I. Isakovich, S. Ryabova, L. Alekseeva
Sep 1, 1996
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Journal
Pharmaceutical Chemistry Journal
Abstract
This work is a continuation of the study of synthesis, chemical and physicochemical properties, and heterocyclization pathways of 3-arninomethyleneindolin-2-one derivatives, representing enamines of the hydroxyindole series [ 1 6]. The annelation reactions of these compounds were previously performed on derivatives that were either unsubnstituted or alkyl-substituted at the N l atom of the indolinone cycle [3]. In this work, we have used 1-(2,6-dichlorophenyl)-3dimethylaminomethylene hydroxyindole derivatives as the initial compounds. The choice of dichlorophenyl substituent in position I of the indole ring was inspired by the fact that this group, possessing high lipophilic properties, may facilitate penetration of the derivative compounds through biological membranes, thus increasing the biological activity of these compounds. Some data on the pharmacological properties of compounds of this type were published earlier [5]. At the same time, the presence of dichlorophenyl substituent at the N I atom in hydroxyindole derivatives may significantly change their properties as compared to those ofNl-unsubsti tuted or N i.alky l-substituted compounds. The electron-acceptor properties of dichlorophenyl residue may differently affect the reactivity of compounds, depending on the nucleophilic or electrophylic character of the base reagent. At the same time, the large dimensions of this group create considerable steric obstacles to any process in the nearest vicinity of the substituent. The main purpose of this work was to establish important features of the derivative compounds and study the possibility of their heterocyclization. We have outlined an approach to solving this task, which includes the following stages. (1) Study of the O-alkylation reaction of 1-(2,6-dichlorophenyl)-3-dimethylaminomethylenehydroxyindole in order to obtain the corresponding alkoxy derivatives. It was expected that the rate of alkylation might decrease as compared to that in N I-unsubstituted (or Nt-alkyl-substituted) hydroxy-