Details for Patent: 6,414,008

Title:	Disubstituted bicyclic heterocycles, the preparation thereof, and their use as pharmaceutical compositions
Abstract:	New disubstituted bicyclic heterocycles of general formula Compounds of general formula I, wherein E is an R.sub.b NH--C(.dbd.NH)-- group, have valuable pharmacological properties, particularly a thrombin-inhibiting effect and the effect of prolonging thrombin time, and those wherein E is a cyano group, are valuable intermediates for preparing the other compounds of general formula I.
Inventor(s):	Hauel; Norbert (Schemmerhofen, DE), Priepke; Henning (Warthausen, DE), Ries; Uwe (Biberach, DE), Stassen; Jean Marie (Warthausen, DE), Wienen; Wolfgang (Biberach, DE)
Assignee:	Boehringer Ingelheim Pharma KG (Ingelheim, DE)
Filing Date:	Oct 13, 2000
Application Number:	09/688,260
Claims:	1. A compound of the formula I wherein: A is a carbonyl or sulfonyl group linked to the benzo moiety of the group Het, wherein the benzo moiety may not contain an R.sub.1 group; B is an ethylene group, wherein a methylene group, linked either to the group Het or Ar, is optionally replaced by an oxygen or sulfur atom or by a sulfinyl, sulfonyl, carbonyl, or --NR.sub.1 -- group, wherein R.sub.1 is a hydrogen atom or a C.sub.1-6 -alkyl group; E is a cyano or R.sub.b NH--C(.dbd.NH)-- group, wherein R.sub.b is a hydrogen atom or a hydroxy, C.sub.1-9 -alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C.sub.1-3 -alkoxycarbonyl, benzoyl, p-C.sub.1-3 -alkyl-benzoyl, or pyridinoyl group, wherein the ethoxy moiety in the 2-position of the abovementioned C.sub.1-9 -alkoxycarbonyl group is unsubstituted or additionally substituted by a C.sub.1-3 -alkylsulfonyl or 2-(C.sub.1-3 -alkoxy)-ethyl group; Ar is a phenylene or naphthylene group optionally substituted by a fluorine, chlorine, or bromine atom or by a trifluoromethyl, C.sub.1-3 -alkyl, or C.sub.1-3 -alkoxy group, or a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene, or pyridazinylene group optionally substituted in the carbon skeleton by a C.sub.1-3 -alkyl group; Het is a bicyclic heterocycle of formula ##STR9## wherein X is a nitrogen atom, and Y is an oxygen or sulfur atom or an imino group optionally substituted by a C.sub.1-6 -alkyl or C.sub.3-7 -cycloalkyl group whilst additionally one or two non-angular methyne groups in the phenyl moiety of the above-mentioned bicyclic heterocycle may each be replaced by a nitrogen atom; or X is a methyne group optionally substituted by the group R.sub.1, wherein R.sub.1 is as hereinbefore defined, and Y is a nitrogen atom optionally substituted by a C.sub.1-6 -alkyl or C.sub.3-7 -cycloalkyl group; R.sub.a is a C.sub.1-6 -alkyl group, a C.sub.3-7 -cycloalkyl group optionally substituted by a C.sub.1-3 -alkyl group, wherein the C.sub.1-3 -alkyl group may additionally be substituted by a carboxyl group or by a group which may be converted in vivo into a carboxy group, or R.sub.a is a R.sub.2 NR.sub.3 -- group, wherein R.sub.2 is a C.sub.1-4 -alkyl group optionally substituted by a carboxy, C.sub.1-6 -alkyloxycarbonyl, benzyloxycarbonyl, C.sub.1-3 -alkylsulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, trifluorosulfonylamino, trifluorosulfonylaminocarbonyl, or 1H-tetrazolyl group, or a C.sub.2-4 -alkyl group substituted at a carbon which is other than the one in the .alpha.-position relative to the adjacent nitrogen atom, by a hydroxy, phenyl-C.sub.1-3 -alkoxy, carboxy-C.sub.1-3 -alkylamino, C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino, N--(C.sub.1-3 -alkyl)-carboxy-C.sub.1-3 -alkylamino or N--(C.sub.1-3 -alkyl)-C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino group, or a piperidinyl group optionally substituted by a C.sub.1-3 -alkyl group; and R.sub.3 is a hydrogen atom, a C.sub.1-6 -alkyl group, a C.sub.3-7 -cycloalkyl group optionally substituted by a C.sub.1-3 -alkyl group or a C.sub.3-6 -alkenyl or alkynyl group, wherein the unsaturated part may not be linked directly to the nitrogen atom of the R.sub.2 NR.sub.3 -- group, or a oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, or imidazolyl group, or R.sub.2 and R.sub.3 together with the nitrogen atom between them are a 5- to 7-membered cycloalkyleneimino group, optionally substituted by a carboxymethyl or C.sub.1-4 -alkoxycarbonyl group, onto which a phenyl ring may additionally be fused, or, if E is a group of the formula R.sub.b NH--C(.dbd.NH)--, a physiologically acceptable salt thereof or, if E is a cyano group, a salt thereof. 