Tubulin inhibitor

A C1-C20, compound technology, applied in the directions of medical preparations containing active ingredients, organic active ingredients, organic chemistry, etc., can solve the problems of large interference of immune system function and weak tumor inhibitory effect, and achieve increased tumor inhibitory effect. , Little interference with immune system function, inhibition of growth and proliferation

Active Publication Date: 2017-04-19
SHENZHEN NEPTUNUS PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Chinese patent application CN1934101A relates to the use of the above compounds, which are used to reduce vascular proliferation and vascular density, and act on tumor blood vessels, but plinabulin alone has a weak inhibitory effect on tumors and a large interference with the function of the immune system

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] step 1:

[0059]

[0060] Compound A was synthesized by referring to the method described in Route A of Example 2 in Chinese Patent CN1684955.

[0061] Step 2:

[0062]

[0063] 4-Trifluoromethoxybenzaldehyde 3 (19.0 g, 0.10 mol), formylmethylenetriphenylphosphine 4 (33.5 g, 0.11 mmol) and toluene (200 ml) were added to a 1 L dry one-necked flask. The reaction was refluxed for 17 hours and then concentrated. The crude product was purified by column chromatography (eluent: volume ratio of petroleum ether / ethyl acetate: 100 / 1 to 80 / 20) to obtain yellow oil 5 (14.9g, yield: 69%).ESI-MS:m / z=217.1 (M+H).

[0064] Step 3:

[0065]

[0066] DMF (100ml), Intermediate A (1.38g, 5mmol), 3-(4-trifluoromethoxyphenyl)acrolein 5 (2.16g, 10mmol) and cesium carbonate (3.26g) were added to a 250ml dry single-necked flask ,10mmol). The reaction system was stirred at 25°C for 12 hours, cooled to room temperature, and then poured into ice water. Extract with ethyl acetate,...

Embodiment 2～11

[0068] Steps 1-2 prepare intermediate A, the same as Steps 1-2 in Example 1. The preparation of other intermediates and final products is shown in the table below:

[0069] Table 2: Preparation methods of other compounds

[0070]

[0071]

[0072]

[0073]

[0074]

Embodiment 14

[0075] Embodiment 14: Cell level inhibition experiment

[0076] Purpose of the experiment: Detect 14 candidate compounds against 5 cell lines using CCK-8 detection kit

[0077] (MDA-MB-231, HT-1080, AGS, A-673 & HUVEC) cytotoxic IC50 value.

[0078] Materials and methods:

[0079] Cell line:

[0080] MDA-MB-231 human breast cancer cell line (ordered from Shanghai Cell Resource Center, Chinese Academy of Sciences)

[0081] HT-1080 human fibrosarcoma cell line (ordered from Shanghai Cell Resource Center, Chinese Academy of Sciences)

[0082] AGS human gastric adenocarcinoma cell line (ordered from Shanghai Cell Resource Center, Chinese Academy of Sciences)

[0083] A-673 human rhabdomyosarcoma cell line (ordered from Shanghai Cell Resource Center, Chinese Academy of Sciences)

[0084] HUVEC human umbilical vein endothelial cell line (ordered from ScienCell Research Laboratories, Cat#8000, Lot#11233)

[0085] Reagents and Consumables:

[0086] Cell Counting Kit-8 (Cat#CK04...

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PUM

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Abstract

The invention provides a novel tubulin inhibitor and an application thereof. The novel tubulin inhibitor is a series of substituted heterocyclic skeleton-based compounds with colchicine binding sites in tubulins as targets. The compounds have the following structure as shown in the specification, wherein the formula is as shown in the specification; n independently represents an integer of 0-5 under the condition that n is less than or equal to 5; A represents a monosubstituted or polysubstituted group; and the group is selected from H, C1-C20 acylamino, C1-C20 acyloxy, C1-C20 alkanoyl, C1-C20 alkoxycarbonyl, C1-C20 alkoxy, C1-C20 alkylamino, C1-C20 alkylcarboxy amino, aroyl, arylalkanoyl, carboxyl, cyano, halogen, hydroxyl, nitro and methylthienyl.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a series of new compounds as tubulin inhibitors and their application. [0002] The invention also relates to pharmaceutical compositions containing the compound. Background technique [0003] As the main means of tumor treatment, anticancer drugs have made considerable contributions to prolonging the survival time of patients and improving their quality of life. Among them, drugs that act on microtubules (microtubule inhibitors) play an important role in tumor drugs. However, the current clinical drugs are affected by the following adverse problems: poor water solubility, unfavorable drug administration and easy to cause allergic reactions, serious side effects and acquired drug resistance, resulting in reduced curative effect, complex chemical structure and difficulty in synthesis The resulting scarcity of sources limits their further use. Therefore, it is urgent to find and design n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06A61K31/496A61P35/00
CPCC07D403/06A61P35/00A61K31/496A61K31/337
Inventor 唐田王彦青刘小柔王进靳如意冯汉林
Owner SHENZHEN NEPTUNUS PHARMA RES INST CO LTD
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