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A kind of progesterone receptor targeting nitrogen heterocyclic carbene intermediate and ruthenium complexes and its preparation method and application

A nitrogen-heterocyclic carbene and progesterone receptor technology, applied in ruthenium organic compounds, chemical instruments and methods, pharmaceutical formulations, etc., can solve the problems of high toxicity and side effects, limited application, lack of targeting, etc., and achieve high targeting Sexuality, high cytotoxicity and targeting, and easy purification

Active Publication Date: 2021-05-11
JIANGSU INST OF NUCLEAR MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the previous work of the applicant, a series of nitrogen-heterocyclic carbene ruthenium complexes with high anti-tumor activity were also designed and synthesized, but their further application was limited due to their lack of targeting and high toxicity and side effects.

Method used

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  • A kind of progesterone receptor targeting nitrogen heterocyclic carbene intermediate and ruthenium complexes and its preparation method and application
  • A kind of progesterone receptor targeting nitrogen heterocyclic carbene intermediate and ruthenium complexes and its preparation method and application
  • A kind of progesterone receptor targeting nitrogen heterocyclic carbene intermediate and ruthenium complexes and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1 Preparation of progesterone receptor targeting ruthenium complex (Pr-S-S-NHC-Ru) represented by formula (II)

[0050] The preparation method of the present embodiment compound Pr-S-S-NHC-Ru, according to figure 1 The synthetic route shown specifically comprises the following steps:

[0051] (1) Preparation of NHC: get 4-hydroxymethylimidazole (1.34g, 10mmol), K 2 CO 3 (4.14g, 30mmol) and p-tert-butylbenzyl chloride (1.82g, 10mmol) were heated to reflux in acetonitrile for 8h, the reaction solution was spin-dried, and the chromatographic column separation (CH 2 Cl 2 / CH 3 OH=10:1, v / v), the reaction intermediate a was obtained as a light yellow solid. Then the obtained compound a and p-tert-butylbenzyl chloride (1.82g, 10mmol) were heated to reflux overnight in acetonitrile, the acetonitrile was spin-dried, and the chromatographic column separation (CH 2 Cl 2 / CH 3 OH=3:1, v / v), to obtain white solid NHC;

[0052] (2)N 3 - Preparation of S-S-NHC: Diss...

Embodiment 2

[0059] Example 2 Preparation of progesterone receptor targeting ruthenium complex (Pr-S-S-NHC-Ru) represented by formula (II)

[0060] The preparation method of the present embodiment compound Pr-S-S-NHC-Ru, according to figure 1 The synthetic route shown specifically comprises the following steps:

[0061] (1) Preparation of NHC: get 4-hydroxymethylimidazole (1.34g, 10mmol), K 2 CO 3 (4.14g, 30mmol) and p-tert-butylbenzyl chloride (1.82g, 10mmol) were heated to reflux in THF for 8h, the reaction solution was spin-dried, and the chromatographic column separation (CH 2 Cl 2 / CH 3 OH=10:1, v / v), the reaction intermediate a was obtained as a light yellow solid. Then the obtained compound a and p-tert-butylbenzyl chloride (1.82g, 10mmol) were heated and refluxed in THF overnight, the THF was spin-dried, and the chromatographic column separation (CH 2 Cl 2 / CH 3 OH=3:1, v / v), to obtain white solid NHC;

[0062] (2)N 3- Preparation of S-S-NHC: Dissolve carbonyldiimidazole ...

Embodiment 3

[0069] Example 3 Preparation of progesterone receptor targeting ruthenium complex (Pr-S-S-NHC-Ru) represented by formula (II)

[0070] The preparation method of the present embodiment compound Pr-S-S-NHC-Ru, according to figure 1 The synthetic route shown specifically comprises the following steps:

[0071] (1) Preparation of NHC: get 4-hydroxymethylimidazole (1.34g, 10mmol), K 2 CO 3 (4.14g, 30mmol) and p-tert-butylbenzyl chloride (1.82g, 10mmol) were heated to reflux in THF for 8h, the reaction solution was spin-dried, and the chromatographic column separation (CH 2 Cl 2 / CH 3 OH=10:1, v / v), the reaction intermediate a was obtained as a light yellow solid. Then the obtained compound a and p-tert-butylbenzyl chloride (1.82g, 10mmol) were heated and refluxed in THF overnight, the THF was spin-dried, and the chromatographic column separation (CH 2 Cl 2 / CH 3 OH=3:1, v / v), to obtain white solid NHC;

[0072] (2)N 3 - Preparation of S-S-NHC: Dissolve carbonyldiimidazole...

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Abstract

The invention belongs to the field of drug synthesis, and specifically relates to a progesterone receptor-targeting nitrogen heterocyclic carbene intermediate and a ruthenium complex, and a preparation method and application thereof. The progesterone receptor-targeting nitrogen shown in formula (I) is synthesized The heterocyclic carbene intermediate further synthesized the progesterone receptor targeting ruthenium complex shown in formula (II), which has specific responsiveness to GSH (glutathione) and progesterone receptor (PR) targeting; cell experiments show that it has high cytotoxicity and targeting to progesterone receptor-positive tumor cells; animal experiments also show that the complex has high targeting to progesterone receptor-positive tumors and anti-tumor activity, and the preparation method of the progesterone receptor-targeting ruthenium complex provided by the invention is simple, and the product is easy to purify. The complex can be used as an anti-breast cancer drug targeting the PR receptor.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a progesterone receptor-targeted azacyclic carbene intermediate and a ruthenium complex, a preparation method and application thereof. Background technique [0002] Breast cancer is one of the major diseases that currently threaten women's health. Its incidence accounts for 7-10% of the incidence of various malignant tumors in the whole body. It is second only to uterine tumors in female tumors and has become a major cause of harm to women's health around the world. Adjuvant chemotherapy is one of the main methods for the treatment of breast cancer. It can reduce the stage and recurrence and metastasis rate of the primary tumor of breast cancer, and improve the operation rate and overall survival rate. However, the current clinical chemotherapy drugs are unsatisfactory for advanced patients, and they are limited to relieving the disease and cannot be cured. Moreover, due...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J43/00C07F15/00A61K31/555A61P35/00
CPCA61P35/00C07F15/0046C07J43/003
Inventor 吕高超林建国邱玲李珂刘清竹
Owner JIANGSU INST OF NUCLEAR MEDICINE
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