Synthesis and biological action of aminotetrahydroisoquinocarbazoles and related compounds: a new class of compounds with antiarrhythmic activity

Abstract

A series of 12-aminotetrahydroisoquinocarbazoles and related compounds were synthesized using an intramolecular Diels-Alder reaction and screened for antiarrhythmic activity in chloroform-induced ventricular arrhythmias in mice. Several compounds showed more potent activity than disopyramide. There was some correlation between substituents on aromatic ring and angular position, and antiarrhythmic activity. An amino group or some functional groups containing an amino group on C-12 seemed to be essential to exhibit the activity. Ring size also influenced the activity. The compound (+)-10 (RS-2135) had the most favorable combination of antiarrhythmic activity and toxicity and was selected for further evaluation.

Intramolecular Diels−Alder Reactions of 3-(Tetrahydropyridinyl)indoles: Stereoselective Synthesis of Novel Pentacyclic Ring Systems

“…Acylation of the indole nitrogen with 4-pentenoyl chloride under anhydrous conditions afforded the Diels−Alder precursor 10 in 73% yield (Scheme 2). We anticipated that the intramolecular Diels−Alder reaction would occur at temperatures higher than or comparable to those reported for analogous intramolecular cyclization of 3-vinylindoles (>160 °C), as there are no electron-withdrawing substituents on the dieneophile. Indeed, no reaction was detected in refluxing toluene or xylene for 48 h. However, we were able to effect cycloaddition by conducting the reaction in boiling mesitylene for 120 h to give 11 as a stable crystalline solid in 79% yield.…”

Indole‐2‐Carboxaldehyde: An Emerging Precursor for the Construction of Diversified Imperative Skeleton

“…. [42][43][44][45][46][47] using N-methylindole-2-carboxaldehyde as one of the starting materials by P. Balczewski et al in 2010 (Scheme 3). [55] Protected 6-bromopiperonal 27 reacted with N-methylindole-2-carboxaldehyde 28 in the presence of nBuLi at -78°C in THF to form diaryl methanol 29 in 66% yield.…”

“…Initially, the reaction of 37 with either acetamidine hydrochloride (45) (1.0 equiv.) or benzamidine hydrochloride (46) (1.0 equiv.) afforded a mixture of indole-2-carboxaldehyde and the corresponding products 2-(4,6-dimethyl-1,3,5-triazin-2yl)-1H-indole (47) or 2-(4,6-diphenyl-1,3,5-triazin-2-yl)-1H-indole Scheme 3.…”

“…Most of these compounds are prepared from naturally occurring compounds such as steroids, opioids, taxane, and diterpenoids, where the quaternary stereogenic centers are provided by the natural product precursor. [42,43] Indole derivatives containing benzylic quaternary stereogenic centers are found in the indole alkaloid haplophytine [44] and polycyclic indoles with antiandrogenic, [45] antiarrythmic [46] and antihypertensive [47] activities (Figure 4).…”

Coupling Catalytic Alkene Hydroacylation and α-Arylation: Enantioselective Synthesis of Heterocyclic Ketones with α-Chiral Quaternary Stereocenters

“…However, the majority of the metal-catalyzed, enantioselective α-arylation studies have focused on reactions of ketones with carbocyclic backbones or lactones. , Enantioselective α-arylation of nitrogen-containing heterocycles to form benzylic quaternary stereogenic centers has been studied to a much lesser extent and is largely limited to reactions of oxindoles . We focused on our studies on developing strategies to synthesize indole and pyrrole derivatives containing benzylic quaternary stereogenic centers due to the presence of this structural feature in the indole alkaloid haplophytine and polycyclic indoles with antiandrogenic, antiarrhythmic, and antihypertensive activities (Figure ).…”