SK285432B6 - Distributed bicyclic heterocycles, method of their preparation, pharmaceuticals containing them and their use - Google Patents

Distributed bicyclic heterocycles, method of their preparation, pharmaceuticals containing them and their use Download PDF

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SK285432B6
SK285432B6 SK1121-99A SK112199A SK285432B6 SK 285432 B6 SK285432 B6 SK 285432B6 SK 112199 A SK112199 A SK 112199A SK 285432 B6 SK285432 B6 SK 285432B6
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methyl
amide
carboxylic acid
phenyl
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SK112199A3 (en
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Norbert Hauel
Uwe Ries
Henning Priepke
Wolfgang Wienen
Jean Marie Stassen
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Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Priority claimed from DE19706229A external-priority patent/DE19706229A1/en
Priority claimed from DE1997151939 external-priority patent/DE19751939A1/en
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Abstract

Distributed bicyclic heterocycles of the general formula (I): Ra-A-Het-B-Ar-E. The invention also relates to their tautomers, their stereoisomers and their salts, which have valuable properties, as well pharmaceuticals containing them, a method of their preparation and their use.

Description

Oblasť technikyTechnical field

Predložený vynález sa týka nových disubstituovaných heterocyklických zlúčenín, ktoré majú všeobecný vzorec (I):The present invention relates to novel disubstituted heterocyclic compounds having the general formula (I):

Ra-A-Het-B-Ar-E (I), ich tautomérov, stereoizomérov, ich zmesi a ich solí, najmä ich fyziologicky prijateľných solí s anorganickými alebo organickými kyselinami alebo zásadami, ktoré majú cenné vlastnosti.R and -A-Het-B-Ar-E (I), their tautomers, stereoisomers, mixtures thereof and salts thereof, in particular their physiologically acceptable salts with inorganic or organic acids or bases having valuable properties.

Zlúčeniny, ktoré majú všeobecný vzorec (I), v ktorom E znamená skupinu kyano-, sú cennými medziproduktmi na výrobu uvedených zlúčenín, ktoré majú všeobecný vzorec (I); zlúčeniny, ktoré majú všeobecný vzorec (I), v ktorom E znamená skupinu RbNH-C(=NH)-, ako aj ich tautoméry a ich stereoizoméry, majú cenné farmakologické vlastnosti, najmä inhibičný účinok na trombín a predlžujú trombínový čas.Compounds having the general formula (I) in which E represents a cyano group are valuable intermediates for the preparation of said compounds having the general formula (I); the compounds having the general formula (I) in which E represents the group R b NH-C (= NH) -, as well as their tautomers and their stereoisomers, have valuable pharmacological properties, in particular thrombin inhibitory activity and prolong thrombin time.

Podstata vynálezuSUMMARY OF THE INVENTION

Podstatou tohto vynálezu sú teda zlúčeniny s uvedeným všeobecným vzorcom (I),Accordingly, the present invention provides compounds of formula (I):

Ra-A-Het-B-Ar-E (I), ako aj spôsobu ich výroby, ďalej farmaceutických prostriedkov, ktoré obsahujú uvedené farmakologicky účinné zlúčeniny a ich použitie.R and -A-Het-B-Ar-E (I) as well as a process for their preparation, pharmaceutical compositions containing said pharmacologically active compounds and their use.

V uvedenom všeobecnom vzorciIn the above general formula

A znamená karbonylovú skupinu alebo sulfonylovú skupinu, viazanú na benzo-, pyrido- alebo tieňovú časť skupiny Het,A represents a carbonyl group or a sulfonyl group bonded to the benzo, pyrido- or shadow part of the Het group,

B znamená etylénovú skupinu, v ktorej jedna metylénová skupina, viazaná na zvyšok Ar môže byť nahradená atómom kyslíka alebo síry, alebo skupinou -NR1-, pričom R1 znamená vodíkový atóm, alebo Cb4- alkylovú skupinu,B represents an ethylene group in which one methylene group bonded to the radical Ar may be replaced by an oxygen or sulfur atom, or a group -NR 1 -, wherein R 1 represents a hydrogen atom, or a C 4 - 4 alkyl group,

E znamená skupinu RbNH-C(=NH)-, v ktorejE is R b NH-C (= NH) - in which

Rb znamená vodíkový atóm, hydroxylovú skupinu, C1.9-alkoxykarbonylovú skupinu, cylohexyloxykarbonylovú skupinu, fenyl-Ci.j-alkoxykarbonylovú skupinu, benzoylovú skupinu,/>-Ci.3-alkylbenzoylovú alebo pyridinoylovú skupinu, pričom etoxyčasť v polohe 2 uvedenej C|_9-alkoxykarbonylovej skupiny môže byť navyše substituovaná Cjj-alkyl-sulfonylovou alebo 2-(C|.3-alkoxy)-etylovou skupinou,R b represents a hydrogen atom, a hydroxyl group, C 1 . 9- alkoxycarbonyl, cylohexyloxycarbonyl, phenyl-C 1-6 -alkoxycarbonyl, benzoyl, n-C 1-6 -alkyloxycarbonyl, benzoyl, C 1-6 -alkyloxycarbonyl; A 3- alkylbenzoyl or pyridinoyl group, wherein the ethoxy moiety at the 2-position of said C 1-9 -alkoxycarbonyl group may additionally be substituted by a C 1-8 -alkylsulfonyl or 2- (C 1-3 -alkoxy) -ethyl group,

Ar znamená 1,4-fenylénovú skupinu, voliteľne substituovanú atómom chlóru alebo metylovou skupinou, etylovou skupinou alebo metoxylovou skupinou, alebo znamená 2,5tienylénovú skupinu,Ar represents a 1,4-phenylene group, optionally substituted by a chlorine atom or a methyl group, an ethyl group or a methoxy group, or represents a 2,5-thienylene group,

Het znamená l-(Ci_3-alkyl)-2,5-benzimidazolylénovú skupinu, l-cyklopropyl-2,5-benzimidazoIylénovú skupinu, 2,5-benztiazolylénovú skupinu, l-(Ci.3-alkyl)-2,5-indolylénovú skupinu, 1 -(C].3-alkyl)-2, 5-imidazo[4,5-A]pyridinylénovú skupinu, 3-(C1.3-alkyl)-2,7-imidazo[l ,2-a]pyridinylénovú skupinu alebo l-CC^-alkylj-ž.á-tienop^-dJimidazolylénovú skupinu aHet represents 1- (C 1-3 -alkyl) -2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolyllene, 2,5-benzothiazolylene, 1- (C 1-3 -alkyl) -2,5- indolylénovú, 1 - (C]. 3-alkyl) -2, 5-imidazo [4,5-A] pyridinylénovú, 3- (C1 .3 alkyl) -2,7-imidazo [l, 2- a] pyridinylene or 1-C 1-6 -alkyl-1-thienop-4-imidazolylene and

Ra znamená skupinu R2NR3-, v ktorejR a represents a group R 2 NR 3 - in which

R2 znamená C1.4-alkylovú skupinu, ktorá môže byť substituovaná karboxylovou skupinou, C1.6-alkyloxykarbonylovou skupinou, benzyloxykarbonylovou skupinou, Cu-alkylsulfonylaminokarbonylovou skupinou alebo \H-tetrazol-5-ylovou skupinou,R 2 is C first A 4- alkyl group, which may be substituted by a carboxyl group, C 1 . 6- alkyloxycarbonyl, benzyloxycarbonyl, C 1-6 alkylsulfonylaminocarbonyl or 1 H -tetrazol-5-yl,

C2.4-alkylovú skupinu, substituovanú skupinou hydroxy-, benzyloxy-, karboxy-C|.3-alkylamino-, C|.3-alkoxykarbonyl-Ct.j-alkylamino-, N-(Cl.3-alkyl)-karboxy-Cw-alkylamino- alebo N-(Cb3-alkyl)-C|.3-alkoxykarbonyl-Cj.j-alkylaminoskupinou. pričom uvedené skupiny nemôžu byť substituované na α-uhlíkový atóm v susedstve atómu dusíka,C 2 . A 4- alkyl group substituted with a hydroxy-, benzyloxy-, carboxy-C1-6 group; 3- alkylamino-; -Alkoxycarbonyl-3-Ct.j alkylamino, N- (Art. 3 alkyl) carboxy-C N -alkylamino or N (C b3 alkyl) C |. 3- alkoxycarbonyl-C 1-6 -alkylamino. wherein said groups cannot be substituted for an α-carbon atom adjacent to a nitrogen atom,

R3 znamená C, 7-cykloalkyíovú skupinu, propargylovú skupinu, pričom nenasýtená časť nemôže byť viazaná priamo na dusíkový atóm skupiny R2NR3-, fenylovú skupinu, voliteľne substituovanú atómom fluóru alebo chlóru, metylovou alebo metoxylovou skupinou, alebo znamená voliteľne metylovou skupinou substituovanú pyrazolylovú skupinu, pyridazinylovú skupinu alebo pyridinylovú skupinu, aleboR 3 represents C 7 -cycloalkyl, propargyl, the unsaturated moiety cannot be bonded directly to the nitrogen atom of R 2 NR 3 -, a phenyl group optionally substituted by a fluorine or chlorine atom, a methyl or methoxy group, or is optionally a methyl group substituted pyrazolyl, pyridazinyl or pyridinyl, or

R2 a R3 spolu s medzi nimi ležiacim atómom dusíka znamenajú 5- až 7-člennú cykloalkylénimínovú skupinu, voliteľne substituovanú karboxylovou skupinou alebo C]4-alkoxykarbonylovú skupinu, na ktorej môže byť navyše nakondenzovaný fenylový kruh, ich tautoméry, stereoizoméry a ich soli.R 2 and R 3 together with the intervening nitrogen atom represent a 5- to 7-membered cycloalkyleneimine group, optionally substituted with a carboxyl group or a C 1-4 -alkoxycarbonyl group on which the phenyl ring may be additionally fused, their tautomers, stereoisomers and their salts .

Výhodné zlúčeniny, ktoré majú uvedený vzorec (I) sú také, v ktorýchPreferred compounds having the above formula (I) are those in which

A znamená karbonylovú skupinu alebo sulfonylovú skupinu, viazanú na benzo-, pyrido- alebo tieňovú časť skupiny Het,A represents a carbonyl group or a sulfonyl group bonded to the benzo, pyrido- or shadow part of the Het group,

B znamená etylénovú skupinu, v ktorej metylénová skupina, viazaná na zvyšok Ar môže byť nahradená atómom kyslíka alebo síry, alebo skupinou -NR1-, pričom R1 znamená vodíkový atóm alebo metylovú skupinu, E znamená skupinu RbNH-C(=NH)-, v ktorejB represents an ethylene group in which the methylene group attached to the Ar radical can be replaced by an oxygen or sulfur atom, or -NR 1 -, wherein R 1 represents a hydrogen atom or a methyl group, E represents a group R b NH-C (= NH )-, in which

Rb znamená vodíkový atóm, hydroxylovú skupinu, C|.9-alkoxykarbonylovú skupinu, cylohexyloxykarbonylovú skupinu, benzyloxykarbonylovú skupinu, benzoylovú skupinu, p-Cl.3-alkylbenzoylovú alebo nikotinoylovú skupinu, pričom etoxy- časť v polohe 2 uvedenej Cpj-alkoxvkarbonylovej skupiny môže byť navyše substituovaná Ci_3-alkylsulfonylovou alebo 2-(C.3-aikoxy)-etylovou skupinou,R b represents a hydrogen atom, a hydroxyl group, C 1-6. 9 -alkoxycarbonyl, cylohexyloxykarbonylovú, benzyloxycarbonyl, benzoyl, pC l. A 3- alkylbenzoyl or nicotinoyl group, wherein the ethoxy moiety at the 2-position of said C 1-6 -alkoxycarbonyl group may additionally be substituted by C 1-3 -alkylsulfonyl or 2- (C 3 -alkoxy) ethyl,

Ar znamená 1,4-fcnylénovú skupinu voliteľne substituovanú atómom chlóru alebo metylovou skupinou, etylovou skupinou alebo metoxylovou skupinou, alebo znamená 2,5tienylénovú skupinu,Ar represents a 1,4-phenylene group optionally substituted by a chlorine atom or a methyl group, an ethyl group or a methoxy group, or represents a 2,5-thienylene group,

Het znamená l-metyl-2,5-benzimidazolylénovú skupinu, 1-cyklopropyl-2,5-benzimidazolylénovú skupinu, 2,5-benztiazolylénovú skupinu, l-metyl-2,5-indolylénovú skupinu, l-metyl-2,5-imidazo[4,5-b]pyridinylénovú skupinu, 3-metyl-2,7-imidazo[l,2-u]pyridinylénovú skupinu alebo 1-metyl-2,5-tieno[2,3-r/]-imidazo-lylénovú skupinu aHet means 1-methyl-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene, 1-methyl-2,5- imidazo [4,5-b] pyridinylene, 3-methyl-2,7-imidazo [1,2-u] pyridinylene or 1-methyl-2,5-thieno [2,3-d] imidazo a lylene group; and

Ra znamená skupinu R2NR3-, v ktorejR a represents a group R 2 NR 3 - in which

R2 znamená Ci_3-alkylovú skupinu, ktorá môže byť substituovaná karboxylovou skupinou, C|.6-alkyloxykarbonylovou skupinou, benzyloxykarbonylovou skupinou, metylsulfonylaminokarbonylovou skupinou, alebo l//-tetrazoi-5-ylovou skupinou,R 2 represents a C 1-3 -alkyl group which may be substituted by a carboxyl group, C 1-6 -alkyl; 6- alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl, or 1H-tetrazol-5-yl,

Ci j-alkylovú skupinu, substituovanú skupinou hydroxy-, benzyloxy-, karboxy-C^-alkylamino-, CI?-alkoxykarbonyl-C].3-alkylamino-, N-ľCj.j-alkylj-karboxy-Cj.j-alkylamino- alebo N-fCl.3-alkyl)-C1_3-alkoxykarbonyl-C1.3-alkylamino- skupinou, pričom uvedené skupiny nemôžu byť substituované na α-uhlíkový atóm v susedstve atómu dusíka,C-j alkyl, substituted by hydroxy, benzyloxy, carboxy-C ^ -alkylamino, C? -alkoxycarbonyl-C] .3-alkylamino, N-ľCj.j -alkyl is C i-j-carboxy-alkylamino or N-fC-l .3 alkyl) -C 1 _3-alkoxycarbonyl-C first A 3- alkylamino group, wherein said groups cannot be substituted for an α-carbon atom adjacent to a nitrogen atom,

R3 znamená propargylovú skupinu, pričom nenasýtená časť nemôže byť viazaná priamo na dusíkový atóm skupiny R2NR3-, fenylovú skupinu, voliteľne substituovanú atómom fluóru alebo chlóru, metylovou alebo metoxylovou, alebo znamená pyridinylovú skupinu,R 3 represents a propargyl group, the unsaturated moiety cannot be bonded directly to the nitrogen atom of the group R 2 NR 3 -, a phenyl group optionally substituted by a fluorine or chlorine atom, a methyl or methoxy group, or a pyridinyl group,

SK 285432 Bú ich tautoméry, stereoizoméry a ich soli.They are tautomers, stereoisomers and salts thereof.

Najvýhodnejšie zlúčeniny, ktoré majú uvedený všeobecný vzorec (I) sú také, v ktorýchThe most preferred compounds having the aforementioned general formula (I) are those in which

A znamená karbonylovú skupinu, viazanú na benzo- alebo tienočasť skupiny Het,A represents a carbonyl group bonded to the benzo or thieno moiety of the group Het,

B znamená etylénovú skupinu, v ktorej metylénová skupina, viazaná na zvyšok Ar, môže byť nahradená skupinou -NR1-, pričomB represents an ethylene group in which the methylene group bonded to the radical Ar can be replaced by -NR 1 -, wherein

R1 znamená vodíkový atóm alebo metylová skupinu,R 1 represents a hydrogen atom or a methyl group,

E znamená skupinu RbNH-C(=NH)-, v ktorejE is R b NH-C (= NH) - in which

Rb znamená vodíkový atóm, hydroxylovú skupinu, Ci_9-alkoxykarbonylová skupinu, cylohexyloxykarbonylovú skupinu, benzyloxykarbonylová skupinu, benzoylová skupinu, p-C:.3-alkylbenzoylová skupinu alebo nikotinoylová skupinu, pričom etoxy- časť v polohe 2 uvedenej Cý,-alkoxykarbonylovej skupiny môže byť navyše substituovaná metylsulfonylovou skupinou alebo 2-etoxy-etylovou skupinou,R b is hydrogen, hydroxy, C 9 -alkoxycarbonyl, cylohexyloxykarbonylovú, benzyloxycarbonyl, benzoyl, pC. A 3- alkylbenzoyl or nicotinoyl group, wherein the ethoxy moiety at the 2-position of said C 6 -alkoxycarbonyl group may additionally be substituted by methylsulfonyl or 2-ethoxyethyl,

Ar znamená 1,4-fenylénovú skupinu, voliteľne substituovanú metoxylovou skupinou alebo znamená 2,5-tienylénová skupinu,Ar is 1,4-phenylene, optionally substituted with methoxy, or is 2,5-thienylene,

Het znamená l-metyl-2,5-benzimidazolylénová skupinu, 2,5-benztiazolylénová skupinu, l-metyl-2,5-indolylénovú skupinu alebo l-metyl-2,5-tieno[2,3-d]-imidazolylénovú skupinu aHet means 1-methyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene or 1-methyl-2,5-thieno [2,3-d] imidazolylene and

Ra znamená skupinu R2NR3-, v ktorejR a represents a group R 2 NR 3 - in which

R2 znamená Cu-alkylovú skupinu, ktorá môže byť substituovaná karboxylovou, C].6-alkyloxykarbonylovou, benzyloxykarbonylovou, metyl-sulfonylaminokarbonylovou alebo l//-tetrazol-5-ylovou skupinou,R 2 represents a C 1-6 alkyl group which may be substituted by a carboxyl group, C 1. 6- alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl,

C2.3-alkylovú skupinu, substituovanú skupinou hydroxy-, benzyloxy-, karboxy-C1.3-alkylamino-, C].3-alkoxykarbonyl-Cij-alkylamino-, N-(C,.3-alkyl)-karboxy-Ci.3-alkylamino- alebo N-jCýj-alkylJ-Ci.j-alkoxykarbonyl-C j-alkylaminoskupinou, pričom uvedené skupiny nemôžu byť substituované na α-uhlíkový atóm v susedstve atómu dusíka,C 2 . 3- alkyl, substituted with hydroxy, benzyloxy, carboxy-C 1 . 3- alkylamino-, C 1. 3- alkoxycarbonyl-C 1-6 -alkylamino-, N- (C 1-3 -alkyl) -carboxy-C 1-6 -alkyloxycarbonyl- 3- alkylamino- or N-C 1-6 -alkyl-C 1-6 -alkoxycarbonyl-C 1-6 -alkylamino, wherein said groups cannot be substituted for the α-carbon atom adjacent to the nitrogen atom,

R3 znamená fenylovú skupinu, prípadne substituovanú atómom fluóru, alebo znamená 2-pyridinylovú skupinu, tautoméme formy uvedených zlúčenín, ich stereoizoméry a soli.R 3 represents a phenyl group optionally substituted by a fluorine atom, or represents a 2-pyridinyl group, tautomeric forms of said compounds, stereoisomers and salts thereof.

Ako príklady najvýhodnejších zlúčenín podľa tohto vynálezu možno uviesť:Examples of the most preferred compounds of the present invention include:

(a) N-fenyl-N-(2-karboxyetyl)-amid kyseliny 2-[N-(4-amidinofenyl)-aminometyl]-benztiazol-5-karboxylovej, (b) N-fenyl-N-(2-hydroxykarbonyletyl)-amid kyseliny 2-[N-(4-amidinofenyl)-N-metyl-aminometyl]-benztiazol-5-yl-karboxylovcj, (c) N-fenyl-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, (d) N-fenyl-N-(3-hydroxykarbonylpropyl)-amid kyseliny 1-metyl-2-[N-(4-amidino-fenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, (e) N-(2-pyridyl)-N-(hydroxykarbonyletyl)-amid kyseliny 1 -metyl-2-[N-(4-amidino-fenyl)-aminometyl] -benzimidazol-5-yl-karboxylovej, (f) N-(2-pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1 -metyl-2-[2-(2-amidino-tiofen-5-yl) etyl]-benzimidazol-5-yl-karboxylovej, (g) N-(2-pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1 -metyl-2-[N-(4-amidino-fenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, (h) N-(2-pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny l-metyl-2-[2-(4-amidino-fenyl)-etyl]-benzimidazol-5-yl-karboxylovej, (i) N-fenyl-N-(2-hydroxykarbonyletyl)-amid kyseliny 1(a) 2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-carboxyethyl) -amide, (b) N-phenyl-N- (2-hydroxycarbonylethyl) 2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzothiazol-5-yl-carboxylic acid-amide, (c) 1-methyl-N-phenyl-N- (2-hydroxycarbonylethyl) -amide 1-Methyl-2- [N- (N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid) -2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid 4-amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid, (e) 1-methyl-2- [N- (4-amidino) - (2-pyridyl) -N- (hydroxycarbonylethyl) -amide -phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid 1-methyl-2- [2- (2-amidino-) - (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide; thiophen-5-yl) ethyl] -benzimidazol-5-yl-carboxylic acid, 1-methyl-2- [N- (4-) - (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide; 1-Methyl-2- [2- (4-amidino) - (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide (amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid phenyl) ethyl] benzimidazole-5-yl-ka (i) N-phenyl-N- (2-hydroxycarbonylethyl) -amide 1

-metyl-2-[2-(4-amidinofenyl)-etyl]-benzimidazol-5-yl-karboxylovej, (j) N-fenyl-N-[2-(l//-tetrazol-5-yl) etyl]-amid kyseliny 1-metyl-2-[2-(4-amidinofenyl)-etyl]-benzimidazol-5-ylkarboxylovej, (k) N-fenyl-N-[2-(IH-tetrazol-5-yl) etylj-amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, (l) N-(2-pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny l-metyl-2-[N-(4-amidino-fenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboxylovej, (m) N-(3-pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny l-metyl-2-[N-(4-amidino-fenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboxylovej, (n) N-fenyl-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboxylovej, (o) N-fenyl-N-[(2-hydroxykarbonyletyl-N-metyl)-2-aminoetylj-amid kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5 -yl-karboxylovej, (p) N-(3-fluórfenyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, (q) N-(4-fluórfenyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovcj, (r) N-fenyl-N-(2-hydroxykarbonyletyl)-amid kyseliny 1 -metyl-2-[N-(4-amidino-2-metoxy-fenyl)-aminometyl] -benzimidazol-5 -yl-karboxylovej, (s) N-(2-pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny l-nietyl-2-[N-(4-amidino-2-metoxy-fenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, (t) N-fenyl-N-(2-metoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-aminometyl]-indol-5-yl-karboxylovej a (u) N-fenyl-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-aminometyl]-tieno[2,3-d]-imidazol-5-yl-karboxylovej, a ich tautoméry, stereoizoméry a ich soli.-methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazol-5-yl-carboxylic acid, (j) N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] 1-methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazol-5-ylcarboxylic acid amide, (k) N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] - 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid amide, (1) N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide 1 -methyl-2- [N- (4-amidino-phenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid, (m) N- (3-pyridyl) -N- (2-hydroxycarbonylethyl) - 1-methyl-2- [N- (4-amidino-phenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid amide, (n) N-phenyl-N- (2-hydroxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid, (o) N-phenyl-N - [(2-hydroxycarbonylethyl-N-methyl)] 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid -2-aminoethyl] -amide, (p) N- (3-fluorophenyl) -N- (2-hydroxycarbonylethyl) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole) -amide 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-yl-5-yl-carboxylic acid, (q) N- (4-fluorophenyl) -N- (2-hydroxycarbonylethyl) -amide 1-Methyl-2- [N- (4-amidino-2-methoxy-phenyl) -aminomethyl] -benzimidazole-5-yl-carboxylic acid, (r) N-phenyl-N- (2-hydroxycarbonylethyl) -amide 1-Methyl-2- [N- (4-amidino-2-methoxy-phenyl) -aminomethyl] -benzimidazole (1-methyl-2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide; 5-yl-carboxylic acid, 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -indol-5-yl-carboxylic acid, N-phenyl-N- (2-methoxycarbonylethyl) -amide, and (u) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -thieno [2,3-d] -imidazol-5-yl- N-phenyl-N- (2-hydroxycarbonylethyl) -amide- carboxylic acid, and tautomers, stereoisomers, and salts thereof.

Zlúčeniny podľa vynálezu sa môžu pripraviť všeobecne známymi spôsobmi, napríklad ďalej opísaným spôsobom.The compounds of the invention may be prepared by methods known per se, for example by the method described below.

a) Prípravu zlúčeniny, ktorá má všeobecný vzorec (I), v ktorom E znamená skupinu R^H-C^bM)-, v ktorej Rb znamená vodíkový atóm, skupinu hydroxy alebo C..3-alkýlovú skupinu možno uskutočniť:a) The preparation of a compound having the general formula (I) in which E represents a group R (HC) b) in which R b represents a hydrogen atom, a hydroxy group or a C 1-3 -alkyl group can be carried out by:

premenou zlúčeniny, prípadne priamo v reakčnej zmesi vytvorenej zlúčeniny so všeobecným vzorcomby converting the compound, optionally directly in the reaction mixture of the compound of the general formula formed

Ra-A-Het-B-Ar-C(=NH)-Z’ (II), v ktoromR and -A-Het-B-Ar-C (= NH) -Z '(II) in which

A, B, Ar, Het a Ra sú určené vpredu aA, B, Ar, Het and R and are designated in front and

Z1 znamená alkoxylovú alebo aralkoxylovú skupinu, ako je metoxylová skupina, etoxylová skupina, n-propoxylová skupina, izopropoxylová skupina alebo benzyloxyskupina, alebo Z1 znamená alkyltioskupinu alebo aralkyltioskupinu ako je skupina metyltio-, etyltio-, n-propyltio- alebo skupina benzyltio-, s amínom, ktorý má všeobecný vzorecZ 1 is alkoxy or aralkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy, or Z 1 is alkylthio or aralkylthio such as methylthio, ethylthio, n-propylthio or benzylthio , with an amine having the general formula

H2N - Rb' (III), v ktoromH 2 N - R b '(III) in which

Rb znamená atóm vodíka, hydroxylovú skupinu alebo C12-alkylovú skupinu.R b represents a hydrogen atom, a hydroxyl group or a C 12 -alkyl group.

Premena zlúčeniny so všeobecným vzorcom (II) sa účelne uskutoční v prostredí rozpúšťadla ako je metanol, etanol, n-propanol, voda, metanol/voda, tetrahydrofurán alebo dioxán pri teplotách medzi 20 a 120 °C so zlúčeninou, ktorá má všeobecný vzorec (III) alebo so zodpovedajúcou adičnou soľou s kyselinou, ako je napríklad uhličitan amónny.Conversion of the compound of formula (II) is conveniently carried out in a solvent environment such as methanol, ethanol, n-propanol, water, methanol / water, tetrahydrofuran or dioxane at temperatures between 20 and 120 ° C with the compound of formula (III) ) or a corresponding acid addition salt such as ammonium carbonate.

Zlúčenina, ktorá má všeobecný vzorec (II), sa môže získať napríklad premenou zlúčeniny, ktorá má všeobecný vzorec (I), v ktorom E znamená skupinu kyano-, s príslušným alkoholom ako je metanol, etanol, n-propanol, izopropanol alebo benzylalkohol v prítomnosti kyseliny, ako je kyselina chlorovodíková, alebo premenou zodpovedajúcich amidov s trialkyloxóniovou soľou, ako je trietyloxóniumtetrafluórborát v prostredí rozpúšťadla ako je metylénchlorid, tetrahydrofurán alebo dioxán pri teplotách medzi 0 a 50 CC, výhodne pri 20 °C, alebo premenou zodpovedajúcich nitrilov so sírovodíkom, vhodne v prostredí rozpúšťadla, ako je pyridín alebo dimetylformamid a v prítomnosti zásady, ako je trietylamín a následnou alkyláciou vytvoreného tioamidu so zodpovedajúcim alkylhalogenidom alebo aralkylhalogenidom.A compound having the general formula (II) can be obtained, for example, by converting a compound having the general formula (I) in which E represents a cyano group, with an appropriate alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in in the presence of an acid such as hydrochloric acid, or by converting the corresponding amides with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 50 ° C, preferably at 20 ° C, or , suitably in a solvent environment such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and subsequent alkylation of the formed thioamide with the corresponding alkyl halide or aralkyl halide.

b) Na prípravu zlúčeniny, ktorá má všeobecný vzorec (I), v ktorom skupina Ra-A- a E sú definované s tým, že Ra-Askupina obsahuje karboxylovú skupinu a E je definované, alebo skupina Ra-A- je určená a E je skupina NH2-C(=NH)-, alebo skupina Ra-A- obsahuje karboxylovú skupinu a E znamená skupinu NH2-C(=NH)-, sa premení zlúčenina, ktorá má všeobecný vzorec (IV)b) For a compound of general formula (I), wherein R a -A- group and E are as defined with the proviso that R and -Askupina contains a carboxy group and E is as defined, or a group R a -A- is and E is NH2-C (= NH) -, or R and -A- contains a carboxyl group and E is NH2-C (= NH) -, a compound of formula (IV) is converted

Ra-A-Het - B - Ar - C - E‘ (IV), v ktoromR and -A-Het-B-Ar-C-E '(IV) wherein

A, B, Ar a Het sú už určené vpredu a skupina Ra -A a E‘ majú rovnaký význam ako pre skupinu Ra-A- s tým, že skupina Ra‘-A- obsahuje skupinu premeniteľnú hydrolýzou, spracovaním kyselinou alebo zásadou, termolýzou alebo hydrogenáciou na karboxylovú skupinu a E je určené ako vpredu, alebo E‘ znamená skupinu premeniteľnú hydrolýzou, spracovaním s kyselinou alebo zásadou, termolýzou alebo hydrogenolýzou na skupinu NH2-C(=NH)- a skupina Ra-A- má rovnaký význam ako má skupina Ra-A-, alebo skupina Ra -A- obsahuje skupinu, ktorá je hydrolýzou, spracovaním s kyselinou alebo zásadou, termolýzou alebo hydrogenolýzou premeniteľná na karboxylovú skupinu a E‘ znamená skupinu, ktorá je hydrolýzou, pôsobením kyseliny alebo zásady, termolýzou alebo hydrogenolýzou premeniteľná na skupinu NH2-C(=NH)-, hydrolýzou, spracovaním s kyselinou alebo zásadou, termolýzou alebo hydrogenolýzou na zlúčeninu, ktorá má všeobecný vzorec (I), v ktorej skupina Ra-A- a E je určená vpredu s tým, že skupina Ra-A- obsahuje karboxylovú skupinu a E je určené vpredu, alebo skupina Ra-A- má rovnaký význam ako vpredu a E znamená skupinu NH2-C(=NH)-, alebo skupina Ra-A- obsahuje karboxylovú skupinu a E znamená skupinu NH2-C(=NH)-.A, B, Ar and Het are as defined above and R and -A and E 'have the same meaning as for R and -A- except that R and ' -A- contain a group convertible by hydrolysis, acid treatment or and E 'is as defined above, or E' is a group convertible by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis to NH2-C (= NH) -, and R and -A- have a radical, thermolysis or hydrogenation to a carboxyl group; same as R and -A-, or R and -A- contains a group which is convertible into a carboxyl group by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis, and E 'is an acid hydrolysis group or a base, by thermolysis or by hydrogenolysis convertible into the group NH2-C (= NH) -, by hydrolysis, treatment with an acid or base, by thermolysis or by hydrogenolysis to a compound of the general formula (I) in which: j the group R and -A- and E is as defined above, with the group R and -A- containing a carboxyl group and E being as defined at the front, or the group R and -A- having the same meaning as above and E being the group NH2-C (= NH) -, or the group R and -A- contains a carboxyl group and E represents the group NH2-C (= NH) -.

Ako skupinu, ktorá je premeniteľná na karboxylovú skupinu prichádzajú do úvahy napríklad ochrannou skupinou chránená karboxylová skupina, ako aj jej funkčné deriváty, napríklad jej nesubstituovaný alebo substituovaný amid, ester, tioester, trimetylsilylester, ortoester alebo iminoester, ktoré sú vhodne premeniteľné na karboxylovú skupinu hydrolýzou, jej ester s terciámymi alkoholmi, napríklad ŕerc-butylcster, ktorý sa vhodne premení na karboxylovú skupinu spracovaním s kyselinou alebo termolýzou, a jej ester s aralkanolmi, napríklad benzylester, ktorý sa vhodne premení na karboxylovú skupinu hydrogenolýzou.Suitable carboxyl-convertible groups include, for example, a carboxyl-protected protecting group as well as functional derivatives thereof, for example unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or iminoesters, which are suitably convertible to carboxyl groups by hydrolysis an ester thereof with tertiary alcohols, for example a tert-butyl ester, which is conveniently converted to a carboxyl group by treatment with acid or thermolysis, and an ester thereof with aralkanols, for example a benzyl ester, which is conveniently converted to a carboxyl group by hydrogenolysis.

Hydrolýza sa účelne uskutoční buď v prítomnosti kyseliny, ako je kyselina chlorovodíková, sírová, fosforečná, octová, trichlóroctová, trifluóroctová alebo ich zmesi, alebo v prítomnosti zásady ako je hydroxid lítny, hydroxid sodný alebo hydroxid draselný vo vhodnom rozpúšťadle ako je voda, voda/metanol, voda/etanol, voda/izopropanol, metanol, etanol, voda/tetrahydrofurán alebo voda/dioxán pri teplotách medzi -10 a 120 °C, napríklad pri teplotách medzi teplotou miestnosti a teplotou varu reakčnej zmesi.The hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric, sulfuric, phosphoric, acetic, trichloroacetic, trifluoroacetic or mixtures thereof, or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, water / ethanol, water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane at temperatures between -10 and 120 ° C, for example at temperatures between room temperature and the boiling point of the reaction mixture.

Ak skupina Ra‘-A- a/alebo E‘ obsahuje v zlúčenine, ktorá má vzorec (IV), napríklad rerc-butylovú alebo terc-butyloxykarbonylovú skupinu, možno túto skupinu odštiepiť spracovaním s kyselinou, ako je kyselina trifluóroctová, mravčia, p-toluénsulfónová, sírová, chlorovodíková, fosforečná alebo polyfosforečná kyselina vhodne v prostredí inertného rozpúšťadla, ako je metylénchlorid, chloroform, benzén, toluén, dietyléter, tetrahydrofurán alebo dioxán, výhodne pri teplotách medzi -10 a 120 °C, napríklad pri teplotách medzi 0 a 60 °C, alebo vhodne tepelným spracovaním v prostredí inertného rozpúšťadla ako je metylénchlorid, chloroform, benzén, toluén, tetrahydrofurán, alebo dioxán a výhodne v prítomnosti katalytického množstva kyseliny, ako je napríklad kyslina p-toluénsulfónová, kyselina sírová, kyselina fosforečná alebo polyfosforečná kyselina, výhodne pri teplote varu použitých rozpúšťadiel, napríklad medzi teplotami 40 a 120 °C.If the group R a '-A- and / or E' contains, for example, a tert-butyl or tert-butyloxycarbonyl group in the compound of formula (IV), this group can be cleaved by treatment with an acid such as trifluoroacetic acid, formic, p -toluenesulfonic, sulfuric, hydrochloric, phosphoric or polyphosphoric acid suitably in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane, preferably at temperatures between -10 and 120 ° C, for example at temperatures between 0 and 60 ° C, or suitably by heat treatment in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran, or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid preferably at the boiling point of the solvents used, for example between heat 40 and 120 ° C.

Ak skupina Ra-A- a/alebo E* obsahuje v zlúčenine, ktorá má vzorec (IV), napríklad skupinu benzyloxy- alebo skupinu benzyloxykarbonylovú, potom ju možno odštiepiť tiež hydrogcnolyticky v prítomnosti hydrogenačných katalyzátorov, ako je paládium/uhlie, vo vhodnom rozpúšťadle ako je metanol, etanol, etanol/voda, ľadová kyselina octová, etylester kyseliny octovej, dioxán alebo dimetylformamid, výhodne pri teplotách medzi 0 a 50 °C, napríklad pri teplote miestnosti, a pod tlakom vodíka od 0,1 do 0,5 MPa.If the group R and -A- and / or E * contains, for example, a benzyloxy- or benzyloxycarbonyl group in the compound of formula (IV), it can also be cleaved by hydrolysis in the presence of hydrogenation catalysts such as palladium / carbon in a suitable a solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50 ° C, for example at room temperature, and under a hydrogen pressure of from 0.1 to 0.5 bar.

c) Prípravu zlúčeniny, ktorá má všeobecný vzorec (I) a ktorá už v definovanej skupine Ra-A- obsahuje esterové skupiny, možno uskutočniť premenou zlúčeniny, ktorá má všeobecný vzorec (V)c) The preparation of a compound having the general formula (I) and which already contains ester groups in the defined group R and -A- can be carried out by converting a compound having the general formula (V)

Ra“ - A - Het - B - Ar - E (V), v ktoromR a '- A - Het - B - Ar - E (V) in which

B, E, Ar a Het boli už určené a skupina Ra“-A- má rovnaký význam ako skupina Ra-A- s tým, že skupina Ra“-A- obsahuje karboxylovú skupinu alebo obsahuje skupinu, ktorú možno prostredníctvom alkoholu previesť na esterovú skupinu, s alkoholom, ktorý má všeobecný vzorec (VI)B, E, Ar and Het have already been determined and the group R a '-A- has the same meaning as the group R a -A- except that the group R a ' -A- contains a carboxyl group or contains a group which may be via alcohol to an ester group, with an alcohol of formula (VI)

HO - R7 (VI), v ktoromHO - R 7 (VI) in which:

R7 znamená R7, znamená Ci.6-alkylovú alebo benzylovú skupinu, alebo s jej formamidacetálmi, alebo so zlúčeninou, ktorá má všeobecný vzorec (VII)R 7 is R 7 , is C 1-6. A 6- alkyl or benzyl group, or formamidacetals thereof, or a compound having the general formula (VII)

Z2 - R7 (VII), v ktoromFrom 2 - R 7 (VII) in which

R7 bola už určená aR 7 has already been identified and

Z2 znamená vymeniteľnú skupinu ako je atóm halogénu, napríklad atóm chlóru alebo brómu.Z 2 represents a replaceable group such as a halogen atom, for example a chlorine or bromine atom.

Premena s alkoholom, ktorý má všeobecný vzorec (VI) sa účelne uskutoční v prostredí rozpúšťadla alebo v zmesi rozpúšťadiel, ako je metylénchlorid, benzén, toluén, chlórbenzén, tetrahydrofurán, benzén/tetrahydrofurán, alebo dioxán, výhodne v prostredí alkoholu, ktorý má všeobecný vzorec (VI), pripadne v prítomnosti kyseliny ako je kyselina chlorovodíková alebo v prítomnosti činidla na viazanie vody, napríklad v prítomnosti izobutylesteru kyseliny chlórmravčej, tionylchloridu, trimetylchlórsilánu, kyseliny chlorovodíkovej, kyseliny sírovej, metánsulfónovej kyseliny, p-toluénsulfónovej kyseliny, chloridu fosforitého, chloridu fosforečného, Ν,Ν'-dicyklohexylkarbodiimidu, N,N'-dicyklohcxylkarbodiimid/N-hydroxysukcínimidu, N,N '-karbonyldiimidazolu alebo Ν,Ν'-tionyldiimidazolu, trifenylfosfín/tetrachlórmetánu alebo trifenylfosfín/azodikarboxydietylesteru, prípadne v prítomnosti zásady ako je uhličitan draselný, N-etyl-diizopropylamín alebo N,N-dimetylamino-pyridín, účelne pri teplotách medzi 0 a 150 °C, výhodne pri teplotách medzi 0 a 80 °C.Conversion with an alcohol of formula (VI) is conveniently carried out in a solvent environment or in a solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, or dioxane, preferably in an alcohol environment of formula (VI) optionally in the presence of an acid such as hydrochloric acid or in the presence of a water-binding agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorous trichloride Ν, Ν'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or Ν, Ν'-thionyldiimidazole, triphenylphosphine / carbon tetrachloride or triphenylphosphine diethyl ester, or triphenylphosphine diethyl ester N-ethyl-diisopropyl preferably amine or N, N-dimethylaminopyridine, conveniently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C.

Premena so zlúčeninou, ktorá má všeobecný vzorec (VII), sa účelne vykoná v prostredí rozpúšťadla ako je metylénchlorid, tetrahydrofurán, dioxán, dimetyl-sulfoxid, dimetylformamid alebo acetón, prípadne v prítomnosti urýchľovača reakcie, ako je jodid sodný alebo jodid draselný a výhodne v prítomnosti zásady, ako je napríklad uhličitan sodný alebo uhličitan draselný, alebo v prítomnosti terciámej organickej zásady, ako je N-etyldiizopropylamín alebo N-metyl-morfolín, ktorá môže súčasne pôsobiť ako rozpúšťadlo, alebo prípadne v prítomnosti uhličitanu strieborného alebo oxidu strieborného pri teplotách medzi -30 a 100 °C, výhodne pri teplotách -10 a 80 °C.Conversion with the compound of formula (VII) is conveniently carried out in a solvent environment such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or acetone, optionally in the presence of a reaction accelerator such as sodium iodide or potassium iodide and preferably in a solvent. in the presence of a base such as sodium carbonate or potassium carbonate, or in the presence of a tertiary organic base such as N-ethyldiisopropylamine or N-methylmorpholine, which may simultaneously act as a solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 ° C, preferably at -10 and 80 ° C.

d) Príprava zlúčeniny, ktorá má všeobecný vzorec (I), v ktorom Rb znamená in vivo odštiepiteľný zvyšok sa uskutoční premenou zlúčeniny, ktorá má všeobecný vzorec (VIII)d) Preparation of a compound of formula (I) wherein R b is an in vivo cleavable residue is accomplished by conversion of a compound of formula (VIII)

Ra-A-Het - B - Ar-C(=NH)-NH2 (VIII), v ktoromR and -A-Het-B-Ar-C (= NH) -NH 2 (VIII) in which

Ra, A, Het, Ba Ar už boli určené, so zlúčeninou, ktorá má všeobecný vzorec (IX) And R, A, Het, B and Ar have been defined, with a compound of general formula (IX)

Z2-R8 (IX), v ktoromZ 2 -R 8 (IX) wherein

R8 znamená C1.9-alkoxykarbonylovú skupinu, cyklohexyloxykarbonylovú skupinu, fenyl-C^-alkoxykarbonylovú skupinu, benzoylovú skupinu, p-Ci_3-alkylbenzoylovú skupinu, alebo pyridinoylovú skupinu, pričom etoxy- časť v polohe 2 uvedenej C1_9-alkoxykarhonylovcj skupiny môže byť navyše substituovaná Cj.j-alkylsulfonylovou skupinou alebo 2-(C!.3-alkoxy)-etylovou skupinou, aR 8 is C 1 . 9 alkoxycarbonyl group, a cyclohexyloxy group, a phenyl-C ^ alkoxycarbonyl, benzoyl, p-C 3 -alkylbenzoylovú group, or pyridinoyl group, wherein the ethoxy moiety in the 2 position of said C 1 _ 9 -alkoxykarhonylovcj group is further optionally substituted C 1-6 -alkylsulfonyl or 2- (C 1-3 -alkoxy) -ethyl, and

Z2 vymeniteľnú skupinu ako je atóm halogénu, napríklad atóm chlóru, brómu alebo jódu.Z 2 is a displaceable group such as a halogen atom, for example a chlorine, bromine or iodine atom.

Premena sa výhodne uskutoční v prostredí rozpúšťadla ako je metanol, etanol, metylénchlorid, tetrahydrofurán, toluén, dioxán, dimetylsulfoxid lebo dimetylformamid, prípadne v prítomnosti anorganickej alebo terciámej organickej zásady, výhodne pri teplotách medzi 20 °C a teplotou varu použitého rozpúšťadla.The conversion is preferably carried out in a solvent environment such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base, preferably at temperatures between 20 ° C and the boiling point of the solvent used.

Premena so zlúčeninou, ktorá všeobecný vzorec (IX), v ktorej Z2 znamená vymeniteľnú skupinu, sa vykoná výhodne v prostredí rozpúšťadla ako je metylénchlorid, acetonitril, tetrahydrofurán, toluén, dimetylformamid alebo dimetylsulfoxid, prípadne v prítomnosti zásady ako je hydrid sodný, uhličitan draselný, kalium-/erc-butylát alebo N-etyldiizopropylamín pri teplotách medzi 0 a 60 °C .Conversion with a compound of formula (IX) wherein Z 2 is a displaceable group is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethylsulfoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate , potassium tert-butylate or N-ethyldiisopropylamine at temperatures between 0 and 60 ° C.

e) Na prípravu benzimidazolylovej alebo benztiazolylovej zlúčeniny, ktorá má všeobecný vzorec (I), v ktorom B znamená etylénovú skupinu, sa nechá reagovať zlúčenina, ktorá má všeobecný vzorec (XV)e) To prepare a benzimidazolyl or benzothiazolyl compound having the general formula (I) in which B is an ethylene group, a compound having the general formula (XV) is reacted.

v ktoromin which

Ra, A boli už určené a Y znamená atóm síry alebo dusíka substituovaný C].3-alkylovou skupinou alebo cyklopropylovou skupinou, so zlúčeninou, ktorá má všeobecný vzorecR a , A have already been defined and Y represents a sulfur or nitrogen atom substituted by C 1. A 3- alkyl group or a cyclopropyl group, with a compound having the general formula

HO - CO - CH2CH2 - Ar - E (XVI), v ktoromHO - CO - CH 2 CH 2 - Ar - E (XVI) in which

Ar a E boli už určené, alebo s reaktívnym derivátom uvedenej zlúčeniny (XVI).Ar and E have already been determined, or with a reactive derivative of said compound (XVI).

Táto premena sa vhodne uskutoční v prostredí rozpúšťadla alebo v zmesi rozpúšťadiel, ako je metylénchlorid, dimetylformamid, benzén, toluén, chlórbenzén, tetrahydrofurán, benzén/tetrahydrofurán alebo dioxán, prípadne v prítomnosti činidla, ktoré odníma vodu, napríklad v prítomnosti izobutylesteru kyseliny chlórmravčej, tetraetylesteru kyseliny ortouhličitej, trimetylesteru kyseliny ortooctovej, 2,2-dimetoxypropánu, tetrametoxysilánu, tionylchloridu, trimetylchlórsilánu, chloridu fosforitého, chloridu fosforečného, Ν,Ν'-dicyklohexyl-karbodiimidu, N,N'-dicyklohexylkarbodiimidu/N-hydroxysukcínimidu, N,N'-dicyklohexylkarbodiimidu/1 -hydroxybenztriazolu, 2-( 1 //-benztriazol-l-yl)-l,l,3,3-tetrametyl-urónium-tetrafluórborátu, 2-(1 H-benztriazol-1 -yl)-1,1,3,3-tetrametyluróniumtetrafluórborátu/l-hydroxy-benztriazolu, N,N'-karbonyldiimidazolu alebo trifenyl-fosfínu/-tetrachlórmetánu a pripadne s pridaním zásady, ako je pyridín, 4-dimetyl-aminopyridín, N-metyl-morfolín alebo trietylamin, vhodne pri teplotách medzi 0 a 150 °C, výhodne pri teplotách medzi 0 a 100 °C. Premena príslušného reaktívneho derivátu zlúčeniny, ktorá má všeobecný vzorec (XVI), ako je jej ester, imidazolid alebo halogenid, s amínom, ktorý má všeobecný vzorec (XV), sa vhodne uskutoční v prostredí rozpúšťadla, ako je metylénchlorid, éter alebo terahydrofurán a výhodne v prítomnosti terciámej organickej zásady, ako je trietylamín, N-etyldiizopropylamín alebo N-metyl-morfolín, ktorá súčasne môže slúžiť ako rozpúšťadlo, pri teplotách medzi 0 a 150 °C, výhodne pri teplotách medzi 50 a 100 °C.This conversion is conveniently carried out in a solvent environment or in a solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, optionally in the presence of a water scavenger, e.g. in the presence of isobutyl chloroformate, tetraethyl ester carbonic acid, orthoacetic acid trimethyl ester, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentachloride, Ν, Ν'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1,1-dicyclohexylcarbodiimide 3,3-tetramethyluronium tetrafluoroborate (1-hydroxybenztriazole, N, N'-carbonyldiimidazole or triphenylphosphine) -tetrachloromethane and optionally with the addition of a base such as pyridine, 4-dimethylamino pyridine, N-methylmorpholine or triethylamine, suitably at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C. Conversion of an appropriate reactive derivative of a compound of formula (XVI), such as an ester, imidazolide or halide thereof, with an amine of formula (XV) is conveniently carried out in a solvent environment such as methylene chloride, ether or terahydrofuran and preferably in the presence of a tertiary organic base, such as triethylamine, N-ethyldiisopropylamine or N-methylmorpholine, which may also serve as a solvent, at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C.

f) Na prípravu zlúčeniny, ktorá má všeobecný vzorec (I), v ktorom R2 znamená C].4-alkylovú skupinu, ktorá je substituovaná alkylsulfonylaminokarbonylovou skupinou, sa uskutoční premena zlúčeniny, ktorá má všeobecný vzorec (IXX) *2\ . ČN - A - Het - B - Ar - E (ixx), v ktoromf) For the preparation of a compound of formula (I) wherein R 2 is C 1 . The 4- alkyl group, which is substituted by an alkylsulfonylaminocarbonyl group, is converted to a compound having the general formula (IXX) * 2 ' . CN - A - Het - B - Ar - E (ixx) in which

R3, A, B, E, Ar a Het už boli určené aR 3 , A, B, E, Ar and Het have already been identified and

R2' znamená C1.4-alkylovú skupinu, ktorá je substituovanou karboxylovou skupinou, alebo jej reaktívnych derivátov so soľou zlúčeniny, ktorá má vzorec (XX)R 2 represents C first A 4- alkyl group which is a substituted carboxyl group, or reactive derivatives thereof, with a salt of a compound of formula (XX)

Cw-alkyl-SO2-NH2 (XX).C 1-6 -alkyl-SO 2 -NH 2 (XX).

Premena sa výhodne uskutoční s príslušným reaktívnym derivátom zlúčeniny, ktorá má všeobecný vzorec (XIX), ako je jej ester, imidazolid alebo halogenid so soľou zlúčeniny, ktorá má všeobecný vzorec (XX), výhodne s jej alkalickou soľou, ako je sodná soľ, v prostredí rozpúšťadla ako je metylénchlorid, éter, etanol, tetrahydrofurán alebo dimetylformamid pri teplotách medzi 0 a 150 “C, výhodne pri teplotách medzi 50 a 100 °C.The conversion is preferably carried out with an appropriate reactive derivative of a compound having the general formula (XIX), such as an ester, imidazolide or halide thereof with a salt of a compound having the general formula (XX), preferably its alkali salt such as the sodium salt. a solvent environment such as methylene chloride, ether, ethanol, tetrahydrofuran or dimethylformamide at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C.

V doteraz opísaných premenách sa prípadne môžu reaktívne skupiny, ako sú skupiny hydroxy-, karboxy-, amino-, alkylamino- alebo iminoskupiny počas premeny chrániť bežnými ochrannými skupinami, ktoré sa po uskutočnení premeny môžu opäť odštiepiť.In the conversions described so far, optionally, reactive groups such as hydroxy, carboxy, amino, alkylamino or imino groups can be protected during the conversion with conventional protecting groups, which can be cleaved again after the conversion.

Ako ochranná skupina hydroxylovej skupiny prichádzajú do úvahy skupiny trimetylsilylová, acetylová, benzoylová, /erc-butylová, tritylová, benzylová alebo tetrahydropyranylová skupina.Suitable hydroxyl protecting groups are trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl.

Ako ochranná skupina karboxylovej skupiny prichádzajú do úvahy skupiny trimetylsilylová, metylová, etylová, íerc-butylová, benzylová alebo tetrahydro-pyranylová skupina a na ochranu amino-, alkylamino- alebo iminoskupín prichádzajú do úvahy skupiny acetylová, trifluóracetylová, benzoylová, etoxy-karbonylová, terc-butoxykarbo-nylová, benzyloxykarbonylová, benzylová, metoxy-benzylová alebo 2,4-dimetoxybenzylová a na ochranu aminoskupiny navyše ešte skupina ftalylová.Suitable carboxyl protecting groups are trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydro-pyranyl and acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butyl or tert-butyl are suitable for protecting amino, alkylamino or imino groups. butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl and, in addition, a phthalyl group for protecting the amino group.

Prípadné následné odštiepenie použitej ochrannej skupiny sa uskutoční napríklad hydrolyticky vo vodnom rozpúšťadle, napríklad vo vode, izopropanole/-vode, tetrahydrofuráne/vode alebo dioxáne/vode v prítomnosti kyseliny ako je trifluóroctová kyselina, kyselina chlorovodíková alebo kyselina sírová, alebo v prítomnosti alkalického hydroxidu ako je hydroxid lítny, hydroxid sodný alebo hydroxid draselný, alebo éterovým štiepením, napríklad v prítomnosti jódtrimetylsilánu, pri teplotách medzi 0 a 100 °C, výhodne pri teplotách medzi 10 a 50 °C.Optional subsequent cleavage of the protecting group used is carried out, for example, hydrolytically in an aqueous solvent such as water, isopropanol / water, tetrahydrofuran / water or dioxane / water in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or is lithium hydroxide, sodium hydroxide or potassium hydroxide, or by ether cleavage, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

Odštiepenie benzylového, metoxybenzylového alebo benzyloxykarbonylového zvyšku sa ale uskutoční napríklad hydrogenolýzou, napríklad vodíkom v prítomnosti katalyzátora ako je paládium na uhlí, v prostredí rozpúšťadla ako je metanol, etanol, etylester kyseliny octovej, dimetylformamid, dimetylformamid/-acetón alebo ľadová kyselina octová, prípadne s pridaním kyseliny ako je kyselina chlorovodíková pri teplotách medzi 0 a 50 °C, výhodne ale pri teplote miestnosti, a pri tlaku vodíka 0,1 až 0,7 MPa, výhodne ale pri tlaku od 0,3 do 0,5 MPa.However, cleavage of the benzyl, methoxybenzyl or benzyloxycarbonyl radical is carried out, for example, by hydrogenolysis, for example with hydrogen in the presence of a catalyst such as palladium on carbon, in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid. by adding an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, preferably at room temperature, and at a hydrogen pressure of 0.1 to 0.7 MPa, preferably at a pressure of from 0.3 to 0.5 MPa.

Odštiepenie metoxybenzylovej skupiny sa môže uskutočniť tiež v prítomnosti oxidačného činidla, ako je dusičnan ceričitoamónny v prostredí rozpúšťadla, ako je metylénchlorid, acetonitril alebo v zmesi acetonitril/voda pri teplotách medzi 0 a 50 °C, výhodne ale pri teplote miestnosti.The cleavage of the methoxybenzyl group may also be carried out in the presence of an oxidizing agent such as cerium ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C, preferably at room temperature.

Odštiepenie 2,4-dimetoxybenzylového zvyšku sa ale výhodne uskutoční v trifluóroctovej kyseline v prítomnosti anizolu.However, the cleavage of the 2,4-dimethoxybenzyl residue is preferably carried out in trifluoroacetic acid in the presence of anisole.

Odštiepenie rerc-butylového alebo terc-butyloxykarbonylového zvyšku sa výhodne uskutoční spracovaním s kyselinou, ako je kyselina trifluóroctová alebo kyselina chlorovodíková, prípadne s použitím rozpúšťadla, ako je metylénchlorid, dioxan alebo éter.The cleavage of the tert-butyl or tert-butyloxycarbonyl residue is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.

Odštiepenie ftalylovcho zvyšku sa výhodne uskutoční v prítomnosti hydrazínu alebo primárneho amínu ako je metylamín, etylamín alebo n-butylamin v prostredí rozpúšťadla ako je metanol, etanol, izopropanol, toluén/voda alebo dioxán pri teplotách medzi 20 a 50 °C.Cleavage of the phthalyl residue is preferably carried out in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent environment such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.

Odštiepenie alyloxyalkylového zvyšku sa uskutoční spracovaním s katalytickým množstvom tetrakis-(trifenylfosfín)-paládia(O), výhodne v rozpúšťadle ako je tetrahydrofurán a výhodne v prítomnosti nadbytku zásady ako je morfolin alebo 1,3-dimedon pri teplotách medzi 0 a 100 °C, výhodne pri teplote miestnosti a v ochrannej atmosfére inertného plynu, alebo spracovaním s katalytickým množstvom tris-(trifenyldosfín)-chloridu rodného v prostredí rozpúšťadla, ako je vodný etanol a prípadne v prítomnosti zásady, ako je 1,4-diazobicyklo[2.2.2]oktán pri teplotách medzi 20 a 70 “C.Cleavage of the allyloxyalkyl moiety is accomplished by treatment with a catalytic amount of tetrakis (triphenylphosphine) palladium (O), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100 ° C, preferably at room temperature and under an inert gas protective atmosphere, or by treatment with a catalytic amount of native tris- (triphenyldosphine) chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazobicyclo [2.2.2] octane at temperatures between 20 and 70 ° C

Zlúčeniny so všeobecnými vzorcami (II) až (XX), použité ako východiskové látky, sú sčasti známe z literatúry a možno ich pripraviť v literatúre opísanými spôsobmi, príprava iných zlúčenín sa opisuje v ďalej uvedených príkladoch uskutočnenia tohto vynálezu.The compounds of formulas (II) to (XX) used as starting materials are in part known in the literature and can be prepared in the literature by the methods described herein, the preparation of other compounds is described in the Examples below.

Napríklad zlúčeninu s všeobecným vzorcom (II) možno pripraviť premenou príslušného nitrilu, ktorý sa môže vhodne pripraviť spôsobmi f až h, s príslušným tio- alebo alkoholom v prítomnosti chlorovodíka alebo bromovodíka. Zlúčeniny so všeobecnými vzorcami (IV), (V), (VIII), (X) a (XIX), použité ako východiskové látky, možno vhodne získať spôsobom podľa tohto vynálezu.For example, a compound of formula (II) may be prepared by converting the corresponding nitrile, which may conveniently be prepared by methods f to h, with the appropriate thio- or alcohol in the presence of hydrogen chloride or hydrogen bromide. The compounds of formulas (IV), (V), (VIII), (X) and (XIX) used as starting materials may conveniently be obtained by the process of the invention.

Východisková zlúčenina, ktorá má všeobecný vzorec (XI), v ktorom U znamená halogénmetylovú skupinu, sa môže vhodne pripraviť zatvorením kruhu príslušného esteru, ktorý je v ω-polohe substituovaný vhodným halogénovým atómom a metoxyacetamidovou skupinou k zodpovedajúcej bicyklickej 2-alkoxy-metylovej zlúčenine, prípadne s nasledujúcou hydrolýzou a prípadne s nasledujúcou amidáciou pripravenej karboxylovej kyseliny s príslušným amínom, prevedením získaného alkoxymetylu na príslušnú halogénmetylovú zlúčeninu, ktorá, ak sa vyžaduje, sa potom pomocou zodpovedajúcej zlúčeniny môže previesť na vyžadovanú zlúčeninu. Zatvorenie kruhu sa pritom vykoná s vhodným derivátom karboxylovej kyseliny a získa sa tak východisková zlúčenina, ktorá má všeobecný vzorec (XI), v ktorom U znamená skupinu hydroxy-, merkapto- alebo amino-.The starting compound of formula (XI) in which U is a halomethyl group may conveniently be prepared by ring closure of the corresponding ester which is substituted in the ω-position with a suitable halogen atom and a methoxyacetamide group to the corresponding bicyclic 2-alkoxymethyl group, optionally followed by hydrolysis, and optionally followed by amidation of the prepared carboxylic acid with the appropriate amine, converting the obtained alkoxymethyl to the corresponding halomethyl compound, which, if desired, can then be converted to the desired compound using the corresponding compound. The ring closure is carried out with a suitable carboxylic acid derivative to give a starting compound having the general formula (XI) in which U represents a hydroxy-, mercapto- or amino- group.

Východisková zlúčenina, ktorá má všeobecný vzorec (XIII), sa pripraví zatvorením kruhu príslušného ωdisubsti-tuovaného esteru, následným zmydelnením získaného esteru a potom amidáciou pripravenej karboxylovej kyseliny príslušným amínom.The starting compound having the general formula (XIII) is prepared by ring closure of the corresponding disubstituted ester, followed by saponification of the obtained ester and then amidation of the prepared carboxylic acid with the appropriate amine.

Zatvorením kruhu získaný imidazopyridín, substituovaný v polohe 5 metylovou skupinou, možno okrem toho previesť cez príslušný N-oxid na zodpovedajúcu hydroxymctylovú zlúčeninu, ktorá sa oxidáciou premení na vyžadovanú karboxylovú kyselinu so všeobecným vzorcom (XIII).In addition, the ring-substituted imidazopyridine obtained in the 5-position with a methyl group can be converted via the corresponding N-oxide to the corresponding hydroxymethyl compound which is converted to the desired carboxylic acid of formula (XIII) by oxidation.

