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Camptothecin derivative, and preparation method and application thereof to preparation of medicament for treating tumor

A tumor drug, camptothecin technology, applied in the direction of anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve the problems of limited curative effect and dosage, and achieve the effects of increasing water solubility, improving efficiency, and improving biological activity

Inactive Publication Date: 2012-10-17
广州融新生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Two camptothecin derivatives, topotecan and irinotecan, have been used worldwide for the treatment of small cell lung cancer / ovarian cancer and colorectal cancer respectively, although compared with the dissolution of camptothecin However, their toxicity and adverse reactions are still strong, including diarrhea, hematuria, vomiting, nausea, etc., which limits their curative effect and dosage, and an oral preparation has not yet been developed

Method used

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  • Camptothecin derivative, and preparation method and application thereof to preparation of medicament for treating tumor
  • Camptothecin derivative, and preparation method and application thereof to preparation of medicament for treating tumor
  • Camptothecin derivative, and preparation method and application thereof to preparation of medicament for treating tumor

Examples

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Effect test

Embodiment 1

[0065] A camptothecin derivative with a chemical name: 20-{[(2Z)-3-carboxy-2-acryloyl]amino}acetoxycamptothecin, whose chemical structural formula is as follows:

[0066]

[0067] The preparation method of above-mentioned camptothecin derivatives comprises the following steps, and its synthetic route is shown in image 3 :

[0068] Camptothecin (compound 60, 1.2g, 3.45mmol) aqueous solution, scandium trifluoromethanesulfonate (1.018g, 2.07mmol), dimethylaminopyridine (DMAP, 1.264g, 10.3mmol), 80mL of anhydrous dichloro After mixing methane (DCM), cool to -8°C in an ice-salt bath, add 1.8g (10.3mmol) 2-(tert-butoxy-carbonyl amido)-acetic acid after 30min, stir at -8°C for 30min, add 3.557g (17.2mmol) dicyclohexylcarbodiimide (DCCI), continue to stir at -8°C for 30min, then place at room temperature for 24h, filter the reaction mixture, and successively wash with 2×30mL 0.1N hydrochloric acid, 30mL distilled water, 30mL saturated NaCl Solution wash. The organic phase of th...

Embodiment 2

[0072] A camptothecin derivative, chemical name: 20-{[(2Z)-3-carboxy-2-acryloyl]amino}acetoxy-10-propanesulfonyloxy-9-(dimethylamino) Methylcamptothecin, its chemical structural formula is as follows:

[0073]

[0074] The preparation method of above-mentioned camptothecin derivatives comprises the following steps, and its synthetic route is shown in Figure 4 :

[0075] Topotecan (compound 80, 0.2g, 0.44mmol) and dimethylaminopyridine (0.04g, 0.33mmol) were mixed, then dissolved in 10mL DMF, the solution was cooled to 0°C, 0.62mL triethylamine was added, and then Add 5mL of n-propylsulfonyl chloride (0.40mL, 3.52mmol) aqueous solution dropwise, react under magnetic stirring at 0°C for 6h, add 20mL of water to the reaction mixture, extract with 20mL×3 times of dichloromethane, and dissolve with 10% hydrochloric acid The pH of the solution layer was adjusted to 7, and then the precipitated solid was filtered by suction to obtain 0.11g bright yellow compound 85 ( Figure 4 )...

Embodiment 3

[0080] A camptothecin derivative, chemical name: 20-{[(2Z)-3-carboxy-2-acryloyl]amino}acetoxy-10-isopropylsulfonyloxy-9-(dimethylamino ) methyl camptothecin, its chemical structural formula is as follows:

[0081]

[0082] The preparation method of above-mentioned camptothecin derivatives comprises the following steps, and its synthetic route is shown in Figure 5 :

[0083] Mix topotecan (compound 80, 0.2g, 0.44mmol) and dimethylaminopyridine (0.04g, 0.33mmol), then dissolve in 10mL DMF, cool the solution to 0°C, add 0.92mL triethylamine, and gradually Add 5mL of isopropylsulfonyl chloride (0.76mL, 6.60mmol) aqueous solution dropwise, react for 5h under magnetic stirring at 0°C, add 30mL of water to the reaction mixture, extract with 20mL×3 times of dichloromethane, and dissolve with 10% hydrochloric acid The pH of the solution layer was adjusted to 7, and then the precipitated solid was filtered with suction to obtain 0.14 g of bright yellow compound 105, with a yield o...

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Abstract

The invention discloses a camptothecin derivative, and a preparation method and application thereof to preparation of medicament for treating tumor. The camptothecin derivative has a following structural formula; and the derivative, salts and composition thereof can be applied to preparation of medicaments for treating mammalian cell proliferative diseases, such as cancer. Through its own medicament molecular design and further biological activity determinations in vitro and in vivo, the prepared and synthesized compound is proved to have obvious inhibitory activity on various cancers, and shows good results in models for inhibiting growth of mouse tumor.

Description

technical field [0001] The present invention relates to camptothecin derivatives, their preparation method and their application in the preparation of drugs for treating tumors. Background technique [0002] Cancer is currently the number one killer of human health. According to statistics released by the Ministry of Health in 2010, malignant tumors have become the leading cause of death in China, and more than 1 million patients die of tumors every year. According to the statistics of the World Health Organization (WHO), nearly 700,000 people die of malignant tumors in the world every year on average, and about 8.7 million new cases are reported, and the number of new cases is still increasing every year. Cerebrovascular disease. Therefore, the treatment of cancer is urgent. [0003] Camptothecin (CPT) is a cytotoxic alkaloid extracted from Camptotheca involucrata in 1966, and its structural formula is as follows: [0004] [0005] Camptothecin belongs to tryptophan-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22A61K31/4745A61P35/00
CPCY02P20/55
Inventor 岑国亮林洁贞余慧东侯廷军
Owner 广州融新生物科技有限公司
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