Details for Patent: 6,469,039

Title:	Disubstituted bicyclic heterocycles, the preparation and the use thereof as pharmaceutical compositions
Abstract:	New disubstituted bicyclic heterocycles of general formula Compounds of the above general formula I, wherein E denotes 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 denotes a cyano group, are valuable intermediates for preparing the other compounds of general formula I. Exemplary compounds of formula I are: (a) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (b) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide, (c) 1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl- carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide, and (d) 1-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]-benzimid azol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide.
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:	Apr 06, 2000
Application Number:	09/544,931
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; 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 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; Het is a bicyclic heterocycle of formula ##STR9## wherein X is a nitrogen atom, and Y is an imino group optionally substituted by a C.sub.1-6 -alkyl or C.sub.3-7 -cycloalkyl group; and 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, 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, a C.sub.3-6 -alkenyl or alkynyl group, wherein the unsaturated part is not linked directly to the nitrogen atom of the R.sub.2 NR.sub.3 -- group, a benzyl group, or phenyl group optionally substituted by a fluorine, chlorine, or bromine atom or by a C.sub.1-3 -alkyl or C.sub.1-3 -alkoxy group, or a physiologically acceptable salt thereof. 2. The compound of the formula I according to claim 1, 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, or a physiologically acceptable salt thereof. 3. The compound of the formula I according to claim 2, wherein: B is an ethylene group in which the 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 C.sub.1-4 -alkyl group; Ar is a 1,4-phenylene group optionally substituted by a chlorine atom or by a methyl, ethyl, or methoxy group; Het is a 1-(C.sub.1-3 -alkyl)-2,5-benzimidazolylene or 1-cyclopropyl-2,5-benzimidazolylene group; and R.sub.a is an R.sub.2 NR.sub.3 -- group, 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 or 1H-tetrazol-5-yl 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 phenyl group optionally substituted by a fluorine, chlorine, or bromine atom or by a C.sub.1-3 -alkyl or C.sub.1-3 -alkoxy group, or a physiologically acceptable salt thereof. 4. The compound of the formula I according to claim 1, wherein B is an ethylene group in which the 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; 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, or a C.sub.2-3 -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, 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, chlorine, or bromine atom or by a C.sub.1-3 -alkyl or C.sub.1-3 -alkoxy group, or a physiologically acceptable salt thereof. 5. A compound of the formula I according to claim 2, wherein A is a carbonyl group linked to the benzo moiety of the group Het; B is an ethylene group in which the 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; Ar is a 1,4-phenylene group optionally substituted by a methoxy group, Het is a 1-methyl-2,5-benzimidazolylene 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-tetrazolyl group, or a C.sub.2-3 -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, 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, chlorine, or bromine atom or by a C.sub.1-3 -alkyl or C.sub.1-3 -alkoxy group, or a physiologically acceptable salt thereof. 6. A compound selected from the group consisting of: (a) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide; (b) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl)-amide; (c) 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide; (d) 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide, (e) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide; (f) 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-ca rboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide; (g) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-hydroxycarbonylethyl-N-methyl)-2-aminoethyl]-amide; (h) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide; (i) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide; (j) 1-Methyl-2-[N-(4-amidino-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-c arboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide; (k) 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide; and (l) 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]-thieno[2. 3-d]imidazol-5-y-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide; or a physiologically acceptable salt thereof. 7. 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, or a physiologically acceptable salt thereof. 8. A physiologically acceptable salt of a compound according to one of claims 1, 2, 3, 4, 5, 6, or 7. 9. A pharmaceutical composition containing a compound according to one of claims 1, 2, 3, 4, 5, 6, or 7, or a physiologically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. 10. A method for the prophylaxis or treatment of venous and arterial thrombotic disease in 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, or 7, or a physiologically acceptable salt thereof. 11. The method of claim 10, 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. 12. 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 to one of claims 1, 2, 3, 4, 5, 6, or 7, or a physiologically acceptable salt thereof. 13. 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 to one of claims 1, 2, 3, 4, 5, 6, or, 7, or a physiologically acceptable salt thereof.