Giorgio Fedrizzi

A GENERAL, 1+4 APPROACH TO THE SYNTHESIS OF 3(5)-SUBSTITUTED PYRAZOLES FROM ALDEHYDES

Abstract A new, one-pot preparation of 3(5)-substituted-1H-pyrazole is described that employs Horner-Emmons reaction of aldehydes with dianion of novel phosphonate 1 and proceeds through cyclization of N-sodium salt of α,β-unsaturated tosylhydrazones 2 .

Novel Analogues of Istaroxime, a Potent Inhibitor of Na+,K+-ATPase: Synthesis and Structure−Activity Relationship†

We report the synthesis and biological properties of novel inhibitors of the Na(+),K(+)-ATPase as positive inotropic compounds. Following our previously described model from which Istaroxime was generated, the 5alpha,14alpha-androstane skeleton was used as a scaffold to study the space around the basic chain of our lead compound. Some compounds demonstrated higher potencies than Istaroxime on the receptor and the (E)-3-[(R)-3-pyrrolidinyl]oxime derivative, 15, was the most potent; as further confirmation of our model, the E isomers of the oxime are more potent than the Z form. The compounds tested in the guinea pig model induced positive inotropic effects, which are correlated to the in vitro inhibitory potency on the Na(+),K(+)-ATPase. The finding that all tested compounds resulted less proarrhythmogenic than digoxin, a currently clinically used positive inotropic agent, suggests that this could be a feature of the 3-aminoalkyloxime derivative class of 5alpha,14alpha-androstane.

New digitalis steroids. Synthesis of 17α-amino 5β,14β-steroids by thermolysis of 17β-azidocarbonyloxymethyl derivatives

An efficient procedure for the synthesis of otherwise difficult to access 17α-amino derivatives of the digitalis series is described. The key reaction is the stereospecific thermocyclisation of 3β-acetoxy-l7β-azidocarbonyloxymethyl-5β-androstan-14β-ol 3b to (17R)-3β-acetixy-14β-hydroxyspiro[5β-androstane-17,4′-oxazolidin]-2′-one 4.