Technetium-labeled estradiol derivative and reference compound thereof, and preparation method, application and intermediate thereof

A compound, the technology of estradiol, which is applied in the field of technetium-labeled estradiol derivatives and their reference compounds, can solve the problems of poor imaging effect, poor target tissue selectivity, and high lipophilicity

Inactive Publication Date: 2013-03-20
SHANGHAI INST OF APPLIED PHYSICS - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem to be solved by the present invention is to overcome the disadvantages of existing estradiol-like technetium complexes, such as too high lipophilicity or rapid metabolism in the body, resulting in poor selectivity to target tissues and poor final imaging effect, etc., providing A compound shown in formula VII and compound shown in formula VIII and their preparation method, application and intermediates thereof

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  • Technetium-labeled estradiol derivative and reference compound thereof, and preparation method, application and intermediate thereof
  • Technetium-labeled estradiol derivative and reference compound thereof, and preparation method, application and intermediate thereof
  • Technetium-labeled estradiol derivative and reference compound thereof, and preparation method, application and intermediate thereof

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Experimental program
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preparation example Construction

[0090] (1) The specific steps of the preparation method are as follows: after dissolving 5g (18.7mmol) of estrone in 25ml of methylene chloride, add 0.8g (3.2mmol) of pyridinium p-toluenesulfonate under magnetic stirring, and then add 4.8ml ( 46.6mmol) of 3,4-dihydropyran was reacted at 22°C for 20 hours. After the reaction, an appropriate amount of distilled water was added and extracted with dichloromethane (3×20ml). The organic phase was respectively washed with saturated sodium bicarbonate solution, water and saturated brine, and then dried with anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, several white solids were obtained with a yield of 99% and a melting point m.p. of 137.1-139.2°C.

[0091] The identification data of Compound I are as follows:

[0092] IR(KBr): v(=C-H)3019, v(C-H)2978, v(C=O)1736cm -1 .

[0093] 1 HNMR (CDCl 3 ): δ0.90(s, 3H, 18-CH 3 ), 1.41~1.71(m, 9H), 1.82~1.85(m, 2H), 1.94~2.07(m, 4H), 2.09~2.17(m, 1H), 2.23~...

Embodiment 3

[0104] Example 3 Compound III a～d Synthesis

[0105]

[0106] (1) Compound III a : 16α-butyl bromide-16β-methoxycarbonyl-3-(tetrahydropyran-2-methyleneoxy)estrogen-1,3,5(10)-trien-17-one synthesis

[0107] Among them, A is the group -(CH 2 CH 2 ) x -, x is 2; R is bromine.

[0108] The specific steps of the preparation method are as follows: Dissolve 0.5g (1.22mmol) of compound II in 10mL of dichloromethane, then add 0.1g of benzyltriethylammonium chloride, 1.05g of 1,4-dibromobutane and 5ml of 10% NaOH solution (w / v), react under reflux conditions for 16h, spin off the solvent under reduced pressure, add water, extract with ethyl acetate, wash the organic phase with water and saturated brine once, dry over anhydrous sodium sulfate, filter, evaporate under reduced pressure After removing the solvent, flash column chromatography (eluent: petroleum ether / ethyl acetate volume ratio: 20:1) gave a colorless oily liquid with a yield of 79%.

[0109] Compound III a The id...

Embodiment 4

[0132] Example 4 Compound IV a～d Synthesis

[0133]

[0134] (1) Compound IV a : Synthesis of 16α-butyl bromide-16β-hydroxymethyl-3-(tetrahydropyran-2-methyleneoxy)estrogen-1,3,5(10)-triene-17β-ol

[0135] Among them, A is the group -(CH 2 CH 2 ) x -, x is 2; R is bromine.

[0136] The specific steps of the preparation method are as follows: under nitrogen protection conditions, 0.93g (1.7mmol) of compound III a Dissolve in a mixed solvent of 10ml diethyl ether, 3ml dichloromethane and 5ml tetrahydrofuran, add 74mg (3.4mmol) lithium borohydride under ice-water bath cooling condition, first react at 0°C for 3 hours, then react at room temperature for 18 hours , then add 4ml of water, evaporate most of the solvent under reduced pressure, add water, extract with ethyl acetate, wash the organic phase with water and saturated brine once, dry over anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure, and obtain some white Solid, yield 95%, melting...

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Abstract

The invention discloses a technetium-labeled estradiol derivative and a reference compound thereof, and a preparation method, an application and an intermediate thereof. The technetium-labeled estradiol derivative is shown in the formula VII, wherein A is a group -(CH2CH2)x- or -(CH2CH2O)m(CH2CH2)n-; and x, m and n are integral numbers, x is 1-6, m is 1-3, and n is 1-3. The technetium-labeled estradiol derivative has a moderate lipid / water partition coefficient, and can be used for preparing imaging drugs for diagnosing breast cancer. The in-vitro experiment indicates that the technetium-labeled estradiol derivative has favorable affinity with an estrogen receptor, and has favorable in-vitro stability and moderate metabolism speed in phosphate buffer solution (PBS), 1mM histidine solution, 1mM cysteine solution, 1mM diethylene triamine pentacetic acid (DTPA) solution and newborn calf serum. The technetium-labeled estradiol derivative is hopeful to become a radioactive drug which has good targeting property, is suitable for continuing deep research in organisms and is used for diagnostic imaging.

Description

technical field [0001] The invention relates to a technetium-labeled estradiol derivative and its reference compound, its preparation method, application and its intermediate. Background technique [0002] Nuclear medicine can use the special physical properties of labeled nuclides in certain radiopharmaceuticals to image a variety of tumors and their lesions. This unique method of tumor diagnosis has been paid more and more attention in clinic. Currently, radionuclides used for imaging mainly include 131 I. 153 Sm, 117 mSn, 186 Re, 188 Re and 99m Tc et al. in, 99m Tc has attracted much attention in the field of tumor diagnosis because of its excellent physical and chemical properties. 99m The half-life of Tc is 6.02 hours, the energy of gamma rays is 140keV, the radiation damage is small, and it has good imaging resolution, and it can be easily obtained from 99 Mo- 99m Tc generator rinses to get Na 99m TCO 4 solution. Because of its cheap and easy to obtain, l...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J43/00C07J1/00C07J17/00A61K51/04A61K103/10
Inventor 沈玉梅黄立梁朱华
Owner SHANGHAI INST OF APPLIED PHYSICS - CHINESE ACAD OF SCI
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