SYNTHESIS AND ANTIULCER ACTIVITY OF NEW DERIVATIVES OF GLYCYRRHETIC, OLEANOLIC AND URSOLIC

A review is made of the literature describing the structural changes t o glycyrrhetic, oleanolic and ursolic acids and their influence on ant iulcer activity.For the glycyrrhetic acid derivatives some analogues w ere prepared in which the ketonic group in position 11 was removed and the carboxylic function at position 30 was either intact, reduced to alcohol or transformed into ketone. This first series of compounds sug gests the possibility of obtaining compounds devoid of the conjugated ketonic group, maintaining anti-ulcer activity but with reduced or lac king mineralocorticoid activity. Based on these findings, a series of carbenoxolone analogues in the beta-amyrin series of glycyrrhetic and oleanolic acid was prepared. In particular, the Delta(9,11) unsaturate d compounds 14b and 23b and the 11-methylene derivative 18 present adv antages in terms of acute toxicity and mineralocorticoid activity as c ompared to the reference compound. The derivative 14b in the volunteer showed an increase of gastric PGE(2) levels with minor pseudoaldoster onic effect. Among the ursolic acid derivatives, the dihemisuccinate s odium salt 35b demonstrated a good separation between anti-ulcer and m ineralocorticoid activities. Nevertheless, kidney and liver toxicity w as observed in the monkey thus jeopardizing its further development. B etter results were obtained with the uvaol dihemiphthalate sodium salt and the diene analogue 39b. In particular, 38b and 39b showed a poten t anti-ulcer activity, 3- to 25-fold higher than carbenoxolone. Furthe rmore, compound 38b does not show signs of liver toxicity in the monke y. (C) 1998 Elsevier Science S.A.