Coumarin ether compounds and new use of composition

A technology of coumarin and compounds, applied in the field of pharmacy, can solve the problems of mitochondrial toxicity, easy drug resistance, and too expensive interferon

Active Publication Date: 2009-07-29
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AI-Extracted Technical Summary

Problems solved by technology

In addition, the price of interferon is too expensive, which brings a heavy economic burden to most patients
Nucleoside drugs are prone to drug resistance, and the drug resistance rate of virus mutations in the third year after oral administration of Heptin is as high as 49%, and most patients rebound after stopping the drug
Therefore, it is difficult to determine the course of treatment of nucleoside antivira...
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The invention belongs to the pharmacology field and discloses a tonka-bean grass ether compound or pharmaceutically acceptable salt or ester, or the function of extractives of the compound in preparing antiviral drugs. Compositions containing the tonka-bean grass ether compound or the pharmaceutically acceptable salt or ester or the extractives of the compound are also disclosed.

Application Domain

Organic chemistryAntivirals +2

Technology Topic

EtherAntiviral drug +2


  • Coumarin ether compounds and new use of composition
  • Coumarin ether compounds and new use of composition
  • Coumarin ether compounds and new use of composition


  • Experimental program(5)

Example Embodiment

[0072] Example 1
[0073] Eclipta alba extract compound Wedelia lactone
[0074] (1) Soaking and filtering
[0075] Eclipta prostrata 300kg, completely immersed in 0.75 tons of ethanol (concentration 95%) → soaked overnight (10 hours) → coarse filtration to remove the whole plant residue (retention) → net filtration (suction filtration) or high-speed centrifugation (10000rpm, 10 minutes) to remove dust and fine residue → green clear filtrate.
[0076] (2) Ethanol recovery
[0077] Distillation and recovery of ethanol, the temperature does not exceed 60 ℃ → back distillation for 2 hours each time, remove the extract in the reactor to the collection bucket (the extract is dark green, slightly viscous) → repeat the above steps until all the ethanol is recovered .
[0078] (3) Secondary soaking and back distillation
[0079] Recover 0.75 tons of ethanol, re-soak the whole grass residue → soak overnight, and the requirements for coarse filtration, net filtration and distillation recovery are the same as before. Get the extract.
[0080] (4) Ethyl acetate extraction
[0081] Take the above extract at 50-80°C (more preferably at 60-70°C), heat water and shake and mix, and add hot water 50 times the volume of the extract, and filter with suction to obtain a hot water phase liquid. Add the ethyl acetate for extraction according to the volume ratio of the water phase: the ester phase of 1:1, mix thoroughly and shake, and then stand still until the water phase/ester phase separates. The ethyl acetate layer was removed, vacuum distilled to dryness at 50°C, a small amount of ethanol was added to dissolve, and it was stored in a beaker at 4°C overnight, and a precipitate appeared at the bottom. The precipitate was obtained by suction filtration under reduced pressure, and dried in an oven at 50° C. to obtain a crude product.
[0082] (5) Separation and refining of products
[0083] Take 5g of the crude product, mix the sample on 10g 200-300 mesh silica gel, perform silica gel column chromatography (200g, 200-300 mesh), elution with petroleum ether-acetone gradient, collect once every 100mL, get different polar parts respectively, and combine (TLC petroleum ether-acetone 1:1, Rf=1/3) spots. After concentrating the combined components, the samples were mixed on silica gel for column chromatography, eluted with a dichloromethane-acetone gradient, and collected every 50mL to obtain different polar parts respectively, and combined (TLC dichloromethane-acetone 3: 1. Rf=1/6) spots. After concentrating the combined components, the samples were mixed on silica gel for column chromatography, eluted with a gradient of toluene-acetone-formic acid, and collected every 50 mL to obtain different polar parts respectively, and combined (TLC toluene-acetone-formic acid 10: 10:1, Rf=1/2) spots. After concentrating the combined components, the samples were mixed on silica gel for column chromatography, eluted with a dichloromethane-methanol gradient, and collected every 25mL to obtain different polar parts respectively, and combined (TLC dichloromethane-methanol 20: 1. Rf=1/6) spots. A product with a purity of >90% is obtained, and the yield is about 1%.
[0084] (6) Refined standard products
[0085] Dissolve 30 mg of samples with a purity of >90% in 70% methanol, use a Lichroprep RP-18 (40~63μ) column for reversed phase elution, detect by TLC, collect the 70% eluted samples, and combine them to obtain a purity of >98 % Of standard products. The yield is about 90%. The character, molecular formula, melting point and IR, EIMS, 1 HNMR, 13 The CNMR peaks are assigned as follows:
[0086] Off-white powder, molecular formula: C 16 H 10 O 7 , Mp 315°C (decomposition), UV λmax (MeOH, nm): 211.5 (4.65), 247 (4.40), 304 (4.01) (sh), 350 (4.48). IR(KBr)cm -1 3300, 1715, 1640, 1620, 1445, 1415, 1320, 1205, 1155, 1070. EIMS m/z(%): 314(M + , 100), 313(22), 299([M-CH 3 ], 28), 285(5), 271([M-CH 3-CO], 8), 243([M-CH 3 -CO-CO], 28), 187(17), 69(42). 1 HNMR(δ): 7.23(s), 7.14(s), 6.58(d, J=2.3Hz), 6.42(d, J=2.3Hz), 3.90(s)
[0087] 13 CNMR(δ): 158.0(C-1), 101.1(C-2), 159.6(C-3), 95.6(C-4), 99.3(C-5), 161.1(C-6), 95.0(C -7), 155.5(C-8), 155.0(C-9), 104.7(C-10), 145.2(C-11), 144.3(C-12), 99.0(C-13), 114.0(C- 14), 148.7 (C-15), 55.7 (C-16).
[0088] The results show that the obtained compound is a wedelia lactone of formula II:
[0090] The wedelia lactone (hereinafter referred to as APL-1) extracted by the above method was used in the following examples.

