US 7,517,879 B2
Pyrrolidine derivatives as factor Xa inhibitors
Chuen Chan, Stevenage (United Kingdom); Julie Nicole Hamblin, Stevenage (United Kingdom); Henry Anderson Kelly, Stevenage (United Kingdom); Nigel Paul King, Harlow (United Kingdom); Andrew McMurtrie Mason, Stevenage (United Kingdom); Vipulkumar Kantibhai Patel, Stevenage (United Kingdom); Stefan Senger, Stevenage (United Kingdom); Gita Punjabhai Shah, Stevenage (United Kingdom); Nigel Stephen Watson, Stevenage (United Kingdom); Helen Elisabeth Weston, Stevenage (United Kingdom); Caroline Whitworth, Stevenage (United Kingdom); and Robert John Young, Stevenage (United Kingdom)
Assigned to Glaxo Group Limited, Greenford, Middlesex (United Kingdom)
Filed on Oct. 11, 2006, as Appl. No. 11/548,402.
Application 11/548402 is a division of application No. 10/479545, granted, now 7,186,717, previously published as PCT/GB02/02721, filed on Jun. 06, 2002.
Claims priority of application No. 0114005.2 (GB), filed on Jun. 08, 2001.
Prior Publication US 2007/0142374 A1, Jun. 21, 2007
Int. Cl. A61K 31/5377 (2006.01)
U.S. Cl. 514—235.5 18 Claims
 
1. A method of treating a patient suffering from one or more conditions selected from the group consisting of coronary thrombosis, myocardial infarction, unstable angina, thromboembolism, acute vessel closure, transient ischemic attacks, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion, and restenosis, comprising administering a therapeutically effective amount of a compound of formula (I):

OG Complex Work Unit Drawing
wherein:
R1 represents hydrogen, —C1-6alkyl, —C3-6alkenyl, —C2-3alkylNRbRc, —C2-3alkylNHCORb, phenyl being optionally substituted by halogen, or R1 represents a group X—W, wherein X represents —C1-3alkylene- and W represents —CN, —CO2H, —CONRbRc, —COC1-6alkyl, —CO2C1-6alkyl, or phenyl, the phenyl being optionally substituted by one or more substitutents selected from: —C1-3alkyl, —C1-3alkoxy, —C1-3alkylOH, halogen, —CN, —CF3, —NH2, —CO2H and —OH;
R2 and R3 independently represent hydrogen, —C1-3alkyl or —CF3 with the proviso that one of R2 and R3 is —C1-3alkyl or —CF3 and the other is hydrogen;
Rb and Rc independently represent hydrogen or —C1-3alkyl;
A represents:

OG Complex Work Unit Drawing
Z represents one or two optional substituents independently selected from halogen and OH,
B represents one or more optional substituents on ring carbon atoms selected from:
(i) one or more substituents selected from —CF3, —F, —CO2H, —C1-6alkyl, —C1-6alkylOH, —(C1-3alkyl)NRbRc, —(C0-3alkyl)CONRbRc and —(C0-3alkyl)CO2C1-3alkyl, —CONHC2-3alkylOH, —CH2NHC2-3alkylOH, —CH2OC1-3alkyl and —CH2SO2C1-3alkyl;
(ii) a group —Y—Re,
Y represents —C1-3alkylene-, —CO—, —C1-3alkylNH—, —C1-3alkylNHCO—, —C1-3alkylNHSO2—, —CH2NHSO2CH2— or a direct link,
Re represents phenyl, a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocycle consisting of at least one heteroatom selected from O or S, each of which is optionally substituted by one or more substituents selected from: —C1-3alkyl, —C1-3alkoxy, —C1-3alkylOH, halogen, —CN, —CF3, —NH2, —CO2H and —OH; or
(iii) a second ring Rf which is fused to the heterocyclic ring, wherein Rf represents phenyl, a 5- or 6-membered cycloalkyl group or a 5- or 6-membered aromatic heterocyclic group consisting of at least one heteroatom selected from O, N or S, and the fused bicyclic group is optionally substituted by one or more substituents selected from: —C1-3alkyl, —C1-3alkoxy, —C1-3alkylOH, halogen, —CN, —CF3, —NH2, —CO2H and —OH;
or a pharmaceutically acceptable salt thereof.