformate. <br><br> Yield: 34 % of theory, <br><br> C33H39N705 (613.7) <br><br> EKA mass spectrum: (M+H)+ = 614 <br><br> (M+H+Na)++ = 318.7 15 (M+Na)+ =■ 636 <br><br> Example 123 <br><br> l-Methyl-2-[N-[4-(N-benzoylamidino)phenyl]-N-methyl-amino-20 methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-25 carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and benzoyl chloride. <br><br> Yield: 63 % of theory, <br><br> C35H35N7O4 (617.7) <br><br> EKA mass spectrum: (M+H)+ = 618 <br><br> 30 (M+H+Na)++ = 320.7 <br><br> (M+Na) + = 640 <br><br> Example 124 <br><br> 35 l-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-(1-ethoxycarbonylmethyl-cyclohex-l-yl)-ketone-hydrochloride <br><br> AS AMENDED <br><br> - 102 - <br><br> a) 4-Chlorophenyl-(1-hydroxycarbonylmethyl-cyclohex-l-yl)-ketone <br><br> 8.4 g (40 mMol) of 3-(4-chlorobenzoyl)-propionic acid were 5 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 10 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 15 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). Yield: 6.2 g (55% of theory) of oily product, <br><br> c15h17c103 (280.8) <br><br> 20 Rf value: 0.56 (silica gel; dichloromethane/ethanol = 19:1) <br><br> b) 4-Chloro-3-nitrophenyl-(1-hydroxycarbonylmethyl-cyclohex-l-yl)-ketone <br><br> 7.0 g (25 mMol) of 4-chlorophenyl-(1-hydroxycarbonyl-25 methylcyclohex-l-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, <br><br> then stirred into 200 ml of ice-water, the precipitated product was then washed with water and dried. <br><br> 30 Yield: 7.8 g (96% of theory), <br><br> C15H16C1N05 (325.8) <br><br> Rf value: 0.41 (silica gel; petroleum ether/ethyl acetate <br><br> 4:6) <br><br> 35 c) 4-Methylamino-3-nitrophenyl-(1-hydroxycarbonylmethyl-cyclohex-l-yl)-ketone <br><br> AS AMENDED " 1UJ " <br><br> 7.8 g ( 23.9 mMol) of 4-chloro-3-nitrophenyl-(1-hydroxycarbonylmethyl-cyclohex-l-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 <br><br> 5 water and made slightly acidic with glacial acetic acid. The precipitated product was suction filtered, washed with water and dried. <br><br> Yield: 7.1 g (93% of theory), <br><br> c16h20n2°5 (320.4) <br><br> 10 Rf value: 0.34 (silica gel; dichloromethane/ethanol = 19:1) <br><br> d) 4-Methylamino-3-nitrophenyl-(1-methoxycarbonylmethyl-cyclohex-l-yl)-ketone <br><br> 4.9 g (15 mMol) of 4-methylamino-3-nitrophenyl-(1- <br><br> 15 hydroxycarbonylmethyl-cyclohex-l-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 off, 30 ml of methanol were added and the mixture was 20 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, <br><br> eluant: dichloromethane with 1 to 5% ethanol). <br><br> Yield: 2.4 g (48% of theory), <br><br> 25 C17H22N2O5 (334.4) <br><br> Rf value: 0.76 (silica gel; dichloromethane/ethanol = 19:1) <br><br> e) 3-Amino-4-methylaminophenyl-(1-methoxycarbonylmethyl-cyclohex-l-yl)-ketone <br><br> 30 2.4 g (7.2 mMol) of 4-methylamino-3-nitrophenyl-(1-methoxycarbonylmethyl-cyclohex-l-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 35 reacted without purification. <br><br> Yield: 2.1 g (96% of theory), <br><br> Rf value: 0.34 (silica gel; dichloromethane/ethanol = 19:1) <br><br> AS AMENDED ~ ~ <br><br> f) 3- (4-Cyano.phenyloxyacetylamino) -4-methylaminophenyl- <br><br> (1-methoxycarbonylmethyl-cyclohex-l-yl)-ketone <br><br> 620 mg (3.5 mMol) of 4-cyanophenyloxyacetic acid and 570 mg <br><br> 5 (3.5 mMol) of 1,11-carbonyl-diimidazole were refluxed in 50 ml of tetrahydrofuran for 15 minutes. Then 1.0 g (3.28 mMol) of 3-amino-4-methylaminophenyl-(1-methoxycarbonylme-thyl-cyclohex-l-yl)-ketone were added and the mixture was boiled for a further 4 hours. Then the solvent was 10 evaporated off and the crude product thus obtained was purified by column chromatography (150 g silica gel; <br><br> eluant: dichloromethane with 0 to 2% ethanol). <br><br> Yield: 1.4 g (93% of theory), <br><br> C26H29N3O5 (463.5) <br><br> 15 Rf value: 0.44 (silica gel; dichloromethane/ethanol = 19:1) <br><br> g) l-Methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-(1-methoxycarbonylmethyl-cyclohex-l-yl)-ketone <br><br> 1.4 g (3.02 mMol) of 3-(4-cyanophenyloxyacetylamino)-4-20 methylaminophenyl-(1-methoxycarbonylmethyl-cyclohex-l-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 25 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: dichloromethane with 0 to 2% ethanol). Yield: 700 mg (52% of theory), <br><br> 30 C26H27N3O4 (445.5) <br><br> h) l-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-(1-ethoxycarbonylmethyl-cyclohex-l-yl)-ketone-hydrochloride <br><br> 35 Prepared analogously to Example 25d from 700 mg (1.57 mMol) of l-methyl-2-(4-cyanophenyloxymethyl)-benzimidazol-5-yl- <br><br> AS AMENDED " 105 " <br><br> (1-methoxycarbonylmethyl-cyclohex-l-yl)-ketone with ethanolic hydrochloric acid and ammonium carbonate. <br><br> Yield: 390 mg (50% of theory), <br><br> C27H32N4O4 (476.6) <br><br> 5 EKA mass spectrum: (M+H)+ = 477 <br><br> 1-H-NMR spectrum (dg-DMSO) : 1.10 (t,3H); 1.0-2.15 (m,10H) ; <br><br> 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 (m,2H); 7.90 (d,2H); 9.20 (broad s,4H) ppm. <br><br> 10 <br><br> 15 <br><br> 25 <br><br> Example 125 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-tert.butyl-ketone-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-tert.butyl-ketone, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> 20 Yield: 59 % of theory, <br><br> C21H25N5O (363.5) <br><br> EKA mass spectrum: (M+H)+ = 364 <br><br> Example 12 6 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-(1-methylcyclopent-l-yl)-ketone-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-30 cyanophenyl)-aminomethyl]-benzimidazol-5-yl-(1- <br><br> methylcyclopent-l-yl)-ketone, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 63.5 % of theory, <br><br> C23H27N5O (389.5) <br><br> 35 EKA mass spectrum: (M+H)+ = 390 <br><br> AS AMENDED <br><br> Example 127 <br><br> - 106 - <br><br> 2-[(4-amidinophenyl)sulphinylmethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-5 hydrochloride <br><br> A solution of 0.15 g (0.27 mMol) of 2-[(4-amidinophenyl)thiomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride 10 in 10 ml of acetic acid was mixed with 0. [sic] ml (about <br><br> 0.81 mMol) of 30% 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 15 of the solvent in vacuo the crude product obtained was purified by flash chromatography (silica gel; methylene chloride/ethanol = 10:1 to 4:1). <br><br> Yield: 58 % of theory, <br><br> C27H26N4O4S2 (534.66) <br><br> 20 Rf value: 0.24 (silica gel; methylene chloride/ethanol <br><br> = 4:1 <br><br> + a few drops of acetic acid) <br><br> EKA mass spectrum: (M+H)+ = 535 <br><br> 25 Example 128 <br><br> l-Methyl-2-[(4-amidinophenyl)sulphonylmethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 30 <br><br> A solution of 0.40 g (0.70 mMol) of l-methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride in 10 ml of formic acid was mixed with 2 ml 35 of 30% hydrogen peroxide solution and the mixture was stirred for 16 hours at room temperature. Then the solvent was distilled off in vacuo, whereupon the desired compound <br><br> AS AMENDED ' 1UI ~ <br><br> was obtained as a beige solid (contaminated with some <br><br> 1-methyl-2-[(4-amidinophenyl)sulfinylmethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride). <br><br> 5 Yield: 95 % of theory, <br><br> c25h31n6°5s (513.62) <br><br> Rf value: 0.50 (silica gel; ethyl acetate/ethanol/lN hydrochloric acid <br><br> = 50:45:5) <br><br> 10 EKA mass spectrum: (M+H)+ = 514 Example 129 <br><br> 2-[N-(4-amidinophenyl)-aminomethyl]-thiazolo[5,4-b]pyridin-15 6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)- <br><br> amide-hydrochloride a) Methyl 5-amino-6-chloro-nicotinate <br><br> A solution of 1.08 g (5.00 mMol) of methyl 6-chloro-5-20 nitro-nicotinate (see A.H. Berrie, G.T. Newbold, F.S. <br><br> 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 mMol) of iron powder and 0.030 ml of concentrated hydrochloric acid and heated to boiling for 25 one hour. Then equal quantities of water, iron powder and hydrochloric acid were added and 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. <br><br> 30 Yield: 0.75 g (81% of theory) of greenish-yellow solid, <br><br> Rf value: 0.31 (silica gel;ethyl acetate/petroleum ether = 1:4) <br><br> C7H7C1N202 (186.60) <br><br> YEF- Mass spectrum: M+ = 186 and 188 (chlorine isotopes). <br><br> AS AMENDED <br><br> b) Methyl 6-chloro-5-methoxyacetamido-nicotinate <br><br> A solution of 0.75 g (4.02 mMol) of methyl 5-amino-6-chloro-nicotinate and 0.43 g = 0.35 ml (4.5 mMol) of methoxyacetylchloride in 20 ml of chlorobenzene was stirred 5 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; methylene chloride/ethanol = 100:1), evaporated down again in vacuo and then digested with petroleum ether. <br><br> 10 Yield: 0.55 g (53% of theory) light yellow amorphous solid, Rf value: 0.33 (silica gel; ethyl acetate/petroleum ether = 1:4) <br><br> c) Methyl 2-methoxymethyl-thiazolo[5,4-b]pyridin-6-yl-15 carboxylate <br><br> A mixture of 0.53 g (2.05 mMol) of methyl 6-chloro-5-methoxyacetamido-nicotinate and 0.42 g (1.0 mMol) of Lawessons reagent was refluxed for 16 hours in 25 ml of xylene. After the solvent had been removed in vacuo the 20 crude product obtained was purified by flash chromatography (silica gel; methylene chloride/ethanol = 100:1) and evaporated down again in vacuo. <br><br> Yield: 0.33 g (67% of theory) of yellow amorphous solid, Rf value: 0.52 (silica gel; ethyl acetate/petroleum ether = 25 1:4) <br><br> d) 2-Methoxymethyl-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid <br><br> A mixture of 1.1 g (4.62 mMol) of methyl 2-methoxymethyl-30 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 35 phase was acidified with concentrated hydrochloric acid whilst cooling with ice, the beige precipitate formed was filtered off, then washed with water and dried. <br><br> AS AMENDED <br><br> Yield: 1.03 g (100% of theory), <br><br> Rf value: 0.10 (silica gel; ethyl acetate/petroleum ether = 3:7) <br><br> 5 e) 2-Methoxymethyl-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide <br><br> 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 10 mMol) of thionyl chloride and refluxed for 90 minutes, <br><br> 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 15 (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-ethoxycarbonylethyl) aniline