26-Desmethyl-2-methylene-22-ene-19-nor-1α,25-dihydroxyvitamin D3 compounds selectively active on intestine

Abstract

Six new analogs of 2-methylene-19-nor-1α,25-dihydroxyvitamin D3, 6–7 and 8a,b–9a,b, have been synthesized. All compounds are characterized by a trans double bond located in the side chain between C-22 and C-23. While compounds 6 and 7 possess C-26 and C-27 methyls, compounds 8a,b and 9a,b lack one of these groups. A Lythgoe-based synthesis, employing the Wittig–Horner reaction was used for these preparations. Two different types of Δ22E-25-hydroxy Grundmann’s ketone, having either only one stereogenic center located at position C-20 (20 and 21), or two stereogenic centers located at 20- and 25-positions (24a,b–25a,b) were obtained by a multi-step procedure from commercial vitamin D2. The introduction of a double bond at C-22 appeared to lower biological activity in vitro and in vivo. Further removal of a 26-methyl in these analogs had little effect on receptor binding, HL-60 differentiation and CYP24A expression but markedly diminished or eliminated in vivo activity on bone calcium mobilization while retaining activity on intestinal calcium transport.