Novel 9-Alkyl- and 9-Alkylidene-Substituted 1 alpha,25-Dihydroxyvitamin D-3 Analogues: Synthesis and Biological Examinations

摘要

Continuing the structure activity relationship studies in the vitamin D area, we designed and synthesized novel C-9 substituted calcitriol analogues, possessing different nonpolar groups at this position. 9a-Methyl-1 alpha,25-(OH)(2)D-3, both epimers of 9-methylene-10,19-dihydro-1 alpha,25-(OH)(2)D-3 as well as the parent vitamin with the "reversed" triene system, 9-methylene-19-nor-1 alpha,25-(OH)(2)D-3, were obtained from the previtamin D precursors, constructed by either Suzuki Miyaura, Sonogashira, or Stile couplings of the corresponding A- and C,D-ring fragments. An alternative synthetic path, leading to the latter vitamin and its homologue with 9-ethylidene group, involved formation of dienynes as precursors of the respective 19-norprevitamin D compounds. 9 beta-Methyl-19-nor-1 alpha,25-(OH)(2)D-3 was prepared by homogeneous hydrogenation with Wilkinson catalyst, and this analogue was found to be the most active in vitro. Moreover, 9 alpha-methyl-1 alpha,25-(OH)(2)D-3 and 9-methylene-19-nor-1 alpha,25-(OH)(2)D-3 showed some in vitro activity, however, the in vivo assays indicated only weak calcemic potency of these compounds in the intestinal calcium transport.