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Nitroimidazole derivative and preparation method and application thereof

A technology for nitroimidazoles and nitroimidazoles, which is applied in the field of nitroimidazole derivatives and their preparation, can solve problems such as poor pharmacokinetics, and achieves improved pharmacokinetic properties, improved signal-to-noise ratio, High intake effect

Active Publication Date: 2021-10-15
首都医科大学脑重大疾病研究中心
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In order to overcome the above [ 18 F] A series of poor pharmacokinetic problems caused by FMISO passive diffusion, the present invention uses nitroimidazole as the basic framework, and obtains a series of nitroimidazole derivatives containing amino acid characteristic groups by introducing different types of amino acids. material, the object of the present invention is to provide a suitable 18 F-labeled novel nitroimidazole derivatives and their corresponding 18 F-labeled nitroimidazole derivatives, their 19 F-labeled analogs and other uses as reference standards, methods of preparing such compounds, compositions comprising such compounds, kits comprising such compounds or compositions, and such compounds, compositions or kits for Positron emission tomography (PET) for major diseases related to hypoxia such as tumor, stroke, and atherosclerosis

Method used

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  • Nitroimidazole derivative and preparation method and application thereof
  • Nitroimidazole derivative and preparation method and application thereof
  • Nitroimidazole derivative and preparation method and application thereof

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preparation example Construction

[0045] The preparation method of the compound shown in formula II is shown in reaction formula I:

[0046] The intermediate compound is obtained through fluorination by using a marked precursor compound of formula V containing an activating group, and then the compound of formula I is obtained through hydrolysis.

[0047]

[0048] The preparation method of the compound shown in formula III is shown in reaction formula II:

[0049] The intermediate compound is obtained through fluorination by using the marked precursor compound of formula VI containing an activating group, and then the compound of formula III is obtained through hydrolysis.

[0050]

[0051] The preparation method of the compound shown in formula IV is shown in reaction formula III:

[0052] Using a marked precursor compound of formula VII containing an activating group, the intermediate compound is obtained through fluorination, and then the compound of formula IV is obtained through hydrolysis.

[005...

Embodiment 1

[0060] Example 1 (S)-2-amino-3-(4-(2-(N-(3-fluoropropyl)-2-(2-nitro-1H-imidazol-1-yl)acetamido) Ethoxy)phenyl)propionic acid

[0061] The structural formula is as follows:

[0062]

[0063] The synthetic route is as follows:

[0064] 1) tert-butyl (2S)-3-(4-(2-(benzyl(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)amino)ethoxy)benzene base)-2-((tert-butoxycarbonyl)amino)propionate

[0065] Dissolve (S)-tert-butyl 2-((tert-butoxycarbonyl)amino)-3-(4-(2-(methylphenoxy)ethoxy)phenyl)propanoate (2 g, 3.74 mmol) in In 40mL of acetonitrile, N-benzyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-1-amine (1.02g, 4.11mmol), sodium iodide (500mg, 2.24 mmol) and potassium carbonate (1.03g, 7.48mmol), reflux at 100°C for 28h. Then filter, and the filtrate is spin-dried to mix the sample, and the tert-butyl (2S)-3-(4-(2-(benzyl(3-( (tetrahydro-2H-pyran-2-yl)oxy)propyl)amino)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propionate (1.4 g, 70.0%) . 1 H NMR (300MHz, CDCl 3 )δ7.40–7.28(m,5H),7....

Embodiment 2

[0079] Example 2 (2S, 4R)-2-amino-4-(3-(N-(3-fluoropropyl)-2-(2-nitro-1H-imidazol-1-yl)acetamido)propane base) glutaric acid

[0080] The structural formula is as follows:

[0081]

[0082] The synthetic route is as follows:

[0083] 1) Di-tert-butyl (2S, 4R)-2-((tert-butoxycarbonyl)amino)-4-(3-(p-tolyloxy)propyl) glutarate

[0084] Dissolve di-tert-butyl (2S, 4R)-2-((tert-butoxycarbonyl)amino)-4-(3-hydroxypropyl) glutarate (900mg, 2.16mmol) in 25mL dichloromethane, ice Add p-toluenesulfonyl chloride (1.64g, 8.63mmol), triethylamine (6.67mL) and 4-dimethylaminopyridine (10mg, 0.08mmol) under bath conditions, react at room temperature for 12h, then wash with water three times, Na 2 SO 4 After drying, pass through flash chromatography (petroleum ether: ethyl acetate = 80:20) to obtain di-tert-butyl (2S, 4R)-2-((tert-butoxycarbonyl)amino)-4-(3-(para Tolyloxy)propyl)glutarate (790mg, 64.1%). 1 H NMR (300MHz, CDCl 3 )δ7.80(d, J=8.2Hz, 2H), 7.36(d, J=8.0Hz, 2H), 4.86(d, J=...

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Abstract

The invention provides a nitroimidazole derivative. The structural formula of the nitroimidazole derivative is shown as a formula I, wherein R1 is any one selected from H or C1-8 alkyl, saturated alkoxy or amido, R5 is selected from C1-8 alkyl, saturated alkoxy or amido, a substituent group is selected from-(CH2) n and-(OCH2CH2) n-, and n is an integer of 1-4; R2 is selected from C1-8 alkyl, saturated alkoxy or acylamino, a substituent group is selected from any one of -(CH2) n and-(OCH2CH2) n-, and n is an integer of 1-4; R3 is selected from -(CH2) m and-(CH2) m-CH-COOH, and m is an integer of 1-7. The invention also provides a preparation method and application of the nitroimidazole derivative. The nitroimidazole derivative provided by the invention improves the pharmacokinetics of the imaging agent.

Description

technical field [0001] The invention relates to the field of nuclear medicine PET imaging agents, in particular to a nitroimidazole derivative that can be used to prepare imaging agents, a preparation method and application thereof. Background technique [0002] Hypoxia, also called hypoxia, is a state in which intracellular oxygen concentrations are too low to meet metabolic demands, and is caused by an imbalance between oxygen supply and consumption. Hypoxia can generally be divided into perfusion-associated (acute) hypoxia due to insufficient blood flow, diffusion-associated (chronic) hypoxia as tumor growth spreads over distance, and anemic hypoxia due to decreased oxygen transport capacity. Hypoxia is a common feature of most solid malignancies and directly affects clinical response to therapy by affecting tumor growth, metastatic ability, and resistance to cell death. As an important effect phenomenon of ischemia, hypoxia is the main factor of diseases such as stroke ...

Claims

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Application Information

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IPC IPC(8): C07D233/91C07B59/00A61K51/04A61K101/02
CPCC07D233/91C07B59/002A61K51/0453C07B2200/07C07B2200/05Y02P20/55
Inventor 吉训明吴泽辉孙雨丽程雪波陈华龙
Owner 首都医科大学脑重大疾病研究中心
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