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20-esterifiable camptothecine derivative and method for making same and pharmaceutical combination and uses

A compound, C1-C6 technology, applied in the field of anti-tumor drugs, can solve the problems of low anti-tumor activity and high toxicity

Inactive Publication Date: 2008-06-11
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since camptothecin and 10-hydroxycamptothecin are unmodified natural products, they are highly toxic and have low anti-tumor activity, which limits their clinical application; moreover, patients are prone to drug resistance after long-term use of these drugs. Anticancer drugs with high efficiency and low toxicity need to be found

Method used

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  • 20-esterifiable camptothecine derivative and method for making same and pharmaceutical combination and uses
  • 20-esterifiable camptothecine derivative and method for making same and pharmaceutical combination and uses
  • 20-esterifiable camptothecine derivative and method for making same and pharmaceutical combination and uses

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] 20S-camptothecin ester of embodiment 1.5-nitro-2-furancarboxylic acid (compound 1)

[0105] In a 10mL round bottom flask, add 10mg (0.028mmol) camptothecin, 9.0mg (0.057mmol) 5-nitro-2-furancarboxylic acid, 25mg (0.13mmol) 1-(3-dimethylaminopropyl)-3 - Ethylcarbimide hydrochloride (EDCI), 2 mg (0.019 mmol) 4-dimethylaminopyridine (DMAP) and 3 mL dichloromethane. After the reaction mixture was stirred at room temperature for 12 hours (clear), it was diluted with 20 mL of chloroform, and the chloroform layer was washed with water (15 mL), saturated sodium bicarbonate solution (15 mL) and saturated brine (15 mL), and dried over anhydrous magnesium sulfate . After removing magnesium sulfate by filtration, it was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: chloroform-methanol 97:3) to obtain 12.0mg 20-O-5-nitro-2-furanoic acid camptothecin ester, yield: 85.0%, mp 228- 230°C.

[0106] 1 HNMR (CDCl 3 , 300MH...

Embodiment 2

[0107] 20S-camptothecin ester of embodiment 2.5-bromo-2-furancarboxylic acid (compound 2)

[0108] In a 10mL round bottom flask, add 10mg (0.028mmol) camptothecin, 10mg (0.052mmol) 5-bromo-2-furancarboxylic acid, 25mg (0.13mmol) 1-(3-dimethylaminopropyl)-3-ethane Ethylcarbimide hydrochloride (EDCI), 2mg (0.019mmol) 4-dimethylaminopyridine (DMAP) and 3mL dichloromethane. After the reaction mixture was stirred at room temperature for 36 hours, it was diluted with 20 mL of chloroform, and the chloroform layer was washed with water (15 mL), saturated sodium bicarbonate solution (15 mL) and saturated brine (15 mL), and dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, it was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: chloroform-methanol 97:3) to obtain 3.0 mg 20-O-5-bromo-2-furanic acid camptothecin ester, yield: 20.0%, mp 203-206 ℃.

[0109] 1 HNMR (CDCl 3 , 300MHz): δ8.41(s...

Embodiment 3

[0110] 20S-7-ethylcamptothecin ester of embodiment 3.5-nitro-2-furancarboxylic acid (compound 3)

[0111] In a 10mL round bottom flask, add 10mg (0.027mmol) 7-ethylcamptothecin, 8.0mg (0.052mmol) 5-nitro-2-furancarboxylic acid, 25mg (0.13mmol) 1-(3-dimethylaminopropyl Dimethyl)-3-ethylcarbimide hydrochloride (EDCI), 2mg (0.019mmol) 4-dimethylaminopyridine (DMAP) and 3mL dichloromethane. After the reaction mixture was stirred at room temperature for 12 hours (clear), it was diluted with 20 mL of chloroform, and the chloroform layer was washed with water (15 mL), saturated sodium bicarbonate solution (15 mL) and saturated brine (15 mL), and dried over anhydrous magnesium sulfate . After removing magnesium sulfate by filtration, it was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: chloroform-methanol 97:3) to obtain 11.2 mg of 20-O-5-nitro-2-furancarboxylic acid-7-ethylcamptothecin ester, yield: 81.8 %, mp 297-299° ...

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Abstract

A 20-position esterified camptothecine derivative, its preparing process, the composite medicine contaiing it, and its application in medicine, especially in antineoplastic medicine are disclosed.

Description

field of invention [0001] The present invention relates to novel 20-esterified camptothecin derivatives, their preparation method, their pharmaceutical composition, and their use as medicine, especially as antitumor medicine. [0002] Background technique [0003] Camptothecin (CPT) is an alkaloid isolated from Camptotheca acuminata. Experiments have proved that camptothecin has anticancer activity on many solid tumors. It mainly acts on DNA topoisomerase I (Topo I, an enzyme highly expressed in many cancer cells), and is the most classic specific inhibitor of Topo I. agent. Topo I is currently one of the most popular targets for designing new anticancer drugs. The National Cancer Institute (NCI) drug mechanism analysis computer network system has listed Topo I inhibitors as one of the six major anti-tumor drugs for key research. In addition to the United States and Japan, France, Germany, Italy and South Korea are also conducting research on camptothecin derivatives. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/22A61K31/4375A61P35/00
Inventor 潘显道陈晓光孙飘扬杨晶朱承根袁开红李燕
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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