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A class of new compounds with radioprotective effect, its preparation method and its pharmaceutical application

A compound and drug technology, applied in the field of medicine, can solve the problems of limiting the wide application of radiotherapy, short half-life, high price, etc., and achieve the effects of prolonging the survival period and survival rate of animals, alleviating the side effects of radiotherapy, and reducing biological damage.

Active Publication Date: 2018-09-07
SHANGHAI KECHOW PHARMA
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AI Technical Summary

Problems solved by technology

[0005] On the other hand, the incidence of malignant tumors and the number of patients have been on the rise in recent years. Radiation therapy, as one of the main treatment methods, plays an indispensable role, but high-dose radiation exposure will inevitably lead to normal Acute radiation damage to tissues, organs and even the whole body, the side effects caused by radiation damage seriously limit the wide application of radiation therapy in tumor treatment, and also significantly affect the curative effect of radiation therapy and the quality of life of cancer patients after treatment
[0006] At present, the existing drugs related to the treatment of radiation damage mainly include: sulfur-containing compounds, hormones, cytokines, and Chinese herbal medicines, etc., which have their own inherent defects: for example, sulfur-containing compounds generally have relatively large side effects, and amifostine (also known as amifostine ) as the representative of this type of compound is currently recognized as the compound with the best protective effect, and is the first selective broad-spectrum cytoprotective agent passed by the international regulatory agency, but the half-life is extremely short (7 minutes) and expensive (domestic The medical market price is 400-500 yuan / branch) which limits its application; while the prevention and treatment of hormonal drugs to radiation damage is mainly to bone marrow nucleated cells, hematopoietic stem cells and progenitor cells, and the impact of such drugs on sexual organs and reproductive system It limits its wide use; cytokine drugs such as interleukins and colony-stimulating factor drugs can alleviate and treat the damage to the bone marrow hematopoietic function system caused by radiation, but its radiation protection effect is closely related to the time of administration (used for prevention and In the medical practice of rescue and treatment, such drugs require high levels of medical testing and attention), have obvious inflammatory effects, are expensive, and are difficult to store at room temperature; anti-radiation components of Chinese herbal medicines mainly include phenols, polysaccharides, natural Flavonoids have the characteristics of unclear active ingredients and low toxicity. After years of research, there are no similar drugs on the market or to be listed

Method used

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  • A class of new compounds with radioprotective effect, its preparation method and its pharmaceutical application
  • A class of new compounds with radioprotective effect, its preparation method and its pharmaceutical application
  • A class of new compounds with radioprotective effect, its preparation method and its pharmaceutical application

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Experimental program
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preparation example Construction

[0062] The preparation method of general formula (I) compound:

[0063]

Embodiment 1

[0064] Example 1: 4-(3,7-bis((2,2-dimethylthiazole-3-carbonyl)oxy)-5-hydroxy-4-oxo-4hydro-benzopyran-2-yl) -Synthesis of 1,2-phenylbis((2,2-dimethylthiazole-3-carbonyl) (compound 1)

[0065] Step 1: Synthesis of 2,2-dimethylthiazolidine-3-carbonyl chloride

[0066]

[0067] 2,2-Dimethylthiazole (1.17g, 10.0mmol) was dissolved in anhydrous dichloromethane (40ml), triphosgene (1.50g, 5mmol) was added in an ice-water bath, and then DIPEA (2.58g, 20.0 mmol). Remove the ice-water bath and stir at room temperature for half an hour. After the reaction, water (20ml) was added, extracted with dichloromethane (30ml×3), and the combined organic phases were washed with saturated brine (20ml). Drying in vacuo gave a crude orange oil (1.8 g, 99%) which was used directly in the next step.

[0068] Step 2: 4-(3,7-Bis((2,2-dimethylthiazole-3-carbonyl)oxy)-5-hydroxy-4-oxo-4hydro-benzopyran-2-yl)- Synthesis of 1,2-phenylbis((2,2-dimethylthiazole-3-carbonyl)(compound 1)

[0069]

[00...

Embodiment 2

[0071] Example 2: 2-(3,4-bis((2,2-dimethylthiazole-3-carbonyl)oxy)phenyl)-4-oxo-4hydro-benzopyran-3,5,7 -Synthesis of tri-based tris(2,2-dimethylthiazole-3-carbonyl)

[0072]

[0073] Dissolve quercetin (302mg, 1.0mmol) in DMF (1ml), dilute with dichloromethane (15ml), add 2,2-dimethylthiazole-3-carbonyl chloride crude product (1.8g ), triethylamine (707mg, 7.0mmol) and DMAP (122mg, 1.0mmol). The reaction mixture was stirred overnight at 30 °C. After the reaction, water (20ml) was added, extracted with dichloromethane (20ml×3), and the combined organic phases were washed with saturated brine (20ml). Then distilled under reduced pressure to obtain a yellow oil, the crude product was separated and purified by silica gel column chromatography (eluent: dichloromethane:methanol=100:1) to obtain a white solid (175mg, 17.2%): 1 H NMR (400MHz, CDCl 3 )δ7.82(s, 2H), 7.58(m, 1H), 7.46(s, 1H), 7.18(s, 1H), 4.04(m, 10H), 3.00(s, 10H), 1.84(m, 30H ).MS: C45H55N5O12S5, calculated 10...

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Abstract

The present invention provides novel compounds with radioprotective effects and pharmaceutically acceptable salts, prodrugs, and solvates thereof as shown in formula (I). Ar is selected from astaxanthin, anthocyanins, proanthocyanidins, resveratrol, VitaminA, VitaminC, VitaminE and flavonoids such as apigenin, luteolin, kaempferide, quercetin, glycyrrhizin, hesperidin, dihydroquercetin, Dihydromorin, (+) catechin, (-) epicatechin, ginkgetin, Ophiopogonone A, rubrofusarin, baicalein and the like, R1 is selected from the following groups shown in the specification, further, the present invention provides a preparation method and use of the compounds and the derivatives thereof in treatment of radiation injuries.

Description

technical field [0001] The invention relates to the field of medicine, in particular to the aspect of ionizing radiation damage protection, in particular to a class of new compounds with radiation protection effect. [0002] The present invention also relates to the preparation method of the compound. [0003] The present invention also relates to the application of the compound in the prevention and treatment of related damage and disease treatment caused by ionizing radiation. Background technique [0004] With the vigorous development of the global nuclear industry, nuclear technology has been widely used in various fields such as nuclear power plants, aerospace, national defense, and biomedicine. Human beings are more likely to be exposed to ionizing radiation and cause damage. The hidden dangers of nuclear war and nuclear terrorism, the protection and treatment of body damage caused by ionizing radiation (referred to as radiation damage) are receiving more and more att...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/14C07D277/04A61K31/427A61P39/00
CPCC07D277/04C07D417/14
Inventor 田红旗张倩如程瑛朱知梅王月英樊赛军
Owner SHANGHAI KECHOW PHARMA
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