Zlúčeniny so všeobecným vzorcom (III), (VI), (VII), (IX) a (XII), použité ako východiskové látky, možno pripraviť celkom bežnými spôsobmi, napríklad redukciou aromatického esteru, ktorý je v polohe ω substituovaný prípadne substituovanou amínovou skupinou a nitroskupinou, a následným zatvorením kruhu pripravenej o-diaminozlúčcniny s vhodnou karboxylovou kyselinou.The compounds of formulas (III), (VI), (VII), (IX) and (XII) used as starting materials can be prepared by conventional methods, for example by reducing the aromatic ester which is substituted in the ω position with an optionally substituted amino group and nitro, followed by ring closure of the prepared o-diamino compound with a suitable carboxylic acid.

Pripravené zlúčeniny, ktoré majú všeobecný vzorec (I), možno ďalej deliť na ich enantioméry a/alebo diastereoméry·Prepared compounds having the general formula (I) can be further subdivided into their enantiomers and / or diastereomers.

Napríklad, pripravené zlúčeniny so všeobecným vzorcom (I), ktoré sú vo forme racemátu, možno deliť známym spôsobom (pozri Allinger N. L. a Eliel E. L. v: Topics in Stereochemistry, Vol. 6., Wiley Interscience 1971) na optické antipódy a zlúčeniny so vzorcom (I) s najmenej 2 asymetrickými uhlíkmi možno deliť známymi spôsobmi na základe ich fyzikálne chemických rozdielností, napríklad pomocou chromatografie a/alebo frakčnej kryštalizácie, na diastereoméry; ak sa získajú v racemickej forme, možno ich následne už uvedeným spôsobom deliť na cnantioméry.For example, the prepared compounds of formula (I), which are in the form of a racemate, can be resolved in a known manner (see Allinger NL and Eliel EL in: Topics in Stereochemistry, Vol. 6, Wiley Interscience 1971) into optical antipodes and compounds of formula (I) with at least 2 asymmetric carbons can be separated into diastereomers by known methods on the basis of their physical chemical differences, for example by chromatography and / or fractional crystallization; if obtained in racemic form, they can then be separated into the enantiomers as described above.

Delenie enantiomérov sa výhodne uskutoční delením na stĺpci na chirálne fázy alebo rekryštalizáciou z opticky aktívneho rozpúšťadla, alebo premenou s opticky aktívnou látkou, najmä s kyselinami a ich aktívnymi derivátmi alebo s alkoholmi, ktoré vytvárajú s racemickou zlúčeninou soli alebo deriváty ako je ester alebo amid, a delením takto získaných zmesí diastereomémych solí alebo derivátov napríklad na základe rozdielnych rozpustností; pritom sa z čistých diasteromémych solí alebo derivátov môžu pôsobením vhodného činidla uvoľniť voľné antipódy. Použiteľné sú najmä opticky aktívne kyseliny ako sú napríklad D- a L-formy kyseliny vínnej alebo dibenzoylvínnej, di-o-tolylvínnej kyseliny, jablčnej kyseliny, mandľovej kyseliny, kyseliny gáfrovej, glutamínovej, asparágovej alebo kyseliny chĺnovej. Vhodný opticky aktívny alkohol je napríklad (+) alebo (-) mentol a vhodný opticky aktívny acylový zvyšok v amidoch je napríklad (+) alebo (-) metyloxy-karbonylový zvyšok.Separation of the enantiomers is preferably effected by column chromatography on chiral phases or by recrystallization from an optically active solvent, or by conversion with an optically active substance, in particular acids and their active derivatives or with alcohols which form salts or derivatives such as ester or amide with the racemic compound, and separating the mixtures of diastereomeric salts or derivatives thus obtained, for example, based on different solubilities; free antipodes can be liberated from the pure diasteromeric salts or derivatives by treatment with a suitable reagent. Particularly useful are optically active acids such as the D- and L-forms of tartaric or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphoric acid, glutamic acid, aspartic acid or choline acid. A suitable optically active alcohol is, for example, (+) or (-) menthol and a suitable optically active acyl residue in the amides is, for example, a (+) or (-) methyloxycarbonyl radical.

Pripravené zlúčeniny, ktoré majú vzorec (I), sa môže premeniť na soli, najmä na farmaceutické účely na fyziologicky prijateľné soli uvedených zlúčenín, s anorganickými alebo organickými kyselinami. Príkladmi takých kyselín môžu byť kyselina chlorovodíková, kyselina bromovodíková, kyselina sírová, kyselina fosforečná, kyselina fumárová, kyselina jantárová, kyselina mliečna, kyselina citrónová, kyselina vínna alebo kyselina maleínová.The prepared compounds having the formula (I) can be converted into salts, in particular for pharmaceutical purposes, into physiologically acceptable salts of said compounds, with inorganic or organic acids. Examples of such acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

V prípade, že získané nové zlúčeniny, ktoré majú vzorec (1) obsahujú karboxylovú skupinu, môžu sa podľa požiadaviek previesť na soli s anorganickými alebo organickými zásadami, najmä na farmaceutické účely na fyziologicky prijateľné soli. Vhodné zásady na tento účel sú napríklad hydroxid sodný, hydroxid draselný, cyklohexylamín, dietanolamín a trietanolamín.Where the novel compounds of formula (1) obtained contain a carboxyl group, they can be converted into salts with inorganic or organic bases as required, in particular for pharmaceutical purposes into physiologically acceptable salts. Suitable bases for this purpose are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, diethanolamine and triethanolamine.

Už bolo uvedené, že nové zlúčeniny so všeobecným vzorcom (I) a ich soli majú cenné vlastnosti. Zlúčeniny so všeobecným vzorcom (I), v ktorých E znamená skupinu kyano- sú cenným medziproduktom na prípravu iných zlúčenín so vzorcom (I); zlúčeniny so všeobecným vzorcom (I), v ktorých E znamená skupinu RbNH-C(=NH)-, ako aj ich tautoméry, stereoizoméry, ich fyziologicky prijateľné soli majú cenné farmakologické vlastnosti, najmä inhibičný trombínový účinok, predlžujú trombínový čas a majú inhibičný účinok na príbuzné sérinové proteázy ako je napríklad trypsín, urokinázový faktor Vila, faktor Xa, faktor IX, faktor XI a faktor XII, pričom niektoré zlúčeniny, napríklad zlúčenina z príkladu 16 súčasne majú určitý inhibičný účinok na tiež agregáciu trombocytov.It has already been stated that the novel compounds of the general formula (I) and their salts have valuable properties. Compounds of formula (I) in which E represents a cyano group are valuable intermediates for the preparation of other compounds of formula (I); the compounds of the general formula (I) in which E represents the group R b NH-C (= NH) - as well as their tautomers, stereoisomers, their physiologically acceptable salts have valuable pharmacological properties, in particular thrombin inhibitory action, prolong thrombin time and have an inhibitory effect on related serine proteases such as trypsin, urokinase factor VIIa, factor Xa, factor IX, factor XI and factor XII, wherein some compounds, for example the compound of Example 16, simultaneously have some inhibitory effect on platelet aggregation.

Napríklad sa skúšal účinok ďalej uvedených zlúčenín A až G na trombínový čas spôsobom, ktorý sa uvádza ďalej: A = N-fenyl-N-(2-karboxyetyl)-amid kyseliny 2-[N-(4-amidinofenyl)-aminometyl]-benztiazol-5-karboxyIovej, B = N-fenyl-N-(3-hydroxykarbonylpropyl)-amid kyseliny l-metyl-2-[2-(4-amidino-fenyl)-etyl]-benzimidazol-5-yl-karboxylovej,For example, the effect of the following compounds A to G on thrombin time was tested as follows: A = 2- [N- (4-amidinophenyl) aminomethyl] - N-phenyl-N- (2-carboxyethyl) -amide benzothiazole-5-carboxylic acid, B = 1-methyl-2- [2- (4-amidino-phenyl) -ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxycarbonylpropyl) -amide,

C = N-fenyl-N-(3-hydroxykarbonylmetyl)-amid kyseliny 1-metyl-2-[(4-amidinofenyl)-oxyetyl]-benzimidazol-5-yl-karboxylovej,C = 1-methyl-2 - [(4-amidinophenyl) -oxyethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxycarbonylmethyl) -amide,

D = N-fenyl-N-(3-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej,D = 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxycarbonylethyl) -amide,

E = N-(2-pyridyl)-N-(hydroxykarbonylmetyl)-amid kyseliny 1 -metyl-2-[N-(4-amidino-fenyl)-aminometyl]-benzimidazol-5 -yl-karboxylovej,E = 1-methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -amide,

F = N-fenyl-N-[2-(///-tetrazol-5-yl) etyl]-amid kyseliny I-metyl-2-[2-(4-amidinofenyl)-etyl]-benzimidazol-5-yl-karboxylovej aF = N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -amide 1-methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazol-5-yl -carboxylic and

G = N-(2-pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1 -metyl-2-[N-(4-amidino-fenyl)-aminometyl]-benzimidazol-5-yl-karboxylo vej.G = 1-Methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide.

Podmienky skúšky; materiály:Test conditions; materials:

- plazma, z humánnej citrokrvi,- plasma, from human citrus

- skúšobný trombín (hovädzí), 30 U/ml, Behring Werke, Marburg- test thrombin (bovine), 30 U / ml, Behring Werke, Marburg

- dietylbarbiturátový acetátový tlmivý roztok, ORWH 60/61, Behring Werke, Marburg- Diethyl barbiturate acetate buffer, ORWH 60/61, Behring Werke, Marburg

- Koagulometer, typ Biomatic B10, Sarstedt.- Coagulometer, type Biomatic B10, Sarstedt.

Postup skúšky:Test procedure:

Stanovenie trombínového času sa vykonalo pomocou zariadenia Koagulometer, typ B10 firmy Sarstedt.The determination of the thrombin time was performed using a Coagulometer, type B10 from Sarstedt.

Skúšaná látka sa pridala do výrobcom predpísaných skúšobných nádob spolu s 0,1 ml humánnej citrátovej plazmy a 0,1 ml dietylbarbiturátového ( v ďalšom DBA tlmivý roztok) tlmivého roztoku. Obsah nádobky sa jednu minútu inkuboval pri 37 °C. Zrážacia reakcia sa začala prídavkom 0,3 U skúšobného trombínu v 0,1 ml DBA tlmivého roztoku. Po prídavku trombínu sa pomocou uvedeného prístroja meral čas do vyzrážania násady. Ako kontrolné -The test substance was added to the manufacturer's prescribed test containers along with 0.1 mL of human citrate plasma and 0.1 mL of diethyl barbiturate (in another DBA buffer) buffer. The contents of the vial were incubated at 37 ° C for one minute. The precipitation reaction was initiated by the addition of 0.3 U of test thrombin in 0.1 ml DBA buffer. After the addition of thrombin, the time to precipitate the stick was measured using the apparatus. As a control -

- porovnávacie vzorky slúžili násady, do ktorých sa pridalo 0,1 ml DBA tlmivého roztoku.comparative samples served batches to which 0.1 ml DBA buffer was added.

Podľa definície sa z krivky závislosti dávka - účinok vyhodnotila účinná koncentrácia príslušnej látky, pri ktorej sa dosiahol dvojnásobný trombínový čas v porovnaní s kontrolnou vzorkou.By definition, the effective concentration of the compound at which the thrombin time was doubled compared to the control was evaluated from the dose-effect curve.

V nasledujúcej tabuľke sú uvedené získané výsledky.The results obtained are shown in the following table.

Látka substance trombínový čas (ED20o v μΜ)thrombin time (ED 20 ov μΜ) A A 0,04 0.04 B B 0,06 0.06 C C 0,15 0.15 D D 0,03 0.03 E E 0,09 0.09 F F 0,03 0.03 G G 0,03 0.03

Pri použití zlúčenín A, D, E a G až do dávky 1 mg na 1 kg i.v. na krysách sa napríklad nemohli zistiť nijaké akútne toxické vedľajšie účinky. Uvedené zlúčeniny preto organizmus dobre znáša.Using compounds A, D, E and G up to a dose of 1 mg per kg i.v. for example, no acute toxic side effects could be detected in rats. The compounds are therefore well tolerated by the organism.

Nové zlúčeniny a ich fyziologicky prijateľné soli sú na základe svojich farmakologických vlastností vhodné na profylaxiu a liečbu cievnych a arteriálnych trombotických ochorení, ako je napríklad liečba hlbokých cievnych trombóz dolných končatín, potlačenie reokluzií po bypassových operáciách alebo angiosplastii (PT(C)A), ako aj okluzií pri periférnych arteriálnych ochoreniach, ako sú pľúcna embólia, rozptýlené intravaskuláme zrazeniny, na profylaxiu koronárnej trombózy, na profylaxiu mozgovej porážky a na potlačenie oklúzií umelých ciev alebo stenóz. Zlúčeniny podľa tohto vynálezu sú navyše vhodné na antitrombotickú podporu pri trombolytickej liečbe, ako je napríklad liečba s rt-PA alebo streptokinázou, na potláčanie dlhodobých restenóz po PT(C)A, na zamedzenie metastázovania a rastu koagulačne závislých nádorov a fibrínozávislých zápalových procesov.Because of their pharmacological properties, the novel compounds and their physiologically acceptable salts are suitable for the prophylaxis and treatment of vascular and arterial thrombotic diseases, such as the treatment of deep vascular thrombosis of the lower extremities, suppression of reoclusion following bypass surgery or angiosplastia (PT (C) A). occlusion in peripheral arterial diseases such as pulmonary embolism, scattered intravascular clots, for the prophylaxis of coronary thrombosis, for the prophylaxis of cerebral slaughter, and for the suppression of occlusion of artificial vessels or stenosis. In addition, the compounds of the invention are useful for antithrombotic support in thrombolytic treatment, such as treatment with rt-PA or streptokinase, for suppressing long-term restenosis after PT (C) A, for preventing metastasis and growth of coagulation-dependent tumors and fibrin-dependent inflammatory processes.

Na dosiahnutie zodpovedajúceho účinku bude účelne potrebné dávkovanie pri intravenóznom podávaní 0,1 až 30 mg.kg1, výhodne 0,3 až 10 mg.kg' a pri orálnom podávaní 0,1 až 50 mg.kg'1, výhodne 0,3 až 30 mg.kg'1, vždy 1 až 4-krát denne. Zlúčeniny podľa tohto vynálezu, ktoré majú vzorec (I), pripravené na tento účel sa môžu spracovať voliteľne v kombinácii s ďalšími účinnými látkami, spolu s jedným alebo viacerými bežnými inertnými nosičmi a/alebo riedidlami, napríklad s kukuričným škrobom, mliečnym cukrom, surovým cukrom, mikrokryštalickou celulózou, steranom horečnatým, polyvinypyrolidónom, kyselinou citrónovou, vínnou, vodou, vodou/etanolom, vodou/glycerolom, vodou/sorbitolom, vodou/polyetylénglykolom, propylénglykolom, cetylstearylalkoholom, karboxymetyl-celulózou alebo s látkami obsahujúcimi tuky a oleje ako je stužený tuk alebo vhodné tukové zmesi, na bežné formy liekových prípravkov ako sú tablety, dražé, kapsuly, prášky, suspenzie alebo čapíky.Dosages for intravenous administration of 0.1 to 30 mg.kg -1 , preferably 0.3 to 10 mg.kg -1 , and for oral administration of 0.1 to 50 mg.kg -1 , preferably 0.3 up to 30 mg.kg -1 , 1 to 4 times daily. The compounds of the invention having the formula (I) prepared for this purpose can be optionally processed in combination with other active ingredients, together with one or more conventional inert carriers and / or diluents, for example corn starch, milk sugar, raw sugar , microcrystalline cellulose, magnesium stearate, polyvinypyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose or stearate or cellulose fatty acids or suitable fat blends, for conventional forms of pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.

Vynález sa ďalej bližšie ozrejmuje pomocou príkladov.The invention is illustrated by the following examples.

Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION

Úvodné poznámky k príkladomIntroductory notes to examples

Pri stanovení hodnôt Rf sa použili platne Polygram-Kieselgel firmy E. Merck, Darmstadt, pokiaľ sa v jednotlivých príkladoch neuvádza inak.Polygram-Kieselgel plates from E. Merck, Darmstadt were used to determine Rf values unless otherwise indicated in the individual examples.

EKA-hmotnostné spektrá (ElektrosprayMassenspektren von Kationen) sú opísané napríklad v Chemie unserer Zeit 6, 308 až 316 (1991).EKA mass spectra (ElektrosprayMassenspektren von Kationen) are described, for example, in Chemie unserer Zeit 6, 308-316 (1991).

Príklad 1Example 1

N-Fenyl-N-(2-ctoxykarbonyletyl)-amid kyseliny 3-metyl-2-[2-(4-amidinofenyl)-etyl]-imidazo[4,5-b]pyridín-6-karboxylovej3-Methyl-2- [2- (4-amidinophenyl) -ethyl] -imidazo [4,5-b] pyridine-6-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

a) Metylester kyseliny 6-metylamino-5-nitro-nikotínoveja) 6-Methylamino-5-nitro-nicotinic acid methyl ester

1,6 g (7,4 mmolu) metylesteru 6-chlór-5-nitronikotínovej kyseliny (pozri Bemie et al., J. Chem. Soc, 2950 (1951)) sa miešalo 30 minút v 20 ml vodného 40%ného roztoku metylamínu pri teplote miestnosti. Reakčná zmes sa potom zriedila ľadovou vodou a vylúčená žltá zrazenina sa odfiltrovala a sušila.1.6 g (7.4 mmol) of 6-chloro-5-nitronicotinic acid methyl ester (see Bemie et al., J. Chem. Soc, 2950 (1951)) was stirred for 30 minutes in 20 ml of an aqueous 40% methylamine solution. at room temperature. The reaction mixture was then diluted with ice water and the precipitated yellow precipitate was filtered off and dried.

Výťažok bol 1,2 g (80 % teoretického výťažku).The yield was 1.2 g (80% of theory).

Rf hodnota: 0,66 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/ľadovákyselina octová = 90:5:5). Rf value: 0.66 (silica gel; ethyl acetate / ethanol / acetic ľadovákyselina = 90: 5: 5).

b) Metylester kyseliny 5-amino-6-metylamino-nikotínovejb) 5-Amino-6-methylamino-nicotinic acid methyl ester

Do roztoku 3,1 g (15 mmolov) metylesteru kyseliny 6-metylamino-5-nitro-nikotínovej v 100 ml etanolu v dichlórmetáne (3 : 1) sa pridal 1 g paládia na uhlí (10%-né paládium) a výsledná suspenzia sa hydrogenovala pod tlakom 0,5 MPa vodíka 1,5-hodiny. Katalyzátor sa potom odfiltroval a rozpúšťadlo sa odparilo vo vákuu. Získaný olejový produkt sa priamo použil na ďalšiu syntézu.To a solution of 3.1 g (15 mmol) of methyl 6-methylamino-5-nitro-nicotinate in 100 mL of ethanol in dichloromethane (3: 1) was added 1 g of palladium on carbon (10% palladium) and the resulting suspension was hydrogenated under 0.5 MPa of hydrogen for 1.5 hours. The catalyst was then filtered off and the solvent was evaporated in vacuo. The obtained oil product was directly used for further synthesis.

Výťažok bol 2,4 g (92 % teoretického výťažku).The yield was 2.4 g (92% of theory).

Rf hodnota: 0,44 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 90:10:1). Rf value: 0.44 (silica gel; ethyl acetate / ethanol / ammonia 90: 10: 1).

c) Metylester kyseliny 5-[2-(4-kyanofcnyl) etylkarbonylamino]-6-metylamino-nikotínovejc) 5- [2- (4-Cyanophenyl) ethylcarbonylamino] -6-methylamino-nicotinic acid methyl ester

Roztok 2,6 g (15 mmolov) kyseliny 3-(kyanofenyl)propiónovej v 25 ml absolútneho tetrahydrofuránu sa zmiešal s 2,4 g (15 mmolov) Ν,Ν'-karbonyl-diimidazolu a zmes sa 20 minút miešala pri teplote miestnosti, potom sa imidazolid zmiešal s roztokom 2,3 g (13 mmolov) metylesteru kyseliny 5-amino-6-metylamino-mkotínovevej v 25 ml dimetylformamidu a zmes sa zahrievala 3 hodiny na 100 °C. Po odstránení rozpúšťadla vo vákuu sa získaný produkt rozmiešal v etylesteri kyseliny octovej, organická fáza sa premyla vodou a sušila nad síranom sodným a opäť sa zbavila rozpúšťadla. Získaný zvyšok sa čistil rýchlou chromatografiou (gél kyseliny kremičitej; gradient: dichlórmetán až dichlórmetán/etanol = 19:1).A solution of 2.6 g (15 mmol) of 3- (cyanophenyl) propionic acid in 25 ml of absolute tetrahydrofuran was mixed with 2.4 g (15 mmol) of Ν, Ν'-carbonyl-diimidazole and stirred at room temperature for 20 minutes, then a solution of 2.3 g (13 mmol) of methyl 5-amino-6-methylaminotinic acid ester in 25 ml of dimethylformamide was added to the imidazolide and the mixture was heated at 100 ° C for 3 hours. After removal of the solvent in vacuo, the product obtained was triturated in ethyl acetate, the organic phase was washed with water and dried over sodium sulphate and again freed from the solvent. The obtained residue was purified by flash chromatography (silica gel; gradient: dichloromethane to dichloromethane / ethanol = 19: 1).

Výťažok bol 2,1 g béžovej tuhej látky (50 % teoretického výťažku).The yield was 2.1 g of a beige solid (50% of theory).

Rf hodnota: 0,54 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 90 : 10 : 1). Rf value: 0.54 (silica gel; ethyl acetate / ethanol / ammonia 90: 10: 1).

d) Metylester kyseliny 3-metyl-2-[2-(4-kyanofenyl) etylj-imidazo[4,5-/>]pyridín-6-karboxylovejd) 3-Methyl-2- [2- (4-cyanophenyl) ethyl] imidazo [4,5- d] pyridine-6-carboxylic acid methyl ester

Roztok 2,0 g (5,9 mmolu) metylesteru kyseliny 5-(2-(4-kyanofenyl)-etylkarbonylamino]-6-metylaminonikotínovej v 50 ml ľadovej kyseliny octovej sa zahrieval 1 hodinu na 100 °C. Po odstránení rozpúšťadla sa zvyšok rozpustil v dichlórmetáne, premyl roztokom hydrogenuhličitanu sodného, sušil síranom sodným a rozpúšťadlo sa opäť oddestilovalo.A solution of 2.0 g (5.9 mmol) of methyl 5- (2- (4-cyanophenyl) ethylcarbonylamino) -6-methylaminonicotinic acid in 50 ml of glacial acetic acid was heated at 100 ° C for 1 hour. It was dissolved in dichloromethane, washed with sodium bicarbonate solution, dried with sodium sulfate and the solvent was distilled off again.

Výťažok bol 1,7 g hnedej tuhej látky (89 % teoretického výťažku).The yield was 1.7 g of a brown solid (89% of theory).

Rr hodnota: 0,50 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 90 : 10 : 1). R f value: 0.50 (silica gel; ethyl acetate / ethanol / ammonia 90: 10: 1).

e) Kyselina 3-metyl-2-[2-(4-kyanofenyl) etyl]-imidazo[4,5-b]pyridín-6-karboxylováe) 3-Methyl-2- [2- (4-cyanophenyl) ethyl] imidazo [4,5-b] pyridine-6-carboxylic acid

Roztok 3,2 g (10 mmolov) metylesteru kyseliny 3-metyl-2-[2-(4-kyanofenyl) etyl]-imidazo[4,5-b]pyridin-6-karboxylovej v 150 ml rnetanolu sa zmiešal s roztokom 1,5 g hydroxidu lítneho v 20 ml vody a zmes sa miešala 24 hodín pri teplote miestnosti. Potom sa zmes zriedila 50 ml vody, alkohol sa oddestiloval a vodná fáza sa premyla esterom kyseliny octovej. Po okyslení zriedenou kyselinou chlorovodíkovou sa roztok viackrát extrahoval dichlórmetánom/metanolom (9:1), organická fáza sa sušila síranom sodným a rozpúšťadlo sa oddestilovalo.A solution of 3.2 g (10 mmol) of methyl 3-methyl-2- [2- (4-cyanophenyl) ethyl] imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester in 150 ml of methanol was mixed with solution 1. 1.5 g of lithium hydroxide in 20 ml of water and the mixture was stirred at room temperature for 24 hours. Then the mixture was diluted with 50 ml of water, the alcohol was distilled off and the aqueous phase was washed with acetic acid ester. After acidification with dilute hydrochloric acid, the solution was extracted several times with dichloromethane / methanol (9: 1), the organic phase was dried over sodium sulfate and the solvent was distilled off.

Výťažok bol 2,1 g béžovej tuhej látky (70 % teoretického výťažku).The yield was 2.1 g of a beige solid (70% of theory).

Rf hodnota: 0,38 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50 : 45 : 5). Rf value: 0.38 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5).

f) N-Fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny 3-metyl-2-[2-(4-kyanofenyl) etyl]-imidazo(4,5-/>]pyridín-6-karboxylovejf) 3-Methyl-2- [2- (4-cyanophenyl) ethyl] imidazo (4,5->) pyridine-6-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Roztok 2,0 g (6,5 mmolu) kyseliny 3-metyl-2-[2-(4-kyanofenyl) etyl]-imidazo(4,5-b]pyridín-6-karboxylovej v 100 ml dichlórmetánu sa zmiešal s 20 ml tionylchloridu a 2 hodiny varil pod spätným chladičom. Po oddestilovaní kvapalných zložiek sa surový produkt ešte dva razy zmiešal a odparil s dichlórmetánom. Týmto spôsobom získaný surový chlorid kyseliny (2 g) sa potom suspendoval v 100 ml tetrahydrofuránu a zmiešal s 1,2 g (6,5 mmolu) N-(2-etoxykarbonyletyljanilinu. Potom sa v priebehu 5 minút po kvapkách pridával trietylamín (0,73 g, 7,2 mmolu). Po 1-hodinovom miešaní sa rozpúšťadlo odparilo vo vákuu, zvyšok sa rozmiešal v esteri kyseliny octovej, organická fáza sa premyla vodou a sušila síranom sodným. Po oddestilovani rozpúšťadla sa rýchlou chromatografiou (gél kyseliny kremičitej; dichlórmetán až dichlórmetán/etanol = 49 : 1) izolovala vyžadovaná zlúčenina vo forme hnedkastého oleja.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 of dichloromethane was mixed with 20 ml of dichloromethane. ml of thionyl chloride and refluxed for 2 hours After distilling off the liquid components, the crude product was mixed twice more and evaporated with dichloromethane, and the crude acid chloride (2 g) was then suspended in 100 ml of tetrahydrofuran and mixed with 1.2 g. (6.5 mmol) of N- (2-ethoxycarbonylethyljaniline) was then added dropwise over 5 minutes triethylamine (0.73 g, 7.2 mmol). After stirring for 1 hour, the solvent was evaporated in vacuo, the residue was stirred in acetic acid ester, the organic phase was washed with water and dried over sodium sulfate After distilling off the solvent, the title compound was isolated as a brownish oil by flash chromatography (silica gel; dichloromethane to dichloromethane / ethanol = 49: 1).

Výťažok bol 1,9 (65 % teoretického výťažku).The yield was 1.9 (65% of theory).

Rf hodnota: 0,44 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 90:10:1). Rf value: 0.44 (silica gel; ethyl acetate / ethanol / ammonia 90: 10: 1).

g) N-Fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny 3-metyl-2-[2-(4-amidinofenyl) etyl]-imidazo[4,5-b]pyridin-6-karboxylovejg) 3-Methyl-2- [2- (4-amidinophenyl) ethyl] imidazo [4,5-b] pyridine-6-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

1,8 g (3,7 mmolu) n-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 3-metyl-2-[2-(4-kyanofcnyl) etyl]-imidazo[4,5-Z>]pyridín-6-karboxylovej sa v 100 ml etanolu, nasýteného chlorovodíkom, miešalo 16 hodín pri 0 °C a potom pri teplote miestnosti tak dlho, kým sa chromatografiou v tenkej vrstve nezistila neprítomnosť východiskovej látky. Potom sa rozpúšťadlo oddestilovalo, olej ovitý zvyšok sa rozpustil v 50 ml absolútneho etanolu a pridalo sa 3,6 g (37 mmolov) uhličitanu amónneho. Po 4 hodinách sa rozpúšťadlo oddestilovalo vo vákuu. Získaný surový produkt sa čistil rýchlou chromatografiou (gél kyseliny kremičitej; gradient: dichlórmetán/etanol 19 : 1 až 4 : 1) a čistenie sa opakovalo.1.8 g (3.7 mmol) of 3-methyl-2- [2- (4-cyanophenyl) ethyl] imidazo [4,5-a] pyridine, n-phenyl-N- (2-ethoxycarbonylethyl) amide The -6-carboxylic acid was stirred at 0 ° C for 16 hours in 100 ml of ethanol saturated with hydrogen chloride, and then at room temperature until the absence of starting material was detected by thin layer chromatography. After the solvent was distilled off, the oily residue was dissolved in 50 ml of absolute ethanol and 3.6 g (37 mmol) of ammonium carbonate was added. 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 the purification was repeated.

Výťažok bol 1,6 g béžovo sfarbenej tuhej látky (80 % teoretického výťažku).The yield was 1.6 g of a beige-colored solid (80% of theory).

Rf hodnota: 0,30 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 90 : 5 : 5). Rf value: 0.30 (silica gel; ethyl acetate / ethanol / ammonia 90: 5: 5).

Príklad 2Example 2

N-Fenyl-N-(2-hydroxykarbonyletyl)-amid kyseliny 3-metyl-2-[2-(4-amidinofenyl) etyl]-imidazo[4,5-/>]pyridín-6-karboxylovej3-Methyl-2- [2- (4-amidinophenyl) ethyl] imidazo [4,5- d] pyridine-6-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

Roztok 535 mg (1,0 mmol) N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 3-metyl-2-[2-(4-amidinofenyl) etyl]-imidazo[4,5-6]pyridín-6-karboxylovej v 10 ml etanolu sa zmiešal s 5 ml roztoku NaOH (cNa0H = 2 mol.dnť3) a 2 hodiny sa miešal pri teplote miestnosti. Potom sa zriedil 10 ml vody, alkohol sa oddestiloval, vodná fáza sa premyla 20 ml esteru kyseliny octovej a okyslila koncentrovanou kyselinou chlorovodíkovou, pričom sa vylúčili biele kryštály vyžadovanej zlúčeniny Výťažok bol 375 mg (74 % teoretického výťažku).A solution of 535 mg (1.0 mmol) of 3-methyl-2- [2- (4-amidinophenyl) ethyl] -imidazo [4,5-6] pyridine- N-phenyl-N- (2-ethoxycarbonylethyl) -amide. Of 6-carboxylic acid in 10 ml of ethanol was mixed with 5 ml of NaOH solution (c NaOH = 2 molar 3 ) and stirred at room temperature for 2 hours. It was then diluted with 10 mL of water, the alcohol was distilled off, the aqueous phase was washed with 20 mL of acetic acid ester and acidified with concentrated hydrochloric acid to give white crystals of the title compound. Yield 375 mg (74%).

Rf hodnota: 0,23 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 90:5:5). Rf value: 0.23 (silica gel; ethyl acetate / ethanol / ammonia 90: 5: 5).

C26H26N6O3 (470,54) Hmotnostné spektrum: (M+H)+ = 471.C 26 H 26 N 6 O 3 (470.54) Mass Spectrum: (M + H) + = 471.

Príklad 3Example 3

Hydrochlorid N-(2-pyridyl)-N-(2-metoxykarbonyletyl)-amidu kyseliny 3-metyl-2-[2-(4-amidinofenyl) etyl]-imidazo[4,5-6]pyridin-6-karboxylovej3-Methyl-2- [2- (4-amidinophenyl) ethyl] -imidazo [4,5-6] pyridine-6-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 1 z N-(2-pyridyl)-N-(2-metoxykarbonyletyl)-amidu kyseliny 3-metyl-2-[2-(4-kyanofenyl) etyl]-imidazo[4,5-6]-pyridin-6-karboxylovej, metanolového roztoku chlorovodíka, metanolu a uhličitanu amónneho.The compound was prepared analogously to Example 1 from N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide 3-methyl-2- [2- (4-cyanophenyl) ethyl] -imidazo [4,5- 6] -pyridine-6-carboxylic acid, methanolic solution of hydrogen chloride, methanol and ammonium carbonate.

Výťažok bol 75 % teoretického výťažku,The yield was 75% of the theoretical yield,

C26H27N7O3 (485,55)C 26 H 27 N 7 O 3 (485.55)

Rf hodnota: 0,31 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50:45:5).Rf value: 0.31 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5).

EKA-hmotnostné spektrum: (M+H)+ = 486.EKA-MS: (M + H) < + > = 486.

Príklad 4Example 4

Hydrochlorid N-fenyl-N-etoxykarbonylmetyl-amidu kyseliny 3-metyl-2-[2-(4-amidino-fenyl) etyl]-imidazo[4,5-Z>]pyridín-6-karboxylovej3-Methyl-2- [2- (4-amidino-phenyl) -ethyl] -imidazo [4,5-a] pyridine-6-carboxylic acid N-phenyl-N-ethoxycarbonylmethyl-amide hydrochloride

Zlúčenina sa pripravila obdobne ako v príklade 1 z N-fenyl-N-etoxy-karbonylmetyl-amidu kyseliny 3-metyl-2-[2-(4-kyanofenyl) etyl]-imidazo[4,5-ú]-pyridín-6-karboxylovej, etanolového roztoku chlorovodíka, etanolu a uhličitanu amónneho.The compound was prepared analogously to Example 1 from 3-methyl-2- [2- (4-cyanophenyl) ethyl] -imidazo [4,5-a] pyridine-6-N-phenyl-N-ethoxycarbonylmethyl-amide. -carboxylic, ethanolic solution of hydrogen chloride, ethanol and ammonium carbonate.

Výťažok bol 84 % teoretického výťažku,The yield was 84% of the theoretical yield,

C26H27N7O3 (484,56)C 26 H 27 N 7 O 3 (484.56)

Rf hodnota: 0,44 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50:45:5). Rf value: 0.44 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5).

EKA-hmotnostné spektrum: (M+H)+ = 485.EKA-MS: (M + H) < + > = 485.

Príklad 5Example 5

Hydrochlorid N-fenyl-N-hydroxykarbonylmetyl-amidu kyseliny 3-metyl-2-[2-(4-amidinofenyl) etyl]-imidazo[4,5-ú]pyridín-6-karboxylovej3-Methyl-2- [2- (4-amidinophenyl) ethyl] -imidazo [4,5-a] pyridine-6-carboxylic acid N-phenyl-N-hydroxycarbonylmethyl-amide hydrochloride

Zlúčenina sa pripravila obdobne ako v príklade 2 z N-fenyl-N-etoxy-karbonylmctyl-amidu-hydrochloridu kyseliny 3-metyl-2-[2-(4-amidinofenyl) etyl]-imidazo[4,5-6]pyridín-6-karboxylovej a hydroxidu sodného.The compound was prepared analogously to Example 2 from 3-methyl-2- [2- (4-amidinophenyl) ethyl] imidazo [4,5-6] pyridine-, N-phenyl-N-ethoxycarbonylmethyl amide hydrochloride. 6-carboxylic acid and sodium hydroxide.

Výťažok bol 85 % teoretického výťažku, C25H24N6O3 (456,51)The yield was 85% of the theoretical yield, C 25 H 24 N 6 O 3 (456.51)

Rf hodnota: 0,19 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50:45:5).Rf value: 0.19 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5).

EKA-hmotnostné spektrum: (M+H)* = 457.EKA-MS: (M + H) @ + = 457.

Príklad 6Example 6

Hydrochlorid 2-[2-(4-amidinofenyl) etyl]-3-metyl-6-(2-metoxykarbonyl-2,3 -dihydro-indol-1 -yl-karbonyl)-imidazo[4,5-ŕ>]pyridínu2- [2- (4-amidinophenyl) ethyl] -3-methyl-6- (2-methoxycarbonyl-2,3-dihydro-indol-1-ylcarbonyl) imidazo [4,5-a] pyridine hydrochloride

Zlúčenina sa pripravila obdobne ako v príklade 1 z 2-[2-(4-kyanofenyl) etyl]-3-metyl-6-(2-metoxykarbonyl-2,3-dihydroindol-l-yl-karbonyl)-imidazo[4,5-Z>]pyridínu, metanolového roztoku chlorovodíka, metanolu a uhličitanu amónneho.The compound was prepared analogously to Example 1 from 2- [2- (4-cyanophenyl) ethyl] -3-methyl-6- (2-methoxycarbonyl-2,3-dihydroindol-1-ylcarbonyl) -imidazo [4, 5-Z] pyridine, methanolic solution of hydrogen chloride, methanol and ammonium carbonate.

Výťažok bol 20 % teoretického výťažku,The yield was 20% of the theoretical yield,

C27H26N6O3 (482,54)C 27 H 26 N 6 O 3 (482.54)

Rf hodnota: 0,30 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50:45:5).Rf value: 0.30 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5).

EKA-hmotnostné spektrum: (M+H)+ = 483.EKA-MS: (M + H) < + > = 483.

Príklad 7Example 7

Hydrochlorid 2-[2-(4-amidinofenyl) etyl]-3-metyl-6-(2-karboxy-2,3-dihydroindol-l-yl-karbonyl)-imidazo[4,5-bjpyridínu2- [2- (4-amidinophenyl) ethyl] -3-methyl-6- (2-carboxy-2,3-dihydroindol-1-ylcarbonyl) imidazo [4,5-b] pyridine hydrochloride

Zlúčenina sa pripravila obdobne ako v príklade 2 z hydrochloridu 2-[2-(4-amidinofenyl) etyl]-3-metyl-6-(2-metoxykarbonyl-2,3-dihydroindol-1 -yl-karbonyl)-imidazo[4,5-b]pyridínu ahydoxidu sodného.The compound was prepared analogously to Example 2 from 2- [2- (4-amidinophenyl) ethyl] -3-methyl-6- (2-methoxycarbonyl-2,3-dihydroindol-1-ylcarbonyl) imidazo [4] hydrochloride. 5-b] pyridine and sodium hydride.

Výťažok bol 90 % teoretického výťažku, C26H24N6O3 (468,52)The yield was 90% of the theoretical yield, C 26 H 24 N 6 O 3 (468.52)

Rf hodnota: 0,24 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50:45:5). Rf value: 0.24 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5).

EKA-hmotnostné spektrum: (M+H)+ = 469, (M+Na) = = 491.EKA-MS: (M + H) < + > = 469, (M + Na) = 491.

Príklad 8Example 8

N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[(4-amidinofenyl) oxymetyl]-imidazo[4,5-6]pyridín-5-yl-karboxylovej1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -imidazo [4,5-6] pyridin-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

a) 2-Amino-3 -metylamino-6-metyl-pyridína) 2-Amino-3-methylamino-6-methyl-pyridine

V 300 ml esteru kyseliny octovej sa rozpustilo 8,35 g (50 mmolov) 2-metyl-5-metylamino-6-nitro-pyridínu (Heterocycles 38, 529 (1994)), pridalo sa 1,5 g Raneyovho niklu a suspenzia sa hydrogenovala 3,5-hodiny pri teplote miestnosti. Potom sa katalyzátor odfiltroval a fíltrát sa skoncentroval. Zvyšok sa potom kryštalizoval z prostredia petroléteru, čím sa získalo 5,75 g (84 % teoretického výťažku) olivovo zelených kryštálov.8.35 g (50 mmol) of 2-methyl-5-methylamino-6-nitro-pyridine (Heterocycles 38, 529 (1994)) was dissolved in 300 ml of acetic acid ester, 1.5 g of Raney nickel were added and the suspension was hydrogenated for 3.5 hours at room temperature. Then, the catalyst was filtered off and the filtrate was concentrated. The residue was then crystallized from petroleum ether to give 5.75 g (84% of theory) of olive green crystals.

C17HnN3 (137,40)C 17 H n N 3 (137.40)

Teplota topenia produktu bola 112 až 113 °C.Mp 112-113 ° C.

b) 1,5-Dimetyl-2-[(4-kyanofenyl)oxymetyl]-imidazo[4,5-bjpyridínb) 1,5-Dimethyl-2 - [(4-cyanophenyl) oxymethyl] -imidazo [4,5-b] pyridine

V 200 ml absolútneho tetrahydrofuránu sa rozpustilo 11,4 g (63 mmolov) 4-kyanoxyoctovej kyseliny a pri teplote miestnosti sa pridalo 10,2 g (63 mmolov) N,N'-karbonyldiimidazolu. Po 15 minútach pri 60 °C sa pridalo 5,70 g (41,5 mmolov) 2-amino-3-metylamino-6-metylpyridínu. Po 2 hodinách pri 60 °C sa rozpúšťadlo oddestilovalo, kryštalický zvyšok sa zmiešal s vodou, premyl vodou a vysušil. Po kryštalizácii z prostredia etanolu sa získalo 9,95 g (91 % teoretického výťažku) bielych kryštálov. C16H14N4O (278,32)11.4 g (63 mmol) of 4-cyanoxyacetic acid were dissolved in 200 ml of absolute tetrahydrofuran and 10.2 g (63 mmol) of N, N'-carbonyldiimidazole were added at room temperature. After 15 minutes at 60 ° C, 5.70 g (41.5 mmol) of 2-amino-3-methylamino-6-methylpyridine was added. After 2 hours at 60 ° C, the solvent was distilled off, the crystalline residue was mixed with water, washed with water and dried. After crystallization from ethanol, 9.95 g (91% of theory) of white crystals were obtained. C 16 H 14 N 4 O (278.32)

Hmotnostné spektrum: M+ = 278.Mass Spectrum: M + = 278.

c) 1,5-Dimetyl-2-[(4-kyanofenyl)oxymetyl]-imidazo[4,5-ó]pyridín-4-N-oxidc) 1,5-Dimethyl-2 - [(4-cyanophenyl) oxymethyl] -imidazo [4,5-a] pyridine-4-N-oxide

V 125 ml dichlórmetánu sa suspendovalo 2,62 g (10 mmolov) l,5-dimetyl-2-[(4-kyanofenyl)oxymetyl]-imidazo[4,5-ó]pyridín a pridalo sa 2,62 g (12,7 mmolov) m-chlór-peroxybenzoovej kyseliny, pričom vznikol číry roztok. Po dvoch hodinách pri teplote miestnosti sa rozpúšťadlo oddestilovalo a zvyšok sa rozmiešal v roztoku hydrogenuhličitanu sodného. Po 30 minútach sa vzniknutý biely kryštalický produkt odfiltroval s odsávaním, premy] vodou a sušil pri 40 °C.2.62 g (10 mmol) of 1,5-dimethyl-2 - [(4-cyanophenyl) oxymethyl] imidazo [4,5-a] pyridine were suspended in 125 ml of dichloromethane and 2.62 g (12, 7 mmol) of m-chloroperoxybenzoic acid, giving a clear solution. After two hours at room temperature, the solvent was distilled off and the residue was stirred in sodium bicarbonate solution. After 30 minutes, the resulting white crystalline product was filtered off with suction, washed with water and dried at 40 ° C.

Výťažok produktu bol 2,45 g (83 % teoretického výťažku), C16H14N4O2 (294,30)Yield: 2.45 g (83%) of C 16 H 14 N 4 O 2 (294.30)

Hmotnostné spektrum: M+ = 294.Mass Spectrum: M + = 294.

d) 1 -Metyl-2-[(4-kyanofenyl)oxymetyl]-5-hydroxymetyIimidazo[4,5-b]pyridínd) 1-Methyl-2 - [(4-cyanophenyl) oxymethyl] -5-hydroxymethylimidazo [4,5-b] pyridine

V 75 ml dichlórmetánu sa suspendovalo 2,40 g (8,2 mmolu) 1,5-dimetyl-2-[(4-kyanofenyl)oxymetyl]-imidazo[4,5-ú]pyridin-4-N-oxidii a pridalo sa 2,4 ml anhydridu kyseliny trifluóroctovej (16,9 mmolov), pričom vznikol číry roztok. Po 16 hodinách pri teplote miestnosti sa rozpúšťadlo oddestilovalo, získaný viskózny zvyšok sa rozpustil v 50 ml dichlórmetánu a roztok sa potom prevrstvil roztokom hydrogenuhličitanu sodného. Po 3 hodinách silného miešania sa vzniknutá zrazenina odfiltrovala pomocou odsávania, premyla vodou a sušila pri 40 °C.2.40 g (8.2 mmol) of 1,5-dimethyl-2 - [(4-cyanophenyl) oxymethyl] imidazo [4,5-a] pyridine-4-N-oxide was suspended in 75 ml of dichloromethane and added with 2.4 mL of trifluoroacetic anhydride (16.9 mmol) to give a clear solution. After 16 hours at room temperature, the solvent was distilled off, the viscous residue obtained was dissolved in 50 ml of dichloromethane, and the solution was then overlaid with sodium bicarbonate solution. After 3 hours of vigorous stirring, the resulting precipitate was filtered off with suction, washed with water and dried at 40 ° C.

Výťažok bol 1,85 bieleho práškového produktu (78 % teoretického výťažku),The yield was 1.85 of white powder (78% of theory),

Ci6Hi4N4O2 (294,30) Teplota topenia produktu bola 172 °C.C 16 H 4 N 4 O 2 (294.30) The melting point of the product was 172 ° C.

e) 1 -Metyl-2-[(4-kyanofenyl)oxymetyl]-imidazo[4,5-b]pyridín-5-karbaldehyde) 1-Methyl-2 - [(4-cyanophenyl) oxymethyl] -imidazo [4,5-b] pyridine-5-carbaldehyde

V 500 ml dichlórmetánu sa rozpustilo 3,65 g (12,5 mmolov) 1 -metyl-2-[(4-kyanofenyl)oxymetyl]-5-hydroxymetyl-imidazo[4,5-b]pyridinu a pridalo sa 15,0 g oxidu manganičitého. Po 96 hodinách pri teplote miestnosti sa zmes filtrovala cez kremelinu a rozpúšťadlo sa oddestilovalo. Získaný filtrát sa skoncentroval, kryštalická zrazenina sa rozotierala v éteri, odfiltrovala s odsávaním a sušila. Výťažok bieleho práškového produktu bol 3,05 g (84 % teoretického výťažku),3.65 g (12.5 mmol) of 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -5-hydroxymethyl-imidazo [4,5-b] pyridine was dissolved in 500 ml of dichloromethane and 15.0 was added. g of manganese dioxide. After 96 hours at room temperature, the mixture was filtered through diatomaceous earth and the solvent was distilled off. The filtrate was concentrated, the crystalline precipitate was triturated in ether, filtered off with suction and dried. The yield of white powder product was 3.05 g (84% of theory),

CI6H12N4O2 (292,30) Teplota topenia produktu bola 231 až 234 °C.C 16 H 12 N 4 O 2 (292.30) Melting point: 231-234 ° C.

f) 1 -Metyl-2-[(4-kyanofenyl)oxymetyl]-5-karboxy-imidazo[4,5-ú]pyridínf) 1-Methyl-2 - [(4-cyanophenyl) oxymethyl] -5-carboxyimidazo [4,5-a] pyridine

V 10 ml kyseliny mravčej sa rozpustilo 1,25 g (4,3 mmolu) 1 -metyl-2-[(4-kyanofenyl)oxymetyl]-imidazo[4,5-ŕ>]pyridín-5-karbaldehydu a pri 0 °C sa pridal 1 ml peroxidu vodíka (33 %-ného). Zmes sa udržiavala 12 hodín pri 4 °C, počas ktorých sa vytvorila bicia zrazenina, ktorá sa odfiltrovala s odsávaním, premyla vodou a sušila pri 40 °C. Výťažok produktu bol 0,81 g (61 % teoretického výťažku), C16H12N4O3 (308,7).1.25 g (4.3 mmol) of 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -imidazo [4,5- d] pyridine-5-carbaldehyde was dissolved in 10 ml of formic acid at 0 ° C was added 1 mL of hydrogen peroxide (33%). The mixture was kept at 4 ° C for 12 hours, during which time a precipitate formed, which was filtered off with suction, washed with water and dried at 40 ° C. Yield: 0.81 g (61%), C 16 H 12 N 4 O 3 (308.7).

g) N-(2-Pyridyl)-N-(2-metoxykarbonyletyl)-amid kyseliny 1 -metyl-2-[(4-kyanofenyl) oxymetyl]-imidazo[4,5-/>]pyridín-5-yl-karboxylovejg) 1-Methyl-2 - [(4-cyanophenyl) oxymethyl] -imidazo [4,5- d] pyridin-5-yl- N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide; carboxylic acid

V 5 ml dimetylformamidu sa suspendovalo 308 mg (1,0 mmol) 1 -metyl-2-[(4-kyanofcnyl)oxymetyl]-5-karboxyimidazo[4,5-/>]pyridínu a pridalo sa 303 mg (3,0 mmoly) N-metyl-morfolínu a 321 mg (1,0 mol) O-(benztriazol-l-yl)-N,N,N',N'-tetrametylurónium tetrafluórborátu. Po 10 minútach pri teplote miestnosti sa pridal roztok 215 mg (1,2 mmolu) metylesteru kyseliny N-(2-pyridyl)-3-aminopropiónovej v 2 ml dimetylformamidu, čím sa získal číry roztok. Po 12 hodinách pri teplote miestnosti sa reakčná zmes vmiešala do ľadovej vody. Po trojnásobnej extrakcii esterom kyseliny octovej sa spojené organické extrakty premyli roztokom kuchynskej soli, sušili nad síranom sodným a odparili. Získaný zvyšok sa chromatografoval na kremičitom géli s použitím dichlórmetánu/etanolu (90 : 1 až 25 : 1).308 mg (1.0 mmol) of 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -5-carboxyimidazo [4,5- d] pyridine was suspended in 5 ml of dimethylformamide and 303 mg (3.0 ml) was added. N-methylmorpholine and 321 mg (1.0 mol) of O- (benztriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate. After 10 minutes at room temperature, a solution of 215 mg (1.2 mmol) of N- (2-pyridyl) -3-aminopropionic acid methyl ester in 2 mL of dimethylformamide was added to give a clear solution. After 12 hours at room temperature, the reaction mixture was stirred into ice water. After extraction three times with acetic acid ester, the combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The residue obtained was chromatographed on silica gel using dichloromethane / ethanol (90: 1 to 25: 1).

Výťažok produktu vo forme bieleho prášku bol 165 mg (35 % teoretického výťažku),The yield of the product as a white powder was 165 mg (35%).

C25H12N6O4 (407,50) Teplota topenia produktu bola 139 až 140 °C.C 25 H 12 N 6 O 4 (407.50) Mp 139-140 ° C.

h) N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[(4-amidinofenyl) oxymetyl]-imidazo[4,5-ó]pyridín-5 -yl-karboxylovejh) 1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -imidazo [4,5-a] pyridin-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila premenou 140 mg (0,3 mmolu) N-(2-pyridyl)-N-(2-metoxykarbonyletyl)-amidu kyseliny 1-metyl-2-[(4-kyanofenyl) oxymetyl]-imidazo-[4,5-Ŕ]pyridín-5-yl-karboxylovej s etanolom, nasýteným chlorovodíkom a s uhličitanom amónnym/etanolom obdobne, ako sa uvádza v príklade lg. Získaný produkt sa čistil chromatografícky na géli kyseliny kremičitej s použitím dichlórmetánu/etanolu (19:1 až 4:1) ako elučného činidla.The compound was prepared by converting 140 mg (0.3 mmol) of 1-methyl-2 - [(4-cyanophenyl) oxymethyl] imidazo [4, N- (2-methoxycarbonylethyl) amide N- (2-methoxycarbonylethyl) amide. 5-Ŕ] pyridin-5-yl-carboxylic acid with ethanol, saturated hydrogen chloride and ammonium carbonate / ethanol analogously to Example 1g. The product obtained was purified by chromatography on a silica gel using dichloromethane / ethanol (19: 1 to 4: 1) as eluent.

Výťažok produktu vo forme bieleho prášku bol 48 mg (36 % teoretického výťažku),The yield of the product as a white powder was 48 mg (36% of theory),

C26H27N7O4 (501,57) Hmotnostné spektrum: (M+H)+ = 502.C 26 H 27 N 7 O 4 (501.57) Mass Spectrum: (M + H) + = 502.

Príklad 9Example 9

N-Fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny 2-[N-[(4-amidinofenyl)-aminometyl]-benztiazol-5-karboxylovej2- [N - [(4-amidinophenyl) -aminomethyl] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) Etylester kyseliny 4-fluór-3-metoxyacetamido-benzoovej Roztok 2,8 g (15,3 mmolu) etylesteru kyseliny 3-amino-4-fluór-benzoovej (pozri L. S. Fosdick, A. F. Dodds, J. Amer. Chem. Soc. 65, 2305 (1943)) a 1,56 ml (1,85 g = = 17,0 mmolov) metoxyacetylchloridu v 50 ml chlórbenzénu sa 1 hodinu miešal pri teplote 50 °C a potom 15 minút pri teplote varu reakčnej zmesi pod spätným chladičom. Rozpúšťadlo sa potom vo vákuu oddestilovalo a získaný surový produkt sa čistil rýchlou chromatografiou (gél kyseliny kremičitej; dichlór-metán/etanol = 100 : 1). Získala sa vyžadovaná zlúčenina najprv vo forme olejovitej látky, ktorá počas niekoľkých dní stuhla.a) 4-Fluoro-3-methoxyacetamido-benzoic acid ethyl ester A solution of 2.8 g (15.3 mmol) of 3-amino-4-fluoro-benzoic acid ethyl ester (see LS Fosdick, AF Dodds, J. Amer. Chem. Soc.) 65, 2305 (1943)) and 1.56 ml (1.85 g = 17.0 mmol) of methoxyacetyl chloride in 50 ml of chlorobenzene were stirred at 50 ° C for 1 hour and then at reflux for 15 minutes. condenser. The solvent was then distilled off in vacuo and the crude product obtained was purified by flash chromatography (silica gel; dichloromethane / ethanol = 100: 1). The desired compound was initially obtained as an oily substance which solidified for several days.

Výťažok produktu bol 3,8 g (98 % teoretického výťažku), Rf hodnota: 0,38 (gél kyseliny kremičitej; dichlórmetán/etanol —19:1).Yield: 3.8 g (98% of theory) Rf value: 0.38 (silica gel; dichloromethane / methanol -19: 1).

b) Etylester kyseliny 2-metoxymetyl-benztiazol-5-karboxylovejb) 2-Methoxymethyl-benzothiazole-5-carboxylic acid ethyl ester

Zmes 0,3 g (11,7 mmolov) kyseliny 4-fluór-3-metoxyacetamidobenzoovej a 2,1 g (5,2 mmolu) Lawessonovho činidla v 90 ml toluénu sa 6 hodín zahrievala na teplotu varu pod spätným chladičom, opäť sa pridalo Lawessonovo činidlo (1 g) a reakčná zmes sa potom zahrievala 6 hodín na 120 °C. Po náhrade rozpúšťadla xylénom sa zmes zahrievala ďalších 8 hodín v tlakovej nádobe na 180 °C. Potom sa rozpúšťadlo vo vákuu oddestilovalo, získaný surový produkt sa čistil rýchlou chromatografiou (gél kyseliny kremičitej; ester kyseliny octovej/petroléter = 5 : 95) a znova skoncentroval.A mixture of 0.3 g (11.7 mmol) of 4-fluoro-3-methoxyacetamidobenzoic acid and 2.1 g (5.2 mmol) of Lawesson's reagent in 90 ml of toluene was refluxed for 6 hours, added again. Lawesson's reagent (1 g) and the reaction mixture was then heated at 120 ° C for 6 hours. After the solvent was replaced with xylene, the mixture was heated at 180 ° C for an additional 8 hours. Then the solvent was distilled off in vacuo, the crude product obtained was purified by flash chromatography (silica gel; acetic acid ester / petroleum ether = 5:95) and concentrated again.

Výťažok produktu vo forme žltých kryštálov bol 2,1 g (72 % teoretického výťažku),Yield of product as yellow crystals was 2.1 g (72% of theory),

Rf hodnota: 0,55 (gél kyseliny kremičitej; ester kyseliny octovej/petroléter = 3:7).Rf value: 0.55 (silica gel; acetic acid ester / petroleum ether = 3: 7).

c) Kyselina 2-metoxymetyl-benztiazol-5-karboxylovác) 2-Methoxymethyl-benzothiazole-5-carboxylic acid

Zmes 2,1 g (8,36 mmolu) etylesteru kyseliny 2-metoxymetyl-benztiazol-5-karboxylovcj a 16 ml roztoku hydroxidu sodného (cNa0H = 2 mol.dm'3) spolu s 60 ml etanolu sa miešala 1 hodinu pri teplote miestnosti. Potom sa alkohol oddestiloval. Surový produkt sa rozmiešal s vodou (20 ml), premyl 50 ml dietyléteru a vodná fáza sa s použitím chladenia ľadom okyslila koncentrovanou kyselinou chlorovodíkovou. Pritom sa vylúčila v nadpise uvedená zlúčenina vo forme béžovoružovej látky, ktorá sa pomocou odsávania odfiltrovala, premyla vodou a sušila. Výťažok produktu bol 1,6 g (86 % teoretického výťažku), Rf hodnota: 0,12 (gél kyseliny kremičitej; dichlórmetán/etanol = 29 : 1).A mixture of 2.1 g (8.36 mmol) of 2-methoxymethyl- benzothiazole-5-karboxylovcj and 16 ml of sodium hydroxide solution (c = 2 to 0 mol.dm H '3), together with 60 ml of ethanol was stirred for 1 hour at room temperature. Then the alcohol was distilled off. The crude product was stirred with water (20 mL), washed with 50 mL of diethyl ether, and the aqueous phase was acidified with concentrated hydrochloric acid using ice cooling. The title compound precipitated as a beige-pink material, which was filtered off with suction, washed with water and dried. Yield: 1.6 g (86% of theory) Rf value: 0.12 (silica gel; dichloromethane / ethanol = 29: 1).

d) N-Fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny 2-metoxymetylbenztiazol-5-karboxylovejd) 2-methoxymethylbenzthiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Suspenzia 1,6 g (7,2 mmolu) kyseliny 2-metoxymetylbenztiazol-5-karboxylovej v 60 ml dichlórmetánu sa zmiešala s 1,6 ml (22 mmolov) tionylchloridu a reakčná zmes sa varila 1 hodinu pri teplote varu pod spätným chladičom. V priebehu 20 minút sa tuhá látka rozpustila. Po oddestilovaní kvapalných zložiek sa zvyšok ešte dvakrát rozmiešal v dichlórmetáne a rozpúšťadlo sa vždy oddestilovalo. Týmto spôsobom získaný surový chlorid kyseliny sa zmiešal s 50 ml tetrahydrofuránu. Táto zmes sa po kvapkách pridala do zmesi 1,4 g (21 mmolov) trietylamínu v 50 ml tetrahydrofuránu; po pridaní sa reakčná zmes miešala cez noc pri teplote miestnosti. Potom sa rozpúšťadlo vo vákuu oddestilovalo, zvyšok sa rozmiešal v 30 ml dichlórmetánu, tento roztok sa premyl vodou a sušil s použitím síranu sodného. Po oddestilovaní rozpúšťadla sa rýchlou chromatografiou (gél kyseliny kremičitej; gradient dichlórmetán/etanol 98,5 : 1,5 až 80 : 20) izolovala vyžadovaná zlúčenina vo forme hnedého oleja.A suspension of 1.6 g (7.2 mmol) of 2-methoxymethylbenzothiazole-5-carboxylic acid in 60 ml of dichloromethane was mixed with 1.6 ml (22 mmol) of thionyl chloride and the reaction mixture was heated under reflux for 1 hour. The solid dissolved within 20 minutes. After distilling off the liquid components, the residue was stirred twice more in dichloromethane and the solvent was always distilled off. The crude acid chloride thus obtained was mixed with 50 ml of tetrahydrofuran. This mixture was added dropwise to a mixture of 1.4 g (21 mmol) of triethylamine in 50 ml of tetrahydrofuran; after the addition, the reaction mixture was stirred overnight at room temperature. Then the solvent was distilled off in vacuo, the residue was stirred in 30 ml of dichloromethane, this solution was washed with water and dried using sodium sulfate. After distilling off the solvent, the title compound was isolated as a brown oil by flash chromatography (silica gel; dichloromethane / ethanol gradient 98.5: 1.5 to 80: 20).

