Design and synthesis of substituted N-methylbenzamide analogues derived from SR 48,968 as neurokinin-2 receptor antagonists

A series of N-methylbenzamide analogues (2–18) that is structurally derived from SR 48,968, a potent neurokinin-2 (NK2) receptor antagonist (pKb 9.1), has been obtained using asymmetric synthesis. Isothiocyanato-N-methylbenzamide (10–12) and bromoacetamido-N-methylbenzamide derivatives (16–18) have been designed to serve as potential electrophilic affinity labels. Nitro-N-methylbenzamide (4–6) and acetamido-N-methylbenzamide (13–15) were designed to serve as the nonelectrophilic controls for these ligands. Functional assay results using guinea pig trachea indicate that electrophilic N-methylbenzamide analogues exhibit potent but surmountable NK2 receptor antagonist activity. Several members of this series (2, 3, 7–9) exhibit potent NK2 receptor antagonist potencies with pKb values in the range of 9.1–9.7. para-Fluoro substituted analogue 3 was found to be highly potent with a pKb of 9.7.