2. The compound of the formula I according to claim 1, wherein E is an R.sub.b NH--C(.dbd.NH)-- group, wherein: R.sub.b is a hydrogen atom or a hydroxy, C.sub.1-9 -alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C.sub.1-3 -alkoxycarbonyl, benzoyl, p-C.sub.1-3 -alkyl-benzoyl, or pyridinoyl group, wherein the ethoxy moiety in the 2-position of the abovementioned C.sub.1-9 -alkoxycarbonyl group is unsubstituted or additionally substituted by a C.sub.1-3 -alkylsulfonyl or 2-(C.sub.1-3 -alkoxy)-ethyl group. 3. The compound of the formula I according to claim 1, wherein: X is a nitrogen atom, and Y is an oxygen or sulfur atom or an imino group optionally substituted by a C.sub.1-6 -alkyl or C.sub.3-7 -cycloalkyl group whilst additionally one or two non-angular methyne groups in the phenyl moiety of the above-mentioned bicyclic heterocycle may each be replaced by a nitrogen atom. 4. The compound of the formula I according to claim 1, wherein: X is a methyne group optionally substituted by the group R.sub.1, wherein R.sub.1 is hydrogen atom or a C.sub.1-6 -alkyl group, and Y is a nitrogen atom optionally substituted by a C.sub.1-6 -alkyl or C.sub.3-7 -cycloalkyl group. 5. The compound of the formula I according to claim 1, wherein R.sub.a is a R.sub.2 NR.sub.3 -- group and wherein: R.sub.2 is a C.sub.1-4 -alkyl group optionally substituted by a carboxy, C.sub.1-6 -alkyloxycarbonyl, benzyloxycarbonyl, C.sub.1-3 -alkylsulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, trifluorosulfonylamino, trifluorosulfonylaminocarbonyl, or 1H-tetrazolyl group, or a C.sub.2-4 -alkyl group substituted at a carbon which is other than the one in the .alpha.-position relative to the adjacent nitrogen atom, by a hydroxy, phenyl-C.sub.1-3 -alkoxy, carboxy-C.sub.1-3 -alkylamino, C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino, N--(C.sub.1-3 -alkyl)-carboxy-C.sub.1-3 -alkylamino or N--(C.sub.1-3 -alkyl)-C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino group, or a piperidinyl group optionally substituted by a C.sub.1-3 -alkyl group; and R.sub.3 is a hydrogen atom, a C.sub.1-6 -alkyl group, a C.sub.3-7 -cycloalkyl group optionally substituted by a C.sub.1-3 -alkyl group or a C.sub.3-6 -alkenyl or alkynyl group, wherein the unsaturated part may not be linked directly to the nitrogen atom of the R.sub.2 NR.sub.3 -- group, or a oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, or imidazolyl group, or R.sub.2 and R.sub.3 together with the nitrogen atom between them are a 5- to 7-membered cycloalkyleneimino group, optionally substituted by a carboxymethyl or C.sub.1-4 -alkoxycarbonyl group, onto which a phenyl ring may additionally be fused, or, if E is a group of the formula R.sub.b NH--C--(.dbd.NH)--, a physiologically acceptable salt thereof or, if E is a cyano group, a salt thereof. 6. The compound of the formula I according to claim 1, wherein R.sub.a is a R.sub.2 NR.sub.3 -- group and wherein: R.sub.2 is a C.sub.1-4 -alkyl group substituted by a carboxy, C.sub.1-6 -alkyloxycarbonyl, benzyloxycarbonyl, C.sub.1-3 -alkylsulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, trifluorosulfonylamino, trifluorosulfonylaminocarbonyl, or 1H-tetrazolyl group, or a C.sub.2-4 -alkyl group substituted at a carbon which is other than the one in the .alpha.