Výťažok produktu bol 2,05 g (72 % teoretického výťažku), Rf hodnota: 0,40 (gél kyseliny kremičitej; ester kyseliny octovej/petroléter = 1:1).Yield: 2.05 g (72% of theory) Rf value: 0.40 (silica gel; ethyl acetate / petroleum ether = 1: 1).

e) N-Fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny 2-[N-(4-kyanofenyl)-aminometyl]-benztiazol-5-karboxyloveje) 2- [N- (4-Cyanophenyl) aminomethyl] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zmes 2,05 g (5,14 mmolu) N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-metoxymetyibenztiazol-5-karboxylovej a 5,7 ml (5,7 mmolu) roztoku bromidu boritého (cBBr3= 1 mol.dm'3) v dichlórmetáne sa rozpustila v ďalšom podieli dichlór-metánu (60 ml) a zmes sa miešala 16 hodín pri teplote miestnosti. Reakčná zmes sa potom premyla 40 ml nasýteného roztoku hydrogenuhličitanu sodného, organická fáza sa sušila síranom sodným a rozpúšťadlo sa odparilo. Týmto spôsobom získaný surový N-fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny 2-brómmetyl-benztiazol-5-karboxylovej (2,4 g) sa rozmiešal s 5,0 ml Ν,Ν-diizopropyletylamínu a zmiešal s 0,64 g (5,4 mmolu) 4-amino-benznitrilu. Po 1 hodinovom zahrievaní na teplotu 130 °C sa rozpúšťadlo vo vákuu oddestilovalo a získaný surový produkt sa čistil rýchlou chromatografiou (gél kyseliny kremičitej; gradient: ester kyseliny octovej/petroléter = 1 : 3 až 1 : 1), pričom po skoncentrovaní eluátu sa získala oranžovo sfarbená tuhá pena.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 boron tribromide solution (c BBr3 = 1 mol.dm 3 ) in dichloromethane was dissolved in another portion of dichloromethane (60 ml) and stirred at room temperature for 16 hours. The reaction mixture was then washed with 40 ml of saturated sodium bicarbonate solution, the organic phase was dried over sodium sulfate and the solvent was evaporated. The crude 2-bromomethyl-benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide (2.4 g) thus obtained was stirred with 5.0 ml of Ν, Ν-diisopropylethylamine and mixed with O, 64 g (5.4 mmol) of 4-aminobenzonitrile. After heating at 130 ° C for 1 hour, the solvent was distilled off in vacuo and the crude product obtained was purified by flash chromatography (silica gel; gradient: acetic acid ester / petroleum ether = 1: 3 to 1: 1) to give the eluate after concentration. orange colored rigid foam.

Výťažok produktu bol 1,1 g (44 % teoretického výťažku), Rf hodnota: 0,35 (gcl kyseliny kremičitej; ester kyseliny octovej/petroléter = 7:3).Yield: 1.1 g (44% of theory) Rf value: 0.35 (GCL silica, ethyl acetate / petroleum ether = 7: 3).

f) N-Fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny 2-[N-[(4-amidinofenyl)-aminometyl]-benztiazol-5-karboxylovejf) 2- [N - [(4-amidinophenyl) -aminomethyl] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

V 100 ml chlorovodíkom nasýteného etanolu sa rozpustilo 1,1 g (2,27 mmolu) N-fenyl-N-(2-etoxykarbo-nyletyl)amidu kyseliny 2-[N-[(4-kyanofenyl)-aminometyl]benztiazol-5-karboxylovej a zmes sa miešala 5 hodín najprv pri 0 °C a potom pri teplote miestnosti tak dlho, až sa chromatografiou v tenkej vrstve nepreukázala neprítomnosť východiskového materiálu. Rozpúšťadlo sa potom pri teplote kúpeľa najviac 30 °C oddestilovalo, olejovitý zvyšok sa rozpustil v 100 ml absolútneho etanolu a zmiešal s1.1 g (2.27 mmol) of 2- [N - [(4-cyanophenyl) aminomethyl] benzothiazole-5-N-phenyl-N- (2-ethoxycarbonylethyl) amide was dissolved in 100 ml of hydrogen-saturated ethanol. The mixture was stirred at 0 ° C for 5 hours and then at room temperature until thin layer chromatography showed no starting material. The solvent was then distilled off at a bath temperature of not more than 30 ° C, the oily residue was dissolved in 100 ml of absolute ethanol and mixed with

1,6 g (22 mmolu) uhličitanu amónneho. Po 18 hodinovom miešaní pri teplote miestnosti sa rozpúšťadlo oddestilovalo vo vákuu a surový produkt sa čistil rýchlou chromatografiou (gél kyseliny kremičitej; gradient: voda/metanol = = 19 : 1 až 4:1). Skoncentrovaním eluátu sa získala v nadpise uvedená zlúčenina vo forme bielej peny.1.6 g (22 mmol) of ammonium carbonate. After stirring at room temperature for 18 hours, 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). Concentration of the eluate afforded the title compound as a white foam.

Výťažok produktu bol 0,77 g (63 % teoretického výťažku), Rf hodnota: 0,19 (gél kyseliny kremičitej; dichlórmetán/etanol = 3:7)Yield: 0.77 g (63% of theory) Rf value: 0.19 (silica gel; dichloromethane / ethanol = 3: 7)

C27H27N5O3S (501,60)C 27 H 27 N 5 O 3 S (501.60)

Hmotnostné spektrum: (M+H)+ = 502.Mass Spectrum: (M + H) + = 502.

Príklad 10Example 10

N-Fenyl-N-(2-karboxyletyl)-amid kyseliny 2-[N-(4-amidinofenyl)-aminometyl]-benztiazol-5-karboxylovej2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-carboxy-ethyl) -amide

V 15 ml etanolu sa rozpustilo 0,45 g (0,84 mmolu) N-fenyl-N-(2-etoxy-karbonyletyl)-amidu kyseliny 2-[N-(4-amidinofenyl)-aminometyl]-benztiazol-5-karboxylovej a roztok sa zmiešal s 2 m roztoku NaOH (cNa0H = 2 mol.dm'3); reakčná zmes sa miešala 4 hodiny pri teplote miestnosti. Potom sa okyslila 3 ml kyseliny chlorovodíkovej (cHci = = 2 mol.dm'3) a rozpúšťadlo sa oddestilovalo. Získaný surový produkt sa rozpustil v 5 ml zmesi dichlórmetánu/etanolu (2 : 1) a nerozpusený chlorid sodný sa odfiltroval. Po oddestilovaní rozpúšťadla sa získala vyžadovaná zlúčenina vo forme žltej peny.0.45 g (0.84 mmol) of 2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazole-5- N -phenyl-N- (2-ethoxycarbonylethyl) -amide was dissolved in 15 ml of ethanol. carboxylic acid and the solution was mixed with 2 m NaOH solution (c NaOH = 2 mol.dm < 3 >); the reaction mixture was stirred at room temperature for 4 hours. It was then acidified with 3 ml of hydrochloric acid (c H c = = 2 mol.dm 3 ) and the solvent was distilled off. The crude product obtained was dissolved in 5 ml of dichloromethane / ethanol (2: 1) and the undissolved sodium chloride was filtered off. After distilling off the solvent, the title compound was obtained as a yellow foam.

Výťažok produktu bol 0,26 g (67 % teoretického výťažku), Rf hodnota: 0,47 (gél kyseliny kremičitej; metanol/5 %-ný vodný roztok chloridu sodného = 6:4),Yield: 0.26 g (67% of theory) Rf value: 0.47 (silica gel; methanol / 5% aqueous saline solution = 6: 4).

C25H23N5O3S (476,55) Hmotnostné spektrum: (M+H)+ = 474.C 25 H 23 N 5 O 3 S (476.55) Mass Spectrum: (M + H) + = 474.

Príklad 11Example 11

Dihydrochlorid N-(2-pyridyl)-N-(2-metoxykarbonyletyl)amidu kyseliny 2-[N-(4-amidinofenyl)-aminometyl]-benztiazol-5-yl-karboxylovej2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide dihydrochloride

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 9 z N-(2-pyridyl)-N-(2-metoxykarbonyletyl)-amidu kyseliny 2-[N-[(4-kyanofenyl)-aminometyl]-benztiazol-5-yl-karboxylovej, metanolového roztoku kyseliny chlorovodíkovej, metanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 9, from 2- [N - [(4-cyanophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide. , a methanolic solution of hydrochloric acid, methanol and ammonium carbonate.

Výťažok produktu bol 68 % teoretického výťažku, C25H24N6O3S (488,57)Yield: 68%. C 25 H 24 N 6 O 3 S (488.57)

Rf hodnota: 0,13 (gél kyseliny kremičitej; metylénchlorid/etanol = 4:1+ niekoľko kvapiek kyseliny octovej), EKA-hmotnostné spektrum: (M+H)+ = 489. Rf value: 0.13 (silica gel; methylene chloride / ethanol 4: 1 + a few drops of acetic acid) EKA mass spectrum: (M + H) + = 489th

Príklad 12Example 12

Dihydrochlorid N-(2-pyridyl)-N-(2-etoxykarbonylmetyl)amidu kyseliny 2-[2-(4-amidinofenyI) etyl]-benztiazol-5-yl-karboxylovej2- [2- (4-amidinophenyl) ethyl] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylmethyl) amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 9 z N-(2-pyridyl)-N-(etoxykarbonylmetyl)-amidu kyseliny 2-[2-(4-kyanofenyl)-etyl]-benztiazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 9 from 2- [2- (4-cyanophenyl) -ethyl] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide, ethanol solution hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 95 % teoretického výťažku, C26H25N5O3S (487,58)Yield: 95% of theory. C 26 H 25 N 5 O 3 S (487.58)

Rf hodnota: 0,20 (gél kyseliny kremičitej; metylénchlorid/etanol = 4:1+ niekoľko kvapiek kyseliny octovej), EKA-hmotnostné spektrum: (M+H)+ = 488.Rf value: 0.20 (silica gel; methylene chloride / ethanol = 4: 1+ a few drops of acetic acid), EKA mass spectrum: (M + H) + = 488.

Príklad 13Example 13

Dihydrochlorid N-(2-pyridyl)-N-(etoxykarbonylmetyl)amidu kyseliny 2-[N-(4-amidino-fenyl)-aminometyl]-benztiazol-5-yl-karboxylovej2- [N- (4-amidino-phenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 9 z N-(2-pyridyl)-N-(etoxykarbonylmetyl)-amidu kyseliny 2-[N-(4-kyanofenyl)-aminometyl]-benztiazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 9 from 2- [N- (4-cyanophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide, ethanol solution hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 68 % teoretického výťažku, C25H24N6O3S (488,57)Yield: 68%. C 25 H 24 N 6 O 3 S (488.57)

Rf hodnota: 0,14 (gél kyseliny kremičitej; metylénchlorid/etanol = 4:1+ niekoľko kvapiek kyseliny octovej), EKA-hmotnostné spektrum: (M+H)+ = 489. Rf value: 0.14 (silica gel; methylene chloride / ethanol 4: 1 + a few drops of acetic acid) EKA mass spectrum: (M + H) + = 489th

Príklad 14Example 14

Dihydrochlorid N-(2-pyridyl)-N-(hydroxykarbonylmetyl)amidu kyseliny 2-[N-(4-amidinofenyl)-aminometyl]-benztiazol-5-yl-karboxylovej2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) amide dihydrochloride

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 10 z dihydrochloridu N-(2-pyridyI)-N-(etoxykarbonylmetylj-amidu kyseliny 2-[N-(4-amidinofenyl)aminometyl]-benztiazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 10 from 2- [N- (4-amidinophenyl) aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide and sodium hydroxide dihydrochloride.

Výťažok produktu bol 90 % teoretického výťažku, C23H20N6O3S (460,52)Yield: 90% of theory. C 23 H 20 N 6 O 3 S (460.52)

Rf hodnota: neudaná,R f value: not given,

EKA-hmotnostné spektrum: (M+H)+ = 461, (M+Na)+ = = 483, (M+2Na)+ = 253.EKA-MS: (M + H) < + > = 461, (M + Na) < + > = 483, (M + 2Na) + = 253.

Príklad 15Example 15

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-[N-(4-amidinofenyl)-N-metyl-aminometyl]-benztiazol-5-yl-karboxylovej2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) N-Fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny 2-[N-(4-kyanofenyl)-N-metyl-aminometyl]-benztiazol-5-yl-karboxyloveja) 2- [N- (4-Cyanophenyl) -N-methyl-aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 9e z 4-kyano-N-metyl-anilínu a N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-metoxymetyl-benztiazol-5-karboxylovej.The compound was prepared in a manner analogous to Example 9e from 4-cyano-N-methyl-aniline and 2-methoxymethyl-benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide.

Výťažok produktu bol 57 % teoretického výťažku, Rf hodnota: 0,46 (gél kyseliny kremičitej; dichlórmetán/etanol = 19 : 1).Yield: 57% of theory. Rf value: 0.46 (silica gel; dichloromethane / ethanol = 19: 1).

b) Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-[N-(4-amidino-fenyl)-N-metyl-aminometyl]-benztiazol-5-yl-karboxylovejb) 2- [N- (4-amidino-phenyl) -N-methyl-aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 9 z N-fenyl-N-(2-ctoxykarbonyletyl)-amidu kyseliny 2-[N-(4-kyanofenyl)-N-metyl-aminometyl]-benztiazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 9 from 2- [N- (4-cyanophenyl) -N-methyl-aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 73 % teoretického výťažku, C28H29N5O3S (515,64)Yield: 73% of theory. C 28 H 29 N 5 O 3 S (515.64)

Rf hodnota: 0,29 (gél kyseliny kremičitej; metylénchlorid/etanol = 4:1+ niekoľko kvapiek kyseliny octovej). EKA-hmotnostné spektrum: (M+H)+ = 516. Rf value: 0.29 (silica gel; methylene chloride / ethanol 4: 1 + a few drops of acetic acid). EKA-MS: (M + H) < + > = 516.

Príklad 16Example 16

Hydrochlorid N-fenyl-N-(2-hydroxykarbonyletyl)-amidu kyseliny 2-[N-(4-amidino-fenyl)-N-metyl-aminometyl]benztiazol-5-yl-karboxylovej2- [N- (4-amidino-phenyl) -N-methyl-aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 10 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-[N-(4-amidinofenyl)-N-metyl-aminometyl]-benztiazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner similar to Example 10 from 2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide. and sodium hydroxide.

Výťažok produktu bol 96 % teoretického výťažku, C26H25N5O3S (487,58)The yield of the product was 96% of the theoretical yield, C 26 H 25 N 5 O 3 S (487.58)

Rf hodnota: 0,48 (Merck RP-8; metanol/5 %-ný roztok NaCl = 6 : 4),Rf value: 0.48 (Merck RP-8; methanol / 5% NaCl = 6: 4),

EKA-hmotnostné spektrum: (M=H)+ = 488, (M+2Na)+ = = 266,5.EKA-MS: (M = H) + = 488, (M + 2Na) + = 266.5.

Príklad 17Example 17

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-[(4-amidinofenyl)-tiometyl]-benztiazol-5-yl-karboxylovej2 - [(4-amidinophenyl) -thiomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 9 z N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-[(4-kyanofenyl)-tiometyl]-benztiazol-5-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner similar to Example 9 from 2 - [(4-cyanophenyl) -thiomethyl] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic hydrochloric acid, ethanol and carbonate solution.

Výťažok produktu bol 61 % teoretického výťažku, C27H26N4O3S2 (518,66)The yield of the product was 61% of the theoretical yield, C 27 H 26 N 4 O 3 S 2 (518.66)

Rf hodnota: 0,27 (gél kyseliny kremičitej; metylénchlorid/etanol = 4:1+ niekoľko kvapiek kyseliny octovej), EKA-hmotnostné spektrum: (M+H)+ = 519.Rf value: 0.27 (silica gel; methylene chloride / ethanol = 4: 1 + a few drops of acetic acid), EKA-MS: (M + H) < + > = 519.

Príklad 18Example 18

Hydrochlorid N-fenyl-N-(2-hydroxykarbonyletyl)-amidu kyseliny 2-[(4-amidinofenyl)-tiometyl]-benztiazol-5-yl-karboxylovej2 - [(4-amidinophenyl) -thiomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 10 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-[(4-amidinofenyl)-tiometyl]-benztiazol-5-yl-karboxylovej a hydroxidu sodného. Výťažok produktu bol 95 % teoretického výťažku, C25H22N4O3S2 (490,61)The compound was prepared in a similar manner to Example 10 from 2 - [(4-amidinophenyl) -thiomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and sodium hydroxide. The product yield was 95% of the theoretical yield, C 25 H 22 N 4 O 3 S 2 (490.61)

Rf hodnota: 0,25 (Merck RP-8; metanol/5 %-ný roztok NaCl = 6:4),Rf value: 0.25 (Merck RP-8; methanol / 5% NaCl = 6: 4),

EKA-hmotnostné spektrum: (M+H)+ = 491, (M+Na)+ = = 513.EKA-MS: (M + H) + = 491, (M + Na) + = 513.

Príklad 19Example 19

Hydrochlorid N-fenyl-N-(etoxykarbonylmetyl)-amidu kyseliny 2-[N-(4-amidinofenyl)-aminometyl] -benztiazol-5 -yl-karboxylovej2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 9 z N-fenyl-N-(etoxykarbonyletyl)-amidu kyseliny 2The compound was prepared in a manner analogous to Example 9 from N-phenyl-N- (ethoxycarbonylethyl) -amide 2

SK 285432 Β6SK 285432 Β6

-[N-(4-kyanofenyl)-aminometyl]-benztiazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.- [N- (4-cyanophenyl) aminomethyl] -benzothiazol-5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 82 % teoretického výťažku, C26H25N5O3S (487,58)Yield: 82%. C 26 H 25 N 5 O 3 S (487.58)

Rf hodnota: 0,21 (gél kyseliny kremičitej; metylénchlorid/etanol = 4:1+ niekoľko kvapiek kyseliny octovej), EKA-hmotnostné spektrum: (M+H)+ = 488. Rf value: 0.21 (silica gel; methylene chloride / ethanol 4: 1 + a few drops of acetic acid) EKA mass spectrum: (M + H) + = 488th

Príklad 20Example 20

Hydrochlorid N-fenyl-N-(2-hydroxykarbonylmetyl)-amidu kyseliny 2-[N-(4-amidino-fenyl)-aminometyl]-benztiazol-5-yl-karboxylovej2- [N- (4-amidino-phenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylmethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 10 z hydrochloridu N-fenyl-N-(etoxykarbonylmetyl)-amidu kyseliny 2-[N-(4-amidinofenyl)-aminometyl]-benztiazol-5-yl-karboxylovej a hydroxidu sodného. Výťažok produktu bol 75 % teoretického výťažku, C24H2|N5O3S (459,53)The compound was prepared in a manner analogous to Example 10 from 2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide and sodium hydroxide. The yield of the product was 75% of the theoretical yield, C 24 H 2 N 5 O 3 S (459.53)

Rf hodnota: 0,14 (gél kyseliny kremičitej; metylénchlorid/etanol = 4:1 + niekoľko kvapiek kyseliny octovej), EKA-hmotnostné spektrum: (M+H)+ = 460, (M+Na)+ = = 482. Rf value: 0.14 (silica gel; methylene chloride / ethanol 4: 1 + a few drops of acetic acid) EKA mass spectrum: (M + H) + = 460, (M + Na) + = 482nd

Príklad 21Example 21

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-[2-(4-amidinofenyl)-etyl]-benztiazol-5-yl-karboxylovej2- [2- (4-amidinophenyl) -ethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 9 z N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-[2-(4-kyanofenyl)-etyl]-benztiazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner similar to Example 9 from 2- [2- (4-cyanophenyl) -ethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic hydrochloric acid solution. , ethanol and ammonium carbonate.

Výťažok produktu bol 80 % teoretického výťažku, C28H2gN4O3S (500,62)The yield of the product was 80% of the theoretical yield, C 28 H 2 N 4 O 3 S (500.62)

Rf hodnota: 0,30 (gél kyseliny kremičitej; metylénchlorid/etanol = 4:1+ niekoľko kvapiek kyseliny octovej), EKA-hmotnostné spektrum: (M+H)+ = 501. Rf value: 0.30 (silica gel; methylene chloride / ethanol 4: 1 + a few drops of acetic acid) EKA mass spectrum: (M + H) + = five hundred and first

Príklad 22Example 22

Hydrochlorid N-fenyl-N-(2-hydroxykarbonyletyl)-amidu kyseliny 2-[2-(4-amidinofenyl)-etyl]-benztiazol-5-yI-karboxylovej2- [2- (4-amidinophenyl) -ethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 10 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-[2-(4-amidinofenyl)-etyl]-benztiazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 10 from 2- [2- (4-amidinophenyl) -ethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide and sodium hydroxide.

Výťažok produktu bol 77 % teoretického výťažku, C26H24N4O3S (472,57)Yield: 77% of theory. C 26 H 24 N 4 O 3 S (472.57)

Rf hodnota: 0,18 (gél kyseliny kremičitej; metylénchlorid/etanol = 4:1+ niekoľko kvapiek kyseliny octovej), EKA-hmotnostné spektrum: (M+H)+ = 473, (M+Na)+ = = 495, (M+H+Na) = 259. Rf value: 0.18 (silica gel; methylene chloride / ethanol 4: 1 + a few drops of acetic acid) EKA mass spectrum: (M + H) + = 473, (M + Na) + = 495. (M + H + Na) = 259.

Príklad 23Example 23

Hydrochlorid N-(n-propyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-[N-(4-amidinofenyl)-aminometyl]-benztiazol-5-yl-karboxylovej2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 9 z N-(n-propyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-[N-(4-kyanofenyl)-aminometyl]-benztiazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 9, from 2- [N- (4-cyanophenyl) aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 83 % teoretického výťažku, C24H29N5O3 (467,59)The yield of the product was 83% of the theoretical yield, C 24 H 29 N 5 O 3 (467.59)

Rf hodnota: 0,31 (gél kyseliny kremičitej; metylénchlorid/etanol = 4:1+ niekoľko kvapiek kyseliny octovej),Rf value: 0.31 (silica gel; methylene chloride / ethanol = 4: 1+ a few drops of acetic acid),

EKA-hmotnostné spektrum: (M+H)+ = 468, (2M+H)+ = = 935.EKA-MS: (M + H) < + > = 468, (2M + H) < + > = 935.

Príklad 24Example 24

Hydrochlorid N-(n-propyl)-N-(2-hydroxykarbonyletyl)amidu kyseliny 2-[N-(4-amidinofenyl)-aminometyl]-benztiazol-5-yl-karboxylovej2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-hydroxycarbonylethyl) amide hydrochloride

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 10 z hydrochloridu N-(n-propyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-[N-(4-amidinofenyl)-aminometyl]-benztiazol-5-yl-karboxylovej a hydroxidu sodného. Výťažok produktu bol 75 % teoretického výťažku, C22H25N5O3S (439,54)The compound was prepared in a manner similar to Example 10 from 2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide. and sodium hydroxide. The product yield was 75% of the theoretical yield, C 22 H 25 N 5 O 3 S (439.54)

Rf hodnota: 0,14 (gél kyseliny kremičitej; metylénchlorid/etanol = 4:1+ niekoľko kvapiek kyseliny octovej), EKA-hmotnostné spektrum: (M+H)+ = 440, (M+H+Na)4“3 = = 231,6.Rf value: 0.14 (silica gel; methylene chloride / ethanol = 4: 1+ a few drops of acetic acid), EKA mass spectrum: (M + H) + = 440, (M + H + Na) 4 ' 3 = = 231.6.

Príklad 25Example 25

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) N-Fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny 4-metylamino-3 -nitrobenzoovej(a) 4-methylamino-3-nitrobenzoic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Do roztoku 24,7 g (0,115 molu) chloridu kyseliny 4-metylamino-3-nitrobenzoovej a 22,3 g (0,115 molu) N-(2-etoxykarbonyletyl)-anilinu v 300 ml tetrahydrofuránu sa pri teplote miestnosti v priebehu 15 minút po kvapkách a za miešania pridalo 13,1 g (0,13 molu) trietylamínu. Po dvojhodinovom miešaní sa rozpúšťadlo oddestilovalo vo vákuu vodnej vývevy a zvyšok sa rozmiešal s 700 ml vody. Zmes sa trikrát extrahovala vždy s 200 ml dichlórmetánu, organický extrakt sa premyl 200 ml kyseliny chlorovodíkovej (cHC|= 2 mol.dm-’) a dvakrát vždy s 300 ml vody. Potom sa sušil síranom sodným. Rozpúšťadlo sa oddestilovalo a týmto spôsobom získaný olejovitý produkt sa čistil stĺpcovou chromatografiou (1 kg gélu kyseliny kremičitej; elučné činidlo: petroléter/ester kyseliny octovej = 2 : 1).To a solution of 24.7 g (0.115 mol) of 4-methylamino-3-nitrobenzoic acid chloride and 22.3 g (0.115 mol) of N- (2-ethoxycarbonylethyl) -aniline in 300 ml of tetrahydrofuran at room temperature for 15 minutes after 13.1 g (0.13 mol) of triethylamine was added dropwise with stirring. After stirring for two hours, the solvent was distilled off under a water pump vacuum and the residue was stirred with 700 ml of water. The mixture was extracted three times with 200 ml of dichloromethane, the organic extract was washed with 200 ml of hydrochloric acid (HC c | = 2 mol.dm - "), and twice with 300 ml of water. It was then dried over sodium sulfate. The solvent was distilled off and the oily product thus obtained was purified by column chromatography (1 kg of silica gel; eluent: petroleum ether / acetic acid ester = 2: 1).

Výťažok produktu bol 35,0 g (82 % teoretického výťažku), Rf hodnota: 0,28 (gél kyseliny kremičitej; dichlórmetán/etanol = 50 : 1).Yield: 35.0 g (82% of theory) Rf value: 0.28 (silica gel; dichloromethane / ethanol = 50: 1).

b) N-Fenyl-(2-etoxykarbonyletyl)-amid kyseliny 3-amino-4-metylaminobenzoovejb) 3-Amino-4-methylaminobenzoic acid N-phenyl- (2-ethoxycarbonylethyl) -amide

V 300 ml etanolu a 150 ml dichlórmetánu a s prísadou asi 4 g paládia na uhlí (10 %-né paládium) sa pri teplote miestnosti a pod tlakom vodíka 0,5 MPa hydrogenovalo 12,1 g (0,0326 molu) n-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 4-metylamino-3-nitrobenzoovej. Potom sa katalyzátor odfiltroval a fíltrát sa skoncentroval. Získaný surový produkt sa použil bez ďalšieho čistenia.12.1 g (0.0326 mol) of n-phenyl- were hydrogenated at room temperature and under a hydrogen pressure of 0.5 MPa in 300 ml of ethanol and 150 ml of dichloromethane and about 4 g of palladium on carbon (10% palladium) added. 4-methylamino-3-nitrobenzoic acid N- (2-ethoxycarbonylethyl) -amide. Then, the catalyst was filtered off and the filtrate was concentrated. The crude product obtained was used without further purification.

Výťažok produktu bol 10,6 g (95 % teoretického výťažku), Rf hodnota: 0,19 (gél kyseliny kremičitej; dichlórmetán/etanol = 50 : 1).Yield: 10.6 g (95% of theory), Rf value: 0.19 (silica gel; dichloromethane / ethanol = 50: 1).

c) N-Fenyl-(2-etoxykarbonyletyl)-amid kyseliny l-metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovejc) 1-Methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl- (2-ethoxycarbonylethyl) -amide

6,17 g (0,035 molu) N-(4-kyanofenyl)glycínu a 5,68 g (0,035 molu) Ν,Ν'-karbonyldiimidazolu sa v zahrievalo v 300 ml tetrahydrofuránu 30 minút na teplotu varu pod spätným chladičom. Potom sa pridalo 10,6 g (0,032 molu) N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 3-amíno-4-metylaminobenzoovej a zmes sa zahrievala ďalších 5 hodín na teplotu varu pod spätným chladičom. Rozpúšťadlo sa potom oddestilovalo vo vákuu. Zvyšok sa rozpustil v6.17 g (0.035 mol) of N- (4-cyanophenyl) glycine and 5.68 g (0.035 mol) of Ν, Ν'-carbonyldiimidazole were heated under reflux in 300 ml of tetrahydrofuran for 30 minutes. Then 10.6 g (0.032 mol) of 3-amino-4-methylaminobenzoic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide was added and the mixture was heated under reflux for a further 5 hours. The solvent was then distilled off in vacuo. The residue was dissolved in

150 ml ľadovej kyseliny octovej a roztok sa 1 hodinu zahrieval na teplotu varu pod spätným chladičom. Potom sa ľadová kyselina octová vo vákuu oddestilovala, zvyšok sa rozpustil v približne 300 ml dichlórmetánu, roztok sa premyl dvakrát vždy s 150 ml vody a potom sa roztok sušil síranom sodným. Po odparení rozpúšťadla sa týmto spôsobom získaný surový produkt čistil stĺpcovou chromatografiou (800 g gélu kyseliny kremičitej; elučné činidlo: dich(órmetán s 1 až 2 % etanolu).150 ml of glacial acetic acid and the solution was refluxed for 1 hour. The glacial acetic acid was then distilled off in vacuo, the residue was dissolved in approximately 300 ml of dichloromethane, the solution was washed twice with 150 ml of water each time, and then the solution was dried over sodium sulfate. After evaporation of the solvent, the crude product thus obtained was purified by column chromatography (800 g of silica gel; eluent: dichloromethane (1 to 2% ethanol)).

Výťažok produktu bol 8,5 g (57 % teoretického výťažku), Rf hodnota: 0,51 (gél kyseliny kremičitej; dichlórmetán/etanol = 19 : 1).Yield: 8.5 g (57% of theory) Rf value: 0.51 (silica gel; dichloromethane / ethanol = 19: 1).

d) Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny l-mety1-2-[N-(4-amidinofenyl)-aminometyl]benzimidazol-5-yl-karboxylovejd) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

V 100 ml etanolu nasýteného kyselinou chlorovodíkovou sa 6 hodín pri teplote miestnosti miešalo 1,2 g (2,49 mmolu) N-fenyl-(2-etoxykarbonyIetyl)-amidu kyseliny 1-metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej. Reakčná zmes sa potom vo vákuu skoncentrovala do sucha, zvyšok sa rozpustil v 100 ml etanolu, pridalo sa 2,5 g (26 mmolov) uhličitanu amónneho a zmes sa nechala miešať cez noc pri teplote miestnosti. Po oddestilovaní rozpúšťadla sa pripravený surový produkt čistil stĺpcovou chromatografiou (100 g gélu kyseliny kremičitej, elučné činidlo: dichlórmetán/etanol = 4 : 1). Odparením eluátu sa získala v nadpise uvedená zlúčenina vo forme bielej amorfnej tuhej látky.1.2 g (2.49 mmol) of N-phenyl- (2-ethoxycarbonyl-ethyl) -amide 1-methyl-2- [N- (4-cyanophenyl) -amide was stirred in 100 ml of ethanol saturated with hydrochloric acid at room temperature for 6 hours. aminomethyl] benzimidazol-5-yl-carboxylic acid. The reaction mixture was then concentrated to dryness in vacuo, the residue was dissolved in 100 mL of ethanol, 2.5 g (26 mmol) of ammonium carbonate was added, and the mixture was allowed to stir overnight at room temperature. After distilling off the solvent, the crude product prepared was purified by column chromatography (100 g silica gel, eluent: dichloromethane / ethanol = 4: 1). Evaporation of the eluate gave the title compound as a white amorphous solid.

Výťažok produktu bol 1,10 g (83 % teoretického výťažku), Rf hodnota: 0,18 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1 ).Yield: 1.10 g (83% of theory) Rf value: 0.18 (silica gel; dichloromethane / ethanol = 4: 1).

C28H30N6O3. HC1 (498,6), EKA -hmotnostné spektrum: (M+H)+ = 499, (M+2H)++ = = 250, (M+H+Na)++ = 261.C 28 H 30 N 6 O 3 . HCl (498.6), EKA-MS: (M + H) + = 499, (M + 2H) ++ = 250, (M + H + Na) ++ = 261.

Príklad 26Example 26

N-Fcnyl-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-Fcnyl-N- (2-hydroxycarbonylethyl) -amide

Zmes 300 mg (0,56 mmolu) hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, 15 ml etanolu, 4 ml vody a 120 mg (3,0 mmoly) hydroxidu sodného sa miešala 2 hodiny pri teplote miestnosti. Potom sa reakčná zmes zriedila 20 ml vody a ľadovou kyselinou octovou sa upravila reakciou zmesi na slabo kyslú. Pri tom vykryštalizoval produkt, ktorý sa oddelil filtráciou s odsávaním, premyl vodou a sušil pri 60 °C vo vákuu. Výťažok produktu bol 250 mg (95 % teoretického výťažku),A mixture of 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide 300 mg (0.56 mmol), 15 ml of ethanol, 4 ml of water and 120 mg (3.0 mmol) of sodium hydroxide were stirred at room temperature for 2 hours. The reaction mixture was then diluted with 20 mL of water and made glacial with acetic acid to make it acidic. The product crystallized out, which was collected by suction filtration, washed with water and dried at 60 [deg.] C. in vacuo. The product yield was 250 mg (95% of theory),

C26H26N6O3 (470,5)C 26 H 26 N 6 O 3 (470.5)

EKA -hmotnostné spektrum: (M+H)+ = 471, (M+2Na)++ = = 258, (M+H+Na)++ = 247.EKA-Mass Spectrum: (M + H) + = 471, (M + 2Na) ++ = = 258, (M + H + Na) ++ = 247.

Príklad 27Example 27

Hydrochlorid N-(n-propyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[(4-amidinofenyl)-tiometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2 - [(4-amidinophenyl) -thiomethyl] -benzimidazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide

a) N-(n-Propyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 4-metylamino-3-chlóracetamidobenzooveja) 4-methylamino-3-chloroacetamidobenzoic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide

Roztok 1,8 g (5,9 mmolu) N-(n-propyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 3-amino-4-metylaminobenzoovej (jeho príprava sa vykonala obdobne ako N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 3-amino-4-etylaminobenzoovej), 1,1 g (6,8 mmolu) N,N'-karbonyl diimidazolu a 0,65 g (6,9 mmolu) kyseliny chlóroctovej v 75 ml tetrahydrofuránu sa miešal 1 hodinu pri teplote miestnosti. Rozpúšťadlo sa potom vo vákuu oddestilovalo a surový produkt sa čistil rýchlou chromatografiou (gél kyseliny kremičitej; metylénchlorid/etanol = 49 : 1). Výťažok produktu bol 1,7 g (77 % teoretického výťažku), Rf hodnota: 0,58 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 90:10:1).A solution of 1.8 g (5.9 mmol) of 3-amino-4-methylaminobenzoic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide (prepared in analogy to N-phenyl-N- ( 2-ethoxycarbonylethyl) 3-amino-4-ethylaminobenzoic acid amide), 1.1 g (6.8 mmol) of N, N'-carbonyl diimidazole and 0.65 g (6.9 mmol) of chloroacetic acid in 75 ml of tetrahydrofuran was stirred for 1 hour at room temperature. The solvent was then distilled off in vacuo and the crude product was purified by flash chromatography (silica gel; methylene chloride / ethanol = 49: 1). Yield: 1.7 g (77% of theory) Rf value: 0.58 (silica gel; ethyl acetate / ethanol / ammonia 90: 10: 1).

b) N-(n-Propyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 2-chlórmetyl-1 -metyl-benzimidazol-5-yl-karboxylovejb) 2-Chloromethyl-1-methyl-benzimidazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide

Roztok 1,6 g (4,3 mmolu) N-(n-propyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 4-metylamino-3-chlóracetamidobenzoovej v 25 ml kyseliny octovej sa zahrieval 1 hodinu na 100 °C. Potom sa rozpúšťadlo oddestilovalo, surový produkt sa rozmiešal s 40 ml zmesi metylénchloridu a etanolu (9 : 1) a premyl 20 ml nasýteného roztoku hydrogenuhličitanu sodného. Organická fáza sa sušila síranom sodným a skoncentrovala.A solution of 4-methylamino-3-chloroacetamidobenzoic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) amide (1.6 g, 4.3 mmol) in 25 ml of acetic acid was heated at 100 ° C for 1 hour. After the solvent was distilled off, the crude product was stirred with 40 ml of a 9: 1 mixture of methylene chloride and ethanol and washed with 20 ml of saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated.

Výťažok bol 1,5 g (100 % teoretického výťažku) produktu vo forme hnedej olejovitej látky;The yield was 1.5 g (100% of theory) of the product as a brown oil;

Rf hodnota: 0,63 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 90 : 10 : 1). Rf value: 0.63 (silica gel; ethyl acetate / ethanol / ammonia 90: 10: 1).

c) N-(n-Propyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[(4-kyanofenyl)tio-mctyl]-benziimidazol-5-yl-karboxylovejc) 1-Methyl-2 - [(4-cyanophenyl) thiomethyl] -benzimidazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide

Zmes 1,5 g (4,1 mmolu) N-(n-propyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-chlórmetyl-l-metyl-benziimidazol-5-yl-karboxylovej a 0,65 g (4,8 mmolu) p-kyanotiofenolu v 10 ml dimetylformamidu a 10 ml diizopropyletylamínu sa 1 hodinu zahrieval na 100 °C. Rozpúšťadlo sa potom oddestilovalo vo vákuu, surový produkt sa rozpustil v 30 ml esteru kyseliny octovej, premyl 30 ml vody a nakoncentrovaní sa čistil rýchlou chromatografiou (gél kyseliny kremičitej; metylénchlorid/etanol = 49 : 1 až 19 : 1). Výťažok bol 1,5 g (79 % teoretického výťažku) produktu vo forme hnedej olejovitej látky,A mixture of 2-chloromethyl-1-methyl-benziimidazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide (1.5 g, 4.1 mmol) and 0.65 g ( 4.8 mmol) of p-cyanothiophenol in 10 ml of dimethylformamide and 10 ml of diisopropylethylamine was heated at 100 ° C for 1 hour. The solvent was then distilled off in vacuo, the crude product was dissolved in 30 ml of acetic acid ester, washed with 30 ml of water, and concentrated by flash chromatography (silica gel; methylene chloride / ethanol = 49: 1 to 19: 1). The yield was 1.5 g (79% of theory) of the product as a brown oil,

Rt hodnota: 0,65 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 90:10:1). Rt value: 0.65 (silica gel; ethyl acetate / ethanol / ammonia 90: 10: 1).

d) Hydrochlorid N-(n-propyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[(4-amidinofeny])-tiometylj-benzimidazol-5 -yl-karboxylo vejd) 1-Methyl-2 - [(4-amidinophenyl) -thiomethyl] benzimidazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride

1,4 g (3,01 mmolu) N-(n-propyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[(4-kyanofenyl)tiomctyl]-benziimidazol-5-yl-karboxylovej v 50 ml chlorovodíkom nasýteného etanolu sa miešala 5 hodín najprv pri 0 °C, neskoršie pri teplote miestnosti, kým sa chromatografiou v tenkej vrstve nezistilo neprítomnosť východiskového materiálu. Rozpúšťadlo sa potom oddestilovalo pri teplote kúpeľa najviac 30 °C, olejovitý zvyšok a rozmiešal do 40 ml absolútneho etanolu a zmiešal s 2,8 g uhličitanu amónneho. Po 18 hodinách sa rozpúšťadlo oddestilovalo vo vákuu a surový produkt sa čistil rýchlou chromatografiou (gél kyseliny kremičitej; metylénchlorid/etanol = 19 : 1 až 4:1).1.4 g (3.01 mmol) of 1-methyl-2 - [(4-cyanophenyl) thiomethyl] -benzimidazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide in 50 ml of hydrogen chloride-saturated ethanol was stirred for 5 hours at 0 ° C, later at room temperature, until the absence of starting material was detected by thin layer chromatography. The solvent was then distilled off at a bath temperature of not more than 30 ° C, the oily residue was slurried 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 = 19: 1 to 4: 1).

Výťažok bol 1,3 g (83 % teoretického výťažku) produktu vo forme svetlej béžovej tuhej látky;The yield was 1.3 g (83% of theory) of the product as a light beige solid;

Rf hodnota: 0,29 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50 : 45 : 5).Rf value: 0.29 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5).

C25H31N6O3S (481,62) EKA-hmotnostné spektrum: (M+H)+ = 482.C 25 H 31 N 6 O 3 S (481.62) EKA-MS: (M + H) + = 482.

Príklad 28Example 28

Hydrochlorid N-(n-propyl)-N-(2-hydroxykarbonyletyl)-amidu kyseliny l-metyl-2-[(4-amidinofenyl)-tiometyl]-benzimidazol-5-yl-karboxylovej1-methyl-2 - [(4-amidinophenyl) -thiomethyl] -benzimidazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-hydroxycarbonylethyl) -amide

V 15 ml etanolu sa rozpustilo 0,52 g (1,0 mmol) hydrochloridu N-(n-propyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1-metyl-2-[(4-amidinofenyl)-tiometyl]-benzimidazol-5-yl-karboxylovej, roztok sa zmiešal s 5 ml roztoku hydroxidu sodného (cNa0H = 2 mol.dm'3) a zmes sa miešala 2 hodiny pri teplote miestnosti. Potom sa pridalo 5 ml vody a alkohol sa oddestiloval. Zmes sa okyslila koncentrovanou kyselinou chlorovodíkovou. Voda sa potom oddestilovala vo vákuu a surový produkt sa rozmiešal v 5 ml etanolu a roztok sa odfiltroval od nerozpusteného chloridu sodného. Po oddestilovaní rozpúšťadla sa získala v nadpise uvedená zlúčenina vo forme bielej tuhej látky0.52 g (1.0 mmol) of 1-methyl-2 - [(4-amidinophenyl) thiomethyl] N- (n-propyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride was dissolved in 15 ml of ethanol. -benzimidazol-5-yl-carboxylic acid, 5 ml of sodium hydroxide solution (c NaOH = 2 mol.dm < 3 > ) was added and the mixture was stirred at room temperature for 2 hours. Then 5 ml of water was added and the alcohol was distilled off. The mixture was acidified with concentrated hydrochloric acid. The water was then distilled off in vacuo and the crude product was slurried in 5 ml of ethanol and the solution was filtered from undissolved sodium chloride. After distilling off the solvent, the title compound was obtained as a white solid

Výťažok bol 0,43 g (88 % teoretického výťažku) produktu vo forme svetlej béžovej tuhej látky;Yield: 0.43 g (88% of theory) of the product as a light beige solid;

Rf hodnota: 0,19 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50 : 45 : 5).Rf value: 0.19 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5).

C23H27N5O3S (453,57) EKA-hmotnostné spektrum: (M+H)+ = 454, (M+Na)+ = = 476.C 23 H 27 N 5 O 3 S (453.57) EKA-MS: (M + H) + = 454, (M + Na) + = 476.

Príklad 29Example 29

Hydrochlorid N-(2-metylpropyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[(4-amidinofenyl)-tiometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2 - [(4-amidinophenyl) -thiomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-methylpropyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 27 z N-(2-metylpropyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[(4-kyanofenyl)-tiometyl]benzimidazol-5-yl-karboxylovej, etanolovej kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 27 from 1-methyl-2 - [(4-cyanophenyl) thiomethyl] benzimidazol-5-yl-carboxylic acid N- (2-methylpropyl) -N- (2-ethoxycarbonylethyl) amide , ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 83 % teoretického výťažku, C25H3IN6O3S (495,65)Yield: 83% of theory, C 25 H 3 I N 6 O 3 S (495.65)

Rf hodnota: 0,30 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50 : 45 : 5), Rf value: 0.30 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5).

EKA-hmotnostné spektrum: (M+H)+ = 496.EKA-MS: (M + H) < + > = 496.

Príklad 30Example 30

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[(4-amidinofenyl)-tiometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2 - [(4-amidinophenyl) -thiomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 27 z N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[(4-kyanofenyl)-tiometyl]-benzimidazol-5-yl-karboxylovej, etanolovej kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner similar to Example 27 from 1-methyl-2 - [(4-cyanophenyl) -thiomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic acid hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 90 % teoretického výťažku, C28H29N5O3S (515,64)The product yield was 90% of the theoretical yield, C 28 H 29 N 5 O 3 S (515.64)

Rf hodnota: 0,24 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50:45:5), Rf value: 0.24 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5).

EKA-hmotnostné spektrum: (M+H)+ = 516, (M+H+Na)++ = 269,7.EKA-MS: (M + H) + = 516, (M + H + Na) ++ = 269.7.

Príklad 31Example 31

Hydrochlorid N-fenyl-N-(2-hydroxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[(4-amidinofenyl)-tiometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2 - [(4-amidinophenyl) -thiomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 28 z N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[(4-kyanofenyl)-tiometyl]-benz-imidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 28 from 1-methyl-2 - [(4-cyanophenyl) -thiomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide and sodium hydroxide.

Výťažok produktu bol 76 % teoretického výťažku, C25H25N5O3S (487,58)Yield: 76% of theory. C 25 H 25 N 5 O 3 S (487.58)

Rf hodnota: 0,31 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50 : 45 : 5), Rf value: 0.31 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5).

EKA-hmotnostné spektrum: (M+H)+ = 488, (M+Na)+ = = 510.EKA-MS: (M + H) + = 488, (M + Na) + = 510.

Príklad 32Example 32

Hydrochlorid N-(l-metyl-piperidin-4-yl)-N-metyl-amidu kyseliny 1 -metyl-2-[(4-amidinofenyl)-oxymetyl]-benzimidazol-5-sulfónovej1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazole-5-sulfonic acid N- (1-methyl-piperidin-4-yl) -N-methyl-amide hydrochloride

a) N-(l-Metyl-piperidin-4-yl)-N-metyl-amid kyseliny 4-chlór-3 -nitrobenzénsulfónoveja) 4-Chloro-3-nitrobenzenesulfonic acid N- (1-methyl-piperidin-4-yl) -N-methyl-amide

K roztoku 2,2 ml (15 mmolov) l-metyl-4-metylaminopiperidínu v 60 ml sa pri chladení ľadom po častiach pridalo 3,8 g (15 mmolov) chloridu 4-chlór-3-nitrobenzénsulfónovej kyseliny. Reakčná zmes sa potom 2 hodiny miešala za stáleho chladenia a následne sa odparila do sucha. Zvyšok sa rozmiešal v približne 50 ml vody a za silného miešania sa amoniakom upravil do alkalickej reakcie. Vyzrážaný surový produkt sa pomocou odsávania oddelil a čistil stĺpcovou chromatografiou (250 g gélu kyseliny kremičitej; elučné činidlo: dichlórmetán s 1,5 % etanolu). Výťažok produktu bol 1,6 g (31 % teoretického výťažku), C13H18C1N3O4S (347,8)To a solution of 2.2 mL (15 mmol) of 1-methyl-4-methylaminopiperidine in 60 mL was added portionwise 3.8 g (15 mmol) of 4-chloro-3-nitrobenzenesulfonic acid chloride while cooling with ice. The reaction mixture was then stirred with cooling for 2 hours and then evaporated to dryness. The residue was stirred in about 50 ml of water and made alkaline with ammonia with vigorous stirring. The precipitated crude product was collected by suction and purified by column chromatography (250 g silica gel; eluent: dichloromethane with 1.5% ethanol). Yield: 1.6 g (31% of theory), C 13 H 18 ClN 3 O 4 S (347.8)

Rf hodnota: 0,19 (gél kyseliny kremičitej; dichlórmetán/etanol = 19 : 1).Rf value: 0.19 (silica gel; dichloromethane / ethanol = 19: 1).

b) N-Metyl-N-(l-metylpiperidin-4-yl)-amid kyseliny 4-metylamino-3-nitrobenzén-sulfónovejb) 4-methylamino-3-nitrobenzenesulfonic acid N-methyl-N- (1-methylpiperidin-4-yl) -amide

V 30 ml 40%-ného roztoku metylamínu sa rozmiešaloIt was stirred in 30 ml of a 40% methylamine solution

1,6 g (4,6 mmolu) N-metyl-N-(l-metyl-piperidin-4-yl)-amidu kyseliny 4-chlór-3-nitrobenzénsulfónovej a v uzavretej banke sa zmes 4 hodiny premiešavala pri teplote miestnosti. Potom sa zmes zriedila 40 ml vody, vylúčený produkt sa odfiltroval s odsávaním, premyl vodou a vysušil. Výťažok produktu bol 1,5 g (95 % teoretického výťažku), C14H22N4O4S (343,4)1.6 g (4.6 mmol) of 4-chloro-3-nitrobenzenesulfonic acid N-methyl-N- (1-methyl-piperidin-4-yl) -amide and in a sealed flask were stirred at room temperature for 4 hours. The mixture was then diluted with 40 ml of water, the precipitated product was filtered off with suction, washed with water and dried. Yield: 1.5 g (95% of theory), C 14 H 22 N 4 O 4 S (343.4)

Rf hodnota: 0,45 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1). Rf value: 0.45 (silica gel; dichloromethane / ethanol = 4: 1).

c) N-Metyl-N-(l-metylpiperidin-4-yl)-amid kyseliny 3-amino-4-metylaminobenzén-sulfónovejc) 3-Amino-4-methylaminobenzenesulfonic acid N-methyl-N- (1-methylpiperidin-4-yl) -amide

V 100 ml metanolu sa rozpustilo 1,5 g (4,4 mmolu) N-metyl-N-(l-metyl-piperidin-4-yl)-amid kyseliny 4-metylamino-3-nitrobenzénsulfónovej. Roztok sa pri teplote miestnosti a pod tlakom vodíka (0,5 MPa) katalytický hydrogenoval (katalyzátor 10%-né paládium na uhli). Katalyzátor sa potom odfiltroval a filtrát sa skoncentroval. Získaný olejovitý produkt sa bez čistenia použil v ďalšom reakčnom kroku.1.5 g (4.4 mmol) of 4-methylamino-3-nitrobenzenesulfonic acid N-methyl-N- (1-methyl-piperidin-4-yl) -amide was dissolved in 100 ml of methanol. The solution was catalytically hydrogenated (10% palladium on carbon catalyst) at room temperature and under hydrogen pressure (0.5 MPa). The catalyst was then filtered off and the filtrate was concentrated. The oily product obtained was used in the next reaction step without purification.

Výťažok produktu bol 1,4 g (100 % teoretického výťažku), CI4H24N4O2S (312,4)Yield of product was 1.4 g (100% of theory), C 14 H 24 N 4 O 2 S (312.4)

Rf hodnota: 0,33 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1). Rf value: 0.33 (silica gel; dichloromethane / ethanol = 4: 1).

d) N-Metyl-N-(l-metylpiperidin-4-yl)-amid kyseliny 1-metyl-2-[(4-kyanofenyl)oxy-metyl]-benzimidazol-5-sulfónovejd) 1-Methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazole-5-sulfonic acid N-methyl-N- (1-methylpiperidin-4-yl) -amide

V 40 ml tetrahydrofuránu sa rozpustilo 532 mg (3,0 mmoly) 4-kyanofenyloxyoctovej kyseliny a 486 mg (3,0 mmoly) 1,1 ‘-karbonyldiimidazolu. Roztok sa zahrieval 15 minút na teplotu varu pod spätným chladičom. Potom sa pridalo 700 mg (2,24 mmolu) N-metyl-N-(l-metylpiperidin-4-yl)-amidu kyseliny 3-amino-4-metylaminobenzénsulfónovej a zmes sa varila pod spätným chladičom ďalších 8 hodín. Potom sa odparila a získaný olejovitý zvyšok sa zmiešal s 30 ml ľadovej kyseliny octovej a hodinu zahrieval pri teplote varu pod spätným chladičom. Ľadová kyselina octová sa potom oddestilovala, zvyšok sa rozmie šal s približne 30 ml vody a koncentrovaným amoniakom upravil do alkalickej reakcie. Potom sa trikrát extrahoval vždy s 20 ml dichlórmetánu. Spojené organické fázy sa sušili a skoncentrovali. Získaný produkt sa použil bez čistenia v ďalšom reakčnom kroku.532 mg (3.0 mmol) of 4-cyanophenyloxyacetic acid and 486 mg (3.0 mmol) of 1,1'-carbonyldiimidazole were dissolved in 40 ml of tetrahydrofuran. The solution was heated to reflux for 15 minutes. 700 mg (2.24 mmol) of 3-amino-4-methylaminobenzenesulfonic acid N-methyl-N- (1-methylpiperidin-4-yl) amide was then added and the mixture was refluxed for an additional 8 hours. It was then evaporated and the resulting oily residue was treated with 30 ml of glacial acetic acid and refluxed for 1 hour. The glacial acetic acid was then distilled off, the residue was stirred with approximately 30 ml of water and made alkaline with concentrated ammonia. It was then extracted three times with 20 ml of dichloromethane each time. The combined organic phases were dried and concentrated. The obtained product was used in the next reaction step without purification.

Výťažok produktu bol 400 mg (39 % teoretického výťažku),The product yield was 400 mg (39% of theory),

C23H27N5O3S (453,6)C 23 H 27 N 5 O 3 S (453.6)

Rf hodnota: 0,37 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1). Rf value: 0.37 (silica gel; dichloromethane / ethanol = 4: 1).

e) Hydrochlorid N-metyl-N-(l-metylpiperidin-4-yl)-amidu kyseliny 1 -metyl-2-[(4-amidinofenyl)-oxymetyl]-benzimidazol-5-sulfónoveje) 1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazole-5-sulfonic acid N-methyl-N- (1-methylpiperidin-4-yl) -amide hydrochloride

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-metyl-N-(l-metylpiperidín-4-yl)-amidu kyseliny 1 -metyl-2-[(4-kyanofenyl)-oxymetyl]-benzimidazol-5-sulfónovej, etanolovej kyseliny chlorovodíkovej a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazole-5-sulfonic acid N-methyl-N- (1-methylpiperidin-4-yl) -amide, ethanolic hydrochloric acid and ammonium carbonate.

Výťažok produktu bol 370 mg (83 % teoretického výťažku),Yield: 370 mg (83% of theory);

C23H30N6O3S (470,6)C 23 H 30 N 6 O 3 S (470.6)

EKA-hmotnostné spektrum: (M+H)+ = 471, (M+2H)++ = = 236.EKA mass spectrum: (M + H) + = 471, (M + 2H) ++ = 236th

Príklad 33Example 33

Hydrochlorid N-metyl-N-fenyl-amidu kyseliny l-metyl-2-[(4-amidinofenyl)-oxymetyI]-benzimidazol-5-suIfónovej1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazole-5-sulfonic acid N-methyl-N-phenyl-amide hydrochloride

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 32 z N-metyl-N-fenyl-amidu kyseliny l-metyl-2-[(4-kyanofenyl)-oxymetyI]-benzimidazol-5-sulfónovej, etanolovej kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a similar manner to Example 32 from 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazole-5-sulfonic acid N-methyl-N-phenyl-amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate .

Výťažok produktu bol 46 % teoretického výťažku, C2JH23N5O3S (449,5)The yield of the product was 46% of the theoretical yield, C 2 H 23 N 5 O 3 S (449.5)

EKA-hmotnostné spektrum: (M+H)+ = 450, (M+2H)++ = = 223, (M+H+metanol) = 482.EKA-MS: (M + H) < + > = 450, (M + 2H) < + > = = 223, (M + H + methanol) = 482.

Príklad 34Example 34

Hydrochlorid N-(3-etoxykarbonyl-n-propyl)-N-fenylami-du kyseliny 1 -metyl-2-[(4-amidinofenyl)-oxymetyl]-benzimidazol-5 -sulfónovej1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazole-5-sulfonic acid, N- (3-ethoxycarbonyl-n-propyl) -N-phenylamide hydrochloride

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 32 z N-(3-etoxykarbonyl-n-propyl)-N-fenyl-amidu kyseliny 1 -metyl-2-[(4-kyanofenyl)-oxymetyl]-benzimidazol-5-sulfónovej, etanolovej kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 32 from 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazole-5-sulfonic acid N- (3-ethoxycarbonyl-n-propyl) -N-phenyl-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 57 % teoretického výťažku, C28H3IN5O5S (549,7)Yield: 57% of theory, of C 28 3 I N 5 O 5 S (549.7)

EKA-hmotnostné spektrum: (M+H)+ = 550.EKA-MS: (M + H) < + > = 550.

Príklad 35Example 35

Hydrochlorid pyrolididu kyseliny l-metyl-2-[(3-amidinofenyl)-oxymetyl]-benzimidazol-5-sulfónovej1-Methyl-2 - [(3-amidinophenyl) -oxymethyl] -benzimidazole-5-sulfonic acid pyrrolidide hydrochloride

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 32 z pyrolididu kyseliny l-metyl-2-[(3-kyano-fenyl)oxymetyl]-benzimidazol-5-sulfónovej, etanolovej kyseliny chlorovodíkovej,etanolu a uhličitanu amónneho. Výťažok produktu bol 71 % teoretického výťažku, C20H23N5O3S (413,5)The compound was prepared in a similar manner to Example 32 from 1-methyl-2 - [(3-cyano-phenyl) oxymethyl] -benzimidazole-5-sulfonic acid pyrrolidide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 71%. C 20 H 23 N 5 O 3 S (413.5)

EKA-hmotnostné spektrum: (M+H)+ = 414.EKA-MS: (M + H) < + > = 414.

Príklad 36Example 36

Dihydrochlorid N-fenyl-N-(3-metoxykarbonylpropyl)-amidu kyseliny l-metyl-2-[2-(4-amidinofenyl)etyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-methoxycarbonylpropyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(3-/erc-butyloxykarbonylpropyl)-N-fenylamidu kyseliny 1 -metyl-2-[2-(4-kyanofenyl) etylj-benzimidazol-5-yl-karboxylovej, metanolovej kyseliny chlorovodíkovej, metanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (4-cyanophenyl) ethyl] benzimidazol-5-yl-carboxylic acid N- (3- tert -butyloxycarbonylpropyl) -N-phenylamide, methanol hydrochloric acid, methanol and ammonium carbonate.

Výťažok produktu bol 83,5 % teoretického výťažku, Rf hodnota: 0,17 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1);Yield: 83.5% of theory. Rf value: 0.17 (silica gel; dichloromethane / ethanol = 4: 1);

C29H31N5O3 (497,6)C 29 H 31 N 5 O 3 (497.6)

EKA-hmotnostné spektrum: (M+H)+ = 498, (M+H+NaJ = = 260,7.EKA-MS: (M + H) < + > = 498, (M + H + Na < + > = 260.7).

Príklad 37Example 37

Hydrochlorid N-fenyl-N-(3-hydroxykarbonylpropyl)-amidu kyseliny 1 -metyl-2-[2-(4-amidinofenyl)etyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxycarbonylpropyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z N-fenyl-N-(3-metoxykarbonylpropyl)-amidu kyseliny l-metyl-2-[(amidinofenyl) aminometylj-benzímidazol-5-yl-karboxylovej a hydroxidu sodného. Výťažok produktu bol 92 % teoretického výťažku, Rf hodnota: 0,09 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1);The compound was prepared in a manner analogous to Example 26 from 1-methyl-2 - [(amidinophenyl) aminomethyl] benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-methoxycarbonylpropyl) -amide and sodium hydroxide. The product yield was 92% of theory, Rf value: 0.09 (silica gel; dichloromethane / ethanol = 4: 1);

C28H29N5O3 (483,6)C 28 H 29 N 5 O 3 (483.6)

EKA-hmotnostné spektrum: (M+H)+ = 484, (M+Na)’ = = 506, (M+H+Na)++ = 253,7.EKA-MS: (M + H) + = 484, (M + Na) + = 506, (M + H + Na) ++ = 253.7.

Príklad 38Example 38

Dihydrochlorid N-fenyl-N-(3-etoxykarbonylpropyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-ethoxycarbonylpropyl) -amide

a) N-fenyl-N-(3-íerc-butyloxykarbonylpropyl)-amid kyseliny l-metyl-2-[N-(4-kyano-fenyl)-amínometyl]-benzimidazol-5-yl-karboxyloveja) 1-Methyl-2- [N- (4-cyano-phenyl) -amino-methyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-tert-butyloxycarbonyl-propyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25c z N-(4-kyanofenyl)-glycínu a N-fenyl-N-(3-Zerc-butyloxykarbonylpropyl)-amidu kyseliny 3-amino-4-metylaminobenzoovej.The compound was prepared in a manner analogous to Example 25c from 3-amino-4-methylaminobenzoic acid N- (4-cyanophenyl) glycine and N-phenyl-N- (3-tert-butyloxycarbonylpropyl) -amide.

Výťažok produktu bol 65 % teoretického výťažku, Rf hodnota: 0,17 (gél kyseliny kremičitej; dichlórmetán/metanol = 19:1);Yield: 65%. Rf value: 0.17 (silica gel; dichloromethane / methanol = 19: 1);

b) Dihydrochlorid N-fenyl-N-(3-etoxykarbonylpropyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovejb) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-ethoxycarbonyl-propyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-fenyl-N-(3-zerc-butyloxykarbonylpropyl)-amidu kyseliny l-metyl-2-[N-(4-kyanofenyl) aminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-tert-butyloxycarbonylpropyl) -amide. , ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 68 % teoretického výťažku, Rf hodnota: 0,12 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1);Yield: 68% of theory, Rf value: 0.12 (silica gel; dichloromethane / ethanol = 4: 1);

C29H32N6O3 (512,6)C 29 H 32 N 6 O 3 (512.6)

EKA-hmotnostné spektrum: (M+H)+ = 513, (M+H+Na)++ = = 268.EKA mass spectrum: (M + H) + = 513, (M + H + Na) ++ = 268th

Príklad 39Example 39

Hydrochlorid N-fenyI-N-(3-hydroxykarbonylpropyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxycarbonylpropyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z dihydro-chloridu N-fenyl-N-(3-etoxykarbonylpropyl)-amidu kyseliny l-metyl-2-[N-(4-amidino fenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 26 from N-phenyl-N- (3-ethoxycarbonylpropyl) -amide 1-methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazole-5- dihydrochloride. ylcarboxylic acid and sodium hydroxide.

