Helmut Hofmeister

Synthesis and activities of anti-aldosterones

Publisher Summary This chapter discusses the synthesis and activities of anti-aldosterones. An aldosterone antagonist can prevent or decrease edema formation by competitively inhibiting aldosterone at the receptor level. The antagonist functions as a diuretic agent and causes decreased blood pressure. In a study described in the chapter, the anti-aldosterone activity of a bis-methylene derivative was compared to that of spironolactone by a method involving a continuous i.v. infusion of aldosterone in rats and in man. In this study, adrenalectomized rats were pretreated with fluocortolone caproate and fluocortolone. Five days after adrenalectomy, these rats received a continuous infusion of aldosterone. Spironolactone and a bis-methylene derivative were given orally l h before beginning aldosterone infusion. Urine production, volume and electrolyte concentration were measured hourly. The bis-methylene derivative was found to reverse the strong depression of the urinary Na/K ratio induced by the mineralocorticoid effect of aldosterone in a dose-dependent manner and had more than five times the potency of spironolactone. A study with healthy human subjects also confirmed this result.

Synthesis of 17α-bromovinyl- and 17α-iodovinylnortestosterone derivatives

Depending upon the reaction conditions, norethisterone (1) and its ketal 2 can be transformed with tributyltin hydride to either the (E)-or(Z)-17α-(2-tributylstannylvinyl)-nortestosterone derivatives 3, 8 and 13. Further treatment with N-bromo- or N-iodosuccinimide yields the corresponding (E)- and (Z)-17α-halovinyl steroids 6,7,10 and 11. Radio-labelled (Z)-17α-(2-iodovinyl)-nortestosterone was prepared by reaction of the 17α-stannylvinyl derivative 13 with Na125I.