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Nitroimidazole derivative for preparing hypoxic developer, preparation method and application thereof

A technology of nitroimidazoles and derivatives, which is applied in the fields of medical imaging materials and medicinal chemistry, can solve the problems of low brain intake, low hypoxia sensitivity, and low brain intake.

Active Publication Date: 2021-09-14
首都医科大学脑重大疾病研究中心
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main hypoxic imaging agent currently used clinically is [ 18 F]FMISO, but because of its low brain volume, slow clearance of normal tissue, poor sensitivity to hypoxia and other unfavorable factors, [ 18 F] FMISO still needs optimization
In recent years, based on [ 18 F] The structure of FMISO has developed [ 18 F] FAZA, [ 18 F]FETNIM, [ 18 F] HX4 and [ 18 F] EF5 etc., meanwhile, based on metal chelates [ 64 Cu]ATSM and [ 64 Cu]ATSE has also been studied, and the newly developed imaging agent has improved tumor hypoxia, but there are also major shortcomings, such as low hypoxia sensitivity and low brain volume, which seriously restrict the diagnosis of hypoxia

Method used

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  • Nitroimidazole derivative for preparing hypoxic developer, preparation method and application thereof
  • Nitroimidazole derivative for preparing hypoxic developer, preparation method and application thereof
  • Nitroimidazole derivative for preparing hypoxic developer, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0035] Example 1 1-(4-(2-fluoroethyl)piperidin-1-yl)-2-(2-nitro-1H-imidazol-1-yl)ethan-1-one

[0036] The structural formula is as follows:

[0037]

[0038] The synthetic route is as follows:

[0039]

[0040] 1) 2-(2-nitro-1H-imidazol-1-yl)-1-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperidine- 1-yl)ethane

[0041]Dissolve 2-(2-nitro-1H-imidazol-1-yl)acetic acid (120mg, 0.70mmol) in DMF, add 5mL triethylamine, stir at room temperature for 15min, then add 4-(2-((tetrahydro -2H-pyran-2-yl)oxy)ethyl)piperidine (150mg, 0.70mmol), 1-hydroxybenzotriazole (HOBT, 30mg, 0.19mmol), O-benzotriazole-tetra Methylurea hexafluorophosphate (HBTU, 800mg, 2.11mmol), react at room temperature for 1h, then extract with ethyl acetate, wash with saturated brine three times, collect the organic layer, and wash with Na 2 SO 4 dry. Purification by flash chromatography (ethyl acetate) afforded 2-(2-nitro-1H-imidazol-1-yl)-1-(4-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethyl)piperidin-1-yl)eth...

Embodiment 2

[0048] Example 2 4-(2-fluoroethyl)-1-(2-(2-nitro-1H-imidazol-1-yl)ethyl)piperidine

[0049] The structural formula is as follows:

[0050]

[0051] The synthetic route is as follows:

[0052]

[0053] 1) 2-(1-(2-(2-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)ethan-1-ol

[0054] Dissolve 2-(2-nitro-1H-imidazol-1-yl)ethyl 4-methylbenzenesulfonate (353mg, 1.13mmol) and 4-piperidineethanol (220mg, 1.70mmol) in acetonitrile, add K 2 CO 3 2-(1-(2-( 2-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)ethan-1-ol (200 mg, 66.0%). 1 H NMR (300MHz, CDCl 3 )δ7.14(s,1H),7.00(s,1H),4.42(t,J=6.1Hz,2H),3.55(t,J=6.5Hz,2H),3.04(s,1H),2.68( d,J=11.2Hz,2H),2.58(t,J=6.1Hz,2H),2.01(s,2H),1.56(d,J=12.4Hz,2H),1.39(dd,J=12.7,6.3 Hz,3H),1.14–0.91(m,2H). 13 C NMR (75MHz, CDCl 3 )δ145.00,127.87,126.38,59.88,58.24,54.05,47.41,39.11,32.14,31.95.HRMS calcd for C12H20N4O3 268.1535;found,269.2187[M+H] + .

[0055] 2) 2-(1-(2-(2-(2-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)ethyl 4-methylbenzenesul...

Embodiment 3

[0059] Example 3 1-(4-(2-fluoroethyl)piperidin-1-yl)-3-(2-nitro-1H-imidazol-1-yl)propanol

[0060] The structural formula is as follows:

[0061]

[0062] The synthetic route is as follows:

[0063]

[0064] 1) 2-(1-(3-(2-nitro-1H-imidazol-1-yl)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl)piperidine- 4-yl)ethanol

[0065] 3-(2-nitro-1H-imidazol-1-yl)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl 4-toluenesulfonate (150mg, 0.35mmol ) and 4-piperidine ethanol (68mg, 0.52mmol) were dissolved in acetonitrile, added K 2 CO 3 (487mg, 3.52mmol), reflux at 90°C for 24h, then spin dry and mix the sample, and pass through flash purification chromatography (ethyl acetate) to obtain 2-(1-(3-(2-nitro-1H-imidazole-1- yl)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl)piperidin-4-yl)ethanol (100 mg, 74.8%). 1 H NMR (300MHz, CDCl 3 )δ7.19(s,1H),7.09(s,1H),4.99(dd,J=14.0,2.9Hz,1H),4.36–4.28(m,2H),4.10(d,J=5.0Hz,1H ),3.82–3.65(m,1H),3.82–3.65(m,3H),3.42-3.39(m,1H),2.91(d,J=10.5Hz,1H),2.76(d,J=10.7...

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Abstract

The invention provides a nitroimidazole derivative for preparing a hypoxic developer. The nitroimidazole derivative is selected from compounds with structural formulas as shown in a formula I, a formula II or a formula III, wherein R is C1-8 alkyl, saturated alkoxy or acylamino. The invention also provides a preparation method of the nitroimidazole compound and application of the nitroimidazole compound in preparation of a PET imaging agent. The nitroimidazole derivative provided by the invention has proper molecular weight and fat solubility, greatly improves the ability of an imaging agent to cross a blood brain barrier, and has higher sensitivity to hypoxia due to introduction of an azide hypoxia response group.

Description

technical field [0001] The invention relates to the technical fields of medical imaging materials and medicinal chemistry, in particular to nitroimidazole derivatives used for preparing hypoxic imaging agents and their preparation methods and applications. Background technique [0002] Hypoxia is a state in which intracellular oxygen concentrations are too low to meet metabolic demands, caused by an imbalance between oxygen supply and consumption. Hypoxia is a common feature of most solid malignancies, leading to reduced oxygen and nutrient availability and impaired drug delivery. The heterogeneity of hypoxia will promote tumor invasion, metastasis, angiogenesis and increase drug resistance, these factors will greatly reduce the therapeutic effect of anticancer drugs, which in turn will cause huge obstacles to tumor treatment and drug development. At the same time, hypoxia is also a major factor in diseases such as stroke and myocardial infarction, and plays a role in the s...

Claims

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Application Information

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IPC IPC(8): C07D401/06C07D233/91C07B59/00A61K51/04A61K101/02
CPCC07D401/06C07D233/91C07B59/002A61K51/0455A61K51/0453C07B2200/05
Inventor 吴泽辉吉训明孙雨丽陈华龙程雪波
Owner 首都医科大学脑重大疾病研究中心
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