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In a continuing effort to explore the 2-methylene-1α-hydroxy-19-norvitamin D3 class of pharmacologically important vitamin D compounds, two novel 2-methylene-19-nor-25-dehydro-1α-hydroxyvitamin D3-26,23-lactones, GC-3 and HLV, were synthesized and biologically tested. Based on reports of similarly structured molecules, it was hypothesized that these compounds might act as antagonists, at least in vitro. The pathway designed to synthesize these compounds was based on two key steps: first, the Lythgoe-type Wittig–Horner coupling of Windaus–Grundmann-type ketone 18, with phosphine oxide 15, followed, later in the synthesis, by the Zn-mediated Reformasky-type allylation of aldehyde 20 with methylbromomethylacrylate 8. Our biological data show that neither compound has antagonistic activity but acts as weak agonists in vitro and in vivo.

Twelve new analogs of 19-nor-1α,25-dihydroxyvitamin D 3 (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16), were prepared by convergent syntheses, employing the Wittig-Horner reaction. The necessary Grundmann-type ketones (45, 46, 47 and 48), possessing fixed configurations of the hydroxyl group at C-25, were obtained by a multi-step procedure from commercial vitamin D 2 and enantiomers of 1,3-butanediol (23 and 24). We have examined the influence of removal of one of the methyl groups located at C-25 on the biological in vitro and in vivo activity. The in vivo tests showed that the synthesized vitamin D compounds (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16) exhibit reduced calcemic activity both in bone and in the intestine. But in vitro potency of 2-methylene and 2α-methyl compounds (5, 6, 7, 8, 9, 10, 13 and 14) remained similar or enhanced compared to that of 1α,25-(OH) 2 D 3 .

The 18-nor (7), 21-nor (8) and 18,21-dinor (9) analogs of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D3 (6, 2MD) were prepared by convergent syntheses. The known phosphine oxide 10 was coupled by the Wittig–Horner process with the corresponding C,D-fragments (13–15), obtained by a multi-step procedure from commercial vitamin D2. The goal of our studies was to examine the influence of removal of the methyl groups located at carbons 13 and 20 on the biological potency of 2MD in the hope of finding analogs with improved therapeutic profiles. Replacement of the 20-methyl with hydrogen in 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) did not affect binding to the rat vitamin D receptor and had little effect on transcription activity and on HL-60 differentiation. However, the mobilization of calcium from bone was largely eliminated while intestinal calcium transport remained strong. Curiously, removal of both the C-13-methyl and 20-methyl restored slightly the bone calcium mobilizing activity. Thus, the 21-nor analog of 2MD may provide a potent analog with a greater margin of safety than 2MD.

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