20-alkyl, gemini vitamin D3 compounds and methods of use thereof

A technology of compounds and vitamins, applied in organic chemistry, drug combinations, pharmaceutical formulations, etc.

Inactive Publication Date: 2008-06-11
BIOXELL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Furthermore, despite many efforts in developing synthetic analogs, the clinical use of vitamin D and its structural analogs has been limited by undesired side effects for known indications / applications of vitamin D compounds in After administration to patients, caused by these compounds

Method used

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  • 20-alkyl, gemini vitamin D3 compounds and methods of use thereof
  • 20-alkyl, gemini vitamin D3 compounds and methods of use thereof
  • 20-alkyl, gemini vitamin D3 compounds and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0487] Synthesis of 1,25-dihydroxy-20-(4-hydroxy-4-methyl-pentyl) cholecalciferol (1)

[0488]

[0489] (1R, 3aR, 4S, 7aR)-4-(tert-butyl-dimethyl-silyloxy)-7a-methyl-1-(5-methyl-1-methylene-5-trimethyl silyloxy-hexyl)-octahydro-indene (41)

[0490] A 50 mL round bottom flask equipped with a stir bar and a Claisen adapter with a rubber gasket was charged with 1.78 g (4.510 mmol) of 6-[(1R,3aR,4S,7aR)-4-(tert-butyl-di Methyl-silanyloxy)-7a-methyl-octahydro-inden-1-yl]-2-methyl-hept-6-en-2-ol (40) and 15 mL of dichloromethane. 1.98 mL (13.53 mmol) of 1-(trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for 2 hours. 15 ml of water were added, and the mixture was stirred for 10 minutes. 100 ml of water was added to dissolve the resulting mixture. The aqueous layer was extracted three times with 50 mL of dichloromethane. The combined organic layers were washed with 30 mL brine, washed with Na 2 SO 4 Dry and evaporate. In the column ...

Embodiment 2

[0539] Synthesis of 1,25-dihydroxy-20-(4-hydroxy-4-methyl-pentyl)-19-nor-cholecalciferol (2)

[0540]

[0541] 1,25-Dihydroxy-20-(4-hydroxy-4-methyl-pentyl)-19-nor-cholecalciferol (2)

[0542] A 25 mL round bottom flask equipped with a stir bar and a Claisen adapter with a rubber gasket was charged with 1.023 g (1.792 mmol) of (1R,3R)-1,3-di-((tert-butyldimethyl) Silyloxy)-5-[2-(diphenylphosphoryl)ethylidene]-cyclohexane (53) and 5 ml tetrahydrofuran. The reaction mixture was cooled to -70°C, and 1.12 mL (1.792 mmol) of 1.6M n-butyllithium BuLi was added dropwise. The resulting dark red solution was stirred at -78°C for 25 minutes, and 350 mg (0.667 mmol) (1R, 3aR, 4S, 7aR)-1-[1,5-dimethyl-1-(4-methanol) was added dropwise A solution of 4-trimethylsilyloxy-pentyl)-5-trimethylsilyloxy-hexyl]-7a-methyl-octahydro-inden-4-one (51) in 1 ml of tetrahydrofuran . The reaction mixture was stirred for 5 hours after which time the dry ice was removed from the bath and the solution...

Embodiment 3

[0550] Synthesis of 1α-fluoro-25-hydroxy-20-(4-hydroxy-4-methyl-pentyl)-cholecalciferol (3)

[0551]

[0552] 1α-fluoro-25-hydroxy-20-(4-hydroxy-4-methyl-pentyl)-cholecalciferol (3)

[0553] A 25 mL round bottom flask equipped with a stir bar and a Claisen adapter with a rubber gasket was charged with 680 mg (1.445 mmol) of (1S,5R)-1-((tert-butyldimethyl)silyloxy )-3-[2-(diphenylphosphoryl)-e-(Z)-ylidene]-5-fluoro-2-methylene-cyclohexane (54) and 5 ml THF. The reaction mixture was cooled to -70°C, and 0.9 mL (1.44 mmol) of 1.6M n-butyllithium was added dropwise. The resulting dark red solution was stirred at -78°C for 25 minutes, and 300 mg (0.571 mmol (1R, 3aR, 4S, 7aR)-1-[1,5-dimethyl-1-(4-methyl -4-Trimethylsilyloxy-pentyl)-5-trimethylsilyloxy-hexyl]-7a-methyl-octahydro-inden-4-one (51) in 1 ml THF. The reaction mixture was stirred for 4 hours, then the dry ice was removed from the liquid tank, and the solution was warmed to -40°C over 1 hour. The mixture was poured i...

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Abstract

The invention provides for methods of using 20-methyl Gemini vitamin D3 compounds to treat osteoporosis and secondary hyperparathyroidism.

Description

[0001] related application [0002] This application claims U.S. Provisional Patent Application Serial No. 60 / 664,397 filed March 23, 2005 (Attorney Docket No. 49949-63097P1) and U.S. Provisional Patent Application Serial No. 60 / 664,367 filed March 23, 2005 Interest in Provisional Patent Application (Attorney Docket No. 49949-63097P2). The application relates to International Patent Application No. PCT / US2006 / XXXXXX (Organization Docket No. 49949-63097PCT(B), Express Mail Label No. EV756031935US) filed on March 23, 2006. The disclosures of all three of the aforementioned patent applications are incorporated herein by reference. Background of the invention [0003] Since Mellanby discovered vitamin D in 1920 (vitamin D 3 ), people have recognized its importance in the biological systems of higher animals (Mellanby, E. (1921) Spec. Rep. Ser. Med. Res. Council (GB) SRS 61: 4). During the period 1920-1930, vitamin D was formally classified as: the "vitamin" indispensable for th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/593C07C401/00
CPCA61K31/593A61P19/10A61P5/20
Inventor P·扬科夫斯基M·R·乌斯科科维克L·阿多里尼
Owner BIOXELL
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