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Novel vinblastine derivative, preparation method and use thereof, and medical composition containing the derivative

A technology of vinblastine and its derivatives, applied in the field of medicinal chemistry, which can solve the problems of poor linear correlation of binding activity, inhibition of cell growth, etc.

Inactive Publication Date: 2008-08-06
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The Linear Correlation between Binding Activity of Vinblastine Antineoplastic Drugs to Microtubules and Its Inhibitory Activity on Cell Growth Is Not Good

Method used

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  • Novel vinblastine derivative, preparation method and use thereof, and medical composition containing the derivative
  • Novel vinblastine derivative, preparation method and use thereof, and medical composition containing the derivative
  • Novel vinblastine derivative, preparation method and use thereof, and medical composition containing the derivative

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0070] Preparation of Example 1 Compound A

[0071]

[0072] Under the protection of argon, take 456mg (1mmol) of Wendolin and dissolve it in 20mL of anhydrous tetrahydrofuran, slowly add 230mg (6mmol) of aluminum tetrahydrogen lithium in an ice bath at 0°C, stir at room temperature for 4 hours, add 0.23mL of water to quench Then add 0.23mL of 15% sodium hydroxide and 0.69mL of water successively, stir for 5 minutes, filter with sand star funnel, dry over anhydrous magnesium sulfate, concentrate under reduced pressure, and recrystallize with acetone to obtain white solid compound A, product Rate 85%-90%.

[0073] 1 H NMR (CDCl 3 , 300MHz): δ: 8.73(brs, 1H), 6.82(d, J=8.1Hz, 1H), 6.24(d, J=8.1Hz, 1H), 6.06(s, 1H), 5.80(dd, J= 10.2, 4.8Hz, 1H), 5.60(d, J=10.2Hz, 1H), 3.93(d, J=14.1Hz, 1H), 3.71(s, 3H), 3.54(s, 1H), 2.95(s, 3H), 2.51(s, 1H), 2.43(m, 1H), 2.16(m, 1H), 1.77(m, 1H), 1.30(m, 1H), 0.86(m, 1H), 0.56(t, J = 8.4Hz, 3H);

[0074] 13 C NMR (CDCl 3 , 75MHz): δ: 1...

preparation Embodiment 2

[0076] Preparation of Example 2 Compound B

[0077]

[0078] In a 100mL two-neck round bottom flask, 3.86g (10.00mmol) of compound A was dissolved in 25mL of THF, and 50% NaOH (1g NaOH: 1g H 2O) Stir at 50° C. for half an hour, then add 2.10 g (1.1 eq, 11.00 mmol) of toluene-4-sulfonyl chloride, raise the temperature to 80° C., and stir for 1 h. After the reaction was completed, it was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an epoxy oily intermediate without purification, and then proceeded to the next step of reaction. In a 250mL round bottom flask, dissolve the oily intermediate in 80mL of methanol and 10mL of water, add 3.25g (5eq) of sodium azide and 1.4g (3eq) of ammonium chloride in sequence, and reflux at 90°C for 24h. After the reaction was completed, it was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel ...

preparation Embodiment 3

[0081] Preparation of Example 3 Compound C1

[0082]

[0083] Under the protection of argon, take 386mg (1mmol) of compound A and dissolve it in 0mL tetrahydrofuran, add 50% aqueous sodium hydroxide solution (1g sodium hydroxide dissolved in 1g water), stir the reaction at 60°C for 0.5h, then add 0.15mL Bromoethane and 50mg tetra-n-butylammonium iodide, continue to react for 6h, then cool to room temperature, transfer the reaction solution to a separatory funnel, add 50mL water, then extract with dichloromethane (10mL×3), wash over anhydrous Dry over magnesium sulfate, and concentrate under reduced pressure to obtain a concentrate. Under the protection of argon, dissolve the concentrated solution in 1 mL of pyridine, add 1 mL of acetic anhydride, stir the reaction at room temperature for 8 h, then inject 30 mL of ethyl acetate and 10 mL of saturated sodium bicarbonate solution and continue stirring for 2 minutes, remove the water layer, and use Pyridine (20 mL×3) was washe...

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Abstract

The invention provides a vinblastine derivative of the formula at right or relative physiological acceptable salt, a relative preparation method, an application and a drug compound of the derivative, wherein the vinblastine derivative has inhibitory activity on tumor cell lines, which can be used as drug for treating malignant tumor.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular, the invention relates to a new class of vinblastine derivatives, a preparation method and application thereof, and a pharmaceutical composition comprising the derivatives. The vinblastine derivative has inhibitory activity on tumor cell lines and can be used as a medicine for treating malignant tumors. Background technique [0002] Tumor is one of the malignant diseases that threaten human life. The number of deaths due to tumors in the world is more than 5 million every year. In China, there are more than 1.6 million new cancer patients and more than 1.3 million deaths every year. Therefore, all countries in the world pay special attention to anti-tumor drugs. Research. [0003] Vinca alkaloids (Vinca alkaloids) antineoplastic drugs are obtained from the plants of the genus Vinca (Catharanthus roseus (L.) G.Don) and yellow vinca (Catharanthus roseus (L.) G.Don cv. Flavus) A cl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/04A61K31/475A61P35/00
CPCA61P35/00C07D519/04
Inventor 胡立宏沈旭蒋华良楼丽广丁宏邵勇章涵堃
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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