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Camptothecin 20- position cholic acid derivative and preparation method thereof

A derivative, camptothecin technology, applied in the field of preparation of camptothecin derivatives, can solve problems such as poor targeting, light and heat instability, poor solubility, etc., to increase bioavailability, maintain pharmacological activity, reduce toxic effect

Inactive Publication Date: 2012-06-13
NORTHEAST FORESTRY UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The object of the present invention is to provide a camptothecin derivative that fully maintains the anti-tumor pharmacological activity of camptothecin and solves the problems of poor solubility, light and heat instability, poor targeting, low bioavailability, and large toxic and side effects.

Method used

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  • Camptothecin 20- position cholic acid derivative and preparation method thereof
  • Camptothecin 20- position cholic acid derivative and preparation method thereof
  • Camptothecin 20- position cholic acid derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1: cholic acid-20-O-glutamic acid-camptothecin synthesis:

[0043] (1) Synthesis of 20-O-camptothecin glutamate:

[0044] Add 174mg (0.5mmol) of camptothecin, 303mg (1mmol) of N-tert-butoxycarbonyl-glutamic acid 5-tert-butyl ester, 1-[(3-dimethylamino)propyl]-3 in a 25ml three-necked flask -Ethylcarbimide hydrochloride (EDCI) 286.5mg (1.5mmol), 4-dimethylaminopyridine (DMAP) 18mg (0.17mmol), anhydrous dichloromethane 10ml, stirring at room temperature for 3.5 hours, by TLC Track reactions. After the reaction was complete, 20ml of chloroform was added to the reaction solution, followed by 50ml of water, 50ml of saturated NaHCO 3 The solution was washed 3 times with anhydrous MgSO 4 Dry, filter under reduced pressure to remove MgSO 4 Concentrate under reduced pressure, add hydrochloric acid methanol solution to dissolve, stir at room temperature for 3 hours, follow the reaction by TLC, and concentrate under reduced pressure after the reaction is complete. ...

Embodiment 2

[0052] Embodiment 2: Synthesis of deoxycholic acid-20-O-glutamic acid-camptothecin:

[0053] (1) Synthesis of 20-O-camptothecin glutamate:

[0054] The method is the same as example 1(1)

[0055] (2) Synthesis of deoxycholic acid activated ester:

[0056] In a 25ml three-necked flask, add deoxycholic acid 196 (0.5mmol), N-hydroxysuccinimide 172.5mg (1.5mmol), 1-[(3-dimethylamino)propyl]-3-ethylcarbonyl Imine hydrochloride (EDCI) 286.5 mg (1.5 mmol), anhydrous dichloromethane 10 ml, stirred at room temperature for 3 hours, followed by TLC reaction. After the reaction was complete, 20ml of chloroform was added to the reaction solution, followed by 50ml of water, 50ml of saturated NaHCO 3 The solution was washed 3 times with anhydrous MgSO 4 Dry, filter under reduced pressure to remove MgSO 4 After concentrating under reduced pressure, 153 mg of white solid was obtained, with a yield of 64.9%; molecular weight 489; structural formula is as follows:

[0057]

[0058] (3) ...

Embodiment 3

[0061] Embodiment 3: Synthesis of ursodeoxycholic acid-20-O-glutamic acid-camptothecin:

[0062] (1) Synthesis of 20-O-camptothecin glutamate:

[0063] The method is the same as example 1(1)

[0064] (2) Synthesis of ursodeoxycholic acid activated ester:

[0065] In a 25ml three-necked flask, add deoxycholic acid 196 (0.5mmol), N-hydroxysuccinimide 172.5mg (1.5mmol), 1-[(3-dimethylamino)propyl]-3-ethylcarbonyl Imine hydrochloride (EDCI) 286.5 mg (1.5 mmol), anhydrous dichloromethane 10 ml, stirred at room temperature for 3 hours, followed by TLC reaction. After the reaction was complete, 20ml of chloroform was added to the reaction solution, followed by 50ml of water, 50ml of saturated NaHCO 3 The solution was washed 3 times with anhydrous MgSO 4 Dry, filter under reduced pressure to remove MgSO 4 Concentrate under reduced pressure to obtain a white solid with a yield of 77%; the molecular weight is 489; the structural formula is as follows:

[0066]

[0067] (3) Synt...

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Abstract

The invention relates to a camptothecin derivative of the formula (I) and a medicine thereof, relating to a method for preparing the compound, in particular an application in treating a tumour using the compound as the medicine. R1 in the formula (I) is hydrogen and ethyl, and R2 is hydrogen and nitryl, and R3 and R4 are hydrogen and hydroxyl.

Description

technical field [0001] The invention relates to a preparation method of a class of camptothecin derivatives and their application in antitumor therapy. Background technique [0002] In 1966, camptothecin was discovered by American scientist Monroe E.Wall et al. who studied natural products due to its remarkable anti-tumor activity. In the past 38 years, medicinal chemists have made researches on the structural modification of camptothecin. A lot of work, the United States, Japan, the United Kingdom, Canada and other countries have actively invested in the research and development of camptothecin derivatives, and have made great achievements. A large number of camptothecin derivatives have been designed and synthesized, and there are two camptothecin derivatives successively. Derivatives Topotecan and Irinotecan have been approved as anti-tumor drugs and have been marketed around the world, and more than a dozen other camptothecin derivatives are in different stages of clinic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00A61K31/585A61P35/00
CPCY02P20/55
Inventor 李庆勇祖元刚赵腾飞张宝友高文轻张黎朱翘楚孙佰贺
Owner NORTHEAST FORESTRY UNIVERSITY