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Vinblastine derivative, preparation method of vinblastine derivative, and application of vinblastine derivative in medicines

A technology of compounds, general formulas, applied in the field of pharmaceutical compounds

Inactive Publication Date: 2012-07-11
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In the existing literature, there has been no report on the structural modification of the aromatic ring of the lower part of vinorelbine or vinflunine, and as mentioned above, vinorelbine or vinflunine are more effective and toxic than The existing vinblastine, vincristine, and vindesine all have advantages. Therefore, it is possible to discover new and more potential drug molecules by structurally modifying the aromatic ring of vinorelbine or vinflunine

Method used

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  • Vinblastine derivative, preparation method of vinblastine derivative, and application of vinblastine derivative in medicines
  • Vinblastine derivative, preparation method of vinblastine derivative, and application of vinblastine derivative in medicines
  • Vinblastine derivative, preparation method of vinblastine derivative, and application of vinblastine derivative in medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 Preparation of 17'-chlorovinorelbine

[0042]

[0043]

[0044] Under argon atmosphere, vinorelbine (0.387 g, 0.5 mmol) and ferrocene chloride [Cp 2 TiCl 2 , 25 mg, 0.1 mmol] dissolved in 10-80 ml of dichloromethane solvent under stirring, at ambient temperature, add chlorosuccinimide (0.2 g, 1.5 mmol) in batches or at one time, continue stirring, point After following the reaction, the raw materials disappeared. The reaction solution was poured into saturated sodium bisulfite solution (50 ml), the pH of the solution was adjusted to 8 with ammonia water, and the reaction solution was extracted with ethyl acetate (100 ml×3). The organic phases were combined, washed successively with saturated sodium bicarbonate solution (50 ml) and saturated sodium chloride solution (50 ml), the ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography. ...

Embodiment 2

[0046] Embodiment 2: Preparation of 17'-chloro vinflunine

[0047]

[0048]

[0049] Under argon atmosphere, in a dry three-necked flask, vinflunine (0.7 g, 0.857 mmol) and ferrocene chloride [Cp 2 TiCl 2 , 21 mg, 0.0857 mmol] dissolved in 10-80 ml of dichloromethane solvent under stirring, at ambient temperature, add chlorosuccinimide (0.458 g, 3.43 mmol) in batches or at one time, continue stirring, point After following the reaction, the raw materials disappeared. The reaction solution was poured into saturated sodium bisulfite solution (50 ml), the pH of the solution was adjusted to 8 with ammonia water, and the reaction solution was extracted with ethyl acetate (100 ml×3). The organic phases were combined, washed successively with saturated sodium bicarbonate solution (50 ml) and saturated sodium chloride solution (50 ml), the ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified...

Embodiment 3

[0052] (1) Materials: human lung adenocarcinoma A549 cell line (purchased from Shanghai Institute of Cell Biology); recombinant human tumor necrosis factor (rhTNF-α, referred to as TNF); recombinant human interferon γ (rhIFN-γ, referred to as IFN); RPMI-1640 medium (Japan).

[0053] (2) Method: The whole experiment was set up as a blank zero group (plus 200 μl of medium), a cell control group (100 μl of single cell suspension + 100 μl of medium), an experimental group (100 μl of single cell suspension + 100 μl of each treatment factor ). Using Mossman [1] tetramethyl azolium blue (MTT) colorimetric method. A549 cells were cultured in RPMI-1640 medium containing 15% calf serum at 37°C and 5% CO 2 Cultivate in an incubator, digest with 0.25% trypsin and passage after 2 to 3 days. Adjust the digested and counted single-cell suspension to 4×105 / ml and add it to a 96-well culture plate, 100 μl per well, add 100 μl of drug to the experimental group, set 3 replicate wells in each ...

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Abstract

The invention belongs to the field of pharmaceutical compounds, and relates to a new vinblastine derivative, a preparation method of the vinblastine derivative, a pharmaceutical composition containing the derivative, and application of the vinblastine derivative as a therapeutic agent. The vinblastine derivative provided by the invention is a compound shown in a general formula (I) or salt thereof. The compound provided by the invention or salt thereof can be used as a pharmaceutical ingredient for inhibiting the cell proliferation of mammals or preparing a pharmaceutical composition for treating tumors so as to treat the solid tumor, cancer, lymphoma, Hodgkin's disease, tumor disease, neoplastic disease and the like of mammals.

Description

technical field [0001] The invention belongs to the field of pharmaceutical compounds, and relates to a new vinblastine derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent. Background technique [0002] Vinblastine, also known as vinblastine, is a kind of alkaloid contained in the vinca flower of the Apocynaceae plant. There are studies on vinblastine and incristine isolated from Vinca (R. L. Noble, etal, Biochem. Pharmacol, 1958, 1, 347-348; G. H. Svoboda, Lloydia, 1961, 24 , 173-178), which was first used in the treatment of Hodgkins lymphoma in 1960. Then began to study the synthesis of vinblastine and its derivatives and their anti-tumor mechanism. It was found that two of the semi-synthetic vinblastine derivatives can have a greater effect in the treatment of cancer, they are vindesine and vinorelbine (R.J. Gersosimo, et al, Pharmacotherapy, 1983, 3, 259- 274; Langlois N., et al. J. Am. C...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/04A61K31/475A61P35/00
Inventor 雷新胜林国强
Owner FUDAN UNIV
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