Výťažok produktu bol 73,5 % teoretického výťažku, C27H28N6O3 (484,6)Yield: 73.5% of theory. C 27 H 28 N 6 O 3 (484.6)

EKA-hmotnostné spektrum: (M+H)+ = 485, (M+2H) = = 243, (M+H+Na)++ = 254.EKA-MS: (M + H) + = 485, (M + 2H) = 243, (M + H + Na) ++ = 254.

Príklad 40Example 40

Hydrochlorid N-fenyl-N-(etoxykarbonylmetyl)-amidu kyseliny 1 -metyl-2-[2-(4-amidinofenyl)etyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-fenyl-N-(ctoxykarbonylmetyl)-amidu kyseliny 1 -metyl-2-[2-(4-kyanofenyl)etyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (4-cyanophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide, ethanolic acid solution. hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 73 % teoretického výťažku,The product yield was 73% of the theoretical yield,

Rf hodnota: 0,15 (gél kyseliny kremičitej; dichlórmetán/etanol = 4:1);Rf value: 0.15 (silica gel; dichloromethane / ethanol = 4: 1);

C28H29N5O3 (483,6)C 28 H 29 N 5 O 3 (483.6)

EKA-hmotnostné spektrum: (M+H)+ = 484, (M+H+Na)++ = = 253,7.EKA mass spectrum: (M + H) + = 484, (M + H + Na) ++ = 253.7.

Príklad 41Example 41

Hydrochlorid N-fenyl-N-(hydroxykarbonylmetyl)amidu kyseliny 1 -metyl-2-[2-(4-amidi-nofenyl)etyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-yl-carboxylic acid N-phenyl-N- (hydroxycarbonylmethyl) amide hydrochloride

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z dihydrochloridu N-fenyl-N-(etoxykarbonylmetyl)-amidu kyseliny l-metyl-2-[2-(4-amidinofenyl) etyl]benzimidazol-5-yl-karboxylovej a hydroxidu sodného. Výťažok produktu bol 97 % teoretického výťažku, C26H25N5O3 (455,5)The compound was prepared in a similar manner to Example 26 from 1-methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide dihydrochloride and sodium hydroxide. Yield: 97% of theory. C 26 H 25 N 5 O 3 (455.5)

EKA-hmotnostné spektrum: (M+H)+ = 456, (M+Na)+ = = 478, (M+2Na)++ = 250,6.EKA-MS: (M + H) + = 456, (M + Na) + = 478, (M + 2Na) ++ = 250.6.

Príklad 42Example 42

Hydrochlorid N-fenyl-N-(etoxykarbonylmetyl)-amidu kyseliny 1 -metyl-2-[(4-amidinofenyl)oxymetyl]-benzimidazol-5 -yl-karboxylovej1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-fenyl-N-(etoxykarbonylmetyl)-amidu kyseliny l-metyl-2-[(4-kyanofenyl) oxymetyl]-bcnzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 76 % teoretického výťažku,The product yield was 76% of the theoretical yield,

Rf hodnota: 0,17 (gél kyseliny kremičitej; dichlórmetán/etanol = 4:1);Rf value: 0.17 (silica gel; dichloromethane / ethanol = 4: 1);

C27H27N5O4 (485,6)C 27 H 27 N 5 O 4 (485.6)

EKA-hmotnostné spektrum: (M+H)+ = 486, (M+H+Na)++ = = 254,7.EKA mass spectrum: (M + H) + = 486, (M + H + Na) ++ = 254.7.

Príklad 43Example 43

Hydrochlorid N-fenyl-N-(hydroxykarbonylmetyl)-amidu kyseliny l-metyl-2-[(4-amidi-nofenyl)oxymetyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (hydroxycarbonylmethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-fenyl-N-(etoxykarbonylmetyl)-amidu kyseliny l-metyl-2-[(4-amidinofenyl)oxymetyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 26 from 1-methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide hydrochloride and sodium hydroxide.

Výťažok produktu bol 58 % teoretického výťažku, C2SH23N5O4 (457,5)The yield of the product was 58% of the theoretical yield, C 2 S H 23 N 5 O 4 (457.5)

EKA-hmotnostné spektrum: (M+H)+ = 458, (M+Na)+ = = 480, <'M+2Na} = 251,6.EKA-MS: (M + H) < + &gt; = 458, (M + Na) &lt; + &gt; = = 480, &lt; + &gt;

Príklad 44Example 44

Hydrochlorid N-fenyl-N-(etoxykarbonylmetyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-fenyl-N-(etoxykarbonylmetyl)-amidu kyseliny l-metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 74 % teoretického výťažku, Rf hodnota: 0,12 (gél kyseliny kremičitej; dichlórmetán/ctanol = 4 : 1);The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide, ethanol solution hydrochloric acid, ethanol and ammonium carbonate. Yield: 74%. Rf value: 0.12 (silica gel; dichloromethane / ethanol = 4: 1);

C27H28N6O} (484,6)C 27 H 28 N 6 O} (484.6)

EKA-hmotnostné spektrum: (M+H)+ = 485, (M+H+Na)++ = = 254.EKA mass spectrum: (M + H) + = 485, (M + H + Na) ++ = 254th

Príklad 45Example 45

Hydrochlorid N-fenyl-N-(hydroxykarbonylmetyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (hydroxycarbonylmethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-fenyl-N-(etoxykarbonylmetyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 26 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide hydrochloride and hydroxide solution.

Výťažok produktu bol 84 % teoretického výťažku, C25H24N6O3 (456,5)Yield: 84%. C 25 H 24 N 6 O 3 (456.5)

EKA-hmotnostné spektrum: (M+H)+ = 457, (M+Na)+ = = 479, (M+2Na)+* = 251.EKA-MS: (M + H) &lt; + &gt; = 457, (M + Na) &lt; + &gt; = 479, (M + 2Na) &lt; + &gt; = 251.

Príklad 46Example 46

Hydrochlorid N-(4-pyrimidyl)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[(4-amidinofenyl)oxymetyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N- (4-pyrimidyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(4-pyrimidyl)-N-(2-etoxykarbonyletyl)amidu kyseliny 1 -metyl-2-[(4-kyanofenyl) oxymetyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 14 % teoretického výťažku, C26H27N7O4 (501,6) EKA-hmotnostné spektrum: (M+H)+ = 502.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N- (4-pyrimidyl) -N- (2-ethoxycarbonylethyl) amide, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 14% of theory, 2 C 6 H 27 N 7 O 4 (501.6) EKA mass spectrum: (M + H) + = 502nd

Príklad 47Example 47

Dihydrochlorid N-(2-pyridyl)-N-(etoxykarbonylmetyl)-amidu kyseliny l-metyl-2-[(4-amidinofenyl)oxymetyl]-benzimidazol-5-yl-karboxylovej1-methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(2-pyridyl)-N-(etoxykarbonylmetyl)-amidu kyseliny 1 -metyl-2-[(4-kyanofenyl) oxymetylj-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 44 % teoretického výťažku, Rf hodnota: 0,12 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1);The compound was prepared in a manner analogous to Example 25d from 1-methyl-2 - [(4-cyanophenyl) oxymethyl] benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide, ethanol solution hydrochloric acid, ethanol and ammonium carbonate. Yield: 44% of theory, Rf value: 0.12 (silica gel; dichloromethane / ethanol = 4: 1);

C26H26N6O3 (486,5)C 26 H 26 N 6 O 3 (486.5)

EKA-hmotnostné spektrum: (M+H)+ = 487, (M+2H)++ = = 244, (M+H+Naf = 255.EKA-MS: (M + H) &lt; + &gt; = 487, (M + 2H) &lt; + &gt; = = 244, (M + H + Naf = 255).

Príklad 48Example 48

Hydrochlorid N-(2-pyridyl)-N-(hydroxykarbonylmetyl)-amidu kyseliny l-metyl-2-[(4-amidinofenyl)oxymetyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z dihydrochloridu N-(2-pyridyl)-N-(etoxykarbonylmetyl)-amidu kyseliny l-metyl-2-[(4-amidinofenyl) oxymetyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 26 starting from 1-methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide and sodium hydroxide.

Výťažok produktu bol 85 % teoretického výťažku, C24H22NÓO4 (458,5)The yield of the product was 85% of the theoretical yield, C 24 H 22 N 6 O 4 (458.5)

EKA-hmotnostné spektrum: (M+H)+ = 459, (M+Na)+ = = 481, (M+2Na)++= 252.EKA-MS: (M + H) &lt; + &gt; = 459, (M + Na) &lt; + &gt; = 481, (M + 2Na) ++ = 252.

Príklad 49Example 49

Dihydrochlorid N-(2-pyridyl)-N-(etoxykarbonylmetyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) amide

a) N-(2-pyridyl)-N-etoxykarbonylmetyl-amidu kyseliny 1-metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl-karboxyloveja) 1-Methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-ethoxycarbonylmethyl-amide

Zlúčenina sa pripravila obdobne ako v príklade 25c z N-(4-kyanofenyl)-glycínu a N-(2-pyridyl)-N-etoxykarbonylmetylamidu kyseliny 3-amino-4-metylaminobenzoovej.The compound was prepared analogously to Example 25c from N- (4-cyanophenyl) -glycine and N- (2-pyridyl) -N-ethoxycarbonylmethylamide 3-amino-4-methylaminobenzoic acid.

Výťažok produktu bol 24 % teoretického výťažku.The product yield was 24% of the theoretical yield.

Rf hodnota: 0,56 (gél kyseliny kremičitej; dichlórmetán/metanol = 4:1); Rf value: 0.56 (silica gel; dichloromethane / methanol = 4: 1);

b) Dihydrochlorid N-(2-pyridyl)-N-(etoxykarbonylmetyl)amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovejb) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(2-pyridyl)-N-(etoxykarbonylmetyl)-amidu kyseliny 1 -metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 70 % teoretického výťažku, Rf hodnota: 0,16 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1);The compound was prepared in a manner analogous to EXAMPLE 25d from 1-methyl-2- [N- (4-cyanophenyl) aminomethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide; of a carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 70% of theory, Rf value: 0.16 (silica gel; dichloromethane / ethanol = 4: 1);

C26H27N7O3 (485,6)C 26 H 27 N 7 O 3 (485.6)

EKA-hmotnostné spektrum: (M+H)+ = 486, (M+2H)+t = = 243,7, (M+H+Na)++ = 254,6.EKA-MS: (M + H) + = 486, (M + 2H) + t = 243.7, (M + H + Na) ++ = 254.6.

Príklad 50Example 50

Hydrochlorid N-(2-pyridyl)-N-(hydroxykarbonyImetyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) amide hydrochloride

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z dihydrochloridu N-(2-pyridyl)-N-(etoxykarbonylmetyl)-amidu kyseliny l-metyI-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 26 starting from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide dihydrochloride. carboxylic acid and sodium hydroxide.

Výťažok produktu bol 91 % teoretického výťažku, C24H23N7O3 (457,5)The yield of the product was 91% of the theoretical yield, C 24 H 23 N 7 O 3 (457.5)

EKA-hmotnostné spektrum: (M+H)+ = 458, (M+Na)+ = = 480, (M+2Na)++ = 251,7.EKA-MS: (M + H) + = 458, (M + Na) + = 480, (M + 2Na) ++ = 251.7.

Príklad 51Example 51

Dihydrochlorid N-(2-pyridyl)-N-(etoxykarbonylmetyl)-amidu kyseliny l-metyl-2-[2-(4-amidinofenyl) etylj-benzimidazol-5-yl-karboxylovej1-Methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(2-pyridyl)-N-(etoxykarbonylmetyl)-amidu kyseliny l-metyl-2-[2-(4-kyanofenyl) etylj-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 90 % teoretického výťažku, Rf hodnota: 0,17 (gél kyseliny kremičitej; dichlórmetán/ctanol = 4 : 1);The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (4-cyanophenyl) ethyl] benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) amide, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 90% of theory, Rf value: 0.17 (silica gel; dichloromethane / CTAN = 4: 1);

C27H28N6O3 (484,6)C 27 H 28 N 6 O 3 (484.6)

EKA-hmotnostné spektrum: (M+H)+ = 485, (M+2H)++ = = 243, (M+H+Na)+t = 254.EKA mass spectrum: (M + H) + = 485, (M + 2H) ++ = 243 (M + H + Na) + t = 254th

Príklad 52Example 52

Hydrochlorid N-(2-pyridyl)-N-(hydroxykarbonylmetyl)amidu kyseliny l-metyl-2-[2-(4-amidinofenyl) etyl]-benzimidazol-5-yl-karboxylovej1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z dihydro-chloridu N-(2-pyridyl)-N-(etoxykarbonylmetyl)-amidu kyseliny l-metyl-2-[2-(4-amidinofenyl) etyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 26 starting from 1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazole-5- (2-pyridyl) -N- (ethoxycarbonylmethyl) amide dihydrochloride. ylcarboxylic acid and sodium hydroxide.

Výťažok produktu bol 89 % teoretického výťažku, C25H24N6O3 (456,5)The yield of the product was 89% of the theoretical yield, C 25 H 24 N 6 O 3 (456.5)

EKA-hmotnostné spektrum: (M+H)+ = 457, (M+Na)’ = = 479.EKA-MS: (M + H) + = 457, (M + Na) + = 479.

Príklad 53Example 53

Hydrochlorid N-fenyl-N-(2-metoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5 -yl-karboxylo vej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-fenyl-N-(2-metoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, metanolového roztoku kyseliny chlorovodíkovej, metanolu a uhličitanu amónneho. Výťažok produktu bol 87 % teoretického výťažku, Rf hodnota: 0,11 (gél kyseliny kremičitej; dichlórmetán/etanol - 4 : 1);The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide, methanolic solution of hydrochloric acid, methanol and ammonium carbonate. Yield: 87% of theory, Rf value: 0.11 (silica gel; dichloromethane / ethanol - 4: 1);

C27H28N6O3 (484,6)C 27 H 28 N 6 O 3 (484.6)

EKA-hmotnostné spektrum: (M+H)+ = 485, (M+2H)“ = = 243, (M+H+Na)++= 254.EKA-MS: (M + H) + = 485, (M + 2H) + = 243, (M + H + Na) ++ = 254.

Príklad 54Example 54

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[(4-amidino-fenyl)oxymetyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[(4-kyanofenyl) oxymetyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic acid solution. hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 79,5 % teoretického výťažku, C28H29N5O4 (499,6),The product yield was 79.5% of the theoretical yield, C 28 H 29 N 5 O 4 (499.6),

Rf hodnota: 0,15 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1); Rf value: 0.15 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-hmotnostné spektrum: (M+H)+ = 500, (M+H+Na)++ = = 261,7.EKA-MS: (M + H) + = 500, (M + H + Na) ++ = 261.7.

Príklad 55Example 55

Hydrochlorid N-fenyl-N-(2-hydroxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[(4-amidinofenyl)oxymetyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[(4-amidinofenyl)oxymetyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného. Výťažok produktu bol 82 % teoretického výťažku, C26H25N5O4 (471,5)The compound was prepared in a similar manner to Example 26 from 1-methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and sodium hydroxide. The yield of the product was 82% of the theoretical yield, C 26 H 25 N 5 O 4 (471.5)

EKA-hmotnostné spektrum: (MHI)+ = 472, (M+Na)+ = = 494, (M+H+Na)+ = 247,1, (M+2Na)++ = 258,6.EKA-MS: (MHI) + = 472, (M + Na) + = 494, (M + H + Na) + = 247.1, (M + 2Na) ++ = 258.6.

Príklad 56Example 56

Hydrochlorid N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[2-(2-amidinotiofen-5-yl) etyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [2- (2-amidinothiophen-5-yl) ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

a) N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-mctyl-2-[2-(2-kyanotiofen-5-yl) etyl]-benzimidazol-5-yl-karboxyloveja) 1-Methyl-2- [2- (2-cyanothiophen-5-yl) ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 25c z 3-(2-kyanotiofen-5-yl)-propíónovej kyseliny a N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 3-amino-4-metylaminobenzoovej.The compound was prepared analogously to Example 25c from 3- (2-cyanothiophen-5-yl) -propionic acid and 3-amino-4-methylaminobenzoic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide.

Výťažok produktu bol 18 % teoretického výťažku. Rf hodnota: 0,66 (gél kyseliny kremičitej; dichlórmetán/metanol = 9 : 1);The product yield was 18% of the theoretical yield. Rf value: 0.66 (silica gel; dichloromethane / methanol = 9: 1);

b) Hydrochlorid N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[2-(2-amidinotiofen-5-yl) etyl]-benzimidazol-5-yl-karboxylovejb) 1-Methyl-2- [2- (2-amidinothiophen-5-yl) ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1-metyl-2-[2-(2-kyanotiofen-5-yl) etyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 53 % teoretického výťažku, C26H28N6O3S (504,6);The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (2-cyanothiophen-5-yl) ethyl] -benzimidazole N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide 5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 53%. C 26 H 28 N 6 O 3 S (504.6);

Rf hodnota: 0,22 (gél kyseliny kremičitej; dichlórmetán/etanol = 5 : 1); Rf value: 0.22 (silica gel; dichloromethane / ethanol = 5: 1);

EKA-hmotnostné spektrum: (M+H)+ = 505, (M-H+Na)++ = 264.EKA-MS: (M + H) @ + = 505, (M-H @ + Na) @ + = 264.

Príklad 57Example 57

N-(2-Pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[2-(2-amidinotiofen-5-yl) etyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [2- (2-amidinothiophen-5-yl) ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[2-(2-amidinotiofen-5-yl) etyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to EXAMPLE 26 from 1-methyl-2- [2- (2-amidinothiophen-5-yl) ethyl] - N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride. benzimidazol-5-yl-carboxylic acid and sodium hydroxide.

Výťažok produktu bol 98 % teoretického výťažku, C24H24N6O3S (476,6);Yield: 98% of theory, C 24 H 24 N 6 O 3 S (476.6);

EKA-hmotnostné spektrum: (M+H)+ = 477, (M+Na)+ = = 499, (M+2H)++ = 239.EKA-MS: (M + H) @ + = 477, (M + Na) @ + = 499, (M + 2H) @ + = 239.

Príklad 58Example 58

Hydrochlorid N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]benzimidazol-5 -yl-karboxylovej1-methyl-2- [N- (4-amidinophenyl) aminomethyl] benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide

a) N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl-karboxyloveja) 1-Methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 25c z N-(4-kyanofenyl)-glycínu a N-(2-pyridyl)-N-(2-etoxykarbonyletyljamidu kyseliny 3-amino-4-metylaminobenzoovej.The compound was prepared analogously to Example 25c from N- (4-cyanophenyl) glycine and N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide 3-amino-4-methylaminobenzoic acid.

Výťažok produktu bol 61 % teoretického výťažku.The yield of the product was 61% of the theoretical yield.

Rf hodnota: 0,62 (gél kyseliny kremičitej; dichlórmetán/metanol =19:1); Rf value: 0.62 (silica gel; dichloromethane / methanol = 19: 1);

b) Hydrochlorid N-(2-pyridyl)-N-(2-etoxykarbonyletyl)amid kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovejb) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 71 % teoretického výťažku, C27H29N7O3 (499,6);The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazole-5- (N- (2-ethoxycarbonylethyl) -amide) - (2-ethoxycarbonylethyl) -amide. of carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 71%. C 27 H 29 N 7 O 3 (499.6);

Rf hodnota: 0,28 (gél kyseliny kremičitej; dichlórmetán/etanol = 5 : 1);Rf value: 0.28 (silica gel; dichloromethane / ethanol = 5: 1);

EKA-hmotnostné spektrum: (M+H)+ = 500, (M+H+Na)++ = = 261,8, (M+2H)++ = 250,8.EKA-MS: (M + H) + = 500, (M + H + Na) ++ = = 261.8, (M + 2H) ++ = 250.8.

Príklad 59Example 59

N-(2-Pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 26 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-N- (2-ethoxycarbonylethyl) -amide hydrochloride. -yl-carboxylic acid and sodium hydroxide.

Výťažok produktu bol 91 % teoretického výťažku, C25H25N7O3 (471,5);Yield: 91% of theory. C 25 H 25 N 7 O 3 (471.5);

EKA-hmotnostné spektrum: (M+H)+ = 472, (M+H+Na)+ = 247,6, (M+2H)++ = 236,7, (M~2Na)' ‘ = 258,6.EKA-MS: (M + H) &lt; + &gt; = 472, (M + H &lt; + &gt; Na) &lt; + &gt; = 247.6, (M + 2H) &lt; + &gt; .

Príklad 60Example 60

Hydrochlorid N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[2-(4-amidinofenyl) etyl]-benzimidazol-5-yl-karboxylovej1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

a) N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[2-(4-kyanofenyl)-etyl]-benzimidazol-5-yl-karboxyloveja) 1-Methyl-2- [2- (4-cyanophenyl) -ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 149a z 3-(4-kyano-fenyl)propiónovej kyseliny a N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 3-amino-4-metylaminobenzoovej.The compound was prepared analogously to Example 149a from 3- (4-cyano-phenyl) -propionic acid and 3-amino-4-methylaminobenzoic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide.

Výťažok produktu bol 22 % teoretického výťažku.The product yield was 22% of the theoretical yield.

Rf hodnota: 0,68 (gél kyseliny kremičitej; dichlórmetán/metanol = 19:1); Rf value: 0.68 (silica gel; dichloromethane / methanol = 19: 1);

b) Hydrochlorid N-(2-pyridyl)-N-(2-etoxykarbonyletyl)amid kyseliny l-metyl-2-[2-(4-amidinofenyl) etyl]-benzimidazol-5-yl-karboxylovejb) 1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[2-(4-kyanofenyl) etyl]-benzimidazol-5-yI-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (4-cyanophenyl) ethyl] -benzimidazol-5-yl-N- (2-ethoxycarbonylethyl) -amide. -carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 85 % teoretického výťažku, C28H30N6O3 (498,6);The product yield was 85% of the theoretical yield, C 28 H 30 N 6 O 3 (498.6);

Rf hodnota: 0,30 (gél kyseliny kremičitej; dichlórmetán/etanol = 5 : 1); Rf value: 0.30 (silica gel; dichloromethane / ethanol = 5: 1);

EKA-hmotnostné spektrum: (M+H)+ = 499, (M+H+Na)++ = = 261.EKA mass spectrum: (M + H) + = 499, (M + H + Na) ++ = 261st

Príklad 61 N-(2-Pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[2-(4-amidinofenyl) etyl]-benzimidazol-5-yl-karboxylovejExample 61 1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[2-(4-amidinofenyl)-etyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 26 from 1-methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazole-5, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride. -yl-carboxylic acid and sodium hydroxide.

Výťažok produktu bol 97 % teoretického výťažku, C26H26N6O3 (470,5);Yield: 97% of theory. C 26 H 26 N 6 O 3 (470.5);

EKA-hmotnostné spektrum: (M+H)+ = 471, (M+H+Na) = = 247, (M+Na)+ = 493.EKA-MS: (M + H) + = 471, (M + H + Na) = 247, (M + Na) + = 493.

Príklad 62Example 62

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny l-metyl-2-[2-(4-amidino-fenyl)etyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

SK 28S432 B6SK 28S432 B6

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[2-(4-kyanofenyl) etyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (4-cyanophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanol solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 86 % teoretického výťažku, C29H31N5O3 (497,6);Yield: 86% of theory, C 29 H 31 N 5 O 3 (497.6);

Rf hodnota: 0,11 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1); Rf value: 0.11 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-hmotnostné spektrum: (M+H)+ = 498, (M+H+Na)+I = = 249,8.EKA-MS: (M + H) @ + = 498, (M + H @ + Na) @ + = 249.8.

Príklad 63Example 63

Hydrochlorid N-fenyl-N-(2-hydroxykarbonyletyl)-amid kyseliny 1 -metyl-2-[2-(4-amidinofenyl) etyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[2-(4-amidinofenyl)-etyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného. Výťažok produktu bol 71 % teoretického výťažku, C27H27N5O3 (469,6);The compound was prepared in a manner similar to Example 26 from 1-methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide. and sodium hydroxide. Yield: 71%. C 27 H 27 N 5 O 3 (469.6);

EKA-hmotnostné spektrum: (M+H)+ = 470, (M+H+Na)+ = = 246,6, (M+Na)+ = 492, (M+2H)++ = 235,6.EKA-MS: (M + H) + = 470, (M + H + Na) + = 246.6, (M + Na) + = 492, (M + 2H) ++ = 235.6.

Príklad 64Example 64

Dihydrochlorid N-(2-pyridyl)-N-(metoxykarbonylmetyl)amid kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl] -bcnzimidazol-5 -yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (methoxycarbonylmethyl) amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(2-pyridyl)-N-(metoxykarbonylmetyl)-amidu kyseliny 1 -metyl-2-[N-(4-kyanofenyl)-aminometyl]benzimidazol-5-yl-karboxylovej, metanolového roztoku kyseliny chlorovodíkovej, metanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) aminomethyl] benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (methoxycarbonylmethyl) amide , a methanolic solution of hydrochloric acid, methanol and ammonium carbonate.

Výťažok produktu bol 73 % teoretického výťažku, C23H25N7O3 (471,5);Yield: 73%. C 23 H 25 N 7 O 3 (471.5);

Rf hodnota: 0,12 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1);Rf value: 0.12 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-hmotnostné spektrum: (M+H)+ = 472, (M+H+Na)++ = 247,8.EKA-MS: (M + H) @ + = 472, (M + H @ + Na) @ + = 247.8.

Príklad 65Example 65

Hydrochlorid N-(2-pyridyl)-N-(2-metoxykarbonyletyI)-amid kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometylj-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(2-pyridyl)-N-(2-metoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-kyanofenyl)-aminomctyl]-benzimidazol-5-yl-karboxylovej, metanolového roztoku kyseliny chlorovodíkovej, metanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazole-5- (N- (2-methoxycarbonylethyl) -amide) - (2-methoxycarbonylethyl) -amide. of carboxylic acid, methanolic solution of hydrochloric acid, methanol and ammonium carbonate.

Výťažok produktu bol 78 % teoretického výťažku, C26H27N7O3 (485,6);Yield: 78% of theory. C 26 H 27 N 7 O 3 (485.6);

Rf hodnota: 0,31 (gél kyseliny kremičitej; dichlórmetán/etanol = 5 : 1); Rf value: 0.31 (silica gel; dichloromethane / ethanol = 5: 1);

EKA-hmotnostné spektrum: (M+H)+ = 486, (M+H -Naf = = 254,8.EKA-MS: (M + H) &lt; + &gt; = 486, (M + H-Naf = = 254.8).

Príklad 66Example 66

Hydrochlorid N-fenyl-N-[2-(l/7-tetrazol-5-yl)etyl]-amidu kyseliny 1 -metyl-2-[2-(4-amidinofenyl)etyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -amide

a) N-Fenyl-N-[2-(///-tetrazol-5-yl)etyl]-amid kyseliny 1-metyl-2-[2-(4-kyanofenyl)-etyl]-benzimidazol-5-yl-karboxyloveja) 1-Methyl-2- [2- (4-cyanophenyl) ethyl] benzimidazol-5-yl N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -amide carboxylate

Zlúčenina sa pripravila obdobne ako v príklade 25c z 3-(4-kyanofenyl)propiónovej kyseliny a N-fenyl-N-[2-(l//-tetrazol-5-yl)letyl]-amidu kyseliny 3-amino-4-metylaminobenzoovej.The compound was prepared analogously to Example 25c from 3-amino-4- (3- (4-cyanophenyl) propionic acid and N-phenyl-N- [2- (1H-tetrazol-5-yl) -ethyl] -amide. methylaminobenzoic.

Výťažok produktu bol 67 % teoretického výťažku.The product yield was 67% of the theoretical yield.

IČ spektrálna analýza (KBr): charakteristické pásy pri 3 439,5 cm’1 (N-H), 2 235,5 cm’1 (ON), 1631,6 cm’ (OO);IR spectral analysis (KBr): characteristic bands at 3 439.5 cm -1 (NH) 2 235.5 cm "1 (ON), 1631.6 cm" (C = O);

b) Hydrochlorid N-fenyl-N-[2-(17/-tetrazol-5-yl)etyl]-amidu kyseliny l-metyl-2-[2-(4-amidinofenyl) etyl]-benzimidazol-5-yl-karboxylovejb) 1-Methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-yl- N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] amide hydrochloride carboxylic acid

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-fenyl-N-[2-(17/-tetrazol-5-yl)etyl]-amidu kyseliny 1 -metyl-2-[2-(4-kyanofenyl) etyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (4-cyanophenyl) ethyl] N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] amide -benzimidazol-5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 92 % teoretického výťažku, C27H27N9O (493,6);Yield: 92% of theory, C 27 H 27 N 9 O (493.6);

EKA-hmotnostné spektrum: (M+H)+ = 494, (M+Na)+ = = 516, (M+2H)++= 258,7.EKA-MS: (M + H) + = 494, (M + Na) + = 516, (M + 2H) ++ = 258.7.

Príklad 67Example 67

Hydrochlorid N-fenyl-N-[2-(l//-tetrazo]-5-yl)etyl]-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzímidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-N-phenyl-N- [2- (1H-tetrazo-5-yl) -ethyl] -amide hydrochloride carboxylate

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-fenyl-N-[2-(l//-tetrazol-5-yl)etyl]-amidu kyseliny 1 -metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 29 % teoretického výťažku, C26H26N,oO (494,6);The compound was prepared in a manner analogous to Example 25d from N-phenyl-N- [2- (1H-tetrazol-5-yl) -ethyl] -amide 1-methyl-2- [N- (4-cyanophenyl) - aminomethyl] -benzimidazol-5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. The product yield was 29% of theory, C 26 H 26 N 10 O (494.6);

EKA-hmotnostné spektrum: (M+H)+ = 495.EKA-MS: (M + H) &lt; + &gt; = 495.

Príklad 68Example 68

Hydrochlorid N-(2-pyridyl)-N-(2-n-hexyloxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyI]-benzimidazol-5-yl-karboxylovej1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-n-hexyloxycarbonylethyl) -amide

K približne 30 ml chlorovodíkom nasýteného n-hexanolu sa pridalo 0,60 g (1,1 mmolu) hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a zmes sa miešala 19 hodín pri teplote miestnosti. Hexán sa potom oddestiloval vo vákuu. Zvyšok sa rozmiešal s 5 ml roztoku amoniaku (cNH3 = 1 mol.dm'3) a znova odparil. Týmto spôsobom získaný surový produkt sa čistil stĺpcovou chromatografiou (gél kyseliny kremičitej; dichlórmetán/metanol = 5 : 1).To about 30 ml of hydrogen chloride-saturated n-hexanol was added 0.60 g (1.1 mmol) of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide 1-methyl-2- [N- (2-ethoxycarbonylethyl) amide hydrochloride. 4-Aminophenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid was added and the mixture was stirred at room temperature for 19 hours. The hexane was then distilled off in vacuo. The residue was stirred with 5 ml of ammonia solution (c NH 3 = 1 mol.dm 3 ) and evaporated again. The crude product thus obtained was purified by column chromatography (silica gel; dichloromethane / methanol = 5: 1).

Výťažok produktu bol 53 % teoretického výťažku, C31H37N7O3 (555,7);The product yield was 53% of theory, C 31 H 37 N 7 O 3 (555.7);

Rf hodnota: 0,36 (gél kyseliny kremičitej; dichlórmetán/etanol = 5:1);Rf value: 0.36 (silica gel; dichloromethane / ethanol = 5: 1);

EKA-hmotnostné spektrum: (M+H)+ = 556.EKA-MS: (M + H) &lt; + &gt; = 556.

Príklad 69Example 69

Hydrochlorid N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboxylovej1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

a) N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-kyanofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboxyloveja) 1-Methyl-2- [N- (4-cyanophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 25c z N-(4-kyanofenyl)-N-metylglycínu a N-(2-pyridyI)-N-(2-etoxykarbonyletyl)-amidu kyseliny 3-amino-4-metylaminobenzoovej.The compound was prepared in analogy to Example 25c from 3-amino-4-methylaminobenzoic acid N- (4-cyanophenyl) -N-methylglycine and N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide.

Výťažok produktu bol 71 % teoretického výťažku.The yield of the product was 71% of the theoretical yield.

Rf hodnota: 0,66 (gél kyseliny kremičitej; dichlórmetán/metanol = 19:1). Rf value: 0.66 (silica gel; dichloromethane / methanol = 19: 1).

b) Hydrochlorid N-(2-pyridyl)-N-(2-etoxykarbonyletyl)amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-N-metylaminometyl]-benzimidazol-5-yl-karboxylovejb) 1-Methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-kyanofenyl)-N-metyl-aminometyl]benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 77 % teoretického výťažku, C28H31N7O3 (513,6);The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -N-methylaminomethyl] benzimidazole N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide 5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 77% of theory. C 28 H 31 N 7 O 3 (513.6);

EKA-hmotnostné spektrum: (M+H)+ = 514, (M+H+Na)++ = = 268,7.EKA mass spectrum: (M + H) + = 514, (M + H + Na) ++ = 268.7.

Príklad 70Example 70

N-(2-Pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidino-fenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidino-phenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-N-metyl-aminometylJ-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 26 starting from 1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -N- (2-ethoxycarbonylethyl) -amide hydrochloride. benzimidazol-5-yl-carboxylic acid and sodium hydroxide.

Výťažok produktu bol 66 % teoretického výťažku, C26H27N7O3 (485,6);Yield: 66%. C 26 H 27 N 7 O 3 (485.6);

EKA-hmotnostné spektrum: (M+H)+ = 486, (M+Na)+ = = 508, (M+2Na)++ = 265,6.EKA-MS: (M + H) + = 486, (M + Na) + = 508, (M + 2Na) ++ = 265.6.

Príklad 71Example 71

Hydrochlorid N-cyklopentyl-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[2-(4-amidinofenyl)-etyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-cyklopentyl-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[2-(4-kyanofenyl)-etyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 65 % teoretického výťažku, C28H33N5O3 (489,6);The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (4-cyanophenyl) -ethyl] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 65%. C 28 H 33 N 5 O 3 (489.6);

EKA-hmotnostné spektrum: (M+H)+ = 490.EKA-MS: (M + H) &lt; + &gt; = 490.

Príklad 72Example 72

N-Cyklopentyl-N-(2-hydroxykarbonyletyl)-amid kyseliny l-metyl-2-[2-(4-amidinofenyl)etyl]-benzimidazol-5-yl-karboxylovej1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-cyklopentyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[2-(4-amidinofenyl) etyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného. Výťažok produktu bol 89 % teoretického výťažku, C26H31N5O3 (461,6);The compound was prepared in a manner analogous to Example 26 from 1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide and sodium hydroxide. Yield: 89% of theory, C26 H 31 N 3 O 5 (461.6);

EKA-hmotnostné spektrum: (M+H)+ = 462, (M+Na)+ = = 484, (M+H+Na)*' = 242,6, (M+2H) = 231,6.EKA-MS: (M + H) + = 462, (M + Na) + = 484, (M + H + Na) + = 242.6, (M + 2H) = 231.6.

Príklad 73Example 73

Hydrochlorid N-cyklopentyl-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-cyklopentyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 60 % teoretického výťažku,The yield of the product was 60% of the theoretical yield,

C27H34N6O3 (490,6);C2 7 H 34 N 6 O 3 (490.6);

EKA-hmotnostné spektrum: (M+H)+ = 491.EKA-MS: (M + H) &lt; + &gt; = 491.

Príklad 74Example 74

N-Cyklopentyl-N-(2-hydroxykarbonyletyl)-amid kyseliny l-metyl-2-[N-(4-amidino-fenyl)-aminometyl]-benzimidazo 1-5 -yl-karboxylo vej1-methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazo-5-yl-carboxylic acid N-cyclopentyl-N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-cyklopentyl-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofeny1)-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to EXAMPLE 26 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and sodium hydroxide.

Výťažok produktu bol 45 % teoretického výťažku, C25H30N3O4 (462,6);Yield: 45% of theory, C 25 H 30 N 3 O 4 (462.6);

EKA-hmotnostné spektrum: (M+H)+ = 463, (M+Na)+ = = 485, (M+H+Na)++ = 243, (M+2Na)++ = 254.EKA-MS: (M + H) + = 463, (M + Na) + = 485, (M + H + Na) ++ = 243, (M + 2Na) ++ = 254.

Príklad 75Example 75

Hydrochlorid N-(2-pyridyl)-N-(etoxykarbonylmetyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-N-metylaminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(2-pyridyl)-N-(etoxykarbonylmetyl)-amidu kyseliny 1 -metyl-2-[N-(4-kyanofenyl)-N-metylaminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 54 % teoretického výťažku, C27H25,N7O3 (499,6);The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -N-methylaminomethyl] -benzimidazole-5- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide. of carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 54% of theory, 2 C 7 H 5 2, N 7 O 3 (499.6)

EKA-hmotnostné spektrum: (M+H)+ = 500, (M+2H)++ = = 250,7.EKA mass spectrum: (M + H) + = 500, (M + 2H) ++ = 250.7.

Príklad 76 N-(2-Pyridyl)-N-(hydroxykarbonylmetyl)-amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-N-metyl-aminometyl]-benzimidazol-5 -yl-karboxylovejExample 76 1-Methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-(2-pyridyl)-N-(etoxykarbonylmetyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-N-metylaminometyl]benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 26 from N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] benzimidazole-5- ylcarboxylic acid and sodium hydroxide.

Výťažok produktu bol 68 % teoretického výťažku, C25H25N7O3 (471,5);Yield: 68%. C 25 H 25 N 7 O 3 (471.5);

EKA-hmotnostné spektrum: (M+H)+ = 472, (M+Na)+ = = 494, (M+2Na)++ = 258,6.EKA-MS: (M + H) + = 472, (M + Na) + = 494, (M + 2Na) ++ = 258.6.

Príklad 77Example 77

Hydrochlorid N-(3-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[2-(4-amidinofenyl)-etyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(3-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[2-(4-kyanofenyl) etyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (4-cyanophenyl) ethyl] -benzimidazol-5-yl N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) amide -carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 91 % teoretického výťažku, C28H30N6O3 (498,6);Yield: 91% of theory. C 28 H 30 N 6 O 3 (498.6);

Rf hodnota: 0,19 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1); Rf value: 0.19 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-hmotnostné spektrum: (M+H)+ = 499.EKA-MS: (M + H) &lt; + &gt; = 499.

Príklad 78Example 78

Dihydrochlorid N-(3-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(3-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-kyanofenyl)-aminometyl]The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] - N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide.

SK 285432 Β6 benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 86 % teoretického výťažku, C27H29N7O3 (499,6);6-benzimidazol-5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 86% of theory. C 27 H 29 N 7 O 3 (499.6);

Rf hodnota: 0,09 (gél kyseliny kremičitej; dichlórmetán/etanol = 4:1); Rf value: 0.09 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-hmotnostné spektrum: (M+H)+ = 500.EKA-MS: (M + H) &lt; + &gt; = 500.

Príklad 79Example 79

N-(3-Pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z dihydrochloridu N-(3-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 26 starting from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-N- (2-ethoxycarbonylethyl) -amide- dihydrochloride. -yl-carboxylic acid and sodium hydroxide.

Výťažok produktu bol 85 % teoretického výťažku, C23H25N7O3 (471,5);The product yield was 85% of theory, C 23 H 25 N 7 O 3 (471.5);

EKA-hmotnostné spektrum: (M+H)+ = 472, (M+2H)++ = = 236,6, (M+2Na)++ = 258,6.EKA-MS: (M + H) + = 472, (M + 2H) ++ = = 236.6, (M + 2Na) ++ = 258.6.

Príklad 80Example 80

Hydrochlorid N-(3-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-N-metylaminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(3-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-kyanofenyl)-N-metylaminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 64 % teoretického výťažku, C28H31N7O3 (513,6);The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -N-methylaminomethyl] -benzimidazole N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide; Of 5-yl-carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 64%. C 28 H 31 N 7 O 3 (513.6);

EKA-hmotnostné spektrum: (M+H)+ = 514.EKA-MS: (M + H) &lt; + &gt; = 514.

Príklad 81Example 81

N-(3-Pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-N-metyl-aminomctyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-(3-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 26 from 1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride -benzimidazol-5-yl-carboxylic acid and sodium hydroxide.

Výťažok produktu bol 70 % teoretického výťažku, C26H27N7O3 (485,6);Yield: 70%. C 26 H 27 N 7 O 3 (485.6);

EKA-hmotnostné spektrum: (M+H)+ = 486, (M+Na)+ = = 508, (M+ŽNa)” = 265,6.EKA-MS: (M + H) &lt; + &gt; = 486, (M + Na) &lt; + &gt; = = 508, (M + Na) &lt; + &gt; = 265.6.

Príklad 82Example 82

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) N-Fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-kyanofenyl)-N-metyl-aminometyl]-benzimidazoI-5-yl-karboxyloveja) 1-Methyl-2- [N- (4-cyanophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 25c z N-(4-kyanofenyl)-N-metylglycínu a N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 3-amino-4-metylaminobenzoovej.The compound was prepared analogously to Example 25c from 3-amino-4-methylaminobenzoic acid N- (4-cyanophenyl) -N-methylglycine and N-phenyl-N- (2-ethoxycarbonylethyl) amide.

Výťažok produktu bol 71 % teoretického výťažku.The yield of the product was 71% of the theoretical yield.

Rf hodnota: 0,38 (gél kyseliny kremičitej; dichlórmetán/metanol = 19 : 1). Rf value: 0.38 (silica gel; dichloromethane / methanol = 19: 1).

b) Hydrochlorid N-fenyl-N-(2-ctoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-N-metylaminometyl]-benzimidazol-5-yl-karboxylovejb) 1-Methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-kyanofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 74 % teoretického výťažku, C29H32NČO3 (512,6);The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -N-methyl-aminomethyl] -benzimidazole-5- N-phenyl-N- (2-ethoxycarbonylethyl) -amide. of carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 74% of theory, C 29 H 32 N 3 O NO (512.6);

EKA-hmotnostné spektrum: (M+H)+ = 513, (M+H+Na)++ = = 268, (M+2H)++ = 257.EKA-MS: (M + H) &lt; + &gt; = 513, (M + H + Na) &lt; + &gt; = = 268, (M + 2H) &lt; + &gt; = 257.

Príklad 83Example 83

Hydrochlorid N-fenyl-N-(2-hydroxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 26 from 1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazole-5, N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride. -yl-carboxylic acid and sodium hydroxide.

Výťažok produktu bol 80 % teoretického výťažku, C27H28N6O3 (484,6);Yield: 80% of theory, C 27 H 28 N 6 O 3 (484.6);

EKA-hmotnostné spektrum: (M+H)+ = 485, (M-H+Naf ' = = 254, (M+Na)+ = 507, (M-2Na) + = 265.EKA-MS: (M + H) + = 485, (M-H + Na +) = 254, (M + Na) + = 507, (M-2Na) + = 265.

Príklad 84Example 84

Hydrochlorid N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-etyl-2-[N-(4-amidinofenyl)-aminometylj-benzimidazol-5-yl-karboxylovej1-Ethyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-kyanofenyI)-N-metyl-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 85 % teoretického výťažku, C28H31N7O3 (513,6);The compound was prepared in a manner analogous to EXAMPLE 25d from 1-methyl-2- [N- (4-cyanophenyl) -N-methyl-aminomethyl] -N- (2-ethoxycarbonylethyl) -N- (2-ethoxycarbonylethyl) amide - benzimidazol-5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. The product yield was 85% of the theoretical yield, C 28 H 31 N 7 O 3 (513.6);

Rf hodnota: 0,21 (gél kyseliny kremičitej; dichlórmetán/metanol = 5:1), Rf value: 0.21 (silica gel; dichloromethane / methanol = 5: 1).

EKA-hmotnostné spektrum: (M+H)+ = 514, (M+H+Na)++ = 268,6, (Μ+2ΗΓ = 257,7.EKA-MS: (M + H) &lt; + &gt; = 514, (M + H + Na) &lt; + &gt;

Príklad 85Example 85

N-(2-Pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-etyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Ethyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-etyl-2-[N-(4-amidinofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodné-ho (cNa0H - 1 mol.dm'3).The compound was prepared in a manner analogous to Example 26 starting from 1-ethyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride. benzimidazol-5-yl-carboxylic acid, and sodium hydroxide-be (c Na0H - 1 mol.dm '3).

Výťažok produktu bol 49 % teoretického výťažku, C26H27N7O3 (485,6);Yield: 49%. C 26 H 27 N 7 O 3 (485.6);

EKA-hmotnostné spektrum: (M+H)+ = 486, (M+H+Na)++ = = 254,6, (M+2H)+ = 243,6, (M+2Na)++ = 265,7.EKA-MS: (M + H) + = 486, (M + H + Na) ++ = = 254.6, (M + 2H) + = 243.6, (M + 2Na) ++ = 265, 7th

Príklad 86 N-(2-Fluórfenyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidino-fenyl)-aminometyl]-benzimidazol-5-yl-karboxylovejExample 86 1-Methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-fluorophenyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(2-fluórfenyl)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-kyanofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -N-methyl-aminomethyl] -benzimidazole N- (2-fluorophenyl) -N- (2-ethoxycarbonylethyl) amide 5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 88 % teoretického výťažku, C28H29FN6O3 (516,6);The yield of the product was 88% of theory, C 28 H 29 FN 6 O 3 (516.6);

Rf hodnota: 0,08 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1); Rf value: 0.08 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-hmotnostné spektrum: (M+H)+ = 517, (M+H+Na)++ = = 270, (M+2H)++ = 259.EKA-MS: (M + H) &lt; + &gt; = 517, (M + H + Na) &lt; + &gt; = 270, (M + 2H) &lt; + &gt; = 259.

Príklad 87Example 87

N-(2-Fluórfenyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-fluorophenyl) -N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-(2-fluórfenyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 26 starting from 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5-N- (2-fluorophenyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride. -yl-carboxylic acid and sodium hydroxide.

Výťažok produktu bol 45 % teoretického výťažku, C26H25FN6O3 (488,5);The product yield was 45% of theory, C 26 H 25 FN 6 O 3 (488.5);

Rf hodnota: 0,05 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1); Rf value: 0.05 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-hmotnostné spektrum: (M+H)+ = 489, (M+H+Na)++ = 267, (M+2H)+ = 256.EKA-MS: (M + H) + = 489, (M + H + Na) ++ = 267, (M + 2H) + = 256.

Príklad 88Example 88

N-(3 -Metylfenyl)-N-(2-etoxykarbonyletyl)-amid kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (3-methylphenyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(3-metylfenyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-kyanofenyl)-N-metyl-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -N-methylaminomethyl] -N- (2-ethoxycarbonylethyl) -N- (2-ethoxycarbonylethyl) amide - benzimidazol-5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 79 % teoretického výťažku, C29H32N6O3 (512,6);Yield: 79% of theory, C 29 H 32 N 6 O 3 (512.6);

Rf hodnota: 0,10 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1); Rf value: 0.10 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-hmotnostné spektrum: (M+H)+ = 513, (M+H+Na)++ = = 268, (M+2H)++ = 259.EKA-MS: (M + H) &lt; + &gt; = 513, (M + H + Na) &lt; + &gt; = = 268, (M + 2H) &lt; + &gt; = 259.

Príklad 89 N-(3-Metylfenyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1 -metyl-2-[N-(4-amidino-fenyl)-aminometyl]-benzimidazol-5-yl-karboxylovejExample 89 1-Methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (3-methyl-phenyl) -N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-(3-metylfenyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 26 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-N- (2-ethoxycarbonylethyl) -amide hydrochloride. -yl-carboxylic acid and sodium hydroxide.

Výťažok produktu bol 62 % teoretického výťažku, C27H28N6O3 (484,6);Yield: 62%. C 27 H 28 N 6 O 3 (484.6);

EKA-hmotnostné spektrum: (M+H)+ = 485, (M+H+Na)4”*' = = 254, (M+Na)+ = 507, (M+2Na)++ = 265.EKA-MS: (M + H) &lt; + &gt; = 485, (M + H &lt; + &gt; Na) &lt; 4 &gt; = 254, (M + Na) + = 507, (M + 2Na) ++ = 265.

Príklad 90Example 90

N-(Fenyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-n-hexyloxy-karbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-ethoxycarbonylethyl) -amide

V zmesi 40 ml tetrahydrofuránu a 10 ml vody sa rozpustilo 1,1 g (2,06 mmolu) hydrochloridu N-fenyl-N-(2-etoxykarbonyletyljamidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]benzimidazol-5-yl-karboxylovej, pridalo sa 570 mg (4,12 mmolu) uhličitanu draselného a 362 mg (2,2 mmolu) n-hexylesteru kyseliny chlórmravčej a reakčná zmes sa miešala 2 hodiny pri teplote miestnosti. Potom sa rozpúšťadlo oddestilovalo, zvyšok sa rozmiešal v približne 50 ml nasýteného roztoku kuchynskej soli a zís kaný roztok sa trikrát extrahoval, vždy s 20 ml dichlórmetánu. Extrakty sa sušili nad síranom sodným a skoncentrovali. Získaný surový produkt sa čistil stĺpcovou chromatografiou (100 g gélu kyseliny kremičitej; dichlórmetán + 5 % etanolu).1.1 g (2.06 mmol) of 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] N-phenyl-N- (2-ethoxycarbonylethyl) amide hydrochloride was dissolved in a mixture of 40 ml of tetrahydrofuran and 10 ml of water. benzimidazol-5-yl-carboxylic acid, 570 mg (4.12 mmol) of potassium carbonate and 362 mg (2.2 mmol) of n-hexyl chloroformate were added, and the reaction mixture was stirred at room temperature for 2 hours. The residue was taken up in approximately 50 ml of saturated sodium chloride solution and the resulting solution was extracted three times with 20 ml of dichloromethane each, the extracts were dried over sodium sulphate and concentrated. 5% ethanol).

Výťažok produktu bol 78 % teoretického výťažku; C33H42N6O3 (626,8);The product yield was 78% of the theoretical yield; C 33 H 42 N 6 O 3 (626.8);

Rf hodnota: 0,49 (gél kyseliny kremičitej; dichlórmetán/etanol = 19:1); Rf value: 0.49 (silica gel; dichloromethane / ethanol = 19: 1);

EKA - hmotnostné spektrum: (M+H)+ = 627, (M+H+Na)++ = 325, (M+2H)+*= 314.EKA-MS: (M + H) &lt; + &gt; = 627, (M + H + Na) &lt; + &gt; = 325, (M + 2H) &lt; + &gt; = 314.

Príklad 91Example 91

N-(Fenyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-metoxykarbonyl-amidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-methoxycarbonyl-amidino) -phenyl] -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(fenyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-bcnzimidazol-5-yl-karboxylovej a metylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from N- (phenyl) -N- (2-ethoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl- carboxylic acid and methyl chloroformate.

Výťažok produktu bol 41 % teoretického výťažku; C30H32N6O3 (556,6);The product yield was 41% of the theoretical yield; C 30 H 32 N 6 O 3 (556.6);

Rf hodnota: 0,85 (gél kyseliny kremičitej; dichlórmetán/etanol = 4: 1);Rf value: 0.85 (silica gel; dichloromethane / ethanol = 4: 1);

EKA - hmotnostné spektrum: (M+H)+ = 557, (M+H+Naf' = 290, (M+Na)+=579.EKA-MS: (M + H) + = 557, (M + H + Na +) = 290, (M + Na) + = 579.

Príklad 92Example 92

N-(Fenyl)-N-(2-metoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-etoxykarbonyl-amidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-ethoxycarbonyl-amidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-methoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(fenyl)-N-(2-metoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-amino-metyl]-benzimidazol-5-yl-karboxylovej a etylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from N- (phenyl) -N- (2-methoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) -amino-methyl] -benzimidazole-5- hydrochloride. yl carboxylic acid and ethyl chloroformate.

Výťažok produktu bol 62 % teoretického výťažku; C30H32N6O3 (556,6);The yield of the product was 62% of the theoretical yield; C 30 H 32 N 6 O 3 (556.6);

Rf hodnota: 0,51 (gél kyseliny kremičitej; dichlórmetán/etanol = 19:1);Rf value: 0.51 (silica gel; dichloromethane / ethanol = 19: 1);

EKA - hmotnostné spektrum: (M+H)+ = 557, (M+H+Na)++ = 290, (M+2H)t+ = 279.EKA-MS: (M + H) &lt; + &gt; = 557, (M + H + Na) &lt; + &gt; = 290, (M + 2H) &lt; + &gt; = 279.

Príklad 93Example 93

N-(Fenyl)-N-(2-metoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-cyklohexyloxy-karbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-cyclohexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-methoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(fenyl)-N-(2-metoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-amino-metyl]benzimidazol-5-yl-karboxylovej a cyklohexylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from N- (phenyl) -N- (2-methoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) amino-methyl] benzimidazol-5-yl hydrochloride carboxylic acid and cyclohexyl chloroformate.

Výťažok produktu bol 25 % teoretického výťažku; C34H38N6O5 (610,7);The product yield was 25% of the theoretical yield; C 34 H 38 N 6 O 5 (610.7);

Rf hodnota: 0,44 (gél kyseliny kremičitej; dichlórmetán/etanol = 19: 1);Rf value: 0.44 (silica gel; dichloromethane / ethanol = 19: 1);

EKA - hmotnostné spektrum: (M+H)+ = 611, (M-2H)4+ = = 306.EKA - MS (M + H) + = 611, (M-2H) 4+ = 306th

Príklad 94Example 94

N-(Fenyl)-N-(2-etoxykarbonyletyl)amid kyseliny 1-metyl-2-[N-[4-[N-[2-(metylsulfonyl)-etyloxykarbonyl]-amidino]fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-methyl-2- [N- [4- [N- [2- (methylsulfonyl) -ethyloxycarbonyl] -amino] phenyl] -aminomethyl] -benzimidazole N- (phenyl) -N- (2-ethoxycarbonylethyl) amide 5-yl-carboxylic acid

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(fenyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a 2-(mctylsulfonyl)-etylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from N- (phenyl) -N- (2-ethoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl- carboxylic acid and 2- (methylsulfonyl) ethyl chloroformate.

Výťažok produktu bol 66 % teoretického výťažku; C32H36N6O7S (648,8);The yield of the product was 66% of the theoretical yield; C 32 H 36 N 6 O 7 S (648.8);

Rf hodnota: 0,44 (gél kyseliny kremičitej; dichlórmetán/etanol =19:1);Rf value: 0.44 (silica gel; dichloromethane / ethanol = 19: 1);

EKA - hmotnostné spektrum: (M+Hf = 649, (Μ+2Η)'~ = = 325, ÍM11U Na)'* = 336.EKA-Mass Spectrum: (M + H + = 649, (Η + 2Η) + - = 325, M @ 11 U Na) @ + = 336.

Príklad 95Example 95

N-(Fenyl)-N-(2-metoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-n-oktyloxykarbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-n-octyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-methoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(fenyl)-N-(2-metoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]benzimidazol-5-yl-karboxylovej a n-oktylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from N- (phenyl) -N- (2-methoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] benzimidazol-5-yl-carboxylic acid hydrochloride and n-octyl chloroformate.

Výťažok produktu bol 41 % teoretického výťažku; C36H44N6O5 (640,8);The product yield was 41% of the theoretical yield; C 36 H 44 N 6 O 5 (640.8);

Rf hodnota: 0,43 (gél kyseliny kremičitej; dichlórmetán/etanol = 19:1);Rf value: 0.43 (silica gel; dichloromethane / ethanol = 19: 1);

EKA - hmotnostné spektrum: (M+H)+ = 641, (M+Na)+ = = 663.EKA-MS: (M + H) + = 641, (M + Na) + = 663.

Príklad 96Example 96

N-(Fenyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-hydroxyl-amidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-hydroxyl-amidino) -phenyl] -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-ethoxycarbonylethyl) -amide

V 80 ml etanolu sa rozpustilo 1,44 g (3,0 mmolu) N-(fenyl)-N-(2-etoxy-karbonyletyl)-amidu kyseliny 1-metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, 0,625 g (9,0 mmolov) hydroxylamínhydrochloridu a 0,425 g (4,0 mmoly) uhličitanu sodného a zmes sa Ί hodín zahrievala pri teplote varu pod spätným chladičom. Potom sa pridal ďalší podiel hydroxylamínhydrochloridu (210 mg) a uhličitanu sodného (170 mg) a zmes sa varila ďalších 5 hodín pod spätným chladičom. Potom sa zmes skoncentrovala vo vákuu. Zvyšok sa rozpustil v približne 30 ml dichlórmetánu, získaný roztok sa premyl 20 ml vody, organická fáza sa sušila a skoncentrovala. Získaný surový produkt sa čistil stĺpcovou chromatografiou (200 g gélu kyseliny kremičitej; dichlórmetán + 4 % etanolu). Výťažok produktu bol 39 % teoretického výťažku; C28H30N6O4 (514,6);1.44 g (3.0 mmol) of 1-methyl-2- [N- (4-cyanophenyl) aminomethyl] N- (phenyl) -N- (2-ethoxycarbonylethyl) amide was dissolved in 80 ml of ethanol. 1-benzimidazol-5-yl-carboxylic acid, 0.625 g (9.0 mmol) of hydroxylamine hydrochloride and 0.425 g (4.0 mmol) of sodium carbonate, and the mixture was heated at reflux for Ί hour. An additional portion of hydroxylamine hydrochloride (210 mg) and sodium carbonate (170 mg) was then added and the mixture was refluxed for an additional 5 hours. The mixture was then concentrated in vacuo. The residue was dissolved in about 30 mL of dichloromethane, the resulting solution was washed with 20 mL of water, the organic phase was dried and concentrated. The crude product obtained was purified by column chromatography (200 g silica gel; dichloromethane + 4% ethanol). The product yield was 39% of the theoretical yield; C 28 H 30 N 6 O 4 (514.6);

Rf hodnota: 0,15 (gél kyseliny kremičitej; dichlórmetán/etanol = 19 : 1); Rf value: 0.15 (silica gel; dichloromethane / ethanol = 19: 1);

EKA - hmotnostné spektrum: (M+H)+ = 515, (M+Na)+ = = 537, (2M+H)+ = 1 029, (2M+Na)+ = 1 051.EKA-MS: (M + H) + = 515, (M + Na) + = 537, (2M + H) + = 1,029, (2M + Na) + = 1,051.

Príklad 97Example 97

N-(Fenyl)-N-(2-metoxykarbonyletyl)-amid kyseliny 1 -metyl-2-[N-[4-(N-n-heptyloxy-karbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-n-heptyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-methoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(fenyl)-N-(2-metoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a n-heptylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from N- (phenyl) -N- (2-methoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl- carboxylic acid and n-heptyl chloroformate.

Výťažok produktu bol 43 % teoretického výťažku; C3SH42N6O5 (626,8);The product yield was 43% of the theoretical yield; C 3 H 42 N 6 O 5 (626.8);

Rr hodnota: 0,40 (gél kyseliny kremičitej; dichlórmetán/etanol =19:1); R f value: 0.40 (silica gel; dichloromethane / ethanol = 19: 1);

EKA - hmotnostné spektrum: (M+H)+ = 627, (M+H+Na)++ = 325, (M+Na)+= 649.EKA-MS: (M + H) @ + = 627, (M + H @ + Na) @ + = 325, (M + Na) @ + = 649.

Príklad 98Example 98

N-(Fcnyl)-N-(2-metoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-benzoylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-benzoylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (Fcnyl) -N- (2-methoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(fenyl)-N-(2-metoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a benzoylchloridu. Výťažok produktu bol 88 % teoretického výťažku; C34H32N6O4 (588,7);The compound was prepared analogously to Example 90 from N- (phenyl) -N- (2-methoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl- carboxylic acid and benzoyl chloride. The yield of the product was 88% of the theoretical yield; C 34 H 32 N 6 O 4 (588.7);

Rf hodnota: 0,37 (gél kyseliny kremičitej; dichlórmetán/etanol = 19 : 1); Rf value: 0.37 (silica gel; dichloromethane / ethanol = 19: 1);

’H NMR spektrum (D6-DMSO) : 2,61 (t, 2H), 3,54 (s, 3H), 3,76 (s, 3H), 4,10 (t, 2H), 4,61 (d, 2H), 6,83 (d, 2H), 7,05 až 7,55 (m, 12H), 8,03 (d, 2H), 8,25 (dd, 2H), 8,98 (s, 1 H), 10,48 (s, 1H).1 H NMR Spectrum (D 6 -DMSO): 2.61 (t, 2H), 3.54 (s, 3H), 3.76 (s, 3H), 4.10 (t, 2H), 4.61 (d, 2H), 6.83 (d, 2H), 7.05-7.55 (m, 12H), 8.03 (d, 2H), 8.25 (dd, 2H), 8.98 ( s, 1H), 10.48 (s, 1H).

Príklad 99Example 99

N-(Fenyl)-N-(2-metoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-n-hexyloxy-karbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-methoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(fenyl)-N-(2-metoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a n-hexylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from N- (phenyl) -N- (2-methoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl- carboxylic acid and n-hexyl chloroformate.

Výťažok produktu bol 54 % teoretického výťažku; C34H40N6Os (612,7);The yield of the product was 54% of the theoretical yield; C 34 H 40 N 6 O, (612.7);

Rf hodnota: 0,45 (gél kyseliny kremičitej; dichlórmetán/etanol =19:1); Rf value: 0.45 (silica gel; dichloromethane / ethanol = 19: 1);

EKA-hmotnostné spektrum: (M+H)+ = 613.EKA-MS: (M + H) &lt; + &gt; = 613.

