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Difunctional macrocyclic chelate, conjugate, metal complex and application thereof

A metal complex and bifunctional technology, applied in the field of bifunctional macrocyclic chelates, can solve the problems of destroying the activity of target molecules and the inability to accurately realize the integration of diagnosis and treatment, and achieve good in vivo and in vitro stability and precise targeting Effect of diagnosis or treatment

Active Publication Date: 2022-08-02
NANJING PET TRACER
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, DOTA chelated 89 Zr requires a higher temperature, which will destroy the activity of the target molecule, while 89 The commonly used bifunctional chelating agent for Zr is DFO, so if you want to try 89 Zr assessment treatment 177 The effect of therapeutic drugs such as Lu requires the replacement of the labeling precursor (ie, chelating agent-target molecule), which cannot accurately achieve the purpose of integration of diagnosis and treatment

Method used

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  • Difunctional macrocyclic chelate, conjugate, metal complex and application thereof
  • Difunctional macrocyclic chelate, conjugate, metal complex and application thereof
  • Difunctional macrocyclic chelate, conjugate, metal complex and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] The present embodiment provides a bifunctional macrocyclic chelate (denoted as Dar), whose structural formula is as follows:

[0057]

[0058] The present embodiment also provides a preparation method of the above-mentioned bifunctional macrocyclic chelate, which is synthesized with reference to the following synthetic route:

[0059]

[0060] The specific operations are as follows:

[0061] step one:

[0062] 2,6-Bis(hydroxymethyl)-4-methylphenol (16.8 g, 0.1 mol) was dissolved in dichloromethane (20 mL). Concentrated hydrochloric acid (100 mL) was added and stirred at room temperature for 24 h. The reaction mixture was concentrated to dryness to give compound A.

[0063] Step 2:

[0064]A solution of urotropine (18.9 g, 0.14 mol) in methanol (380 mL) was added rapidly to the freshly dissolved Compound A (0.061 mol) under vigorous stirring at room temperature. After a few seconds, a fine microcrystalline colorless solid was isolated. The mixture was left at...

Embodiment 2

[0079] The present embodiment provides a bifunctional macrocyclic chelate, and its structural formula is as follows:

[0080]

[0081] The present embodiment also provides a method for preparing the above-mentioned bifunctional macrocyclic chelate, which is synthesized with reference to the following synthetic route:

[0082]

[0083] The specific operations are as follows:

[0084] step one:

[0085] 6,6'-Dimethyl-2,2'-bipyridine (22.1g), NBS (44.7g), benzoyl peroxide (250mg) were added to 1200mL carbon tetrachloride solution, refluxed for 6h, hot filtered, The filtrate was cooled to 0-10°C for insulation, suction filtered, the obtained solid was added to 100 mL of methanol to make a slurry, suction filtered, and the solid was dried to obtain 6.91 g of compound 1.

[0086] LC-MS: 340.9 [M+H] + .

[0087] Step 2:

[0088] Compound 1 (4.25 g) was dissolved in 160 mL of chloroform, heated and refluxed to dissolve, 3.8 g of hexamethylenetetramine was dissolved in 100 m...

Embodiment 3

[0101] The present embodiment provides a bifunctional macrocyclic chelate (denoted as Dar-PEG) whose structural formula is as follows:

[0102]

[0103] The bifunctional macrocyclic chelate in this example is prepared from the bifunctional macrocyclic chelate Dar (1.1eq) of Example 1 and compound G (1eq) through Fmoc solid-phase synthesis reaction, and the condensing agent used is HOAt (2.2eq) And DIC (2.2eq), and then obtained by deprotection. Wherein, the structural formula of compound G is as follows:

[0104] LC-MS: 509.9 [M / 2+H] + , 1018.7[M+H] + .

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Abstract

The invention relates to the technical field of chelating agents, in particular to a difunctional macrocyclic chelate, a conjugate, a metal complex and application of the difunctional macrocyclic chelate, the conjugate and the metal complex. The difunctional macrocyclic chelate is a compound shown in the following formula I or an isomer thereof, R1, R3, R5 and R7 are respectively and independently selected from alkyl or long-chain polymer groups, R2, R4, R6 and R8 are respectively and independently selected from functional groups, and R1, R2, R4, R6 and R8 are respectively and independently selected from alkyl or long-chain polymer groups. Ra, Rb, Rc and Rd are respectively and independently selected from any one of H, substituted or unsubstituted alkyl, halogen, substituted or unsubstituted cyano, substituted or unsubstituted ester, substituted or unsubstituted alkoxy, substituted or unsubstituted amido and substituted or unsubstituted aryl, and the ring or the difunctional macrocyclic chelate can chelate most nuclides. The application of the difunctional macrocyclic chelate is expanded, and the metal complex chelated with different nuclides can realize integration of treatment and diagnosis.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application requires the application number CN202110139386.4 to be submitted to the Chinese Patent Office on February 01, 2021, and the Chinese patent application titled "bifunctional macrocyclic chelates, conjugates, metal complexes and their applications". Priority, the entire contents of which are incorporated herein by reference. technical field [0003] The present invention relates to the technical field of chelating agents, in particular, to bifunctional macrocyclic chelates, conjugates, metal complexes and applications thereof. Background technique [0004] Radioactive metal nuclides usually need to be linked to target molecules through bifunctional chelators to form radioactive probes. The stability of radioactive probes in vivo is an important criterion for judging their performance. Because radioactive metal nuclides have their own advantages and disadvantages, ideal radionuclides do not exist. Before ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/18C07D471/22C07F9/6561A61K51/04A61P35/00
CPCC07D471/18C07D471/22C07F9/6561A61P35/00A61K51/0482C07B2200/05A61K51/0402A61K51/1072A61K51/1093A61K51/065A61K51/088A61K51/1021
Inventor 徐建锋王正范文斌蔡飞殷欢欢罗志刚
Owner NANJING PET TRACER
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