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A series of compounds related to 3-deoxydigitoxigenin was prepared and assayed for inhibition of myocardial Na+,K+- adenosine triphosphatase. Although the relatively high activity of 3-deoxydigitoxin was confirmed, the corresponding 3beta,4beta-epoxide and a mixture of 2,3-olefins and 3,4-olefins were less active. 3-Deoxy compounds with variations at the 14-position and the butenolide ring were much less active than the corresponding 3beta-hydroxy analogs. Thus the activity of 3-deoxydigitoxigenin appears to be particularly susceptible to structural changes elsewhere in the molecule.

The synthesis of a 3beta-thiocyanatocardenolide is described. The compound exhibited about 0.1 times the cardiotonic effect of digitoxyigenin in the isolated frog heart preparation. At a dosage of 20 mg/kg in the intact rat, it elicited ECG changes similar to those seen with a 10-mg/kg dose of digitoxigenin. Studies also revealed the new cardenolide to be a reversible inhibitor of sodium- and potassium-activated adenosine triphosphatase.

In order to determine the influence of a 6alpha-methyl group activity, the 6alpha-methyl derivative of digitoxigenin 3-acetate 14 was prepared and pharmacologically tested in comparison with digitoxigenen 3-acetate. The synthesis of 6alpha-methyldigitoxigenin 3-acetate (14) was performed starting from 21-hydroxy-4-pregnene-3,20-dione (1). According to the cardiac activity determined on guinea-pig isolated heart and by slow infusion in the cat, the 6alpha-methyldigitoxigenin 3-acetate (14) is not more active than digitoxigenin 3-acetate.

(20R)-20,22-Dihydrodigitoxigenin (3a) and (20S)-20,22-dihydrodigitoxigenin (3b) were isolated from (20R,S)-20,22-dihydrodigitoxigenin (3) by three fractional crystallizations each from ethyl acetate. The two diastereomers have distinct NMR spectra and similar (Na+,K+)ATPase inhibitory activities (I50 = 1.1-1.4 X 10(-5) M)--about 1/100 as active as digitoxigenin (1). Their activity compared with other cardenolide analogues suggests a passive geometric role for the 20(22) double bond in eliciting (Na+,K+)ATPase inhibition, keeping the lactone carbonyl in the proper orientation. (20S)-3 beta,14 beta-Dihydroxy-22-methylene-5 beta,14 beta-cardanolide (7a) was then synthesized from 3a, and (20R)-3 beta,14 beta-dihydroxy-22-methylene-5 beta,14 beta-cardanolide (7b) from 3b. They were found to be equivalently active in inhibiting (Na+,K+)ATPase, with I50 values of 7.0 x 10(-5) M. Although it has been usually believed that the 14 beta-hydroxyl of cardenolides increases binding to the receptor, 2b (the 14-ene derivative of 7b) was more than twice as active (I50 = 3.0 X 10(-5)) than either 7a or 7b.