and 2.1 ml (13.8 mMol) of triethylamine in 30 ml of tetrahydrofuran and stirred for 2 hours at room temperature. Then it was diluted with 200 ml 20 of ethyl acetate, washed with 100 ml of 14% saline solution and the organic phase was dried with sodium sulphate. <br><br> After the solvent had been removed in vacuo the crude product obtained was purified by flash chromatography (silica gel; methylene chloride/ethanol = 100:1). <br><br> 25 Yield: 1.57 g (87% of theory)of yellow oil, <br><br> Rf value: 0.55 (silica gel; methylene chloride/ethanol = 19:1) <br><br> f) 2-[N-(4-Cyanophenyl)-aminomethyl]-thiazolo[5,4-b]-30 pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide <br><br> A mixture of 1.54 g (3.85 mMol) of 2-methoxymethyl-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and 4.3 ml (4.3 mMol) of a 1 35 molar solution of boron tribromide in methylene chloride was dissolved in a further 30 ml of methylene chloride and stirred for 5 hours at room temperature. Then the mixture <br><br> AS AMENDED " 1±u " <br><br> 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-5 ethylamine, mixed with 0.50 g (4.2 mMol) of <br><br> 4-aminobenzonitrile and heated to boiling for one hour. <br><br> 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 10 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. <br><br> Yield: 0.45 g (24% of theory) of yellow amorphous solid, 15 Rf value: 0.34 (silica gel; ethyl acetate/petroleum ether = 1:1) <br><br> g) 2-[N-(4-amidinophenyl)-aminomethyl]-thiazolo[5,4-b]-pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-20 ethoxycarbonylethyl)-amide-hydrochloride <br><br> 0.39 g (0.803 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 chloride for 5 hours first at 0°C 25 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 30 carbonate. After 18 hours the solvent was removed in vacuo and the crude product obtained was purified by flash chromatography (silica gel; methylene chloride/ethanol = 9:1 to 4:1). <br><br> Yield: 78 % of theory of yellow foam, <br><br> 35 C26H26N5O3S (502.60) <br><br> Rf value: 0.19 (silica gel; methylene chloride/ethanol = 4:1 <br><br> AS AMENDED <br><br> + a few drops of acetic acid) <br><br> EKA mass spectrum: (M+H)+ = 503 <br><br> Example 130 <br><br> 5 <br><br> l-Methyl-2-[(4-amidinophenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 10 a) l-Methyl-2-mercapto-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl)-amide <br><br> 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 15 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 20 ether/ethyl acetate = 100:0 to 65:35). <br><br> Yield: 6.8 g (93 % of theory) of beige crystalline solid, Rf value: 0.55 (silica gel; ethyl acetate) <br><br> b) l-Methyl-2-[(4-cyanophenyl)methylthio]-benzimidazol-5-25 yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide A solution of 1.30 g (3.4 mMol) of l-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-30 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 35 sulphate. After filtration and distillation of the solvent the desired compound was obtained as a beige-white solid. Yield: 1.8 g (100 % of theory), <br><br> AS AMENDED " 11Z " <br><br> Rf value: 0.64 (silica gel; ethyl acetate) <br><br> c) l-Methyl-2-[(4-amidinophenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-5 amide-hydrochloride <br><br> 1.5 g (3.0 mMol) of l-methyl-2-[(4-cyanophenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were stirred in 80 ml of ethanol saturated with hydrogen chloride for 6.5 hours first at 10 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 15 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). <br><br> Yield: 78 % of theory of light beige solid, <br><br> 20 C28H29N5O3S (515.63) <br><br> Rf value: 0.19 (silica gel; methylene chloride/ethanol = <br><br> 4:1) <br><br> EKA mass spectrum: (M+H)+ = 516 <br><br> (M+H+Na)++ = 269.7 25 (M+2H)++ =258.7 <br><br> Example 131 <br><br> l-Methyl-2-[(4-amidinophenyl)methylthio]-benzimidazol-5-yl-30 carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 10 from l-methyl-2-[(4-amidinophenyl)methylthio]-benzimidazol-5-yl-carboxylic 35 acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 57 % of theory, <br><br> AS AMENDED " " <br><br> c26h25n5°3S (487.58) <br><br> Rf value: 0.23 (Reversed Phase silica gel RP-8; Methanol/5% <br><br> saline solution = 6:4) <br><br> EKA mass spectrum: (M+H)+ = 488 <br><br> 5 (M+Na)+ = 510 <br><br> (M+Na+H)++ = 255.6 <br><br> Example 132 <br><br> 10 l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-propargyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-15 cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-propargyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 81 % of theory, <br><br> c25h28n6°3 (460.6) <br><br> 20 Rf value: 0.094 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ = 461 <br><br> (M+H+Na)++ = 242 (M+2H)++ = 231 <br><br> 25 Example 133 <br><br> l-Methyl-2-[2-[4-(N-n- <br><br> hexyloxycarbonylamidino)phenyl]ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-30 amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride 35 and n-hexyl chloroformate. <br><br> Yield: 72 % of theory, <br><br> AS AMENDED " 114 " <br><br> c35h42n6°5 (626.8) <br><br> Rf value: 0.54 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 627 <br><br> (M+Na)+ = 649 <br><br> 5 <br><br> Example 134 <br><br> l-Methyl-2-[2-[4-(N-benzoylamidino)phenyl]ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-10 ethoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride 15 and benzoyl chloride. <br><br> Yield: 79 % of theory, <br><br> C35H34N6O4 (602.7) <br><br> Rf value: 0.52 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 603 20 (M+Na)+ = 625 <br><br> Example 135 <br><br> l-Methyl-2-[2-[4-(N-nicotinoylamidino)phenyl]ethyl]-25 benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-30 (2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and nicotinic acid chloride. <br><br> Yield: 56 % of theory, <br><br> c34h33n7°4 (603.7) <br><br> Rf value: 0.52 (silica gel; dichloromethane/methanol = 9:1) 35 EKA mass spectrum: (M+H)+ = 604 <br><br> (M+Na)+ = 626 <br><br> AS AMENDED <br><br> Example 136 <br><br> - 115 - <br><br> l-Cyclopropyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-5 ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-Cyclopropyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, 10 ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 31 % of theory, <br><br> c30h33n6°3 (524.6) <br><br> Rf value: 0.40 (silica gel; dichloromethane/methanol = 5:1) 15 EKA mass spectrum: (M+H)+ = 525 <br><br> (M+H+Na)++ = 274 (M+2H)++ = 263 <br><br> Example 137 <br><br> 20 <br><br> l-Cyclopropyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide <br><br> 25 Prepared analogously to Example 26 from l-cyclopropyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 64 % of theory, <br><br> 30 C28H28n6°3 (496.6) <br><br> EKA mass spectrum: (M+H)+ = 497 <br><br> (M+H+Na)++ = 260 (M+Na)+ = 519 (M+2Na)++ = 271 <br><br> AS AMENDED <br><br> Example 138 <br><br> - 116 - <br><br> l-Methyl-2-[N-(4-amidinophenyl)-N-(n-butyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-5 ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl)-N-(n-butyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, 10 ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 62 % of theory, <br><br> C32H38N603 (554.7) <br><br> EKA mass spectrum: (M+H)+ = 555 <br><br> 15 (M+H+Na)++ = 289 <br><br> (M+2H)++ = 278 <br><br> Example 139 <br><br> 20 l-Methyl-2-[N-(4-amidino-2-chloro-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-25 cyano-2-chloro-phenyl)-aminomethyl]-benzimidazol-5-yl- <br><br> carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 82 % of theory, <br><br> 30 C28H29C1N603 (533.1) <br><br> EKA mass spectrum: (M+H)+ = 533/5 <br><br> (M+H+Na)++ = 278/9 <br><br> 35 <br><br> AS AMENDED <br><br> Example 140 <br><br> - 117 - <br><br> l-Methyl-2-[N-[4-(n-octyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-5 (2-ethoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride 10 and n-octyl chloroformate. <br><br> Yield: 34 % of theory, <br><br> C37H46N5O5 (654.8) <br><br> Rf value: 0.15 (silica gel; dichloromethane/ethanol = 19:1) EKA mass spectrum: (M+H)+ = 655 <br><br> 15 (M+H+Na)++ = 339 <br><br> (M+Na)+ = 677 <br><br> Example 141 <br><br> 20 l-Methyl-2-[N-(4-amidino-2-ethyl-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-25 cyano-2-ethyl-phenyl)-aminomethyl]-benzimidazol-5-yl- <br><br> carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 61 % of theory 30 C30H34N6O3 (526.6) <br><br> EKA mass spectrum: (M+H)+ = 527 <br><br> (M+H+Na)++ = 275 (M+2H)++ = 264 <br><br> 35 <br><br> AS AMENDED <br><br> Example 142 <br><br> - 118 - <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-benzylamide-hydrochloride <br><br> 5 <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-benzylamide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> 10 Yield: 63 % of theory, <br><br> C24H24N60 (412.5) <br><br> Rf value: 0.7 6 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ = 413 <br><br> 15 Example 143 <br><br> l-Methyl-2-[N-[4-(N-(2-(2-ethoxyethoxy)ethyloxy)-carbonylamidino)-phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-20 amide <br><br> 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-25 hydrochloride and diethyleneglycolmonoethylether chloroformate. <br><br> Yield: 43 % of theory, <br><br> C34H41N7O7 (659.8) <br><br> Rf value: 0.56 (silica gel; dichloromethane/methanol = 9:1) 30 EKA mass spectrum: (M+H)+ = 660 <br><br> (M+H+Na)++ = 341.7 <br><br> Example 144 <br><br> 35 l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(l-methylpyrazol-4-yl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> AS AMENDED <br><br> - 119 - <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide, 5 ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 60 % of theory, <br><br> c26h30n8°3 (502.6) <br><br> Rf value: 0.13 (silica gel; dichloromethane/ethanol = 4:1) 10 EKA mass spectrum: (M+H)+ = 503 <br><br> (M+H+Na)++ = 263 (M+2H)++ = 252 <br><br> Example 145 <br><br> 15 <br><br> 3-Methyl-2-[(4-amidinophenyl)-thiomethyl]-imidazo[4,5-b]-pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 20 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. <br><br> 25 Yield: 88 % of theory, <br><br> C27H28N6O3S (516.63) <br><br> Rf value: 0.23 (silica gel; ethyl