3, 4, 5-tri-substituted aminothiopene chemical compound and preparation and application thereof

A technology of aminothiophene and compounds, which is applied in the field of synthesis of organic compounds, can solve the problems of drug resistance, high toxicity and side effects, etc., and achieve the effect of strong in vitro proliferation inhibition, low production cost and high yield

Inactive Publication Date: 2014-07-02
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Traditional chemotherapeutic drugs such as alkylating agents and anti-metabolites generally have the disadvantages of high toxicity and side effects, and are prone to drug resistance. However, anti-tumor drugs designed for key proteins or kinases in the signaling pathway are making remarkable achievements in the field of tumor treatment. inspiring effect

Method used

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  • 3, 4, 5-tri-substituted aminothiopene chemical compound and preparation and application thereof
  • 3, 4, 5-tri-substituted aminothiopene chemical compound and preparation and application thereof
  • 3, 4, 5-tri-substituted aminothiopene chemical compound and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1, 1,2-bis(4-chlorophenyl)ethanone (compound IIa):

[0032] Prepared according to literature method (Lütjens et al.J.Med.Chem.2003,46,1870-1877). Put 50ml of dry chlorobenzene in the reaction flask, add 15.46g (100mmol) of 4-chlorophenylacetyl chloride, stir well, then add 40g (300mmol) of aluminum trichloride in batches under ice bath. After the addition, the ice bath was removed, and the mixture was stirred overnight at room temperature. The reaction solution was poured onto ice to quench the reaction, diluted with water, extracted with ethyl acetate (300ml×3), washed with saturated sodium chloride solution (300ml×3), and dried over anhydrous sodium sulfate. After filtration, the filtrate was recovered under reduced pressure to obtain a white solid. After adding petroleum ether (100ml), it was suction-filtered, washed with ice petroleum ether (30ml×3) and ice ether (30ml×3), and dried in vacuo. The yield was 71%.

Embodiment 2

[0033] Example 2, (Z,E)-methyl-3,4-bis(4-chlorophenyl)-2-cyano-2-acetic acid methyl ester (compound IIIa):

[0034]200ml of anhydrous THF was placed in the reaction flask, and 20.6g (110mmol) of titanium tetrachloride was slowly added dropwise under ice cooling. A THF solution (100 ml) of 5.0 g (22 mmol) of compound IIa and 4.3 g (44 mmol) of methyl cyanoacetate was slowly added dropwise to the reaction system. After the addition, remove the ice bath, add 0.8ml of pyridine, stir for 1 hour, then add 2.4ml of pyridine, and stir overnight at room temperature. The reaction solution was evaporated to remove the solvent under reduced pressure, diluted with water, extracted with ethyl acetate (300ml×3), washed with saturated sodium chloride solution (300ml×3), and dried over anhydrous sodium sulfate. After filtration, the filtrate was recovered under reduced pressure to obtain an oil, and the crude product was directly subjected to the next reaction without purification.

Embodiment 3

[0035] Example 3, methyl 2-amino-4,5-bis(4-chlorophenyl)thiophene-3carboxylate (Compound IVa):

[0036] Compound IIIa was dissolved in THF (200ml), added sulfur powder 1.4g (44mmol) and diethylamine 4.0ml, stirred at room temperature for 2h. The reaction liquid was evaporated to remove the solvent under reduced pressure, diluted with water, extracted with ethyl acetate (100ml×3), washed with saturated sodium chloride solution (100ml×3), and dried over anhydrous sodium sulfate. After filtration, the filtrate was recovered under reduced pressure, and the crude product was recrystallized from ethanol to obtain 5.3 g of a white solid, with a two-step yield of 65%.

[0037] MS(m / z): 377.95[M+H] + .

[0038] 1 H NMR (500MHz, CDCl 3 )δ7.26(d,J=8.4Hz,2H),7.11(dd,J=6.4,4.6Hz,1H),7.07(dd,J=6.2,4.5Hz,1H),6.91(d,J=8.5 Hz,2H),6.17(br,2H),3.51(s,3H).

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Abstract

The invention provides a 3, 4, 5-tri-substituted aminothiopene chemical compound. Substituted benzene is used as a raw material to produce derivatives of the 3, 4, 5-tri-substituted aminothiopene chemical compound after being subjected to Friedel-Crafts acylation reaction, Knoevenagel condensation, cyclization, hydrolysis reaction and condensation. The chemical compound and salt thereof have evident effect on blocking interaction of p53-MDM2 (murine double minute 2) and evident inhibitory activity for proliferation in vitro of tumor cells according to demonstration of pharmacological experiments, and the IC 50 (half maximal inhibitory concentration) can reach the mu M level. The 3, 4, 5-tri-substituted aminothipene is reasonable in design, simple and convenient in preparation method and applicable to practical use and can be applied to preparation of antineoplastic medicines, raw materials for the 3, 4, 5-tri-substituted aminothipene are rich in sources, reaction conditions are mild and yield of each step of the preparation method is high. The structural formula of the 3, 4, 5-tri-substituted aminothipene is shown in the description.

Description

technical field [0001] The invention belongs to the synthesis of organic compounds, and relates to a preparation method of a class of 3,4,5,-trisubstituted aminothiophene compounds and their application in the preparation of antitumor drugs. Background technique [0002] With the continuous increase of the global population and the deepening trend of population aging, and because of the widespread existence of various unhealthy lifestyles including smoking, cancer has become the number one killer of human health in developed countries and a threat to developing countries. The No. 2 killer of human health (Jemal, et al., CA-Cancer J. Clin. 2011, 61, 69-90). Traditional chemotherapeutic drugs such as alkylating agents and anti-metabolites generally have the disadvantages of high toxicity and side effects, and are prone to drug resistance. However, anti-tumor drugs designed for key proteins or kinases in the signaling pathway are making remarkable achievements in the field of t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/36C07D333/38C07D409/06A61K31/381A61K31/4535A61K31/496A61K31/4025A61K31/5377A61P35/00
Inventor 王味思胡永洲胡纯琦盛荣刘滔何俏军杨波
Owner ZHEJIANG UNIV
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