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Tetrahydroxy furfuryl piperazine compound bonded with sigma-1 receptor and preparation method and application of compound

A compound, tetrahydroxyl technology, applied in the fields of radiopharmaceutical chemistry and nuclear medicine, can solve problems such as transportation restrictions and development constraints, and achieve the effects of high labeling rate, broad clinical application prospects, and high radiochemical purity.

Active Publication Date: 2016-12-14
BEIJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the half-life of the C-11 nuclide (T 1 / 2 =20min) is short, its transportation is limited, and it needs to use an online accelerator, which restricts its development; and 18 F due to its suitable half-life (T 1 / 2 =109min), easy to prepare, and can also be used for excellent properties such as PET noninvasive and quantitative analysis, so the research has suitable affinity and selectivity, and excellent metabolic properties in vivo 18 F marked σ 1 Receptor PET imaging agents have important clinical application prospects and practical significance

Method used

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  • Tetrahydroxy furfuryl piperazine compound bonded with sigma-1 receptor and preparation method and application of compound
  • Tetrahydroxy furfuryl piperazine compound bonded with sigma-1 receptor and preparation method and application of compound
  • Tetrahydroxy furfuryl piperazine compound bonded with sigma-1 receptor and preparation method and application of compound

Examples

Experimental program
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Embodiment 1

[0029] Example 1 Combining σ 1 Synthesis of Tetrahydroxyfurfurylpiperazines as Acceptors (R is F)

[0030] Tetrahydroxyfurfurylpiperazine (227mg, 1.33mmol), p-fluorobenzyl bromide (208mg, 1.10mmol), K 2 CO 3 (190mg, 1.37mmol), a catalytic amount (1-2mg) of KI was dissolved in CH 3 In CN (35mL), stir and reflux overnight at 80°C, filter and spin off acetonitrile, purify through a 200-300 mesh silica gel column, use methanol:dichloromethane=1:20 (volume ratio) as eluent, and obtain 203mg of light yellow liquid (Yield 66%). The structure of the product was detected by nuclear magnetic resonance analysis and high-resolution mass spectrometry, and the results are as follows: 1 H NMR (400MHz, CDCl 3 )δ7.33–7.20(m,2H),6.97(t,J=8.7Hz,2H),4.07–3.97(m,1H),3.90–3.81(m,1H),3.79–3.68(m,1H) ,3.45(s,2H),2.67–2.37(m,10H),2.03–1.91(m,1H),1.89–1.77(m,2H),1.52–1.41(m,1H). 13 C NMR (100MHz, CDCl 3 )δ161.94(d,J C-F =243Hz), 130.60, 114.90, 109.94, 77.17, 68.08, 63.31, 62.16, 53.70, 52.79,...

Embodiment 2

[0033] Example 2 Combining σ 1 Synthesis of tetrahydroxyfurfurylpiperazines as acceptors (R is -OCH 2 CH 2 F)

[0034] P-fluorooxyethylbenzyl bromide (260mg, 1.12mmol), tetrahydroxyfurfurylpiperazine (330mg, 1.34mmol) and K 2 CO 3 (231mg, 1.67mmol), a catalytic amount (1-2mg) of KI was dissolved in CH 3 In CN (35mL), stir and reflux overnight at 80°C, filter and spin off acetonitrile, purify through a 200-300 mesh silica gel column, use methanol:dichloromethane=1:20 (volume ratio) as eluent, and obtain 300mg of light yellow liquid (Yield 83%). The structure of the product was detected by nuclear magnetic resonance analysis and high-resolution mass spectrometry, and the results are as follows: 1 HNMR (400MHz, CDCl 3 )δ7.17(d, J=8.5Hz, 2H), 6.79(d, J=8.5Hz, 2H), 4.67(dt, J=47.5, 4.1Hz, 2H), 4.11(dt, J=28.0, 4.1 Hz,2H),4.04–3.95(m,1H),3.83–3.74(m,1H),3.70–3.61(m,1H),3.43(s,2H),2.73–2.27(m,10H),1.98– 1.85(m,1H),1.83–1.72(m,2H),1.49–1.33(m,1H). 13 C NMR (100MHz, CDCl 3 )...

Embodiment 3

[0037] Example 3 Combining σ 1 Synthesis of Acceptor Tetrahydroxyfurfurylpiperazines (R is I)

[0038] P-Iodobromobenzyl (234mg, 0.78mmol), tetrahydroxyfurfurylpiperazine (111mg, 0.65mmol), K 2 CO 3 (107mg, 0.65mmol) catalytic amount (1-2mg) of KI dissolved in CH 3 In CN (35mL), stir and reflux overnight at 80°C, filter and spin off acetonitrile, purify through a 200-300 mesh silica gel column, use methanol:dichloromethane=1:30 (volume ratio) as eluent, and obtain 259 mg of light yellow solid (Yield 63%). The structure of the product was detected by nuclear magnetic resonance analysis and high-resolution mass spectrometry, and the results are as follows: 1 H NMR (400MHz, CDCl 3 )δ7.55(d,J=8.2Hz,2H),7.00(d,J=8.2Hz,2H),4.07–3.97(m,1H),3.84–3.77(m,1H),3.73–3.63(m ,1H),3.39(s,2H),2.70–2.38(m,10H),2.00–1.89(m,1H),1.87–1.73(m,2H),1.48–1.34(m,1H). 13 C NMR (100MHz, CDCl 3 )δ137.55, 137.23, 131.08, 92.45, 76.11, 68.15, 62.91, 62.09, 53.45, 52.32, 30.23, 25.27. ESI-MS: [M+H] +...

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Abstract

The invention provides a tetrahydroxy furfuryl piperazine compound bonded with a sigma-1 receptor and a preparation method and application of the compound. The structural formula of the compound is shown as the formula (I) (please see the formula I in the description), wherein R is F, 18F, I or OCH2CH2F. The ligand compound of the tetrahydroxy furfuryl piperazine sigma-1 receptor has proper affinity and selectivity for the sigma-1 receptor and is one of few sigma-1 receptor ligands with nanomole-scale affinity and low fat solubility. When the R group in the compound of the formula (I) is 18F, 18 F is marked in two steps through p-fluorine[18F]benzaldehyde. The compound has high marking rate, high radiochemical purity and excellent biological property, can be applied to a PET developing tracer agent, and has wide clinical application prospects.

Description

technical field [0001] The present invention relates to the field of radiopharmaceutical chemistry and nuclear medicine technology, in particular to a combination of sigma-1 (σ 1 ) receptor tetrahydroxyfurfurylpiperazine compound, its preparation method and application. Background technique [0002] The sigma (σ) receptor is a new type of receptor different from opioid receptors, including sigma-1 (σ 1 ) and sigma-2(σ 2 ) of two subtypes. σ 1 The receptors are highly expressed in the brain and peripheral organs such as heart, spleen, kidney, liver, ovary, testis, placenta, etc. Among them, σ 1 The high expression and function of receptors in the central nervous system also makes σ 1 The receptor is related to the treatment and diagnosis of various central nervous system diseases such as Alzheimer's disease, depression, stroke, and drug addiction. Taking Alzheimer's disease (AD) as an example, Jansen et al. found that σ 1 The expression of receptors in the hippocampus...

Claims

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Application Information

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IPC IPC(8): C07D307/14A61K51/04A61K101/02
CPCA61K51/0459C07B59/002C07B2200/05C07D307/14
Inventor 贾红梅何颖芳谢芳陆洁
Owner BEIJING NORMAL UNIVERSITY
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