Author/Authors :
Robert A. GalemmoJr.، نويسنده , , Brian L. Wells، نويسنده , , Karen A. Rossi، نويسنده , , Richard S. Alexander، نويسنده , , Celia Dominguez، نويسنده , , Thomas P. Maduskuie، نويسنده , , Pieter F. W. Stouten، نويسنده , , Matthew R. Wright، نويسنده , , Bruce J. Aungst، نويسنده , , Pancras C. Wong، نويسنده , , Robert M. Knabb، نويسنده , , Ruth R. Wexler، نويسنده ,
Abstract :
In this report refinements to the S4 ligand group leads to compound 19, an inhibitor of fXa with good potency in vitro and an improved pharmacokinetic profile in rabbit. The X-ray crystallographic study of a representative analogue confirms our binding model for this series.
Scheme 1. Synthesis of 2,4-diazepin-3-one analogues. Reagents: (i) 3-cyanophenylisocyanate, DMF, 18 h; (ii) 3 equiv NaH, 2 equiv BrCh2CH2CH2CH2Br, DMF, 70 °C, 3 h, then HCl:Et2O; (iii) R-Cl (see Table 1), Et3N, THF, then HCl(g), CH3CO2CH3:CH3OH (5:1), 0–10 °C, 18 h, then 5 equiv NH4CO3, CH3OH, 18 h; (iv) R-Cl (2-, 3-, 4-nitrophenylsulfonyl chlorides), Et3N, THF, then HCl(g), CH3CO2CH3:CH3OH (5:1), 0–10 °C, 18 h, then 5 equiv (NH4)2CO3, CH3OH, 18 h, then H2, Pd-C, MeOH.
