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Details for Patent: 6,710,055

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Details for Patent: 6,710,055

Title: Disubstituted bicyclic heterocycles, the preparation thereof, and their use as pharmaceutical compositions
Abstract:Disubstituted bicyclic heterocycles of general formula I 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 GmbH & Co., KG (Ingelheim, DE)
Filing Date:Jul 10, 2002
Application Number:10/192,041
Claims:1. A compound of the formula I:

wherein: A is a carbonyl or sulfonyl group linked to the pyridino moiety of the group Het; 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 3-methyl-2,6-imidazo[4,5-b]pyridinylene group; and 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, C.sub.1-6 -alkoxycarbonyl, cyclohexyloxcarbonyl, or phenyl-C.sub.1-3 -alkoxycarbonyl 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, 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 -alkyl-amino, 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 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, and

or a tautomer or salt thereof.

2. The compound of the formula I according to claim 1, wherein 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, 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 -alkyl-amino, 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 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, and

or a tautomer or salt thereof.

3. The compound of the formula I according to claim 1, wherein R.sub.3 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.

4. The compound of the formula I according to claim 1, wherein R.sub.3 is a propargyl group, wherein the unsaturated moiety is not linked directly to the nitrogen atom of the R.sub.2 NR.sub.3 -- group, or a tautomer or salt thereof.

5. The compound of the formula I according to claim 1, wherein R.sub.3 is a phenyl group optionally substituted by a fluorine or chlorine atom, or by a methyl or methoxy group, or a tautomer or salt thereof.

6. The compound of the formula I according to claim 1, wherein R.sub.3 is a pyridinyl group, or a tautomer or salt thereof.

7. The compound of the formula I according to claim 1, wherein A is a carbonyl group linked to the benzo moiety of the group Het, or a tautomer or salt thereof.

8. The compound of the formula I according to claim 1, wherein A is a sulfonyl group linked to the benzo moiety of the group Het, or a tautomer or salt thereof.

9. The compound of the formula I according to claim 1, wherein R.sub.b is a hydrogen atom, or a tautomer or salt thereof.

10. The compound of the formula I according to claim 1, wherein R.sub.b is 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, or a tautomer or salt thereof.

11. 3-Methyl-2-[(4-amidinophenyl)thiomethyl]imidazo[4,5-b]pyridin-6-yl-carboxy lic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide, or a tautomer or salt thereof.

12. 3-Methyl-2-[N-(4-amidinophenyl)aminomethyl]imidazo[4,5-b]-pyridin-6-yl-car boxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide, or a tautomer or salt thereof.

13. 3-Methyl-2-[(4-amidinophenyl)thiomethyl]imidazo[4,5-b]pyridin-6-yl-carboxy lic acid-N-phenyl-N-(2-hydroxycarbonylethyl)amide, or a tautomer or salt thereof.

14. 3-Methyl-2-[N-(4-amidinophenyl)aminomethyl]imidazo[4,5-b]-pyridin-6-yl-car boxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)amide, or a tautomer or salt thereof.

15. A physiologically acceptable salt of a compound according to one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14.

16. A pharmaceutical composition comprising a compound according to one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, or a tautomer or salt thereof and a pharmaceutically acceptable carrier or diluent.

17. A method for the prophylaxis or treatment of venous and arterial thrombotic disease which comprises administering an antithrombotic amount of a compound according one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, or a physiologically acceptable salt thereof.

18. The method of claim 17, 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.

19. A method for providing antithrombotic support in thrombolytic treatment utilizing rt-PA or streptokinase, which comprises administering a therapeutically effective amount of a compound according one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, or a physiologically acceptable salt thereof.

20. A method for preventing metastasis or the growth of clot-dependent tumors, which comprises administering a therapeutically effective amount of a compound according one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, or a physiologically acceptable salt thereof.

21. A method for treating or preventing fibrin-dependent inflammatory processes, which comprises administering a therapeutically effective amount of a compound according one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, or a physiologically acceptable salt thereof.
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