Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Patent
1996-06-28
2000-01-25
Barts, Samuel
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
552653, A61K 3159
Patent
active
060179074
DESCRIPTION:
BRIEF SUMMARY
This invention describes a hitherto unknown and therefore new class of compounds which are analogues of 1.alpha.,25-(OH).sub.2 D.sub.3 and show selective activity on cell functions.
GENERAL INTRODUCTION
Vitamin D of either nutritional (vitamin D.sub.2 or D.sub.3) origin or produced in the skin under the influence of ultraviolet light is metabolized in several tissues to produce firstly 25-hydroxyvitamin D.sub.3 [25-OHD.sub.3 ] and later 1.alpha.,25-dihydroxyvitamin D.sub.3 [1.alpha.,25-(OH).sub.2 D.sub.3 ] and numerous other vitamin D metabolites (1-6). Several hydroxylases present in different tissues (e.g. liver, kidney, placenta, keratinocytes, fibroblasts, monocytes, lymphocytes, bone cells . . . ) are responsible for both the activating and inactivating pathways of the parent vitamin D molecules. 1.alpha.,25-(OH).sub.2 D.sub.3 behaves as a classical steroid hormone as its synthesis is feedback controlled by several hormones, ions and humoral factors to maintain a normal body homeostasis of plasma and bone minerals. Moreover the vitamin D hormone(s) act via binding and activation of specific vitamin D receptors, present in most tissues and cells. The steroid-receptor complex then functions as a transactivating factor by binding to specific DNA sequences known as vitamin D responsive elements so that transcription of numerous genes is either activated or inactivated (7,8). This gene (in)activation occurs in collaboration with other nuclear accessory factor(s) of which the vitamin A receptor (RXR) is part of (9,10). Moreover there is some evidence for the activity of vitamin D, its metabolites and analogues to act via nongenomic mechanisms, either by activating calcium channels or other membrane or second messenger signals (11-13). Vitamin D, its metabolites and analogues have potent effects on calcium and phosphate metabolism, and therefore they can be used for prevention and therapy of vitamin D deficiency and other disorders of plasma and bone mineral homeostasis (e.g. osteomalacia, osteoporosis, renal osteodystrophy, disorders of the parathyroid function). Moreover vitamin D receptors are found in numerous tissues and cells that do not belong to the target tissues responsible for the just mentioned calcium homeostasis. Such cells include most cells belonging to the endocrine system and vitamin D, its metabolites and analogues are capable of influencing the hormonal secretion of these glands or tissues (e.g. insulin, parathyroid, calcitonin, pituitary hormones). Vitamin D receptors and vitamin D activity have also been documented in calcium transporting tissues other than the intestine and bone (e.g. placenta and mammary glands). In addition vitamin D receptors and vitamin D action have been observed in most other cells (e.g. cells belonging to the immune system, skin cells). These cells or tissues can be of a benign, adenomatous or of a malignant type. These so-called non-calcemic effects of vitamin D, its metabolites and analogues create the possibility to use such compounds for various therapeutic applications such as modification of the immune system, modification of hormone secretion, altering calcium transport in several tissues, modification of intracellular calcium concentration, induction of cell differentiation or inhibition of cell proliferation (14,15). In particular such compounds may be useful in the therapy of disorders characterized by increased cell proliferation (e.g. psoriasis, cancer) (16-18).
To increase the therapeutic potential of the natural vitamin D hormone(s), analogues can be synthesized with increased potency for a specific action and reduction of another type of action. For example to obtain an anti-psoriasis drug analogues can be synthesized with an increased activity on keratinocytes and lymphocytes present in the affected skin areas but with decreased effects on serum, urinary or bone calcium (19-23). Similarly analogues can have an increased potency to inhibit proliferation of cancer cells (e.g. leukemia or breast cancer cells) and/or increase the differentiation o
REFERENCES:
patent: 5486636 (1996-01-01), DeLuca et al.
patent: 5581006 (1996-12-01), DeLuca et al.
patent: 5583125 (1996-12-01), Steinmeyer et al.
patent: 5587497 (1996-12-01), DeLuca et al.
patent: 5597932 (1997-01-01), DeLuca et al.
patent: 5599958 (1997-02-01), DeLuca et al.
Olah et al., "13C NMR Spectroscopic Study of Potential tris-and bishomocyclopropenyl cations" Journal of the American Chemical Society, vol. 101, No. 14, Jul. 4, 1979, Washington, D.C., pp. 3935-3939.
Rees et al., "Cyclopropane Ring Opening of Bicyclo[3.1.0]hexan-3-ols in Fluorosulphuric Acid" Journal of the Chemical Society, Perkin Transactions 2, No. 6, Jun. 1981, Letchworth GB, pp. 948-952.
Okamura et al., "Synthesis and Biological Activity of 9,11-dehydrovitamin D3 Analogues: Stereoselective Preparation of 6 beta-vitamin D Vinylallenes and a Concise Enynol Synthesis for preparing the A-ring," The Journal of Organic Chemistry, vol. 54, No. 17, Aug. 18, 1989, Washington, pp. 4072-4083.
Perlman et al., "1-alpha-Hydroxy-19-nor-vitamin D C-22 aldehyde. A Valuable Intermediate in the Synthesis of Side Chain Modified 1 alpha,25-dihydroxy-19-nor-vitamin D3," Tetrahedron Letters, vol. 33, No. 21, May 19, 1992, Oxford, pp. 2937-2940.
Hanekamp et al., "25-Hydroxydihydrotachysterol2. An innovative Synthesis of a Key Metabolite of Dihydrotychysterol2," Tetrahedron, vol. 48, No. 42, Oct. 16, 1992, Oxford, pp. 9283-9294.
Trost et al., "New Strategies for the Synthesis of Vitamin D Metabolites via Pd-catalyzed Reactions," Journal of the American Chemical Society, vol. 114, No. 25, Dec. 2, 1992, Washington, pp. 9836-9845.
Bouillon Roger
de Clercq Pierre Jean
Vandewalle Maurits
Barts Samuel
Laboratoire Theramex S.A.
LandOfFree
Structural analogues of vitamin D does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Structural analogues of vitamin D, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Structural analogues of vitamin D will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2316050