A series of 3-fluro-4-alkoxyphenylalkanoic acids III was synthetized and their antiinflammatory activity and fibrinolytic capacity was evaluated. The suitable fluorinated derivative with better pharmacological profile than 3-chloro-4-benzyloxyphenylacetic acid (benzofenac) was selected. Experimental, biological activities of acids III were compared with those calculated by introducing the physico-chemical parameters into the formerly derived regression equations. Good coincidence was found out, as well as similarity of the regression derived for the original series of acids extended by the acids III. Lipophilicity of the acids under study was evaluated by partition thin-layer chromatography; the values of log P of benzyloxy derivatives IIIc-IIIf were lower than tabulated values - probably due to the intramolecular hydrophobic interactions of aromatic nuclei.

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Analogs of 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (I, flobufen), containing a double bond (II, IV, V, VII, VIII) or a methyl group in position 3 (VI) were prepared. Their antiinflammatory activity was evaluated and compared with that of flobufen. None of the mentioned analogs reached the activity of the standard. Isomerization of the unsaturated derivatives is connected with a shift of the double bond, Z-E transformation or lactonization. Reaction conditions and spectra of the compounds prepared are described.

The antiinflammatory effect of a series of aryloxoalkanoic acids II and of their biphenyl derivatives III was examined by measuring the inhibition of the development of carageenan- and adjuvant-induced edemas. The quantitative relations between the antiinflammatory effect and physicochemical and structural parameters of the compounds tested were evaluated. The equations obtained by the method of regression analysis showed a significant linear dependence of both inhibitory activities on the lipophilicity of the compounds and a considerable effect of some structural changes as expressed by indicator variables. The antiinflammatory effect is especially enhanced in both tests by the presence of a cyclic substituent at the aromatic ring. The high antiinflammatory effect of biphenylyl derivatives III is paralleled by their prolonged action. The prolongation of the effect is most likely a result of a suitable biotransformation of acid III to an efficient metabolite. The structural requirements which resulted from both the regression analysis and from the hypothesis of biotransformation of acids III were utilized in the synthesis of suitably substituted biphenylyloxoalkanoic acids. By this approach derivatives IIIe-i were obtained some of which showed a high antiinflammatory and also protracted effect. 4-(2',4'-Difluorbiphenylyl)-4-oxo-2-methylbutanoic acid (VÚFB-16 066, Flobufen) was chosen for further preclinical development.

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