New antiarrhythmic agents. 2,2,5,5-Tetramethyl-3-pyrroline-3-carboxamides and 2,2,5,5-tetramethylpyrrolidine-3-carboxamides.

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.

Synthesis and study of new 4-quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP)

“…Regarding the structure-activity relationship (SAR), the principal ring compound protecting activity greatly varied depending on the substituent. Compounds 1, 2 exhibited good activity, compound 3 exhibited limited activity, 4, 5 and H-2641 with cardioprotective activity 8 were inactive in PARP inhibitory assay. The ω-amino S-alkylated compounds 15a-d exhibited better protection activity than the S-ethyl one (4).…”

“…6,7 In our laboratory we have synthesized 4-quinazolinone derivative, H-2641 as an antiarrhythmic drug candidate. 8 It was a real challenge to test and compare this compound with basic quinazolines 1-3 ( Figure 1) on PARP inhibitory activity assay as well as synthesizing new quinazolinone derivatives attached to 1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole or 1-oxyl-2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridine and their amine precursors, because these rings exhibited radical scavenging activity and protected against oxidative stress. This fact can be a significant contribution in designing new PARP inhibitors against cell damage induced by antiviral 11 and anticancer drugs.…”

Synthesis of six mexiletine derivatives with isoindolines attached as potential antioxidants and their evaluation as cardioprotective agents

“…Thus the N-oxides and N-hydroxyl amines of both series of compounds were shown to have no antiarrhythmic effect but to be less toxic than the active amines. Similarly, Hankovszky et al 4 showed that the nitroxides and hydroxylamines prepared from different compounds chemically close to Class I antiarrhythmic agents, showed no or decreased antiarrhythmic effects relative to the amino compounds.…”

Novel antioxidants in anthracycline cardiotoxicity

“…observations prompted us to test our experimental drug H-2545 and its metabolite H-2954 (Scheme 2: compounds 3 and 4) in order to determine whether they can prevent the acute deterioration of cardiac function following DOX administration [10]. It was reported that compound 3 ( Fig.…”