Príklad 100Example 100

N-(Fenyl)-N-(2-n-propyloxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-n-hexyl-oxykarbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-n-propyloxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(fenyl)-N-(2-n-propyloxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a n-hexylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-N- (2-n-propyloxycarbonylethyl) -amide hydrochloride and n-hexyl chloroformate.

Výťažok produktu bol 31 % teoretického výťažku; C36H44N6O5 (640,8);The product yield was 31% of the theoretical yield; 3 C 6 H 44 N 6 O 5 (640.8);

Rf hodnota: 0,42 (gél kyseliny kremičitej; dichlórmetán/etanol =19:1); Rf value: 0.42 (silica gel; dichloromethane / ethanol = 19: 1);

EKA-hmotnostné spektrum: (M+H)+ = 641, (M+Na)+ = = 663, (M+H+Na)++ = 332.EKA-MS: (M + H) + = 641, (M + Na) + = 663, (M + H + Na) ++ = 332.

Príklad 101 N-(2-Pyridyl)-N-(2-metoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-etoxy-karbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovejExample 101 1-Methyl-2- [N- [4- (N-ethoxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide carboxylate

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-metoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a etylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5- (N- (2-methoxycarbonylethyl) -amide) hydrochloride. yl carboxylic acid and ethyl chloroformate.

Výťažok produktu bol 72 % teoretického výťažku; C29H31N7O5 (557,6);The yield of the product was 72% of the theoretical yield; C 29 H 31 N 7 O 5 (557.6);

Rf hodnota: 0,58 (gél kyseliny kremičitej; dichlórmetán/etanol = 9:1);Rf value: 0.58 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 558, (M+N'a)’ = = 580, (M+H+Na)++ = 290,8.EKA-MS: (M + H) + = 558, (M + N'a) - = 580, (M + H + Na) ++ = 290.8.

Príklad 102 N-(2-Pyridyl)-N-(2-metoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-n-oktyloxykarbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovejExample 102 1-Methyl-2- [N- [4- (N-n-octyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-metoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a n-oktylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide hydrochloride and n-octyl chloroformate.

Výťažok produktu bol 57 % teoretického výťažku; C35H43N7O3 (641,8);The yield of the product was 57% of the theoretical yield; C 35 H 43 N 7 O 3 (641.8);

Rf hodnota: 0,60 (gél kyseliny kremičitej; dichlórmetán/etanol = 9 : 1); Rf value: 0.60 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 642, (M+Na)+ = = 664, (M+H+Na)++ = 332,8.EKA-MS: (M + H) + = 642, (M + Na) + = 664, (M + H + Na) ++ = 332.8.

Príklad 103 N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)amid kyseliny 1-metyl-2-[N-[4-(N-metoxykarbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovejExample 103 1-Methyl-2- [N- [4- (N-methoxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a etylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride carboxylic acid and ethyl chloroformate.

Výťažok produktu bol 48 % teoretického výťažku; C29H3IN7O5 (557,6);The yield of the product was 48% of the theoretical yield; 3 I C 29 N 7 O 5 (557.6);

Rf hodnota: 0,62 (gél kyseliny kremičitej; dichlórmetán/etanol = 9 : 1);Rf value: 0.62 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 558, (M+Na)+ = = 580, (M+H+Na)’* = 290,7.EKA-MS: (M + H) &lt; + &gt; = 558, (M + Na) &lt; + &gt; = 580, (M + H + Na) &lt; + &gt; = 290.7.

Príklad 104Example 104

N-(2-Pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-n-oktyloxykarbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-n-octyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

Zmes 0,12 g (3,0 mmoly) hydroxidu sodného, 5 ml vody a 10 ml metanolu s 0,7 g (1,1 mmolu) N-(2-pyridyl)-N-(2-metoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-[4-(N-n-oktyloxykarbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej sa miešala 1 hodinu pri teplote miestnosti. Potom sa zmes zriedila 20 ml vody a pH zmesi sa nastavilo ľadovou kyselinou octovou na hodnotu 6. Potom sa pridalo približne 5 ml dietyléteru a zmes sa hodinu intenzívne miešala. Pri miešaní sa vylúčil produkt, ktorý sa oddelil filtráciou s odsávaním, premyl malým množstvom vody, potom dietyléterom a vysušil sa.A mixture of 0.12 g (3.0 mmol) of sodium hydroxide, 5 ml of water and 10 ml of methanol with 0.7 g (1.1 mmol) of N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide The 1-methyl-2- [N- [4- (Nn-octyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid was stirred at room temperature for 1 hour. Then the mixture was diluted with 20 ml of water and the pH of the mixture was adjusted to 6 with glacial acetic acid. Approximately 5 ml of diethyl ether was added and the mixture was stirred vigorously for one hour. Upon stirring, the product precipitated, which was collected by suction filtration, washed with a small amount of water, then with diethyl ether and dried.

Výťažok produktu bol 80 % teoretického výťažku; C34H4IN7O5 (627,8);The yield of the product was 80% of the theoretical yield; C 34 H 41 N 7 O 5 (627.8);

EKA-hmotnostné spektrum: (M+H)+ = 628, (M~H=N'a)” = = 325,7, (M+Na)+ = 650, (M+2Na)++ = 337,7.EKA-MS: (M + H) &lt; + &gt; = 628, (M-H = N &apos; a) &gt; = = 325.7, (M + Na) &lt; + &gt; = 650, (M + 2Na) ++ = 337.7 .

Príklad 105 N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-[N-(2-metylsulfonyletyloxykarbonyl)amidino]fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonylctyl)-amidu kyseliny I -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a 2-(metylsulfonyl)-etylesteru kyseliny chlórmravčej.Example 105 1-Methyl-2- [N- [4- [N- (2-methylsulfonylethyloxycarbonyl) amidino] phenyl] aminomethyl] -benzimidazole N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide 5-yl-carboxylic acid The compound was prepared analogously to Example 90 from N- (2-pyridyl) -N- (2-ethoxycarbonyl-ethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] hydrochloride benzimidazol-5-yl-carboxylic acid; and 2- (methylsulfonyl) ethyl chloroformate.

Výťažok produktu bol 65 % teoretického výťažku; C3|H35N7O7S (649,7);The product yield was 65% of the theoretical yield; C 3 H 35 N 7 O 7 S (649.7);

Rf hodnota: 0,54 (gél kyseliny kremičitej; dichlórmetán/etanol = 9 : 1);Rf value: 0.54 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 650, (M+Na)+ = = 672, (M+H+Na)++ = 336,6, (M+2Na)++ = 347,6.EKA-MS: (M + H) + = 650, (M + Na) + = 672, (M + H + Na) ++ = 336.6, (M + 2Na) ++ = 347.6.

Príklad 106 N-(2-Pyridyl)-N-(2-metoxykarbonyletyl)-amid kyseliny 1 -metyl-2-[N-[4-(N-n-butyloxykarbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovejExample 106 1-Methyl-2- [N- [4- (N-n-butyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-metoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a n-butylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5- yl carboxylic acid and n-butyl chloroformate.

Výťažok produktu bol 30 % teoretického výťažku; C31H35N7O5 (585,7);The product yield was 30% of the theoretical yield; C 31 H 35 N 7 O 5 (585.7);

Rf hodnota: 0,62 (gél kyseliny kremičitej; dichlórmetán/etanol = 9: 1); Rf value: 0.62 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 586, (M+H+Na) = = 304,7, (Μ+2ΗΓ = 293,7.EKA-MS: (M + H) &lt; + &gt; = 586, (M + H &lt; + &gt; Na) = 304.7, ([delta] + 2H) = 293.7.

Príklad 107Example 107

N-(2-Pyridyl)-N-(2-metoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-n-hexyloxykarbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-metoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a n-hexylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide hydrochloride and n-hexyl chloroformate.

Výťažok produktu bol 51 % teoretického výťažku; C33H39N7O5 (613,7);The product yield was 51% of the theoretical yield; C 33 H 9 N 3 O 7 5 (613.7);

Rf hodnota: 0,56 (gél kyseliny kremičitej; dichlórmetán/ctanol = 9 : 1);Rf value: 0.56 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)’ = 614, (M+H+Na)^ = = 318,7, (M+2H)++ = 307,6.EKA-MS: (M + H) + = 614, (M + H + Na) + = 318.7, (M + 2H) ++ = 307.6.

Príklad 108Example 108

N-(2-Pyridyl)-N-(2-metoxykarbonyletyl)amid kyseliny 1-metyl-2-[N-[4-(N-n-heptyloxykarbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-n-heptyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-metoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a n-heptylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide hydrochloride and n-heptyl chloroformate.

Výťažok produktu bol 21 % teoretického výťažku; C34H41N7O5 (627,8);The product yield was 21% of the theoretical yield; C 34 H 41 N 7 O 5 (627.8);

Rf hodnota: 0,60 (gél kyseliny kremičitej; dichlórmetán/etanol = 9:1);Rf value: 0.60 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 628, (M+H+Na)++ = = 325,7, (M+2H)++= 314,7.EKA-MS: (M + H) + = 628, (M + H + Na) ++ = = 325.7, (M + 2H) ++ = 314.7.

Príklad 109 N-(2-Pyridyl)-N-(2-metoxykarbonyletyl)amid kyseliny 1-metyl-2-[N-[4-(N-n-pentyloxykarbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovejExample 109 1-Methyl-2- [N- [4- (N-n-pentyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-metoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a n-pentylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide hydrochloride and n-pentyl chloroformate.

Výťažok produktu bol 661 % teoretického výťažku; C32H37N7O5 (599,7);The product yield was 661% of the theoretical yield; C 32 H 37 N 7 O 5 (599.7);

Rf hodnota: 0,58 (gél kyseliny kremičitej; dichlórmetán.'etanol = 9 : 1);Rf value: 0.58 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostnc spektrum: (M+H)+ = 600, (M+H+Na) = = 311,7, (M+Na)+ = 622.EKA-MS: (M + H) + = 600, (M + H + Na) = 311.7, (M + Na) + = 622.

Príklad 110 N-(2-Pyridyl)-N-(2-metoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-n-nonyloxy-karbonylamidino)fenyl]aminometyl]-benzimidazol-5-yl-karboxylovejExample 110 1-Methyl-2- [N- [4- (N-nonyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide- carboxylic acid

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-metoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a n-nonylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide hydrochloride -carboxylic acid and n-nonyl chloroformate.

Výťažok produktu bol 60 % teoretického výťažku; C36H45N7O5 (655,8);The product yield was 60% of the theoretical yield; C 36 H 45 N 7 O 5 (655.8);

Rf hodnota: 0,48 (gél kyseliny kremičitej; dichlórmetán/etanol = 9 : 1);Rf value: 0.48 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 656, (M+H+Na)t+ = = 339,8, (M+Na)+ = 678.EKA-MS: (M + H) @ + = 656, (M + H @ + Na) t @ + = 339.8, (M + Na) @ + = 678.

Príklad 111 N-(2-Pyridyl)-N-(2-metoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-benzoylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovejExample 111 1-Methyl-2- [N- [4- (N-benzoylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-metoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a benzoylchloridu. Výťažok produktu bol 62 % teoretického výťažku; C33H31N7O4 (589,7);The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide hydrochloride and benzoyl chloride. The yield of the product was 62% of the theoretical yield; C 33 H 31 N 7 O 4 (589.7);

Rf hodnota: 0,50 (gél kyseliny kremičitej; dichlórmetán/etanol = 9 : 1); Rf value: 0.50 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 590, (M+Na)+ = = 612.EKA-MS: (M + H) + = 590, (M + Na) + = 612.

Príklad 112Example 112

N-(2-Pyridyl)-N-(2-metoxykarbonyletyl)-amid kyseliny 1 -metyl-2-[N-[4-(N-nikotinoylamidino)fenyl]-aminometylj-benzimidazol-5 -yl-karboxylovej1-Methyl-2- [N- [4- (N-nicotinoylamidino) phenyl] aminomethyl] benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-metoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a nikotinoylchloridu.The compound was prepared analogously to Example 90 from N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5- ylcarboxylic and nicotinoyl chloride.

Výťažok produktu bol 40 % teoretického výťažku; C32H30N8O4 (590,7);The product yield was 40% of the theoretical yield; C 32 H 30 N 8 O 4 (590.7);

Rf hodnota: 0,47 (gél kyseliny kremičitej; dichlórmetán/etanol = 9:1); Rf value: 0.47 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 591, (M+H+Na)+ = = 307, (M+Na)+ = 613.EKA-MS: (M + H) + = 591, (M + H + Na) + = 307, (M + Na) + = 613.

Príklad 113 N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-n-hexyloxy-karbonylamidino)fenyl]aminometyl]-benzimidazol-5-yl-karboxylovejExample 113 1-Methyl-2- [N- [4- (N-hexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide- carboxylic acid

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyIJ-benzimidazol-5-yl-karboxylovej a n-hexylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-N- (2-ethoxycarbonylethyl) amide hydrochloride. carboxylic acid and n-hexyl chloroformate.

Výťažok produktu bol 51 % teoretického výťažku; C34H4iN7C>5 (627,8);The product yield was 51% of the theoretical yield; C 34 H 4 N 7 C 5 (627.8);

Rf hodnota: 0,53 (gél kyseliny kremičitej; dichlórmetán/etanol = 9 : 1); Rf value: 0.53 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 628, (M+H+Na)++ = = 325,7, (M+2H)++ = 314,7.EKA-MS: (M + H) + = 628, (M + H + Na) ++ = = 325.7, (M + 2H) ++ = 314.7.

Príklad 114Example 114

N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-n-oktyloxykarbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-n-octyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzímidazol-5-yI-karboxylovej a n-oktylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5-, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride. γ-carboxylic acid and n-octyl chloroformate.

Výťažok produktu bol 57 % teoretického výťažku; C36H45N7O5 (655,8);The yield of the product was 57% of the theoretical yield; C 36 H 45 N 7 O 5 (655.8);

Rf hodnota: 0,46 (gél kyseliny kremičitej; dichlórmetán/etanol = 9 : 1); Rf value: 0.46 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 656, (M+H+Na)++ = = 339,7, (M+2H) = 328,7.EKA-MS: (M + H) + = 656, (M + H + Na) ++ = 339.7, (M + 2H) = 328.7.

Príklad 115Example 115

N-(2-Pyridyl)-N-etoxykarbonylmetyl-amid kyseliny 1-metyl-2-[N-[4-[N-(2-metylsulfonyl-etyloxykarbonyl)amidino]-fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- [N- (2-methylsulfonyl-ethyloxycarbonyl) -amidino] -phenyl] -aminomethyl] -benzimidazol-5-yl-N- (2-pyridyl) -N-ethoxycarbonylmethyl-amide carboxylate

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-etoxykarbonylmetyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a 2-(metylsulfonyl)-etylesteru kyseliny chlór-mravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-ethoxycarbonylmethyl) -amide. and 2- (methylsulfonyl) ethyl formate.

Výťažok produktu bol 72 % teoretického výťažku; C30H33N7O7S (635,7);The yield of the product was 72% of the theoretical yield; C 30 H 33 N 7 O 7 S (635.7);

Rf hodnota: 0,23 (gél kyseliny kremičitej; dichlórmetán/etanol =19:1);Rf value: 0.23 (silica gel; dichloromethane / ethanol = 19: 1);

EKA-hmotnostné spektrum: (M+H)+ = 636, (M+H+Na)++ = = 329,8.EKA mass spectrum: (M + H) + = 636, (M + H + Na) ++ = 329.8.

Príklad 116 N-(2-Pyridyl)-N-(metoxykarbonylmetyl)-amid kyseliny 1-metyl-2-[N-[4-(N-cyklohexyl-oxykarbonylamidino)-fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovejExample 116 1-Methyl-2- [N- [4- (N-cyclohexyl-oxycarbonylamidino) -phenyl] -aminomethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (methoxycarbonylmethyl) -amide- carboxylic acid

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-metoxykarbonylmetylamidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a cyklohexylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-methoxycarbonylmethylamide hydrochloride and cyclohexyl ester chloroformate.

Výťažok produktu bol 40 % teoretického výťažku; C32H35N7O5 (597,7);The product yield was 40% of the theoretical yield; C 32 H 35 N 7 O 5 (597.7);

Rf hodnota: 0,26 (gél kyseliny kremičitej; dichlórmetán/etanol =19:1); Rf value: 0.26 (silica gel; dichloromethane / ethanol = 19: 1);

EKA-hmotnostné spektrum: (M+H)+ = 598, (M+Na)+ = = 620.EKA-MS: (M + H) + = 598, (M + Na) + = 620.

Príklad 117Example 117

N-(2-Pyridyl)-N-etoxykarbonylmetylamid kyseliny 1-metyl-2-[N-[4-(N-metoxykarbonylamidino)-fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-methoxycarbonylamidino) -phenyl] -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-ethoxycarbonylmethylamide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-etoxykarbonylmetylamidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a metylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-ethoxycarbonylmethylamide hydrochloride and methyl ester chloroformate.

Výťažok produktu bol 62 % teoretického výťažku; C28H29N7O5 (543,6);The yield of the product was 62% of the theoretical yield; C 28 H 29 N 7 O 5 (543.6);

Rf hodnota: 0,19 (gél kyseliny kremičitej; dichlórmetán/etanol = 19 : 1)Rf value: 0.19 (silica gel; dichloromethane / ethanol = 19: 1)

EKA-hmotnostné spektrum: (M+H)+ = 544, (M+H+Na)++ = = 283,8, (M+Na)+ = 566.EKA-MS: (M + H) + = 544, (M + H + Na) ++ = = 283.8, (M + Na) + = 566.

Príklad 118Example 118

N-(2-Pyridyl)-N-metoxykarbonylmetylamid kyseliny 1-metyl-2-[N-[4-(N-etoxykarbonylamidino)-fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-ethoxycarbonylamidino) -phenyl] -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-methoxycarbonylmethylamide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-metoxykarbonylmetylamidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a etylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-methoxycarbonylmethylamide hydrochloride and ethyl ester chloroformate.

Výťažok produktu bol 42 % teoretického výťažku; C28H29N7O5 (543,6);The product yield was 42% of the theoretical yield; C28H29N7O5 (543.6);

Rf hodnota: 0,20 (gél kyseliny kremičitej; dichlórmetán/etanol= 19 : 1); Rf value: 0.20 (silica gel; dichloromethane / ethanol = 19: 1);

EKA-hmotnostné spektrum: (M~H)+ = 544.EKA-MS: (M-H) + = 544.

Príklad 119Example 119

N-(3-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-n-oktyloxy-karbonylamidino)-fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (Nn-octyloxycarbonylamidino) -phenyl] -aminomethyl] -benzimidazol-5-yl- N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide- carboxylic acid

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(3-pyridyl)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-amino-metyl]benzimidazol-5-yl-karboxylovej a n-oktylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) amino-methyl] benzimidazole-5- (N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride) yl carboxylic acid and n-octyl chloroformate.

Výťažok produktu bol 35 % teoretického výťažku; C36H45N7O5 (655,8);The product yield was 35% of the theoretical yield; C 36 H 45 N 7 O 5 (655.8);

Rf hodnota: 0,28 (gél kyseliny kremičitej; dichlórmetán/etanol =19:1);Rf value: 0.28 (silica gel; dichloromethane / ethanol = 19: 1);

EKA-hmotnostné spektrum: (M+H)' = 656, (M+2H)'1 = = 328,7.EKA mass spectrum: (M + H) + = 656, (M + 2H) '1 = 328.7.

Príklad 120 N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-n-hexyloxykarbonylamidino)-fenyl]-N-metyl-aminometyl]-benzimidazol-5-yl-karboxylovejExample 120 1-Methyl-2- [N- [4- (N-hexyloxycarbonylamidino) -phenyl] -N-methyl-aminomethyl] -benzimidazole N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide 5-yl-carboxylic acid

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-N-metylaminometyl]-benzimidazol-5-yl-karboxylovej a n-hexylesteru kyseliny chlór-mravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazole hydrochloride, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride. 5-yl-carboxylic acid and n-hexyl chloroformate.

Výťažok produktu bol 58 % teoretického výťažku; C35H43N7O5 (641,2);The yield of the product was 58% of the theoretical yield; C 35 H 43 N 7 O 5 (641.2);

Rf hodnota: 0,42 (gél kyseliny kremičitej; dichlórmetán/etanol = 19 : 1); Rf value: 0.42 (silica gel; dichloromethane / ethanol = 19: 1);

EKA-hmotnostné spektrum: (M+H)+ = 642, (M+H+Na)++ = = 332,7.EKA mass spectrum: (M + H) + = 642, (M + H + Na) ++ = 332.7.

Príklad 121Example 121

N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-n-oktyloxykarbonylamidino)-fenyl]-N-metyl-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (Nn-octyloxycarbonylamidino) -phenyl] -N-methyl-aminomethyl] -benzimidazole-5- N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide yl-carboxylic acid

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-N-metylaminometyl]-benzimidazol-5-yl-karboxylovej a n-oktylesteru kyseliny chlór-mravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazole hydrochloride, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide, 5-yl-carboxylic acid and n-octyl chloroformate.

Výťažok produktu bol 36 % teoretického výťažku; C37H47N7O5 (669,8);The product yield was 36% of the theoretical yield; C 37 H 47 N 7 O 5 (669.8);

EKA-hmotnostné spektrum: (M+H)+ = 670, (M+H+Na)++ = = 346,8, (M+2H)' * = 335,6.EKA-MS: (M + H) + = 670, (M + H + Na) ++ = = 346.8, (M + 2H) + = 335.6.

Príklad 122Example 122

N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-n-butyloxy-karbonylamidino)-fenyl]-N-metylaminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-butyloxycarbonylamidino) -phenyl] -N-methylaminomethyl] -benzimidazole-5- N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide yl-carboxylic acid

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-N-metylaminometyl]-benzimidazol-5-yl-karboxylovej a n-butylesteru kyseliny chlór-mravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazole hydrochloride, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide, 5-yl-carboxylic acid and n-butyl chloroformate.

Výťažok produktu bol 34 % teoretického výťažku; C33H39N7O5 (613,7);The product yield was 34% of the theoretical yield; C 33 H 39 N 7 O 5 (613.7);

EKA-hmotnostné spektrum: (M+H)+ = 614, (M+H+Na)++ = = 318,7, (M+Na)+ = 636.EKA-MS: (M + H) + = 614; (M + H + Na) ++ = = 318.7; (M + Na) + = 636.

Príklad 123Example 123

N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-benzoylamidino)-fenyl]-N-metylaminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-benzoylamidino) -phenyl] -N-methylaminomethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide- carboxylic acid

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-N-metylaminometyl]-benzimidazol-5-yl-karboxylovej a benzoylchloridu.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazole hydrochloride, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride. 5-yl-carboxylic acid and benzoyl chloride.

Výťažok produktu bol 63 % teoretického výťažku; C35H35N7O4 (617,7);The yield of the product was 63% of the theoretical yield; C 35 H 35 N 7 O 4 (617.7);

EKA-hmotnostné spektrum: (M+H)+ = 618, (M+H+Na)++ = = 320,7, (M+Na)+ = 640.EKA-MS: (M + H) + = 618, (M + H + Na) ++ = = 320.7, (M + Na) + = 640.

Príklad 124Example 124

-Metyl-2-[N-(4-amidinofenyl) oxymetyl]-benzimidazol-5-yl-( 1 -etoxykarbonylmetyl-cyklohex-1 -yl)-ketónhydrochlorid-Methyl-2- [N- (4-amidinophenyl) oxymethyl] -benzimidazol-5-yl- (1-ethoxycarbonylmethyl-cyclohex-1-yl) -ketone hydrochloride

a) Chlórfenyl-( 1 -hydroxykarbonylmetyl-cyklohex-1 - yl)-ketóna) Chlorophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) ketone

V 300 ml tetrahydrofuránu sa rozpustilo 8,4 g (40 mmolov) 3-(4-chlórbenzoyl)propiónovej kyseliny a do tohto roztoku sa po častiach pridávalo 5,8 g (120 mmolov) hydridu sodného (50 - 60%-ná suspenzia v parafínovom 0leji). Reakčná zmes sa potom miešala a zahrievala 1,5 hodinu pri teplote varu pod spätným chladičom, potom sa po kvapkách pridalo 8,9 ml (60 mmolov) 1,5-dijódpentánu a zmes sa ďalej varila 3 hodiny. Po ochladení sa roztok rozmiešal do 200 ml ľadovej vody; tetrahydrofurán sa oddestiloval vo vákuu, získaný vodný roztok sa okyslil kyselinou chlorovodíkovou (cHci = 2 mol.drrí3) a trikrát extrahoval, vždy s 150 ml dichlórmetánu. Organická fáza sa sušila a skoncentrovala. Získaný surový produkt sa čistil stĺpcovou chromatografiou (500 g gélu kyseliny kremičitej; elučné činidlo dichlórmetán s 1 - 2 % etanolu)8.4 g (40 mmol) of 3- (4-chlorobenzoyl) propionic acid were dissolved in 300 ml of tetrahydrofuran and 5.8 g (120 mmol) of sodium hydride (50-60% suspension in sodium hydride) was added in portions to this solution. paraffin oil). The reaction mixture was then stirred and refluxed for 1.5 hours, then 1,5-diiodo-pentane (8.9 mL, 60 mmol) was added dropwise and the mixture was further boiled for 3 hours. After cooling, the solution was stirred into 200 ml of ice water; tetrahydrofuran was distilled off in vacuo, the aqueous solution was acidified with hydrochloric acid (c = ci H 2 mol.drrí 3) and extracted three times with 150 ml of dichloromethane. The organic phase was dried and concentrated. The crude product obtained was purified by column chromatography (500 g silica gel; eluent dichloromethane with 1-2% ethanol)

Výťažok bol 6,2 g (55 % teoretického výťažku) olejovitého produktu;The yield was 6.2 g (55% of theory) of the oily product;

C15H|7C1O3 (280,8);C 15 H | 7 C1O 3 (280.8);

Rf hodnota: 0,56 (gél kyseliny kremičitej; dichlórmetán/etanol = 19 : 1);Rf value: 0.56 (silica gel; dichloromethane / ethanol = 19: 1);

b) 4-Chlór-3-nitrofenyl-( 1 -hydroxykarbonylmetyl-cyklohex-l-yl)-ketónb) 4-Chloro-3-nitrophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) ketone

7,0 g (25 mmolov) chlórfenyl-(l-hydroxykarbonylmetylcyklohex-l-yl)ketónu sa po častiach vnášalo za miešania pri teplote -5 až -10 °C do 80 ml dýmivej kyseliny dusičnej. Potom sa zmes ešte 10 minút miešala. Reakčná zmes sa potom zamiešala do 200 ml ľadovej vody, vylúčený produkt sa premyl vodou a sušil.7.0 g (25 mmol) of chlorophenyl- (1-hydroxycarbonylmethylcyclohex-1-yl) ketone were introduced portionwise with stirring at -5 to -10 ° C into 80 ml of fuming nitric acid. The mixture was then stirred for a further 10 minutes. The reaction mixture was then stirred in 200 ml of ice water, the precipitated product was washed with water and dried.

Výťažok bol 7,8 g (96 % teoretického výťažku) produktu; C|5H16C1NO5 (325,8);Yield: 7.8 g (96% of theory); C | 5 H 16 ClNO 5 (325.8);

Rf hodnota: 0,41 (gél kyseliny kremičitej; petroléter/ester kyseliny octovej = 4:6); Rf value: 0.41 (silica gel; petroleum ether / ethyl acetate = 4: 6);

c) 4-Metylamino-3-nitrofenyl-(l -hydroxykarbonylmetylcyklohex-1 -yl)-ketónc) 4-Methylamino-3-nitrophenyl- (1-hydroxycarbonylmethylcyclohex-1-yl) ketone

7.8 g (23,9 nimolov) 4-chlór-3-nitrofenyl-(l-hydroxykarbonylmetyl-cyklohex-l-yl)ketónu sa pri teplote miestnosti miešalo 14 hodín v 100 ml 40%-ného vodného roztoku metylamínu, potom sa zmes zriedila približne 150 ml vody a okyslila do mierne kyslej reakcie ľadovou kyselinou octovou. Vylúčený produkt sa oddelil filtráciou s odsávaním, premyl vodou a sušil.7.8 g (23.9 nmoles) of 4-chloro-3-nitrophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) ketone was stirred at room temperature for 14 hours in 100 ml of a 40% aqueous methylamine solution, then diluted. 150 ml of water and acidified to a slightly acidic reaction with glacial acetic acid. The precipitated product was collected by suction filtration, washed with water and dried.

Výťažok bol 7,1 g (93 % teoretického výťažku) produktu; C,6H20N2O5 (320,4);Yield: 7.1 g (93% of theory); C 6 H 20 N 2 O 5 (320.4);

Rf hodnota: 0,34 (gél kyseliny kremičitej; dichlórmetán/etanol = 19 : 1) Rf value: 0.34 (silica gel; dichloromethane / ethanol = 19: 1)

d) 4-Metylamino-3-nitrofenyl-(l -metoxykarbonylmetylcyklohex-1 -yl)-ketónd) 4-Methylamino-3-nitrophenyl- (1-methoxycarbonylmethylcyclohex-1-yl) ketone

4.9 g (15 mmolov) 4-metylamino-3-nitrofenyl-(l-hydroxykarbonylmetyl-cyklohex-1 -yl)-ketónu sa rozpustilo v 100 ml tetrahydrofuránu, pridalo sa 2,4 g (15 mmolov) Ι,Γ-karbonyldiimidazolu a zmes sa zahrievala 15 minút pri teplote varu pod spätným chladičom. Potom sa rozpúšťadlo odparilo, pridalo sa 30 ml metanolu a zmes sa opäť varila pod spätným chladičom 3 hodiny. Po oddestilovaní metanolu sa získaný surový produkt čistil stĺpcovou chromatografiou (250 g gélu kyseliny kremičitej; elučné činidlo : dichlórmetán s 1 až 5 % etanolu).4.9 g (15 mmol) of 4-methylamino-3-nitrophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) ketone were dissolved in 100 ml of tetrahydrofuran, 2.4 g (15 mmol) of Ι, Γ-carbonyldiimidazole were added and the mixture was refluxed for 15 minutes. Then the solvent was evaporated, 30 ml of methanol were added and the mixture was again refluxed for 3 hours. After distilling off the methanol, the crude product obtained was purified by column chromatography (250 g of silica gel; eluent: dichloromethane with 1-5% ethanol).

Výťažok bol 2,4 g (48 % teoretického výťažku) produktu; C17H22N2O5 (334,4);Yield: 2.4 g (48% of theory); C 17 H 22 N 2 O 5 (334.4);

Rf hodnota: 0,76 (gél kyseliny kremičitej; dichlórmetán/etanol = 19 : 1).Rf value: 0.76 (silica gel; dichloromethane / ethanol = 19: 1).

e) 3-Amino-4-metylaminofenyl-( 1 -metoxykarbonylmetylcyklohex-1 -yl)-ketóne) 3-Amino-4-methylaminophenyl- (1-methoxycarbonylmethylcyclohex-1-yl) ketone

2.4 g (7,2 mmolu) 4-metylamino-3-nitrofenyl-(l-metoxykarbonylmetyl-cyklohex-l-yl)ketónu v 100 ml metanolu sa pri teplote miestnosti a tlaku 0,5 MPa vodíka katalytický hydrogenovalo s použitím 10%-ného paládia na uhlí. Získaný surový produkt sa bez čistenia použil v ďalšom reakčnom kroku.2.4 g (7.2 mmol) of 4-methylamino-3-nitrophenyl- (1-methoxycarbonylmethyl-cyclohex-1-yl) ketone in 100 ml of methanol at room temperature and 0.5 MPa of hydrogen were catalytically hydrogenated using 10% - palladium on coal. The crude product obtained was used in the next reaction step without purification.

Výťažok bol 2,1 g (96 % teoretického výťažku) produktu; Rf hodnota: 0,34 (gél kyseliny kremičitej; dichlórmetán/etanol = 19 : 1).Yield: 2.1 g (96% of theory); Rf value: 0.34 (silica gel; dichloromethane / ethanol = 19: 1).

f) 3-(4-Kyanofenyloxyacetylamino)-4-metylaminofenyl-(l-metoxykarbonylmetylcyklohex-1 -yl)-kctónf) 3- (4-Cyanophenyloxyacetylamino) -4-methylaminophenyl- (1-methoxycarbonylmethylcyclohex-1-yl) octone

620 mg ((3,2 mmolu) kyseliny 4-kyanofenyloxyoctovej a 570 mg (3,5 mmolu) l,l‘-karbonyl-diimidazolu v 50 ml tetrahydrofuránu sa zahrievalo 15 minút pri teplote varu pod spätným chladičom. Potom sa pridal 1,0 g (3,28 mmolu) 3-amino-4-metylaminofenyl-(l-metoxykarbonyl-metylcyklohex-l-yl)ketónu a reakčná zmes sa varila ďalšie 4 hodiny. Potom sa rozpúšťadlo odparilo a získaný surový produkt sa čistil stĺpcovou chromatografiou (150 g gélu kyseliny kremičitej; elučné činidlo: dichlórmetán s 0 až 2 % ctanolu).620 mg (3.2 mmol) of 4-cyanophenyloxyacetic acid and 570 mg (3.5 mmol) of 1,1'-carbonyl-diimidazole in 50 ml of tetrahydrofuran were heated under reflux for 15 min. 0 g (3.28 mmol) of 3-amino-4-methylaminophenyl- (1-methoxycarbonylmethylcyclohex-1-yl) ketone and the reaction mixture was boiled for an additional 4 hours, then the solvent was evaporated and the crude product obtained was purified by column chromatography ( 150 g of silica gel, eluent: dichloromethane with 0-2% ethanol).

Výťažok bol 1,4 g (93 % teoretického výťažku) produktu; C26H29N3O5 (463,5);Yield: 1.4 g (93% of theory); C 26 H 29 N 3 O 5 (463.5);

Rf hodnota: 0,44 (gél kyseliny kremičitej, dichlórmetán/etanol =19:1).Rf value: 0.44 (silica gel, dichloromethane / ethanol = 19: 1).

g) 1 -Metyl-2-[(4-kyanofenyl)oxymetyl]-benzimidazol-5-yl-(1 -metoxykarbonylmetyl-cyklohex-1 -yljketóng) 1-Methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazol-5-yl- (1-methoxycarbonylmethyl-cyclohex-1-yl) ketone

1.4 g (3,02 mmolu) 3-(4-kyanofenyloxyacetylamino)-4-metylaminofenyl-( 1 -metoxykarbonylmetyl-cyklohex-1 -yl)ketónu v 50 ml ľadovej kyseliny octovej sa zahrievalo hodinu pri teplote varu pod spätným chladičom. Potom sa kyselina octová oddestilovala, zvyšok sa rozmiešal s 20 ml vody a koncentrovaným roztokom amoniaku sa reakcia zmesi upravila na zásaditú. Roztok sa trikrát extrahoval, vždy s 20 ml dichlórmetánu. Organické extrakty sa sušili a skoncentrovali. Získaný surový produkt sa čistil stĺpcovou chromatografiou (100 g gélu kyseliny kremičitej; elučné činidlo: dichlórmetán s 0 až 2 % etanolu).1.4 g (3.02 mmol) of 3- (4-cyanophenyloxyacetylamino) -4-methylaminophenyl- (1-methoxycarbonylmethyl-cyclohex-1-yl) ketone in 50 ml of glacial acetic acid was heated at reflux for 1 hour. The acetic acid was then distilled off, the residue was stirred with 20 ml of water, and the concentrated ammonia solution was made basic. The solution was extracted three times, each time with 20 ml of dichloromethane. The organic extracts were dried and concentrated. The crude product obtained was purified by column chromatography (100 g silica gel; eluent: dichloromethane with 0-2% ethanol).

Výťažok bol 700 mg produktu (52 % teoretického výťažku ); C26H27N3O4 (445,5).The yield was 700 mg of product (52% of theory); C 26 H 27 N 3 O 4 (445.5).

h) 1 -Metyl-2-[(4-amidinofenyl)oxymetyl]-benzimidazol-5-yl-( 1 -etoxykarbonylmetyl-cyklohex-1 -yl)-ketón-hydrochloridh) 1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl- (1-ethoxycarbonylmethyl-cyclohex-1-yl) -ketone hydrochloride

Zlúčenina sa pripravila obdobne ako v príklade 25d z 700 mg (1,57 mmolu) l-metyI-2-[(4-kyanofenyl)oxymetyl]-benzimidazol-5-yl-( 1 -metoxykarbonylmetyl-cyklohex-l-yl)-ketónu, etanolového roztoku kyseliny chlorovodíkovej a uhličitanu amónneho.The compound was prepared analogously to Example 25d from 700 mg (1.57 mmol) of 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazol-5-yl- (1-methoxycarbonylmethyl-cyclohex-1-yl) - ketone, ethanolic hydrochloric acid and ammonium carbonate.

Výťažok bol 390 mg (50 % teoretického výťažku) produktu;Yield: 390 mg (50% of theory);

C27H32N4O4 (476,6);C 27 H 32 N 4 O 4 (476.6);

EKA hmotnostné spektrum: (M+H)+ = 477;EKA mass spectrum: (M + H) + = 477;

‘H NMR spektrum (d6-DMSO): 1,10 (t, 3H), 1,0 až 2,15 (m, 10H), 3,36 (s, 3H), 3,90 (s, 2H), 3,94 (q, 2H), 5,60 (s, 2H), 7,25 až 7,40 (m, 3H), 7,56 až 7,75 (m, 2H), 7,90 (d, 2H), 9,20 (široký s, 4H) ppm.1 H NMR Spectrum (d 6 -DMSO): 1.10 (t, 3H), 1.0-2.15 (m, 10H), 3.36 (s, 3H), 3.90 (s, 2H) 3.94 (q, 2H), 5.60 (s, 2H), 7.25 to 7.40 (m, 3H), 7.56 to 7.75 (m, 2H), 7.90 (d , 2H), 9.20 (br s, 4H) ppm.

Príklad 125 l-Metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-/erc-butylketón-hydrochloridExample 125 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl- tert -butyl ketone hydrochloride

Zlúčenina sa pripravila obdobne ako v príklade 25d 1 -metyl-2-[(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl-to-c-butylketónu, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared analogously to Example 25d of 1-methyl-2 - [(4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-to-c-butyl ketone, ethanolic hydrochloric acid solution, ethanol and ammonium carbonate.

Výťažok produktu bol 59 % teoretického výťažku ; C21H25N5O (363,5);The yield of the product was 59% of the theoretical yield; C 21 H 25 N 5 O (363.5);

EKA hmotnostné spektrum: (M+H)+ = 364.EKA mass spectrum: (M + H) + = 364.

Príklad 126 l-Mety)-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-(l-metylcyklopent-l-yl)-ketón-hydrochloridExample 126 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl- (1-methyl-cyclopent-1-yl) -ketone hydrochloride

Zlúčenina sa pripravila obdobne ako v príklade 25d 1-metyl-2-[(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl(l-metylcyklopent-l-yl)-ketónu, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 63,5 % teoretického výťažku ; C23H27N3O (389,5);The compound was prepared analogously to Example 25d of 1-methyl-2 - [(4-cyanophenyl) aminomethyl] -benzimidazol-5-yl (1-methylcyclopent-1-yl) ketone, ethanolic hydrochloric acid, ethanol, and ammonium carbonate . The yield of the product was 63.5% of the theoretical yield; C 23 H 27 N 3 O (389.5);

EKA hmotnostné spektrum: (M+H)+ = 390.EKA mass spectrum: (M + H) + = 390.

Príklad 127Example 127

Hydrochlorid N-fenyl-N-(2-etoxykarbonyietyl)amidu kyseliny 2-[(4-amidinofenyl)-suIfinylmetyl]-benztiazol-5-yl-karboxylovej2 - [(4-amidinophenyl) -sulfinylmethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

K roztoku 0,15 g (0,27 mmolu) N-fenyl-N-(2-etoxykarbonyletyljamidu kyseliny 2-[(4-amidinofenyl)tiometyl]benztiazol-5-yl-karboxylovej v 10 ml kyseliny octovej sa pridalo 0,09 ml (približne 0,81 mmolu) 30%-ného roztoku peroxidu vodíka a reakčná zmes sa miešala pri teplote miestnosti. Po 4 dňoch sa pridal ďalší podiel roztoku peroxidu vodíka (0,18 ml) a zmes sa miešala ďalšie dva dni. Po odstránení rozpúšťadla vo vákuu sa získaný surový produkt čistil rýchlou chromatografiou (gél kyseliny kremičitej; elučné činidlo metylénchlorid/etanol = 10 : 1 až 4 : 1). Výťažok produktu bol 58 % teoretického výťažku ; C27H26N4O4S2 (534,66).To a solution of 0.15 g (0.27 mmol) of 2 - [(4-amidinophenyl) thiomethyl] benzothiazol-5-ylcarboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl iamide) in 10 ml of acetic acid was added 0.09 ml (approximately 0.81 mmol) of a 30% hydrogen peroxide solution and the reaction mixture was stirred at room temperature After 4 days, an additional portion of hydrogen peroxide solution (0.18 ml) was added and the mixture stirred for a further two days. solvent in vacuo, the crude product obtained was purified by flash chromatography (silica gel; eluent methylene chloride / ethanol = 10: 1 to 4: 1) to yield 58% of the theoretical yield; C 27 H 26 N 4 O 4 S 2 (534 , 66).

Rf hodnota: 0,24 (gél kyseliny kremičitej; metylénchlorid/etanol = 4:1+ niekoľko kvapiek kyseliny octovej); EKA hmotnostné spektrum: (M+H)+ = 535.Rf value: 0.24 (silica gel; methylene chloride / ethanol = 4: 1+ a few drops of acetic acid); EKA mass spectrum: (M + H) + = 535.

Príklad 128Example 128

Hydrochlorid N-(n-propyl)-N-(2-etoxykarbonyletyl)amidu kyseliny 1 -metyl-2-[(4-amidinofenyl)sulfonylmetyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2 - [(4-amidinophenyl) sulfonylmethyl] -benzimidazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) amide

K roztoku 0,40 g (0,70 mmolu) hydrochloridu N-(n-propyl)-N-(2-etoxy-karbonyletyl)-amidu kyseliny 1 -metyl -2-[(4-amidmofenyl)tiometyl]-benzimidazol-5-yl-karboxylovej v 10 ml kyseliny mravčej sa pridali 2 ml 30%-ného roztoku peroxidu vodíka a zmes sa miešala 16 hodín pri teplote miestnosti. Rozpúšťadlo sa potom oddestilovalo vo vákuu, pričom sa získala vyžadovaná zlúčenina vo forme béžovo sfarbenej tuhej látky (s malým podielom hydrochloridu N-(n-propyl)-N-(2-etoxy-karbonyletyl)amidu kyseliny l-metyl-2-[(4-amidinofenyl)sulfinylmetyl]-benz-imidazol-5-yl-karboxylovej.To a solution of 0.40 g (0.70 mmol) of N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide 1-methyl-2 - [(4-amidophenyl) thiomethyl] -benzimidazole hydrochloride 5-yl-carboxylic acid in 10 ml formic acid was added 2 ml of 30% hydrogen peroxide solution and the mixture was stirred at room temperature for 16 hours. The solvent was then distilled off under vacuum to give the title compound as a beige-colored solid (with a small proportion of 1-methyl-2 - [(N- (n-propyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride). 4-amidinophenyl) sulfinylmetyl] benzimidazol-5-yl-carboxylic acid.

Výťažok produktu bol 95 % teoretického výťažku ; C25H31N6O5S (513,62);The product yield was 95% of the theoretical yield; C 25 H 31 N 6 O 5 S (513.62);

Rf hodnota: 0,50 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/kyselina chlorovodíková (cHa = 1 mol.dm’3) = 50 : 45 : 5);Rf value: 0.50 (silica gel; acetic acid / ethanol / hydrochloric acid ester ( cHa = 1 mol.dm &lt; 3 &gt; ) = 50: 45: 5);

EKA hmotnostné spektrum: (M+H)+ = 514.EKA mass spectrum: (M + H) + = 514.

Príklad 129Example 129

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 2-[N-(4-amidinofenyl)-aminometyl]-tiazolo[5,4-b]pyridín-6-yl-karboxylovej2- [N- (4-amidinophenyl) -aminomethyl] -thiazolo [5,4-b] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) Metylester kyseliny 5-amino-6-chlór-nikotínoveja) 5-Amino-6-chloro-nicotinic acid methyl ester

Do roztoku 1,08 g (5,00 mmolov) metylesteru 6-chlór-5-nitro-nikotínovej kyseliny (pozri: A. H. Berrie, G. T. Newbold, F. S. Spring: J. Chem. Soc. 2 590 (1951)) v 25 ml absolútneho etanolu sa postupne pridalo 0,53 ml (29 mmolov) vody, 3,2 g (57 mmolov) práškového železa a 0,030 ml koncentrovanej kyseliny chlorovodíkovej a reakčná zmes sa zahrievala na teplotu varu. Potom sa ešte raz pridalo rovnaké množstvo vody, práškového železa a kyseliny chlorovodíkovej a zmes sa zahrievala 30 minút pri teplote varu. Ochladením vylúčená zrazenina sa odfiltrovala, premyla etanolom a rozpúšťadlo sa vo vákuu oddestilovalo. Výťažok žltozeleného tuhého produktu bol 0,75 g (81 % teoretického výťažku);To a solution of 1.08 g (5.00 mmol) of 6-chloro-5-nitro-nicotinic acid methyl ester (see: AH Berrie, GT Newbold, FS Spring: J. Chem. Soc. 2 590 (1951)) in 25 mL of absolute ethanol was gradually added 0.53 mL (29 mmol) of water, 3.2 g (57 mmol) of iron powder and 0.030 mL of concentrated hydrochloric acid, and the reaction mixture was heated to boiling. Then, an equal amount of water, iron powder and hydrochloric acid was added once more, and the mixture was heated at reflux for 30 minutes. The precipitate formed was filtered off, washed with ethanol and the solvent was distilled off in vacuo. The yield of a yellow-green solid was 0.75 g (81% of theory);

C7H7C1N2O2 (186,60);C 7 H 7 C1N 2 O 2 (186.60);

Rf hodnota: 0,31 (gél kyseliny kremičitej; ester kyseliny octovej/petroléter =1:4);Rf value: 0.31 (silica gel; acetic acid ester / petroleum ether = 1: 4);

YEF hmotnostné spektrum: M+ = 186 a 188 (izotop chlóru).YEF mass spectrum: M + = 186 and 188 (chlorine isotope).

b) Metylester kyseliny 6-chlór-5-metoxyacetamidonikotínovejb) 6-Chloro-5-methoxyacetamidonicotinic acid methyl ester

Roztok 0,75 g (4,02 mmolu) metylesteru kyseliny 5-amino-6-chlór-nikotínovej a 0,43 g = 0,35 ml (4,5 mmolu) metoxyacetylchloridu v 20 ml chlórbenzénu sa hodinu miešal pri teplote 110 °C. Po odstránení rozpúšťadla vo vákuu sa získaný produkt čistil rýchlou chromatografiou (gél kyseliny kremičitej; metylénchlorid/etanol = 100 : 1); eluát sa znova skoncentroval vo vákuu a následne sa digeroval petroléterom.A solution of 0.75 g (4.02 mmol) of 5-amino-6-chloro-nicotinic acid methyl ester and 0.43 g = 0.35 ml (4.5 mmol) of methoxyacetyl chloride in 20 ml of chlorobenzene was stirred at 110 ° C for 1 hour. C. After removal of the solvent in vacuo, the product obtained was purified by flash chromatography (silica gel; methylene chloride / ethanol = 100: 1); the eluate was concentrated again in vacuo and subsequently digested with petroleum ether.

Výťažok svetložltého amorfného tuhého produktu bol 0,55 g (53 % teoretického výťažku);The yield of pale yellow amorphous solid product was 0.55 g (53% of theory);

Rf hodnota: 0,33 (gél kyseliny kremičitej; ester kyseliny octovej/petroléter =1:4).Rf value: 0.33 (silica gel; acetic acid ester / petroleum ether = 1: 4).

c) Metylester kyseliny 2-mctoxymetyl-tiazolo[5,4-í>]pyridín-6-yl-karboxylovejc) 2-Methoxymethyl-thiazolo [5,4- d] pyridin-6-yl-carboxylic acid methyl ester

Zmes 0,53 g (2,05 mmolu) metylesteru kyseliny 6-chlór-5-metoxyacetamidonikotínovej a 0,42 g (1,0 mmol) Lawessonovho činidla v 25 ml xylénu sa zahrievala 16 hodín pri teplote varu pod spätným chladičom. Po odstránení rozpúšťadla vo vákuu sa získaný produkt čistil rýchlou chromatografiou (gél kyseliny kremičitej; metylénchlorid/etanol = 100 : 1); eluát sa znova skoncentroval vo vákuu.A mixture of 0.53 g (2.05 mmol) of 6-chloro-5-methoxyacetamidonicotinic acid methyl ester and 0.42 g (1.0 mmol) of Lawesson's reagent in 25 ml of xylene was heated at reflux for 16 h. After removal of the solvent in vacuo, the product obtained was purified by flash chromatography (silica gel; methylene chloride / ethanol = 100: 1); the eluate was concentrated again in vacuo.

Výťažok do žlta sfarbenej amorfnej tuhej látky bol 0,33 g (67 % teoretického výťažku);The yield of a yellow-colored amorphous solid was 0.33 g (67% of theory);

Rf hodnota: 0,52 (gél kyseliny kremičitej; ester kyseliny octovej/petroléter =1 :4). Rf value: 0.52 (silica gel; ethyl acetate / petroleum ether = 1: 4).

d) Kyselina 2-metoxymetyl-tiazolo[5,4-ô]pyridín-6-yl-karboxylovád) 2-Methoxymethyl-thiazolo [5,4-a] pyridin-6-yl-carboxylic acid

Zmes 1,1 g (4,62 mmolu) metylesteru kyseliny 2-metoxymetyltiazolo[5,4-b]pyridín-6-karboxylovej a 9,2 ml roztoku hydroxidu sodného (cNa0H = 2 mol.dm-3) s 50 ml etanolu sa hodinu miešala pri teplote miestnosti. Potom sa pridalo 9,2 kyseliny chlorovodíkovej (cHci = 2 mol.dm-3), alkohol sa oddestiloval a zmes sa zriedila 20 ml vody. Vodná fáza sa chladila ľadom a okyslila koncentrovanou kyselinou chlorovodíkovou, pričom sa vylúčila do béžová sfarbená zrazenina; zrazenina sa odfiltrovala, premyla vodou a vysušila.A mixture of 1.1 g (4.62 mmol) of 2-methoxymethylthiazolo [5,4-b] pyridine-6-carboxylic acid methyl ester and 9.2 ml of sodium hydroxide solution (c NaOH = 2 mol.dm -3 ) with 50 ml of ethanol was stirred at room temperature for 1 hour. Thereafter, 9.2 hydrochloric acid (c = ci H 2 mol.dm -3), the alcohol was distilled off, and the mixture was diluted with 20 ml of water. The aqueous phase was ice-cooled and acidified with concentrated hydrochloric acid, whereupon a beige colored precipitate formed; the precipitate was filtered off, washed with water and dried.

Výťažok produktu bol 1,03 g (100 % teoretického výťažku);Yield of the product was 1.03 g (100% of theory);

Rf hodnota: 0,10 (gél kyseliny kremičitej; ester kyseliny octovej/petroléter = 3:7).Rf value: 0.10 (silica gel; acetic acid ester / petroleum ether = 3: 7).

e) N-Fenyl-N-(2-etoxykarbonyletyl)amid kyseliny 2-metoxymetyl-tiazolo[5,4-b]-pyridín-6-yl-karboxyloveje) 2-Methoxymethyl-thiazolo [5,4-b] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide

Suspenzia 1,03 g (4,62 mmolu) kyseliny 2-metoxymetyltiazolo[5,4-b]pyridín-6-yl-karboxylovcj v 40 ml metylénchloridu sa zmiešala s 1,6 g = 1,0 ml (13,5 mmolov) tionylchloridu a reakčná zmes sa zahrievala na teplotu varu pod spätným chladičom. Pritom sa tuhá látka pomaly rozpustila. Po oddestilovaní tekutých zložiek sa surový produkt ešte dva razy rozmiešal s metylénchloridom a znova skoncentroval. Získaný chlorid kyseliny (1,2 g) sa rozmiešal v 40 ml tetrahydrofuránu a po kvapkách sa pridal do zmesi 0,94 g (4,86 mmolu) N-(2-etoxykarbonylmetyl)anilínu a 2,1 ml (13,8 mmolu) trietylamínu v 30 ml tetrahydroťuránu; reakčná zmes sa miešala 2 hodiny pri teplote miestnosti. Potom sa zmes zriedila 200 ml esteru kyseliny octovej, premyla 100 ml 14%-ného roztoku kuchynskej soli a organická fáza sa sušila síranom sodným. Po odstránení rozpúšťadla vo vákuu sa získaný surový produkt čistil rýchlou chromatografiou (gél kyseliny kremičitej; metylénchlorid/etanol 100: 1).A suspension of 1.03 g (4.62 mmol) of 2-methoxymethylthiazolo [5,4-b] pyridin-6-yl-carboxylic acid in 40 ml of methylene chloride was mixed with 1.6 g = 1.0 ml (13.5 mmol) of thionyl chloride and the reaction mixture was heated to reflux. The solid dissolved slowly. After distilling off the liquid components, the crude product was mixed with methylene chloride two more times and concentrated again. The obtained acid chloride (1.2 g) was slurried in 40 ml of tetrahydrofuran and added dropwise to a mixture of 0.94 g (4.86 mmol) of N- (2-ethoxycarbonylmethyl) aniline and 2.1 ml (13.8 mmol). triethylamine in 30 ml of tetrahydrofuran; the reaction mixture was stirred at room temperature for 2 hours. The mixture was then diluted with 200 mL of acetic acid ester, washed with 100 mL of 14% brine, and the organic phase was dried over sodium sulfate. After removal of the solvent in vacuo, the crude product obtained was purified by flash chromatography (silica gel; methylene chloride / ethanol 100: 1).

Výťažok produktu vo forme žltého oleja bol 1,57 g (87 % teoretického výťažku);Yield of the product as a yellow oil was 1.57 g (87% of theory);

Rf hodnota: 0,55 (gél kyseliny kremičitej; metylénchlorid/etanol = 19:1).Rf value: 0.55 (silica gel; methylene chloride / ethanol = 19: 1).

f) N-Fenyl-N-(2-etoxykarbonyletyl)amid kyseliny 2-[N-(4-kyanofenyl)-aminometyl]-tiazolo[5,4-ó]pyridín-6-yl-karboxylovejf) 2- [N- (4-Cyanophenyl) -aminomethyl] -thiazolo [5,4-a] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zmes 1,54 g (3,85 mmolu) N-fcnyl-N-(2-etoxykarbonyletyl)amidu kyseliny 2-metoxymetyl-tiazolo[5,4-b]pyridín-6-yl-karboxylovej a 4,3 ml (4,3 mmolu) roztoku bromidu boritého (cBBr3 = 1 mol.dm-3) v metylénchloride sa rozpustila v ďalších 30 ml metylénchloridu a miešala sa 5 hodín pri teplote miestnosti. Reakčná zmes sa potom pre29 myla 40 ml nasýteného roztoku hydrogenuhličitanu sodného, organická fáza sa sušila síranom sodným a rozpúšťadlo sa oddestilovalo. Surový produkt 1,9 g sa rozmiešal v 15,0 ml Ν,Ν-diizopropyl-etylamínu, pridalo sa 0,50 g (4,2 mmolu) 4-aminobenzonitrilu a zmes sa hodinu zahrievala na teplotu varu. Po oddestilovaní rozpúšťadla vo vákuu sa surový produkt rozmiešal v 100 ml metylénchloridu, organická fáza sa premyla 100 ml vody a sušila síranom sodným. Po odstránení rozpúšťadla vo vákuu sa získaný surový produkt čistil rýchlou chromatografiou (gél kyseliny kremičitej; ester kyseliny octovej/petroléter = 35 : 65 až : 1) a eluát sa znova odparil vo vákuu.A mixture of 2-methoxymethyl-thiazolo [5,4-b] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide (1.54 g, 3.85 mmol) and 4.3 ml (4 Solution of boron tribromide (c BBr 3 = 1 mol.dm -3 ) in methylene chloride was dissolved in an additional 30 ml of methylene chloride and stirred at room temperature for 5 hours. The reaction mixture was then washed with 40 ml of saturated sodium bicarbonate solution, the organic phase was dried over sodium sulfate and the solvent was distilled off. The crude product (1.9 g) was stirred in 15.0 ml of Ν, opropyl-diisopropylethylamine, 0.50 g (4.2 mmol) of 4-aminobenzonitrile was added and the mixture was heated at reflux for 1 hour. After distilling off the solvent in vacuo, the crude product was stirred in 100 ml of methylene chloride, the organic phase was washed with 100 ml of water and dried over sodium sulfate. After removal of the solvent in vacuo, the crude product obtained was purified by flash chromatography (silica gel; acetic acid ester / petroleum ether = 35: 65 to: 1) and the eluate was again evaporated in vacuo.

Výťažok žltej amorfnej tuhej látky bol 0,45 g (24 % teoretického výťažku);The yield of yellow amorphous solid was 0.45 g (24% of th.);

Rf hodnota: 0,34 (gél kyseliny kremičitej; ester kyseliny octovej/petroéter = 1 : 1). Rf value: 0.34 (silica gel; ethyl acetate / petroleum ether = 1: 1).

g) Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 2-[N-(4-amidino-fenyl)-aminometyl]-tiazolo[5,4-b]pyridín-6-yl-karboxylovejg) 2- [N- (4-amidino-phenyl) -aminomethyl] -thiazolo [5,4-b] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

0,39 g (0,803 mmolu) N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 2-[N-(4-kyanofenyl)-aminometyl]tiazolo[5,4-b]pyridín-6-yl-karboxylovej sa miešalo v 40 ml chlorovodíkom nasýteného etanolu 5 hodín najprv pri 0 °C a potom pri teplote miestnosti, kým sa chromatografiou v tenkej vrstve nepreukázalo, že zmes už neobsahuje východiskový materiál. Potom sa pri teplote kúpeľa najviac 30 °C odestilovalo rozpúšťadlo, olejový zvyšok sa rozmiešal v 40 ml absolútneho etanolu a pridalo sa 0,5 g uhličitanu amónneho. Po 18 hodinách sa vo vákuu odstránilo rozpúšťadlo a získaný surový produkt sa čistil rýchlou chromatografiou (gél kyseliny kremičitej; metylénchlorid/etanol = 9 : 1 až 4 : 1).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 The reaction mixture was stirred in 40 ml of hydrogen chloride-saturated ethanol for 5 hours at 0 ° C and then at room temperature until thin layer chromatography showed that the mixture no longer contained the starting material. Thereafter, the solvent was distilled off at a bath temperature of not more than 30 ° C, the oily residue was stirred in 40 ml of absolute ethanol and 0.5 g of ammonium carbonate was added. 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).

Výťažok produktu vo forme žltej peny bol 78 % teoretického výťažku;Yield of the product as a yellow foam was 78% of the theoretical yield;

C26H26N6O3S (502,60);C 26 H 26 N 6 O 3 S (502.60);

Rf hodnota: 0,19 (gél kyseliny kremičitej; metylénchlorid/etanol = 4 : 1);Rf value: 0.19 (silica gel; methylene chloride / ethanol = 4: 1);

EKA hmotnostné spektrum: (M+H)+ = 503.EKA mass spectrum: (M + H) + = 503.

Príklad 130Example 130

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 1 -metyl-2-[(4-amidinofenyl)metyltiobenzimidazol-5-yl-karboxylovej1-Methyl-2 - [(4-amidinophenyl) methylthiobenzimidazol-5-ylcarboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide hydrochloride

a) N-Fenyl-N-(2-etoxykarbonyletyl)amid kyseliny 1 -metyl-2-merkapto-benzimidazol-5 -yl-karboxyl oveja) 1-Methyl-2-mercapto-benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Roztok 6,5 g (19 mmolov) N-fenyl-N-(2-etoxykarbonyletyljamidu kyseliny 3-amino-4-metylaminobenzoovej aA solution of 6.5 g (19 mmol) of 3-amino-4-methylaminobenzoic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide and

4,5 g ( 22,8 mmolu) N,N‘-tiokarbonyldiimidazolu sa pod ochrannou atmosférou dusíka rozpustil v 100 ml tetrahydrofuránu, 4 hodiny sa zahrieval na 90 °C a potom sa nechal stať 16 hodín pri teplote miestnosti. Po odstránení rozpúšťadla vo vákuu sa získaný surový produkt čistil rýchlou chromatografiou (gél kyseliny kremičitej; petroléter/ester kyseliny octovej = 100 : 0 až 65 : 35).4.5 g (22.8 mmol) of N, N‘-thiocarbonyldiimidazole were dissolved in 100 ml of tetrahydrofuran under a nitrogen atmosphere, heated at 90 ° C for 4 hours and then allowed to stand at room temperature for 16 hours. After removal of the solvent in vacuo, the crude product obtained was purified by flash chromatography (silica gel; petroleum ether / acetic acid ester = 100: 0 to 65: 35).

