A kind of n2s2 bromobenzyl ether derivative, preparation method and application

A technology of bromobenzyl ether and derivatives, which is applied in the fields of radiopharmaceutical chemistry and clinical nuclear medicine, can solve the problems of unmet PD-L1 expression level monitoring requirements, achieve strong cell uptake ability, and overcome the effect of immunohistochemical methods

Active Publication Date: 2022-04-19
无锡市江原实业技贸有限公司
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Problems solved by technology

[0006] In order to solve the technical problem of long-standing and unmet PD-L1 expression level monitoring requirements in PD-1 / PD-L1 immunotherapy existing in the prior art, the purpose of the present invention is to provide a suitable 99m Tc-labeled N2S2 bromobenzyl ether derivatives, preparation method and application

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  • A kind of n2s2 bromobenzyl ether derivative, preparation method and application
  • A kind of n2s2 bromobenzyl ether derivative, preparation method and application
  • A kind of n2s2 bromobenzyl ether derivative, preparation method and application

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preparation example Construction

[0028] The preparation method of N2S2 bromobenzyl ether derivatives comprises the following steps:

[0029]

[0030] S1, preparation of 2-bromo-3-phenyltoluene

[0031] Under nitrogen, add 100-5000mg of 2-bromo-3-iodotoluene into a 100mL three-necked flask, add dioxane (60%-90%) in 30-70mL of aqueous solution to dissolve it, and stir evenly Then add 50-2500mg of phenylboronic acid, 100-8000mg of cesium carbonate and 10-300mg of triphenylphosphine palladium in sequence, stir at 70-90°C for 12-24h, stop the reaction, cool down to room temperature, and remove the solvent by rotary evaporation , adding water and ethyl acetate to extract 3 times, combining the organic phases, drying with anhydrous sodium sulfate, evaporating the organic phases, and passing through a silica gel column to obtain 2-bromo-3-phenyltoluene as a colorless oil;

[0032] S2, preparation of 2-bromo-3-phenylbenzyl bromide

[0033]Under nitrogen, dissolve 100-2000mg of 2-bromo-3-phenyltoluene and anhydrou...

Embodiment 1

[0047] Such as Figure 1-2 As shown, a kind of N2S2 bromobenzyl ether derivatives have the following structural formula (I):

[0048]

[0049] A preparation method of N2S2 bromobenzyl ether derivatives, comprising the steps of:

[0050] Preparation of S1, 2-bromo-3-phenyltoluene:

[0051] Under nitrogen, add 1400mg of 2-bromo-3-iodotoluene into a 100mL three-necked flask, add 50mL of dioxane / water (volume ratio 5 / 1) to dissolve it, stir for 10min, then add 700mg of benzene Boric acid, 3600mg cesium carbonate and 160mg triphenylphosphine palladium were stirred at 75°C for 18h, the reaction was stopped, and the temperature was lowered to room temperature. Dry over sodium sulfate, evaporate the organic phase to dryness, and pass through a silica gel column to obtain 1015 mg of a colorless oil, with a yield of 87.2%. 1 H NMR (400MHz, DMSO-d 6 )δ7.42-7.31(m, 5H, Ar-H), 7.25-7.20(d, 2H, Ar-H), 7.12-7.08(m, 1H, Ar-H), 2.45(s, 3H, Ar- CH 3 ).

[0052] Preparation of S2, 2-br...

Embodiment 2

[0063] A sort of 99m Tc-labeled N2S2 bromobenzyl ether derivatives ( 99m Tc-N2S2-CBMBC), prepared by N2S2 bromobenzyl ether derivatives, comprising the following steps:

[0064] Dissolve 100 μg of the labeling precursor (N2S2 bromobenzyl ether derivative) in 100 μL of ethanol, add 120 μL of 50 mg / mL sodium glucoheptonate, 50 μL of 20 mg / mL disodium edetate, 10 μL of 10 mg / mL of stannous chloride and 0.5mL pertechnetic acid solution (1mCi / mL), shake well, heat at 90-100°C for 30min, then take it out and cool it down to obtain the desired 99m Tc-N2S2-CBMBC.

[0065] 99m Detection of Tc-N2S2-CBMBC labeling rate

[0066] prepared by the above method 99m Tc-N2S2-CBMBC detects the labeling rate by isotope high-performance liquid phase, C18 reverse phase column, mobile phase is water / methanol=1 / 1 (v / v), flow rate is 1mL / min, labeling rate is greater than 94%, such as figure 1 shown. No tagged precursor, other conditions are the same as tagged 99m Tc-blank, as in figure 2 sh...

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Abstract

The invention discloses an N2S2-like bromobenzyl ether derivative, a preparation method and an application thereof. The N2S2-like bromobenzyl ether derivative is used as a ligand and used 99m Complexes formed by Tc labeling 99m Tc-N2S2-CBMBC can be used as an imaging agent to detect PD-L1 expression, realize real-time, comprehensive and convenient detection of tumor PD-L1 levels, and overcome the shortcomings of immunohistochemical methods. N2S2 bromobenzyl ether derivatives provided by the present invention, preparation method and application, prepared 99m The labeling rate of Tc-N2S2-CBMBC is above 94%. After 6 hours at room temperature, the radiochemical purity remains above 90%. It is stable in vitro at room temperature and is suitable for clinical application. The lipid-water partition coefficient is 0.91, which can reflect biological The distribution of drugs between the aqueous phase and the lipid phase in the body, and the cell uptake ability is strong, and PD‑L1 is highly expressed.

Description

technical field [0001] The invention belongs to the technical fields of radiopharmaceutical chemistry and clinical nuclear medicine, and specifically relates to an N2S2 bromobenzyl ether derivative, a preparation method and an application. Background technique [0002] In recent years, immunotherapy has become a research hotspot in tumor treatment, and the immune escape of tumor cells plays a very important role in the occurrence and development of tumors. Tumor cells bind to the programmed death molecule 1 (PD-1) of T cells through the programmed death ligand (PD-L1) produced on their surface, inhibit the proliferation of T cells and release cytotoxins, resulting in tumor-specific The vitality of T cells is exhausted and apoptotic, so that tumor cells escape the attack of the immune system and survive. PD-1 / PD-L1-based immunotherapy is a new generation of immunotherapy that is currently attracting attention. It aims to use the body's own immune system to resist tumors and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C323/41C07C319/06C07F13/00A61K51/04A61K103/10
CPCC07C323/41C07F13/005A61K51/0482C07B2200/05
Inventor 陆春雄谭成徐希杰俞惠新徐栋钦晓峰邹美芬
Owner 无锡市江原实业技贸有限公司
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