Synthesis of cyclohexylaliphatic acids and their pharmacological properties

Abstract

A series of substituted cyclohexylacetic acids I has been obtained by hydrogenation of the unsaturated analogues II and III. Esters of these analogues were prepared by the Horner-Wittig reaction of the corresponding cyclohexanones IV and/or 2-cyclohexenones V with triethyl phosphonoacetate. These esters were obtained in two isomeric forms (Z and E), differing in the double bond in the exo-position. The derivatives with a substituent in the 2-position exhibited a partial shift of the double bond to the cyclohexane ring; this shift was especially marked in the 2-phenyl derivative. With the acids I-III, activation of fibrinolysis was assessed by the hanging clot method; the anti-inflammatory effect was assessed by inhibition of two experimental model inflammations. The regression equation relating fibrinolytic capacity to lipophilicity was a quadratic one, the logarithm of optimum lipophilicity being log Popt = 5.55. A qualitative assessment of the anti-inflammatory effect in relation to lipophilicity suggests that log Popt is probably higher than with arylaliphatic acids. These acids seem to have an active site different from that of the acids I-III.