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The chemical structure of the indometacin molecule was systematically modified with the aim of producing a substance with increased anti-inflammatory activity and improved tolerance. In addition to the variations of the methylene group of the indole-3-acetic acid and substituents on the indole nucleus of indometacin, particular attention was paid to the modification of the carboxyl group of the acetic acid side chain. Among the indometacin esters, one derivative, the [1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetoxy] acetic acid (54), showed an activity approximately twice that of indometacin in the kaolin edema test in the rat paw. Chemical modification of the new compound 54 did not further improve the activity. These studies suggest that specific substitutions on the indole nucleus, in combination with the acetic acid side chain as in 1, and especially the acetoxy acetic acid side chain in 54 are responsible for the high anti-inflammatory activity of this class of substances. Several methods for the synthesis of acemetacin are described.

Synthesis of six nuclear hydroxylated derivatives of flufenamic acid and etofenamate (5-OH-, 4'-OH and 5,4'-(OH2) on a preparative scale is described. All compounds show low toxicity, but only weak anti-inflammatory activity in the rat paw kaolin edema test as compared to 2-(2-hydroxyethoxy)ethyl-N-(a,a,a-trifluoro-m-tolyl)-anthranilate (etofenamate, active substance of Rheumon Gel).

Etofenamate is 2-(2-hydroxyethoxy)ethyl-N-(a,a,a,-trifluorom-tolyl)anthranilate and has been selected as an antiphlogistic agent for percutaneous therapy. Its characteristic alcohol-ether-ester structure brings about an increase in lipophilia and in its ability to penetrate through the intact skin. Furthermore, its oily consistency renders it ideal for pharmaceutical formulation in gels. The physico-chemical material constants, partition coefficients (RM values) as a measure for lipophilia, spectra and molecular models of etofenamate are described. Various methods of synthesis of etofenamate and of its intermediates are described. Structural identification is made of by-products simultaneously obtained in the reaction. Pure etofenamate is obtained through repeated molecular distillation. The synthesis is carried out uniformly with protected reaction components and, after splitting off the protective groups, extremely pure etofenamate is obtained.