-position relative to the adjacent nitrogen atom, by a hydroxy, phenyl-C.sub.1-3 -alkoxy, carboxy-C.sub.1-3 -alkylamino, C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino, N--(C.sub.1-3 -alkyl)-carboxy-C.sub.1-3 -alkylamino or N--(C.sub.1-3 -alkyl)-C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino group; and R.sub.3 is a hydrogen atom, a C.sub.1-6 -alkyl group, a C.sub.3-7 -cycloalkyl group substituted by a C.sub.1-3 -alkyl group or a C.sub.3-6 -alkenyl or alkynyl group, wherein the unsaturated part may not be linked directly to the nitrogen atom of the R.sub.2 NR.sub.3 -- group, or an oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, or imidazolyl group, or R.sub.2 and R.sub.3 together with the nitrogen atom between them are a 5- to 7-membered cycloalkyleneimino group, optionally substituted by a carboxymethyl or C.sub.1-4 -alkoxycarbonyl group, onto which a phenyl ring may additionally be fused, or, if E is a group of the formula R.sub.b NH--C--(.dbd.NH)--, a physiologically acceptable salt thereof or, if E is a cyano group, a salt thereof. 7. The compound of the formula I according to claim 1, wherein Het is a 1-(C.sub.1-3 -alkyl)-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-(C.sub.1-3 -alkyl)-2,5-indolylene, 1-(C.sub.1-3 -alkyl)-2,5-imidazo[4,5-b]pyridinylene, 3-(C.sub.1-3 -alkyl)-2,7-imidazo[1,2-a]pyridinylene, or 1-(C.sub.1-3 -alkyl)-2,5-thieno[2,3-d]imidazolylene group. 8. A compound selected from the group consisting of: (a) 3-Methyl-2-[2-(4-amidinophenyl)ethyl]imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide; (b) 3-Methyl-2-[2-(4-amidinophenyl)ethyl]imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)amide; (c) 3-Methyl-2-[2-(4-amidinophenyl)ethyl]imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)amide hydrochloride; (d) 3-Methyl-2-[2-(4-amidinophenyl)ethyl]imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-ethoxycarbonylmethylamide hydrochloride; (e) 3-Methyl-2-[2-(4-amidinophenyl)ethyl]imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-hydroxycarbonylmethylamide hydrochloride; (f) 2-[2-(4-amidinophenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl-2,3-dihydroindo l-1-yl-carbonyl)imidazo[4,5-b]pyridine hydrochloride; (g) 2-[2-(4-amidinophenyl)ethyl]-3-methyl-6-(2-carboxy-2,3-dihydroindol-1-yl-c arbonyl)imidazo[4,5-b]pyridine hydrochloride; (h) 1-Methyl-2-[(4-amidinophenyl)oxymethyl]imidazo[4,5-b]pyridin-5-yl-carboxyl ic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide; (i) 1,5-Dimethyl-2-[(4-cyanophenyl)oxymethyl]imidazo[4,5-b]pyridine; (j) 2-[N-(4-amidinophenyl)aminomethyl]benzothiazole-5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)amide; (k) 2-[N-(4-amidinophenyl)aminomethyl]benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)amide dihydrochloride; (l) 2-[2-(4-amidinophenyl)ethyl]benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide dihydrochloride; (m) 2-[N-(4-amidinophenyl)aminomethyl]benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide dihydrochloride; (n) 2-[N-(4-amidinophenyl)aminomethyl]benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)amide dihydrochloride; (o) 2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride; (p) 2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)amide hydrochloride; (q) 2-[(4-amidinophenyl)thiomethyl]benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride; (r) 2-[(4-amidinophenyl)thiomethyl]benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)amide hydrochloride; (s) 2-[N-(4-amidinophenyl)aminomethyl]benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)amide hydrochloride; (t) 2-[N-(4-amidinophenyl)aminomethyl]benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)amide hydrochloride; (u) 2-[2-(4-amidinophenyl)ethyl]benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride; (v) 2-[2-(4-amidinophenyl)ethyl]benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)amide hydrochloride; (w) 2[N-(4amidinophenyl)aminomethyl]benzothiazol-5-yl-carboxylic acid-N-(n-propyl)-N-2-ethoxycarbonylethyl)amide hydrochloride; (x) 2-[N-(4-amidinophenyl)aminomethyl]benzothiazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-hydroxycarbonylethyl)amide hydrochloride, or a physiologically acceptable salt thereof. 