acetate/ethanol/ammonia = <br><br> 50:45:5) <br><br> EKA mass spectrum: (M+H)+ = 517 <br><br> 30 (M+H+Na)++ = 270 <br><br> Example 14 6 <br><br> 3-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-35 imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> AS AMENDED <br><br> - 120 - <br><br> Prepared analogously to Example 1 from 3-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide, 5 ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 82 % of theory, <br><br> c27h29n7°3 (499.58) <br><br> Rf value: 0.20 (silica gel; ethyl acetate/ethanol/ammonia = 10 50:45:5) <br><br> EKA mass spectrum: (M+H)+ = 500 <br><br> (M+H+Na)++ = 261.7 <br><br> Example 147 <br><br> 15 <br><br> 3-Methyl-2-[(4-amidinophenyl)-thiomethyl]- <br><br> imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N- <br><br> (2-hydroxycarbonylethyl)-amide-hydrochloride <br><br> 20 Prepared analogously to Example 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. <br><br> Yield: 88 % of theory, <br><br> 25 C25H24N6O3S (488.56) <br><br> Rf value: 0.21 (silica gel; ethyl acetate/ethanol/ammonia = <br><br> 50:45:5) <br><br> EKA mass spectrum: (M+H)+ = 489 <br><br> (M+Na)+ = 511 <br><br> 30 <br><br> Example 148 <br><br> 3-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-35 (2-hydroxycarbonylethyl)-amide-hydrochloride <br><br> AS AMENDED " " <br><br> 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. <br><br> 5 Yield: 80 % of theory, <br><br> c25h25n7°3 (471.52) <br><br> Rf value: 0.19 (silica gel; ethyl acetate/ethanol/ammonia = <br><br> 50:45:5) <br><br> EKA mass spectrum: (M+H)+ = 472 10 (M+Na)+ = 494 <br><br> (M+2Na)++ = 258.6 <br><br> Example 14 9 <br><br> 15 l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-sulphonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) l-Methyl-2[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-20 5-yl-sulphonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide <br><br> 2.54 g (6,2 mMol) of 3-nitro-4-methylamino-benzenesulphonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were hydrogenated at room temperature under 5 bar hydrogen 25 pressure over palladium/charcoal (10%) in a mixture of 75 ml of ethanol and 7 5 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 phosphorus oxychloride, without purification, 30 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 7 0 ml of water with cooling and in this way the excess phosphorus oxychloride was destroyed. The resulting 35 solution was neutralised with solid sodium carbonate and extracted three times with 30 ml of ethyl acetate. After evaporation of the solvent the crude product was purified <br><br> AS AMENDED " " <br><br> by column chromatography (100 g silica gel; eluant: cyclohexane/ethyl acetate = 2:3). <br><br> Yield: 860 mg (26.8 % of theory), <br><br> Melting point: 188-191°C 5 C27H27N5O3S (517.6) <br><br> Rf value: 0.52 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 518 <br><br> (M+Na)+ = 540 <br><br> 10 b) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-sulphonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-sulphonic acid-15 N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 87 % of theory, <br><br> C27H30N6O4S (534.6) <br><br> Rf value: 0.13 (silica gel; dichloromethane/ethanol = 9:1) 20 EKA mass spectrum: (M+H)+ = 535 <br><br> (M+H+Na)++ = 279 <br><br> Example 150 <br><br> 25 l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-sulphonic acid-N-(l-methylpyrazol-4-yl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-30 cyanophenyl)-aminomethyl]-benzimidazol-5-yl-sulphonic acid-N-(l-methylpyrazol-4-yl)-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 38 % of theory, <br><br> 35 C25H30N8O4S (538.6) <br><br> Rf value: 0.09 (silica gel; dichloromethane/ethanol = 9:1) <br><br> AS AMENDED " <br><br> EKA mass spectrum: (M+H)+ = 539 <br><br> Example 151 <br><br> 5 l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]- <br><br> 5-(2.3-dihydroindol-l-yl-sulphonyl)-benzimidazole-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-10 (4-cyanophenyl)-aminomethyl]-5-(2.3-dihydroindol-l-yl- <br><br> sulphonyl) -benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 15 % of theory, <br><br> Rf value: 0.36 (silica gel; dichloromethane/methanol = 4:1) 15 C24H24N602S (460.6) <br><br> EKA mass spectrum: (M+H)+ = 461 <br><br> Example 152 <br><br> 20 l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazole-5-yl-sulphonic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide <br><br> Prepared analogously to Example 2 6 from 1-methyl-25 2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl- <br><br> sulphonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 24 % of theory, <br><br> Rf value: 0.55 (Reverse-Phase RP-18 silica gel; methanol/5% 30 saline solution = 3:2) <br><br> c25h26n6°4s (506.6) <br><br> EKA mass spectrum: (M+H)+ = 507 <br><br> (M+Na)+ = 529 (M+2Na)++ = 276 <br><br> 35 <br><br> AS AMENDED <br><br> Example 153 <br><br> - 124 - <br><br> 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-5-(isoindolin- <br><br> 2-yl-sulphonyl)-benzimidazol-hydrochloride <br><br> 5 <br><br> Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-5-(isoindolin-2-yl-sulphonyl)-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> 10 Yield: 33 % of theory, <br><br> Rf value: 0.32 (silica gel; dichloromethane/methanol = 4:1) <br><br> C24H24N5O2S (460.6) <br><br> EKA mass spectrum: (M+H)+ = 461 <br><br> 15 Example 154 <br><br> 2-[2-(4-Amidinophenyl)-ethyl]-quinazolin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 20 a. Ethyl 4-methyl-3-nitro-benzoate <br><br> 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 25 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. <br><br> Yield: 5.7 g (90 % of theory), <br><br> 30 Rf value: 0.81 (silica gel, ethyl acetate/cyclohexane = <br><br> 1:1) <br><br> b. Methyl 4-(2-dimethylaminovinyl)-3-nitro-benzoate 1.0 g (4.8 mmol) of ethyl 4-methyl-3-nitro-benzoate, 0.74 g 35 (6.2 mmol) of dimethylformamide dimethylacetal and 2 ml of dimethylformamide were heated to 140°C with stirring for 3 hours. Then the solvent was distilled off and the crude <br><br> AS AMENDED " " <br><br> product thus obtained was reacted without any further purification. <br><br> Yield: 1.2 g (100 % of theory), <br><br> Rf value: 0.54 (silica gel, ethyl acetate/cyclohexane = 5 1:1) <br><br> c. Methyl 4-formyl-3-nitro-benzoate <br><br> 1.2 g (4.8 mmol) of methyl 4-(2-dimethylaminovinyl)-3-nitro-benzoate were dissolved in 120 ml of 10 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 ambient temperature. The suspension was then diluted with water and methylene chloride and extracted with methylene chloride. The combined organic 15 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). <br><br> Yield: 0.6 g (63 % of theory), <br><br> 20 Rf value: 0.63 (silica gel, ethyl acetate/cyclohexane = <br><br> 1:1) <br><br> d. Methyl 3-Amino-4-formyl-benzoate <br><br> To a solution of 25 ml of ethanol/glacial acetic acid/water 25 (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 for 15 minutes. Then the iron was separated off, the solution was diluted with water and 30 extracted with methylene chloride. The combined organic extracts were washed with water, dried and evaporated down. <br><br> Yield: 0.3 g (58 % of theory), <br><br> Rf value: 0.74 (silica gel, methylene chloride/methanol = 35 9.5:0.5) <br><br> AS AMENDED " 1Z0 " <br><br> e. Methyl 3- [3- (4-cyanophenyl) -propionylami.no] -4-formyl-benzoate <br><br> 1.0 g (5.6 mmol) of methyl 3-amino-4-formyl-benzoate and <br><br> 1.1 g (5.6 mmol) of 4-cyanophenylpropionic acid chloride <br><br> 5 were dissolved in 50 ml of methylene chloride and after the addition of 0.7 g (5.6 mmol) of N-ethyl-diisopropylamine the mixture was stirred for 24 hours at ambient temperature. Then it was extracted with sodium hydrogen carbonate solution, the combined organic extracts were 10 dried and evaporated down. The residue was chromatographed on silica gel and eluted with ethyl acetate/cyclohexane (1:3) . <br><br> Yield: 0.6 g (32 % of theory), <br><br> Rf value: 0.60 (silica gel, ethyl acetate/cyclohexane = 15 1:1) <br><br> f. Methyl 2-[2-(4-cyanophenyl)-ethyl]-quinazoline-7-carboxylate <br><br> 20 0.6 g (1.8 mmol) of ethyl 3-[3-(4-cyanophenyl)- <br><br> 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 25 chloride containing 0 to 1 % methanol. <br><br> Yield: 0.35 g (62 % of theory), <br><br> Rf value: 0.38 (silica gel, ethyl acetate/cyclohexane = <br><br> 1:1) <br><br> 30 g. 2-[2-(4-Cyanophenyl)-ethyl]-quinazolin-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 IN lithium hydroxide solution and 4 ml of tetrahydrofuran and stirred for 3 hours at ambient temperature. Then 4.7 ml of 35 IN hydrochloric acid were added and the mixture was stirred for 30 minutes. The product precipitated was suction filtered, washed with water and dried. <br><br> AS AMENDED " ~ <br><br> Yield: 0.30 g (100 % of theory), <br><br> Rf value: 0.1 (silica gel, ethyl acetate/cyclohexane = 1:1) <br><br> h. 2-[2-(4-Cyanophenyl)-ethyl]-quinazolin-7-yl-carboxylic 5 acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide <br><br> 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 at 50°C. Then the thionyl <br><br> 10 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 15 residue was chromatographed on silica gel and eluted with methylene chloride containing 1 % methanol. <br><br> Yield: 230 mg (37 % of theory), <br><br> Rf value: 0.64 (silica gel, methylene chloride/methanol = 9:1) <br><br> 20 <br><br> 1. 2-[2-(4-Amidinophenyl)-ethyl]-quinazolin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 230 mg (0.5 mmol) of 2-[2-(4-cyanophenyl)-ethyl]-25 quinazolin-7-yl-carboxylic acid-N-phenyl- <br><br> 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 30 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). <br><br> 35 Yield: 100 mg (39 % of theory), <br><br> Rf value: 0.5 (silica gel, methylene chloride/ethanol = <br><br> 4:1) <br><br> AS AMENDED <br><br> C29H29N5O3 (495.59) <br><br> Mass spectrum: (M+H)+ = 496 <br><br> Example 155 <br><br> 5 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-sulphonic acid-N-(l-methylpyrazol-4-yl)-N-(2-hydroxycarbonylethyl)-amide <br><br> 10 <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-sulphonic acid-N-(l-methylpyrazol-4-yl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. 