Aminoalkynyldithianes. A new class of calcium channel blockers

Abstract

Several dithiane derivatives, prepared as intermediates for compounds structurally related to the therapeutically useful antimuscarinic agent oxybutynin, were effective inhibitors of calcium ion induced contraction of guinea pig ileal strips and of KCl-induced calcium entry into neuronal cells. Although the first member of this series, 2-[5-(diethylamino)-3-pentynyl]-1,3-dithiane (2a), was only marginally effective, its condensation product with diphenyl ketone, i.e. 2-[5-(diethylamino)-3-pentynyl]-2-(a,a-diphenyl-a- hydroxymethyl)-1,3-dithiane (3a), demonstrated weak, but significant, calcium channel antagonist activity. As part of a structure-activity relationship (SAR) study, various structural analogues of 2a and 3a were prepared and examined for calcium antagonist properties. In addition to these structural types, ring bridged (tricyclic) congeners of 3, i.e. 4, related bicyclic compounds 5, dehydroxylated derivatives 6, some homologous 2-[[[(N,N-disubstituted-amino)methyl]2- phenyl-1,3-dithianes (7), and a series of 2-[6-[N,N-disubstituted-amino)methyl]-1-hydroxy-1-phenyl- 4-hexynyl]-1,3-dithianes (8) were prepared and studied for calcium channel blocking activity. In general, greatest potency was noted in the tricyclic series 4; however, a definitive SAR could not be established. A structural similarity between several potent calcium antagonists having the structures 7c, 8b, and 8d and the well-known calcium channel blockers verapamil and tiapamil suggests these compounds may act at the same site. Compounds in the other classes (2-6) failed to show clearly defined SAR and their potency differed markedly in two tests for calcium channel antagonist activity. These results may indicate that the dithiane derivatives 2-6 produce their effects in a manner differing from that of the calcium channel antagonists diltiazem, verapamil, and nitrendepine.

One hundred years of benzotropone chemistry

“…Tribenzotropone ( 400 ) was also used as starting material for host molecules 425 – 427 ( Fig. 26 ) [ 212 – 213 ].…”

Identification, Synthesis, and Enzymology of Non‐natural Glucosinolate Chemopreventive Candidates

“…[69] In contrast, alkylation of (biphenyl-2-yl)methyl bromide (52) with 1,3-dithiane anion produced 53 in moderate yield. [70] Dethioacetylization of 53 by treatment with Dess-Martin periodinane resulted in aldehyde 54.…”

The Dibenzosuberenone Scaffold as a Privileged Substructure: From Synthesis to Application

“…was synthesized as a new class of calcium channel blocker ( Figure 13). 96 Sisak reported the preparation of various new η 3 -and η 5 -coordinated cobalt-carbonyl derivatives and the silylation of several α,β-unsaturated and aromatic carbonyl compounds with these cobalt carbonyls. 97 as the electrophile (Figure 13).…”