Výťažok bol 6,8 g (93 % teoretického výťažku) béžovo sfarbenej kryštalickej látky;The yield was 6.8 g (93% of theory) of a beige-colored crystalline solid;

Rf hodnota: 0,55 (gél kyseliny kremičitej; ester kyseliny octovej).Rf value: 0.55 (silica gel; acetic acid ester).

b) N-Fenyl-N-(2-etoxykarbonyletyl)amid kyseliny 1-metyl-2[(4-kyanofenyl)metyltio]-benzimidazol-5-yI-karboxylovejb) 1-Methyl-2 [(4-cyanophenyl) methylthio] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide

Roztok 1,30 g (3,4 mmolu) N-fenyl-N-(2-etoxykarbonyletyljamid kyseliny l-metyl-2-merkapto-benzimidazol-5A solution of 1.30 g (3.4 mmol) of 1-methyl-2-mercapto-benzimidazole-5 N-phenyl-N- (2-ethoxycarbonylethyl) -amide.

-yl-karboxylovej, 0,52 g (3,74 mmolu) uhličitanu draselného a 0,66 g (3,4 mmolu) 4-brómmetylbenzonitrilu v 40 ml absolútneho etanolu sa miešal 4 hodiny pri 60 °C a 16 hodín pri teplote miestnosti. Rozpúšťadlo sa potom oddestilovalo vo vákuu, surový produkt sa rozmiešal v 30 ml metylénchloridu, premyl 40 ml vody a sušil síranom sodným. Po filtrácii a oddestilovaní rozpúšťadla sa získala vyžadovaná zlúčenina ako bielo-béžová tuhá látka.-ylcarboxylic acid, 0.52 g (3.74 mmol) of potassium carbonate and 0.66 g (3.4 mmol) of 4-bromomethylbenzonitrile in 40 ml of absolute ethanol were stirred for 4 hours at 60 ° C and 16 hours at room temperature. . The solvent was then distilled off in vacuo, the crude product was stirred in 30 ml of methylene chloride, washed with 40 ml of water and dried over sodium sulfate. Filtration and distillation of the solvent gave the title compound as a white-beige solid.

Výťažok produktu bol 1,8 g (100 % teoretického výťažku); Rf hodnota: 0,64 (gél kyseliny kremičitej; ester kyseliny octovej).Yield: 1.8 g (100%); Rf value: 0.64 (silica gel; ethyl acetate).

c) Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[(4-amidinofenyl) metyltio-benzimidazol-5-yl-karboxylovejc) 1-Methyl-2 - [(4-amidinophenyl) methylthiobenzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide hydrochloride

1,5 g (3,0 mmoly) N-fenyl-N-(2-etoxykarbonyletyl)amid kyseliny 1 -metyl-2[(4-kyanofenyl)metyltio]-benzimidazol-5-yl-karboxylovcj v 80 ml chlorovodíkom nasýteného etanolu sa miešalo 6 hodín najprv pri teplote 0 °C a potom pri teplote miestnosti, kým sa chromatografiou v tenkej vrstve nepreukázalo, že zmes už neobsahuje východiskový materiál. Potom sa rozpúšťadlo oddestilovalo pri teplote kúpeľa najviac do 30 °C, olejovitý zvyšok sa rozmiešal v 80 ml absolútneho etanolu a pridal sa 1,0 g (10,5 mmolu) uhličitanu amónneho. Po 18 hodinách sa rozpúšťadlo oddestilovalo vo vákuu a získaný surový produkt sa čistil rýchlou chromatografiou (gél kyseliny kremičitej; metylénchlorid/etanol = 19 : 1 až 10 : 1).1.5 g (3.0 mmol) of 1-methyl-2 [(4-cyanophenyl) methylthio] -benzimidazol-5-ylcarboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide in 80 ml of hydrogen chloride-saturated ethanol The mixture was stirred at 0 ° C for 6 hours and then at room temperature until thin layer chromatography showed the mixture to be free of starting material. Then the solvent was distilled off at a bath temperature of not more than 30 ° C, the oily residue was stirred in 80 ml of absolute ethanol, and 1.0 g (10.5 mmol) of ammonium carbonate was added. 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).

Výťažok bol 78 % teoretického výťažku svetlobéžovo sfarbenej tuhej látky;The yield was 78% of the theoretical yield of a pale beige solid;

C28H29N5O3S (515,3);C 28 H 29 N 5 O 3 S (515.3);

Rf hodnota: 0,19 (gél kyseliny kremičitej; metylénchlorid/etanol = 4 : 1); Rf value: 0.19 (silica gel; methylene chloride / ethanol = 4: 1);

EKA hmotnostné spektrum: (M+H)+ = 516, (M+H+Na)++ = = 269,7, (M+2Hf+ = 258,7.EKA mass spectrum: (M + H) + = 516, (M + H + Na) ++ = = 269.7, (M + 2H + + = 258.7).

Príklad 131Example 131

Hydrochlorid N-fenyl-N-(2-hydroxykarbonyletyl)amidu kyseliny 1 -metyl-2-[(4-amidi-nofenyl)metyltio]-benzimidazol-5-yl-karboxylovej1-Methyl-2 - [(4-amidinophenyl) methylthio] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) amide hydrochloride

Zlúčenina sa pripravila obdobne ako v príklade 10 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 1 -metyl-2-[(4-amidinofenyl)-metyltio]-bcnzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared analogously to Example 10 from 1-methyl-2 - [(4-amidinophenyl) methylthio] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide and sodium hydroxide.

Výťažok produktu bol 57 % teoretického výťažku ; C26H25N3O3S (487,58);The yield of the product was 57% of the theoretical yield; C 26 H 25 N 3 O 3 S (487.58);

Rf hodnota: 0,23 (gél kyseliny kremičitej RP-8 s reverznou fázou; etanol/5%-ný roztok kuchynskej soli = 6:4);Rf value: 0.23 (reversed phase RP-8 silica gel; ethanol / 5% saline = 6: 4);

EKA hmotnostné spektrum: (M+H)+ = 488, (M+Na)+ = = 510, (M+H+Na)++ = 255,6.EKA mass spectrum: (M + H) + = 488, (M + Na) + = 510, (M + H + Na) ++ = 255.6.

Príklad 132Example 132

Hydrochlorid N-propargyl-N-(2-etoxykarbonyletyl)amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-propargyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 25d z hydrochloridu N-propargyl-N-(2-etoxykarbonyletyl)amidu kyseliny 1 -metyl-2-[N-(4-kyanofenyl)-amino-metyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 81 % teoretického výťažku ; C25H28N6O3 (460,6);The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) amino-methyl] -benzimidazol-5-yl-carboxylic acid N-propargyl-N- (2-ethoxycarbonylethyl) -amide. , ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. The yield of product was 81% of the theoretical yield; C 25 H 28 N 6 O 3 (460.6);

Rf hodnota: 0,094 (gél kyseliny kremičitej; dichlórmetán/etanol/= 4:1);Rf value: 0.094 (silica gel; dichloromethane / ethanol) = 4: 1);

EKA hmotnostné spektrum: (M+H)+ = 461, (M+H+Na)++ = = 242, (M+2H)+ = 231.EKA mass spectrum: (M + H) + = 461, (M + H + Na) + = = 242, (M + 2H) + = 231.

Príklad 133 N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[2-[4-(N-n-hexyloxy-karbonylamidino)fenyl]etyl]-benzimidazol-5-yl-karboxylovejExample 133 1-Methyl-2- [2- [4- (N-hexyloxycarbonylamidino) phenyl] ethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide carboxylic acid

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[2-(4-amidinofenyl) etyl]-benzimidazol-5-yl-karboxylovej a n-hexylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride. carboxylic acid and n-hexyl chloroformate.

Výťažok produktu bol 72 % teoretického výťažku; C35H42NA (626,8);The yield of the product was 72% of the theoretical yield; C35H42NA (626.8);

Rf hodnota: 0,54 (gél kyseliny kremičitej; dichlórmetán/metanol = 9:1); Rf value: 0.54 (silica gel; dichloromethane / methanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 627, (M+Na)+ = = 649.EKA-MS: (M + H) + = 627, (M + Na) + = 649.

Príklad 134 N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[2-[4-(N-benzoyl-amidino)fenyl]-etyl]-benzimidazol-5-yl-karboxylovejExample 134 1-Methyl-2- [2- [4- (N-benzoyl-amidino) -phenyl] -ethyl] -benzimidazol-5-yl N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide carboxylate

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[2-(4-amidinofenyl) etylj-benzimidazol-5-yl-karboxylovej a benzoylchloridu.The compound was prepared analogously to Example 90 from 1-methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-yl-, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride. carboxylic acid and benzoyl chloride.

Výťažok produktu bol 79 % teoretického výťažku; C35H34N6O4 (602,7);The product yield was 79% of the theoretical yield; C 35 H 34 N 6 O 4 (602.7);

Rf hodnota: 0,52 (gél kyseliny kremičitej; dichlórmetán/metanol = 9 : 1);Rf value: 0.52 (silica gel; dichloromethane / methanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 603, (M+Na)+ = = 625.EKA-MS: (M + H) + = 603, (M + Na) + = 625.

Príklad 135 N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[2-[4-(N-nikotinoyl-amidino)fenyl]-etyl]-benzimidazol-5-yl-karboxylovejExample 135 1-Methyl-2- [2- [4- (N-nicotinoyl-amidino) -phenyl] -ethyl] -benzimidazol-5-yl N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide carboxylate

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[2-(4-amidinofenyl) etyl]-benzimidazol-5-yl-karboxylovej a chloridu kyseliny nikotínovej.The compound was prepared analogously to Example 90 from 1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride. carboxylic acid and nicotinic acid chloride.

Výťažok produktu bol 56 % teoretického výťažku; C34H33N7O4 (603,7);The yield of the product was 56% of the theoretical yield; C 34 H 33 N 7 O 4 (603.7);

Rf hodnota: 0,52 (gél kyseliny kremičitej; dichlórmetán/metanol = 9 : 1); Rf value: 0.52 (silica gel; dichloromethane / methanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 604, (M+Na)+ = = 626.EKA-MS: (M + H) + = 604, (M + Na) + = 626.

Príklad 136Example 136

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 1 -cyklopropyl-2-[N-(4-amidinofenyl)-aminometyl]benzimidazol-5 -yl-karboxylovej1-Cyclopropyl-2- [N- (4-amidinophenyl) aminomethyl] benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide hydrochloride

Zlúčenina sa pripravila obdobne ako v príklade 25d z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 1 -cyklopropyl-2-[N-(4-kyanofenyl)-amino-metyl]benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 31 % teoretického výťažku ; Cj0H33N6O3 (524,6);The compound was prepared analogously to Example 25d from 1-cyclopropyl-2- [N- (4-cyanophenyl) amino-methyl] benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. The product yield was 31% of the theoretical yield; C 3 H 33 N 6 O 3 (524.6);

Rf hodnota: 0,40 (gél kyseliny kremičitej; dichlórmetán/metanol = 5:1); Rf value: 0.40 (silica gel; dichloromethane / methanol = 5: 1);

EKA hmotnostné spektrum: (M+H)+ = 525, (M+H+Na)++ = = 274, (M-2H)' = 263.EKA mass spectrum: (M + H) + = 525, (M + H + Na) ++ = = 274, (M-2H) - = 263.

Príklad 137Example 137

N-Fenyl-N-(2-hydroxykarbonyletyl)amid kyseliny 1-cyklopropyl-2-[N-(4-amidino-fenyl)-aminometyl]-benzimidazol-5-yl-karboxylo vej1-Cyclopropyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 26 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 1 -cyklopropyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného. Výťažok produktu bol 64 % teoretického výťažku ;The compound was prepared analogously to Example 26 from 1-cyclopropyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and hydroxide solution. The yield of the product was 64% of the theoretical yield;

(496,6);(496.6);

EKA hmotnostné spektrum: (M+H)+ = 497, (M+H+Na)4^4 = = 260, (M+Na)+ = 519, (M+2Na)++ = 271.EKA mass spectrum: (M + H) + = 497, (M + H + Na) = 4 ^ 4 = 260, (M + Na) + = 519, (M + 2Na) ++ 271st

Príklad 138Example 138

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-N-(n-butyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -N- (n-butyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 25d z N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-kyanofenyl)-N-(n-butyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -N- (n-butyl) -aminomethyl] -benzimidazole N-phenyl-N- (2-ethoxycarbonylethyl) amide. Of 5-yl-carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 62 % teoretického výťažku; C32H38N6O3 (554,7);The yield of the product was 62% of the theoretical yield; C 32 H 38 N 6 O 3 (554.7);

EKA hmotnostné spektrum: (M+H)+ = 555, (M+H+Na)4-4 = = 289, (M+2H)+ = 278.EKA mass spectrum: (M + H) + = 555, (M + H + Na) 4-4 = 289, (M + 2H) + = 278.

Príklad 139Example 139

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 1 -metyl-2-[N-(4-amidino-2-chlórfenyl)-N-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidino-2-chlorophenyl) -N-aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide hydrochloride

Zlúčenina sa pripravila obdobne ako v príklade 25d z N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-kyano-2-chlórfenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyano-2-chloro-phenyl) -aminomethyl] -benzimidazol-5-yl-, N-phenyl-N- (2-ethoxycarbonylethyl) -amide. of a carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 82 % teoretického výťažku ; C28H29C1N6O3 (533,1);The yield of the product was 82% of the theoretical yield; C 28 H 29 C1N 3 O 6 (533.1);

EKA hmotnostné spektrum: (M+H)+ = 533/5, (M+H-Na)++ = 278/9.EKA mass spectrum: (M + H) + = 533/5, (M + H-Na) ++ = 278/9.

Príklad 140Example 140

N-Fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny l-metyl-2-[N-[4-(n-oktyloxykarbonylamidino)fenyl]-aminometyl]benzimidazol-5-yl-karboxylovej1-methyl-2- [N- [4- (n-octyloxycarbonylamidino) phenyl] aminomethyl] benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl) aminometyl]-benzimidazol-5-yl-karboxylovej a n-oktylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and n. -octyl chloroformate.

Výťažok produktu bol 34 % teoretického výťažku; C37H46N6OS (654,8);The product yield was 34% of the theoretical yield; C 37 H 46 N 6 O S (654.8);

Rf hodnota: 0,15 (gél kyseliny kremičitej; dichlórmetán/etanol = 19 : 1); Rf value: 0.15 (silica gel; dichloromethane / ethanol = 19: 1);

EKA-hmotnostné spektrum: (M+H)+ = 655, (M+H+Na)++ = = 339, (M+Na)+= 677.EKA mass spectrum: (M + H) + = 655, (M + H + Na) ++ = 339 (M + Na) + = 677th

Príklad 141Example 141

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 1 -metyl-2-[N-(4-amidino-2-etylfenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidino-2-ethyl-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 25d z N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 1 -metyl-2-[N-(4-kyano-2-etyl-fenyl)-ammometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyano-2-ethyl-phenyl) -ammomethyl] -benzimidazole-5- N-phenyl-N- (2-ethoxycarbonylethyl) -amide. of carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 61 % teoretického výťažku ; C30H34N6O3 (526,6);The yield of the product was 61% of the theoretical yield; C 30 H 34 N 6 O 3 (526.6);

EKA hmotnostné spektrum: (M+H)+ = 527, (M+H+Na)*+ = = 275, (M+2H)++ = 264.EKA mass spectrum: (M + H) + = 527, (M + H + Na) + = = 275, (M + 2H) ++ = 264.

Príklad 142Example 142

Hydrochlorid benzylamidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-bcnzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid benzylamide hydrochloride

Zlúčenina sa pripravila obdobne ako v príklade 25d z benzylamidu kyseliny l-metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid benzylamide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate.

Výťažok produktu bol 63 % teoretického výťažku ; C24H24N6O (412,5);The yield of the product was 63% of the theoretical yield; C 24 H 24 N 6 O (412.5);

Rf hodnota: 0,76 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1);Rf value: 0.76 (silica gel; dichloromethane / ethanol = 4: 1);

EKA hmotnostné spektrum: (M+H)+ = 413.EKA mass spectrum: (M + H) + = 413.

Príklad 143Example 143

N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-(2-(2-etoxy-etoxy) etyloxy) karbonylamidino)-fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N- (2- (2-ethoxy-ethoxy) -ethyloxy) -carbonylamidino) -phenyl] -N- (2-ethoxycarbonylethyl) -amide N- (2-pyridyl) -amide aminomethyl] benzimidazol-5-yl-carboxylic acid

Zlúčenina sa pripravila obdobne ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl) aminometyl]-benzimidazol-5-yl-karboxylovej a esteru kyseliny chlórmravčej s dietylén-glykolmonoetyléterom. Výťažok produktu bol 43 % teoretického výťažku; C34H41N7O7 (659,8);The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride. carboxylic acid and chloroformic acid ester with diethylene glycol monoethyl ether. The product yield was 43% of the theoretical yield; C 34 H 41 N 7 O 7 (659.8);

Rf hodnota: 0,56 (gcl kyseliny kremičitej; dichlórmetán/metanol = 9 : 1);Rf value: 0.56 (gcl of silica; dichloromethane / methanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 660, (M+H+Na)++ = = 341,7.EKA mass spectrum: (M + H) + = 660, (M + H + Na) ++ = 341.7.

Príklad 144Example 144

Hydrochlorid N-(l -metylpyrazol-4-yl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyI-2-[N-(4-amidinofenyl)aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (1-methylpyrazol-4-yl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 25d z N-(2-pyridyl)-N-(2-etoxykarbonyletyl)amidu kyseliny 1-metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide. of a carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 60 % teoretického výťažku ; C26H30N8O3 (502,6);The product yield was 60% of the theoretical yield; C 26 H 30 N 8 O 3 (502.6);

Rf hodnota: 0,13 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1); Rf value: 0.13 (silica gel; dichloromethane / ethanol = 4: 1);

EKA hmotnostné spektrum: (M+H)1 = 503, (M+H+Na)++ = = 263, (M+2H)+* = 252.EKA mass spectrum: (M + H) + 1 = 503, (M + H + Na) ++ = 263 (M + 2H) + = * 252nd

Príklad 145Example 145

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 3-metyl-2-[(4-amidinofenyl)-tiometyl]-imidazo[4,5-£]-pyridín-6-yl-karboxylovej3-Methyl-2 - [(4-amidinophenyl) -thiomethyl] -imidazo [4,5- b] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 1 z N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 3-metyl-2-[(4-kyanofenyl)-tiometyl]- imidazo[4,5-6]-pyridín-6-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared analogously to Example 1 from 3-methyl-2 - [(4-cyanophenyl) thiomethyl] imidazo [4,5-6] pyridine-6 N-phenyl-N- (2-ethoxycarbonylethyl) amide. -yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 88 % teoretického výťažku ; C27H28N6O3S (516,63);The yield of the product was 88% of the theoretical yield; C 27 H 28 N 6 O 3 S (516.63);

Rf hodnota: 0,23 (gél kyseliny kremičitej; ester kyseliny octovej/ctanol/amoniak = 50 : 45 : 5); Rf value: 0.23 (silica gel; ethyl acetate / CTAN / ammonia 50: 45: 5);

EKA hmotnostné spektrum: (M+H)+ =517, (M+H+Na)++ = = 270.EKA mass spectrum: (M + H) + = 517, (M + H + Na) ++ = 270.

Príklad 146Example 146

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 3-metyl-2-[N-(4-amidinofenyl)-aminometyl]-imidazo[4,5-b]pyridín-6-yl-karboxylovej3-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -imidazo [4,5-b] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 1 z N-fenyl-N-(2-metoxykarbonyletyl)amidu kyseliny 3-metyl-2-[N-(4-kyanofenyl)-atninometyl]- imidazo[4,5-6]pyridín-6-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in analogy to Example 1 from 3-methyl-2- [N- (4-cyanophenyl) aminomethyl] imidazo [4,5-6] pyridine-, N-phenyl-N- (2-methoxycarbonylethyl) amide. 6-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 82 % teoretického výťažku ; C27H29N7O3 (499,58);The yield of the product was 82% of the theoretical yield; C 27 H 29 N 7 O 3 (499.58);

Rf hodnota: 0,20 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50 : 45 : 5);Rf value: 0.20 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5);

EKA hmotnostné spektrum; (M+H)+ = 500, (M+H+Na)++ = = 261,7.EKA mass spectrum; (M + H) + = 500, (M + H + Na) ++ = 261.7.

Príklad 147Example 147

Hydrochlorid N-fenyl-N-(2-hydroxykarbonyletyl)-amidu kyseliny 3-metyl-2-[(4-amidinofcnyl)-tiometyl]-imidazo[4,5-b]pyridín-6-yl-karboxylovej3-Methyl-2 - [(4-amidinophenyl) -thiomethyl] -imidazo [4,5-b] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 2 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 3-metyl-2-[(4-amidmofenyl)-tiometyl]-imidazo-[4,5-ó]-pyridín-6-yl-karboxylovej a hydroxidu sodného. Výťažok produktu bol 88 % teoretického výťažku ; C25H24N6O3S (488,56);The compound was prepared analogously to Example 2 from 3-methyl-2 - [(4-amidophenyl) -thiomethyl] -imidazo [4,5-a] pyridine hydrochloride, N-phenyl-N- (2-ethoxycarbonylethyl) amide hydrochloride 6-yl-carboxylic acid and sodium hydroxide. The yield of the product was 88% of the theoretical yield; C 25 H 24 N 6 O 3 S (488.56);

Rf hodnota: 0,21 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50 : 45 : 5);Rf value: 0.21 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5);

EKA hmotnostné spektrum: (M+H)+ = 489, (M+Na)+ = = 511.EKA mass spectrum: (M + H) + = 489, (M + Na) + = 511.

Príklad 148Example 148

Hydrochlorid N-fenyl-N-(2-hydroxykarbonyletyl)-amidu kyseliny 3-metyl-2-[N-(4-amidinofenyl)-aminometyl]-imidazo[4,5-6]pyridín-6-yl-karboxylovej3-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -imidazo [4,5-6] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 2 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)amídu kyseliny 3-metyl-2-[(4-amidinofenyl)aminometyl]-imidazo-[4,5-b]-pyridín-6-yI-karboxylovej a hydroxidu sodného. Výťažok produktu bol 80 % teoretického výťažku ; C35H25N7O3 (471,52);The compound was prepared analogously to Example 2 from 3-methyl-2 - [(4-amidinophenyl) aminomethyl] -imidazo- [4,5-b] pyridine-, N-phenyl-N- (2-ethoxycarbonylethyl) amide hydrochloride. 6-yl-carboxylic acid and sodium hydroxide. The yield of the product was 80% of the theoretical yield; C 35 H 2 5 N 7 O 3 (471.52);

Rf hodnota: 0,19 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50 : 45 : 5); Rf value: 0.19 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5);

EKA hmotnostné spektrum: (M+H)+ = 472, (M+Na)+ = = 494, (M+2Na)++= 258,6.EKA mass spectrum: (M + H) + = 472, (M + Na) + = 494, (M + 2Na) ++ = 258.6.

Príklad 149Example 149

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5 -sulfónovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-sulfonic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) N-Fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-kyanoťenyl)-amino-metyl]-benzimidazol-5-sulfónoveja) 1-Methyl-2- [N- (4-cyano-phenyl) -amino-methyl] -benzimidazole-5-sulfonic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

V zmesi 75 ml etanolu a 75 ml dichlórmetánu sa hydrogenovalo 2,54 g (6,2 mmolu) N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 3-nitro-4-metylaminobenzénsulfónovej. Hydrogenácia sa vykonala pri teplote miestnosti pod tlakom 0,5 MPa vodíka s použitím paládia na uhlí (10%-né) ako katalyzátora. Získaný surový N-fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny 3-amino-4-metylaminobenzénsulfónovej sa bez čistenia rozmiešal v 30 ml oxychloridu fosforitého a potom sa pridalo 1,1 g (6,2 mmolu)2.54 g (6.2 mmol) of 3-nitro-4-methylaminobenzenesulfonic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide was hydrogenated in a mixture of 75 ml of ethanol and 75 ml of dichloromethane. Hydrogenation was carried out at room temperature under 0.5 MPa of hydrogen using palladium on carbon (10%) as a catalyst. The obtained crude 3-amino-4-methylaminobenzenesulfonic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide was stirred without purification in 30 ml of phosphorus oxychloride and then 1.1 g (6.2 mmol) were added.

N-(4-kyanofenyl)-glycínu a zmes sa 2 hodiny varila pod spätným chladičom. Reakčná zmes sa po ochladení na teplotu miestnosti a za chladenia pomaly naliala do 70 ml vody a týmto spôsobom sa rozložil nadbytočný oxychlorid fosforitý. Získaný roztok sa neutralizoval práškovým uhličitanom sodným a trikrát extrahoval vždy 30 ml esteru kyseliny octovej. Po odparení rozpúšťadla sa surový produkt čistil stĺpcovou chromatografiou (100 g gélu kyseliny kremičitej; elučné činidlo: cyklohexán/ester kyseliny octovej = = 2:3).N- (4-cyanophenyl) glycine and the mixture was refluxed for 2 hours. After cooling to room temperature and cooling, the reaction mixture was poured slowly into 70 ml of water, and the excess phosphorus oxychloride was decomposed. The resulting solution was neutralized with powdered sodium carbonate and extracted three times with 30 ml of acetic acid ester each. After evaporation of the solvent, the crude product was purified by column chromatography (100 g silica gel; eluent: cyclohexane / acetic acid ester = 2: 3).

Výťažok produktu bol 860 mg (26,8 % teoretického výťažku);Yield: 860 mg (26.8% of theory);

Teplota topenia: 188 až 191 °C;Mp: 188-191 ° C;

C27H27N5O3S (517,6); 27 C H 27 N 5 O 3 S (517.6);

Rf hodnota: 0,52 (gél kyseliny kremičitej; dichlórmetán/metanol = 9 : 1); Rf value: 0.52 (silica gel; dichloromethane / methanol = 9: 1);

EKA hmotnostné spektrum: (M+H)+ = 518, (M+Na)+ = = 540.EKA mass spectrum: (M + H) + = 518, (M + Na) + = 540.

b) Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometylj-benzimidazol-5 -sulfónovejb) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-sulfonic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 25d z N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1-metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-sulfónovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazole-5-sulfonic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic acid solution. hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 87 % teoretického výťažku ; C27H30N6O4S (534,6);The product yield was 87% of the theoretical yield; C 27 H 30 N 6 O 4 S (534.6);

Rf hodnota: 0,13 (gél kyseliny kremičitej; dichlórmetán/etanol = 9 : 1); Rf value: 0.13 (silica gel; dichloromethane / ethanol = 9: 1);

EKA hmotnostné spektrum: (M+H)+ = 535, (M+H+Na)++ = = 279.EKA mass spectrum: (M + H) + = 535, (M + H + Na) ++ = 279th

Príklad 150Example 150

Hydrochlorid N-(l -metylpyrazol-4-yl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)aminometyl]-benzimidazol-5-sulfónovej1-Methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5-sulfonic acid N- (1-methylpyrazol-4-yl) -N- (2-ethoxycarbonylethyl) amide hydrochloride

Zlúčenina sa pripravila obdobne ako v príklade 25d z N-(l-metylpyrazol-4-yl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-sulfónovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazole N- (1-methylpyrazol-4-yl) -N- (2-ethoxycarbonylethyl) -amide. -5-sulfonic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 38 % teoretického výťažku ; C25H30N8O4S (538,6);The product yield was 38% of the theoretical yield; C 25 H 30 N 8 O 4 S (538.6);

Rf hodnota: 0,09 (gél kyseliny kremičitej; dichlórmetán/etanol = 9 : 1); Rf value: 0.09 (silica gel; dichloromethane / ethanol = 9: 1);

EKA hmotnostné spektrum: (M+H)+ = 539.EKA mass spectrum: (M + H) + = 539.

Príklad 151Example 151

Hydrochlorid 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-5-(2.3-dihydroindol-l-yl-sulfonyl]-benzimidazolu1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -5- (2,3-dihydroindol-1-yl-sulfonyl) -benzimidazole hydrochloride

Zlúčenina sa pripravila obdobne ako v príklade 25d z 1 -metyl-2-[N-(4-kyanofenyl)-aminometyl]-5-(2.3-dihydroindol-l-yl-sulfonyl)-benzimidazolu, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 15 % teoretického výťažku ; C24H24N6O2S (460,6);The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -5- (2,3-dihydroindol-1-ylsulfonyl) -benzimidazole, ethanolic hydrochloric acid solution, ethanol and ammonium carbonate. The product yield was 15% of the theoretical yield; C 24 H 24 N 6 O 2 S (460.6);

Rf hodnota: 0,36 (gél kyseliny kremičitej; dichlórmetán/ctanol = 4 : 1);Rf value: 0.36 (silica gel; dichloromethane / ethanol = 4: 1);

EKA hmotnostné spektrum: (M+H)+ = 461.EKA mass spectrum: (M + H) + = 461.

Príklad 152Example 152

N-Fenyl-N-(2-hydroxykarbonyletyl)amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-sulfónovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-sulfonic acid N-phenyl-N- (2-hydroxycarbonylethyl) amide

Zlúčenina sa pripravila obdobne ako v príklade 26 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny 1 -metyl-2-[(4-amidinofenyl)-aminometyl]-benzimidazol-5-sulfónovej a hydroxidu sodného.The compound was prepared analogously to Example 26 from 1-methyl-2 - [(4-amidinophenyl) -aminomethyl] -benzimidazole-5-sulfonic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and sodium hydroxide.

Výťažok produktu bol 24 % teoretického výťažku;The product yield was 24% of the theoretical yield;

Rf hodnota: 0,55 (gél kyseliny kremičitej RP-18 s reverznou fázou; metanol/5%-ný roztok kuchynskej soli = 3:2); C25H26N6O4S (506,6);Rf value: 0.55 (reversed phase RP-18 silica gel; methanol / 5% sodium chloride solution = 3: 2); C 25 H 26 N 6 O 4 S (506.6);

EKA hmotnostné spektrum: (M+H)+ = 507, (M+Na)+ = = 529, (M+2Na)++ = 276.EKA mass spectrum: (M + H) + = 507, (M + Na) + = 529, (M + 2Na) ++ = 276.

Príklad 153Example 153

Hydrochlorid 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]5-(izoindolin-2-yl-sulfonyl)-benzimidazolu1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] 5- (isoindolin-2-yl-sulfonyl) -benzimidazole hydrochloride

Zlúčenina sa pripravila obdobne ako v príklade 25d z 1-metyl-2-[N-(4-kyanofenyl)-aminometyl]-5-(izoindolin-2-yl-sulfonyl)-benzimidazolu, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 33 % teoretického výťažku ;The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -5- (isoindolin-2-yl-sulfonyl) -benzimidazole, ethanolic hydrochloric acid solution, ethanol and ammonium carbonate . The yield of the product was 33% of the theoretical yield;

Rf hodnota: 0,32 (gél kyseliny kremičitej; dichlórmetán/etanol = 4:l);Rf value: 0.32 (silica gel; dichloromethane / ethanol = 4: 1);

C24H24N6O2S (460,6);C 24 H 24 N 6 O 2 S (460.6);

EKA hmotnostné spektrum: (M+Hý =461.EKA mass spectrum: (M + H + = 461).

Príklad 154Example 154

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-[2-(4-amidinofenyl)-etyl]-chinazolin-7-yl-karboxylovej2- [2- (4-amidinophenyl) -ethyl] -quinazolin-7-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) Etylester kyseliny 4-metyl-3-nitro-benzoovej(a) 4-Methyl-3-nitro-benzoic acid ethyl ester

Do roztoku 3 ml koncentrovanej kyseliny chlorovodíkovej a 4 ml koncentrovanej kyseliny sírovej sa za miešania pri 5 °C po kvapkách pridalo 4,9 g (0,03 molu) etylesteru kyseliny p-tolylkarboxylovej a zmes sa hodinu miešala za súčasného chladenia v ľadovom kúpeli. Po ohriatí na teplotu miestnosti sa zmes naliala na zmesi ľadu a vody a následne extrahovala esterom kyseliny octovej. Organické extrakty sa premyli roztokom hydrogenuhličitanu sodného, sušili a odparili.To a solution of 3 ml of concentrated hydrochloric acid and 4 ml of concentrated sulfuric acid, 4.9 g (0.03 mol) of ethyl p-tolylcarboxylic acid ester was added dropwise with stirring at 5 ° C, and the mixture was stirred while cooling in an ice bath. After warming to room temperature, the mixture was poured onto ice-water and then extracted with acetic acid ester. The organic extracts were washed with sodium bicarbonate solution, dried and evaporated.

Výťažok produktu bol 5,7 g (90 % teoretického výťažku); Rf hodnota: 0,81 (gél kyseliny kremičitej; ester kyseliny octovej/cyklohexán = 1:1).Yield: 5.7 g (90% of theory); Rf value: 0.81 (silica gel; ethyl acetate / cyclohexane = 1: 1).

b) Metylester kyseliny 4-(2-dimetylaminovinyl)-3-nitrobenzoovejb) 4- (2-Dimethylaminovinyl) -3-nitrobenzoic acid methyl ester

1,0 g (4,8 mmolu) etylesteru kyseliny 4-metyl-3-nitrobenzoovej, 0,74 g (6,2 mmolu) dimetylacetálu dimetylformamidu a 2 ml dimetylformamidu sa 3 hodiny za miešania zahrievali na 140 °C. Potom sa rozpúšťadlo oddestilovalo a získaný surový produkt sa použil bez ďalšieho čistenia. Výťažok produktu bol 1,2 g (100 % teoretického výťažku); Rf hodnota: 0,54 (gél kyseliny kremičitej; ester kyseliny octovej/cyklohexán =1:1).1.0 g (4.8 mmol) of 4-methyl-3-nitrobenzoic acid ethyl ester, 0.74 g (6.2 mmol) of dimethylformamide dimethyl acetal and 2 ml of dimethylformamide were heated to 140 ° C with stirring for 3 hours. Then, the solvent was distilled off and the crude product obtained was used without further purification. The product yield was 1.2 g (100% of theory); Rf value: 0.54 (silica gel; acetic ester / cyclohexane = 1: 1).

c) Metylester kyseliny 4-formyl-3-nitrobenzoovejc) 4-Formyl-3-nitrobenzoic acid methyl ester

V 120 ml tetrahydrofuránu s vodou (1 : 1) sa rozpustilo 1,2 g (4,8 mmolu) metylesteru kyseliny 4-(2-dimetylaminovinyl)-3-nitrobenzoovej a po prídavku 3,0 g (14,3 mmolu) jodistanu sodného sa zmes miešala 20 hodín pri teplote miestnosti. Suspenzia sa potom zriedila vodou a metylénchloridom a extrahovala metylénchloridom. Spojené organické extrakty sa premyli roztokom hydrogenuhličitanu sodného, sušili a odparili. Zvyšok sa chromatograficky čistil na géli kyseliny kremičitej s použitím esteru kyseliny octovej/cyklohexánu (1 : 3) ako elučným činidlom. Výťažok produktu bol 0,6 g (63 % teoretického výťažku);1.2 g (4.8 mmol) of methyl 4- (2-dimethylaminovinyl) -3-nitrobenzoate were dissolved in 120 ml of tetrahydrofuran with water (1: 1) and after addition of 3.0 g (14.3 mmol) of periodate. The mixture was stirred at room temperature for 20 hours. The suspension was then diluted with water and methylene chloride and extracted with methylene chloride. The combined organic extracts were washed with sodium bicarbonate solution, dried and evaporated. The residue was chromatographed on silica gel using acetic acid / cyclohexane ester (1: 3) as eluent. Yield: 0.6 g (63% of theory);

Rf hodnota: 0,63 (gél kyseliny kremičitej; ester kyseliny octovej/cyklohexán =1:1). Rf value: 0.63 (silica gel; ethyl acetate / cyclohexane = 1: 1).

d) Metylester kyseliny 3-amino-4-formyl-benzoovejd) 3-Amino-4-formyl-benzoic acid methyl ester

Do roztoku 25 ml zmesi etanolu/ľadovej kyseliny octovej/vody (2:2: 1) sa pridalo 0,6 g (2,9 mmolu) metylesteru kyseliny 4-formyl-3-nitrobenzoovej, 1,2 g (21,4 mmolu) práškového železa a 0,01 ml koncentrovanej kyseliny chlorovodíkovej a zmes sa zahrievala pri teplote varu pod spätným chladičom. Potom sa železo oddelilo, roztok sa zriedil vodou a extrahoval metylénchloridom. Spojené organické extrakty sa premyli vodou, sušili a odparili. Výťažok produktu bol 0,3 g (58 % teoretického výťažku); Rf hodnota: 0,74 (gél kyseliny kremičitej; metylénchlorid/metanol = 9,5 : 0,5).To a solution of 25 mL of ethanol / glacial acetic acid / water (2: 2: 1) was added 0.6 g (2.9 mmol) of 4-formyl-3-nitrobenzoic acid methyl ester, 1.2 g (21.4 mmol) of powdered iron and 0.01 ml of concentrated hydrochloric acid, and the mixture was heated to reflux. Then the iron was separated, the solution was diluted with water and extracted with methylene chloride. The combined organic extracts were washed with water, dried and evaporated. Yield: 0.3 g (58% of theory); Rf value: 0.74 (silica gel; methylene chloride / methanol = 9.5: 0.5).

e) Metylester kyseliny 3-[3-(4-kyanofenyl)-propionylamino]-4-formyl-benzooveje) 3- [3- (4-Cyanophenyl) -propionylamino] -4-formyl-benzoic acid methyl ester

1,0 g (5,6 mmolu) metylesteru kyseliny 3-amino-4-formylbenzoovej a 1,1 g (5,6 mmolu) chloridu 4-kyanofenylpropiónovej kyseliny a rozpustilo v 50 ml metylénchloridu a po prídavku 0,7 g (5,6 mmolu) n-etyldiizopropylamínu sa zmes miešala 24 hodín pri teplote miestnosti. Zmes sa potom extrahovala roztokom hydrogenuhličitanu sodného. Spojené organické extrakty sa sušili a odparili, zvyšok sa chromatografícky čistil na géli kyseliny kremičitej s použitím esteru kyseliny octovej/cyklohexánu (1 : 3) ako elučným činidlom. Výťažok produktu bol 0,6 g (32 % teoretického výťažku); Rf hodnota: 0,60 (gél kyseliny kremičitej; ester kyseliny octovej/cyklohexán =1:1).1.0 g (5.6 mmol) of methyl 3-amino-4-formylbenzoate and 1.1 g (5.6 mmol) of 4-cyanophenylpropionic acid chloride were dissolved in 50 ml of methylene chloride and after the addition of 0.7 g N-ethyldiisopropylamine (6 mmol) was stirred at room temperature for 24 hours. The mixture was then extracted with sodium bicarbonate solution. The combined organic extracts were dried and evaporated, the residue was chromatographed on silica gel using acetic acid / cyclohexane ester (1: 3) as eluent. Yield: 0.6 g (32% of theory); Rf value: 0.60 (silica gel; ethyl acetate / cyclohexane = 1: 1).

f) Metylester kyseliny 2-[2-(4-kyanofenyl)-etyl]-chinazolin-7-karboxylovejf) 2- [2- (4-Cyanophenyl) ethyl] quinazoline-7-carboxylic acid methyl ester

0,6 g (1,8 mmolu) etylesteru kyseliny 3-[3-(4-kyanofenyl)-propionylamino]-4-formylbenzoovej a 10 ml metanolového roztoku amoniaku sa pretrepávalo 36 hodín v tlakovej nádobe. Po oddestilovaní rozpúšťadla sa zvyšok chromatografoval na géli kyseliny kremičitej a eluoval metylénchloridom, ktorý obsahoval 0 až 1 % metanolu. Výťažok produktu bol 0,35 g (62 % teoretického výťažku); Rf hodnota: 0,38 (gél kyseliny kremičitej; ester kyseliny octovej/cyklohexán = 1 : 1).0.6 g (1.8 mmol) of 3- [3- (4-cyanophenyl) -propionylamino] -4-formylbenzoic acid ethyl ester and 10 ml of methanolic ammonia solution were shaken in a pressure vessel for 36 hours. After distilling off the solvent, the residue was chromatographed on a silica gel and eluted with methylene chloride containing 0 to 1% methanol. Yield: 0.35 g (62% of theory); Rf value: 0.38 (silica gel; acetic ester / cyclohexane = 1: 1).

g) Kyselina 2-[2-(4-kyanofenyl)-etyl]-chinazolin-7karboxylovág) 2- [2- (4-Cyanophenyl) ethyl] quinazoline-7-carboxylic acid

0,3 g (0,94 mmolu) metylesteru kyseliny 2-[2-(4-kyanofenyl)-etyl]-chinazolin-7-karboxylovej a rozpustilo v 4,7 ml roztoku hydroxidu lítneho (clí0h = 1 mol.drri3) a 4 ml tetrahydrofuránu. Roztok sa 3 hodiny miešal pri teplote miestnosti. Po pridaní 4,7 ml kyseliny chlorovodíkovej sa zmes 30 minút miešala. Vylúčený produkt sa odfiltroval s odsávaním, premyl vodou a sušil.0.3 g (0.94 mmol) of methyl 2- [2- (4-cyanophenyl) ethyl] quinazoline-7-carboxylic acid dissolved in 4.7 ml lithium hydroxide solution (c = 1 h lí0 mol.drri 3 ) and 4 ml of tetrahydrofuran. The solution was stirred at room temperature for 3 hours. After addition of 4.7 ml of hydrochloric acid, the mixture was stirred for 30 minutes. The precipitated product was filtered off with suction, washed with water and dried.

Výťažok produktu bol 0,30 g (100 % teoretického výťažku);Yield of product was 0.30 g (100% of theory);

Rf hodnota: 0,1 (gél kyseliny kremičitej; ester kyseliny octovej/cyklohexán =1:1).Rf value: 0.1 (silica gel; acetic ester / cyclohexane = 1: 1).

h) N-Fenyl-N-(2-metoxykarbonylctyl)-amid kyseliny 2-[2-(4-kyanofenyl)-etyl]-chmazolin-7-yl-karboxylovejh) 2- [2- (4-Cyanophenyl) ethyl] -chazolin-7-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonyl-ethyl) -amide

0,4 g (1,3 mmolu) kyseliny 2-[2-(4-kyanofenyl)-etyl]-chinazolin-7-karboxylovej a 5 ml tionylchloridu sa 60 minút miešalo pri teplote 50 °C. Potom sa tionylchlorid oddestiloval, zvyšok sa rozpustil v metylénchloridc, zmiešal s 0,24 g (1,3 mmolu) metylesteru kyseliny 3-(N-fenylamino)propiónovej a 0,22 ml (1,3 mmolu) N-etyl-diizopropylamínu a násada sa miešala 18 hodín pri teplote miestnosti. Po odparení rozpúšťadla vo vákuu sa produkt chromatografícky čistil s použitím metylénchloridu (obsahujúceho 1 % metanolu) ako elučným činidlom.0.4 g (1.3 mmol) of 2- [2- (4-cyanophenyl) ethyl] quinazoline-7-carboxylic acid and 5 ml of thionyl chloride were stirred at 50 ° C for 60 minutes. The thionyl chloride was then distilled off, the residue was dissolved in methylene chloride, treated with 0.24 g (1.3 mmol) of methyl 3- (N-phenylamino) propionate and 0.22 ml (1.3 mmol) of N-ethyl-diisopropylamine and the batch was stirred at room temperature for 18 hours. After evaporation of the solvent in vacuo, the product was chromatographed using methylene chloride (containing 1% methanol) as eluent.

Výťažok produktu bol 0,230 mg (37 % teoretického výťažku);Yield of product was 0.230 mg (37% of th.);

Rf hodnota: 0,64 (gél kyseliny kremičitej; metylénchlorid/metanol = 9 : 1). Rf value: 0.64 (silica gel; methylene chloride / methanol = 9: 1).

i) Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 2-[2-(4-amidinofenyl)-etyl]-chinazolin-7-yl-karboxyloveji) 2- [2- (4-amidinophenyl) -ethyl] -quinazolin-7-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

230 mg (0,5 mmolu) N-fenyl-N-(2-metoxykarbonyletyl)-amidu kyseliny 2-[2-(4-kyanofenyl)-etyl]-chinazolin-7-yl-karboxylovej v 30 ml etanolu nasýteného chlorovodíkom sa miešalo 8 hodín pri teplote miestnosti. Potom sa zmes odparila do sucha vo vákuu. Zvyšok sa rozmiešal v 20 ml etanolu, pridalo sa 0,5 g (5,0 mmolov) uhličitanu amónneho a zmes sa miešala cez noc pri teplote miestnosti. Po odparení rozpúšťadla sa surový produkt čistil na géli kyseliny kremičitej s použitím metylénchloridu s etanolom (4:1) ako elučným činidlom.230 mg (0.5 mmol) of 2- [2- (4-cyanophenyl) -ethyl] -quinazolin-7-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide in 30 ml of ethanol saturated with hydrogen chloride were added. was stirred at room temperature for 8 hours. Then the mixture was evaporated to dryness in vacuo. The residue was stirred in 20 ml of ethanol, 0.5 g (5.0 mmol) of ammonium carbonate was added, and the mixture was stirred overnight at room temperature. After evaporation of the solvent, the crude product was purified on a silica gel using methylene chloride with ethanol (4: 1) as eluent.

Výťažok produktu bol 100 mg (39 % teoretického výťažku);The product yield was 100 mg (39% of th.);

Rf hodnota: 0,5 (gél kyseliny kremičitej; metylénchlorid/metanol = 4 : 1); Rf value: 0.5 (silica gel; methylene chloride / methanol = 4: 1);

C29H29N5O3 (495,59);C 29 H 29 N 5 O 3 (495.59);

Hmotnostné spektrum: (M+H)+ = 496.Mass Spectrum: (M + H) + = 496.

Príklad 155 N-(l-Metylpyrazol-4-yl)-N-(2-hydroxykarbonylctyl)amid kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-sulfónovejExample 155 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-sulfonic acid N- (1-methyl-pyrazol-4-yl) -N- (2-hydroxycarbonyl-ethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 26 z hydrochloridu N-(l -mctylpyrazol-4-yl)-N-(2-etoxykarbonyletyl)amid kyseliny l-metyl-2-[N-(4-amidino-fenyl)-aminometyl]-benzimidazol-5-sulfónovej a hydroxidu sodného. Výťažok produktu bol 95 % teoretického výťažku ; C23H26N8O4S (510,6);The compound was prepared analogously to Example 26 from 1-methyl-2- [N- (4-amidino-phenyl) -aminomethyl] N- (1-methyl-pyrazol-4-yl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride -benzimidazole-5-sulfonic acid and sodium hydroxide. The product yield was 95% of the theoretical yield; C 23 H 26 N 8 O 4 S (510.6);

Rf hodnota: 0,53 (gél kyseliny kremičitej RP-8 s reverznou fázou; metanol + 5%-ný roztok kuchynskej soli); Rf value: 0.53 (silica gel RP-8 reverse phase column; methanol + 5% saline solution);

EKA hmotnostné spektrum: (M+H)+ = 511, (M+Na)+ = = 533, (M+2Na)++ = 278.EKA mass spectrum: (M + H) + = 511, (M + Na) + = 533, (M + 2Na) ++ = 278.

Príklad 156Example 156

Hydrochlorid N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(3-amidinopyridin-6-yl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (3-amidinopyridin-6-yl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

a) N-(2-Pyridyl)-N-(etoxykarbonyletyl)-amid kyseliny 3-[(N-íerc-butoxykarbonyl-amino)acetylamino]-4-metylaminobenzooveja) 3 - [(N-tert-Butoxycarbonyl-amino) -acetylamino] -4-methylaminobenzoic acid N- (2-pyridyl) -N- (ethoxycarbonylethyl) -amide

19,2 g (0,11 molu) N-Zerc-butyloxykarbonylglycínu sa rozpustilo v 175 ml dimetylformamidu, pridalo sa 35,2 g (0,11 molu) (O-benzotriazol-l-yl)-N,N,N‘,N‘-tetrametyluróniumtetrafluórborátu, 11,0 g trietylamínu a 34,2 g (0,10 molu) N-(2-pyridyl)-N-(2-hydroxykarbonyletyl)-amidu kyseliny 3-amino-4-metylamino-benzoovej a zmes sa miešala19.2 g (0.11 mol) of N-tert-butyloxycarbonylglycine was dissolved in 175 ml of dimethylformamide, 35.2 g (0.11 mol) of (O-benzotriazol-1-yl) -N, N, N 'were added. 3-amino-4-methylamino-benzoic acid, N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide, N'-tetramethyluronium tetrafluoroborate, 11.0 g triethylamine and 34.2 g (0.10 mol) and the mixture was stirred

2,5 hodiny pri teplote miestnosti. Reakčná zmes sa potom rozmiešala do 5 litrov ľadovej vody a 2 hodiny miešala. Vytvorená sivá zrazenina sa odfiltrovala, premyla vodou, sušila a po prísade aktívneho uhlia sa rekryštalizovala z prostredia octanu etylnatého.2.5 hours at room temperature. The reaction mixture was then stirred in 5 liters of ice water and stirred for 2 hours. The gray precipitate formed was filtered off, washed with water, dried and recrystallized from ethyl acetate after addition of activated carbon.

Výťažok produktu bol 39,85 g (80 % teoretického výťažku);Yield: 39.85 g (80% of theory);

C25H33N5O6 (499,6);C 25 H 33 N 5 O 6 (499.6);

Rf hodnota: 0,55 (gél kyseliny kremičitej; metylénchlorid/etanol= 19 :1). Rf value: 0.55 (silica gel; methylene chloride / ethanol = 19: 1).

b) N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-(N-to-c-butoxy-karbonyl-aminometyl)-benzimidazol-5-yl-karboxylovejb) 1-Methyl-2- (N-t-butoxy-carbonyl-aminomethyl) -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

V 50 ml ľadovej kyseliny octovej sa rozpustilo 10,0 g (0,02 molu) N-(2-pyridyl)-N-(etoxykarbonyletyl)-amidu kyseliny 3-[(N-/erc-butoxykarbonyl-amino)-acetylamino]-4-metylamino-benzoovej a roztok sa zahrieval hodinu pri teplote varu pod spätným chladičom. Po oddestilovaní rozpúšťadla sa zvyšok rozmiešal s ľadovou vodou a prídavkom roztoku amoniaku (cNH3 = 2 mol.dm'3) sa pH upravilo na hodnotu 8. Po trojnásobnej extrakcii esterom kyseliny octovej sa spojené organické fázy premyli roztokom kuchynskej soli a sušili síranom sodným. Po odparení rozpúšťadla sa surový produkt chromatografický čistil, pričom sa najprv použil metylénchlorid, potom metylénchlorid/etanol (50 : 1) a nakoniec metylénchlorid/etanol (25 : 1). Vhodné frakcie sa spojili a odparili.10.0 g (0.02 mol) of N- (2-pyridyl) -N- (ethoxycarbonylethyl) -amide 3 - [(N- tert -butoxycarbonyl-amino) -acetylamino] were dissolved in 50 ml of glacial acetic acid. -4-methylamino-benzoic acid and the solution was heated under reflux for 1 hour. After distilling off the solvent, the residue was stirred with ice water and the pH was adjusted to 8 by addition of ammonia solution (c NH 3 = 2 mol.dm 3 ). After extraction three times with acetic acid ester, the combined organic phases were washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified by chromatography using methylene chloride first, then methylene chloride / ethanol (50: 1) and finally methylene chloride / ethanol (25: 1). The appropriate fractions were combined and evaporated.

Výťažok produktu bol 5,85 g (61 % teoretického výťažku); C25H31N5O5 (481,6);Yield: 5.85 g (61% of theory); C 25 H 31 N 5 O 5 (481.6);

Rf hodnota: 0,70 (gél kyseliny kremičitej; metylénchlorid/etanol = 9 : 1).Rf value: 0.70 (silica gel; methylene chloride / ethanol = 9: 1).

c) Trifluóracetát N-(2-pyridyl)-N-(etoxykarbonyletyl)amidu kyseliny l-metyl-2-amino-metyl-benzimidazol-5-yl-karboxylovejc) 1-Methyl-2-amino-methyl-benzimidazol-5-yl-carboxylic acid trifluoroacetate N- (2-pyridyl) -N- (ethoxycarbonylethyl) amide

V 25 ml metylénchloridu sa rozpustilo 4,81 g (0,10 molu) N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1metyl-2-(N-ŕerc-butoxykarbonylaminometyl)-benzimidazol-5-yl-karboxylovej, pridalo sa 5 ml kyseliny trifluóroctovej a zmes sa miešala 5 hodín pri teplote miestnosti. Potom sa odparilo rozpúšťadlo a zvyšok sa rozmiešal v éteri. Vytvorené kryštály sa odfiltrovali, premyli éterom a vysušili.4-Methyl-2- (N-tert-butoxycarbonylaminomethyl) -benzimidazole-5- (2-methoxycarbonylethyl) -N- (2-ethoxycarbonylethyl) -amide was dissolved in 25 ml of methylene chloride. 5-trifluoroacetic acid was added and the mixture was stirred at room temperature for 5 hours. Then the solvent was evaporated and the residue was stirred in ether. The crystals formed were filtered off, washed with ether and dried.

Výťažok produktu bol 3,15 g (68 % teoretického výťažku) ; C20H23N5O3 (381,4);Yield: 3.15 g (68% of theory); C 20 H 23 N 5 O 3 (381.4);

Rf hodnota: 0,18 (gél kyseliny kremičitej; metylénchlorid/etanol = 9 : 1). Rf value: 0.18 (silica gel; methylene chloride / ethanol = 9: 1).

d) N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(3-kyano-pyridín-6-yl)aminometyl]-benzimidazol-5 -yl-karboxylovejd) 1-Methyl-2- [N- (3-cyano-pyridin-6-yl) aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

V 10 ml N-etyl-diizopropylamínu sa rozmiešalo 1,5 g (3,25 mmolu) trifluóracetátu N-(2-pyridyl)-N-(etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-aminometylbenzimidazol-5-yl-karboxylovej a roztok sa 15 minút zahrieval na teplotu 100 °C. Po prídavku 720 mg (5,25 mmolu) 2-chlór-5-kyano-pyridinu sa reakčná zmes 2 hodiny zahrievala na 125 °C. Po ochladení na teplotu miestnosti a rozmiešaní s približne 20 ml vody sa prídavkom kyseliny chlorovodíkovej (cHC| = 1 mol.drri3) nastavilo pH na hodnotu 4 a zmes sa trikrát extrahovala esterom kyseliny octovej. Spojené organické fázy sa premyli roztokom kuchynskej soli a sušili síranom sodným. Po odparení rozpúšťadla sa surový produkt chromatografický čistil, pričom sa použil najprv metylénchlorid, potom metylénchlorid/etanol (25 : 1) a nakoniec metylénchlorid/etanol (19 : 1). Vhodné frakcie sa spojili a odparili.1.5 g (3.25 mmol) of N- (2-pyridyl) -N- (ethoxycarbonylethyl) -amide 1-methyl-2-aminomethylbenzimidazol-5-yl-carboxylic acid trifluoroacetate was stirred in 10 ml of N-ethyl-diisopropylamine. and the solution was heated to 100 ° C for 15 minutes. After addition of 720 mg (5.25 mmol) of 2-chloro-5-cyanopyridine, the reaction mixture was heated at 125 ° C for 2 h. After cooling to room temperature and stirring with approximately 20 ml of water, the pH was adjusted to 4 by addition of hydrochloric acid (c HCl = 1 mol. Dri 3 ) and the mixture was extracted three times with acetic acid ester. The combined organic phases were washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified by chromatography using first methylene chloride, then methylene chloride / ethanol (25: 1) and finally methylene chloride / ethanol (19: 1). The appropriate fractions were combined and evaporated.

Výťažok produktu bol 1,05 g (67 % teoretického výťažku); C26H25N7O (483,6);Yield of the product was 1.05 g (67% of theory); C 26 H 25 N 7 O (483.6);

Hmotnostné spektrum: (M+H)+ = 484.Mass Spectrum: (M + H) + = 484.

e) Hydrochlorid N-(2-pyridyl)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(3-amidino-pyridín-6-yl)aminometyl]-benzimidazol-5-yl-karboxyloveje) 1-Methyl-2- [N- (3-amidino-pyridin-6-yl) aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride

Zlúčenina sa pripravila obdobne ako v príklade 25d z N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1-metyl-2-[N-(3-kyanopyridín-6-yl)-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 38 % teoretického výťažku; C2SH28N8O3 (500,6);The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (3-cyanopyridin-6-yl) -aminomethyl] -benzimidazole N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide. 5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. The product yield was 38% of the theoretical yield; C 2 H 28 N 8 O 3 (500.6);

EKA hmotnostné spektrum: (M+H)+ = 501.EKA mass spectrum: (M + H) + = 501.

Príklad 157Example 157

Hydrojodid N-fenyl-N-(2-metoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidi-nofenyl)-aminometyl]-indol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide hydroiodide

a) N-Fenyl-N-(2-metoxykarbonyletyl)-amid kyseliny 4-nitrobenzooveja) 4-Nitrobenzoic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

V 50 ml tionylchloridu s 3 kvapkami dimetylformamidu sa varilo pod spätným chladičom 16,7 g (0,1 molu) 4-nitrobenzoovej kyseliny. Po oddestilovaní rozpúšťadla vo vákuu sa surový produkt rozpustil v 150 ml tetrahydrofuránu a po kvapkách sa pridalo do roztoku 18 g (0,1 molu) N-(2-metoxykarbonyletyl)anilínu v 250 ml tetrahydrofuránu a 42 ml (0,3 molu) trietylamínu. Po jednohodinovom miešaní pri teplote miestnosti sa zmes zriedila 250 ml octanu etylnatého a 2 x premyla 200 ml 14%-ného roztoku kuchynskej soli. Po oddestilovaní rozpúšťadla a chromatografickom čistení (gél kyseliny kremičitej; metylénchlorid) sa získala žltá olejovitá látka, ktorá časom tuhla.16.7 g (0.1 mol) of 4-nitrobenzoic acid were refluxed in 50 ml of thionyl chloride with 3 drops of dimethylformamide. After distilling off the solvent in vacuo, the crude product was dissolved in 150 ml of tetrahydrofuran and added dropwise to a solution of 18 g (0.1 mol) of N- (2-methoxycarbonylethyl) aniline in 250 ml of tetrahydrofuran and 42 ml (0.3 mol) of triethylamine. . After stirring at room temperature for 1 hour, the mixture was diluted with 250 mL of ethyl acetate and washed twice with 200 mL of 14% brine. After distilling off the solvent and chromatographic purification (silica gel; methylene chloride), a yellow oil was obtained which solidified over time.

Výťažok produktu bol 32,6 g (100 % teoretického výťažku);Yield: 32.6 g (100% of theory);

Rf hodnota: 0,37 (gél kyseliny kremičitej; metylénchlond/metanol = 50:1).Rf value: 0.37 (silica gel; methylene chloride / methanol = 50: 1).

b) N-Fenyl-N-(2-metoxykarbonyletyl)-amid kyseliny 4-aminobenzoovej g (67 mmolov) N-fenyl-N-(2-metoxykarbonyletyl)amid kyseliny 4-nitro-benzoovej v 500 ml metanolu s 2 g 10%-ného paládia na uhlí sa hydrogenovalo pod tlakom 0,3 MPa vodíka 3 hodiny. Po filtrácii a oddestilovaní rozpúšťadla sa roztok premyl éterom a biely kryštalický produkt sa použil priamo v ďalšej práci.b) 4-aminobenzoic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide g (67 mmol) 4-nitro-benzoic acid N-phenyl-N- (2-methoxycarbonylethyl) amide in 500 ml of methanol with 2 g of 10 % palladium-on-carbon was hydrogenated under 3 bar of hydrogen for 3 hours. After filtration and distillation of the solvent, the solution was washed with ether and the white crystalline product was used directly in the next work.