15 Yield: 95 % of theory, <br><br> c23h26n8°4s (510.6) <br><br> Rf value: 0.53 (Reversed Phase silica gel RP-18, methanol + 5% saline solution) <br><br> EKA mass spectrum: (M+H)+ = 511 20 (M+Na)+ = 533 <br><br> (M+2Na)++ = 278 <br><br> Example 156 <br><br> 25 l-Methyl-2-[N-(3-amidino-pyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 30 a) 3-[(N-tert.Butoxycarbonyl-amino)acetylamino]-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> 35 <br><br> 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-l-yl)-N,N,N',N'- <br><br> AS AMENDED ~ ^ ~ <br><br> tetramethyluronium tetrafluoroborate, 11.0 g of triethylamine and 34.2 g (0.10 mol) of 3-amino-4-methyl-amino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and stirred for 2.5 hours at ambient temperature. <br><br> 5 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), <br><br> 10 C25H33N5O5 (499.6) <br><br> Rf value: 0.55 (silica gel; methylene chloride/ethanol = 19:1) <br><br> b) l-Methyl-2-(N-tert.butoxycarbonyl-aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-15 N-(2-ethoxycarbonylethyl)-amide <br><br> 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 20 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 25 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. <br><br> 30 Yield: 5.85 g (61 % of theory), <br><br> C25H31N5O5 (481.6) <br><br> Rf value: 0.70 (silica gel; methylene chloride/ethanol = 9:1) <br><br> 35 c) l-Methyl-2-aminomethyl-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-trifluoracetate <br><br> AS AMENDED ~ "u ~ <br><br> 4.81 g (0.10 mol) of l-methyl-2-(N-tert.butoxycarbonyl-aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide were dissolved in 25 ml of methylene chloride, mixed with 5 ml 5 of trifluoroacetic acid and stirred 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. <br><br> Yield: 3.15 g (68 % of theory), <br><br> 10 C20H23N5O3 (381.4) <br><br> Rf value: 0.18 (silica gel; methylene chloride/ethanol = 9:1) <br><br> d) l-Methyl-2-[N-(3-cyano-pyridin-6-yl)-aminomethyl]-15 benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> 1.5 g (3.25 mmol) of l-methyl-2-aminomethyl-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-20 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 25 ambient temperature and stirring with about 20 ml of water, the pH was adjusted to 4 by the addition of IN 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 30 evaporation of the solvent the crude product was chromatographed on silica gel, eluting first with methylene chloride, later with methylene chloride/ethanol (25:1) and (19:1). The desired fractions were combined and evaporated down. <br><br> 35 Yield: 1.05 g (67 % of theory), <br><br> c26h25n7° (483.6) <br><br> Mass spectrum: (M+H)+ = 484 <br><br> AS AMENDED " 1J1 " <br><br> e) l-Methyl-2-[N-(3-amidino-pyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride 5 Prepared analogously to Example 25d from l-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. <br><br> 10 Yield: 38 % of theory, <br><br> C28h28n8°3 (500.6) <br><br> Mass spectrum: (M+H)+ = 501 <br><br> Example 157 <br><br> 15 <br><br> l-Methyl-2-[N-(4-amidinophenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydroiodide <br><br> 20 a) 4-Nitro-benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide <br><br> 16.7 g (0.1 mol) of 4-nitrobenzoic acid were refluxed in 50 ml of thionyl chloride and 3 drops of dimethylformamide for 1 hour. After the solvent had been distilled off in 25 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 30 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. <br><br> 35 Yield: 32.6 g (100 % of theory), <br><br> Rf value: 0.37 (silica gel; methylene chloride/methanol = <br><br> 50:1) <br><br> AS AMENDED <br><br> - 132 - <br><br> b) 4-Amino-benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide <br><br> 22 g (67 mmol) of 4-nitro-benzoic acid-N-phenyl-N-(2-5 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 10 further reacted directly. <br><br> Yield: 18.6 g (94 % of theory), <br><br> Rf value: 0.70 (silica gel; methylene chloride/ethanol = 19:1) <br><br> 15 c) 2-Methyl-3-thiomethyl-indol-5-yl-carboxylic acid-N- <br><br> phenyl-N- (2-methoxycarbonylethyl) -amide . <br><br> 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 20 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 25 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 30 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). <br><br> Yield: 24.1 g (69 % of theory), <br><br> 35 Rf value: 0.58 (silica gel; ethyl acetate/petroleum ether = 1:1) <br><br> c21h22n2°3s (382.49) <br><br> AS AMENDED " 133 " <br><br> Mass spectrum: (M)+ = 382 <br><br> d) l-tert-Butoxycarbonyl-2-methyl-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide <br><br> 5 8.9 g (23 mmol) of 2-Methyl-3-thiomethyl-indol-5-yl- <br><br> carboxylic acid-N-phenyl-N-(2-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 P.G. Gassman et al., Organic 10 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 15 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). <br><br> Yield: 10.0 g (98 % of theory), <br><br> 20 Rf value: 0.40 (silica gel; ethyl acetate/petroleum ether <br><br> =3:7) <br><br> e) 2-[N-(4-Cyanophenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide <br><br> 25 3.5 g (8 mmol) of 1-tert.butoxycarbonyl-2-methyl-indol-5- <br><br> yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)- <br><br> amide were dissolved in 80 ml of carbon tetrachloride, <br><br> mixed with 1.5 g (8.4 mmol) of N-bromo-succinimide and 20 <br><br> mg of azobisisobutyronitrile and refluxed for 2.5 hours. <br><br> 30 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-diisopropylamine, mixed with 1.0 g <br><br> 35 (8 mmol) of 4-aminobenzonitrile and refluxed for 2.5 hours. <br><br> The solvent was distilled off in vacuo and the residue <br><br> AS AMENDED " "4 " <br><br> obtained was purified by chromatography (silica gel; ethyl acetate/petroleum ether = 1:4 to 1:1). <br><br> Yield: 1.1 g (30 % of theory), <br><br> Rf value: 0.21 (silica gel; ethyl acetate/petroleum ether = 5 1:1) <br><br> f. l-Methyl-2-[N-(4-thiocarbamoyl-phenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide 10 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. 15 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 20 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 ml of pyridine and mixed with 0.67 ml (1.37 mmol) of triethylamine. Then hydrogen sulphide gas was introduced into the solution thus 25 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 % of theory), <br><br> 30 C28H28N403S (500.62) <br><br> EKA mass spectrum: (M+H)+ = 501 <br><br> (M+Na)+ = 523 <br><br> g) l-Methyl-2-[N-(4-amidinophenyl)aminomethyl]-indol-5-yl-35 carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide- <br><br> hydroiodide <br><br> AS AMENDED ~ lja ~ <br><br> 0.30 g (0.60 mmol) of l-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 5 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 10 was purified by chromatography (silica gel; methylene chloride/ethanol = 9:1 to 4:1). <br><br> Yield: 55 % of theory, <br><br> C28h29n5°3 (483.58) <br><br> Rf value: 0.20 (silica gel; methylene chloride/ethanol = 15 4:1+1 drop of acetic acid) <br><br> EKA mass spectrum: (M+H)+ = 484 <br><br> Example 158 <br><br> 20 l-Methyl-2-[N-(4-amidinophenyl)aminomethyl]- <br><br> thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) Iminoethyl methoxyacetate hydrochloride <br><br> 25 A solution of 35.5 g (0.50 mol) of methoxyacetonitrile in <br><br> 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 <br><br> (0.62 mol) of hydrogen chloride gas was introduced, whilst towards the end of the introduction of gas the reaction <br><br> 30 product crystallised out. To complete the precipitation 130 ml of diethylether were added and the colourless needles were filtered off. <br><br> Yield: 66.4 g (86 % of theory), <br><br> Melting point: 117-118°C. <br><br> 35 <br><br> b) 4-Hydroxymethyl-2-methoxymethyl-imidazole <br><br> AS AMENDED " iJb " <br><br> 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 5 bar (analogously to: P. Dziuron et al. Arch. Pharm. 307, <br><br> 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 10 purified by chromatography (aluminium oxide; methylene chloride/ethanol = 90:10 to 85:15). <br><br> Yield: 26.7 g (94 % of theory), <br><br> Rf value: 0.43 (silica gel; methylene chloride/ethanol = 9:1) <br><br> 15 CgHioN2°2 (142.20) <br><br> Mass spectrum: (M)+ = 142 <br><br> c) 4-Hydroxymethyl-2-methoxymethyl-l-methyl-imidazole as a 1:1 mixture with 5-hydroxymethyl-2-methoxymethyl-l-methyl- <br><br> 20 imidazole <br><br> A mixture of 7.1 g (50 mmol) of 4-hydroxymethyl-2- <br><br> 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 <br><br> 25 hours (analogously to I. Sinclair et al., J. Med. Chem., <br><br> 29, 1986, 261). Then the solvent was distilled off in vacuo and the crude product purified by column chromatography <br><br> (aluminium oxide; methylene chloride/ethanol = 99:1 to <br><br> 95:5). <br><br> 30 Yield: 6.1 g (78 % of theory; 1:1 mixture of the two regioisomers) <br><br> Rf value: 0.32 (silica gel; methylene chloride/ethanol = 19:1) <br><br> 35 d) 5-Chloro-4-hydroxymethyl-2-methoxymethyl-1-methyl- <br><br> imidazole <br><br> AS AMENDED " " <br><br> A 1:1 mixture of 7.7 g (49 mmol) of 4-hydroxymethyl-2-methoxymethyl-l-methyl-imidazole and 5-hydroxymethyl-2-methoxymethyl-l-methyl-imidazole and 7.3 g (55 mmol) of N-chloro-succinimide was heated to 50°C in 48 ml of 5 ethylene glycol monoethylether and 7 0 ml of dioxan for 10 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. <br><br> 10 Yield: 3.4 g (36 % of theory), <br><br> Rf value: 0.40 (silica gel; methylene chloride/ethanol = <br><br> 19:1) <br><br> e) 5-chloro-4-formyl-2-methoxymethyl-l-methyl-imidazole 15 3.4 g (18 mmol) of 5-chloro-4-hydroxymethyl-2- <br><br> methoxymethyl-l-methyl-imidazole 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 20 was eliminated and the crude product obtained was further reacted without any further purification. <br><br> Yield: 3.0 g (89 % of theory), <br><br> Rf value: 0.44 (silica gel; methylene chloride/ethanol = 50:1) <br><br> 25 <br><br> f) Ethyl l-methyl-2-methoxymethyl-thieno[2.3-d]imidazol-5-yl-carboxylate <br><br> To a freshly prepared sodium ethoxide solution (from 391 mg, 17 mMol of sodium) in 15 ml of ethanol were added 30 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-l-methyl-imidazole