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Complex taking amide-amine as side chain, and preparation method and application thereof

A technology of complexes and amides, applied in the preparation of carboxylic acid amides, the preparation of organic compounds, preparations for in vivo tests, etc., can solve the problems of low toxicity and side effects, low relaxation efficiency, etc., and achieve the effect of low toxicity

Inactive Publication Date: 2018-06-29
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Approved clinical small-molecule magnetic resonance contrast agents have the advantages of good stability, low toxicity and side effects, easy excretion from the body, and good biocompatibility, but the relaxation efficiency is generally low, at 3-6 Mm -1 the s -1

Method used

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  • Complex taking amide-amine as side chain, and preparation method and application thereof
  • Complex taking amide-amine as side chain, and preparation method and application thereof
  • Complex taking amide-amine as side chain, and preparation method and application thereof

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preparation example Construction

[0046] The preparation method of the complex with amide-amine as the side chain of the present invention, the steps are as follows:

[0047] Step 1, the synthesis of 1,4-bis(4-oxobutyrate ethyl)benzene

[0048] Dissolve the compound and the base in a ketone solvent, add iodide and ethyl 4-bromobutyrate to obtain a mixed solution A, reflux the mixed solution A at 65-75°C overnight, then stop the reaction, distill off the solvent under reduced pressure, and Add absolute ethanol to the remaining reaction solution, heat and reflux at 65°C to 75°C for 5 to 10 minutes, put it in an ice-water bath to cool, and obtain a light brown solid, which is 1,4-bis(4-oxobutyrate ethyl)benzene;

[0049] Wherein, the compound is shown in formula III or formula IV:

[0050]

[0051] In formula III and formula IV, R 1 , R 2 , R 3 , R 4 All are substituents, the same or different, respectively hydroxyl, amino, carboxyl or alkyl;

[0052] The base is potassium carbonate, sodium carbonate, ce...

Embodiment 1

[0072] The synthesis of embodiment 1 Gd-DBAM

[0073] Step 1, the synthesis of 1,4-bis(4-oxobutyrate ethyl)benzene

[0074] Dissolve 1.1g of hydroquinone and 7.5g of potassium carbonate in 50ml of acetone, add 0.83g of potassium iodide and 4.5ml of ethyl 4-bromobutyrate to obtain a mixed solution A, and reflux the mixed solution A at 65°C overnight to stop the reaction , the solvent acetone was distilled off under reduced pressure, 6ml of absolute ethanol was added to the remaining reaction solution, heated to reflux at 90°C for 10min, cooled and crystallized in an ice-water bath for 30min, filtered under reduced pressure, rinsed with deionized water at 0°C, and dried to obtain shallow 1.34 g of brown solid 1,4-bis(4-oxobutyrate ethyl)benzene.

[0075] Step two, aminolysis reaction

[0076] Mix 30ml of ethylenediamine and 75ml of absolute ethanol evenly to obtain a mixed solution B, add 1.014g of 1,4-bis(4-oxobutyrate ethyl)benzene obtained in step 1 into the mixed solution ...

Embodiment 2

[0083] The synthesis of embodiment 2 Gd-DBAM

[0084] Step 1, the synthesis of 1,3-two (4-oxobutyrate ethyl) benzene

[0085] Dissolve 4.4g of resorcinol and 3.32g of potassium iodide in 200ml of acetone, add 30g of potassium carbonate and 18ml of ethyl 4-bromobutyrate to obtain a mixed solution A, and reflux the mixed solution A at 65°C overnight to stop the reaction. Remove the solvent acetone by distillation under pressure, add 24ml of absolute ethanol to the remaining reaction solution, heat to reflux at 90°C for 10min, put it in an ice-water bath to cool and crystallize for 30min, filter under reduced pressure, rinse with deionized water at 0°C, and dry to obtain a light brown solid 12.56 g of 1,4-bis(4-oxobutyrate ethyl)benzene.

[0086] Step two, aminolysis reaction

[0087]Mix 47.3ml of ethylenediamine and 118ml of absolute ethanol evenly to obtain a mixed solution B, add 1.599g of 1,3-bis(4-oxobutyrate)benzene obtained in step 1 into the mixed solution B, and reflux...

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Abstract

The invention relates to a complex taking amide-amine as a side chain, and a preparation method and application thereof, belongs to the technical field of magnetic resonance imaging contrast agents, and solves the technical problem about how to provide a metal complex which is high in relaxivity and has a novel skeleton structure, and the preparation method and the application thereof. The structural formula of the complex provided by the invention is shown in a formula I or a formula II, wherein R1, R2, R3 and R4 are all substituent groups and are respectively hydrogen, hydroxyl, amino, carboxyl or alkyl; Mn<+> is a paramagnetic ion of a transition metal or a lanthanide-series metal. The complex which is applied as a contrast agent is low in toxicity; the toxicity of the complex which isrepresented by IC50 is 2.1 mmol / L; the relaxivity reaches 18.57 Mm<-1>s<-1>, and is about three times that of nuclear magnetic resonance contrast agent in clinical use; the complex has a fluorescenceeffect, has strong fluorescence when the complex is excited at 328 nm, and has a potential advantage of serving as a magnetic resonance-fluorescence dual functional contrast agent.

Description

technical field [0001] The invention belongs to the technical field of magnetic resonance imaging contrast agents, and in particular relates to a complex with amide-amine as a side chain and a preparation method and application thereof. Background technique [0002] Magnetic resonance imaging (magnetic resonance imaging, referred to as MRI) is one of the most widely used diagnostic imaging techniques in the field of medical molecular imaging. There are significant effects in terms of damage. MRI technology is an imaging technology based on the theory of Nuclear Magnetic Resonance (NMR), which integrates the latest research results in physics, chemistry, biology, computer technology, electronic circuit technology and medicine. MRI contrast agents (MRIcontrast agents) affect the relaxation process of water protons by changing the micro-magnetic field environment that affects free water protons in local tissues, so that the relaxation time is changed, the relaxation efficiency...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C235/20C09K11/06A61K49/10
Inventor 徐经伟金曼玉周华吴存琦赵永霞
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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