Carlo Farina

Synthesis and anti-ulcer activity of new derivatives of glycyrrhetic, oleanolic and ursolic acids

A review is made of the literature describing the structural changes to glycyrrhetic, oleanolic and ursolic acids and their influence on anti-ulcer activity. For the glycyrrhetic acid derivatives some analogues were 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 suggests the possibility of obtaining compounds devoid of the conjugated ketonic group, maintaining anti-ulcer activity but with reduced or lacking 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 unsaturated compounds 14b and 23b and the 11-methylene derivative 18 present advantages in terms of acute toxicity and mineralocorticoid activity as compared to the reference compound. The derivative 14b in the volunteer showed an increase of gastric PGE2 levels with minor pseudoaldosteronic effect. Among the ursolic acid derivatives, the dihemisuccinate sodium salt 35b demonstrated a good separation between anti-ulcer and mineralocorticoid activities. Nevertheless, kidney and liver toxicity was observed in the monkey thus jeopardizing its further development. Better results were obtained with the uvaol dihemiphthalate sodium salt and the diene analogue 39b. In particular, 38b and 39b showed a potent anti-ulcer activity, 3- to 25-fold higher than carbenoxolone. Furthermore, compound 38b does not show signs of liver toxicity in the monkey.

Chiral high-performance liquid chromatography of some related bicyclic lactams

Chromatographic methods utilising a Chiralcel OC cellulose-based column were developed for the chiral resolution of optical isomers of the cognition-enhancing ISF 4185 and related bicyclic lactams. These methods were scaled up for the preparation of purified samples of enantiomers, one pair of which was submitted to X-ray analysis. The resolution of the enantiomers derived from these compounds appears to be mainly dependent on their ability to hydrogen bond to the chiral stationary phase.