THROMBIN INHIBITORS

摘要

The invention relates to a compound having formula (I) wherein R is -NR<1>R<2> and R is R<3>, or R<3> is R<1> and R is -NH-(SO2)m-R<3>, m being 0 or 1; wherein R<1> is -(SO2)n-(1-6C)alkylene-COOH or an ester derivative thereof, n being 0 or 1; and m and n are not 1 at the same time; R<2> is selected from H, (1-12C)alkyl, (2-12C)alkenyl, (3-8C)cycloalkyl, (1-6C)alkylene(3-8C)cycloalkyl, (6-14C)aryl, (7-15C)aralkyl and -(1-6C)alkylene-COOH or an ester derivative thereof; R<3> is a hydrophobic moiety; or R<2> and R<3> are a 5- or 6-membered ring together with "N-C" to which they are bound, which ring may be fused with an aliphatic or aromatic 6-membered ring; A is an amino acid selected from proline, optionally containing a second heteroatom selected from N, O, or S, and optionally substituted with (1-6C)alkyl, (1-6C)alkoxy or halogen, 3,4-dehydroproline, 2-azetidine carboxylic acid, pipecolinic acid, octahydroindole-2-carboxylic acid, 2-amino isobutyric acid or valine; B is lysine or 4-aminocyclohexylglycine; and X is -CHF2, -CF3, -COOR<4> or -CONR<5>R<6>, wherein R<4> is H or (2-6C)alkyl, and R<5> and R<6> are independently H, (1-6C)alkyl or -(1-6C)alkylene-C6H5, or R<5> and R<6> together are (3-6C)alkylene, or X is a heterocycle selected from 2-thiazole, 2-thiazoline, 2-benzothiazole, 2-oxazole, 2-oxazoline, 2-benzoxazole and 2-benzimidazole, which heterocycles are optionally substituted with one or more (1-6C)alkyl, (1-6C)alkoxy or oxo; or a pharmaceutically acceptable salt thereof. The compounds of the invention have anticoagulant activity and can be used in treating or preventing thrombin-related diseases.