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Hederagenin A-cyclopyrazine derivatives as well as preparation method and application thereof

A technology of helexin and pyrazine derivatives, applied in the field of medicine, can solve problems such as poor activity

Active Publication Date: 2018-11-13
YANTAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the technical problem highlighted at the same time is that although the above-mentioned hedera saponin derivatives have significant in vitro activity, their in vivo activity is relatively poor, and they need to be prepared into liposomes by a thin film dispersion method to have corresponding drug administration properties.

Method used

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  • Hederagenin A-cyclopyrazine derivatives as well as preparation method and application thereof
  • Hederagenin A-cyclopyrazine derivatives as well as preparation method and application thereof
  • Hederagenin A-cyclopyrazine derivatives as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1 Synthesis and Characterization of O-(23-Hydroxy-Olean-12-ene-28-Acyl[3,2-b]pyrazine)-1-Hydroxybenzotriazole

[0039] The compound helexin (472.0mg, 1.0mmol) was dissolved in N,N-dimethylformamide (15.0mL), potassium carbonate (300.0mg, 2.1mmol), benzyl bromide (0.2mL, 1.3mmol) were added , Stir at 50°C for 6-10h. The reaction solution was diluted with ethyl acetate (25.0 mL), washed three times with water, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and silica gel column chromatography (V 石油醚 :V 乙酸乙酯 =10:1-5:1), a white solid (470.0 mg, 83.0%) was obtained.

[0040] The above compound (460.0 mg, 0.8 mmol) was dissolved in 20.0 mL of dichloromethane, 4-dimethylaminopyridine (122.0 mg, 1.0 mmol) and tert-butyldimethylsilyl chloride (360.0 mg, 2.4 mmol) were added, Stir at room temperature for 4-8h. Dichloromethane was distilled off, diluted with ethyl acetate (20.0 mL), ...

Embodiment 2

[0046] Example 2 Synthesis and characterization of O-(23-hydroxyl-olean-12-ene-28-acyl[3,2-b]pyrazine)-1-hydroxyl-7-azobenzotriazole

[0047] According to the preparation method of the compound in Example 1 of the present application, compound HBQ reacts with 1-hydroxyl-7-azobenzotriazole to synthesize the compound, and silica gel column chromatography (V 氯仿 :V 甲醇 =200:1), a white solid was obtained with a yield of 92.8%. m.p.161.9~164.8℃. 1 H-NMR (400MHz, CDCl 3 )δ: 8.69 (d, J=3.8Hz, 1H, H-Ar), 8.38 (s, 1H, H-pyrazine), 8.36 (s, 1H, H-pyrazine), 8.32 (s, 1H, H-Ar ), 7.39(dd, J=8.3, 4.5Hz, 1H, H-Ar), 5.42(s, 1H, H-12), 3.81(d, J=10.5Hz, 1H, H-23a), 3.50(d ,J=10.5Hz,1H,H-23b),3.01(d,1H,H-18),2.97(d,2H,H-11),1.32(s,3H,CH 3 ),1.26(s,3H,CH 3 ),0.99(s,3H,CH 3 ),0.96(s,3H,CH 3 ),0.95(s,3H,CH 3 ),0.93(s,3H,CH 3 ).

Embodiment 3

[0048] Example 3 Synthesis and characterization of O-(23-hydroxyl-olean-12-en-28-acyl[3,2-b]pyrazine)-3-dimethylamino-1-propanol

[0049] Dissolve compound H6 (2.0 g, 3.4 mmol) in pyridine (30.0 mL), add acetic anhydride (16.0 mL), stir at room temperature for 8 h, dilute with ethyl acetate, wash with water, wash with saturated brine twice, and dry over anhydrous sodium sulfate. Filtration, concentration, column chromatography (V 石油醚 :V 乙酸乙酯 =20:1), a white solid (1.9 g, 89.0%) was obtained.

[0050] The above compound (1.9g, 3.0mmol) was dissolved in methanol (30.0mL), 10%Pd / C (0.6g, 6.0mmol) was added, hydrogenated at room temperature and pressure for 6 hours, suction filtered, concentrated, column chromatography (V 石油醚 :V 乙酸乙酯 =8:1), a white solid (1.5 g, 92.3%) was obtained.

[0051] The above compound (50.0 mg, 0.1 mmol) was dissolved in dry dichloromethane (6.0 mL), placed in an ice bath for 10 min, then added oxalyl chloride (77.0 μL), stirred at room temperature fo...

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Abstract

The invention belongs to the technical field of medicines, and in particular relates to hederagenin A-cyclopyrazine derivatives with novel structures and a preparation method of the hederagenin A-cyclopyrazine derivatives. The hederagenin A-cyclopyrazine derivatives with the novel structures have the structures as shown in the general formula I. The compounds disclosed by the invention have the same in-vivo drug resistance reversal activity as in vitro and can be directly administered in vivo. The invention further discloses a preparation method of the derivatives and the application of the derivatives to preparation of tumor drug resistance reversal agents directly used in vivo.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to hederinin A-ring pyrazine derivatives with novel structures, their preparation method and their application in the preparation of tumor drug resistance reversal agents directly applied in vivo. technical background [0002] Tumors seriously threaten human health. Chemotherapy is an important means of clinical treatment of tumors, and the generation of tumor drug resistance is one of the main reasons for the failure of chemotherapy. According to statistics, more than 50% of malignant tumors are resistant to traditional chemical drugs, and more than 6 million people die of malignant tumors worldwide every year. Therefore, the development of new tumor drug resistance reversal agents is an urgent problem to be solved in the research of tumor therapeutics and pharmacology. Natural products have the characteristics of rich structure types and low toxicity and side effects...

Claims

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Application Information

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IPC IPC(8): C07J71/00A61P35/00
CPCA61P35/00C07J71/0047C07J71/0057Y02P20/55
Inventor 王洪波毕毅王晓田京伟王炳华刘现轩任倩文郭梦琦
Owner YANTAI UNIV
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