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Annular Gd (III) complex as well as preparation method and application thereof

A complex and ring-type technology, which can be used in pharmaceutical formulations, preparations for in vivo tests, organic chemistry, etc., can solve the problems of polymetallic gadolinium residues, poor stability, and poor targeting, and achieve improved targeting and stability. Sexual enhancement, high stability effect

Pending Publication Date: 2022-05-31
WENZHOU INST UNIV OF CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above-mentioned commercial Gd-based MRI contrast agents have the problems of more metal gadolinium residues due to poor stability, and poor targeting, so there are serious health risks

Method used

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  • Annular Gd (III) complex as well as preparation method and application thereof
  • Annular Gd (III) complex as well as preparation method and application thereof
  • Annular Gd (III) complex as well as preparation method and application thereof

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preparation example Construction

[0081] In the present invention, in the formula I, R is H, R' is H, and R" is When, the preparation method of the cyclic Gd (III) complex comprises the following steps:

[0082] (1) In a nitrogen atmosphere, mix a compound having a structure shown in Formula A-1, DO3A, potassium carbonate and acetonitrile, and carry out an affinity substitution reaction to obtain a compound having a structure shown in Formula A-2;

[0083] (2) Mix the compound having the structure shown in formula A-2 obtained in the step (1) with an aqueous solution of tetrahydrofuran, methanol and lithium hydroxide, and then perform a hydrolysis reaction to obtain a first reaction precursor;

[0084] (3) In a nitrogen atmosphere, the first reaction precursor obtained in step (2) is mixed with HATU, dichloromethane, amine and DIPEA and then subjected to a condensation reaction to obtain a compound having a structure shown in formula A-3;

[0085] (4) Mix the compound having the structure shown in formula ...

Embodiment 1

[0251] A cyclic Gd(III) complex having a chemical structure shown in formula I, in which R is H, R' is H, and R" is Denoted as complex GdL1.

[0252] The preparation method is:

[0253]

[0254] (1) The compound (1.0g, 3mmol) with the structure shown in formula A-1 and DO3A (1.6g, 3mmol), potassium carbonate (0.6g, 6mmol) were dissolved in 20mL acetonitrile, and heated to Stir at 70°C for nucleophilic substitution reaction for 16 hours, concentrate the product of nucleophilic substitution reaction and purify the resulting mixture by silica gel column chromatography (ethyl acetate:methanol=5:1) to obtain a compound with the structure shown in formula A-2 , yield 76%, 1 HNMR (400MHz, CDCl3) δ (ppm): 8.00 (d, 2H, J = 8.40Hz), 7.54 (d, 2H, J = 8.40Hz), 4.52 (s, 1H), 3.92 (s, 3H), 3.33 (s,2H),3.18(s,3H),2.80(m,15H),1.48(s,20H),1.43(s,16H). 13 C NMR (100MHz, CDCl3) δ (ppm) 171.26, 171.09, 170.86, 166.93, 143.16, 129.46, 129.38, 129.10, 81.65, 80.81, 77.41, 77.09, 76.77, 69.45,...

Embodiment 2

[0260] A cyclic Gd(III) complex having a chemical structure shown in formula I, in which R is H, R' is H, and R" is The compound is denoted as complex GdL2.

[0261] Preparation:

[0262]

[0263] Prepare complex GdL2 according to the method for embodiment 1, HPLC-MS (ESI - ) calculated for C 38 h 43 GdN 5 o 9 ,[M] ＝ 871.23, found 871.25;

[0264] The difference from Example 1 is that in the step (2), p-ethoxybenzylamine is replaced by 3,3-diphenylpropylamine.

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Abstract

The invention provides a cyclic Gd (III) complex which has a chemical structure as shown in a formula I, a ring structure of 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid, namely DOTA, is taken as a mother ring, lipophilic groups R'and R ''in the formula I are respectively introduced to an alpha position and a benzene ring structure of phenylacetic acid, and chiral groups are introduced to a large ring position of DOTA, the chiral group R is utilized to increase the rigidity of the macrocyclic structure and improve the stability of the complex, and the lipophilic groups R'and R '' can be combined with organic anion transport polypeptide of hepatocytes, so that the distribution of the cyclic Gd (III) complex as a contrast agent in the liver and gall is greatly improved, namely, the targeting property is good.

Description

technical field [0001] The invention relates to the field of organic complexes, in particular to a cyclic Gd(III) complex and its preparation method and application. Background technique [0002] Magnetic resonance imaging (MRI) is a technology that obtains electromagnetic signals through the magnetic resonance phenomenon of atomic nuclei under the action of a magnetic field, and performs imaging with the help of computer technology and image reconstruction methods. This imaging technology has the advantages of not relying on external radiation, absorption and reflection, nor emitting gamma rays, and is harmless to the human body. Moreover, MRI has unique advantages for the detection of liver cancer, and can provide multi-parameter, multi-directional and high soft tissue contrast imaging. However, the detection sensitivity of MRI is relatively low. About 40% of MRI detection requires the use of contrast agents to improve the detection signal, while for MRI detection of the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/02A61K49/10
CPCC07D257/02A61K49/108
Inventor 戴利雄徐维元叶方富
Owner WENZHOU INST UNIV OF CHINESE ACAD OF SCI
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