title: New antiarrhythmic agents. 2,2,5,5-Tetramethyl-3-pyrroline-3-carboxamides and 2,2,5,5-tetramethylpyrrolidine-3-carboxamindes.
abstract: N-(omega-Aminoalkyl)-2,2,5,5-tetramethyl-3-pyrroline- or -pyrrolidine-3-carboxamides were acylated on the primary amino group of the side chain by means of reactive acid derivatives (acid chlorides, activated esters, phthalic anhydrides, phthalimide, 2-alkyl-4H-3,1-benzoxazin-4-ones) or they were alkylated by forming the Schiff bases and subsequent sodium borohydride reduction. Other tetramethyl-3-pyrrolinecarboxamide compounds were synthesized by acylating the aminoalkyl compounds with 2,2,6,6-tetramethyl-3,5-dibromo-4-piperidinone in a reaction involving Favorskii rearrangement. Saturation of the double bond of some pyrroline derivatives furnished the pyrrolidinecarboxamides. The new compounds of each type were active against aconitine-induced arrhythmia and several of them had higher activity and better chemotherapeutic index than quinidine. A few selected examples from each type of the active new compounds showed strong activity against ouabain-induced arrhythmia; for comparison known drugs such as lidocaine, mexiletine, and tocainide were selected. The most potent compounds were oxidized to the paramagnetic nitroxides and the latter were reduced to the N-hydroxy derivatives; these products had no or only decreased antiarrhythmic effect.
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D009538:Nicotine; D010042:Ouabain; D051381:Rats; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
chemical_list: D000889:Anti-Arrhythmia Agents; D007202:Indicators and Reagents; D010042:Ouabain; D009538:Nicotine