Výťažok produktu bol 18,6 g (94 % teoretického výťažku); Rf hodnota: 0,70 (gél kyseliny kremičitej; metylénchlorid/etanol = 19 : 1).Yield: 18.6 g (94% of theory); Rf value: 0.70 (silica gel; methylene chloride / ethanol = 19: 1).

c) N-Fenyl-N-(2-metoxykarbonyletyl)-amid kyseliny 2-metyl-3-tiometyl-indol-5-yl-karboxylovejc) 2-Methyl-3-thiomethyl-indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

26,8 g (91 mmolov) N-fenyl-N-(2-metoxykarbonyletyl)-amidu kyseliny 4-aminobcnzoovej sa rozpustilo v 500 ml metylénchloridu, roztok sa ochladil na -70 °C a v priebehu 30 minút sa pridal čerstvo pripravený terc-butylchlóman (M. J. Mintz et al., Organic Synthesis Coli., Vol. 5, strana 184). Reakčná zmes sa miešala 2 hodiny pri -70 °C, potom sa po kvapkách v priebehu 30 minút pridalo 9,46 g (91 mmolov) metyltioacetónu v 40 ml metylénchloridu a zmes sa miešala ďalšiu 1,5-hodinu. Potom sa pridalo 12,7 ml (9,1 g, 91 mmolov) trietylamínu v 25 ml metylénchloridu. Zmes sa nechala pri -78 °C 30 minút a potom sa pomaly cez noc nechala teplota zmesi vystúpiť na teplotu miestnosti. Po dvojnásobnom premytí vždy s 50 ml vody sa oddelila organická fáza a sušila sa síranom sodným. Po odstránení rozpúšťadla vo vákuu a po chromatografickom čistení (gél kyseliny kremičitej; ester kyseliny octovej/petroléter = 2 : 8 až 3 : 7) sa získala biela amorfná látka. Výťažok produktu bol 24,1 g (69 % teoretického výťažku); C2IH22N2O3S (382,49);26.8 g (91 mmol) of 4-aminobenzzoic acid N-phenyl-N- (2-methoxycarbonylethyl) amide was dissolved in 500 ml of methylene chloride, the solution was cooled to -70 ° C and freshly prepared tert- butyl chloromethane (MJ Mintz et al., Organic Synthesis Coli., Vol. 5, page 184). The reaction mixture was stirred at -70 ° C for 2 hours, then methyl thioacetone (9.46 g, 91 mmol) in methylene chloride (40 mL) was added dropwise over 30 minutes, and the mixture was stirred for an additional 1.5 hours. Then, 12.7 mL (9.1 g, 91 mmol) of triethylamine in 25 mL of methylene chloride was added. The mixture was left at -78 ° C for 30 minutes and then slowly allowed to warm to room temperature overnight. After washing twice with 50 ml of water each time, the organic phase was separated and dried over sodium sulfate. Removal of the solvent in vacuo and chromatographic purification (silica gel; acetic acid ester / petroleum ether = 2: 8 to 3: 7) gave a white amorphous solid. Yield: 24.1 g (69% of theory); C 2I H 22 N 2 O 3 S (382.49);

Rf hodnota: 0,58 (gél kyseliny kremičitej; ester kyseliny octovej/petroléter =1:1) EKA hmotnostné spektrum: (M+H)+ = 382. Rf value: 0.58 (silica gel; ethyl acetate / petroleum ether = 1: 1) EKA mass spectrum: (M + H) + = 382nd

d) N-Fenyl-N-(2-metoxykarbonyletyl)-amid kyseliny 1-terc-butoxykarbonyl-2-metyl-indol-5-yl-karboxylovejd) 1- tert -Butoxycarbonyl-2-methyl-indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

8,9 g (23 mmolu) N-fenyl-N-(2-metoxykarbonyletyl)amidu kyseliny 2-metyl-3-tiometyl-indol-5-yl-karboxylovej sa rozpustilo v 600 ml etanolu, roztok sa zmiešal s približne 150 mg Raneyovho niklu a zmes sa 2 hodiny miešala pri teplote miestnosti (obdobne ako opisuje P. G. Gassman et ak, Organic Synthesis Coli., Vol 6, strana 601). Zmes sa potom filtrovala a rozpúšťadlo sa odstránilo vo vákuu. Získaný surový produkt (8 g) sa rozpustil v 200 ml absolútneho tetrahydrofuránu, pridalo sa 150 mg dimetylaminopyridínu a 6,84 g (32 mmolov) di(rerc-butyl)esteru kyseliny pyrouhličitej a zmes sa miešala 2,5-hodiny pri 50 °C. Potom sa rozpustidlo oddestilovalo vo vákuu a surový produkt sa chromatograficky čistil (gél kyseliny kremičitej; ester kyseliny octovej/petroléter =1:4)8.9 g (23 mmol) of 2-methyl-3-thiomethyl-indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide were dissolved in 600 ml of ethanol, the solution was mixed with approximately 150 mg Raney nickel and the mixture was stirred at room temperature for 2 hours (as described by PG Gassman et al., Organic Synthesis Coli., Vol 6, page 601). The mixture was then filtered and the solvent was removed in vacuo. The obtained crude product (8 g) was dissolved in 200 ml of absolute tetrahydrofuran, 150 mg of dimethylaminopyridine and 6.84 g (32 mmol) of pyrocarbonate di (tert-butyl) ester were added and the mixture was stirred at 50 ° for 2.5 hours. C. Then the solvent was distilled off in vacuo and the crude product was purified by chromatography (silica gel; acetic acid ester / petroleum ether = 1: 4)

Výťažok produktu bol 10,0 g (98 % teoretického výťažku); Rf hodnota: 0,40 (gél kyseliny kremičitej; ester kyseliny octovej/petroléter = 3 : 7).Yield: 10.0 g (98% of theory); Rf value: 0.40 (silica gel; ethyl acetate / petroleum ether = 3: 7).

e) N-Fenyl-N-(2-metoxykarbonyletyl)-amid kyseliny 2-[N-(4-kyanofenyl) amino-metyl]-indol-5-yl-karboxyloveje) 2- [N- (4-cyanophenyl) amino-methyl] -indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

3.5 g (8 mmolu) N-fenyl-N-(2-metoxykarbonyletyl)amidu kyseliny l-íerc-butoxykarbonyl-2-metyl-indol-5-yI-karboxylovej sa rozpustilo v 80 ml tetrachlórmetánu, pridalo sa 1,5 g (8,4 mmolu) N-brómsukcínimidu a 20 mg azobisizobutyronitrilu a zmes sa zahrievala 2,5-hodiny na teplotu varu pod spätným chladičom. Potom sa ešte teplý roztok filtroval, získaný filtrát sa premyl nasýteným roztokom hydrogenuhličitanu sodného a sušil síranom sodným. Po oddestilovaní rozpúšťadla sa surový produkt rozpustil v 30 ml N-etyl-diizopropylamínu, pridalo sa 1,0 g (8 mmolov) 4-aminobenzonitrilu a zmes sa 2,5-hodiny zahrievala na teplotu varu pod spätným chladičom. Rozpúšťadlo sa potom oddestilovalo vo vákuu a získaný zvyšok sa chromatograficky čistil (gél kyseliny kremičitej; ester kyseliny octovej/petroléter = 1 : 4 až 1 : 1).3.5 g (8 mmol) of 1-tert-butoxycarbonyl-2-methyl-indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) amide was dissolved in 80 ml of carbon tetrachloride, 1.5 g ( 8.4 mmol) of N-bromosuccinimide and 20 mg of azobisisobutyronitrile and the mixture was heated under reflux for 2.5 hours. Then the still warm solution was filtered, the obtained filtrate was washed with saturated sodium bicarbonate solution and dried with sodium sulfate. After distilling off the solvent, the crude product was dissolved in 30 ml of N-ethyl-diisopropylamine, 1.0 g (8 mmol) of 4-aminobenzonitrile was added, and the mixture was heated under reflux for 2.5 hours. The solvent was then distilled off in vacuo and the residue was purified by chromatography (silica gel; acetic acid ester / petroleum ether = 1: 4 to 1: 1).

Výťažok produktu bol 1,1 g (30 % teoretického výťažku); Rf hodnota: 0,21 (gél kyseliny kremičitej; ester kyseliny octovej/petroléter = 1:1).Yield of product was 1.1 g (30% of th.); Rf value: 0.21 (silica gel; ethyl acetate / petroleum ether = 1: 1).

f) N-Fenyl-N-(2-metoxykarbonyletyl)-amíd kyseliny 1-metyl-2-[N-(4-tiokarbamoyl-fenyl) aminometyl]-indol-5-yl-karboxylovejf) 1-Methyl-2- [N- (4-thiocarbamoyl-phenyl) aminomethyl] -indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

1.5 g (3,3 mmolu) N-fenyl-N-(2-metoxykarbonyletyl)amidu kyseliny 2-[N-(4-kyanofenyl) aminometyl]-indol-5-yl-karboxylovej sa rozpustilo v 60 ml xylénu, pridalo sa 0,45 g (3,3 mmolu) uhličitanu draselného a 0,5 ml (3,3 mmolu) metylesteru p-toluénsulfónovej kyseliny a reakčná zmes sa 4 hodiny miešala pri teplote varu pod spätným chladičom. Potom sa pridalo ešte raz rovnaké množstvo uhličitanu draselného a metylesteru p-toluénsul iónovej kyseliny a zmes sa cez noc zahrievala na teplotu varu pod spätným chladičom. Potom sa zmes filtrovala a premyla acetónom. Po skoncentrovaní filtrátu sa získaný zvyšok čistil chromatograficky (gél kyseliny kremičitej; ester kyseliny octovej/petroléter = 1 : 4 až 2 : 3). Získaný metylovaný indol (výťažok 0,64 g, 41 % teoretického výťažku) sa rozpustil v 20 ml pyridínu a pridalo sa 0,67 ml (1,37 mmolu) trietylamínu. Do pripraveného roztoku sa potom privádzal plynný sírovodík. Po 4,5 dňoch sa cez reakčný roztok 30 minút prebublával dusík, rozpúšťadlo sa oddestilovalo a získaný zvyšok sa čistil chromatograficky (gél kyseliny kremičitej; metylénchlorid/etanol = 99 : 1 až 98 : 2). Výťažok produktu boí 0,30 g (43 % teoretického výťažku); C28H28N4O3S (500,62);1.5 g (3.3 mmol) of 2- [N- (4-cyanophenyl) aminomethyl] indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) amide was dissolved in 60 ml of xylene, added 0.45 g (3.3 mmol) of potassium carbonate and 0.5 ml (3.3 mmol) of p-toluenesulfonic acid methyl ester were added and the reaction mixture was stirred at reflux for 4 hours. An equal amount of potassium carbonate and p-toluenesulfonic acid methyl ester was then added once more and the mixture was heated at reflux overnight. Then the mixture was filtered and washed with acetone. After concentrating the filtrate, the residue obtained was purified by chromatography (silica gel; acetic acid ester / petroleum ether = 1: 4 to 2: 3). The methylated indole obtained (yield 0.64 g, 41% of theory) was dissolved in 20 ml of pyridine and 0.67 ml (1.37 mmol) of triethylamine was added. Hydrogen sulfide gas was then added to the prepared solution. After 4.5 days, nitrogen was bubbled through the reaction solution for 30 minutes, the solvent was distilled off and the residue was purified by chromatography (silica gel; methylene chloride / ethanol = 99: 1 to 98: 2). Yield: 0.30 g (43% of theory); C28H28N4O3S (500.62);

EKA hmotnostné spektrum: (M+H)+ = 501, (M+Na)' = = 523.EKA mass spectrum: (M + H) + = 501, (M + Na) + = 523.

g) Hydrojodid N-fenyl-N-(2-metoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-indol-5-yl-karboxylovejg) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

0,30 g (0,60 mmolu) N-fenyl-N-(2-metoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-tiokarbamoyl)fenylaminometyl]-indol-5-yl-karboxylovej sa rozpustilo spolu s 0,75 ml (12 mmolov) metyljodidu v 20 ml acetónu a roztok sa 2 hodiny miešal pri teplote miestnosti. Potom sa odparilo rozpúšťadlo a získaný surový produkt sa zmiešal spolu s 1,0 g octanu amónneho v 12 ml etanolu a 5 ml metylénchloridu a roztok sa 20 hodín miešal pri 40 °C. Rozpúšťadlo sa oddestilovalo vo vákuu a získaný zvyšok sa chromatograficky čistil (gél kyseliny kremičitej; metylénchlorid/etanol = 9 : 1 až 4 : 1).0.30 g (0.60 mmol) of 1-methyl-2- [N- (4-thiocarbamoyl) phenylaminomethyl] indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) amide was dissolved together with 0.75 ml (12 mmol) of methyl iodide in 20 ml of acetone and the solution was stirred at room temperature for 2 hours. The solvent was evaporated and the crude product obtained was mixed with 1.0 g of ammonium acetate in 12 ml of ethanol and 5 ml of methylene chloride, and the solution was stirred at 40 ° C for 20 hours. The solvent was distilled off in vacuo and the residue was purified by chromatography (silica gel; methylene chloride / ethanol = 9: 1 to 4: 1).

Výťažok produktu bol 55 % teoretického výťažku; C28HmN5O3 (483,58);The yield of the product was 55% of the theoretical yield; C 28 H m N 5 O 3 (483.58);

Rf hodnota: 0,20 (gél kyseliny kremičitej; metylénchlorid/etanol = 4:1 + 1 kvapka octovej kyseliny); Rf value: 0.20 (silica gel; methylene chloride / ethanol 4: 1 + 1 drop of acetic acid);

EKA hmotnostné spektrum: (M+H)+ = 484.EKA mass spectrum: (M + H) + = 484.

Príklad 158Example 158

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-ticno[2,3 -</]imidazol-5 -yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -ticno [2,3- d] imidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) Hydrochlorid iminoetylesteru kyseliny metoxyoctovej(a) Methoxyacetic acid iminoethyl ester hydrochloride

Roztok 35,5 g (0,50 molu) metoxyacctonitrilu v 29 ml (23 g, 0,50 molu) etanolu a 30 ml absolútneho etyléteru sa ochladil na 0 °C a počas hodiny sa privádzalo 22,5 g (0,62 molu) plynného chlorovodíka, pričom pri konci privádzania plynu vykryštalizoval reakčný produkt. Na úplné vylúčenie sa pridalo 130 ml dietyléteru a bezfarebné ihličky produktu sa odfiltrovali.A solution of 35.5 g (0.50 mol) of methoxyacetonitrile in 29 ml (23 g, 0.50 mol) of ethanol and 30 ml of absolute ethyl ether was cooled to 0 ° C and 22.5 g (0.62 mol) was fed over an hour. HCl gas, the reaction product crystallized at the end of the gas feed. For complete precipitation, 130 ml of diethyl ether was added and the colorless needles of the product were filtered off.

Výťažok bol 66,4 g (86 % teoretického výťažku); teplota topenia produktu bola 117 až 118 °C.Yield: 66.4 g (86% of theory); mp 117-118 ° C.

b) 4-Hydroxymetyl-2-metoxymetyl-imidazolb) 4-Hydroxymethyl-2-methoxymethyl-imidazole

Zmes 30,6 g (0,20 molu) hydrochloridu iminoetylesteru kyseliny metoxyoctovej, 18 g (0,20 molu) 1,3-dihydroxyacetónu a 200 ml kvapalného amoniaku sa 3 hodiny zahrievalo v autokláve s miešaním pod tlakom 2,7 MPa pri teplote 68 °C (obdobne ako uvádza P. Dzurion et al., Árch. Pharm. 307, 470 (1974)). Potom sa amoniak odstránil a reakčná zmes sa zmiešala s 200 ml metylénchloridu. Vylúčená biela zrazenina sa odfiltrovala a premyla metylénchloridom. Filtrát sa skoncentroval a získaný zvyšok sa chromatograficky čistil (oxid hlinitý; metylénchlorid/etanol = 90 : : 10 až 85 : 15);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 in an autoclave under stirring at 2.7 MPa for 3 hours. 68 ° C (similar to P. Dzurion et al., Pharm. Pharm. 307, 470 (1974)). The ammonia was then removed and the reaction mixture was mixed with 200 ml of methylene chloride. The white precipitate formed was filtered off and washed with methylene chloride. The filtrate was concentrated and the residue obtained was purified by chromatography (alumina; methylene chloride / ethanol = 90: 10 to 85: 15);

Výťažok produktu bol 26,7 g (94 % teoretického výťažku); C6H10N2O2 (142,20);Yield: 26.7 g (94% of theory); C 6 H 10 N 2 O 2 (142.20);

Rf hodnota: 0,43 (gél kyseliny kremičitej; metylénchlorid/etanol -9:1); Rf value: 0.43 (silica gel; methylene chloride / ethanol 9: 1);

Hmotnostné spektrum: (M)* = 142.Mass Spectrum: (M) + = 142.

c) 4-Hydroxymetyl-2-metoxymetyl-l-metyl-imidazol ako zmes 1 : 1 s 5-hydroxymctyl-2-metoxymetyl-l-metylimidazolomc) 4-Hydroxymethyl-2-methoxymethyl-1-methyl-imidazole as a 1: 1 mixture with 5-hydroxymethyl-2-methoxymethyl-1-methylimidazole

Zmes 7,1 g (50 mmolov) 4-hydroxymetyl-2-metoxymetylimidazolu, 3,0 g (53 mmolov) rozpráškovaného hyd roxidu draselného a 3,4 ml (0,55 mmolu) metyljodidu v 100 ml dimetylformamidu sa 4 hodiny zahrievala na 50 °C (obdobne ako uvádza I. Sinclair et al., J. Med. Chem. 29, 261 (1986)). Rozpúšťadlo sa potom oddestilovalo vo vákuu a surový produkt sa chromatograficky čistil (oxid hlinitý; metylénchlorid/-etanol = 99 : 1 až 95 : 5).A mixture of 7.1 g (50 mmol) of 4-hydroxymethyl-2-methoxymethylimidazole, 3.0 g (53 mmol) of sprayed potassium hydroxide and 3.4 ml (0.55 mmol) of methyl iodide in 100 ml of dimethylformamide was heated at room temperature for 4 hours. 50 ° C (analogous to I. Sinclair et al., J. Med. Chem. 29, 261 (1986)). The solvent was then distilled off in vacuo and the crude product was purified by chromatography (alumina; methylene chloride / ethanol = 99: 1 to 95: 5).

Výťažok produktu bol 6,1 g (78 % teoretického výťažku, zmes 1 : 1 obidvoch regioizomérov);Yield: 6.1 g (78% of theory, 1: 1 mixture of both regioisomers);

Rf hodnota: 0,32 (gél kyseliny kremičitej; metylénchlorid/etanol = 19 : 1).Rf value: 0.32 (silica gel; methylene chloride / ethanol = 19: 1).

d) 5-Chlór-4-hydroxymetyl-2-metoxymetyl-l-metyl-imidazold) 5-Chloro-4-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole

Zmes 7,7 g (49 mmolov) 4-hydroxymetyl-2-metoxymetyl-l-metylimidazolu a 5-hydroxymetyl-2-metoxymetyl-l-metylimidazolu (1 : 1) a 7,3 g (55 mmolov) N-chlórsukcínimidu sa v 48 ml monoetyléteru etylénglykolu a 70 ml dioxánu zahrievala 10 hodín na 50 °C. Potom sa rozpúšťadlo oddestilovalo vo vákuu a surový produkt sa chromatograficky čistil (gél kyseliny kremičitej; metylénchlorid/etanol = 99 : 1 až 90 : 10) na izoméme čistú zlúčeninu, uvedenú v nadpise.A mixture of 7.7 g (49 mmol) of 4-hydroxymethyl-2-methoxymethyl-1-methylimidazole and 5-hydroxymethyl-2-methoxymethyl-1-methylimidazole (1: 1) and 7.3 g (55 mmol) of N-chlorosuccinimide is added. in 48 ml of ethylene glycol monoethyl ether and 70 ml of dioxane was heated at 50 ° C for 10 hours. Thereafter, the solvent was distilled off in vacuo and the crude product was purified by chromatography (silica gel; methylene chloride / ethanol = 99: 1 to 90: 10) to give the isomer-pure title compound.

Výťažok produktu bol 3,4 g (36 % teoretického výťažku); Rf hodnota: 0,40 (gcl kyseliny kremičitej; metylénchlorid/etanol = 19 : 1).Yield: 3.4 g (36% of theory); Rf value: 0.40 (silica gcl; methylene chloride / ethanol = 19: 1).

e) 5-Chlór-4-formyl-2-metoxymetyl-l-metyl-imidazole) 5-Chloro-4-formyl-2-methoxymethyl-1-methyl-imidazole

3,4 g (18 mmolov) 5-chlór-4-hydroxymetyl-2-metoxymetyl-l-metylimidazolu sa rozpustilo v 100 ml metylénchloridu a v dvojhodinových intervaloch sa pridával oxid manganičitý (2 x 6,0 g, spolu 0,14 molu). Po 4 hodinách sa anorganické zložky odfiltrovali, rozpúšťadlo sa odstránilo a získaný surový produkt sa bez ďalšieho čistenia použil v ďalšom reakčnom kroku.3.4 g (18 mmol) of 5-chloro-4-hydroxymethyl-2-methoxymethyl-1-methylimidazole were dissolved in 100 ml of methylene chloride and manganese dioxide (2 x 6.0 g, together 0.14 mol) was added at two-hour intervals. . After 4 hours, the inorganic components were filtered off, the solvent was removed and the crude product obtained was used in the next reaction step without further purification.

Výťažok produktu bol 3,0 g (89 % teoretického výťažku); Rf hodnota: 0,44 (gél kyseliny kremičitej; metylénchlorid/etanol = 50 : 1).Yield: 3.0 g (89% of theory); Rf value: 0.44 (silica gel; methylene chloride / ethanol = 50: 1).

f) Etylester kyseliny l-metyl-2-metoxymetyl-tieno[2.3-r/Jimidazol-5-yl-karboxylovejf) 1-Methyl-2-methoxymethyl-thieno [2,3-d] imidazol-5-yl-carboxylic acid ethyl ester

Do čerstvo pripraveného roztoku (391 mg, 17 mmolov sodíka) v 15 ml etanolu sa po kvapkách pridávalo 1,9 ml (2,1 g, 17 mmolov) etylesteru kyseliny tio-glykolovej. Po jednohodinovom miešaní pri teplote miestnosti sa pridaloTo a freshly prepared solution (391 mg, 17 mmol of sodium) in 15 mL of ethanol was added dropwise 1.9 mL (2.1 g, 17 mmol) of thioglycolic acid ethyl ester. After stirring at room temperature for 1 hour, it was added

1,6 g (8,5 mmolu) 5-chlór-4-formyl-2-metoxymetyl-l-metyl-imidazolu v 20 ml absolútneho etanolu a zmes sa zahriala na 80 °C (obdobne ako uvádza B. Iddon et al., J. Chem. Soc. Perkin Trans., I, 1457 (1987)). Po 5 hodinách sa oddestilovalo rozpúšťadlo, zvyšok sa rozmiešal v 50 ml metylénchloridu a premyl 20 ml vody. Vodná fáza sa ešte raz premyla 20 ml metylénchloridu a spojené organické fázy sa sušili síranom sodným. Po odstránení rozpúšťadla vo vákuu sa získaný surový produkt čistil stĺpcovou chromatografiou (oxid hlinitý; metylénchlorid).1.6 g (8.5 mmol) of 5-chloro-4-formyl-2-methoxymethyl-1-methyl-imidazole in 20 ml of absolute ethanol and heated to 80 ° C (analogous to B. Iddon et al. (J. Chem. Soc. Perkin Trans., I, 1457 (1987)). 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. The aqueous phase was washed once more with 20 ml of methylene chloride and the combined organic phases were dried over sodium sulfate. After removal of the solvent in vacuo, the crude product obtained was purified by column chromatography (alumina; methylene chloride).

Výťažok produktu bol 1,0 g (46 % teoretického výťažku); ChHmNjOjS (254,31);Yield of product was 1.0 g (46% of theory); ChHmN3O3S (254.31);

Rf hodnota: 0,48 (gél kyseliny kremičitej; metylénchlorid/etanol = 50 : 1); Rf value: 0.48 (silica gel; methylene chloride / ethanol = 50: 1);

EKA hmotnostné spektrum: (M+H)+ = 255, (M+Na)+ = = 277.EKA mass spectrum: (M + H) + = 255, (M + Na) + = 277.

g) Kyselina l-metyl-2-metoxymetyl-tieno[2.3-rf]imidazol-5-yl-karboxylová(g) 1-Methyl-2-methoxymethyl-thieno [2,3-rf] imidazol-5-yl-carboxylic acid

Do roztoku 0,90 g (3,54 mmolu) etylesteru kyseliny 1-metyl-2-metoxymetyl-tieno[2.3-í/]imidazol-5-yl-karboxylovej v 30 ml etanolu sa prikvapkávalo 5 ml roztoku hyd roxidu sodného (cNíjoh = 2 mol.dm’3) a zmes sa 2 hodiny miešala pri teplote miestnosti. Potom sa vo vákuu oddestilovalo rozpúšťadlo, zvyšok sa rozmiešal v 5 ml vody a premyl 10 ml dietyléteru. Vodná fáza sa okyslila 6 ml kyseliny chlorovodíkovej (cHci = 2 mol.dm3), ochladila na 0 °C a vylúčené kryštály sa odfiltrovali.To a solution of 0.90 g (3.54 mmol) of 1-methyl-2-methoxymethyl-thieno [2,3-d] imidazol-5-yl-carboxylic acid ethyl ester in 30 ml of ethanol was added dropwise 5 ml of sodium hydroxide solution (c). NIJ OH = 2 mol.dm '3), and the mixture was stirred for 2 hours at room temperature. The solvent was then distilled off in vacuo, the residue was stirred in 5 ml of water and washed with 10 ml of diethyl ether. The aqueous phase was acidified with 6 ml of hydrochloric acid (c = ci H 2 mol.dm 3), cooled to 0 DEG C., and the crystals were filtered off.

Výťažok produktu bol 0,50 g (63 % teoretického výťažku); C9H10N2O3S (226,26);Yield: 0.50 g (63% of theory); C 9 H 10 N 2 O 3 S (226.26);

Rf hodnota: 0,21 (gél kyseliny kremičitej; metylénchlorid/etanol = 9:1+ niekoľko kvapiek kyseliny octovej); EKA hmotnostné spektrum: (M+H)+ = 226.Rf value: 0.21 (silica gel; methylene chloride / ethanol = 9: 1+ a few drops of acetic acid); EKA mass spectrum: (M + H) + = 226.

h) N-Fenyl-N-(2-metoxykarbonyletyl)-amid kyseliny 1-metyl-2-metoxymetyltieno-[2.3-d]imidazol-5-yl-karboxylovejh) 1-Methyl-2-methoxymethyl-thieno [2,3-d] imidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

Suspenzia 0,50 g (2,2 mmolu) kyseliny l-metyl-2-metoxymetyl-tieno[2.3-<Z]-imidazol-5-yl-karboxylovej v 20 ml metylénchloridu sa zmiešala s 2,0 ml (3,2 g, 27 mmolov) tionylchloridu a zmes sa 60 minút varila pod spätným chladičom, pričom sa tuhá látka takmer rozpustila. Po oddestilovani prchavých zložiek sa získaný surový produkt ešte 2 x rozmiešal v metylénchloride. Po opätovnom odstránení rozpúšťadla sa surový chlorid kyseliny zmiešal s 20 ml tetrahydrofuránu a zmes sa po kvapkách pridala do zmesi 0,42 g (2,3 mmolu) N-(2-metoxykarbonyletal)anilínu a 0,92 g (6,6 mmolu) trietylaminu v 30 ml tetrahydrofuránu. Po 16 hodinovom miešaní pri 50 °C sa odstránilo rozpúšťadlo a získaný surový produkt sa chromatograficky čistil (gél kyseliny kremičitej; metylénchlorid/etanol = = 100: 1);A suspension of 0.50 g (2.2 mmol) of 1-methyl-2-methoxymethyl-thieno [2,3- (Z) -imidazol-5-yl-carboxylic acid in 20 mL of methylene chloride was mixed with 2.0 mL (3.2 g (27 mmol) of thionyl chloride and the mixture was refluxed for 60 minutes, whereby the solid almost dissolved. After the volatiles were distilled off, the crude product obtained was stirred twice more in methylene chloride. After the solvent was removed again, the crude acid chloride was mixed with 20 ml tetrahydrofuran and the mixture was added dropwise to a mixture of 0.42 g (2.3 mmol) of N- (2-methoxycarbonyletal) aniline and 0.92 g (6.6 mmol). triethylamine in 30 ml of tetrahydrofuran. After stirring at 50 ° C for 16 hours, the solvent was removed and the crude product obtained was purified by chromatography (silica gel; methylene chloride / ethanol = 100: 1);

Výťažok produktu bol 0,66 g (77 % teoretického výťažku); Rf hodnota: 0,47 (gél kyseliny kremičitej; metylénchlorid/etanol = 19:1).Yield: 0.66 g (77% of theory); Rf value: 0.47 (silica gel; methylene chloride / ethanol = 19: 1).

i) N-Fenyl-N-(2-metoxykarbonyletyl)-amid kyseliny 1-metyl-2-(N-4-kyanofenyl-aminometyl)-tieno[2.3-</]imidazol-5-yl-karboxyloveji) 1-Methyl-2- (N-4-cyanophenyl-aminomethyl) -thieno [2,3- d] imidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

Do roztoku 0,73 g (1,88 mmolu) N-fenyl-N-(2-metoxykarbonyletyl)-amidu kyseliny l-metyl-2-metoxymetyltieno[2.3-í(|imidazol-5-yl-karboxylovej v 30 ml metylénchloridu sa po kvapkách pri 5 °C pridávalo 2,9 ml (2,9 mmolu) roztoku bromidu boritého (cBBr3 = 1 mol.dm'3) v metylénchloride. Po 16 hodinovom miešaní pri teplote miestnosti sa zmes premyla 20 ml nasýteného roztoku hydrogenuhličitanu sodného, organická fáza sa oddelila, sušila síranom sodným a filtrovala. K filtrátu sa pridalo 14 ml N-etyldiizopropylamínu a 0,43 g (3,64 mmolu) 4-aminobenzonitrilu. Metylénchlorid sa potom oddestiloval vo vákuu, získaný zvyšok sa zahrieval hodinu na 50 °C a zvyšky rozpúšťadla sa oddestilovali vo vákuu. Po chromatografickom spracovaní (gél kyseliny kremičitej; metylénchlorid/etanol = 99 : 1 až 97 : 3) sa získal žltý, pomaly tuhnúci olej.To a solution of 0.73 g (1.88 mmol) of 1-methyl-2-methoxymethyl-thieno [2,3- f] imidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide in 30 ml of methylene chloride 2.9 ml (2.9 mmol) of a solution of boron tribromide (c BBr 3 = 1 mol.dm 3 ) in methylene chloride was added dropwise at 5 ° C. After stirring at room temperature for 16 hours, the mixture was washed with 20 ml of saturated bicarbonate solution. The organic phase was separated, dried over sodium sulfate and filtered, and 14 ml of N-ethyldiisopropylamine and 0.43 g (3.64 mmol) of 4-aminobenzonitrile were added to the filtrate, and the methylene chloride was then distilled off under vacuum, and the residue was heated to 50 ° C and the solvent residues were distilled off in vacuo to give a yellow, slowly solidifying oil after chromatographic work-up (silica gel; methylene chloride / ethanol = 99: 1 to 97: 3).

Výťažok produktu bol 0,37 g (42 % teoretického výťažku); Rf hodnota: 0,29 (gél kyseliny kremičitej; metylénchlorid/etanol = 50 : 1 + niekoľko kvapiek amoniaku).Yield: 0.37 g (42% of theory); Rf value: 0.29 (silica gel; methylene chloride / ethanol = 50: 1 + a few drops of ammonia).

j) Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-tieno[2,3-í/]imidazol-5-yl-karboxylovejj) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -thieno [2,3-d] imidazol-5-yl- N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride carboxylic acid

0,38 g (0,80 mmolu) N-fenyl-N-(2-metoxykarbonylctyl)-amidu kyseliny l-metyl-2-(N-4-kyanofenylaminometyl)-tieno[2.3-d]imidazol-5-yl-karboxylovej v 40 ml chlorovodíkom nasýteného etanolu sa 5 hodín miešalo najprv pri 0 °C, potom pri teplote miestnosti, kým sa chromatografiou v tenkej vrstve nepreukázala v reakčnej zmesi neprítomnosť východiskového materiálu. Potom sa rozpúšťadlo oddestilovalo pri teplote kúpeľa najviac 28 °C, olejovitý zvyšok sa rozmiešal v 40 ml absolútneho etanolu a pridalo sa 1,1 g uhličitanu amónneho. Po 18 hodinách sa rozpúšťadlo oddestilovalo vo vákuu a surový produkt sa chromatograficky čistil (gél kyseliny kremičitej; metylénchlorid/etanol = 9: 1 až 4:1).0.38 g (0.80 mmol) of 1-methyl-2- (N-4-cyanophenylaminomethyl) thieno [2,3-d] imidazol-5-yl- N-phenyl-N- (2-methoxycarbonyl-ethyl) -amide; of carboxylic acid in 40 ml of hydrogen chloride-saturated ethanol was stirred at 0 ° C for 5 hours, then at room temperature until thin layer chromatography showed the absence of starting material in the reaction mixture. Then the solvent was distilled off at a bath temperature of not more than 28 ° C, the oily residue was stirred in 40 ml of absolute ethanol and 1.1 g of ammonium carbonate was added. After 18 hours, the solvent was distilled off in vacuo and the crude product was purified by chromatography (silica gel; methylene chloride / ethanol = 9: 1 to 4: 1).

Výťažok produktu bol 57 % teoretického výťažku; C26H28N6O3S (504,62);The yield of the product was 57% of the theoretical yield; C 26 H 28 N 6 O 3 S (504.62);

Rf hodnota: 0,21 (gél kyseliny kremičitej; metylénchlorid/etanol = 4:1+ niekoľko kvapiek kyseliny octovej); EKA hmotnostné spektrum: (M+H)+ = 505, ((M+H+Na)++ = 264. Rf value: 0.21 (silica gel; methylene chloride / ethanol 4: 1 + a few drops of acetic acid); EKA mass spectrum: (M + H) + = 505, ((M + H + Na) + = 264.

Príklad 159Example 159

Hydrochlorid N-fenyl-N-(2-hydroxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyljtieno[2,3-rf]imidazol-5-yl-karboxylovcj1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -thieno [2,3-rf] imidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 2 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl) aminometyl]-tieno[2,3-d]imidazol-5-yl-karboxylovej a hydroxidu sodného. Výťažok bol 85 % teoretického výťažku, C24H24N6O3 (476,56)The compound was prepared analogously to Example 2 from N-phenyl-N- (2-ethoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] thieno [2,3-d] imidazole hydrochloride -5-yl-carboxylic acid and sodium hydroxide. The yield was 85% of the theoretical yield, C 24 H 24 N 6 O 3 (476.56)

Rf hodnota: 0,36 (gél kyseliny kremičitej RP-8 s reverznou fázou; metanol + 5%-ný roztok kuchynskej soli);Rf value: 0.36 (reversed phase RP-8 silica gel; methanol + 5% sodium chloride solution);

EKA-hmotnostné spektrum: (M+H)+ = 477, (M+Na)+ = = 499, (M+2Na)++ = 250.EKA-MS: (M + H) &lt; + &gt; = 477, (M + Na) &lt; + &gt; = 499, (M + 2Na) ++ = 250.

Príklad 160Example 160

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-3-[N-(4-amidinofenyl)-tiometyl]-chinoxalin-2-ón-6-yl-karboxylovej1-Methyl-3- [N- (4-amidinophenyl) -thiomethyl] -quinoxalin-2-one-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) N-Fenyl-N-(2-metoxykarbonyletyl)-amid kyseliny 1-metyl-3-[N-(4-kyanofenyl)-tiometyl]-chinoxalin-2-ón-6-yl-karboxyloveja) 1-Methyl-3- [N- (4-cyanophenyl) -thiomethyl] quinoxalin-2-one-6-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

Roztok 2,5 g (7,6 mmolu) N-fenyl-N-(2-metoxykarbonyletylj-amidu kyseliny 3-amino-4-metylaminobenzoovej a 2,4 g (9,6 mmolu) etylesteru kyseliny 3-(4-kyanofenyl)tio-2-oxo-propiónovej v 50 ml etanolu sa 30 minút zahrieval pri teplote varu. Po odstránení rozpúšťadla sa získaný surový produkt čistil chromatografícky (gél kyseliny kremičitej; metylénchlorid). Výťažok produktu bol 1,6 g (40 % teoretického výťažku), Rf hodnota: 0,63 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 90:10: 1).A solution of 2.5 g (7.6 mmol) of 3-amino-4-methylaminobenzoic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide and 2.4 g (9.6 mmol) of 3- (4-cyanophenyl) ethyl ester of thio-2-oxo-propionic acid in 50 ml of ethanol was heated at boiling point for 30 minutes, after removal of the solvent, the crude product obtained was purified by chromatography (silica gel; methylene chloride) to yield 1.6 g (40% of theory). R f value: 0.63 (silica gel; acetic acid / ethanol / ammonia ester = 90:10: 1).

b) Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-3-[N-(4-amidinofenyl)-tiometyl]-chinoxalin-2-ón-6-yl-karboxylovejb) 1-Methyl-3- [N- (4-amidinophenyl) -thiomethyl] -quinoxalin-2-one-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako sa uvádza v príklade 1 z N-fenyl-N-(2-metoxykarbonyletyl)-amidu kyseliny 1 -metyl-3-[N-(4-kyanofenyl)-tiometyl]-chinoxalín-2-ón-6-yl-karboxylovcj a etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared analogously to Example 1 from 1-methyl-3- [N- (4-cyanophenyl) thiomethyl] quinoxaline-2-one-6-N-phenyl-N- (2-methoxycarbonylethyl) -amide. -yl-carboxylic acid and ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok bol 23 % teoretického výťažku, C28H27N5O4S (543,64)The yield was 23% of the theoretical yield, C 28 H 27 N 5 O 4 S (543.64)

Rf hodnota: 0,25 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50 : 45 : 5); Rf value: 0.25 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5);

EKA-hmotnostné spektrum: (M+H)+ = 544, (M+Na)+ = = 566.EKA-MS: (M + H) + = 544, (M + Na) + = 566.

Príklad 161Example 161

Hydrochlorid N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 3-metyl-2-[2-(4-amidinofenyl)-etyl]-imidazo[l,2-ajpyridín-7-yl-karboxylovej3-Methyl-2- [2- (4-amidinophenyl) -ethyl] -imidazo [1,2-a] pyridin-7-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) N-Fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny 3-metyl-2-[2-(4-kyanofenyl)-etyl]-imidazo[l,2-a]pyridín-7-yl-karboxyloveja) 3-Methyl-2- [2- (4-cyanophenyl) -ethyl] -imidazo [1,2-a] pyridin-7-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

1,4 g (4,6 mmolu) kyseliny 3-metyl-2-[2-(4-kyanofenyl)-etyl]-imidazo[ 1,2-íz]pyridín-7-yl-karboxylovej (pripravenej z 4-bróm-l-(4-kyanofenyl)-l-penten-3-ónu a metylesteru kyseliny 2-aminopyridín-4-karboxylovej obdobne ako uvádza Y. Katsura et al., Chem. Pharm. Bull. 40, 1424 až 1438 (1992)) sa suspendovalo v 15 ml tionylchloridu a zmes sa zahrievala k varu do úplného rozpustenia. Po oddestilovaní tionylchloridu sa chlorid kyseliny bez ďalšieho čistenia rozpustil v 15 ml pyridínu a pri 0 °C sa zmiešal s 1,0 g (5,2 mmolu) N-(2-etoxy-karbonyletyl)anilínom. Po hodine sa rozpúšťadlo oddestilovalo, zvyšok sa rozmiešal v 30 ml metylénchloridu, roztok sa premyl kyselinou chlorovodíkovou (cHci = 1 mol.dm'3) a sušil síranom sodným. Po oddestilovaní rozpúšťadla sa po chromatografovaní (gél kyseliny kremičitej; mctylcnchlorid/etanol = 0 až 2 %) získala hnedá olejovitá látka.1.4 g (4.6 mmol) of 3-methyl-2- [2- (4-cyanophenyl) -ethyl] -imidazo [1,2-a] pyridin-7-yl-carboxylic acid (prepared from 4-bromo) 1- (4-cyanophenyl) -1-penten-3-one and 2-aminopyridine-4-carboxylic acid methyl ester analogously to Y. Katsura et al., Chem. Pharm. Bull., 40, 1424-1438 (1992) ) was suspended in 15 ml of thionyl chloride and the mixture was heated to boiling until complete dissolution. After thionyl chloride was distilled off, the acid chloride was dissolved in 15 ml of pyridine without further purification and treated at 0 ° C with 1.0 g (5.2 mmol) of N- (2-ethoxycarbonylethyl) aniline. After one hour, the solvent was distilled off, the residue was taken up in 30 mL of methylene chloride, the solution was washed with hydrochloric acid (c = 1 ci H mol.dm '3) and dried over sodium sulfate. After distilling off the solvent, a brown oil was obtained after chromatography (silica gel; methyl chloride / ethanol = 0-2%).

Výťažok produktu bol 1,48 g (64 % teoretického výťažku), Rf hodnota: 0,73 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 90 : 10 : 1).Yield: 1.48 g (64%), Rf value: 0.73 (silica gel; ethyl acetate / ethanol / ammonia 90: 10: 1).

b) Hydrochlorid N-fenyI-N-(2-etoxykarbonyletyl)-amidu kyseliny 3-metyl-2-[2-(4-amidinofenyl)-etyl]-imidazo[l ,2-u]pyridín-7-yl-karboxylovejb) 3-Methyl-2- [2- (4-amidinophenyl) -ethyl] -imidazo [1,2-a] pyridin-7-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako sa uvádza v príklade 1 z N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 3-metyl-2-[2-(4-kyanofenyl)- etyl]-imidazo[l,2-a]pyridín-7-yl-karboxylovej a etanolového roztoku kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared analogously to Example 1 from 3-methyl-2- [2- (4-cyanophenyl) ethyl] imidazo [1,2-a] N-phenyl-N- (2-ethoxycarbonylethyl) -amide. pyridin-7-yl-carboxylic acid and ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Výťažok bol 62 % teoretického výťažku, C29H31N5O3 (497,6)The yield was 62% of theory. C 29 H 31 N 5 O 3 (497.6)

Rf hodnota: 0,23 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50 : 45 : 5);Rf value: 0.23 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5);

EKA-hmotnostné spektrum: (M+H)+ = 498.EKA-MS: (M + H) &lt; + &gt; = 498.

Príklad 162Example 162

Hydrochlorid N-fenyl-N-(2-hydroxykarbonyletyl)-amidu kyseliny 3-metyl-2-[2-(4-amidinofenyl)-etyl]-imidazo[l,2-a]pyridín-7-yl-karboxylovej3-Methyl-2- [2- (4-amidinophenyl) -ethyl] -imidazo [1,2-a] pyridin-7-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 2 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl) aminometyl]-tieno[2,3-r/]imidazol-5-yl-karboxylovej a hydroxidu sodného. Výťažok bol 92 % teoretického výťažku,The compound was prepared analogously to Example 2 from 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] thieno [2,3-b] N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride. imidazol-5-yl-carboxylic acid and sodium hydroxide. The yield was 92% of the theoretical yield,

C27H27N50j (469,55)C 27 H 27 N 5 0j (469.55)

Rf hodnota: 0,19 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50 : 45 : 5);Rf value: 0.19 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5);

EKA-hmotnostné spektrum: (M+H)+ = 470, (M+Na)+ = = 492, (M+ŽNa)^ = 257,7, (M+2H)++ = 235,7, (M+H+Na)^ = 246,7.EKA-MS: (M + H) &lt; + &gt; = 470, (M + Na) &lt; + &gt; = = 492, (M + 2H) + = 257.7, (M + 2H) ++ = 235.7, (M +) H + Na + = 246.7.

Príklad 163 DihydrochloridN-fenyl-N-[(N-etoxykarbonyletyl-N-metyl)-2-aminoetyl]-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovejExample 163 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl- N-phenyl-N - [(N-ethoxycarbonylethyl-N-methyl) -2-aminoethyl] -amide; carboxylic acid

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-fenyl-N-[(N-etoxykarbonyletyl-N-metyl)-238The compound was prepared in a manner analogous to Example 25d from N-phenyl-N - [(N-ethoxycarbonylethyl-N-methyl) -238

-aminoetylj-amidu kyseliny l-metyl-2-[N-(4-kyano-fenyl)aminometyl]-benzimidazol-5-yl-karboxylovej, etanolovej kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 80 % teoretického výťažku, C31H37N7O3 (555,7)1-methyl-2- [N- (4-cyano-phenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid-amino-ethyl] -amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. The yield of the product was 80% of the theoretical yield, C 31 H 37 N 7 O 3 (555.7)

Rf hodnota: 0,24 (gél kyseliny kremičitej; dichlórmetán/metanol = 4 : 1); Rf value: 0.24 (silica gel; dichloromethane / methanol = 4: 1);

EKA-hmotnostné spektrum: (M+H)+ = 556, (M+2H)++ = = 278,8, (M+H+Na) = 289,8.EKA-MS: (M + H) + = 556, (M + 2H) ++ = = 278.8, (M + H + Na) = 289.8.

Príklad 164Example 164

Hydrochlorid N-fenyl-N-[(N-hydroxykarbonyletyl-N-metyl)-2-aminoetyl]-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N - [(N-hydroxycarbonylethyl-N-methyl) -2-aminoethyl] -amide

Zlúčenina sa pripravila obdobne ako v príklade 26 z hydrochloridu N-fenyl-N-[(N-etoxykarbonyletyl)-N-metyl)-2-aminoetyl]-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl) aminometyl]-benzimiazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared analogously to Example 26 from N-phenyl-N - [(N-ethoxycarbonylethyl) -N-methyl) -2-aminoethyl] -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] hydrochloride 1-benzimiazol-5-yl-carboxylic acid and sodium hydroxide.

Výťažok bol 79 % teoretického výťažku, £-29Η33Ν7Ο3 (527,6)The yield was 79% of the theoretical yield, £ -29Η 33 Ν 7 Ο 3 (527.6)

Rf hodnota: 0,43 (gél kyseliny kremičitej RP-8 s reverznou fázou; metanol + 5%-ný roztok kuchynskej soli = 6:4); EKA-hmotnostné spektrum: (M+H)3 = 528, , (M+2H)33 = = 264,6, (M+H+Na)33 = 275,6. Rf value: 0.43 (silica gel RP-8 reverse phase column; methanol + 5% saline solution = 6: 4); EKA-MS: (M + H) 3 = 528, (M + 2H) 33 = 264.6, (M + H + Na) 33 = 275.6.

Príklad 165Example 165

Hydrochlorid N-fenyl-N-(3-hydroxy-n-propyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxy-n-propyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 26 z hydrochloridu N-fenyl-N-(3-benzyloxy-n-propyl)amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej hydrogenáciou s použitím katalyzátora paládia na uhlí (10%-né paládium) pod tlakom 0,5 MPa vodíka pri teplote miestnosti.The compound was prepared analogously to Example 26 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-hydrochloride N-phenyl-N- (3-benzyloxy-n-propyl) -amide. -carboxylic hydrogenation using a palladium on carbon catalyst (10% palladium) under 0.5 MPa hydrogen at room temperature.

Výťažok bol 61 % teoretického výťažku, C26H2gN6O2 (456,6)The yield was 61% of the theoretical yield, C 6 H 2 gN 6 O 2 (456.6)

Rf hodnota: 0,70 (gél kyseliny kremičitej RP-18 s reverznou fázou; metanol + 5%-ný roztok kuchynskej soli = = 9:1); Rf value: 0.70 (silica gel RP-18 reverse phase column; methanol + 5% saline solution = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 457, (M+H+Na)3+ = = 240.EKA-MS: (M + H) + = 457, (M + H + Na) 3+ = 240.

Príklad 166 N-(2-Pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-n-hexyl-oxykarbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovejExample 166 1-Methyl-2- [N- [4- (N-hexyl-oxycarbonylamidino) -phenyl] -aminomethyl] -benzimidazol-5-yl N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide carboxylate

Zlúčenina sa pripravila obdobne ako v príklade 26 z N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1-metyl-2-[N-[4-(N-n-hexyloxykarbonylamidino)fcnyl]-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared analogously to Example 26 from N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide 1-methyl-2- [N- [4- (N-hexyloxycarbonylamidino) phenyl] aminomethyl] - benzimidazol-5-yl-carboxylic acid and sodium hydroxide.

Výťažok bol 97 % teoretického výťažku,The yield was 97% of the theoretical yield,

C32H37N7O5 (599,7)C 32 H 37 N 7 O 5 (599.7)

Rf hodnota: 0,22 (gél kyseliny kremičitej; dichlórmetán/metanol = 9 : 1); Rf value: 0.22 (silica gel; dichloromethane / methanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)3 = 600, (M+2H)++ = = 300,8, (M+H+Na)33 = 311,7, (M+2Na)‘' = 322,8.EKA-MS: (M + H) 3 = 600, (M + 2H) ++ = = 300.8, (M + H + Na) 33 = 311.7, (M + 2Na) + = 322, 8th

Príklad 167Example 167

N-Fenyl-N-(3-hydroxy-n-propyl)-amid kyseliny l-metyl-2-[N-[4-(N-n-hexyloxy-karbonylamidino) fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxy-n-propyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 165 z N-fenyl-N-(3-benzyloxy-n-propyl)amidu kyseliny 1-metylThe compound was prepared analogously to Example 165 from 1-methyl-N-phenyl-N- (3-benzyloxy-n-propyl) -amide.

-2-[N-[4-(N-n-hexyloxykarbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej katalytickou debenzyláciou.-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid by catalytic debenzylation.

Výťažok bol 26 % teoretického výťažku, C33H40N6O4 (584,7)The yield was 26% of the theoretical yield, C 33 H 40 N 6 O 4 (584.7)

Rf hodnota: 0,39 (gél kyseliny kremičitej; dichlórmetán/etanol = 9:1); Rf value: 0.39 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 585, (M+H+Na)33 = = 304, (M+Na)3 = 607.EKA-MS: (M + H) + = 585, (M + H + Na) 33 = 304, (M + Na) 3 = 607.

Príklad 168Example 168

Hydrochlorid N-(3-fluórfenyl)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (3-fluorophenyl) -N- (2-ethoxycarbonylethyl) amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(3-fluórfenyl)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-kyanofenyl)-aminometyl]benzimidazol-5-yl-karboxylovej, etanolovej kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 42 % teoretického výťažku, C28H29FN6O3 (516,6)The compound was prepared in a manner analogous to EXAMPLE 25d from 1-methyl-2- [N- (4-cyanophenyl) aminomethyl] benzimidazol-5-yl- N- (3-fluorophenyl) -N- (2-ethoxycarbonylethyl) amide. carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 42% of theory. C 28 H 29 FN 6 O 3 (516.6)

Rf hodnota: 0,31 (gél kyseliny kremičitej; dichlórmetán/metanol = 5 : 1);Rf value: 0.31 (silica gel; dichloromethane / methanol = 5: 1);

EKA-hmotnostné spektrum: (M+H)3 = 517, (M+H+Na)33 = = 270.EKA-MS: (M + H) 3 = 517, (M + H + Na) 33 = 270.

Príklad 169Example 169

Hydrochlorid N-(4-fluórfenyl)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (4-fluorophenyl) -N- (2-ethoxycarbonylethyl) amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(4-fluórfenyI)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-kyanofenyl)-aminometyl]benzimidazol-5-yl-karboxylovej, etanolovej kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 90 % teoretického výťažku, C28H29FN<A (516,6)The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) aminomethyl] benzimidazol-5-yl- (N- (4-fluorophenyl) -N- (2-ethoxycarbonylethyl) amide). carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate. The product yield was 90% of theory, C 28 H 29 FN < A (516.6)

Rf hodnota: 0,29 (gél kyseliny kremičitej; dichlórmetán/metanol = 5:1);Rf value: 0.29 (silica gel; dichloromethane / methanol = 5: 1);

EKA-hmotnostné spektrum: (M+H)’ = 517, (M+H+Na)33 = = 270.EKA-MS: (M + H) + = 517, (M + H + Na) 33 = 270.

Príklad 170Example 170

N-(3-Fluórfenyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny l-metyl-2-[N-(4-amidino-fenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (3-fluorophenyl) -N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 26 z hydrochloridu N-(3-fluórfenyl)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného. Výťažok bol 97 % teoretického výťažku, C26H25FN6O3 (488,5)The compound was prepared analogously to Example 26 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl acid N- (3-fluorophenyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride carboxylic acid and sodium hydroxide. The yield was 97% of the theoretical yield, C 26 H 25 FN 6 O 3 (488.5)

Rf hodnota: 0,13 (gél kyseliny kremičitej; dichlórmetán/etanol = 4:1);Rf value: 0.13 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-hmotnostné spektrum: (M+H)3 = 489, (M+Na)3 = = 511, (M+2Na)33 = 267.EKA-MS: (M + H) 3 = 489, (M + Na) 3 = = 511, (M + 2Na) 33 = 267.

Príklad 171Example 171

N-(4-Fluórfenyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny l-metyl-2-[N-(4-amidino-fenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (4-fluorophenyl) -N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 26 z hydrochloridu N-(4-fluórfenyl)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared analogously to Example 26 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-N- (4-fluorophenyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride carboxylic acid and sodium hydroxide.

Výťažok bol 89 % teoretického výťažku,The yield was 89% of the theoretical yield,

C26H25FN6O3 (488,5)C 26 H 25 FN 6 O 3 (488.5)

Rf hodnota: 0,15 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1); Rf value: 0.15 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-hmotnostné spektrum: (M+H)+ = 489, (M+Na)+ = = 511, (M+2Na)++ = 267.EKA-MS: (M + H) + = 489, (M + Na) + = 511, (M + 2Na) ++ = 267.

Príklad 172Example 172

Hydrochlorid N-fcnyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidino-2-metoxy-fenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidino-2-methoxy-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-kyano-2-metoxy-fenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolovej kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 89 % teoretického výťažku, C29H32N6O4 (528,6)The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyano-2-methoxy-phenyl) -aminomethyl] -benzimidazole-N-phenyl-N- (2-ethoxycarbonylethyl) -amide. 5-yl-carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 89% of theory, C 29 H 32 N 6 O 4 (528.6)

Rf hodnota: 0,13 (gél kyseliny kremičitej; dichlórmetán/metanol = 4 : 1); Rf value: 0.13 (silica gel; dichloromethane / methanol = 4: 1);

EKA-hmotnostné spektrum: (M+H)+ = 529, (M+H+Na)++ = = 276, (M+2H)4 ' = 265.EKA-MS: (M + H) &lt; + &gt; = 529, (M + H + Na) &lt; + &gt; = 276, (M + 2H) &lt; 4 &gt; = 265.

Príklad 173Example 173

N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)amid kyseliny 1-metyl-2-[N-[4-(N-4-etylbenzoyl-amidino)-fenyl]-aminometylJ-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-4-ethylbenzoyl-amidino) -phenyl] -aminomethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide carboxylic acid

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 90 z N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-[4-(N-4-etylbenzoylamidino)-fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej a 4-etylbenzoylchloridu.The compound was prepared in a manner analogous to EXAMPLE 90 from 1-methyl-2- [N- [4- (N-4-ethylbenzoylamidino) -phenyl] N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide. aminomethyl] -benzimidazol-5-yl-carboxylic acid and 4-ethylbenzoyl chloride.

Výťažok produktu bol 64 % teoretického výťažku, C36H37N7O4 (631,7)The yield of the product was 64% of the theoretical yield, C 36 H 37 N 7 O 4 (631.7)

Rf hodnota: 0,78 (gél kyseliny kremičitej; dichlórmetán/metanol = 9 : 1);Rf value: 0.78 (silica gel; dichloromethane / methanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 632, (M+H+Na)++ = = 327,8, (M+Na)+ = 654.EKA-MS: (M + H) &lt; + &gt; = 632, (M + H + Na) &lt; + &gt; = = 327.8, (M + Na) + = 654.

Príklad 174 N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-benzyloxy-karbonylamidino)-fenyl]aminomctyl]-benzimidazol-5-yl-karboxylovejExample 174 1-Methyl-2- [N- [4- (N-benzyloxycarbonylamidino) -phenyl] aminomethyl] -benzimidazol-5-yl N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide carboxylate

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)aminometyl]-benzimidazol-5-yl-karboxylovej a benzylesteru kyseliny chlórmravčej.The compound was prepared in a manner analogous to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5-, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride. yl carboxylic acid and benzyl chloroformate.

Výťažok produktu bol 64 % teoretického výťažku, C35H35N7O5 (633,6)The yield of the product was 64% of the theoretical yield, C 35 H 35 N 7 O 5 (633.6)

Rf hodnota: 0,60 (gél kyseliny kremičitej; dichlórmetán/metanol = 9 : 1); Rf value: 0.60 (silica gel; dichloromethane / methanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 634, (M+H+Na)++ = = 328,8, (M+Na)+ = 656.EKA-MS: (M + H) + = 634; (M + H + Na) ++ = = 328.8; (M + Na) + = 656.

Príklad 175Example 175

N-Fenyl-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidino-2-metoxy-fenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidino-2-methoxy-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 26 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidino-2-metoxyfenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared analogously to Example 26 from 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazole-5-, N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride. ylcarboxylic acid and sodium hydroxide.

Výťažok bol 71 % teoretického výťažku,The yield was 71% of the theoretical yield,

C27H28N6O4 (500,6)C 2 7H 28 N 6 O 4 (500.6)

Rf hodnota: 0,15 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1);Rf value: 0.15 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-hmotnostné spektrum: (M+H)+ = 501, (M+Na)+ = = 523, (M+2Na)^ = 273.EKA-MS: (M + H) @ + = 501, (M + Na) @ + = 523, (M + 2Na) @ + = 273.

Príklad 176Example 176

Hydrochlorid N-(2-pyridyl)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidino-2-metoxyfenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-kyano-2-metoxyfenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolovej kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho. Výťažok produktu bol 67 % teoretického výťažku, C28H31N7O4 (529,6)The compound was prepared in a manner analogous to EXAMPLE 25d from 1-methyl-2- [N- (4-cyano-2-methoxyphenyl) aminomethyl] - (2-ethoxycarbonylethyl) -N- (2-ethoxycarbonylethyl) amide - benzimidazol-5-yl-carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 67%. C 28 H 31 N 7 O 4 (529.6)

Rf hodnota: 0,16 (gél kyseliny kremičitej; dichlórmetán/metanol = 4 : 1);Rf value: 0.16 (silica gel; dichloromethane / methanol = 4: 1);

EKA-hmotnostné spektrum: (M+H)+ = 530.EKA-MS: (M + H) &lt; + &gt; = 530.

Príklad 177Example 177

N-(2-Pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidino-2-metoxy-fenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-amidino-2-methoxy-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 26 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidino-2-metoxyfenyl)aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared analogously to Example 26 from 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) aminomethyl] -benzimidazole N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride -5-yl-carboxylic acid and sodium hydroxide.

Výťažok bol 78 % teoretického výťažku, C26H27N7O4 (501,6)The yield was 78% of the theoretical yield, C 26 H 27 N 7 O 4 (501.6)

Rr hodnota: 0,12 (gél kyseliny kremičitej; dichlórmetán/etanol = 4 : 1); R f value: 0.12 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-hmotnostné spektrum: (M+H)+ = 502.EKA-MS: (M + H) &lt; + &gt; = 502.

Príklad 178Example 178

N-(2-Pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-[4-(N-benzyloxy-karbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- [4- (N-benzyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 104 z N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 1-metyl-2-[N-[4-(N-benzyloxykarbonylamidino)-fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared analogously to Example 104 from N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide 1-methyl-2- [N- [4- (N-benzyloxycarbonylamidino) -phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid and sodium hydroxide.

Výťažok bol 62 % teoretického výťažku,The yield was 62% of the theoretical yield,

C33H31N7O5 (605,7)C 33 H 31 N 7 O 5 (605.7)

Rf hodnota: 0,26 (gél kyseliny kremičitej; dichlórmetán/metanol = 9:1); Rf value: 0.26 (silica gel; dichloromethane / methanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 606, (M+Ns)+ = = 628, (M-H+Na)4 1’ = 650, (M+2H)++ = 303,8, (M+H+Na)++ = 314,8, (M+ŽNa)^ =325,7.EKA-MS: (M + H) &lt; + &gt; = 606, (M + N5) &lt; + &gt; = 628, (M-H + Na) &lt; 4 &gt; = 650, (M + 2H) ++ = 303.8, ( M + H + Na + ++ = 314.8, (M + H +) + = 325.7.

Príklad 179Example 179

Hydrochlorid N-fenyl-N-(3-benzyloxy-n-propyl)-amidu kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl)-benzimidazol-5 -yl-karboxylovej1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl) -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-benzyloxy-n-propyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25 z N-fenyl-N-(3-benzyloxy-n-propyl)-amidu kyseliny 1 -metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolovej kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25 from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazole-5- N-phenyl-N- (3-benzyloxy-n-propyl) -amide. yl-carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 61 % teoretického výťažku, C33H34N6O2 (546,7)The yield of the product was 61% of the theoretical yield, C 33 H 34 N 6 O 2 (546.7)

Rf hodnota: 0,19 (gél kyseliny kremičitej; dichlórmctán/etanol = 4 : 1);Rf value: 0.19 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-hmotnostné spektrum: (M+H)+ = 547, (M+H+Na)++ = = 285.EKA mass spectrum: (M + H) + = 547, (M + H + Na) ++ = 285th

Príklad 180Example 180

N-Fenyl-N-(3-benzyloxy-n-propyl)-amid kyseliny 1-metyl2-[N-[4-(N-n-hexyloxy-karbonylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovej1-methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-benzyloxy-n-propyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 90 z hydrochloridu N-fenyl-N-(3-benzyloxy-n-propyl)-amidu kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a n-hexylesteru kyseliny chlórmravčej.The compound was prepared in a manner analogous to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5, N-phenyl-N- (3-benzyloxy-n-propyl) -amide hydrochloride. -yl-carboxylic acid and n-hexyl chloroformate.

Výťažok produktu bol 73 % teoretického výťažku, CÄNA (674,9);The product yield was 73% of theory, CÄNA (674.9);

Rf hodnota: 0,46 (gél kyseliny kremičitej; dichlórmetán/etanol = 9 : 1); Rf value: 0.46 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 675, (M+H+Na)++ = = 349, (M+Na)+ = 697, (M+Kf =713.EKA-MS: (M + H) &lt; + &gt; = 675, (M + H + Na) &lt; + &gt; = = 349, (M + Na) + = 697, (M + Kf = 713).

