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

Abstract

A series of N-methylbenzamide analogues ( 2– 18) that is structurally derived from SR 48,968, a potent neurokinin-2 (NK 2) receptor antagonist (p K b 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 NK 2 receptor antagonist activity. Several members of this series ( 2, 3, 7– 9) exhibit potent NK 2 receptor antagonist potencies with p K b values in the range of 9.1–9.7. para-Fluoro substituted analogue 3 was found to be highly potent with a p K b of 9.7.