9. 3-Methyl-2-[2-(4-amidinophenyl)ethyl]imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)amide, or a physiologically acceptable salt thereof. 10. 2-[N-(4-amidinophenyl)aminomethyl]benzothiazole-5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)amide, or a physiologically acceptable salt thereof. 11. A compound of the formula I according to claim 1, wherein: B is an ethylene group, wherein a methylene group linked to the group Ar, is optionally replaced by an oxygen or sulfur atom or by an --NR.sub.1 -- group, wherein R.sub.1 is a hydrogen atom or a methyl group; E is an R.sub.b NH--C(.dbd.NH)-- group, wherein R.sub.b is a hydrogen atom or a hydroxy, C.sub.1-9 -alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C.sub.1-3 -alkylbenzoyl or nicotinoyl group, wherein the ethoxy moiety in the 2-position of the abovementioned C.sub.1-9 -alkoxycarbonyl group is unsubstituted or additionally substituted by a C.sub.1-3 -alkylsulfonyl or 2-(C.sub.1-3 -alkoxy)-ethyl group, Ar is a 1,4-phenylene group optionally substituted by a chlorine atom or by a methyl, ethyl, or methoxy group, or is a 2,5-thienylene group; Het is a 1-methyl-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene, 1-methyl-2,5-imidazo[4,5-b]pyridinylene, 3-methyl-2,7-imidazo[1,2-a]pyridinylene or 1-methyl-2,5-thieno[2,3-d]imidazolylene group; and R.sub.a is a R.sub.2 NR.sub.3 -- group, wherein R.sub.2 is a C.sub.1-3 -alkyl group optionally substituted by a carboxy, C.sub.1-6 -alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl, or 1H-tetrazol-5-yl group, a C.sub.2-4 -alkyl group substituted at a carbon which is other than the one at the .alpha.-position relative to the adjacent nitrogen atom, by a hydroxy, benzyloxy, carboxy-C.sub.1-3 -alkylamino, C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino, N--(C.sub.1-3 -alkyl)-carboxy-C.sub.1-3 -alkylamino, or N--(C.sub.1-3 -alkyl)-C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino group, and R.sub.3 is a propargyl group, wherein the unsaturated moiety is not be linked directly to the nitrogen atom of the R.sub.2 NR.sub.3 -- group, is a phenyl group optionally substituted by a fluorine or chlorine atom, or by a methyl or methoxy group, or is a pyridinyl group, or a tautomer or salt thereof. 12. A compound of the formula I according to claim 1, wherein: A is a carbonyl group linked to the benzo moiety of the group Het, B is an ethylene group, wherein a methylene group attached to the group Ar is optionally replaced by an --NR.sub.1 group, wherein R.sub.1 is a hydrogen atom or a methyl group; E is an R.sub.b NH--C(.dbd.NH)-- group, wherein R.sub.b is a hydrogen atom, a hydroxy, C.sub.1-9 -alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C.sub.1-3 -alkyl-benzoyl, or nicotinoyl group, wherein the ethoxy moiety in the 2-position of the abovementioned C.sub.1-9 -alkoxycarbonyl group is unsubstituted or additionally substituted by a methylsulfonyl or 2-ethoxyethyl group; Ar is a 1,4-phenylene group optionally substituted by a methoxy group or it is a 2,5-thienylene group; Het is a 1-methyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene, or 1-methyl-2,5-thieno[2,3-d]imidazolylene group; and R.sub.a is an R.sub.2 NR.sub.3 -- group, wherein R.sub.2 is a C.sub.1-3 -alkyl group optionally substituted by a carboxy, C.sub.1-6 -alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl, or 1H-tetrazol-5-yl group, a C.sub.2-3 -alkyl group substituted at a carbon which is other than the one at the .alpha.-position relative to the adjacent nitrogen atom, by a hydroxy, benzyloxy, carboxy-C.sub.1-3 -alkylamino, C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino, N--(C.sub.1-3 -alkyl)-carboxy-C.sub.1-3 -alkylamino, or N--(C.sub.1-3 -alkyl)-C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino group, and R.sub.3 is a phenyl group optionally substituted by a fluorine atom, or is a 2-pyridinyl group, or a tautomer or salt thereof. 