5,6-didehydronorcantharidin derivatives and their antitumor applications

A technology of methylcantharidinol and norcantharidin, applied in the direction of antineoplastic drugs, drug combinations, and active ingredients of heterocyclic compounds, can solve the problems of low bioavailability, unreported, poor water solubility, etc., and achieve easy operation Implementation, good anti-liver cancer effect, low-cost effect

Active Publication Date: 2017-04-12
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, both cantharidin and norcantharidin have been used clinically. Both of these two drugs have their own clinical characteristics, but the disadvantages are: the water solubility of these two drugs is poor, and the bioavailability is not high.
Chinese patents with application numbers ZL201410163619.4, ZL201410163711.0, and ZL201410163705.5 disclose methods for preparing demethylcantharidinate. So far, there has been no report on the design and synthesis of ring-opened 5,6-didehydronortharidin Structure and Synthetic Method of Cantharidin Derivatives

Method used

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  • 5,6-didehydronorcantharidin derivatives and their antitumor applications
  • 5,6-didehydronorcantharidin derivatives and their antitumor applications
  • 5,6-didehydronorcantharidin derivatives and their antitumor applications

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preparation example Construction

[0027] The synthetic method of aforementioned norcantharidin tharidinol derivative I of the present invention specifically comprises the following steps:

[0028] (1) Take maleic anhydride, grind it finely, add an organic solvent to dissolve, add furan dropwise after it is completely dissolved, react at 35°C-45°C for 24 hours, and filter with suction to obtain a white solid product 5,6-didehydrode Acantharidin, dried for later use;

[0029] (2) At room temperature, take the white solid product in step (1), dissolve it after adding an organic solvent, and cool to 0 o C, then slowly add LiAlH in batches 4 , stirred and reacted overnight, suction filtered after the reaction was completed, and was fully washed with tetrahydrofuran and water to obtain a clear liquid 5,6-didehydronorcantharidindiol, which was dried for later use;

[0030] (3) Dissolve 5,6-didehydronorcantharidin diol in an organic solvent and cool to 0 o Under C, first add 60% NaH, then add ethyl bromoacetate, th...

Embodiment 1

[0033] Embodiment 1. The preparation of 5,6-didehydronorcantharidin 1

[0034]

[0035] Take out a certain amount of maleic anhydride from the reagent bottle, place it in a dry grinding body and grind it finely, then weigh 12.021g of the finely ground maleic anhydride with an electronic balance, put it in a dry three-necked flask, and plug it Stopper, add diethyl ether and stir, when the volume of diethyl ether is 90 mL, the maleic anhydride is completely dissolved. After the maleic anhydride was completely dissolved, 13 mL of furan was slowly added with a dropping funnel for 13 minutes (minutes, also abbreviated as min). The temperature was controlled to start the reaction at 38°C. After reacting for 1 hour (hour, also abbreviated as h), white solids appeared in the solution, and the longer the time, the more white solids there were. After reacting for 24 hours, suction filtration was performed to obtain compound 1 as a white solid, namely 5,6-didehydronorcantharidin. T...

Embodiment 2

[0037] Embodiment 2. The preparation of 5,6-didehydronorcantharidin diol 2:

[0038]

[0039] Weigh 2.0 g of compound A that has been generated, add 25 ml of THF to a 25 ml clean flask, and stir in an ice bath until the solution is clear. Slowly add LiAlH in four batches 4 (689mg), reacted for 24h, and spotted the plate. Ethyl acetate was added, and the reaction was quenched with water to stabilize the reaction. Suction filtration, repeated filtration and washing with ethyl acetate and water three times, combined filtrates and spin-dried to obtain 2.05 g of crude product of 5,6-didehydronorcantharidin diol 2. Yield>100% , R f : 0.21 (developing agent is ethyl acetate); 1 HNMR (CDCl 3 ): δ: 6.38 (s, 2H), 4.68 (s, 2H), 3.76-3.85 (m, 4H), 1.94 (t, 2H).

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Abstract

The invention provides a 5, 6-bidehydronorcantharides alcohol derivative and application thereof to tumor resistance. The 5, 6-bidehydronorcantharides alcohol derivative has the structural formula as shown in the formula I as described in the description, wherein R is selected from -H or -CH2COOH. Activity tests prove that the 5, 6-bidehydronorcantharides alcohol derivative I designed and synthesized by the invention has a favorable anti-hepatoma effect and is expected to be applied as an antitumor cantharidin drug in clinic. In addition, the novel synthesis method for the compound has the advantages of available raw materials, low cost, simple synthesis route, high yield and convenience in operation and implementation.

Description

technical field [0001] The invention belongs to the field of new drug design and synthesis, and specifically relates to a novel 5,6-didehydronorcantharidin derivative and its antitumor application. Background technique [0002] Mylabris is a kind of insect, also known as "farting bug", which is a kind of traditional Chinese medicinal materials in my country. my country is the first country to use cantharidin as a medicinal material. There have been records about cantharidin being used as medicine in famous medical works such as "Compendium of Materia Medica" and "Shenlong Bencao Jing". [0003] Cantharidin (cantharidin, C 10 h 12 o 4 ) is a relatively effective anticancer substance extracted from insects. It is an effective ingredient in the folk treatment of malignant tumors. Compared with other antitumor drugs, it has many advantages. For example: it and its analogues will not suppress the immune function of the human body, and in addition, it can increase the white bl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/08A61K31/34A61P35/00
CPCC07D493/08
Inventor 赵长阔王先恒贾佳胡乔乔李晓飞
Owner ZUNYI MEDICAL UNIVERSITY
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