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Epothilone analogue, preparation method as well as medicine composition and application thereof

A technology of epothilone and its analogs is used in the preparation of anti-cancer or auxiliary anti-cancer drugs, and the field of pharmaceutical compositions for treating cancer or adjuvant tumor treatment, achieving fewer synthesis steps, wide anti-cancer activity, and large convenience The effect of mass production

Active Publication Date: 2011-02-16
ACCENDATECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] There is no report on the 9-modified analogue of epothilone and its anticancer activity

Method used

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  • Epothilone analogue, preparation method as well as medicine composition and application thereof
  • Epothilone analogue, preparation method as well as medicine composition and application thereof
  • Epothilone analogue, preparation method as well as medicine composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1: the preparation of formula (III) compound

[0048] Synthesis of compound 3

[0049] Under nitrogen protection, 378mg of compound 1 (1.25mmol), 914mg of compound 2 (4.37mmol) and 7.0mL of dichloromethane were added to a 25mL round bottom flask, and then 306mg of N,N-lutidine (2.5mmol) was added and 959mg 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (5.0mmol), stirred at room temperature for 2h, after the reaction was complete, diethyl ether and water were added to dilute, the aqueous phase was extracted with diethyl ether, and the combined The organic phase was dried with anhydrous magnesium sulfate, filtered with suction, spin-dried to dry the solvent, and purified by column to obtain 470 mg of colorless liquid, yield: 76.3%.

[0050] [α] 20 D =-28.2 (c=10 mg / mL, CHCl 3 ); IR (KBr / cm -1 ): 2954, 2930, 2856, 1737, 1705, 1643, 1505, 1471, 1374, 1293, 1248, 1177, 1088, 1047, 825, 769; 1 H NMR (400MHz, CDCl 3 )δ6.94(s, 1H), 6.48(s, 1H), 5.71(m, 1H), 5...

Embodiment 2

[0067] Embodiment 2: the pharmacological action of epothilone analog

[0068] Take each test cancer cell and make the cells into 2×10 5 / mL cell suspension, add to the 24-well round-bottomed cell culture plate, add the compound of formula (III) respectively, 5 wells for each test concentration, place at 37°C, 5% CO 2 Cultivate under saturated humidity conditions for 48 hours, measure the absorbance (A) value at 570nm wavelength of the enzyme-linked detector by MTT method, and calculate the inhibitory effect of the compound of the present invention on the test cancer cells.

[0069] Table 1 Inhibitory activity of epothilone analogues on cancer cells

[0070]

Compound of formula (III) (IC 50 , μM)

9KB

2.3

Hela

4.5

SGC-7901

8.9

MCF-7

1.3

[0071] PC-3

1.1

SK-RC-42

2.5

A549

9.7

HT-29

7.1

K562

5.5

[0072] Among them, 9KB, Hela, SGC-7901, M...

Embodiment 3

[0074] Embodiment 3: injection

[0075] After the compound of formula (III) prepared in Example 1 was dissolved with a small amount of DMSO, water for injection was added as usual, finely filtered, potted and sterilized to make an injection.

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PUM

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Abstract

The invention relates to an Epothilone analogue, a preparation method as well as a medicine composition and application thereof. Definitely, the invention relates to an analogue obtained by substituting a hydrogen in the C-9 position of Epothilone with methyl, a medicine composition as well as preparation method and application thereof, in particular to an Epothilone analogue medicine compound shown in a formula (I), a medicine composition containing effective amount of Epothilone analogue compound (I) and pharmaceutically acceptable carrier thereof and used for treating cancers or a composition of the Epothilone analogue compound and other anti-cancer medicines, a preparation method of the Epothilone analogue and application thereof in the medicines, especially the application in preparing medicaments for treating cancers, wherein the Epothilone analogue medicine compound is used for treating cancer diseases.

Description

technical field [0001] The present invention belongs to the technical field of medicines, in particular, it relates to epothilone analogues, a pharmaceutical composition for treating cancer or adjuvant treatment of tumors using it as an active ingredient, a preparation method thereof, and the preparation of the pharmaceutical compound and composition Application in anticancer or adjuvant anticancer drugs. Background technique [0002] The discovery of epothilone A and B was in the 1990s. Hofle and his colleagues first found a Sorangium cellulosum (Myxococcales) strain Soce90 from the soil on the banks of the Zambesi River in South Africa. A compound with antifungal activity was isolated from the plant and its properties were studied. Around 1995, Bollag et al. found that epothilone is a kind of pro-tubulin polymerization-promoting properties similar to p-glycotriol, which is strongly expressed in p-glycoprotein-expressing multidrug-resistant tumor cell lines. Antitumor act...

Claims

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Application Information

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IPC IPC(8): A61K31/4178A61P35/02A61K31/4427A61K31/423C07C47/21C07D413/06C07D405/04A61K31/422A61K31/403C07D405/06A61K31/428C07D417/06C07D413/04A61P35/00A61K31/4184C07F7/18A61K31/4709C07D417/04A61K31/427C07C45/56
Inventor 陈悦桑锋冯鹏段希焱张泉翟佳黛李晓茜张斌
Owner ACCENDATECH
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