Example Embodiment

[0091] Example 2
[0092] Inhibitory effect of wedelia lactone on virus in vitro
[0093] Cells and viruses: Herpes simplex virus type I (HSV-I), respiratory syncytial virus (RSV), poliovirus type I (Poliovirus-1), Coxsackie virus type A-7 (CVA-7), Egypt ECHO-11 (ECHO-11) and Vero cells were purchased from the National Institute for the Control of Pharmaceutical and Biological Products of the Ministry of Health.
[0094] Experimental drug: APL-1 (prepared in Example 1).
[0095] Experimental method: Inoculate Vero cells in a 96-well cell culture plate, the number of cells is 25,000/well, and routinely culture them with PRMI1640 medium for 24 hours, and add 100TCID respectively 50 For HSV-I, RSV, Poliovirus-1, CVA-7, ECHO-11, each virus has 6 multiple holes. After 2h, the virus solution is aspirated and washed with Hanks solution for 3 times, and the concentration is 1μg/ ml, 5μg/ml, and 10μg/ml of APL-1 were incubated at 37°C for 96h to observe the degree of cytopathy in each group of cells.
[0096] Grading of the degree of disease:
[0097] Grade 0 (-), cell growth is good, no cytopathic effect;
[0098] Level 1 (+), 25% of cells have cytopathic effects;
[0099] Level 2 (++), 50% of cells have cytopathic effects;
[0100] Level 3 (+++), 75% of cells have cytopathic effects;
[0101] Level 4 (++++), 100% of cells have cytopathic effect.
[0102] See Table 1 for the effects of Wedelia lactone on the virus.
[0103] Table 1 Inhibitory effects of wedelia lactone on virus in vitro
[0105] It can be seen from Table 1 that APL-1 at concentrations of 10μg/ml and 5μg/ml have inhibitory effects on the above groups of viruses, and can inhibit the cytopathic effects of the above groups of viruses in cultured cells in vitro, and the inhibitory effect and drug concentration There is a clear positive correlation.

Example Embodiment

[0106] Example 3
[0107] Antiviral effect of wedelia lactone in mice
[0108] Experimental animals: 70 male SPF BALB/C mice, purchased from Shanghai Slack Experimental Animal Co., Ltd., weighing 18-20g. Raised in an SPF animal house, 12h light/12h dark, free intake of feed and water.
[0109] Virus strain: herpes simplex virus type I (HSV-1) Sm44 strain, purchased from the National Institute for the Control of Pharmaceutical and Biological Products of the Ministry of Health.
[0110] Experimental drugs: APL-1 (prepared in Example 1), ribavirin (ribavirin, purchased from Jiaozuo Kangli Pharmaceutical Co., Ltd., 0.1 g/ml).
[0111] Experimental method: Using different dilutions of virus liquid, the experimental mice were inoculated intracranially with HSV-1 (TCID 50 = 10 -7 ·Ml -1 ), observe for 14 days. Calculate the LD of the virus based on the number of dead mice 50 To determine the amount of virus inoculation. According to the half-effect probability unit method, the intracranial HSV-I (100TCID 50 ) After LD 50 It is 0.03ml.
[0112] Seventy mice were selected and randomly divided into APL-1 high, medium, and low dose groups, ribavirin group, combination medication group, model group, and negative control group, with 10 mice in each group. The model group and the negative control group were given 0.85% normal saline respectively. After 24 hours of intracranial infection with HSV-1 virus in the mice of each drug group, different concentrations of drugs were injected into the tail vein once a day for 6 consecutive days and observation for 14 days , Record the survival days of the mice.
[0113] The experimental data were counted by SPSS10.0 statistical software one-way analysis of variance SNK method. See Table 2 for the effects of APL-1 on mice infected with HSV-1.
[0114] Table 2 The protective effect of APL-1 on mice infected with HSV-1 (n=10)
[0115] Grouping
[0116] *Indicating p<0.05, there is a significant difference compared with the model group
[0117] It can be seen from Table 2 that the high and medium dose groups of APL-1 and the combination medication group can significantly prolong the survival days of mice, which is significantly different from the model group (p<0.05). It is suggested that APL-1 can be used to prevent or treat herpes simplex virus.


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