13. A physiologically acceptable salt of a compound according to claim 1, wherein E is an R.sub.b NH--C(.dbd.NH)-- group. 14. A physiologically acceptable salt of a compound according to claim 2. 15. A physiologically acceptable salt of a compound according to claim 3, wherein E is an R.sub.b NH--C(.dbd.NH)-- group. 16. A physiologically acceptable salt of a compound according to claim 4, wherein E is an R.sub.b NH--C(.dbd.NH)-- group. 17. A physiologically acceptable salt of a compound according to claim 5, wherein E is an R.sub.b NH--C(.dbd.NH)-- group. 18. A physiologically acceptable salt of a compound according to claim 6, wherein E is an R.sub.b NH--C(.dbd.NH)-- group. 19. A physiologically acceptable salt of a compound according to claim 7, wherein E is an R.sub.b NH--C(.dbd.NH)-- group. 20. A physiologically acceptable salt of a compound according to claim 8. 21. A physiologically acceptable salt of a compound according to claim 11. 22. A physiologically acceptable salt of a compound according to claim 12. 23. A pharmaceutical composition comprising a physiologically acceptable compound according to claim 1 and a pharmaceutically acceptable carrier or diluent. 24. A pharmaceutical composition comprising a compound according to claim 2 and a pharmaceutically acceptable carrier or diluent. 25. A pharmaceutical composition comprising a physiologically acceptable compound according to claim 3 and a pharmaceutically acceptable carrier or diluent. 26. A pharmaceutical composition comprising a physiologically acceptable compound according to claim 4 and a pharmaceutically acceptable carrier or diluent. 27. A pharmaceutical composition comprising a physiologically acceptable compound according to claim 5 and a pharmaceutically acceptable carrier or diluent. 28. A pharmaceutical composition comprising a physiologically acceptable compound according to claim 6 and a pharmaceutically acceptable carrier or diluent. 29. A pharmaceutical composition comprising a physiologically acceptable compound according to claim 7 and a pharmaceutically acceptable carrier or diluent. 30. A pharmaceutical composition comprising a compound according to claim 8 and a pharmaceutically acceptable carrier or diluent. 31. A pharmaceutical composition comprising a compound according to claim 11 and a pharmaceutically acceptable carrier or diluent. 32. A pharmaceutical composition comprising a compound according to claim 12 and a pharmaceutically acceptable carrier or diluent. 33. A method for the prophylaxis or treatment of venous and arterial thrombotic disease in a patient in need thereof, which comprises administering to the patient an antithrombotic amount of a compound according one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein E is an R.sub.b NH--C(.dbd.NH)-- group or a physiologically acceptable salt thereof. 34. The method of claim 33, wherein the thrombotic disease is selected from the group consisting of: deep leg vein thrombosis, reocclusion after a bypass operation or angioplasty (PT(C)A), occlusion in peripheral arterial disease, pulmonary embolism, disseminated intravascular coagulation, coronary thrombosis, stroke, and the occlusion of a shunt or stent. 35. A method for providing antithrombotic support in thrombolytic treatment utilizing rt-PA or streptokinase in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of a compound according one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein E is an R.sub.b NH--C(.dbd.NH)-- group or a physiologically acceptable salt thereof. 36. A method for treating or preventing fibrin-dependent inflammatory processes in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of a compound according one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein E is an R.sub.b NH--C(.dbd.NH)-- group or a physiologically acceptable salt thereof.