Water-soluble camptothecine derivative and its preparation process and application thereof

A camptothecin, water-soluble technology, applied in the direction of drug combination, pharmaceutical formula, organic active ingredients, etc., can solve the problem of inability to prepare camptothecin derivatives, etc., and achieve low cost, good water solubility, and broad anti-tumor spectrum Effect

Inactive Publication Date: 2007-08-01
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this reaction condition cannot prepare other alkynyl-substituted camptothecin derivatives

Method used

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  • Water-soluble camptothecine derivative and its preparation process and application thereof
  • Water-soluble camptothecine derivative and its preparation process and application thereof
  • Water-soluble camptothecine derivative and its preparation process and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: the preparation of 7-(3'-dimethylaminopropynyl) camptothecin (CPT-11)

[0052] Add 500mg of 7-chloro-20-acetylcamptothecin, 40mg of palladium acetate, 220mg of BINAP, and 325mg of anhydrous potassium carbonate into the flask, under nitrogen protection, add 0.40ml of 3-dimethylaminopropyne, 75mL of toluene, reflux reaction 22 Hours, the detection reaction was complete, cooled, filtered, and the toluene was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with chloroform:methanol (200:1) to obtain 7-(3'-dimethylaminopropynyl)- 20-acetyl camptothecin 400mg.

[0053]The above product was added to 20 mL of concentrated sulfuric acid, stirred at room temperature until the reaction was complete, the reaction mixture was added to crushed ice, neutralized with NaOH aqueous solution, extracted with chloroform, and column chromatographed to obtain 250 mg of 7-(3'-dimethyl Aminopropynyl) camptothecin (CPT-11...

Embodiment 2

[0056] Embodiment 2: 7-(3'-piperidinyl propynyl) camptothecin (CPT-21) preparation:

[0057] Add 500mg of 7-chloro-20-acetylcamptothecin, 40mg of palladium acetate, 220mg of BINAP, and 325mg of anhydrous potassium carbonate into the flask, under nitrogen protection, add 0.45ml of 3-piperidylpropyne, 75mL of toluene, and reflux reaction 22 After 1 hour, the detection reaction was complete, cooled, filtered, and the toluene was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with chloroform:methanol (200:1) to obtain 7-(3'-piperidinylpropynyl)-20 - Acetyl camptothecin 460mg.

[0058] The above product was added to 20 mL of concentrated sulfuric acid, stirred at room temperature until the reaction was complete, the reaction mixture was added to crushed ice, adjusted to neutrality with NaOH aqueous solution, extracted with chloroform, and column chromatographed to obtain 300 mg of 7-(3'-piperidine ylpropynyl) camptothec...

Embodiment 3

[0061] Example 3: 7-(3'-diisopropylaminopropynyl)camptothecin (CPT-17)

[0062] Add 500mg of 7-chloro-20-acetylcamptothecin, 40mg of palladium acetate, 220mg of BINAP, and 325mg of anhydrous potassium carbonate into the flask, under nitrogen protection, add 0.50ml of 3-diisopropylaminopropyne, 75mL of toluene, and reflux reaction After 22 hours, the reaction was detected to be complete, cooled, filtered, and the toluene was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with chloroform:methanol (200:1) to obtain 7-(3'-diisopropylaminopropyne base)-20-acetylcamptothecin 300mg.

[0063] The above product was added to 20 mL of concentrated sulfuric acid, stirred at room temperature until the reaction was complete, the reaction mixture was added to crushed ice, neutralized with NaOH aqueous solution, extracted with chloroform, and column chromatographed to obtain 150 mg of 7-(3'-diiso Propylaminopropynyl) camptothecin ...

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Abstract

The invention discloses water-soluble camptothecine derivatives with its general formula being (I), its mono-isomer, antimer and relevant mixer, medical-use salt and active metabolism. The definition of R1 and R2 is expressed in instruction manual. The derivatives are prepared through Sonogashira reaction with 7- chloro- camptothecine by using palladium catalyst with existance of organophosphorus ligand and alkali. Said water-soluble camptothecine derivatives can resist tumor and can be used to prepare anti-tumor medicine.

Description

technical field [0001] The present invention relates to compounds with anti-tumor activity, in particular to water-soluble camptothecin derivatives, their preparation methods and their role as drugs in tumor treatment. Background technique [0002] Camptothecin (compound 1) was extracted and isolated from camptothecin for the first time by Wall et al. (J.Am.Chem.Soc., 1966, 88, 3888). The alkaloid contains five rings in its structure, and there is an S-type chiral center at the 20th position of the E ring, and there is a lactone structure next to it. Camptothecin has a certain curative effect on gastric cancer, rectal cancer, etc., but its water solubility and ester solubility are very poor, and its toxic and side effects are large, so the clinical research has been suspended. [0003] [0004] Although camptothecin is an alkaloid, it cannot form a salt with other acids to achieve water solubility. Therefore, many analogues of camptothecin have been synthesized in order...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22A61K31/4745A61P35/00
Inventor 杨波吕伟何俏军罗宇
Owner ZHEJIANG UNIV
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