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20-cycloalkyl,26,27-alkyl/haloalkyl vitamin D3 compounds and methods of use thereof

A halogenated alkyl, compound technology, applied to 20-cycloalkyl

Inactive Publication Date: 2008-01-16
BIOXELL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Furthermore, despite enormous efforts to develop synthetic analogs, the clinical use of vitamin D and its structural analogs has been hampered by undesirable effects arising from the administration of these compounds to individuals for the indications and applications for which vitamin D compounds are known. Limitations of side effects

Method used

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  • 20-cycloalkyl,26,27-alkyl/haloalkyl vitamin D3 compounds and methods of use thereof
  • 20-cycloalkyl,26,27-alkyl/haloalkyl vitamin D3 compounds and methods of use thereof
  • 20-cycloalkyl,26,27-alkyl/haloalkyl vitamin D3 compounds and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0353] (3aR, 4S, 7aR)-7a-methyl-1-[1-(4-hydroxy-4-methyl-pent-2-ynyl)-cyclopropyl]-3a, 4, 5, 6, 7 , Synthesis of 7a-hexahydro-3H-inden-4-ol

[0354]

[0355] At -78°C, to (3aR, 4S, 7aR)-1-{l-[4-(tert-butyl-dimethyl-silyloxy)-7a-methyl-3a, 4, 5, 6 ,7,7a-Hexahydro-3H-inden-1-yl])-cyclopropyl}-ethynyl (1.0 g, 2.90 mmol) in tetrahydrofuran (15 mL) was added n-BuLi (2.72 mL , 4.35 mmol, 1.6 M in hexane). After stirring at -78°C for 1 h, acetone (2.5 mL, 34.6 mmol) was added and stirring continued for 2.5 h. Join NH 4 Cl 水溶液 (15 mL), and the mixture was stirred at room temperature for 15 min, then extracted with AcOEt (2 x 50 mL). The combined extracts were washed with brine (50 mL) and passed through Na 2 SO 4 dry. The residue (2.4 g) after evaporation of the solvent was purified by FC (50 g, 10% AcOEt in hexanes) to give (3aR,4S,7aR)-5-{l-[4-(tert-butyl-dimethyl yl-silyloxy)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-1-yl]-cyclopropyl}-2-methyl-penta-3 - Alkyn-2-ol (1...

Embodiment 2

[0359] (3aR, 4S, 7aR)-7a-methyl-l-[l-(4-hydroxy-4-methyl-pent-2Z-enyl)-cyclopropyl]-3a, 4, 5, 6, 7 , Synthesis of 7a-hexahydro-3H-inden-4-ol

[0360]

[0361] (3aR, 4S, 7aR)-7a-methyl-1-[1-(-4-hydroxy-4-methyl-pent-2-ynyl)-cyclopropyl]-3a, 4, 5,6,7,7a-hexahydro-3H-inden-4-ol (0.72g, 2.50mmol), ethyl acetate (10mL), hexane (24mL), absolute ethanol (0.9mL), quinoline ( 47μL) and Lindlar (Lindlar) catalyst (156mg, 5%Pd on CaCO 3 ) The mixture was hydrogenated for 2h. The reaction mixture was filtered through a celite pad, and the pad was washed with AcOEt. Combine the filtrate and washings, then wash with 1M HCl, NaHCO 3 and washed with brine. by Na 2 SO 4 After drying the solvent was evaporated and the residue (0.79g) was purified by FC (45g, 20% AcOEt in hexanes) to give the title compound (640mg, 2.2mmol, 88%).

Embodiment 3

[0363] (3aR, 4S, 7aR)-7a-methyl-1-[1-(4-hydroxy-4-methyl-pentyl)-cyclopropyl]-3a,4,5,6,7,7a-hexa Synthesis of Hydrogen-3H-Inden-4-ol

[0364]

[0365] Using a Paar instrument, at room temperature and 50 p.s.i. pressure, (3aR, 4S, 7aR)-7a-methyl-1-[1-(4-hydroxy-4-methyl-pent-2Z-enyl)- Cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-ol (100mg, 0.34mmol), 1,4-bis(diphenyl-phosphino)butane 1 , a mixture of 5-cyclooctadiene rhodium tetrafluoroborate (25 mg, 0.034 mmol), dichloromethane (5 mL) and 1 drop of mercury was hydrogenated for 3 h. The reaction mixture was filtered through a pad of celite, which was then washed with ethyl acetate. The combined filtrate and washings were evaporated to dryness (110 mg) and purified by FC (10 g, 20% AcOEt in hexanes) to give the title compound (75 mg, 0.26 mmol, 75%).

[0366] [α] 30 D =-8.5c 0.65, CHCl 3 . 1 HNMR (CDCl 3 ): 5.37(1H, m), 4.14(1H, m), 2.37-1.16(17H, m), 1.19(6H, s), 1.18(3H, s), 0.66-0.24(4H, m);

[0367] Calculated...

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Abstract

The invention provides vitamin D3 analogs of cholecalciferol, substituted at carbon-20 with cycloalkyl, e.g., cyclopropyl, wherein carbon-16 is a double bond, and carbon-23 is a single, double, or triple bond. Various alkyl or haloalkyl substitutions are incorporated at carbon-25. The invention provides pharmaceutically acceptable esters, salts, and prodrugs thereof. Methods for using the compounds to treat vitamin D3 associated states, and pharmaceutical compositions containing the compounds are also disclosed.

Description

[0001] related application [0002] This application claims priority to US Provisional Patent Application Serial No. 60 / 612,732, filed September 24, 2004, the disclosure of which is incorporated herein by reference in its entirety. Background of the invention [0003] Since Mellanby discovered vitamin D (cholecalciferol) in 1920 (Mellanby, E. (1921) Spec. Rep. Ser. Med. Res. Council (GB) SRS 61: 4), it has been found in the biological system of higher animals The importance of it is recognized. Vitamin D was officially classified as a "vitamin" in the 1920-1930's and is required for normal bone development and maintenance of calcium and phosphorus balance. [0004] involving vitamin D 3 The study of metabolism begins with the plasma metabolite 25-hydroxyvitamin D 3 [25(OH)D 3 ] (Blunt, J.W. et al. (1968) Biochemistry 6:3317-3322) and hormone-active 1α, 25(OH) 2 D. 3 (Myrtle, J.F. et al. (1970) J.Biol.Chem.245:1190-1196; Norman, A.W. et al. (1971) Science 173:51-54; Laws...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/351C07D309/04
CPCC07C401/00A61P1/04A61P1/16A61P11/00A61P13/10A61P13/12A61P15/06A61P17/00A61P17/06A61P19/02A61P19/08A61P19/10A61P21/00A61P21/04A61P25/00A61P25/16A61P25/28A61P27/02A61P29/00A61P3/02A61P3/12A61P31/18A61P31/22A61P35/00A61P37/00A61P37/06A61P43/00A61P5/14A61P5/16A61P7/06A61P9/00A61P9/10A61P9/12A61P3/10
Inventor M·R·乌斯科科维克L·阿多里尼G·彭纳E·科利S·马查克
Owner BIOXELL
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