Príklad 181Example 181

Hydrochlorid N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 3-metyl-2-[2-(4-amidinofenyl)-etyl]-imidazo[ 1,2-a]pyridín-7-yl-karboxylovej3-Methyl-2- [2- (4-amidinophenyl) -ethyl] -imidazo [1,2-a] pyridin-7-yl acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide carboxylate

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 1 z N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny 3-metyl-2-[2-(4-kyanofenyl)etyl]-imidazo-[l ,2-aJpyridín-7-yl-karboxylovej, etanolovej kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 1 from N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide 3-methyl-2- [2- (4-cyanophenyl) ethyl] imidazo [1,1-a], m.p. 2-α-pyridin-7-yl-carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Výťažok produktu bol 53 % teoretického výťažku, C28H30N6O3 (498,59)Yield: 53%. C 28 H 30 N 6 O 3 (498.59)

Rf hodnota: 0,42 (gél kyseliny kremičitej; ester kyseliny octovej/etanol/amoniak = 50 : 45 : 5); Rf value: 0.42 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5);

EKA-hmotnostné spektrum: (M+H)+ = 499, (M+H+Na)4^ = = 261, (M-2Na) = 272, (M+2H)++ = 250.EKA-MS: (M + H) &lt; + &gt; = 499, (M + H + Na) &lt; 4 &gt; = 261, (M-2Na) = 272, (M + 2H) ++ = 250.

Príklad 182Example 182

N-(2-Pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(3-amidino-pyridín-6-yl)-aminometyljbenzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (3-amidino-pyridin-6-yl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako v príklade 26 z N-(2-pyridyl)-N-(2-hydroxykarbonyletyl)-amidu kyseliny 1-metyl-2-[N-(3-kyanopyridín-6-yl)-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared analogously to Example 26 from N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide 1-methyl-2- [N- (3-cyanopyridin-6-yl) aminomethyl] -benzimidazole -5-yl-carboxylic acid and sodium hydroxide.

Výťažok bol 40 % teoretického výťažku, C24H24N8O3 (472,9)The yield was 40% of the theoretical yield, C 24 H 24 N 8 O 3 (472.9)

Rf hodnota: 0,67 (gél kyseliny kremičitej RP-8 s reverznou fázou; metanol/5%-ný roztok kuchynskej soli =1:1); EKA-hmotnostné spektrum: (M+H)+ = 473. Rf value: 0.67 (silica gel RP-8 reverse phase; methanol / 5% saline solution = 1: 1); EKA-MS: (M + H) &lt; + &gt; = 473.

Príklad 183 N-(2-Pyridyl)-N-[2-(metánsulfonylaminokarbonyl)-etyl]-amid kyseliny l-metyl-2-[N-[4-(N-hydroxylamidino) fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovejExample 183 1-Methyl-2- [N- [4- (N-hydroxylamidino) phenyl] aminomethyl] -benzimidazole-5-N- (2-pyridyl) -N- [2- (methanesulfonylaminocarbonyl) -ethyl] -amide yl-carboxylic acid

a) N-(2-Pyridyl)-N-[2-(metánsulfonylaminokarbonyl)-etyl]amid kyseliny l-metyl-2-[N-[4-(kyanofenyl)-amino-metyl]benzimidazol-5-yl-karboxyloveja) 1-Methyl-2- [N- [4- (cyanophenyl) amino-methyl] benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- [2- (methanesulfonylaminocarbonyl) ethyl] amide

V 80 ml tetrahydrofuránu a 5 ml dimetylformamidu sa rozpustili 2,0 g (4,5 mmolu) N-(2-pyridyl)-N-(2-hydroxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-kyanofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a 0,73 g (4,7 mmolu) karbonyldiimidazolu. Roztok sa miešal 30 minút pri teplote miestnosti a potom 2 hodiny pri 90 °C. Súbežne sa suspendovalo 0,55 g (5,8 mmolu) amidu kyseliny metánsulfónovej a 0,28 g (5,8 mmolu) hydridu sodného v 15 ml dimetylformamidu a suspenzia sa 2 hodiny miešala pri teplote miestnosti. Potom sa táto suspenzia pri teplote miestnosti pridala do tetrahydrofuránového roztoku. Po 12 hodinách pri teplote miestnosti sa pridalo 50 ml vody a pH zmesi sa nastavilo na 6,8. Roztok sa 4 x extrahoval me tylénchloridom, spojené organické fázy sa sušili síranom sodným, sušili a skoncentrovali. Surový produkt sa chromatografoval na géli kyseliny kremičitej (s použitím metylénchloridu/etanolu = 40 : 1 ako elučným činidlom). Vhodné frakcie sa spojili a odparili.2.0 g (4.5 mmol) of N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide of 1-methyl-2- [N- (4- (4-methoxycarbonylethyl) -amide) were dissolved in 80 ml of tetrahydrofuran and 5 ml of dimethylformamide. cyanophenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid and 0.73 g (4.7 mmol) of carbonyldiimidazole. The solution was stirred at room temperature for 30 minutes and then at 90 ° C for 2 hours. At the same time, 0.55 g (5.8 mmol) of methanesulfonic acid amide and 0.28 g (5.8 mmol) of sodium hydride were suspended in 15 ml of dimethylformamide and stirred at room temperature for 2 hours. Then, the suspension was added to the tetrahydrofuran solution at room temperature. After 12 hours at room temperature, 50 mL of water was added and the pH of the mixture was adjusted to 6.8. The solution was extracted 4 times with methylene chloride, the combined organic phases were dried over sodium sulfate, dried and concentrated. The crude product was chromatographed on a silica gel (using methylene chloride / ethanol = 40: 1 as eluent). The appropriate fractions were combined and evaporated.

Výťažok bol 1,05 g (44 % teoretického výťažku), C26H25N7O4S (531,6)Yield: 1.05 g (44% of theory), C 26 H 25 N 7 O 4 S (531.6)

Rf hodnota: 0,72 (gél kyseliny kremičitej; dichlórmetán/metanol = 9:1). Rf value: 0.72 (silica gel; dichloromethane / methanol = 9: 1).

b) N-(2-Pyridyl)-N-[2-(metánsulfonylaminokarbonyl)etyl]-amid kyseliny l-metyl-2-[N-[4-(N-hydroxylamidino)fenyl]-aminometyl]-benzimidazol-5-yl-karboxylovejb) 1-Methyl-2- [N- [4- (N-hydroxylamidino) phenyl] aminomethyl] -benzimidazole-5- N- (2-pyridyl) -N- [2- (methanesulfonylaminocarbonyl) ethyl] -amide yl-carboxylic acid

Zlúčenina sa pripravila obdobne ako sa uvádza v príklade 96 z N-(2-pyridyl)-N-[2-(metánsulfonylaminokarbonyl)-etyl]-amidu a kyseliny l-metyl-2-[N-(4-kyano-fenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxylamínu.The compound was prepared analogously to Example 96 from N- (2-pyridyl) -N- [2- (methanesulfonylaminocarbonyl) ethyl] -amide and 1-methyl-2- [N- (4-cyano-phenyl) acid]. -aminomethyl] -benzimidazol-5-yl-carboxylic acid and hydroxylamine.

Výťažok bol 27 % teoretického výťažku,The yield was 27% of the theoretical yield,

C26H28NsO5S (564,6)C 26 H 28 N with O 5 S (564.6)

Rf hodnota: 0,75 (gél kyseliny kremičitej; dichlórmetán/etanol = 7:3 + 1% ľadovej kyseliny octovej);Rf value: 0.75 (silica gel; dichloromethane / ethanol = 7: 3 + 1% glacial acetic acid);

EKA-hmotnostné spektrum: (M+H)+ = 565, (M+Na)+ = = 587.EKA-MS: (M + H) + = 565, (M + Na) + = 587.

Príklad 184Example 184

Hydrochlorid N-(2-pyridyl)-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(5-amidino-tiazol-2-yl)-aminometyl] -benzimidazol-5 -yl-karboxylovej1-methyl-2- [N- (5-amidino-thiazol-2-yl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(5-kyanotiazol-2-yl)-aminometyl]-benzimidazol-5-yl-karboxylovej, etanolovej kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (5-cyanothiazol-2-yl) -aminomethyl] -N- (2-ethoxycarbonylethyl) -amide - benzimidazol-5-yl-carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Príklad 185Example 185

N-(2-Pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1 -metyl-2-[N-(5-amidino-tiazol-2-yl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (5-amidino-thiazol-2-yl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(5-amidinotiazol-2-yl)-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to Example 26 starting from 1-methyl-2- [N- (5-amidinothiazol-2-yl) -aminomethyl] N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride. -benzimidazol-5-yl-carboxylic acid and sodium hydroxide.

Príklad 186Example 186

Hydrochlorid N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(2-amidinopyrazin-5-yl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (2-amidinopyrazin-5-yl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 25d z N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(2-kyanopyrazin-5-yl)-aminometyl]benzimidazol-5-yl-karboxylovej, etanolovej kyseliny chlorovodíkovej, etanolu a uhličitanu amónneho.The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (2-cyanopyrazin-5-yl) aminomethyl] benzimidazole N- (2-ethoxycarbonylethyl) amide -5-yl-carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Výťažok bol 19 % teoretického výťažku,The yield was 19% of the theoretical yield,

C25H27N9O3 (501,6)C 25 H 27 N 9 O 3 (501.6)

Rf hodnota: 0,28 (gél kyseliny kremičitej; dichlórmetán/etanol = 4:1 + 1% ľadovej kyseliny octovej);Rf value: 0.28 (silica gel; dichloromethane / ethanol = 4: 1 + 1% glacial acetic acid);

EKA-hmotnostné spektrum: (M+H)+ = 502, (M+H+Na)r‘ = = 262,5.EKA-MS: (M + H) + = 502, (M + H + Na) r '= 262.5.

Príklad 187Example 187

N-(2-Pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(2-amidino-pyrazin-5-yl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (2-amidino-pyrazin-5-yl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobným spôsobom ako v príklade 26 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykar bonyletyi)-amidu kyseliny l-metyl-2-[N-(2-amidinopyrazin-5-yl)-aminometyl]-benzimidazol-5-yl-karboxylovej a hydroxidu sodného.The compound was prepared in a manner analogous to EXAMPLE 26 from 1-methyl-2- [N- (2-amidinopyrazin-5-yl) -aminomethyl] N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride. 1-benzimidazol-5-yl-carboxylic acid and sodium hydroxide.

Výťažok bol 11 % teoretického výťažku,The yield was 11% of the theoretical yield,

C23H23N9O3 (473,5)C 23 H 23 N 9 O 3 (473.5)

Rf hodnota: 0,55 (gél kyseliny kremičitej RP-8 s reverznou fázou; 5 %-ný roztok kuchynskej soli/metanol = 6:4); EKA-hmotnostné spektrum: (M+H)+ = 474, (M+Na)+ = = 496,6. Rf value: 0.55 (silica gel RP-8 reverse phase column, 5% saline solution / methanol = 6: 4); EKA-MS: (M + H) + = 474, (M + Na) + = 496.6.

Príklad 188 N-Fenyl-N-[2-(17/-tetrazol-5-yl)-etyl]-amid kyseliny 1-metyl-2-[2-[4-(N-n-hexyloxy-karbonylamidino)fenyl]etyl]-benzimidazol-5-yl-karboxylovejExample 188 1-Methyl-2- [2- [4- (N-hexyloxycarbonylamidino) phenyl] ethyl] N-phenyl-N- [2- (1H-tetrazol-5-yl) -ethyl] -amide benzimidazol-5-yl-carboxylic acid

Zlúčenina sa pripravila obdobne ako sa uvádza v príklade 90 z N-fenyl-N-[2-(l//-tetrazol-5-yl)-etyl]-amidu kyseliny 1 -metyl-2-[2-(4-amidinofenyl)-etyl]-benzimidazol-5-yl-karboxylovej a n-hexylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [2- (4-amidinophenyl) -N-phenyl-N- [2- (1H-tetrazol-5-yl) -ethyl] -amide. 1-Ethyl] -benzimidazol-5-yl-carboxylic acid and n-hexyl chloroformate.

Príklad 189Example 189

N-Fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny l-metyl-2-(N-(2-metoxy-4-n-pentoxy-karbonylamidino-fenyl)aminometyl]-benzimidazol-5-yl-karboxylovej1-methyl-2- (N- (2-methoxy-4-n-pentoxycarbonylamidino-phenyl) aminomethyl) -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako sa uvádza v príklade 90 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)amidu kyseliny l-metyl-2-[N-(4-amidino-2-metoxyfenyl)aminoetyl]-benzimidazol-5-yl-karboxylovej a n-pentylesteru kyseliny chlórmravčej. Výťažok bol 53 % teoretického výťažku,The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) aminoethyl] -benzimidazole-5- N -phenyl-N- (2-ethoxycarbonylethyl) amide hydrochloride. yl carboxylic acid and n-pentyl chloroformate. The yield was 53% of the theoretical yield,

C35H42N6O6 (642,7)C 35 H 42 N 6 O 6 (642.7)

Rf hodnota: 0,54 (gél kyseliny kremičitej; dichlórmetán/etanol = 9 : 1); Rf value: 0.54 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 643, (M+H+Na)++ = = 333,4.EKA mass spectrum: (M + H) + = 643, (M + H + Na) ++ = 333.4.

Príklad 190Example 190

N-Fenyl-N-(2-etoxykarbonyletyl)-amid kyseliny l-metyl-2-[N-(4-n-heptyloxykarbonyl-amidino-2-metoxyfenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej1-methyl-2- [N- (4-n-heptyloxycarbonyl-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako sa uvádza v príklade 90 z hydrochloridu N-fenyl-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidino-2-metoxyfenyI)-aminoetyl]-benzimidazol-5-yl-karboxylovej a n-heptylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminoethyl] -benzimidazole hydrochloride, N-phenyl-N- (2-ethoxycarbonylethyl) -amide. 5-yl-carboxylic acid and n-heptyl chloroformate.

Výťažok bol 68 % teoretického výťažku, C37H46N6O6 (670,8)The yield was 68% of the theoretical yield, C 37 H 46 N 6 O 6 (670.8)

Rf hodnota: 0,56 (gél kyseliny kremičitej; dichlórmetán/etanol = 9 : 1);Rf value: 0.56 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 671, (M+H+Na) = 347,4.EKA-MS: (M + H) + = 671, (M + H + Na) = 347.4.

Príklad 191Example 191

N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-etoxykarbonyl-amidino-2-metoxyfenyl)aminometyl]-benzimidazol-5-yl-karboxylovej1-Methyl-2- [N- (4-ethoxycarbonyl-amidino-2-methoxyphenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Zlúčenina sa pripravila obdobne ako sa uvádza v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidmo-2-metoxyfenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a etylesteru kyseliny chlórmravčej. Výťažok bol 43 % teoretického výťažku,The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amido-2-methoxyphenyl) -aminomethyl] N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride 1-Benzimidazol-5-yl-carboxylic acid and ethyl chloroformate. The yield was 43% of the theoretical yield,

C31H35N7O6 (601,7)C 31 H 35 N 7 O 6 (601.7)

Rf hodnota: 0,44 (gél kyseliny kremičitej; dichlórmetán/etanol = 9 : 1);Rf value: 0.44 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 602, (M+H+Na)++ = = 312,8.EKA mass spectrum: (M + H) + = 602, (M + H + Na) ++ = 312.8.

Príklad 192 N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(2-metoxy-4-n-pentoxykarbonylamidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovejExample 192 1-Methyl-2- [N- (2-methoxy-4-n-pentoxycarbonylamidinophenyl) -aminomethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide carboxylic acid

Zlúčenina sa pripravila obdobne ako sa uvádza v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidino-2-metoxyfenyl)-aminometyl]-benzimidazol-5-yl-karboxylovej a n-pentylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminomethyl] N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride 1-benzimidazol-5-yl-carboxylic acid and n-pentyl chloroformate.

Výťažok bol 72 % teoretického výťažku, C34H41N7O6 (643,7)The yield was 72% of the theoretical yield, C 34 H 41 N 7 O 6 (643.7)

Rf hodnota: 0,49 (gél kyseliny kremičitej; dichlórmetán/etanol = 9:1); Rf value: 0.49 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 644, (M+H+Na)++ = = 333,9.EKA-MS: (M + H) + = 644, (M + H + Na) ++ = 333.9.

Príklad 193 N-(2-Pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(2-metoxy-4-n-heptyloxykarbonylamidinofenyl)-aminometyl]-benzimidazol-5-yl-karboxylovejExample 193 1-Methyl-2- [N- (2-methoxy-4-n-heptyloxycarbonylamidinophenyl) -aminomethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide carboxylic acid

Zlúčenina sa pripravila obdobne ako sa uvádza v príklade 90 z hydrochloridu N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amidu kyseliny l-metyl-2-[N-(4-amidino-2-metoxyfenyl)-aminometyl]-benzimidazol-5-karboxylovej a n-heptylesteru kyseliny chlórmravčej.The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminomethyl] N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride 1-benzimidazole-5-carboxylic acid and n-heptyl chloroformate.

Výťažok bol 55 % teoretického výťažku, C36H45N7O6 (671,8)The yield was 55% of the theoretical yield, C 36 H 45 N 7 O 6 (671.8)

Rf hodnota: 0,54 (gél kyseliny kremičitej; dichlórmetán/etanol = 9 : 1); Rf value: 0.54 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-hmotnostné spektrum: (M+H)+ = 672, (M+H+Na)++ = = 347,9.EKA mass spectrum: (M + H) + = 672, (M + H + Na) ++ = 347.9.

Príklad 194Example 194

Suchá ampulka s 75 mg účinnej látky na 10 mlDry ampoule with 75 mg of active substance per 10 ml

Zloženie: účinná látka 75 mg manitol 50 mgIngredients: active ingredient 75 mg mannitol 50 mg

Voda na injekčné účely do 10 mlWater for injections up to 10 ml

Príprava:Preparation:

Účinná látka a manitol sa rozpustia vo vode. Po naplnení sa vysuší vymrazovaním. Roztok na použitie sa pripraví s vodou na injekčné účely.The active substance and mannitol are dissolved in water. After filling, freeze-dried. The solution for use is prepared with water for injection.

Príklad 195Example 195

Suchá ampulka s 35 mg účinnej látky na 2 mlDry ampoule with 35 mg of active substance per 2 ml

Zloženie: účinná látka 35 mg manitol 100 mg voda na injekčné účely do 2,0 mlIngredients: active substance 35 mg mannitol 100 mg water for injections up to 2.0 ml

Príprava:Preparation:

Účinná látka a manitol sa rozpustia vo vode. Po naplnení sa suší vymrazením.The active substance and mannitol are dissolved in water. After filling, freeze-dried.

Roztok na použitie sa pripraví s vodou na injekčné účely.The solution for use is prepared with water for injection.

Príklad 196Example 196

Tableta s 50 mg účinnej látkyTablet with 50 mg of the active substance

Zloženie:Ingredients:

1. účinná látka1. the active substance

2. mliečny cukor2. milk sugar

3. kukuričný škrob3. Corn starch

4. polyvinylpyrolidón4. polyvinylpyrrolidone

5. stearan horečnatý5. Magnesium stearate

50,0 mg50.0 mg

98,0 mg98.0 mg

50,0 mg50.0 mg

15,0 mg15.0 mg

2,0 mg2.0 mg

Zložky 1, 2 a 3 sa zmiešajú a granulujú s vodným roztokom zložky 4. K suchému granulátu sa primieša zložka 5.Components 1, 2 and 3 are mixed and granulated with an aqueous solution of component 4. Component 5 is admixed to the dry granulate.

Zo zmesi sa potom lisujú tablety s dvojstrannou fazetou a s drážkou na jednej strane. Priemer tablety: 9 mm.The mixture is then compressed into tablets with a double faced facet and a groove on one side. Tablet diameter: 9 mm.

Príklad 197Example 197

Tableta s 350 mg účinnej látkyTablet with 350 mg of the active substance

Zloženie: 1. účinná látka 2. mliečny cukor 3. kukuričný škrob 4. polyvinylpyrolidón 5. stearan horečnatý Ingredients: 1. the active substance 2. milk sugar 3. Corn starch 4. polyvinylpyrrolidone 5. Magnesium stearate 350,0 mg 136,0 mg 80,0 mg 30,0 mg 4,0 mg 350.0 mg 136.0 mg 80.0 mg 30.0 mg 4.0 mg spolu together 600,0 mg 600.0 mg

Zložky 1, 2 a 3 sa zmiešajú a granulujú s vodným roztokom zložky 4. K suchému granulátu sa primieša zložka 5.Components 1, 2 and 3 are mixed and granulated with an aqueous solution of component 4. Component 5 is admixed to the dry granulate.

Zo zmesi sa potom lisujú tablety s dvojstrannou fazetou a s drážkou na jednej strane. Priemer tablety: 12 mm.The mixture is then compressed into tablets with a double faced facet and a groove on one side. Tablet diameter: 12 mm.

Príklad 198Example 198

Kapsuly s 50 mg účinnej látkyCapsules containing 50 mg of the active substance

Zloženie:Ingredients:

1. účinná látka 50,0 mg1. active substance 50.0 mg

2. kukuričný škrob 58,0 mg2. Corn starch 58,0 mg

3. práškový mliečny cukor 50,0 mg3. Powdered milk sugar 50.0 mg

4. stearan horečnatý_______2,0 mg spolu 160,0 mg4. magnesium stearate _______ 2.0 mg total 160.0 mg

Zložka 1 sa rozotrie so zložkou 3. Táto zmes sa pridá do zmesi 2 a 4 za intenzívneho miešania.Component 1 is triturated with component 3. This mixture is added to mixtures 2 and 4 with vigorous stirring.

Táto prášková zmes sa na plničke kapsúl plní do tvrdých želatínových zásuvných kapsúl veľkosti 3.This powder mixture is filled into size 3 hard gelatin plug capsules at the capsule filler.

Príklad 199Example 199

Kapsuly s 350 mg účinnej látkyCapsules with 350 mg of the active substance

Zloženie:Ingredients:

1. účinná látka 350,0 mg1. active substance 350.0 mg

2. kukuričný škrob 46,0 mg2. Corn starch 46,0 mg

3. práškový mliečny cukor 30,0 mg3. Powdered milk sugar 30.0 mg

4. stearan horečnatý_______4,0 mg spolu 430,0 mg4. magnesium stearate 4.0 mg total 430.0 mg

Zložka 1 sa rozotrie so zložkou 3. Táto zmes sa pridá do zmesi 2 a 4 za intenzívneho miešania.Component 1 is triturated with component 3. This mixture is added to mixtures 2 and 4 with vigorous stirring.

Prášková zmes sa na plničke kapsúl potom plní do tvrdých želatínových zásuvných kapsúl veľkosti 6Be 0.The powder mixture is then filled into hard gelatin push-in capsules of size 6Be 0 on the capsule filler.

Príklad 200Example 200

Capíky s 100 mg účinnej látky čapík obsahuje:Caps with 100 mg of active substance suppository contains:

účinná látka 100,0 mg polyetylénglykol (mol.hmotn. 1500) 600,0 mg polyetylénglykol (mol.hmotn. 6000) 460,0 mg monostearan polyetylénsorbitolu 840,0 mg spolu 2 000 mgActive ingredient 100.0 mg polyethylene glycol (MW 1500) 600.0 mg polyethylene glycol (MW 6000) 460.0 mg polyethylene sorbitol monostearate 840.0 mg total 2,000 mg

Claims (13)

PATENTOVÉ NÁROKYPATENT CLAIMS 1. Disubstituované bicyklické heterocyklické zlúčeniny všeobecného vzorcaDisubstituted bicyclic heterocyclic compounds of general formula Ra-A-Het-B-Ar-E (I), v ktoromR and -A-Het-B-Ar-E (I) wherein A znamená karbonylovú skupinu alebo sulfonylovú skupinu, viazanú na benzo-, pyrido- alebo tieňovú časť skupiny Het,A represents a carbonyl group or a sulfonyl group bonded to the benzo, pyrido- or shadow part of the Het group, B znamená etylénovú skupinu, v ktorej jedna metylénová skupina, viazaná na zvyšok Ar, môže byť nahradená atómom kyslíka alebo síry, alebo skupinou -NR1-, pričom R1 znamená vodíkový atóm, alebo CM- alkylovú skupinu, E znamená skupinu RbNH-C(=NH)-, v ktorejB represents an ethylene group in which one methylene group attached to the Ar radical may be replaced by an oxygen or sulfur atom, or a -NR 1 - group, wherein R 1 represents a hydrogen atom, or a C 1-4 alkyl group, E represents a group R b NH-C (= NH) - in which Rb znamená vodíkový atóm, hydroxylovú skupinu, Ci_9-alkoxykarbonylovú skupinu, cyklohexyloxykarbonylovú skupinu, fenyl-C].3-alkoxykarbonylovú skupinu, benzoylovú skupinu, p-C|j-alkylbenzoylovú alebo pyridinoylovú skupinu, pričom etoxy časť v polohe 2 uvedenej C.r -alkoxykarbonylovej skupiny môže byť navyše substituovaná C].3-alkyl-sulfonylovou alebo 2-(Cj.3-alkoxy)etylovou skupinou,R b represents a hydrogen atom, a hydroxyl group, a C 1-9 -alkoxycarbonyl group, a cyclohexyloxycarbonyl group, a phenyl-C 1-3 -alkoxycarbonyl group, a benzoyl group, a C 1-6 -alkylbenzoyl or a pyridinoyl group, the ethoxy moiety at the 2-position of said C 1-6 alkoxycarbonyl of the group may be additionally substituted with C 1. 3 -alkylsulfonyl or 2- (C 1-3 -alkoxy) ethyl, Ar znamená 1,4-fenylénovú skupinu, voliteľne substituovanú atómom chlóru, alebo metylovou skupinou, etylovou skupinou alebo metoxylovou skupinou, alebo znamená 2,5tienylénovú skupinu,Ar represents a 1,4-phenylene group, optionally substituted by a chlorine atom, or a methyl group, an ethyl group or a methoxy group, or represents a 2,5-thienylene group, Het znamená l-(Cj.3-alkyl)-2,5-benzimidazolyIénovú skupinu, l-cyklopropyl-2,5-benzimidazolylénovú skupinu, 2,5-benztĺazolylénovú skupinu, l-(C].3-alkyl)-2,5-indolylénovú skupinu, l-(C1.3-alkyl)-2,5-imidazo[4,5-6]pyridinylénovú skupinu, 3-(C1.3-alkyl)-2,7-imidazo[l,2-a]-pyridinylénovú skupinu alebo l-(C| 3-alkyl)-2,5-ticno[2,3-r/]imidazolylénovú skupinu aHet denotes 1- (C 1-3 -alkyl) -2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1- (C 1-3 -alkyl) -2, 5-indolylénovú group, a l- (C first 3 -alkyl) -2,5-imidazo [4,5-6] pyridinylénovú, 3- (C first 3 -alkyl) -2,7-imidazo [ 2-a] -pyridinylene or 1- (C 1-3 -alkyl) -2,5-thieno [2,3-d] imidazolylene group; and Ra znamená skupinu R2NR3-, v ktorejR a represents a group R 2 NR 3 - in which R2 znamená CM-alkylovú skupinu, ktorá môže byť substituovaná karboxylovou skupinou, Ci.6-alkyloxykarbonylovou skupinou, benzyloxykarbonylovou skupinou, C,.,-alkylsulfonylaminokarbonylovou skupinou alebo 1/7-tetrazol-5-ylovou skupinou,R 2 represents a C 1-4 alkyl group which may be substituted with a carboxyl group, C 1-6 alkyl; 6- alkyloxycarbonyl, benzyloxycarbonyl, C 1-6 -alkylsulfonylaminocarbonyl or 1 H -tetrazol-5-yl, C2.4-alkylovú skupinu, substituovanú skupinou hydroxy-, benzyloxy-, karboxy-C^-alkylamino-, C,.3-alkoxykarbonyl-C^-alkylamino-, N-jC^-alkylj-karboxy-C^-alkylamino- alebo N-ÍCi.j-alkylj-Cu-alkoxykarbonyl-Ctj-alkylaminoskupinou, pričom uvedené skupiny nemôžu byť substituované na α-uhlíkový atóm v susedstve atómu dusíka,C 2 . A 4- alkyl group substituted with a hydroxy-, benzyloxy-, carboxy-C 1-4 -alkylamino-, C 1-6 -alkyl group; 3- alkoxycarbonyl-C 1-6 -alkylamino-, N-C 1-6 -alkyl-carboxy-C 1-6 -alkylamino- or N-C 1-6 -alkyl-C 1-6 -alkoxycarbonyl-C 1-6 -alkylamino, said groups cannot be substituted on α- a carbon atom adjacent to a nitrogen atom, R3 znamená C3_7-cykloalkylovú skupinu, propargylovú skupinu, pričom nenasýtená časť nemôže byť viazaná priamo na dusíkový atóm skupiny R2NR3-, fenylovú skupinu, voliteľne substituovanú atómom fluóru alebo chlóru, metylovou alebo metoxylovou skupinou, alebo znamená voliteľne metylovou skupinou substituovanú pyrazolylovú skupinu, pyridazinylovú skupinu alebo pyridinylovú skupinu, aleboR 3 is C 3 _ 7 cycloalkyl group, a propargyl group, wherein the unsaturated part may not be linked directly to the nitrogen atom of the group NR 2 R 3 -, phenyl, optionally substituted by fluorine, chlorine, methyl or methoxy, or is an optionally methyl a pyrazolyl, pyridazinyl or pyridinyl substituted group, or R2 a R3 spolu s medzi nimi ležiacim atómom dusíka znamenajú 5- až 7-člennú cykloalkylénimínovú skupinu, voliteľne substituovanú karboxylovou skupinou alebo CM-alkoxykarbonylovú skupinu, na ktorej môže byť navyše nakondenzovaný fenylový kruh, ich tautoméry, stereoizoméry a ich soli.R 2 and R 3 together with the intervening nitrogen atom represent a 5- to 7-membered cycloalkyleneimine group, optionally substituted with a carboxyl group or a C 1-4 -alkoxycarbonyl group on which a phenyl ring, their tautomers, stereoisomers and their salts may be additionally fused. 2. Disubstituované bicyklické heterocyklické zlúčeniny všeobecného vzorca (I) podľa nároku 1, v ktorýchDisubstituted bicyclic heterocyclic compounds of general formula (I) according to claim 1, in which A znamená karbonylovú skupinu alebo sulfonylovú skupinu, viazanú na benzo-, pyrido- alebo tieňovú časť skupiny Het,A represents a carbonyl group or a sulfonyl group bonded to the benzo, pyrido- or shadow part of the Het group, B znamená etylénovú skupinu, v ktorej metylénová skupina, viazaná na zvyšok Ar, môže byť nahradená atómom kyslíka alebo síry, alebo skupinou -NR1-, pričom R1 znamená vodíkový atóm alebo metylovú skupinu, E znamená skupinu RbNH-C(=NH)-, v ktorejB represents an ethylene group in which the methylene group attached to the Ar radical can be replaced by an oxygen or sulfur atom, or -NR 1 -, wherein R 1 represents a hydrogen atom or a methyl group, E represents a group R b NH-C (= NH) - in which Rb znamená vodíkový atóm, hydroxylovú skupinu, C|.9-alkoxykarbonylovú skupinu, cylohexyloxykarbonylovú skupinu, benzyloxykarbonylovú skupinu, benzoylovú skupinu, p-C|.3-alkylbenzoylovú alebo nikotinoylovú skupinu, pričom etoxy- časť v polohe 2 uvedenej C1.9-alkoxykarbonylovej skupiny môže byť navyše substituovaná C|.3-alkylsulfonylovou alebo 2-(C1.3-alkoxy)-etylovou skupinou,R b represents a hydrogen atom, a hydroxyl group, C 1-6. 9- alkoxycarbonyl, cylohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, pC 1-3 -alkylbenzoyl or nicotinoyl, wherein the ethoxy moiety at the 2-position of said C 1 . The 9- alkoxycarbonyl group may additionally be substituted by C 1-6. 3 alkylsulphonyl or 2- (C first 3 -alkoxy) ethyl, Ar znamená 1,4-fenylénovú skupinu voliteľne substituovanú atómom chlóru alebo metylovou skupinou, etylovou skupinou alebo metoxylovou skupinou, alebo znamená 2,5tienylénovú skupinu,Ar represents a 1,4-phenylene group optionally substituted by a chlorine atom or a methyl group, an ethyl group or a methoxy group, or represents a 2,5-thienylene group, Het znamená l-metyl-2,5-benzimidazoIyIénovú skupinu, 1-cyklopropyl-2,5-benzimidazolylénovú skupinu, 2,5-benztiazolylénovú skupinu, l-metyl-2,5-indolylénovú skupinu, l-metyl-2,5-imidazo[4,5-b]pyridinylénovú skupinu, 3-metyl-2,7-imidazo[l,2-<2]pyridinylénovú skupinu alebo 1-metyl-2,5-tieno[2,3-ď]-imidazolylénovú skupinu a Ra znamená skupinu R2NR3-, v ktorejHet means 1-methyl-2,5-benzimidazolyl, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene, 1-methyl-2,5- imidazo [4,5-b] pyridinylene, 3-methyl-2,7-imidazo [1,2- <2] pyridinylene or 1-methyl-2,5-thieno [2,3-d] imidazolylene and R a represents a group R 2 NR 3 - in which R2 znamená C^-alkylovú skupinu, ktorá môže byť substituovaná karboxylovou skupinou, C,.6-alkyloxykarbonylovou skupinou, benzyloxykarbonylovou skupinou, metylsulfonylaminokarbonylovou skupinou alebo \H-tetrazol-5-ylovou skupinou,R 2 represents a C 1-6 alkyl group which may be substituted by a carboxyl group, C 1-6 alkyl; 6- alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl, Cj.j-alkylovú skupinu, substituovanú skupinou hydroxy-, benzyloxy-, karboxy-C ^-alkylamino-, Q^-alkoxykarbonyl-Cj-3-alkylamino-, N-jCu-alkylj-karboxy-Cu-alkylamino- alebo NXC^-alkylj-Ctj-alkoxykarbonyl-Ci.i-alkylamino- skupinou, pričom uvedené skupiny nemôžu byť substituované na α-uhlíkový atóm v susedstve atómu dusíka,C 1-6 -alkyl, substituted with hydroxy-, benzyloxy-, carboxy-C 1-6 -alkylamino-, C 1-6 -alkoxycarbonyl-C 1-3 -alkylamino-, N-C 1-6 -alkyl-carboxy-C 1-6 -alkylamino- or NXC 1-6 -alkyl; -alkyl-C 1-6 -alkoxycarbonyl-C 1-6 -alkylamino-, wherein said groups cannot be substituted at the α-carbon atom adjacent to the nitrogen atom, R3 znamená propargylovú skupinu, pričom nenasýtená časť nemôže byť viazaná priamo na dusíkový atóm skupiny R2NR3-, fenylovú skupinu, voliteľne substituovanú atómom fluóru alebo chlóru, metylovou alebo metoxylovou, alebo znamená pyridinylovú skupinu, ich tautoméry, stereoizoméry a ich soli.R 3 represents a propargyl group wherein the unsaturated moiety cannot be bonded directly to the nitrogen atom of the group R 2 NR 3 -, a phenyl group optionally substituted by a fluorine or chlorine atom, a methyl or methoxy group, or a pyridinyl group, their tautomers, stereoisomers and salts thereof. 3. Disubstituované bicyklické heterocyklické zlúčeniny všeobecného vzorca (I) podľa nároku 1, v ktorýchThe disubstituted bicyclic heterocyclic compounds of formula (I) according to claim 1, wherein: A znamená karbonylová skupinu, viazanú na benzo- alebo tienočasť skupiny Het,A represents a carbonyl group attached to the benzo or thieno moiety of the group Het, B znamená etylénovú skupinu, v ktorej metylénová skupina, viazaná na zvyšok Ar, môže byť nahradená skupinou -NR1-, pričomB represents an ethylene group in which the methylene group bonded to the radical Ar can be replaced by -NR 1 -, wherein R1 znamená vodíkový atóm alebo metylovú skupinu,R 1 represents a hydrogen atom or a methyl group, E znamená skupinu RbNH-C(=NH)-, v ktorejE is R b NH-C (= NH) - in which Rb znamená vodíkový atóm, hydroxylovú skupinu, 014)-alkoxykarbonylovú skupinu, cylohexyloxykarbonylovú skupinu, benzyloxykarbonylovú skupinu, benzoylovú skupinu, p-Ci.3-alkylbenzoylovú skupinu, alebo nikotinoylovú skupinu, pričom etoxy- časť v polohe 2 uvedenej Ci.9-alkoxykarbonylovej skupiny môže byť navyše substituovaná metylsulfonylovou skupinou alebo 2-etoxy-etylovou skupinou,R @ b represents a hydrogen atom, a hydroxyl group, a ( 14) -alkoxycarbonyl group, a cylohexyloxycarbonyl group, a benzyloxycarbonyl group, a benzoyl group, a p-C1. A 3- alkylbenzoyl or nicotinoyl group, wherein the ethoxy moiety at the 2-position of said C 1-6 alkyl; The 9- alkoxycarbonyl group may additionally be substituted by a methylsulfonyl group or a 2-ethoxyethyl group, Ar znamená 1,4-fenylénovú skupinu, voliteľne substituovanú metoxylovou skupinou, alebo znamená 2,5-tienylénovú skupinu,Ar is 1,4-phenylene, optionally substituted with methoxy, or is 2,5-thienylene, Het znamená l-metyl-2,5-benzimidazolylénovú skupinu, 2,5-benztiazolylénovú skupinu, l-metyl-2,5-indolylénovú skupinu alebo l-metyl-2,5-tieno[2,3-(Z]-imidazolylénovú skupinu aHet means 1-methyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene or 1-methyl-2,5-thieno [2,3- (Z) -imidazolylene group and R“ znamená skupinu R2NR3-, v ktorejR "represents a group R 2 NR 3 - in which R2 znamená C^-alkylovú skupinu, ktorá môže byť substituovaná karboxylovou, Ci.j-alkvloxykarbonylovou, benzyloxykarbonylovou, metyl-sulfonylaminokarbonylovou alebo l/f-tetrazol-5-ylovou skupinou,R 2 represents a C 1-6 -alkyl group which may be substituted by a carboxyl, C 1-6 -alkoxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1 H -tetrazol-5-yl group, C2.3-alkylovú skupinu, substituovanú skupinou hydroxy-, benzyloxy-, karboxy-Cu-alkylamino-, C^-alkoxykarbonyl-C1.3-alkylamino-, N-fCu-alkylj-karboxy-Cu-alkylamino- alebo N-fCi.j-alkylj-Ci.j-alkoxykarbonyl-C |_3-alkylaminoskupinou, pričom uvedené skupiny nemôžu byť substituované na α-uhlíkový atóm v susedstve atómu dusíka,C 2 . 3- alkyl, substituted with hydroxy-, benzyloxy-, carboxy-C 1-6 -alkylamino-, C 1-6 -alkoxycarbonyl-C 1 . 3- alkylamino-, N-t-alkyl-carboxy-C 1 -alkylamino- or N-t-C 1-6 -alkyl-C 1-6 -alkoxycarbonyl-C 1-3 -alkylamino, wherein said groups cannot be substituted on the α-carbon atom adjacent to the nitrogen atom, R3 znamená fenylovú skupinu, prípadne substituovanú atómom fluóru, alebo znamená 2-pyridinylovú skupinu, tautoméme formy uvedených zlúčenín, ich stereoizoméry a soli.R 3 represents a phenyl group optionally substituted by a fluorine atom, or represents a 2-pyridinyl group, tautomeric forms of said compounds, stereoisomers and salts thereof. 4. Disubstituované bicyklické heterocyklické zlúčeniny všeobecného vzorca (I) podľa nároku 1:The disubstituted bicyclic heterocyclic compounds of formula (I) according to claim 1: a) N-fcnyI-N-(2-karboxyetyl)-amid kyseliny 2-[N-(4-amidinofenyl)-aminometyl]-benztiazol-5-karboxylovej,(a) 2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-carboxyethyl) -amide, b) N-fenyl-N-(2-hydroxykarbonyletyl)-amid kyseliny 2-[N-(4-amídinofenyl)-N-metyI-aminometyl]-benztiazol-5-karboxylovej,(b) 2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide, c) N-fenyl-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-aminometyI]-benzimidazol-5-karboxylovej,c) 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide, d) N-fenyl-N-(3-hydroxykarbonylpropyl)-amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-karboxylovej,d) 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5-carboxylic acid N-phenyl-N- (3-hydroxycarbonylpropyl) -amide, e) N-(2-pyridyl)-N-(hydroxykarbonylmetyl)-amid kyseliny l-metyl-2-[N-(4-amidino-fenyl)-aminometyl]-benzimidazol-5-karboxylovej,(e) 1-methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazole-5-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -amide, f) N-(2-pyridyl)-N-(2-hydroxykarbonylctyl)-amid kyseliny 1 -metyl-2-[2-(2-amidino-tiofen-5-yl) etyl]-benzimidazol-5-karboxylovej,(f) 1-methyl-2- [2- (2-amidino-thiophen-5-yl) -ethyl] -benzimidazole-5-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonyl-ethyl) -amide, g) N-(2-pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-karboxylovej,(g) 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide, h) N-(2-pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny l-metyl-2-[2-(4-amidinofenyl)-etyl]-benzimidazol-5-karboxylovej,(h) 1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazole-5-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) amide; i) N-fenyl-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[2-(4-amidinofenyl)-etyl]-benzimidazol-5-karboxylovej,(i) 1-methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazole-5-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide, j) N-fenyl-N-[2-(lH-tetrazol-5-yl) etyl]-amid kyseliny 1-metyl-2-[2-(4-amidinofenyl)-etyl]-benzimidazol-5-karboxylovej,(j) 1-methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazole-5-carboxylic acid N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -amide, k) N-fenyl-N-[2-(l//-tetrazol-5-yl) etyl)-amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-karboxylovej,k) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-carboxylic acid N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -amide . l) N-(2-pyridyl)-N-(2-hydroxykarbor)yletyl)-amid kyseliny l-metyl-2-[N-(4-amidinofenyl)-N-metyl-aminometyl]-benzimidazol-5-karboxylovej,(l) 1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazole-5-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarboryl-ethyl) -amide, m) N-(3-pyridyl)-N-(2-hydroxykarbony)etyl)-amid kyseliny 1 -metyl-2-[N-(4-amidinofcnyl)-N-metyl-aminometyl]-benzimidazol-5-karboxylovej,m) 1-Methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazole-5-carboxylic acid N- (3-pyridyl) -N- (2-hydroxycarbonyl-ethyl) -amide, n) N-fenyl-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-N-metyl-aminometyl]-benzimidazol-5-karboxylovej,(n) 1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazole-5-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide, o) N-fenyl-N-[(N-hydroxykarbonyletyl-N-metyl)-2-aminoetyl)-amid kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-karboxylovej,(o) 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-carboxylic acid N-phenyl-N - [(N-hydroxycarbonylethyl-N-methyl) -2-aminoethyl] -amide, p) N-(3-fluórfenyI)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-karboxylovej,(p) 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-carboxylic acid N- (3-fluorophenyl) -N- (2-hydroxycarbonylethyl) amide, q) N-(4-fluórfenyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-karboxylovej,q) 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5-carboxylic acid N- (4-fluorophenyl) -N- (2-hydroxycarbonylethyl) amide, r) N-fenyl-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidino-2-metoxy-fenyl)-aminometyl]-benzimidazol-5-karboxylovej,(r) 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazole-5-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide, s) N-(2-pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny l-metyl-2-[N-(4-amidino-2-metoxyfenyl)-aminometyl]-benzimidazol-5-karboxylovej,(s) 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) aminomethyl] -benzimidazole-5-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) amide, t) N-fenyl-N-(2-metoxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-aminometyl]-indol-5-karboxylovej at) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -indole-5-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide; and u) N-fenyl-N-(2-hydroxykarbonyletyl)-amid kyseliny 1-metyl-2-[N-(4-amidinofenyl)-aminometyl]-tieno[2,3-íZ|-imidazol-5 -karboxylovej, a ich tautoméry, prekurzory, dvojité prekurzory, ich stcrcoizoméry a soli.u) 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -thieno [2,3-b] imidazole-5-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide, and their tautomers, precursors, double precursors, stereoisomers and salts thereof. 5. Disubstituovaná bicyklická heterocyklická zlúčenina podľa nároku 1, ktorou je N-fenyl-N-(2-hydroxykarbonyletyl)-amid kyseliny l-metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-karboxylovej ajeho soli.5. A compound according to claim 1 which is 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide and its salt. 6. Disubstituovaná bicyklická heterocyklická zlúčenina podľa nároku 1, ktorou je N-(2-pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny 1 -metyl-2-[N-(4-amidinofenyl)-aminometyl]-benzimidazol-5-karboxylovej a jeho soli.A 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) amide according to claim 1, wherein the compound is a bicyclic heterocyclic compound according to claim 1. 5-carboxylic acid and its salts. 7. Disubstituovaná bicyklická heterocyklická zlúčenina podľa nároku 1, ktorou je N-(2-pyridyl)-N-(2-hydroxykarbonyletyl)-amid kyseliny l-metyl-2-[N-(4-amidino-2-metoxyfenyl)-aminometyl]-benzimidazol-5-karboxylovej a jeho soli.A 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) aminomethyl] N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) amide according to claim 1 which is a bicyclic heterocyclic compound according to claim 1. 1-benzimidazole-5-carboxylic acid and its salts. 8. Disubstituovaná bicyklická heterocyklická zlúčenina podľa nároku 1, ktorou je N-(2-pyridyl)-N-(2-etoxykarbonyletyl)-amid kyseliny l-metyl-2-[N-[4-(N-n-hexyloxykarbonylamidino)fenyl]-aminometyl]-benzimidazol-5-karboxylovej ajeho soli.A 1-methyl-2- [N- [4- (N-hexyloxycarbonylamidino) phenyl] N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide, the disubstituted bicyclic heterocyclic compound of claim 1 - aminomethyl] -benzimidazole-5-carboxylic acid and its salts. 9. Fyziologicky prijateľné soli disubstituovaných bicyklických hetero-cyklických zlúčenín podľa nárokov 1 až 8.Physiologically acceptable salts of disubstituted bicyclic heterocyclic compounds according to claims 1 to 8. 10. Farmaceutický prostriedok, vyznačujúci sa t ý m , že obsahuje zlúčeninu podľa najmenej jedného z nárokov 1 až 8 alebo soľ podľa nároku 9, voliteľne spolu s jedným alebo viacerými inertnými nosičmi a/alebo riedidlami.A pharmaceutical composition comprising a compound according to at least one of claims 1 to 8 or a salt according to claim 9, optionally together with one or more inert carriers and / or diluents. 11. Použitie disubstituovanej bicyklickej heterocyklickej zlúčeniny podľa najmenej jedného z nárokov 1 až 8 alebo jej soli podľa nároku 9, na prípravu liečiva s predlžujúcim účinkom na trombínový čas (Thrombinzeit), trombínovým brzdiacim účinkom a brzdiacim účinkom na príbuzné sérinové proteázy.Use of a disubstituted bicyclic heterocyclic compound according to at least one of claims 1 to 8, or a salt thereof according to claim 9, for the preparation of a medicament with a thrombin time-delaying effect (Thrombinzeit), a thrombin braking effect and a braking effect on related serine proteases. 12. Spôsob prípravy farmaceutického prostriedku podľa nároku 10, vyznačujúci sa tým, že zlúčenina podľa najmenej jedného z nárokov 1 až 8, alebo soľ podľa nároku 9, sa spracuje nechemickou cestou s jedným alebo viacerými nosičmi a/alebo riedidlami.Process for preparing a pharmaceutical composition according to claim 10, characterized in that the compound according to at least one of claims 1 to 8, or the salt according to claim 9, is treated by a non-chemical route with one or more carriers and / or diluents. 13. Spôsob prípravy disubstituovaných bicyklických heterocyklických zlúčenín podľa nárokov 1 až 8, v y značujúci sa tým, že:A process for the preparation of disubstituted bicyclic heterocyclic compounds according to claims 1 to 8, characterized in that: a) prípravu zlúčeniny, ktorá má všeobecný vzorec (1), v ktorom E znamená skupinu RbNH-C(=NH)-, v ktorej Rb znamená vodíkový atóm, skupinu hydroxy alebo Ομ3-alkylovú skupinu možno uskutočniť premenou zlúčeniny, voliteľne priamo v reakčnej zmesi vytvorenej zlúčeniny, so všeobecným vzorcom(a) the preparation of a compound having the general formula (1) in which E represents a group R b NH-C (= NH) - in which R b represents a hydrogen atom, a hydroxy group or a β 3 -alkyl group can be carried out by converting the compound; optionally directly in the reaction mixture of the compound of the general formula formed Ra- A-Het-B-Ar-C(=NH)-Z‘ (II), v ktoromR a - A-Het-B-Ar-C (= NH) Z '(II) wherein A, B, Ar, Het a Ra sú určené v nárokoch 1 až 8 aA, B, Ar, Het and R a are as defined in claims 1 to 8 a Z1 znamená alkoxylovú, aralkoxylovú skupinu, alkyltio- alebo aralkyltioskupinu s aminom, ktorý má všeobecný vzorecZ 1 represents an alkoxy, aralkoxy, alkylthio or aralkylthio group with an amine of the general formula H2N-Rb' (III), v ktoromH 2 NR b '(III) wherein Rb znamená atóm vodíka alebo hydroxylovú skupinu, aleboR b represents a hydrogen atom or a hydroxyl group, or b) na prípravu zlúčeniny, ktorá má všeobecný vzorec (I), v ktorom skupina Ra-A- a E sú určené v nárokoch 1 až 8 s tým, že Ra-A-skupina obsahuje karboxylovú skupinu a E je určené v nárokoch 1 až 8, alebo skupina Ra-A- je určená ako v nárokoch 1 až 8 a E je skupina NH2-C(=NH)-, alebo skupina Ra-A- obsahuje karboxylovú skupinu a E znamená skupinu NH2-C(=NH)-, sa premení zlúčenina, ktorá má všeobecný vzorec (IV)b) for the preparation of a compound having the general formula (I), wherein the group R and -A- and E are as defined in claims 1 to 8, provided that the R and -A- group contains a carboxyl group and E is as defined in the claims 1-8, or R and -A- is as defined in claims 1-8 and E is NH 2 -C (= NH) -, or R and -A- contains a carboxyl group and E is NH 2 -C ( = NH) -, a compound of formula (IV) is converted Ra -A - Het - B - Ar-C - E‘ (IV), v ktoromR and -A-Het-B-Ar-C-E '(IV) in which A, B, Ar a Het sú určené v nárokoch 1 až 8 a skupina Ra -A a E‘ majú rovnaký význam ako v nárokoch 1 až 8 pre skupinu Ra-A- s tým, že skupina Ra-A- obsahuje skupinu premeniteľnú hydrolýzou, spracovaním kyselinou alebo zásadou, termolýzou alebo hydrogenáciou na karboxylovú skupinu a E je určené nárokmi 1 až 10, alebo E‘ znamená skupinu premeniteľnú hydrolýzou, spracovaním s kyselinou alebo zásadou, termolýzou alebo hydrogenolýzou na skupinu NH2-C(=NH)- a skupina Ra-A- má rovnaký význam ako má skupina Ra-A- v nárokoch 1 až 8, alebo skupina Ra-A- obsahuje skupinu, ktorá je hydrolýzou, spracovaním s kyselinou alebo zásadou, termolýzou alebo hydrogenolýzou premeniteľnú na karboxylovú skupinu a E‘ znamená skupinu, ktorá je hydrolýzou, pôsobením kyseliny alebo zásady, termolýzou alebo hydrogenolýzou premeniteľná na skupinu NH2-C(=NH)hydrolýzou, spracovaním s kyselinou alebo zásadou, termolýzou alebo hydrogenolýzou na zlúčeninu, ktorá má všeobecný vzorec (I), v ktorej skupina Ra-A- a E je určená v nárokoch 1 až 8 s tým, že skupina Ra-A- obsahuje karboxylovú skupinu a E je určené nárokmi 1 až 8, alebo skupina Ra-A- má rovnaký význam ako v nárokoch 1 až 8 a E znamená skupinu NH2-C(=NH)-, alebo skupina Ra-A- obsahuje karboxylovú skupinu a E znamená skupinu NH2-C(=NH)-, aleboA, B, Ar and Het are as defined in claims 1 to 8 and the group R and -A and E 'have the same meaning as in claims 1 to 8 for the group R and -A-, with the group R and -A- containing a group convertible by hydrolysis, acid or base treatment, thermolysis or hydrogenation to a carboxyl group; and E is as defined in claims 1 to 10, or E 'is a group convertible by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis to NH2-C (= NH). - and the group R and -A- has the same meaning as the group R and -A- in claims 1 to 8, or the group R and -A- comprises a group which is hydrolyzable, acid or base treatment, thermolysis or hydrogenolysis convertible to carboxyl group and E 'means a group which is hydrolyzable, acidic or base-treated, thermolysis or hydrogenolysis convertible into an NH2-C (= NH) group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis sition of general formula (I), wherein R a -A- group and E are defined in the claims 1 to 8 with the proviso that the R a -A- group contains a carboxy group and E is defined by the claims 1 to 8, or R and -A- have the same meaning as in claims 1 to 8 and E represents NH2-C (= NH) -, or R and -A- contains a carboxyl group and E represents NH2-C (= NH) - or c) prípravu zlúčeniny, ktorá má všeobecný vzorec (I) a ktorá už v nárokoch 1 až 8 definovanej skupine Ra-A- obsahuje esterové skupiny možno uskutočniť premenou zlúčeniny, ktorá má všeobecný vzorec (V)c) the preparation of a compound having the general formula (I) and which already contains the ester groups in claims 1 to 8 defined by the group R and -A- can be carried out by converting a compound having the general formula (V) Ra“-A-Het-B-Ar-E (V), v ktoromR and -A-Het-B-Ar-E (V) in which B, E, Ar a Het sú určené rovnako ako v nárokoch 1 až 8 a skupina Ra“-A- má rovnaký význam ako skupina Ra-A- určená v nárokoch 1 až 8 s tým, že skupina R3“-A- obsahuje karboxylovú skupinu alebo obsahuje skupinu, ktorú možno prostredníctvom alkoholu premeniť na esterovú skupinu, s alkoholom, ktorý má všeobecný vzorec (VI)B, E, Ar and Het are as defined in claims 1 to 8 and R and "-A- have the same meaning as R and -A- as defined in claims 1 to 8, with the group R 3 " -A - contains a carboxyl group or contains a group which can be converted into an ester group by means of an alcohol, with an alcohol of the general formula (VI) HO-R7 (VI), v ktoromHO-R 7 (VI), in which R7 znamená C,.6-alkylovú alebo benzylovú skupinu, alebo s ich formamidacetálmi, alebo so zlúčeninou, ktorá má všeobecný vzorec (VII)R 7 is C 1-6. A 6- alkyl or benzyl group, or a formamide acetal thereof, or a compound having the general formula (VII) Z2 - R7 (VII), v ktoromFrom 2 - R 7 (VII) in which R7 znamená C^-alkylovú alebo benzylovú skupinu aR 7 represents a C 1-6 -alkyl or a benzyl group and Z znamená vymeniteľnú skupinu, aleboZ represents a removable group, or d) príprava zlúčeniny, ktorá má všeobecný vzorec (I), v ktorom Rb znamená vodíkový atóm, hydroxylovú skupinu, C|.9-alkoxykarbonylovú skupinu, cyklohexyloxykarbonylovú skupinu, benzyloxykarbonylovú skupinu, benzoylovú skupinu, p-CVi-alkylbenzoylovú skupinu alebo nikotinoylovú skupinu, pričom etoxy- časť v polohe 2 uvedenej Cb9-alkoxykarbonylovej skupiny môže byť navyše substituovaná Cb3-alkylsulfonylovou skupinou alebo 2-('Cb1alkoxy)-etylovou skupinou, sa uskutoční premenou zlúčeniny, ktorá má všeobecný vzorec (VIII)d) preparing a compound having the general formula (I) in which R b represents a hydrogen atom, a hydroxyl group, C 1-6. 9 -alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-CVI-alkylbenzoylovú group or a nicotinoyl group, the ethoxy moiety in the 2 position of said C b9 alkoxycarbonyl group is further optionally substituted C b3 alkylsulphonyl or 2- ( 'C b1 alkoxy) ethyl, is carried out by conversion of the compound of general formula (VIII) Ra-A-Het-B-Ar-C(=NH)-NH2 (VIII), v ktoromR and -A-Het-B-Ar-C (= NH) -NH 2 (VIII) in which Ra, A, Het, B a Ar sú určené v nárokoch 1 až 8, so zlúčeninou, ktorá má všeobecný vzorec (IX)R a , A, Het, B and Ar are as defined in claims 1 to 8, with a compound having the general formula (IX) Z2-R8 (IX), v ktoromZ 2 -R 8 (IX) wherein R8 znamená Cb9-alkoxykarbonylovú skupinu, cyklohexyloxykarbonylovú skupinu, fenyl-Cb3-alkoxykarbonylovú skupinu, benzoylovú skupinu, p-Cu-alkylbenzoylovú skupinu alebo pyridinoylovú skupinu, pričom etoxy- časť v polohe 2 uvedenej C>9-alkoxykarbonylovej skupiny môže byť navyše substituovaná Cb3-alkylsulfonylovou skupinou alebo 2-(Ci.3-alkoxy)-etylovou skupinou, aR 8 is C 1-9 -alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C 3-3 -alkoxycarbonyl, benzoyl, p-C 1 -alkylbenzoyl or pyridinoyl, wherein the ethoxy moiety at the 2-position of said C 1-9 -alkoxycarbonyl group may be navyl substituted C b3 alkylsulphonyl or 2- (Ci. 3 -alkoxy) ethyl, and Z2 vymeniteľnú nukleofilnú skupinu, aleboA 2 exchangeable nucleophilic group, or e) na prípravu benzimidazolylovej alebo benztiazolylovej zlúčeniny, ktorá má všeobecný vzorec (I), v ktorom B znamená etylénovú skupinu sa nechá reagovať zlúčenina, ktorá má všeobecný vzorec (XV) sa uskutoční premena zlúčeniny, ktorá má všeobecný vzorec (IXX) Ez\e) for the preparation of a benzimidazolyl or benzothiazolyl compound having the general formula (I) in which B is an ethylene group, a compound having the general formula (XV) is reacted by converting a compound having the general formula (IXX) Ez \ - A - Het - B - Ar - B-A-Het-B-Ar-B V (IXX), v ktoromIn (IXX), in which R5, A, B, E, Ar a Het už boli určené v nárokoch 1 až 8 a R2'znamená C b4-al kýlovú skupinu, ktorá je substituovanou karboxylovou skupinou, alebo jej reaktívnych derivátov so soľou zlúčeniny, ktorá má vzorec (XX)R 5 , A, B, E, Ar and Het have already been defined in claims 1 to 8 and R 2 'represents a C 4 -C 4 -alkylene group which is a substituted carboxyl group, or reactive derivatives thereof with a salt of a compound having the formula ( XX) C,.j-alkyl-SO2-NH2 (XX) aC 1-6 -alkyl-SO 2 -NH 2 (XX) a ak sa vyžaduje, ochranné skupiny, použité počas premeny na ochranu reaktívnych skupín sa odštiepia a/alebo ak sa vyžaduje, pripravené zlúčeniny so všeobecným vzorcom (I) sa následne rozdelia na ich stereoizoméry a/alebo sa pripravená zlúčenina, ktorá má všeobecný vzorec (I), premení na jej soli, najmä na farmaceutické použitie na fyziologicky prijateľné soli s anorganickou alebo organickou kyselinou alebo zásadou.if desired, the protecting groups used during the conversion to protect the reactive groups are cleaved and / or, if desired, the prepared compounds of formula (I) are subsequently resolved into their stereoisomers and / or the prepared compound of formula (I) is prepared. ), into its salts, in particular for pharmaceutical use, into physiologically acceptable salts with an inorganic or organic acid or base. Koniec dokumentu v ktoromEnd of document in which R'a A boli určené v nárokoch 1 až 8 a Y znamená atóm síry alebo dusíka substituovaný Cj.j-alkylovou skupinou alebo cyklopropylovou skupinou, so zlúčeninou, ktorá má všeobecný vzorecR 1 and A are as defined in claims 1 to 8 and Y represents a sulfur or nitrogen atom substituted by a C 1-6 -alkyl or a cyclopropyl group, with a compound having the general formula HO - CO - CH2CH2 - Ar - E (XVI) v ktoromHO - CO - CH 2 CH 2 - Ar - E (XVI) in which Ar a E boli určené v nárokoch 1 až 8, alebo s jej reaktívnym derivátom, aleboAr and E have been defined in claims 1 to 8, or with a reactive derivative thereof, or í) na prípravu zlúčeniny, ktorá má všeobecný vzorec (I), v ktorom R2 znamená Cb4-alkylovú skupinu, ktorá je substituovaná alkylsulfonylaminokarbonylovou skupinou(i) for the preparation of a compound of the general formula (I) in which R 2 represents a C 4 -C 4 -alkyl group which is substituted by an alkylsulfonylaminocarbonyl group
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