Design of Phthalazinone Amide Histamine H1 Receptor Antagonists for Use in Rhinitis

The synthesis of potent amide-containing phthalazinone H-1 histamine receptor antagonists is described. Three analogues 3e, 3g, and 9g were equipotent with azelastine and were longer-acting in vitro. Amide 3g had low oral bioavailability, low brain-penetration, high metabolic clearance, and long duration of action in vivo, and it was suitable for once-daily dosing intranasally, with a predicted dose for humans of approximately 0.5 mg per day.