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Tubulin inhibitor

A C1-C20, compound technology, applied in the field of intermediate compounds for the preparation of the compound, can solve the problems of weak tumor inhibitory effect and large interference with immune system function, achieve less interference with immune system function, increase tumor inhibitory effect, Improve the effect of clinical use

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

[0011] 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

[0061] step 1:

[0062]

[0063] Magnesium chips (14.4 g, 0.60 mol) and dry tetrahydrofuran (1 L) were added to a 5000 ml dry three-necked flask, and 1 ml of 1,2-dibromoethane was added dropwise to initiate the reaction. Then bromoacetaldehyde ethylene acetal (100 g, 0.60 mol) in tetrahydrofuran (500 ml) was slowly added dropwise. After the dropwise addition, stir for two hours until the magnesium chips disappear. Then, a tetrahydrofuran solution (500 ml) of 5-tert-butyl-1H-imidazole-4-carbaldehyde (30 g, 0.20 mol) was slowly added dropwise to the above solution, and stirred overnight. Then it was adjusted to acidic (pH=1) with concentrated hydrochloric acid, and heated to 60° C. and stirred for 30 minutes. The tetrahydrofuran was removed by rotary evaporation, and ethyl acetate was added for extraction. The combined organic phases were washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was puri...

Embodiment 2～11

[0074] Steps 1-2 prepare intermediate B, the same as Steps 1-2 in Example 1. The preparation of other intermediates and final products is shown in the table below:

[0075] Table 2: Preparation methods of other compounds

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

Embodiment 12

[0083] Experimental method: HTRF kinEASE TK kit was used to detect the inhibitory activity of 11 compounds on Lynα, AKT2, KDR, IKK-β, and c-RAF enzymes. The compounds to be tested were diluted from 100 μM to 0.1 μM at 10 concentrations, and the concentration of DMSO was controlled at 1%, each concentration was repeated wells.

[0084] 11 compounds were screened for inhibitory activity on Lynα, AKT2, KDR, IKK-β, c-RAF enzymes at a concentration of 10 μM. The results are shown in the table below:

[0085] Table 3: IC50 values ​​of 11 compounds against 5 kinases

[0086]

[0087]The results showed that these compounds had different degrees of inhibitory effects on Lynα, AKT2, KDR, IKK-β, c-RAF.

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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 intermediate compounds for the preparation of said compounds. [0003] The invention also relates to pharmaceutical compositions containing the compound. Background technique [0004] 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...

Claims

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Application Information

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IPC IPC(8): C07D403/06A61K31/496A61P35/00A61K31/337
CPCA61K31/496C07D403/06A61K31/337A61K2300/00
Inventor 唐田彭江华吴婧冯贻东杨经安佘琴冯汉林
Owner SHENZHEN NEPTUNUS PHARMA RES INST CO LTD
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