Synthetic approaches towards the multi target drug spironolactone and its potent analogues/derivatives.

Spironolactone is a well-known multi-target drug and is specifically used for the treatment of high blood pressure and heart failure. It is also used for the treatment of edema, cirrhosis of the liver, malignant, pediatric, nephrosis and primary hyperaldosteronism. Spironolactone in association with thiazide diuretics treats hypertension and in association with furosemide treats bronchopulmonary dyspepsia. The therapeutic mechanism of action of spironolactone involves binding to intracellular mineralocorticoids receptors (MRs) in kidney epithelial cells, thereby inhibiting the binding of aldosterone. Since its first synthesis in 1957 there are several synthetic approaches have been reported throughout the years, Synthetic community has devoted efforts to improve the synthesis of spironolactone and to synthesize its analogues and derivatives. This review aims to provide comprehensive insight for the synthetic endeavors devoted towards the synthesis of a versatile drug spironolactone and its analogues/derivatives.

The nitration of canrenone with acetic anhydride/nitric acid.

3-Oxo-17 alpha-pregna-4,6-diene-21,17-carbolactone (canrenone, II) is produced from the potassium salt of 17-hydroxy-3-oxo-17 alpha-pregna-4,6-diene-21-carboxylic acid (I) by acid catalyzed lactonization. II reacts with acetic anhydride/nitric acid to give one main product (III) and some minor products. The structure of III was determined by chemical and spectral analysis to the 4-nitro derivative of canrenone. This result is in contrast to the known reactions of II with most other reagents that were found to add at delta(6), and also in contrast to the reactions of acetic anhydride/nitric acid with alkenes. Electrophilic substitution at the ambident C4 is discussed as the reaction path. The 4-nitro group enhances the inhibitory activity of II against Na+/K(+)-ATPase, the target enzyme of the cardioactive digitalis glycosides, which appears to indicate increased cardioactivity.

[Synthesis and reactions of 2-methylene-canrenone]. / Darstellung und Reaktionen von 2-methylen-canrenon.

Starting from the Mannich salt 1 of the aldosterone antagonist canrenone or from 2-methylene-canrenone (2) the A-ring annulated hetero- and carbocycles 5, 6, 8-13 were prepared. Receptor (estradiol, progesterone, androgen, gluco- and mineralocorticoid) binding studies and competition studies with the serum proteins SHBG and CBG were carried out using the compounds 2, 3, 4b, 5, 6b, 8 and 12. The relative binding affinities with CBG are below 1%, in all other cases lower than 0.01%.

[Heterocyclic annulated steroids from 2-hydroxymethylene-canrenone]. / Heterocyclisch anellierte Steroide aus 2-Hydroxymethylen-canrenon.

A-ring annulated heterocycles, the isoxazole 6, the pyrazoles 8 and the pyrimidines 9 are prepared starting from 2-hydroxymethylene canrenone 1. Binding studies were carried out with the compounds 1 and 6-8 using estrogen, progesterone, androgen, gluco- and mineralocorticoid receptors as well as the serum proteins SHBG and CBG: the substances were inactive on the receptor level. 1, 7 and 8a show weak binding affinity to CBG.

Canrenone formation via general-base-catalyzed elimination of 7 alpha-(methylthio)spironolactone S-oxide.

The preparation of the two diastereomeric S-oxides of 7 alpha-(methylthio)spironolactone, the major metabolite of spironolactone in humans, is described. When placed in aqueous solution, these diastereomers undergo elimination reactions to give canrenone. The rate of canrenone formation from 7 alpha-(methylthio)spironolactone S-oxide was carefully investigated spectrophotometrically. In weakly acidic media, canrenone formation was found to proceed at significant rates, and the reaction was catalyzed by basic buffer species. At strongly acidic or basic pH only, specific-acid or specific-base catalysis of sulfoxide elimination, respectively, was observed. The observation that formation of canrenone could occur from nonenzymatic elimination of 7 alpha-(methylthio)spironolactone S-oxide may have toxicological significance since it has been determined that canrenone can be metabolized to mutagenic epoxides in vitro. Our studies demonstrate a novel chemical pathway leading from a major metabolite of spironolactone, 7 alpha-(methylthio)spironolactone S-oxide, to canrenone.