Diazafluorenone il-8 receptor antagonists

摘要

The present invention relates to diazafluorenone derivatives of Formula (I) or a pharmaceutically acceptable salt thereof wherein: X is O or S; R1, R2, and R3 are independently hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, (CH2)nOC(O)CH3, O(CH2)nCO2R4, O(CH2)nC(O)R4 wherein R4 is lower alkyl, OC(O)R5wherein R5 is unsubstituted or substitued phenyl, O(CH2)nR6 wherein R6 is unsubstituted phenyl, substituted phenyl, or heteroaryl, Formula (a), or Formula (b) wherein R7 and R8 are lower alkyl; and n is an integer from 1 to 3; with the proviso that when X is O, R1, and R2, and R3 are not all hydrogen, which are IL-8 receptor antagonists useful as pharmaceutical agents, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to methods of treating a chemokine-mediated disease state in a mammal, including a human. The diazafluorenones of the present invention are useful in the treatment of chemokine-mediated diseases such as, for example, psoriasis or atopic dermatitis, disease associated with pathological angiogenesis (i.e., cancer), asthma, chronic obstructive pulmory disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, gastric ulcer, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, stroke, atherosclerosis, cardiac and renal reperfusion injury, glomerulonephritis, or thrombosis, Alzheimer's disease, graft versus host reaction, or allograft rejections in a mammal, including a human.