2alpha-Methyl and 2beta-Methyl Analogs of 19,26-Dinor-1alpha,25-Dihydroxyvitamin D3 and Their Uses

This invention discloses 2.alpha.-methyl and 2.beta.-methyl analogs of 19,26-dinor-1.alpha.,25-dihydroxyvitamin D.sub.3 and pharmaceutical uses therefor. These compounds exhibit in vitro biological activities evidencing use as an anti-cancer agent and for the treatment of skin diseases such as psoriasis as well as skin conditions such as wrinkles, slack skin, dry skin and insufficient sebum secretion. These compounds have little, if any, in vivo calcemic activity and therefore may be used to treat autoimmune disorders in humans as well as secondary hyperparathyroidism and renal osteodystrophy

2-methylene-19,26-dinor-(20S,22E,25R)-vitamin D analogs

This invention discloses 2-methylene-19,26-dinor-(20S,22E,25R)-vitamin D analogs, and specifically 2-methylene-19,26-dinor-(20S,22E,25R)-1.alpha.,25-dihydroxyvitamin D.sub.3, and pharmaceutical uses therefor. This compound exhibits transcription activity as well as pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as an anti-cancer agent and for the treatment of skin diseases such as psoriasis as well as skin conditions such as wrinkles, slack skin, dry skin and insufficient sebum secretion. This compound also shows no activity in vivo on bone calcium mobilization and relatively low intestinal calcium transport activity compared to the native hormone 1.alpha.,25-dihydroxyvitamin D.sub.3, and therefore may be used to treat autoimmune disorders or inflammatory diseases in humans as well as renal osteodystrophy. This compound may also be used for the treatment or prevention of obesity

A 20<i>S</i> Combined with a 22<i>R</i> Configuration Markedly Increases both in Vivo and in Vitro Biological Activity of 1α,25-Dihydroxy-22-methyl-2-methylene-19-norvitamin D₃

Six new analogues of 1α,25-dihydroxy-19-norvitamin D₃ (<b>3a</b>–<b>4b</b>, <b>5</b>, and <b>6</b>) were prepared by a convergent synthesis applying the Wittig–Horner reaction as a key step. The influence of methyl groups at C-22 on their biological activity was examined. It was established that both in vitro and in vivo activity is strongly dependent on the configuration of the stereogenic centers at C-20 and C-22. Introduction of the second methyl group at C-22 (analogues <b>5</b> and <b>6</b>) generates the compounds that are slightly more potent than 1α,25-(OH)₂D₃ in the in vitro tests but much less potent in vivo. The greatest in vitro and in vivo biological activity was achieved when the C-20 is in the <i>S</i> configuration and the C-22 is in the <i>R</i> configuration. The building blocks for the synthesis, the respective (20<i>R</i>,22<i>R</i>)-, (20<i>R</i>,22<i>S</i>)-, (20<i>S</i>,22<i>R</i>)-, and (20<i>S</i>,22<i>S</i>)-diols, were obtained by fractional crystallization of mixtures of the corresponding diastereomers. Structures and absolute configurations of the diols <b>21a</b>, <b>21b</b>, and <b>22a</b> as well as analogues <b>3a</b>, <b>5</b>, and <b>6</b> were confirmed by the X-ray crystallography