A class of gadolinium-containing magnetic resonance imaging contrast agent and its preparation and application

A magnetic resonance imaging and contrast agent technology, which is applied in the field of gadolinium-containing magnetic resonance contrast agents, can solve problems such as poor thermodynamic stability and dynamic stability, gadolinium ion deposition, and nephrogenic systemic fibrosis in patients, so as to improve thermodynamic and kinetic stability, damage reduction, and enhanced lipophilic performance

Active Publication Date: 2020-05-29
阿克索南京生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The purpose of the present invention is to solve the relatively poor thermodynamic stability and dynamic stability of the chain molecular contrast agent in the prior art, which is more likely to cause nephrogenic systemic fibrosis in some patients and the occurrence of gadolinium ions in the patient's brain. The problem of deposition, at the same time, is also to solve the problem that most of the contrast agents in the prior art have no organ targeting, so as to provide a kind of circular molecular imaging with less toxicity and organ targeting, especially liver targeting Agents and their preparation methods

Method used

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  • A class of gadolinium-containing magnetic resonance imaging contrast agent and its preparation and application
  • A class of gadolinium-containing magnetic resonance imaging contrast agent and its preparation and application
  • A class of gadolinium-containing magnetic resonance imaging contrast agent and its preparation and application

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preparation example Construction

[0032] Wherein, R is located in the ortho, meta or para position, and R represents hydrogen, halogen, alkyl, alkoxy, amine, nitro or aryl; the preparation method of a class of gadolinium-containing magnetic resonance imaging contrast agent , characterized in that the method comprises the following steps:

[0033]

[0034] (i) Add compound 1 and substituted benzaldehyde 2 in turn to the round bottom flask, then add methanol to dissolve, heat to reflux, TLC monitors the reaction process, after the reaction is over, let it stand for cooling, filter, evaporate the solvent to obtain the crude product, and recrystallize Compound 3 is obtained; the recrystallization solvent is ethyl acetate;

[0035] (ii) Under nitrogen protection, dissolve compound 3 in methylene chloride in a round-bottomed flask, then add trifluoroacetic acid, stir and react at room temperature for 24 to 48 hours, after the reaction finishes, evaporate unreacted trifluoroacetic acid under reduced pressure, Pro...

Embodiment 1

[0038] (i) Add 2mmol compound 1 and 2mmol benzaldehyde in a 100mL round bottom flask, add 30mL methanol to dissolve, heat to reflux, TLC monitors the reaction process (10% methanol / methylene chloride), after the reaction is over, let it stand for cooling, filter, evaporate The crude product was obtained by removing the solvent, and recrystallized from ethyl acetate to obtain a white solid 3a with a yield of 85%;

[0039] (ii) Under nitrogen protection, in a 100mL round-bottomed flask, add 1.5mmol of compound 3a and dissolve it in 10mL of dichloromethane, add 10mL of trifluoroacetic acid, stir at room temperature for 48h, after the reaction is over, distill off the unreacted trifluoro Acetic acid, recrystallized from ethyl acetate to obtain white solid 4a with a yield of 98%;

[0040] (Ⅲ) In a round bottom flask, add 1.0mmol compound 4a and dissolve it in 20mL pure water, add 0.05M GdCl 3 22mL aqueous solution, adjust the pH value of the solution to 6.5 with 1M NaOH, react at ...

Embodiment 2

[0042] (i) Add 2mmol compound 1 and 2mmol m-nitrobenzaldehyde in a 100mL round-bottomed flask, add 30mL methanol to dissolve, heat to reflux, TLC monitors the reaction process (10% methanol / methylene chloride), after the reaction finishes, let it stand for cooling, Filtration, evaporation of the solvent to obtain a crude product, recrystallization from ethyl acetate to obtain a white solid 3b, yield 90%;

[0043] (ii) Under nitrogen protection, in a 100mL round bottom flask, add 1.5mmol of compound 3b and dissolve it in 10mL of dichloromethane, add 10mL of trifluoroacetic acid, stir at room temperature for 24h, after the reaction is over, distill off unreacted trifluoroacetic acid under reduced pressure Acetic acid, recrystallized from ethyl acetate to obtain white solid 4b with a yield of 99%;

[0044] (Ⅲ) In a round bottom flask, add 1.0mmol compound 4b and dissolve it in 20mL pure water, add 0.05M GdCl 322mL aqueous solution, adjust the pH value of the solution to 7.0 with...

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Abstract

The invention relates to a gadolinium-containing magnetic resonance imaging contrast agent and preparation and application thereof. The gadolinium-containing magnetic resonance imaging contrast agent is prepared by connecting phenyl groups to DOTA-NHNH2 groups and then chelating the paramagnetic metal ion of Gd+. The structural formula of the gadolinium-containing magnetic resonance imaging contrast agent is shown as the formula. The gadolinium-containing magnetic resonance imaging contrast agent is a phenyl substituent group-containing non-ionic magnetic resonance imaging contrast agent, improves the lipophilic performance by introducing the hydrophobic groups and meanwhile achieves selectivity of liver imaging.

Description

technical field [0001] The invention relates to the field of magnetic resonance imaging, in particular to a class of gadolinium-containing magnetic resonance contrast agent and its preparation and application. Background technique [0002] Since Lauterbur realized Magnetic Resonance Imaging (MRI) for the first time in 1973, MRI technology has been highly valued by the scientific community for its non-invasive, painless, precise positioning and image display similar to anatomical maps. The medical field continues to expand and has become one of the most important medical imaging equipment in imaging examinations. However, the resolution of magnetic resonance imaging cannot meet the clinical requirements in some cases. In order to enhance the imaging effect, it is necessary to give magnetic resonance contrast agent before the magnetic resonance examination. According to literature reports, in current clinical MRI, more than 35% of MRI examinations require the use of contrast ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K49/10C07D257/02
CPCA61K49/108C07D257/02
Inventor 孙宏顺李玉龙陆新华蒋蕻胡瑾潘勇
Owner 阿克索南京生物科技有限公司
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