Method for making hydroxy-25-ene-vitamin D compounds

A technology for vitamins and compounds, applied in the field of preparing hydroxy-25-ene-vitamin D compounds and vitamin D compounds

Inactive Publication Date: 2001-07-11
BONE CARE INT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] Considering the multiple biological activities of vitamin D and its potential as a therapeutic drug, compounds with greater specificity and selectivity, i.e., anti-cell proliferation...

Method used

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  • Method for making hydroxy-25-ene-vitamin D compounds
  • Method for making hydroxy-25-ene-vitamin D compounds
  • Method for making hydroxy-25-ene-vitamin D compounds

Examples

Experimental program
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Embodiment 1

[0075] 1 H-NMR spectra were recorded by Varian VXR-300. Chemical shifts δ (ppm) are marked with reference to TMS. For HPLC analysis, a platinum EPS C18 150×4.6mm column was used, and the mobile phase was CH 3CN-0.1% COOH 70:30, detection wavelength 265nm, flow rate 1ml / min, temperature 22°C. Melting points were determined on a Mettler FP-2 melting point apparatus equipped with a Mettler FP21 microscope. Example 1: Synthesis of 1α-hydroxyl-25-ene-vitamin D Preparation of R-(2,3-dimethyl-3-buten-1-yl) phenyl sulfone (10)

[0076] To a solution of 110ml of diisopropylamine in 750ml of tetrahydrofuran (THF), 315ml of 2.5N n-butyllithium (n-BuLi) was added, and the reaction temperature was between -25°C and -10°C. The mixture was cooled to -70°C, then 150 ml of HMPA was added dropwise, and the reaction mixture was stirred for an additional hour at this temperature. After the solution of 100 g of ethyl dimethacrylate (2) in 100 ml of THF was added dropwise, the reaction mixture...

Embodiment 2

[0094] To a solution of 320 mg (22) in THF was added 400 mg TBAF. The mixture was stirred overnight at room temperature, reacted at 55 °C for 3 hr and poured into saturated NaHCO 3 in solution. The mixture was extracted with EtOAc (2x50ml), the organic phase was washed with brine, dried and the solvent was evaporated. Column chromatography (silica gel, (EtOAc-hexane 2:1)) separated to give a white solid, which was dissolved in 40ml of toluene, after adding 6 drops of NEt 3 And 5mg 9-acetyl anthracene post-irradiation for 1.5hr. Chromatography (silica gel, (EtOAc-hexane 2:1)) after evaporation of the solvent afforded 65 mg (31%) of 1α-hydroxy-25-ene-vitamin D2(1) with a purity of 96.7% (HPLC). UV:λ max 265nm. Example 2: 24-Hydroxy-25-ene-Vitamin D 2 synthesis

[0095]Except that the hydroxylation step at the C-1 position is omitted and no protecting group is added at the C-1 position, 24-hydroxy-25-ene-vitamin D 2 The synthesis of is identical with the step of embodimen...

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Abstract

The present invention provides a method for preparing a novel class of vitamin D compounds in which the C-25 or equivalent position has a double bond. In addition, the side chain is optionally extended by one or two methylene or methyne groups. The compounds prepared by the method of the present invention are of value as prodrugs for active 1 alpha , 24-dihydroxylated vitamin D compounds.

Description

[0001] Cross References to Related Patent Applications [0002] This application claims priority under 35 U.S.C. §119 to U.S. Provisional Patent Application No. 60 / 087,222, filed May 29, 1998. Background of the invention [0003] In general, the present invention relates to vitamin D compounds. More specifically, the present invention relates to vitamin D compounds with double bonds at C-25 or equivalent positions and methods for preparing these compounds. [0004] The important biological role of vitamin D in bone and mineral metabolism has long been known. For example, vitamin D plays a vital role in promoting calcium absorption and regulating calcium metabolism. Meanwhile, it is well known that not vitamin D itself but its metabolites in the body play a role in regulating calcium metabolism. The active form of vitamin D (M.F.Holick et al., 68 Proc.Natl.Acad.Sci.USA, 803-804 (1971); G.Jones et al., 14Biochemistry, 1250-1256 (1975)) and...

Claims

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Application Information

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IPC IPC(8): C07C401/00A61K31/59C07CC07C403/00
CPCC07C67/333C07C401/00C07C29/147C07C303/28C12P7/22C07C315/00C07C67/343C07C33/025C07C69/533C07C317/14C07C309/66
Inventor 汉斯·维因伯格托恩·弗里斯齐斯·鲍沃尔
Owner BONE CARE INT
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