1-substituted benzylidene-2-naphthalenone derivative, preparation method thereof and use thereof

A technology of benzylidene and substituents, which is applied in the preparation of carbon-based compounds, organic compounds, active ingredients of ketones, etc., can solve problems such as drug resistance and damage to normal cells

Active Publication Date: 2013-06-05
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although antineoplastic drugs have made great contributions to prolonging the survival time of patients and improving their quality of life, most of them are cytotoxic drugs, w

Method used

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  • 1-substituted benzylidene-2-naphthalenone derivative, preparation method thereof and use thereof
  • 1-substituted benzylidene-2-naphthalenone derivative, preparation method thereof and use thereof
  • 1-substituted benzylidene-2-naphthalenone derivative, preparation method thereof and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Embodiment 1: the preparation of 6-methoxy-3,4-dihydro-2-naphthone

[0066] 2,6-Dimethoxynaphthalene (20g, 0.1mol) was added to refluxing dehydrated ethanol (200ml), added shredded metal sodium wire (19g, 0.83mol), and refluxed until the metal sodium was completely dissolved for about 1 Hours, down to room temperature, hydrochloric acid (2M, 330ml) was added dropwise in a water bath to adjust the pH=3, and the temperature was continued to rise and reflux for half an hour until clarification. Cool down to room temperature, extract three times with ethyl acetate (50ml), concentrate the aqueous phase, then extract three times with ethyl acetate (50ml), combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. After concentration and high vacuum distillation, a yellow oil (boiling point 160-165°C, 10mmHg) was obtained, which was recrystallized from petroleum ether (60-90°C) to obtain a white needle-like solid with a yield of 75% and a mel...

Embodiment 2

[0067] Example 2: Preparation of (E)-6-methoxy-1-(3,4,5-trimethoxybenzylidene)-3,4-dihydro-2-naphthalenone (1)

[0068] Dissolve 6-methoxy-3,4-dihydro-2-naphthalenone (1.76g, 10mmol), 3,4,5-trimethoxybenzaldehyde (1.96g, 10mmol) in dichloromethane (30ml) Add 4A molecular sieves (3g), glacial acetic acid (50mg), piperidine (50mg), stir at room temperature for 8 hours, filter, wash the filter cake, combine the organic phases, wash with water (25ml), wash with saturated brine (25ml), anhydrous It was dried over sodium sulfate, concentrated, separated by column chromatography (PE:EtOAc=10:1), and recrystallized to obtain yellow crystals (1.68 g, 47%).

[0069] m.p.102-103°C.

[0070] 1 H NMR (300MHz, CDCl 3 )δ7.49(s, 1H), 7.44(d, J=8.6Hz, 1H), 6.80(d, J=2.2Hz, 1H), 6.72(s, 2H), 6.64(dd, J=8.6, 2.2 Hz, 1H), 3.85(d, J=13.9Hz, 6H), 3.71(s, 6H), 3.01(t, J=6.4Hz, 2H), 2.62(t, J=6.4Hz, 2H).

[0071] 13 C NMR (300MHz, CDCl 3 )δ201.78, 159.42, 152.91, 140.23, 138.68, 133.21, 132.59...

Embodiment 3

[0073] Example 3: (E)-6-methoxy-1-(3,4,5-trimethoxybenzylidene)-1,2,3,4-tetrahydro-2-naphthyl alcohol (16) preparation of

[0074] Dissolve (E)-6-methoxy-1-(3,4,5-trimethoxybenzylidene)-3,4-dihydro-2-naphthalenone (2g, 5.6mmol) in 10 % dichloromethane methanol solution, sodium borohydride was added, stirred at room temperature for 20 minutes, concentrated, washed with water, extracted with ethyl acetate, washed with saturated brine, combined organic phases, concentrated, and separated by column chromatography (PE:EtOAc=5:1 ), recrystallized to give white needles (1.7g, yield 85%), m.p.128°C

[0075] 1H NMR (300MHz, CDCl 3 )δ7.60(d, J=9Hz, 1H), 7.00(s, 1H), 6.77-6.81(m, 3H), 6.68(d, J=2.7Hz, 1H), 5.05(t, J=2.44Hz , 1H), 3.93(m, 10H), 3.82(s, 3H), 3.10-3.22(m, 1H), 2.68-2.76(m, 1H), 2.01-2.15(m, 1H), 1.95-2.09(m , 1H)

[0076] 13 C NMR (300MHz, CDCl 3 )δ 159.11, 152.97, 139.31, 139.02, 136.90, 133.31, 131.39, 129.97, 124.60, 122.59, 112.72, 111.51, 106.54, 106.15, 72.58,...

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Abstract

The invention relates to a 1-substituted benzylidene-2-naphthalenone derivative, a preparation method thereof and use thereof, and particularly discloses a derivative shown in the formula (I) or pharmaceutical acceptable salt thereof. The preparation method is as follows: reflux of dimethoxy naphthalene and metallic sodium is conducted in ethanol, and 3, 4-dihydro-2-naphthalenone is generated after the dimethoxy naphthalene and the metallic sodium are acidized; the 3, 4-dihydro-2-naphthalenone is dissolved in dichloromethane and catalyzed by acetic acid piperidine, and then is stirred and reacts at room temperature, and 1-benzylidene-3, 4-dihydro-2-naphthalenone is generated; and the 1-benzylidene-3, 4-dihydro-2-naphthalenone is dissolved in 10% of dichloromethane methanol solution, sodium borohydride is added, and then the 1-substituted benzylidene-2-naphthalenone derivative can be obtained by reduction. The 1-substituted benzylidene-2-naphthalenone derivative has the good effect of treating leukemia, further has the effect of inhibiting microtubulin, and can be used for treating various cancers responding to cell toxicity and cell viability, such as breast cancer or colon cancer, and for treating disease cancer related to abnormal angiogenesis.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a class of 1-substituted benzylidene-2-naphthalenone derivatives, and also relates to a preparation method of the compound and its application in the preparation of antitumor drugs. Background technique [0002] Tumors, especially malignant tumors, have seriously threatened human health. It is estimated that there are about 2.6 million cancer cases and 1.8 million deaths in my country every year. In the past 30 years, cancer mortality in my country has increased by 80%, becoming the first cause of death among Chinese residents. Although antineoplastic drugs have made great contributions to prolonging the survival time of patients and improving their quality of life, most of them are cytotoxic drugs, which lack selectivity and will damage a large number of normal cells, and are prone to drug resistance. Therefore, tumor vascular targeting drugs have become a research hotspot. ...

Claims

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Application Information

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IPC IPC(8): C07C49/755C07C45/74C07C221/00C07C225/22C07C41/18C07C43/23C07C201/12C07C205/45A61K31/09A61K31/12A61K31/136A61P35/00A61P15/14A61P1/00
Inventor 周有骏刘嘉郑灿辉周峰任晓慧朱驹吕加国刘娜
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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