in 20 ml of absolute ethanol were added and the mixture was heated to 80°C (analogously to B. Iddon et al., 35 J. Chem. Soc. Perkin Trans. I, 1987, 1457). After 5 hours the solvent was distilled off, the residue was taken up in 50 ml of methylene chloride and washed with 20 ml of water. <br><br> AS AMENDED ~ " <br><br> 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 5 chromatography (aluminium oxide; methylene chloride). <br><br> Yield: 1.0 g (46 % of theory), <br><br> Rf value: 0.48 (silica gel; methylene chloride/ethanol = 50:1) <br><br> c11h14n2°3s (254.31) <br><br> 10 EKA mass spectrum: (M+H)+ = 255 <br><br> (M+Na)+ = 277 <br><br> g) l-Methyl-2-methoxymethyl-thieno[2.3-d]imidazol-5-yl- <br><br> carboxylic acid <br><br> 15 To a solution of 0.90 g (3.54 mmol) of ethyl l-methyl-2- <br><br> 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 mixture was stirred for 2 hours at ambient temperature. Then the solvent was distilled off 20 in vacuo, the residue was taken up in 5 ml of water and washed with 10 ml of diethylether. The aqueous phase was acidified with 6 ml of 2N hydrochloric acid, cooled to 0°C and the precipitated crystals are filtered off. <br><br> Yield: 0.50 g (63% of theory) <br><br> 25 Rf value: 0.21 (silica gel; methylene chloride/ethanol = 9:1 + a few drops of acetic acid) <br><br> c9h10n2°3s (226.26) <br><br> Mass spectrum: (M)+ = 226 <br><br> 30 h) l-Methyl-2-methoxymethyl-thieno[2.3-d]imidazol-5-yl- <br><br> carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide <br><br> A suspension of 0.50 g (2.2 mmol) of l-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, <br><br> 35 27 mmol) of thionyl chloride and refluxed for 60 minutes, during which time the solid gradually dissolved. After <br><br> AS AMENDED ~ ~ <br><br> 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 5 dropwise to a mixture of 0.42 g (2.3 mmol) of <br><br> 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 10 gel; methylene chloride/ethanol = 100:1). <br><br> Yield: 0.66 g (77% of theory), <br><br> Rf value: 0.47 (silica gel; methylene chloride/ethanol = 19:1) <br><br> 15 i) l-Methyl-2-(N-4-cyanophenylaminomethyl)- <br><br> thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide <br><br> To a solution of 0.73 g (1.88 mmol) of l-methyl-2-methoxymethyl-thieno[2.3-d]imidazol-5-yl-carboxylic acid-N- <br><br> 20 phenyl-N-(2-methoxycarbonylethyl)-amide in 30 ml of methylene chloride were added dropwise at 5°C 2.9 ml (2.9 <br><br> 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 <br><br> 25 sodium hydrogen carbonate solution, the organic phase was separated off, dried with sodium sulphate and filtered. The filtrate was mixed with 14 ml 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 <br><br> 30 obtained was heated to 50°C for 1 hour and then the residual solvent was distilled off in vacuo. After chromatography (silica gel; methylene chloride/ethanol = <br><br> 99:1 to 97:3) a yellow oil was obtained which slowly solidified. <br><br> 35 Yield: 0.37 g (42% of theory), <br><br> Rf value: 0.29 (silica gel; methylene chloride/ethanol = 50:1 + a few drops of ammonia ) <br><br> AS AMENDED <br><br> - 140 - <br><br> j) l-Methyl-2-[N-(4-amidinophenyl)aminomethyl]- <br><br> thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2- <br><br> ethoxycarbonylethyl)-amide-hydrochloride <br><br> 5 0.38 g (0.80 mmol) of l-methyl-2-(N-4- <br><br> 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 10 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 15 solvent was distilled off in vacuo and the crude product was purified by chromatography (silica gel; methylene chloride/ethanol = 9:1 to 4:1). <br><br> Yield : 57 % of theory C26^28^6C)3S (504.62) <br><br> 20 Rf value: 0.21 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid) <br><br> EKA mass spectrum: (M+H) + = 505 <br><br> (M+H+Na)++ = 264 <br><br> Example 159 <br><br> 25 <br><br> l-Methyl-2-[N-(4-amidinophenyl)aminomethyl]- <br><br> thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2- <br><br> hydroxycarbonylethyl)-amide-hydrochloride <br><br> 30 Prepared analogously to Example 2 from l-methyl-2-[N-(4- <br><br> amidinophenyl)aminomethyl]-thieno[2.3-d]imidazol-5-yl- <br><br> carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide- <br><br> hydrochloride and sodium hydroxide solution. <br><br> Yield: 85 % of theory, <br><br> 35 C24H24N5O3S (476.56) <br><br> Rf value: 0.36 (Reversed Phase silica gel RP-8; methanol <br><br> AS AMENDED ~ 1,1 ~ <br><br> + 5 % saline solution) <br><br> EKA mass spectrum: (M+H)+ = 477 <br><br> (M+Na)+ = 499 (M+2-Na) ++ = 250 <br><br> 5 <br><br> Example 160 <br><br> l-Methyl-3-[N-(4-amidinophenyl)thiomethyl]-quinoxalin-2-on-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-10 amide-hydrochloride a) l-Methyl-3-[N-(4-cyanophenyl)thiomethyl]-quinoxalin-2-on-6-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide <br><br> 15 A solution of 2.5 g (7.6 mmol) of 3-amino-4-methylamino- <br><br> benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)-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 the solvent the crude product 20 obtained was purified by chromatography (silica gel; methylene chloride). <br><br> Yield: 1.6 g (40 % of theory), <br><br> Rf value: 0.63 (silica gel; EtOAc/EtOH/ammonia = 90:10:1) <br><br> b) l-Methyl-3-[N-(4-amidinophenyl)thiomethyl]-quinoxalin-2-25 on-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)- <br><br> amide-hydrochloride <br><br> Prepared analogously to Example 1 from l-methyl-3-[N-(4-cyanophenyl)thiomethyl]-quinoxalin-2-on-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic 30 hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 23 % of theory, <br><br> C28H27N5O4S (543.64) <br><br> Rf value: 0.25 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5) <br><br> 35 EKA mass spectrum: (M+H)+ = 544 <br><br> (M+Na)+ = 566 <br><br> AS AMENDED <br><br> - 142 - <br><br> Example 161 <br><br> 3-Methyl-2-[2-(4-amidinophenyl)ethyl]-5 imidazo[1.2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride a) 3-Methyl-2-[2-(4-cyanophenyl)ethyl]- <br><br> imidazo[1.2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-10 ethoxycarbonylethyl)-amide <br><br> 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-l-(4-cyanophenyl)-l-penten-3-one and methyl 2-aminopyridine-4-carboxylate analogously to Y. Katsura et 15 al. Chem. Pharm. Bull. 1992, 40, 1424-1438) were suspended in 15 ml of thionyl chloride and heated to boiling for 1 hour until fully dissolved. After the thionyl chloride had been distilled off the acid chloride was dissolved in 15 ml of pyridine without any further purification and at 0°C 20 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 IN hydrochloric acid and dried with sodium sulphate. After distillation of the solvent and 25 chromatography (silica gel; methylene chloride/ethanol = 0 to 2 %) a brown oil was obtained. <br><br> Yield: 1.48 g (64 % of theory), <br><br> Rf value: 0.73 (silica gel; ethyl acetate/ethanol/ammonia = <br><br> 90:10:1) <br><br> 30 <br><br> b) 3-Methyl-2-[2-(4-amidinophenyl)ethyl]- <br><br> imidazo[1.2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 1 from 3-methyl-2-[2-(4- <br><br> 35 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. <br><br> AS AMENDED ~ i,J ~ <br><br> Yield: 62 % of theory, <br><br> c29h31n5°3 (497.60) <br><br> Rf value: 0.23 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5) <br><br> 5 EKA mass spectrum: (M+H) + = 498 <br><br> Example 162 <br><br> 3-Methyl-2-[2-(4-amidinophenyl)ethyl]-10 imidazo[1.2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 2 from 3-methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[1.2-a]pyridin-7-yl-carboxylic 15 acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 92 % of theory, <br><br> C27H27N5O3 (469.55) <br><br> Rf value: 0.19 (silica gel; ethyl <br><br> 20 <br><br> acetate/ethanol/ammonia = <br><br> 50:45:5) <br><br> EKA mass spectrum: (M+H)+ = <br><br> 470 <br><br> (M+Na)+ <br><br> 492 <br><br> (M+2H)++ <br><br> 235.7 <br><br> (M+H+Na)++ = <br><br> 246.7 <br><br> 25 <br><br> (M+2Na)++ = <br><br> 257.7 <br><br> Example 163 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-30 5-yl-carboxylic acid-N-phenyl-N-[(N-ethoxycarbonylethyl-N-methyl)-2-aminoethyl]-amide-dihydrochloride <br><br> 35 <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-ethoxycarbonylethyl-N-methyl)-2- <br><br> AS AMENDED ~ 149 ~ <br><br> aminoethyl]-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 80 % of theory, <br><br> C31H37N7O3 (555.7) <br><br> 5 Rf value: 0.24 (silica gel; dichloromethane/methanol = 4:1) <br><br> EKA mass spectrum: (M+H)+ = 556 <br><br> (M+H+Na)++ = 289.8 <br><br> (M+2H)++ = 278.8 <br><br> 10 Example 164 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-hydroxycarbonylethyl-N-methyl)-2-aminoethyl]-amide-hydrochloride <br><br> 15 <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-ethoxycarbonylethyl-N-methyl)-2-aminoethyl]-amide-dihydrochloride and sodium hydroxide 20 solution. <br><br> Yield: 79 % of theory, <br><br> c29h33n7°3 (527.6) <br><br> Rf value: 0.43 (Reversed Phase silica gel RP-18; methanol/5% aqueous saline solution = 6:4) <br><br> 25 EKA mass spectrum: (M+H)+ = 528 <br><br> (M+H+Na)++ = 275.6 (M+2H)++ = 264.6 <br><br> Example 165 <br><br> 30 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxy-n-propyl)-amide-hydrochloride <br><br> 35 <br><br> Prepared from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy- <br><br> AS AMENDED " 1,3 " <br><br> n-propyl)-amide-hydrochloride by hydrogenation over palladium/charcoal (10%) at 5 bar hydrogen pressure and at ambient temperature. <br><br> Yield: 61 % of theory, <br><br> 5 c26h28n6°2 (456.6) <br><br> Rf value: 0.70 (Reversed Phase silica gel RP-18; methanol/5% aqueous saline solution = 9:1) <br><br> EKA mass spectrum: (M+H)+ = 457 <br><br> (M+H+Na)++ = 240 <br><br> 10 <br><br> Example 166 <br><br> l-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-15 pyridyl)-N-(2-hydroxycarbonylethyl)-amide <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-20 ethoxycarbonylethyl)-amide and sodium hydroxide solution. Yield: 97 % of theory, <br><br> c32h37n7°5 (599.7) <br><br> Rf value: 0.22 (silica gel; dichloromethane/methanol = 9:1) <br><br> EKA mass spectrum: (M+H)+ = 600 <br><br> 25 (M+H+Na)++ = 311.7 <br><br> (M+2H)++ = 300.8 (M+2Na)++ = 322.8 <br><br> Example 167 <br><br> 30 <br><br> l-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxy-n-propyl)-amide <br><br> 35 <br><br> Prepared analogously to Example 165 from l-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]- <br><br> AS AMENDED ~ 146 ~ <br><br> benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide by catalytic debenzylation. <br><br> Yield: 26 % of theory, <br><br> C33H40N6°4 (584.7) <br><br> 5 Rf value: 0.39 (silica gel; dichloromethane/ethanol = 9:1 ) <br><br> EKA mass spectrum: (M+H)+ = 585 <br><br> (M+H+Na)++ = 304 (M+Na) + = 607 <br><br> 10 Example 168 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 15 <br><br> Prepared analogously to Example 25d from l-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 20 carbonate. <br><br> Yield: 42 % of theory, <br><br> C28H29FN6O3 (516.6) <br><br> Rf value: 0.31 (silica gel; dichloromethane/methanol = 5:1) EKA mass spectrum: (M+H)+ = 517 25 (M+H+Na)++ = 270 <br><br> Example 169 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-30 5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 35 <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide and <br><br> AS AMENDED ~ " <br><br> ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 90 % of theory, <br><br> C28H29FN603 (516.6) <br><br> 5 Rf value: 0.29 (silica gel; dichloromethane/methanol = 5:1) <br><br> EKA mass spectrum: (M+H)+ = 517 <br><br> (M+H+Na)++ = 270 <br><br> Example 170 <br><br> 10 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide <br><br> 15 Prepared analogously to Example 26 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 97 % of theory, <br><br> 20 C26H25FN603 (488.5) <br><br> Rf value: 0.13 (silica gel; dichloromethane/ethanol = 4:1) <br><br> EKA mass spectrum: (M+H)+ = 489 <br><br> (M+Na)+ = 511 (M+2Na)++ = 267 <br><br> 25 <br><br> Example 171 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-30 hydroxycarbonylethyl)-amide <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide- <br><br> 35 hydrochloride and sodium hydroxide solution. <br><br> Yield: 89 % of theory, <br><br> AS AMENDED " 1,8 " <br><br> C26H25™6°3 (488.5) <br><br> Rf value: 0.15 (silica gel; dichloromethane/ethanol = 4:1) <br><br> EKA mass spectrum: (M+H)+ = 489 <br><br> (M+Na)+ = 511 5 (M+2Na)++ = 267 <br><br> Example 172 <br><br> l-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-10 benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 25d from l-methyl-2-[N-(4-cyano-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-15 carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 89 % of theory, <br><br> c29h32n6°4 (528.6) <br><br> 20 Rf value: 0.13 (silica gel; dichloromethane/ethanol = 4:1) <br><br> EKA mass spectrum: (M+H)+ = 529 <br><br> (M+H+Na)++ = 276 (M+2H)++ = 265 <br><br> 25 Example 173 <br><br> l-Methyl-2-[N-[4-(N-4-ethylbenzoylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> 30 <br><br> 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 4-ethylbenzoylchloride. <br><br> 35 Yield: 64 % of theory, <br><br> c36h37n7°4 (631.7) <br><br> AS AMENDED " 1,3 ~ <br><br> Rf value: 0.78 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 632 <br><br> (M+H+Na)++ = 327.8 (M+Na)+ = 654 <br><br> 5 <br><br> Example 174 <br><br> l-Methyl-2-[N-[4-(N-benzyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-10 pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> 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-15 hydrochloride and benzyl chloroformate. <br><br> Yield: 64 % of theory, <br><br> c35h35n7°5 (633.6) <br><br> Rf value: 0.60 (silica gel; dichloromethane/methanol = 9:1) EKA mass spectrum: (M+H)+ = 634 <br><br> 20 (M+H+Na)++ = 328.8 <br><br> (M+Na)+ = 656 <br><br> Example 17 5 <br><br> 25 l-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide <br><br> Prepared analogously to Example 26 from l-methyl-2-[N-(4- <br><br> 30 amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl- <br><br> carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide- <br><br> hydrochloride and sodium hydroxide solution. <br><br> Yield: 71 % of theory, <br><br> C27H28N6O4 (500.6) <br><br> 35 Rf value: 0.15 (silica gel; dichloromethane/ethanol = 4:1) <br><br> EKA mass spectrum: (M+H)+ = 501 <br><br> AS AMENDED <br><br> - 150 - <br><br> (M+Na)+ = 523 (M+2Na)++ = 273 <br><br> Example 176 <br><br> 5 <br><br> l-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 10 Prepared analogously to Example 25d from l-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. <br><br> 15 Yield: 67 % of theory, <br><br> C28H31N7°4 (529.6) <br><br> Rf value: 0.16 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ = 530 <br><br> 20 Example 177 <br><br> l-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide <br><br> Prepared analogously to Example 26 from l-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. <br><br> 30 Yield: 78 % of theory, <br><br> C26H27N7O4 (501.6) <br><br> Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1) EKA mass spectrum: (M+H)+ = 502 <br><br> 35 <br><br> Example 178 <br><br> AS AMENDED " 151 " <br><br> l-Methyl-2-[N-[4-(N-benzyloxycarbonylamidino)phenyl]-aminomethyl] -benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide <br><br> 5 Prepared analogously to Example 104 from l-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, <br><br> 10 C33H3XN7O5 (605.7) <br><br> Rf value: 0.26 (silica gel; dichloromethane/methanol = 9:1) <br><br> EKA mass spectrum: (M+H)+ = 606 <br><br> (M+Na)+ = 628 <br><br> (M-H+2Na)+ = 650 <br><br> 15 (M+2H)++ = 303.8 <br><br> (M+H+Na)++ = 314.8 <br><br> (M+2Na)++ = 325.7 <br><br> Example 17 9 <br><br> 20 <br><br> l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide-hydrochloride <br><br> 25 Prepared analogously to Example 25 from l-methyl-2-[N-(4- <br><br> cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 61 % of theory, <br><br> 30 C33H34N6O2 (546.7) <br><br> Rf value: 0.19 (silica gel; dichloromethane/ethanol = 4:1) <br><br> EKA mass spectrum: (M+H)+ = 547 <br><br> (M+H+Na)++ = 285 <br><br> Example 180 <br><br> 35 <br><br> AS AMENDED " 152 " <br><br> l-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide <br><br> 5 Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide-hydrochloride and n-hexyl chloroformate. <br><br> Yield: 73 % of theory, <br><br> 10 C40H46N6O4 (674.9) <br><br> Rf value: 0.46 (silica gel; dichloromethane/ethanol = 9:1) <br><br> EKA mass spectrum: (M+H)+ = 675 <br><br> (M+H+Na)++ = 349 <br><br> (M+Na) + = 697 <br><br> 15 (M+K) + = 713 <br><br> Example 181 <br><br> 3-Methyl-2-[2-(4-amidinophenyl)ethyl]-20 imidazo[1.2-a]pyridin-7-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[1.2-a]pyridin-7-yl-carboxylic <br><br> 25 acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide- <br><br> hydrochloride and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 53 % of theory, <br><br> C28H30N6O3 (498.59) <br><br> 30 Rf value: 0.42 (silica gel; ethyl acetate/ethanol/ammonia <br><br> =50:45:5) <br><br> EKA mass spectrum: (M+H)+ = 499 <br><br> (M+2Na)++ = 272 <br><br> (M+H+Na)++ = 261 <br><br> 35 (M+2H)++ = 250 <br><br> AS AMENDED <br><br> Example 182 <br><br> - 153 - <br><br> l-Methyl-2-[N-(3-amidino-pyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-5 hydroxycarbonylethyl)-amide <br><br> Prepared analogously to Example 2 6 from 1-methyl-2-[N-(3-cyanopyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-10 amide and sodium hydroxide solution. <br><br> Yield: 40 % of theory, <br><br> C24H24N803 (472.9) <br><br> Rf value: 0.67 (Reversed Phase silica gel RP-8; methanol/5% <br><br> saline solution = 1:1) <br><br> 15 EKA mass spectrum: (M+H)+ = 473 <br><br> Example 183 <br><br> l-Methyl-2-[N-[4-(N-hydroxylamidino)phenyl]-aminomethyl]-20 benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-(methansulphonylaminocarbonyl)-ethyl]-amide a. l-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-25 (methanesulphonylaminocarbonyl)-ethyl]-amide <br><br> 2.0 g (4.5 mmol) of l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide and 0.7 3 g (4.7 mmol) of carbonyldiimidazole were dissolved in 80 ml <br><br> 30 of tetrahydrofuran and 5 ml of dimethylformamide and stirred for 30 minutes at ambient temperature and for <br><br> 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 <br><br> 35 stirred for 2 hours at ambient temperature. Then this suspension was added at ambient temperature to the tetrahydrofuran solution. After 12 hours at ambient <br><br> AS AMENDED ~ 154 ~ <br><br> 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 over sodium sulphate and evaporated down. The crude product 5 was chromatographed on silica gel (methylene chloride/ethanol (40:1)). The desired fractions were combined and evaporated down. Yield: 1.05 g (44 % of theory), <br><br> C26H25N7O4S (531.6) <br><br> 10 Rf value: 0.72 (silica gel; dichloromethane/methanol = 9:1) <br><br> b. l-Methyl-2-[N-[4-(N-hydroxylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-(methansulphonylaminocarbonyl)-ethyl]-15 amide <br><br> Prepared analogously to Example 96 from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-(methanesulphonylaminocarbonyl)-ethyl]-amide and 20 hydroxylamine. <br><br> Yield: 27% of theory, <br><br> C26H28N8O5S (564.6) <br><br> Rf value: 0.75 (silica gel; dichloromethane/ethanol = 7:3 + 1% glacial acetic acid) <br><br> 25 EKA mass spectrum: (M+H)+ = 565 <br><br> (M+Na)+ = 587 <br><br> Example 184 <br><br> 30 l-Methyl-2-[N-(5-amidino-thiazol-2-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride <br><br> 35 <br><br> Prepared analogously to Example 25d from 1-methyl- <br><br> 2-[N-(5-cyano-thiazol-2-yl)-aminomethyl]-benzimidazol-5-yl- <br><br> carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)- <br><br> AS AMENDED " 130 " <br><br> amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Example 185 <br><br> 5 <br><br> l-Methyl-2-[N-(5-amidino-thiazol-2-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide <br><br> 10 Prepared analogously to Example 2 6 from 1-methyl- <br><br> 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. <br><br> 15 <br><br> Example 18 6 <br><br> l-Methyl-2-[N-(2-amidino-pyrazin-5-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-20 ethoxycarbonylethyl)-amide-hydrochloride <br><br> 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)- <br><br> 25 amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. <br><br> Yield: 19 % of theory, <br><br> C25H27N9O3 (501.6) <br><br> Rf value: 0.28 (silica gel; dichloromethane/methanol = 4:1 <br><br> 30 + 1% glacial acetic acid) <br><br> EKA mass spectrum: (M+H)+ = 502 <br><br> (M+H+Na)+ = 262.5 <br><br> 35 <br><br> AS AMENDED <br><br> Example 187 <br><br> - 156 - <br><br> l-Methyl-2-[N-(2-amidino-pyrazin-5-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-5 hydroxycarbonylethyl)-amide <br><br> 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-(2-10 ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. <br><br> Yield: 11 % of theory, <br><br> c23h23n9°3 (473.5) <br><br> Rf value: 0.55 (Reversed Phase silica gel RP-8; 5% saline 15 solution/methanol = 6:4) <br><br> EKA mass spectrum: (M+H)+ = 474 <br><br> (M+H+Na)+ = 496.6 <br><br> Example 188 <br><br> 20 <br><br> l-Methyl-2-[2-[4-(N-n-hexyloxycarbonylamidino)phenyl]-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(lH-tetrazol-5-yl)-ethyl]-amide <br><br> 25 Prepared analogously to Example 90 from l-methyl-2-[2-(4-amidinophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- [2- (lH-tetrazol-5-yl) -ethyl] -amide and n-hexyl chloroformate. <br><br> 30 Example 18 9 <br><br> l-Methyl-2-[N-(2-methoxy-4-n-pentoxycarbonylamidino-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl)-amide <br><br> 35 ■ <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl- <br><br> AS AMENDED " i5'" <br><br> carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-pentyl chloroformate. <br><br> Yield: 53 % of theory, <br><br> C35H42N6°6 (642.7) <br><br> 5 Rf value: 0.54 (silica gel; dichloromethane/ethanol =9:1 ) <br><br> EKA mass spectrum: (M+H)+ = 643 <br><br> (M+H+Na)++ = 333.4 <br><br> Example 190 <br><br> 10 <br><br> l-Methyl-2-[N-(4-n-heptyloxycarbonylamidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl)-amide <br><br> 15 Prepared analogously to Example 90 from l-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. <br><br> Yield: 68 % of theory, <br><br> 20 C37H4gNgOg (670.8) <br><br> Rf value: 0.56 (silica gel; dichloromethane/ethanol =9:1 ) <br><br> EKA mass spectrum: (M+H)+ = 671 <br><br> (M+H+Na)++ = 347.4 <br><br> 25 Example 191 <br><br> l-Methyl-2-[N-(4-ethoxycarbonylamidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> 30 <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4- <br><br> amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl- <br><br> carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)- <br><br> amide-hydrochloride and ethyl chloroformate. <br><br> 35 Yield: 43 % of theory, <br><br> c31h35n7°6 (601.7) <br><br> AS AMENDED " 158 " <br><br> Rf value: 0.44 (silica gel; dichloromethane/ethanol = 9:1) EKA mass spectrum: (M+H)+ = 602 <br><br> (M+H+Na)++ = 312.8 <br><br> 5 Example 192 <br><br> l-Methyl-2-[N-(2-methoxy-4-n-pentoxycarbonylamidino-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> 10 <br><br> Prepared analogously to Example 90 from l-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. <br><br> 15 Yield: 72 % of theory, <br><br> C34H41N7O6 (643.7) <br><br> Rf value: 0.49 (silica gel; dichloromethane/ethanol = 9:1) EKA mass spectrum: (M+H)+ = 644 <br><br> (M+H+Na)++ = 333.9 <br><br> 20 <br><br> Example 193 <br><br> l-Methyl-2-[N-(2-methoxy-4-n-heptyloxycarbonylamidino-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-25 (2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide <br><br> Prepared analogously to Example 90 from l-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)- <br><br> 30 amide-hydrochloride and n-heptyl chloroformate. <br><br> Yield: 55 % of theory, <br><br> C36H45N7°6 (671.8) <br><br> Rf value: 0.54 (silica gel; dichloromethane/ethanol = 9:1) <br><br> EKA mass spectrum: (M+H)+ = 672 <br><br> 35 (M+H+Na)++ = 347.9 <br><br> AS AMENDED <br><br> Example 194 <br><br> - 159 - <br><br> Dry ampoule containing 75 mg of active substance per 10 ml <br><br> 5 <br><br> Composition: <br><br> Preparation: <br><br> Active substance and mannitol are dissolved in water. After packaging the solution is freeze-dried. To produce 15 the solution ready for use, the product is dissolved in water for injections. <br><br> Example 195 <br><br> 20 Dry ampoule containing 35 mg of active substance per 2 ml <br><br> Composition: <br><br> 25 Active substance 35.0 mg <br><br> Mannitol 100.0 mg water for injections ad 2.0 ml <br><br> Preparation: <br><br> 30 Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried. <br><br> To produce the solution ready for use, the product is dissolved in water for injections. <br><br> Active substance Mannitol 10 water for injections <br><br> 75.0 mg 50.0 mg ad 10.0 ml <br><br> 35 <br><br> AS AMENDED <br><br> Example 196 <br><br> - 160 - <br><br> Tablet containing 50 mg of active substance <br><br> 5 <br><br> Composition: <br><br> (1) Active substance 50.0 mg <br><br> (2) Lactose 98.0 mg 10 (3) Maize starch 50.0 mg <br><br> (4) Polyvinylpyrrolidone 15.0 mg <br><br> (5) Magnesium stearate 2.0 mg <br><br> 215.0 mg <br><br> 15 Preparation: <br><br> (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 20 on one side. <br><br> Diameter of the tablets: 9 mm. <br><br> Example 197 <br><br> 25 Tablet containing 350 mg of active substance <br><br> Preparation: <br><br> 30 (1) Active substance 350.0 mg <br><br> (2) Lactose 136.0 mg <br><br> (3) Maize starch 80.0 mg <br><br> (4) Polyvinylpyrrolidone 30.0 mg <br><br> (5) Magnesium stearate 4.0 mg <br><br> 35 600.0 mg <br><br> AS AMENDED ~ 101 ~ <br><br> (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 5 dividing notch on one side. <br><br> Diameter of the tablets: 12 mm. <br><br> Example 198 <br><br> 10 Capsules containing 50 mg of active substance Composition: <br><br> (1) Active substance 50.0 mg <br><br> 15 (2) Dried maize starch 58.0 mg <br><br> (3) Powdered lactose 50.0 mg <br><br> (4) Magnesium stearate 2.0 mg <br><br> 160.0 mg <br><br> 20 Preparation: <br><br> (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing. <br><br> This powder mixture is packed into size 3 hard gelatin 25 capsules in a capsule filling machine. <br><br> Example 199 <br><br> Capsules containing 350 mg of active substance <br><br> 30 <br><br> Composition: <br><br> (1) Active substance 350.0 mg <br><br> 35 (2) Dried maize starch 46.0 mg <br><br> (3) Powdered lactose 30.0 mg <br><br> (4) Magnesium stearate 4.0 mg <br><br></p> </div>

Claims (17)

AS AMENDED ~ ^ ~ 430.0 mg Preparation: (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing. 5 This powder mixture is packed into size 0 hard gelatin capsules in a capsule filling machine. Example 200 10 Suppositories containing 100 mg of active substance 1 suppository contains: 15 Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitan monostearate 840.0 mg 2,000.0 mg AS AMENDED - 163 -Patent Claims
1. Disubstituted bicyclic heterocycles of general formula 5 Ra - A - Het - B - Ar - E , (I) wherein A denotes a carbonyl or sulphonyl group linked to the 10 benzo, pyrido or thieno moiety of the group Het, 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 -NRi- group, wherein 15 Ri denotes a hydrogen atom or a Ci-4-alkyl group, E denotes an RbNH-C(=NH)- group wherein 20 Rb denotes a hydrogen atom, a hydroxyl, Ci-g-alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-Ci-3-alkoxycarbonyl, benzoyl, p-Ci-3-alkyl-benzoyl or pyridinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned Ci-galkoxycarbonyl 25 group may additionally be substituted by a Ci-3-alkyl- sulfonyl or 2-(Ci_3-alkoxy) -ethyl group, Ar denotes a 1,4-phenylene group optionally substituted by a chlorine atom or by a methyl, ethyl 30 or methoxy group or it denotes a 2,5-thienylene group, Het denotes a 1-(Ci_3-alkyl)-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-(Ci-3-alkyl)-2,5-indolylene, 35 1- (Ci-3-alkyl) -2, 5-imidazo (4, 5-b) pyridinylene, 3-(Ci_3- alkyl)-2, 7-imidazo (1, 2-a) pyridinylene or 1-(Chalky!)-2, 5-thieno (2, 3-d) imidazolylene group and NOW AMENDED - 164 - R4 denotes an R2NR3- group wherein R2 is a Ci-4-alkyl group substituted by ej carboxy, Ci-6-alkyloxycarbonyl, benzyloxycarbonyl, Ci-3-alkylsulphonylaminocarbonyl or /LH/tetrazol-5-yl group, 10 15 20 a C2-4~alkyl group substituted b$ hydroxy, benzyloxy, carboxy-Ci-3-alkylamino, Ci_3-a]/co^ycarbonyl-Ci_3-alkylamino, N- (Ci_3-alkyly-c6rboxy-Ci-3-alkylamino or N- (Ci-3-alkyl) -Ci-3-alkoxyffiacE>onyl-Ci-3-alkylamino group, whilst in the abovementioned groups the carbon atom in the a-position tcy tjae adjacent nitrogen atom may be not substituted, R3 denotes a C3-7-cyclaaL^yl group, a propargyl group, wherein the unsaturated part may not be linked directly to the nitto^en atom of the R2NR3 group, a phenyl group opti^n^A-ly substituted by a fluorine or chlorine atom, 0/ 1/y a methyl or methoxy group, a pyrazolyl, pyriyda^olyl or pyridinyl group optionally substituted by a/methyl group or 25 R2 and R3 together with the nitrogen atom between them denote a 5/ to 7-membered cycloalkyleneimino group, optionall/fy Substituted by a carboxy or Ci-4-alk-oxycarb^n^l group, to which a phenyl ring may additionally be fused, 30 the tautome; :s, the stereoisomers and the salts thereof. 2. Disiibstituted bicyclic heterocycles of general formula I according to claim 1, wherein 35 A <#er}6tes a carbonyl or sulphonyl group linked to the b^n/o, pyrido or thieno moiety of the group Het, AS AMENDED - 164 - Received at IPONZ 13 August 2010 Ra denotes an R2NR3- group wherein R2 is a Ci-4-alkyl group substituted by a carboxy, 5 Ci-6-alkyloxycarbonyl, benzyloxycarbonyl, Ci-3-alkylsulphonylaminocarbonyl or lH-tetrazol-5-yl group, a C2-4~alkyl group substituted by a hydroxy, benzyloxy, 10 carboxy-Ci-3-alkylamino, Ci_3-alkoxycarbonyl- Ci-3-alkylamino, N- (Ci_3-alkyl) -carboxy-Ci_3-alkylamino or N- (Ci-3-alkyl) -Ci_3-alkoxycarbonyl-Ci-3-alkylamino group, whilst in the abovementioned groups the carbon atom in the a-position to the adjacent nitrogen atom 15 may be not 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 20 phenyl group optionally substituted by a fluorine or chlorine atom, or by a methyl or methoxy group, a pyrazolyl, pyridazolyl or pyridinyl group optionally substituted by a methyl group or 25 R2 and R3 together with the nitrogen atom between them denote a 5- to 7-membered cycloalkyleneimino group, optionally substituted by a carboxy or Ci_4-alk-oxycarbonyl group, to which a phenyl ring may additionally be fused, 30 the tautomers, the stereoisomers and the salts thereof.
