Preparation of pyrrolidin-3-ylmethylamines as orexin receptor antagonists.

Abstract

The present invention is concerned with compds. of formula I (wherein R1 is halogen; R2 is halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or phenyl; Hetaryl is benzooxazolyl, quinoxalinyl, or benzothiazolyl; Ar is aryl or heteroaryl; n = 0-2; m = 0-2) or pharmaceutically suitable acid addn. salts, optically pure enantiomers, racemates or diastereomeric mixts. thereof. The compds. are orexin receptor antagonists may be useful in the treatment of disorders, in which orexin pathways are involved. Synthetic procedures for prepg. I are exemplified. Example compd. II was prepd. in a 3-step synthesis that culminated in the reaction of (6-chlorobenzoxazol-2-yl)pyrrolidin-3-ylmethylamine and 2,6-dimethoxybenzoyl chloride. In an intracellular Ca2+ mobilization assay run in CHO cells expressing human orexin-2 receptors, II had a kb of 0.0292 uM; kb = IC50/(1+[A]/EC50) where A is the concn. of agonist added and IC50 and EC50 are derived from the antagonist inhibition and orexin-A or B agonist curves, resp. [on SciFinder(R)]