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Disubstituted bicyclic heterocycles, the preparation and the use thereof as pharmaceutical compositions

Imported: 23 Feb '17 | Published: 22 Oct '02

Norbert Hauel, Henning Priepke, Uwe Ries, Jean Marie Stassen, Wolfgang Wienen

USPTO - Utility Patents

Abstract

New disubstituted bicyclic heterocycles of general formula

R

a—A—Het—B—Ar—E  (I)

Compounds of the above general formula I, wherein E denotes an R

bNH—C(═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]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide.

Claims

1. A compound of the formula I

R

a—A—Het—B—Ar—E  (I)

wherein:

or a physiologically acceptable salt thereof.

2. The compound of the formula I according to claim 1, wherein:

or a physiologically acceptable salt thereof.

3. The compound of the formula I according to claim 2, wherein:

or a physiologically acceptable salt thereof.

4. The compound of the formula I according to claim 1, wherein

or a physiologically acceptable salt thereof.

5. A compound of the formula I according to claim 2, wherein

or a physiologically acceptable salt thereof.

6. A compound selected from the group consisting of:

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.