Cardiac-Slowing Amidines Containing the 3-Thioindole Group. Potential Antianginal Agents

Article abstract of DOI:10.1021/jm00356a021

A series of 3-thioindolamidines (and 3-indolamidines) related to mixidine (1) was studied for cardiac-slowing properties, allowing the discovery of activity for prototype thioindole 2.Structure-activity relationships were explored, leading to many potent antitachycardic agents (6-9, 12, 13, 15-17, 20, 23, 24, 30, 34, 35, 45, and 47-49).Relative to 2, cardiac-slowing activity is enhanced by substitution of the indole nitrogen with small (C1-C3) saturated alkyl groups (6-9), unsaturated alkyl groups (12, 13, and 15-17), or a methoxyethyl group (20); replacement of the N-methyl group with alkyl (23) or phenyl groups (24); and extension of the ethylene bridge by two methylene units (34).Dethio (i.e., 3-indole) analogues of 2 with alkyl substitution on the indole nitrogen (47-49) have greater activity as well.Several potent compounds were also found to have minimal myocardial depression (6-9, 13, 45, and 47).Secondary pharmacological testing is reported for thioindoles 2, 6, 7, 9, and 28.