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Derivatives of taxol and taxotere and composition and anti-tumor application of derivatives

A technology of paclitaxel derivatives and compounds, applied in the application field of medicine

Active Publication Date: 2015-10-14
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patents WO9638138 (Protaxol, novel toxoids, Biophysica Foundation), WO9858927 (Buck Norton Pharmaceutical Co., Ltd.), CN00115426.5 (polyhydroxy water-soluble derivatives of paclitaxel and their preparation methods, Fudan University) disclose several new types of soluble paclitaxel Derivatives can be used to treat tumors or other paclitaxel-sensitive diseases, but such new compounds that add water-soluble additional groups to paclitaxel molecules have not been developed into clinical therapeutic drugs so far

Method used

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  • Derivatives of taxol and taxotere and composition and anti-tumor application of derivatives
  • Derivatives of taxol and taxotere and composition and anti-tumor application of derivatives
  • Derivatives of taxol and taxotere and composition and anti-tumor application of derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Example 1 Preparation of 13-[(2'R,3'S)-3'-phenyl-2'-hydroxyl-3'-(thiophene-2-methyl)amino-propionyl]-10-deacetyl- Baccatin III (Ia, R 1 =H,R 2 = Thiophen-2-yl, R 3 =Ph)

[0105]

[0106] step 1

[0107] Add 211 mg (0.2 mmol) of compound III, 19 mg (0.08 mmol) of camphorsulfonic acid, 90 mg (0.8 mmol) of thiophene-2-carbaldehyde and 100 mg of molecular sieves into a dry reaction bottle, seal it, exchange argon and protect it with an argon balloon, and finally add 3 mL of no Water and dichloromethane were reacted for 4 hours under stirring at room temperature. 10 mg (0.16 mmol) of sodium cyanoborohydride was added, and the reaction was continued for 1 hour, and the starting point disappeared as detected by TLC. The reaction solution was filtered, and the filtrate was washed successively with saturated sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. It was filtered, concentrated, and separated by a silica gel column (petroleum eth...

Embodiment 2

[0111] Example 2 Preparation of 13-[(2'R,3'S)-3'-phenyl-2'-hydroxy-3'-(thiophene-3-methyl)amino-propionyl]-10-deacetyl- Baccatin III (Ib, R 1 =H,R 2 = Thiophen-3-yl, R 3 =Ph)

[0112]

[0113] step 1

[0114] Add compound III 400mg (0.378mmol), camphorsulfonic acid 35mg (0.15mmol), thiophene-3-carboxaldehyde 102mg (0.9mmol) and molecular sieve 100mg in dry reaction bottle, seal, exchange argon and protect with argon balloon, finally add 4mL without Water and dichloromethane were reacted for 4 hours under stirring at room temperature. 19 mg (0.30 mmol) of sodium cyanoborohydride was added, and the reaction was continued for 1 hour, and the starting point disappeared as detected by TLC. The reaction solution was filtered, and the filtrate was washed successively with saturated sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. It was filtered, concentrated, and separated by a silica gel column (petroleum ether: acetone = 5:1) to obtain 184...

Embodiment 3

[0118] Example 3 Preparation of 13-[(2'R,3'S)-3'-phenyl-2'-hydroxyl-3'-(thiazole-4-methyl)amino-propionyl]-10-deacetyl- Baccatin III (Ic, R 1 =H,R 2 = Thiazol-4-yl, R 3 =Ph)

[0119]

[0120] step 1

[0121] Add 500 mg (0.47 mmol) of compound III, 45 mg (0.19 mmol) of camphorsulfonic acid, 130 mg (1.15 mmol) of thiazole-4-carbaldehyde and 100 mg of molecular sieve into a dry reaction bottle, seal it, exchange argon and protect it with an argon balloon, and finally add 5 mL of Water and dichloromethane were reacted for 4 hours under stirring at room temperature. 25 mg (0.4 mmol) of sodium cyanoborohydride was added, and the reaction was continued for 1 hour, and the starting point disappeared as detected by TLC. The reaction solution was filtered, and the filtrate was washed successively with saturated sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. It was filtered, concentrated, and separated by a silica gel column (petroleum ether: a...

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PUM

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Abstract

The invention discloses derivatives of taxol and taxotere and a composition and anti-tumor application of the derivatives. Specifically, the invention discloses semi-synthetic taxol derivatives shown in a general formula (A) and pharmaceutically acceptable salts of the derivatives. The preparation method of the compounds comprises two steps; a preferable reducing agent used in the step 1 is sodium cyanoborohydride; a preferable Troc removal protecting group is treated with ammonium chloride and zinc powder. The invention further discloses a medicine composition; the medicine composition comprises an effective dosage of the compounds shown in the general formula (A) or pharmaceutically acceptable salts of the compounds and pharmacodynamically acceptable carriers. The invention also discloses the application of the compounds and the pharmaceutically acceptable salts of the compounds in preparation of anti-tumor medicines (The formula (A) is shown in the specification).

Description

technical field [0001] The present invention relates to a new class of paclitaxel derivatives and salts, a preparation method thereof, a pharmaceutical composition containing the compound, and an application of the compound in preparing medicine for treating cancer. Background technique [0002] Paclitaxel is a natural product isolated from Taxus brevifolia (Wani MC, Taylor HL, Wall ME, The isolation and structure of taxol, a novel antileukemic and antitumor agent from tausbrevifolia, J.Am.Chem.Soc .1971, 93, 2325). The compound can promote microtubule polymerization and prevent its depolymerization in cells (Horwitz SB, Fant J, Schiff PB, Promotion of microtubule assembly in vitro by taxol, Nature, 1979, 277, 665), thereby blocking the process of cell mitosis, and has great Strong cytotoxicity and antitumor effect. Subsequent in-depth research on it also found that it has a broad anti-tumor spectrum, and it has been approved for marketing in many countries around the worl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/12C07D417/12C07D409/14A61K31/381A61K31/427A61P35/00
CPCY02P20/55C07D409/12C07D409/14C07D417/12
Inventor 吴克美叶仙蓉俞晓明陈晓光王凤李永强李燕周玉美梅梅李云峰籍秀娟张福荣
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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