2,7-Dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1,4]diazonine as a new template for the design of CCK(2) receptor antagonists.

A novel series of nonpeptide CCK 2 receptor antagonists has been prepared, in which 2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1,4]diazonine (5) was used as a chemical template. This uncommon ring system was obtained in a highly substituted form and in high yield by ozonolysis of the enamine bond of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole derivatives (4), in which the configuration of the substituents was established stereoselectively via the Pictet-Spengler reaction. Further structural manipulation was guided by molecular modeling through comparison of fieldpoint-based structures of candidate compounds with a selected low-energy conformation of the representative CCK 2 receptor antagonist 5-[[[( 1S)-[[(3,5-dicarboxyphenyl)-amino]carbonyl]-2-phenylethyl]amino]carbonyl]-6-[[(1-adamantylmethyl)amino]carbonyl]-indole (JB93182 (3)). By this approach compounds such as (3R,5S)-4-acetyl-3-(1-adamantyl)-methyl-1-(2-chlorobenzyl)-5-carboxymethylaminocarbonyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1,4]diazonine (32) were prepared. Compound 32 behaved as a competitive CCK 2 receptor antagonist in vitro as judged by its inhibition ofpentagastrin-stimulated acid secretion in an isolated, lumen-perfused, immature rat stomach assay (pK B = 6.74 ± 0.27) and by its displacement of [ 125 I]CCK-8S from CCK 2 sites in mouse cortical homogenates (pK i = 6.99 ± 0.05). Compound 32 was 100-fold selective for CCK 2 over CCK 1 receptors based on the affinity estimate obtained in a guinea pig pancreas radioligand binding assay (pK i = 5.0).