| 摘要 |
<p>4-Oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxamide compounds (I) are new. 4-Oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxamide compounds of formula (I) are new. A : 1-oxidopyridyl substituted by the remainder of the molecule in any one of the positions 2, 3 and 4; m, n : 1 - 3; R 1H or linear or branched (1-6C)alkyl; R 2, R 3hydrogen, halogen, linear or branched (1-6C)alkyl, hydroxy, linear or branched (1-6C)acyloxy or linear or branched (1-6C)alkoxy; R 2+R 33-6C cycloalkane; R 4, R 5H; R 4+R 5benzo ring; Ar : phenyl, biphenylyl or naphthyl (optionally substituted by at least one of T 1) or 5 - 12-membered mono- or bi-cyclic aromatic group (containing 1 - 3 heteroatoms selected from O, N or S; and optionally substituted by at least one of T 1); and T 1halo, linear or branched (1-6C)alkyl (optionally substituted by hydroxy, carboxy or carbamoyl (optionally mono- or di-substituted by linear or branched (1-6C)alkyl, linear or branched (1-6C)alkoxy, hydroxy, trihalo-(1-6C)alkyl (in which the alkyl moiety is linear or branched), amino (optionally mono- or di-substituted by linear or branched (1-6C)alkyl, carboxymethoxy or carbamoylmethoxy (optionally mono- or di-N-substituted by linear or branched (1-6C)alkyl, hydroxy-(1-6C)alkyl (in which the alkyl moiety is linear or branched), alkoxyalkyl (in which the alkoxy and alkyl moieties are each linear or branched 1-6C) or pyridylalkyl (in which the alkyl moiety is linear or branched 1-6C)))). The configuration of the asymmetric centre at the alpha position with respect to the amide is (S). [Image] ACTIVITY : Antianginal; Thrombolytic; Cardiant; Vasotropic; Cardiovascular-Gen.; Antiarteriosclerotic. MECHANISM OF ACTION : Thrombin inhibitors. The inhibitory activity of 3-{[2,2-difluoro-2-(1-oxido-2-pyridyl)ethyl]amino}-4-oxo-N-[2-(2-oxo-2-{[2-(2-pyridyl)ethyl]amino}ethoxy)benzyl]-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide hydrochloride (A) was evaluated on human thrombin. The purified human fibrinogen (4 mM) was added to thrombin (0.7 nM) that had previously been incubated optionally with the inhibitor to be tested (20[deg]C, 10 minutes). Inhibitors, enzymes and substrates were diluted in the same buffer (0.01 mM phosphate buffer, pH 7.4, containing sodium chloride (0.12 M) and bovine serum albumin (0.05%)) and then distributed on a polystyrene microtitre plate in a volume of 50 mu l. The fibrin formed by the thrombin was measured using a spectrophotometer at 405 nm after 10 - 15 minutes reaction at 20[deg]C. The IC 50 value of (A) was found to be 1.4 nM.</p> |
