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Camptothecin derivative and its preparation

A technology of derivatives and camptothecin, which is applied in the field of preparation of camptothecin derivatives, can solve the problems of light and heat instability, poor solubility, large toxic and side effects, etc., to achieve reduced toxicity, good water solubility, and maintain pharmacological activity Effect

Inactive Publication Date: 2009-01-14
NORTHEAST FORESTRY UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] 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, unstable light and heat, and large toxic and side effects.
[0006] In order to accomplish the purpose of the present invention, the inventors have carried out a lot of creative research, on the premise of maintaining the anti-tumor pharmacological activity of camptothecin, to solve the problems of poor solubility, unstable light and heat, and large toxic and side effects, and finally found that A camptothecin derivative substituted by the 10-position haloalkane can be produced by reacting the 10-position hydroxyl of the camptothecin derivative with a haloalkane, and a 20-esterified camptothecin derivative can be generated by reacting the 20-position hydroxyl of the camptothecin with a halogenated carboxylic acid

Method used

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  • Camptothecin derivative and its preparation
  • Camptothecin derivative and its preparation
  • Camptothecin derivative and its preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] 10-O-(3-pyridinium salt) propyl camptothecin

[0074] (1) Synthesis of 10-O-(3-bromo)propyl camptothecin

[0075] Add 182.18mg (0.5mmol) of 10-hydroxycamptothecin in a 25mL round bottom flask, 1.5mL DMSO and 345.94mg (2.5mmol) of anhydrous potassium carbonate, after stirring and dissolving, add 0.86mL of 1,3-dibromopropane ( 10.01mmol), N 2 Heated to 60°C under protection, stirred for 72 hours, and followed the reaction by TLC. After the reaction was complete, the reaction liquid was poured into water, and the solid was precipitated, filtered, and the obtained solid was dissolved in chloroform and methanol with a volume fraction of 8:2, and passed through a silica gel column. Separation and purification by chromatography, and gradient elution with chloroform-methanol (100:1-100:3) gave compound 10-O-(3-bromo)propylcamptothecin. The molecular weight of the compound is: 484.06, and the structural formula is as follows:

[0076]

[0077] (2) Synthesis of 10-O-(3-pyri...

Embodiment 2

[0081] 10-O-(3-(3-acetyl)pyridinium salt-1)propylcamptothecin

[0082] (1) The synthetic method of 10-O-(3-bromo) propyl camptothecin is identical with embodiment 1 (1)

[0083] (2) Synthesis of 10-O-(3-(3-acetyl)pyridinium salt-1)propylcamptothecin

[0084] Add compound 10-O-(3-bromo)propyl camptothecin 97.07mg (0.2mmol) and excess 3-acetylpyridine in a 25mL round bottom flask, heat to 50°C, stir for 12h, track the reaction by TLC, the product The Rf value developed in methanol is zero. After the reaction is complete, trichloromethane is added to the reaction solution to precipitate a yellow solid product, which is filtered, washed fully with trichloromethane, and vacuum-dried at 60°C to obtain the product 10-O-(3-( 3-acetyl)pyridinium salt-1) propylcamptothecin. The compound is light yellow powder, 95.10mg, molecular weight: 526.20; m.p.192°C, yield 90.4%. The structural formula is as follows:

[0085]

Embodiment 3

[0087] 10-O-(3-(3-hydroxy)pyridinium salt-1)propylcamptothecin

[0088] (1) The synthetic method of 10-O-(3-bromo) propyl camptothecin is identical with embodiment 1 (1)

[0089] (2) Synthesis of 10-O-(3-(3-hydroxy)pyridinium salt-1)propylcamptothecin

[0090] Add compound 10-O-(3-bromo)propyl camptothecin 97.07mg (0.2mmol), 1.5mL DMSO and excess 3-phenolhydroxypyridine into a 25mL round bottom flask, heat to 50°C to dissolve the reactant, and stir for 12h , the reaction was tracked by TLC, the Rf value of the product developed in methanol was zero, after the reaction was complete, an appropriate amount of chloroform was added to the reaction solution, and a yellow solid product was precipitated, filtered, and fully washed with a mixture of chloroform and methanol in an appropriate proportion , 60 ℃ vacuum drying to obtain the product 10-O-(3-(3-hydroxy) pyridinium salt-1) propyl camptothecin. The compound is light yellow powder, 80.4mg, m.p.293°C, molecular weight: 500.18; ...

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Abstract

The invention relates to camptothecin derivates in formulas of (I), (II) and (III) as well as acceptable salt in medicine, relating to a method for preparing the compounds as well as applications thereof in tumor therapy particularly by using the compounds as medicines. In the formulas of (I), (II) and (III), R1 is hydrogen and ethyl; R2 is hydrogen and nitryl; R3 is oxhydryl, amido, an amine compound, and a compound containing one or a plurality of five-membered or six-membered nitrogen heterocyclic rings as well as derivates thereof; R4 is hydrogen and oxhydryl; and n can be 2, 3 and 4.

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): C07D491/22A61K31/4745A61P35/00
Inventor 祖元刚李庆勇赵修华姚丽萍吕宏艳王丽敏马瑞萍张宝友金钱光于雪莹
Owner NORTHEAST FORESTRY UNIVERSITY