Fulvestrant phosphate derivative and preparation method and application thereof

A technology of fulvestrant phosphate and fulvestrant, which is applied in the direction of drug combinations, pharmaceutical formulas, steroids, etc., can solve the problems of poor stability of fulvestrant raw materials, achieve simple and fast purification methods, and synthesize Convenience and clear structural features

Inactive Publication Date: 2013-12-04
OCEAN UNIV OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The invention provides a fulvestrant phosphate derivative and its preparation method, stability test method, in vitro metabolism test method and application, which can s

Method used

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  • Fulvestrant phosphate derivative and preparation method and application thereof
  • Fulvestrant phosphate derivative and preparation method and application thereof
  • Fulvestrant phosphate derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] A fulvestrant cyclophosphate derivative of the following general formula was prepared:

[0023]

[0024] 1. Preparation of 3-O-[4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphacyclohexyl]fulvestrant (F01)

[0025] Add fulvestrant (0.2g, 0.33mmol) to a 50ml two-necked bottle, dissolve with anhydrous tetrahydrofuran (10ml), under nitrogen protection, add a solution of N,N-lithium diisopropylamine in tetrahydrofuran (0.34ml, 0.68 mmol), the reaction was stirred at room temperature for 2.5 h, and 4-(3-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-dioxaphosphine was added alkane (0.38 g, 1.0 mmol), and the reaction was stirred for 48 h under nitrogen protection. Adjust the pH to 6-7 with 1M dilute hydrochloric acid, concentrate to remove tetrahydrofuran, add dichloromethane (20ml) to dissolve, wash three times with distilled water and saturated brine successively, and perform silica gel column chromatography (petroleum ether:ethyl acetate=1:3) It was purified and concentrated...

Embodiment 2

[0062] The fulvestrant diethyl phosphate derivatives shown below were prepared.

[0063]

[0064] Add fulvestrant (0.5g, 0.8mmol) to a 100ml three-necked flask, fill with nitrogen protection, add dried dichloromethane (40ml), magnetically stir to dissolve it completely, cool with an ice-salt bath to maintain the temperature of the system At -10°C, phosphorus oxychloride (0.15ml, 1.6mmol) was added dropwise to the reaction system with a syringe, the ice bath was removed after 1 hour, the temperature was raised to 20°C, absolute ethanol (0.5ml, 8mmol) was added, and the reaction was stirred. After 2 hours, after TLC detected the reaction, the solvent was evaporated under reduced pressure, dissolved in dichloromethane, washed with water, dried with anhydrous magnesium sulfate, and subjected to silica gel column chromatography to obtain 0.2 g of the target compound with a yield of 33%.

[0065] 1 H-NMR (CDCl 3 , 500MHz, characteristic hydrogen) δ7.22 (d, J=8.5Hz, 1H), 6.95 (d...

Embodiment 3

[0067] In vitro stability test of fulvestrant cyclophosphate derivatives of the present invention

[0068] The inventors have proved that the fulvestrant cyclic phosphate derivative of the present invention has better stability than the original drug through stability experiments at different temperatures and different times.

[0069] The stability test method of compound F01 of the present invention, F04, F07 and original drug Fulvestrant is as follows:

[0070] The target compound and fulvestrant were stored at -20°C, 0°C, 20°C, and 40°C for 1-4 days. After methanol was dissolved, the purity of the compound was detected by high performance liquid chromatography. The conditions are as follows:

[0071] Instrument model: Agilent1100 high performance liquid chromatograph

[0072] Mobile phase: 85% methanol: 15% water;

[0073] UV detection wavelength: 210nm

[0074] Injection volume: 10μL

[0075] The experimental results are as figure 1 As shown, the results show that th...

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Abstract

The invention discloses a fulvestrant phosphate derivative and a preparation method and application thereof, and aims to solve the problem in the prior that the fulvestrant drug substance is poor in ordinary temperature stability. The fulvestrant phosphate derivative can be used for preparing medicines capable of preventing and treating breast cancers, and is a compound with a novel structure and fulvestrant mother ring 3-phenolic hydroxyl is carried out phosphate. According to a method for fulvestrant phosphate phosphate, the material is easy to obtain, the synthesis method is simple, and the purification manner is simple, convenient and fast. Moreover, the derivative provided by the invention is higher in stability compared with an original drug; under the catalysis of the cytochrome P 450 enzyme CYP3A4 and alkaline phosphatase, the original drug can be released, so that the kind of compound has a broad application prospect in preparing the medicines capable of preventing and treating breast cancers. The derivative has the structural formula as shown in the description.

Description

technical field [0001] The present invention relates to a class of fulvestrant phosphate derivatives with good normal temperature stability and a preparation method thereof, a normal temperature stability test method, an in vitro metabolism test method and applications. Background technique [0002] Phosphate groups, as endogenous substances in the human body, exist in large amounts in nucleic acids, and can be used as carrier molecules to improve the water solubility and transmembrane transport capacity of drugs. Phosphate prodrugs obtained by combining phosphate groups with the original drug through chemical synthesis have It has the advantages of improving drug selectivity, reducing toxic and side effects, masking drug unpleasant odor, enhancing drug stability and improving bioavailability. After the prodrug enters the body, it is oxidized and eliminated by cytochrome P450 (CYP) in the liver cells, and then is hydrolyzed by phospholipase to release the original drug to ex...

Claims

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Application Information

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IPC IPC(8): C07J1/00A61K31/661A61P35/00
Inventor 江涛赵九洋
Owner OCEAN UNIV OF CHINA
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