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Preparation method and medical uses of Nú¿1ú®-hydrocarbyl-3íõ-nitrotylindirubin derivative 1

A technology of indirubin and derivatives, which is applied to the preparation of N(1)-hydrocarbyl-3′-oxime indirubin derivatives (I) and its medical application field, can solve the problem of poor water solubility and oil solubility , the compound polarity is large, the bioavailability is poor, etc., to achieve the effect of economical method

Inactive Publication Date: 2006-04-26
JC (WUXI) CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the bisindole heterocyclic planar structure of indirubin, it has a relatively large polarity. This physical and chemical property determines that its water solubility and oil solubility are very poor, and it is difficult to reach the drug action site through the biomembrane, and the bioavailability is poor.
For example, the compound Indirubin-3'-monoxime-5 Sulphonic acid (IMSA) [EP1079826B1] in the European invention patent, although it has a strong CDK inhibitory effect in a cell-free experimental system, the compound is extremely polar and cannot pass through Cell membrane, so we have proved that there is no biological function in the cell system, see Experimental Example 2

Method used

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  • Preparation method and medical uses of Nú¿1ú®-hydrocarbyl-3íõ-nitrotylindirubin derivative 1
  • Preparation method and medical uses of Nú¿1ú®-hydrocarbyl-3íõ-nitrotylindirubin derivative 1
  • Preparation method and medical uses of Nú¿1ú®-hydrocarbyl-3íõ-nitrotylindirubin derivative 1

Examples

Experimental program
Comparison scheme
Effect test

experiment example 1

[0062] Experimental Example 1, the preparation of N(1)-hydrocarbyl-3'-oximino indirubin:

[0063] Step a, 1-ethyl-indirubin

[0064] [Step a]: Add 0.6 g of NaH (15 mmol) to a solution consisting of 2.62 g of indirubin (10 mmol) and 40 mL of anhydrous DMF, and 2 Stir under ambient conditions, and cool the mixture to 0°C, slowly add dropwise a solution consisting of 1.15mL ethyl iodide (15mmol) and DMF (5mL), return to room temperature slowly after the addition, stir for 3 hours, and detect by TLC (the developer is the same as above) . After the reaction was completed, carefully poured into 300mL ice water under stirring, extracted 3 times with chloroform (150mL×3), combined the organic phases, and washed with anhydrous Na 2 SO 4 After drying, it was concentrated to dryness in vacuo, and the residue was purified by silica gel column chromatography (eluent: chloroform / petroleum ether, 5 / 1 (v / v)) to obtain 1.5 g of purple powder solid 1-ethyl-indirubin , yield 52%; melting poi...

experiment example 2

[0070] Experimental example 2, the in vitro anti-tumor effect of N(1)-hydrocarbyl-3'-oximino indirubin:

[0071] Inhibitory effects of N(1)-alkyl-3'-oximinoindirubin and N(1)-acetyl-indirubin hormones on dependent and independent prostate cancer.

[0072] The following are some examples of tumor treatment by JN-2528 (N(1)-hydrocarbyl-3'-oximino indirubin) compound. Here again, we reiterate that although we only use the treatment of tumors as an example, it does not mean that these compounds are only used to treat tumors.

[0073] (1) Materials and methods

[0074] Reagent: JN-2528 compound, synthesized and purified by our laboratory, the structure was confirmed by mass spectrometry, NMR, infrared, and X-ray diffraction (see Example 1). The purity was >98.0%. JN-2528 is red and dark red crystalline powder. During the experiment, the solution was prepared in DMSO and stored at -20°C. European patent similar compound Indirubin-3'-monoxime-5 Sulphonic acid (IMSA) [EP1079826B1...

experiment example 3

[0091] Experimental example 3, the in vivo anti-tumor effect of N(1)-hydrocarbyl-3'-oximino indirubin

[0092] (1) Materials and methods:

[0093] Materials: C57BL / 6 mice, all male, 25±2g. Provided by Model Animal Center of Nanjing University. Lewis lung cancer cell line, provided by Nanjing University of Traditional Chinese Medicine. JN-2528 freeze-dried powder, batch number: 050418-1. 1mg per bottle, add 1ml of normal saline to make 1mg / ml, provided by Wuxi Jessie Pharmaceutical Company. Cyclophosphamide, produced by Jiangsu Hengrui Pharmaceutical Co., Ltd., batch number 04081921.

[0094] Instrument: Sartorius BP-310 electronic balance. Ultra clean bench. Glass homogenizer. Several sets of surgical instruments.

[0095] Method: Take Lewis lung cancer tumor block under aseptic operation, remove necrotic tissue, mix several tumor blocks, cut into small pieces, add PBS and grind with a glass tissue homogenizer, put it into a centrifuge tube after grinding, and centrifu...

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Abstract

The present invention is preparation process and antitumor effect of N(1)-alkyl-3'-oximino indirubin derivative (I, JN-2528). The new synthesis process uses indirubin as initial material, and under the action of alkaline compound as promoter, indirubin is reacted directly with halohydrocarbon or other halide to obtain N(1)-alkyl indirubin derivative, which is then reacted with hydroxylamine to obtain N(1)-alkyl-3'-oximino indirubin derivative. The MTT and SRB process and transplanting C57 mouse Lewis lung cancer mold test proves the antitumor activity of N(1)-alkyl-3'-oximino indirubin. The compound shows extracorporeal and intracorporeal cancer inhibiting effect.

Description

technical field [0001] The present invention relates to a new method for preparing N(1)-hydrocarbyl-3'-oximino indirubin (structural formula I, JN-2528) using indirubin as a starting material, and its anti-tumor, treatment of senile dementia and anti-aging Medical application of viral infection and other diseases. Background technique [0002] N(1)-Alkyl-3′-oximino indirubin derivatives (I) are known cell cycle kinases (CDKs) [1-4] , Stat3 information conduction system [5] and glycogen synthase kinase-3β (GSK-3β) [6-8] Inhibitors. Since CDKs are overexpressed or / and the corresponding gene amplification occurs in most malignant tumor cells, the inhibition of CDKs is a reasonable target for the treatment of cancer and abnormal cell proliferation. [4，9] ; Nervous degeneration and disorders are related to excessive GSK-3β in the nervous system, so N(1)-hydrocarbyl-3'-oximino indirubin derivatives (I) are used for the treatment of nervous system diseases, such as Alzheimer's d...

Claims

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Application Information

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IPC IPC(8): C07D209/14A61K9/06A61K9/08A61K9/107A61K9/12A61K9/14A61K9/20A61K9/48A61K31/404
Inventor 姚其正王龙贵王朝晖冯明声程景才
Owner JC (WUXI) CO INC
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