Synthesis of 1.alpha.-hydroxy vitamin D

Details Synthesis of 1.alpha.-hydroxy vitamin D Synthesis of 1.alpha.-hydroxy vitamin D

1997-04-17

1999-02-09

Lambkin, Deborah C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

9,10-seco- cyclopentanohydrophenanthrene ring system doai

552653, A61K 3159, C07C40100

Patent

active

058694722

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/US94/08002 filed Jul. 18, 1994.


TECHNICAL FIELD

This invention relates generally to vitamin D compounds and their hydroxylated derivatives. More specifically, the invention relates to a novel synthesis of 1.alpha.-hydroxy vitamin D.
BACKGROUND OF THE INVENTION
The vitamins D are a group of compounds that are steroid derivatives and are known to be important in the regulation of calcium and phosphate metabolism in animals and man, and in the regulation of bone formation. See, Harrison's Principles of Internal Medicine: Part Eleven, "Disorders of Bone and Mineral Metabolism, Chapter 335," E. Braunwald et al., (eds.), McGraw-Hill, New York (1987) pp. 1860-1865.
The naturally occurring form of vitamin D in animals and man is vitamin D.sub.3. Vitamin D.sub.3 is synthesized endogenously in the skin of animals and man. The biological functions of vitamin D require metabolism to hydroxylated metabolites that are the biologically active agents. In animals, including man, vitamin D.sub.3 is activated by being hydroxylated in the C.sub.25 position in the liver, followed by 1.alpha.-hydroxylation in the kidney to produce the hormone 1.alpha.,25-dihydroxy vitamin D.sub.3. See, U.S. Pat. No. 3,880,894 issued to DeLuca et al.
The 1.alpha.,25-dihydroxy vitamin D.sub.3 compound regulates calcium and phosphorus metabolism, bone formation, and subsequent vitamin D.sub.3 activation, by binding to specific cytoplasmic receptor proteins located throughout the body. This binding requires the presence of the 1.alpha.-hydroxy group. Hormonally active vitamin D.sub.3 bound to intestinal receptors stimulates calcium and phosphate transport from the intestinal lumen into the systemic circulation. Activated vitamin D.sub.3 bound to receptors in the parathyroid glands, the kidney, the osteoblasts, and other target tissues, elicits cellular responses which synergistically stabilize the levels of calcium and phosphorus in the blood, control the formation and removal of bone, and regulate further production of 1.alpha.,25-dihydroxy vitamin D.sub.3. Vitamin D.sub.3 has also been reported to play a role in cell proliferation and differentiation. See, U.S. Pat. No. 4,800,198 issued to DeLuca et al. It has been suggested that these compounds might be useful in the treatment of diseases characterized by abnormal cell proliferation and/or cell differentiation, such as leukemia, myelofibrosis and psoriasis.
Vitamin D.sub.2 is the major naturally occurring form of vitamin D in plants. Vitamin D.sub.2 differs structurally from vitamin D.sub.3 by having a methyl group at C.sub.24 and a double bond between C.sub.22 and C.sub.23. Various vitamin D.sub.2 analogues, however, elicit strong physiological responses in animals and human beings, and are valuable substitutes for vitamin D.sub.3 compounds.
Considerable interest has focused on the discovery and synthesis of various hydroxylated and dihydroxylated derivatives of vitamins D. As is generally understood and used herein, the term "vitamin D" is intended to include vitamins D.sub.3, D.sub.2, and D.sub.4. Examples of hydroxylated and dihydroxylated metabolites of vitamins D.sub.3 and D.sub.2 which have been found to occur naturally and/or have been synthesized include 25-hydroxy vitamin D.sub.2, 24, 25-dihydroxy vitamin D.sub.3, 25, 26-dihydroxy vitamin D.sub.3, 1.alpha.-hydroxy vitamin D.sub.2, 23, 25-dihydroxy vitamin D.sub.3, all of which have been found to exhibit vitamin D-like biological activity in vivo.
Unfortunately, while many of these active vitamin D metabolites held great promise as therapeutic agents, this promise has never been fully realized because of the extreme toxicity of these agents due to the well known potent effects of the compounds on calcium metabolism, giving rise to hypercalcemia in high doses. It has been reported, for example, that 1.alpha.-hydroxy vitamin D.sub.3 at a daily dose of 2 .mu.g/day (which has been shown in some studies to be effective in preventing loss of bone) causes toxicity in approximately 67 percent of patients. Rec

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