Water-soluble derivates containing 10-hydroxycamptothecin and preparation method

A technology of hydroxycamptothecin and its derivatives, applied in the field of water-soluble derivatives and its preparation

Inactive Publication Date: 2009-04-01
重庆医科大学医药研究所
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The active ingredient released by hydrolysis in plasma is hydroxycamptothecin, but these compounds do not solve the problem of HCPT water solubility very well

Method used

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  • Water-soluble derivates containing 10-hydroxycamptothecin and preparation method
  • Water-soluble derivates containing 10-hydroxycamptothecin and preparation method
  • Water-soluble derivates containing 10-hydroxycamptothecin and preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Preparation of Hydroxycamptothecin 10-(γ-N,N-Diethylamino)butyrate Hydrochloride

[0032] Under a dry nitrogen flow, add 80 mg of 10-hydroxycamptothecin and 4 ml of anhydrous pyridine into a 25 ml dry three-necked flask, and stir at room temperature until completely dissolved. Dissolve 300 mg (γ-N, N-diethylamino) butyryl chloride hydrochloride in 5 ml of dry dichloromethane, slowly add it dropwise, and react at room temperature for 2-3 hours. After the reaction is complete, add a few drops of water to the reaction solution, stir for 5 minutes, add 15ml of ether, and precipitate a solid, filter it, and rinse the solid with ether. Dissolve the solid in methanol, add diethyl ether dropwise until it becomes turbid, static crystallize, suction filter, rinse with diethyl ether; recrystallize according to the above method, dry under reduced pressure to obtain 60 mg of light yellow solid, m.p221-223°C, harvested rate 54%. IR (KBr, cm -1 ): 3559, 3435, 2942, 2646, 1774, 1743...

Embodiment 2

[0035] Preparation of Hydroxycamptothecin 10-(γ-Amino)butyrate Acetate

[0036] Dissolve 280 mg of CBZ-protected GABA and 250 mg of DCC in 10 ml of CH 2 Cl 2 In, add 40mg DMAP, stir at room temperature for 10min, then add 0.5ml pyridine and 150mg HCPT. After reacting for more than 10 hours, filter, and wash the filtrate with pH3 acid water until the water layer is acidic. NaHCO 3 Wash until the aqueous layer is alkaline, and finally wash with saturated brine until neutral. The organic layer was washed with anhydrous Na 2 SO 4 Dry and evaporate the organic solvent. Dissolve in THF, add 0.5ml of acetic acid, a little 10% palladium-carbon, pass through hydrogen for hydrogenolysis, react for about 1 hour, filter, add ether to crystallize, and obtain 100mg of light yellow solid, yield 46%. IR (KBr, cm -1 ): 3428, 2927, 1745, 1657, 1623, 1591, 1504, 1235, 1193, 1162, 1109, 1047. ESI-MS: 450 (M+ -AcOH)

Embodiment 3

[0038] Preparation of HCPT-γ—aminobutyrate hydrochloride

[0039] Dissolve 230mg of Boc-protected γ-aminobutyric acid and 250mg of DCC in 10ml of CH 2 Cl 2 In, add 40mg DMAP, stir 10min. Add 0.5ml of pyridine and 150mg of HCPT, and react for more than 10 hours. After the reaction is completed, wash with pH3 acidic water until the water layer is acidic, then wash with saturated NaHCO3 until the water layer is alkaline, and finally wash with saturated saline until the water layer To be neutral, the organic layer was dried with anhydrous NaSO4. The organic solvent was evaporated to obtain 200 mg of a light yellow solid with a yield of 85%. Dissolve the solid in a mixture of ethyl acetate and dichloromethane, add HCl-saturated ethyl acetate solution dropwise under ice-bath cooling, filter after the reaction is complete, dissolve the filter cake in water, add acetone, crystallize, and filter 20 mg of HCPT-γ-aminobutyrate hydrochloride was obtained. Yield 11%. ESI-MS: 450 (M ...

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Abstract

The invention discloses a series of amino-acid ester with molecules internally containing 10-hydroxycamptothecin and derivatives thereof and also discloses water-soluble derivatives forming salts with acids, and a preparation method thereof. The water-soluble derivatives have the formula (I), wherein, A represents saturated hydrocarbons; D represents organic groups containing nitrogen atoms; HB represents the acids forming salt with the organic groups. The compounds have better water-solubility and the arylate can be easily hydrolyzed in the body of human and animals to release the 10-hydroxycamptothecin and the derivatives so as to play the role of anti-cancer.

Description

technical field [0001] The invention relates to a series of water-soluble derivatives of amino acid ester salts containing hydroxycamptothecin and a preparation method thereof. Background technique [0002] In 1966, Wall et al. in the United States isolated Camptothecin (CPT) (CPT) (J Am Chem Soc.196688: 3883-3890) from the unique Chinese plant Camptotheca acuminata for the first time, because of its unique chemical structure and Significant anti-tumor activity has attracted the attention of relevant personnel all over the world, but camptothecin has severe side effects, which limits its clinical application. Subsequently, 10-hydroxycamptothecin (HCPT) was isolated from camptothecin, and clinical trials showed that it has a wide anti-cancer spectrum, remarkable curative effect, and less toxic and side effects, especially for primary liver cancer, gastric It has a significant curative effect on malignant tumors such as bowel cancer, bladder cancer, head and neck skin cancer,...

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 李勤耕罗绪王涛袁佩田睿全继平郭彬徐少杰
Owner 重庆医科大学医药研究所
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