2-Alkylidene Analogs of 19-nor-1alfa,25-(OH)2D3: Synthesis and Biological Activity

D3, [1alfa,25-(OH)2D3], extends beyond calcium and phosphorus homeostasis. The vitamin was also found to regulate cellular differentiation and to play a role in immunoregulatory activity. In 1990 we reported a synthesis of the first member of the so-called 19-norvitamins D. This analog, 19-nor-1alfa,25-dihydroxyvitamin D3, was characterized by the replacement of the A-ring exocyclic methylene substituent at C-10 by two hydrogen atoms. Biological testing of this compound revealed its selective activity profile with high potency in inducing cellular differentiation and very low calcium mobilizing response. Several similar 19-norvitamins were prepared to date and the most notable among them is 19-nor-1alfa,25-dihydroxyvitamin D2 (ZemplarŽ), successfully marketed by Abbott for renal osteodystrophy. As a continuation of these studies we synthesized analogs of the natural vitamin D hormone, 1alfa,25-(OH)2D3, characterized by transposition of its A-ring exocyclic methylene group from carbon 10 to carbon 2. Among such vitamins, 2-methylene-19-nor-1alfa,25-(OH)2D3, possessing an unnatural configuration at C-20 (2MD), is most remarkable due to its unique ability to induce bone formation. 2-Methylene-substituted 19-norvitamin D compounds with truncated side chains were also prepared and two of them (2MP and 2MbisP) show great promise in the treatment of secondary hyperparathyroidism, cancer and psoriasis. In an effort to further explore the 19-nor class for pharmacologically important vitamin D compounds, the isomeric 2-ethylidene-19-nor-1alfa,25-(OH)2D3 compounds were successfully prepared. Promising biological potencies of such analogs, especially those with E-geometry of the ethylidene group, encouraged us to further explore this A-ring modification by the synthesis of 2-(3'-hydroxypropylidene)-19-nor-1alfa,25-(OH)2D3 analogs. Biological tests revealed that calcemic activity of E-geometrical isomers considerably exceeds that of the native hormone, 1alfa,25-(OH)2D3.