2. Disubstituted bicyclic heterocycles of general formula I according to claim 1, wherein 35 A denotes a carbonyl or sulphonyl group linked to the benzo, pyrido or thieno moiety of the group Het, AS AMENDED " " 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 -NRi- group, wherein 5 Ri denotes a hydrogen atom or a methyl group, E denotes an RbNH-C(=NH)- group, wherein Rb denotes a hydrogen atom or a hydroxy, 10 Ci-g-alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-Ci-3-alkylbenzoyl or nicotinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned Ci-g-alkoxycarbonyl group may additionally be substituted by a C1-3-15 alkylsulphonyl or 2-(Ci-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 20 Het denotes a l-methyl-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, l-methyl-2,5-indolylene, 1-methyl-2,5-imidazo[4,5-b]pyridinylene, 3-methyl-25 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 30 R2 denotes a Ci-3-alkyl group which may be substituted by a carboxy, Ci_6-alkyloxycarbonyl, benzyloxycarbonyl, methylsulphonylaminocarbonyl or lH-tetrazol-5-yl group, 35 a C2-3_alkyl group substituted by a hydroxy, benzyloxy, carboxy-Ci-3-alkylamino, Ci-3-alkoxycarbonyl-Ci-3-alkylamino, N- (Ci-3-alkyl) -carboxy-Ci_3-alkylamino AS AMENDED " ibb " or N- (Ci_3-alkyl) -Ci-3-alkoxycarbonyl-Ci_3-alkylamino group, whilst in the abovementioned groups the carbon atom in the a-position to the adjacent nitrogen atom may not be substituted, and 5 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 10 methyl or methoxy group or it denotes a pyridinyl group, the tautomers, the stereoisomers and the salts thereof. 15
3. Disubstituted bicyclic heterocycles of general formula I according to claim 1, wherein A denotes a carbonyl group linked to the benzo or thieno moiety of the group Het, 20 B denotes an ethylene group wherein the methylene group attached to the group Ar may be replaced by an -NRi group, whilst 25 Ri denotes a hydrogen atom or a methyl group, E denotes an RbNH-C(=NH)- group wherein Rb is a hydrogen atom, a hydroxy, Ci-g-alkoxycarbonyl, 30 cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p- Ci-3-alkyl-benzoyl or nicotinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned Ci-g-alkoxycarbonyl group may additionally be substituted by a methylsulfonyl or 2-ethoxy-ethyl 35 group, Ar denotes a 1,4-phenylene group optionally substituted by AS AMENDED " 1<w " a methoxy group or it denotes a 2,5-thienylene group, • Het denotes a l-methyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, l-methyl-2,5-indolylene or 1-methyl-5 2,5-thieno[2,3-d]imidazolylene group and Ra denotes an R2NR3- group wherein R2 denotes a Ci_3-alkyl group which may be substituted by a carboxy, Ci-6-alkyl'oxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or lH-tetrazol-5-yl group, a C2-3-alkyl group substituted by a hydroxy, benzyloxy, carboxy-Ci_3-alkylamino, Ci_3-alkoxycarbonyl- Ci-3-alkylamino, N- (Ci_3-alkyl) -carboxy-Ci_3-alkylamino or N-(Ci-3-alkyl) -Ci-3-alkoxycarbonyl-Ci_3-alkylamino group, whilst in the abovementioned groups the carbon atom in the a-position to the adjacent nitrogen atom may not be substituted, and R3 denotes a phenyl group optionally substituted by a fluorine atom, or it denotes a 2-pyridinyl group, the tautomers, stereoisomers and the salts thereof. 25
4. The following compounds of general formula I: (a) 2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazole-5 carboxylic acid-N-phenyl-N-(2-carboxyethyl)-amide, 30 (b) 2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, 10 15 20 35 (c) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, AS AMENDED - 168 - (d) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl)-amide, 5 (e) l-Methyl-2-[N-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide, (f) l-Methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]- 10 benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (g) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- 15 hydroxycarbonylethyl)-amide, (h) l-Methyl-2-[2-(4-amidinophenyl)ethyl}-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, 20 (i) l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, 25 (j) l-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(lH-tetrazol-5-yl)ethyl]-amide, (k) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-30 benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5—yl)ethyl]-amide, (1) l-Methyl-2-{N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-35 hydroxycarbonylethyl)-amide, (m) l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]- AS AMENDED " 163 " benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (n) l-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-5 benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl-amide, (o) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-10 hydroxycarbonylethyl-N-methyl)-2-aminoethyl]-amide, (p) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide, 15 (q) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide, 20 (r) l-Methyl-2-[N-(4-amidino-2- xylmethoxy-phenyl)- aminomethyl]-benzimidazol-5-yl-carboic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (s) l-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-25 aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, (t) l-Methyl-2-[N-(4-amidinophenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-30 amide and (u) l-Methyl-2-[N-(4-amidinophenyl)aminomethyl]-thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, 35 the tautomers, prodrugs, double prodrugs, stereoisomers and the salts thereof. AS AMENDED - 170 -
5. l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, the prodrugs, double prodrugs 5 and the salts thereof.
6. l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N- (2-hydroxycarbonylethyl)-amide, the prodrugs, double 10 prodrugs and the salts thereof.
7. l-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide, the prodrugs, 15 double prodrugs and the salts thereof.
8. l-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and the salts 20 thereof.
9. A compound of claim 4, which is l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide. 25
10. Physiologically acceptable salts of the compounds according to any one of claims 1 to 9.
11. Pharmaceutical compositions containing a compound 30 according to any one of claims 1 to 9, or a salt according to claim 10, optionally together with one or more inert carriers and/or diluents.
12. Use of a compound according to any one of claims 1 to 35 9, or a salt according to claim 10, for preparing a pharmaceutical composition having the effect of prolonging the thrombin time, a thrombin-inhibiting effect and an AS AMENDED " 1,1 " inhibiting effect on related serine protease.
13. Process for preparing a pharmaceutical composition according to claim 11, wherein a compound according to any 5 one of claims 1 to 9, or a salt according to claim 10, is incorporated in one or more inert carriers and/or diluents by a non—chemical method.
14. Process for preparing compounds according to any one 10 of claims 1 to 10, wherein a. in order to prepare a compound of general formula I, wherein E denotes an RbNH-C(=NH)- group, wherein Rb is a hydrogen atom or a hydroxy or Ci-3-alkyl group, a compound 15 of general formula Ra - A - Het - B - Ar - C(=NH) - Zx , (II) optionally formed in the reaction mixture, 20 wherein A, B, Ar, Het and Ra are defined as in claims 1 to 9 and Zi denotes an alkoxy, aralkoxy, alkylthio or aralkylthio 25 group, is reacted with an amine of general formula H2N - Rb' , (III) wherein 30 Rb' denotes a hydrogen atom, a hydroxy or Ci-3-alkyl group, or b. in order to prepare a compound of general formula I, wherein the Ra-A- group and E are defined as in claims 1 to 35 9, with the proviso that the Ra-A- group contains a carboxy group and E is defined as in claims 1 to 9 or the Ra-A-group is defined as in claims 1 to 9 and E denotes an NH2- AS AMENDED " 1,z " C(=NH)- group, or the Ra-A- group contains a carboxy group and E denotes an NH2-C(=NH)- group, a compound of general formula 5 Ra'-A - Het - B - Ar - E' , (IV) wherein A, B, Ar and Het are defined as in claims 1 to 9 and 10 the Ra'-A- group and E' have the meanings given for the Ra-A- group and E in claims 1 to 9, with the proviso that the Ra'-A- group contains a group which can be converted into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and E is defined as in 15 claims 1 to 9 or 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 and the Ra'-A-group has the meanings given for the Ra-A- group in claims 1 to 9, or the Ra'-A- group contains a group which may be 20 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, 25 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 defined as in claims 1 to 9, with the proviso that the Ra-A- group contains a carboxy group and E is defined as in 30 claims 1 to 9 or the Ra-A- group has the meanings given in claims 1 to 9 and E denotes an NH2-C(=NH)- group or the Ra-A- group contains a carboxy group and E denotes an NH2-C(=NH)- group, or 35 c. in order to prepare a compound of general formula I wherein the Ra-A- group contains one of the ester groups mentioned in the definition of the Ra-A- group in claims 1 AS AMENDED " 1,J " to 9, a compound of general formula Ra" - A - Het - B - Ar - E , (V) 5 wherein B, E, Ar and Het are defined as in claims 1 to 9 and Ra"-A-group has the meanings given for the Ra-A- group in claims 1 to 9, with the proviso that the Ra"-A- group contains a carboxyl group or a group which may be converted by means 10 of an alcohol into a corresponding ester group, is reacted with an alcohol of general formula HO - R7 , (VI) wherein 15 R7 denotes a Ci_6-alkyl or benzyl group or with the formamide acetals thereof or with a compound of general formula Z2 - R7, (VII) 20 wherein R7 denotes a Ci_6-alkyl or benzyl group and Z2 denotes a leaving group, or 25 d. in order to prepare a compound of general formula I wherein Rb denotes a Ci_9-alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-Ci-3-alkoxycarbonyl, benzoyl, p-Ci-3-alkyl-benzoyl or pyridinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C1-9-30 alkoxycarbonyl group may additionally be substituted by a Ci-3-alkylsulphonyl or 2-(Ci-3-alkoxy)-ethyl group, a compound of general formula Ra - A - Het - B - Ar -C(=NH)-NH2 , (VIII) 35 wherein Ra, A, Het, B and Ar are defined when as in claims 1 to 9, is reacted with a compound of general formula AS AMENDED - 174 - Z2 ~ Rs (IX) wherein 5 Re denotes a Ci-9-alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-Ci-3-alkoxycarbonyl, benzoyl, p-Ci_3-alkyl-benzoyl or pyridinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned Ci-g-alkoxycarbonyl group may additionally be substituted by a Ci-3-alkylsulphonyl or 2-10 (Ci-3-alkoxy)-ethyl group and Z2 denotes a nucleofugic leaving group, or e. in order to prepare a benzimidazolyl or benzothiazolyl compound of general formula I, wherein B denotes an 15 ethylene group, a compound of general formula 20 Ra and A are defined as in claims 1 to 9 and Y denotes a sulphur atom, or a nitrogen atom substituted by a Ci_3 alkyl or cyclopropyl group, is reacted with a compound of general formula NH2 (XV) Ra-A wherein 25 HO-CO - CH2CH2 - Ar - E (XVI) wherein Ar and E are defined as in claims 1 to 9, or with the reactive derivatives thereof and 30 f. in order to prepare a compound of general formula I wherein R2 denotes a Ci_4-alkyl group substituted by an alkylsulphonylaminocarbonyl group: 35 a compound of general formula AS AMENDED - 175 - R2' ^ N - A - Het - B - Ar - E , (IXX) R3 wherein R3, A, B, E, and Het are defined as in claims 1 to 9 and R2' denotes a Ci-4-alkyl group substituted by a carboxy 10 group, or the reactive derivatives thereof, is reacted with a salt of a compound of general formula Ci-3-Alkyl-S02-NH2 (XX) , 15 and, if necessary, a protecting group used during the reactions in order to protect reactive groups is cleaved and/or subsequently, if desired, a compound of general formula I 20 thus obtained is resolved into the stereoisomers thereof and/or a compound of general formula I thus obtained is converted into the salts thereof, more particularly for 25 pharmaceutical use into the physiologically acceptable salts thereof with an inorganic or organic acid or base.
15. Disubstituted bicylic heterocycles of general formula I substantially as herein described with reference to any 30 one of the Examples.
16. Disubstituted bicylic heterocycles according to any one of claims 1-9, substantially as herein described. 35
17. Physiologically acceptable salts according to claim 10 substantially as herein described.
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