A. Bakibaev, V. Gorshkova, O. Arbit
May 1, 1994
Citations
0
Influential Citations
3
Citations
Journal
Pharmaceutical Chemistry Journal
Abstract
Benzamides are known as physiologically active substances, and individual members of this series of compounds have found application as anticonvulsants, e.g., metaclopramid (4-amino-5-chloro-N'-(2-diethylaminoethyl)-2-methoxybenzamide hydrochloride) [2], procainamide [4-amino-N-(2-diethylaminoethyl)benzamide] [3] and its structural analogues [4, 5], which display pronounced antispasmodic activity. N-Aryltrimethoxybenzamides [6, 7] and N-aryltrifluoromethylbenzamides [8] are among the other compounds of this series known to exhibit antispasmodic properties. In general, research into the antispasmodic properties of N-substituted benzamides has been more comprehensive than for the N-unsubstituted compounds, although a number of isolated reports have appeared on the antispasmodic effects of the latter class. In order to make a more detailed study of the antispasmodic properties of N-unsubstituted benzamides, to assess the effect of the benzene ring substituents on these properties and to provide a more complete picture of their pharmacological activity, we synthesized 15 compounds in this series and determined their toxicity, and antispasmodic and antihypoxic activity. A convenient way of synthesizing N-substituted benzamides is by using urea. Several aromatic hydrocarbons have been directly amidated in the presence of Lewis acids [9] to produce 10-20% yields, while N-unsubstituted benzamides have been obtained in high yield by heating the appropriate acids with urea in oleum [10]. However, the low yields achieved using the former method and the over-aggressive medium of the latter limits their broad application as a preparative technique. We have developed a modified approach to synthesizing N-unsubstituted benzamides with urea. Benzamides I-XV were obtained in moderate yields (up to 58%) by reacting the corresponding acids with urea in formic acid. We have used this system in previous investigations as an effective amidating and azacyclizing reagent in a number of chemical reactions, e.g. for synthesizing benzhydrylformamides [I 1]. The R and R' substituents have virtually no effect on the reaction rate or the product yields.