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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.

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.

A series of methyl 9H-pyridazino[3,4-b]indole-3-carboxylates and related compounds were synthesized using a Diels-Alder reaction of methyl 3-(1H-indol-3-yl)-2-propenoates and dibenzyl azodicarboxylate. Several compounds were found to have high affinity for the benzodiazepine receptor. Their structure-activity relationships are discussed.

Intramolecular Diels-Alder reaction of 3-(1H-indol-3-yl)-2-propenoates having the olefinic substituents at the 1-position of the indole ring gave stereoselectively fused indole compounds

Intramolecular Diels-Alder reaction of 3-(1H-indol-3-yl)-2-propenoates having olefinic substituents as the 1-position of the indole ring gave stereoselectively pentacyclic fused indole compounds in good yield. Aminotetrahydrocarbazoles derivatives (8,21,22) were obtained by Curtius rearrangment via carboxylic acid derivatives. Some of these compounds showed intersting pharmacological activity such as antiarrhytmic activity.

The syntheses for two cis-decahydroquinoline-5-carboxylic acid epimers (1 and 2) which contain the =N(C)3CO2H (gamma-aminobutyric acid; GABA) moiety are described. Both intra-and intermolecular [4 + 2] cycloaddition reactions were employed for the construction of key intermediates. 1H NMR studies provided evidence for the preferred solution conformations of the two diastereomers. Pharmacological studies revealed that these isomers have little affinity for GABA receptors in vitro relative to GABA agonists. However, expected but weak stereoselective activity was observed when these analogues were assessed for their ability to inhibit high-affinity [3H]GABA uptake into rat brain synaptosomes. These data are discussed in light of structure-activity studies of other neurotransmitter analogues, and a preliminary hypothesis based upon conformational analysis is presented to explain the results.

Oxidation of 3-alkoxycarbonyl-substituted pyrrolic compounds with aqueous potassium ferricyanide in the presence of potassium hydroxide afforded 2,2′- and 5,5′-bispyrrolenine derivatives, which were in equilibrium with each other in solution via radical intermediates. The substituent effects on the dimer formation will also be discussed in connection with the characters of the intermediate pyrryl radicals.

The thermochromic properties of the dimers in solution, obtained by oxidation of 3-carbonyl substituted pyrroles, was determined as being due to the reversible dissociation into pyrryl radicals. The structure and character of the pyrryl radicals are discussed on the basis of substituent effect on thermochromism and ESR studies.

Intramolecular Diels-Alder reaction of 3-(1H-indol-3-yl)-2-propenoates having the olefinic substituents at the 1-position of the indole ring gave stereoselectively fused indole compounds