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A kind of interferon-stimulated protein targeting compound, its radiolabel, and their preparation method and application

A compound and interferon technology, which is applied in the field of radiopharmaceuticals and medical imaging, achieves the effect of simple preparation method, strong labeling ability, and broadened application scenarios

Active Publication Date: 2022-03-22
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Today's popular PD-1 / PD-L1 immune checkpoint inhibitors need to quantitatively screen the protein expression in patients in advance to achieve the purpose of precise treatment. Routine biopsy or immunohistochemistry (IHC) due to the heterogeneity of tumor tissue It is impossible to fully accurately and comprehensively evaluate the true expression of PD-1 / PD-L1

Method used

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  • A kind of interferon-stimulated protein targeting compound, its radiolabel, and their preparation method and application
  • A kind of interferon-stimulated protein targeting compound, its radiolabel, and their preparation method and application
  • A kind of interferon-stimulated protein targeting compound, its radiolabel, and their preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1. Dimeric amidobenzimidazole compound——DABI-PEG 2 -NH 2 (compound 12-1)

[0081] The synthetic route is as follows:

[0082]

[0083] Specifically include the following steps:

[0084] 1) Synthesis of compound 3

[0085] With 4-chloro-3 nitro-5 methoxybenzamide (compound 1) and (4-aminobut-2-en-1-yl) tert-butyl carbamate (compound 2) according to 1:1.2 molar ratio Dissolve in an appropriate amount of isopropanol, then add DIPEA in an equimolar ratio to compound 1 dropwise into the reaction bottle, stir and react overnight at room temperature, carry out aromatic nucleophilic substitution reaction, monitor the reaction process by TLC, spin the solvent after the reaction, and pass the crude product through Silica gel column was purified to obtain compound 3.

[0086] 2) Synthesis of Compound 4

[0087] 1) Dissolve the obtained compound 3 with an appropriate amount of methanol, transfer it to the reaction flask, and then slowly add 50 mL of hydrochloric ac...

Embodiment 2

[0098] Example 2. Dimeric amidobenzimidazole compound——DABI-Et 3 -NH 2 (compound 12-2)

[0099] The synthetic route is as follows:

[0100]

[0101] Specifically include the following steps:

[0102] 1) Synthesis of compound 3

[0103] Operation steps are the same as step 1) of embodiment 1.

[0104] 2) Synthesis of Compound 4

[0105] Operation steps are the same as step 2) of embodiment 1.

[0106] 3) Synthesis of compound 7-2

[0107] Weigh an equimolar amount of compound 5 (4-chloro-3 nitro-5 hydroxybenzamide) and compound 6-2 (6-(N-tert-butoxycarbonylamino)-1-hexanol, i.e. HO-Et 3 -NH-Boc) and triphenylphosphine (PPh 3 ) was dissolved in THF, and 2 times the molar amount of diisopropyl azodicarboxylate (DIAD) was added under ice-bath conditions to carry out a bimolecular nucleophilic substitution reaction, and reacted at room temperature for 24 hours. After the reaction was completed, the solvent was removed, and the crude product was passed through Compound 7...

Embodiment 3

[0117] Example 3. Interferon-stimulated protein-targeted radionuclide-labeled compound——[ 18 F]F-NOTA-PEG 2 -DABI

[0118] The synthetic route is as follows:

[0119]

[0120] Specifically include the following steps:

[0121] 1) NOTA-PEG 2 - Synthesis of DABI

[0122] Weigh the DABI-PEG prepared in Example 1 2 -NH 2 Dissolve in appropriate amount of DMF in equimolar ratio with NOTA-NHS, then add triethylamine, react for 48h, after reaction, add appropriate amount of hydrochloric acid to acidify and purify with high performance liquid chromatography (HPLC), mobile phase conditions: semi-preparative chromatographic column (250 ×10mm, 5μm, Thermo), phase A: water + 0.1% trifluoroacetic acid (TFA), phase B: acetonitrile + 0.1% TFA. Gradient elution conditions: 0-5min: 20%-28% B phase; 5-15min: 28% B phase; 15-20 min: 28%-39% B; 20-25min: 39%-95% B; 25 -40min: 20% phase B, flow rate: 3mL / min, UV wavelength: 254nm. The purified solution was dried in vacuo to obtain the ...

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Abstract

The present invention provides a class of dimeric amidobenzimidazole compounds, the structure of which is shown in the following formula (I); wherein, R 0 An integer of 0-5 is taken for n. The present invention also provides a class of compounds with anti-tumor activity and a class of interferon-stimulating protein-targeted radionuclide-labeled compounds based on the dimerized amidobenzimidazole compound. The dimerized amidobenzimidazole compound of the present invention has high affinity and high specificity to interferon-stimulated protein, and the compound with anti-tumor activity described in the present invention has the characteristic of activating the STING pathway in vitro. The radionuclide-labeled compound not only has a clear contrast between target and non-target uptake, but also can change the fat solubility by introducing nuclides of different properties, which greatly broadens the application scenarios. It can be used in combination with therapeutic nuclides for tumor treatment, and even for immune treat.

Description

technical field [0001] The invention belongs to the technical field of radiopharmaceuticals and medical imaging, and in particular relates to a receptor molecular targeting compound and a preparation method thereof. Background technique [0002] Tumor is currently the primary killer threatening human health. In recent years, tumor immunotherapy has made outstanding achievements in improving the treatment of certain types of tumors, completely changing the status quo of tumor treatment, and has become another effective treatment for cancer following surgery, radiotherapy, chemotherapy, and targeted therapy. In 2018, the award of the Nobel Prize in Physiology and Medicine affirmed a completely new principle of cancer treatment by stimulating the innate ability of the body's immune system to attack tumor cells, and changed the treatment paradigm from immune enhancement to immune normalization. Tumor immunotherapy is mainly divided into two types: cellular immunotherapy and imm...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/14A61K31/4184A61K51/04A61P35/00
CPCC07D403/14A61K51/0453A61P35/00Y02P20/55
Inventor 张现忠方建阳郭志德封丽霞
Owner XIAMEN UNIV
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