Andrographolide-19-amide derivative, preparation method and its use in medicine

A technology of andrographolide and amide derivatives, which is applied in the fields of antineoplastic drugs, drug combinations, organic chemistry, etc., and can solve the problem of no compound pharmacological activity test, etc.

Inactive Publication Date: 2014-02-19
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[Das, B.; Chowdhury, C.; Kumar, D., et al. Bioorg Med Chem Lett. 2010, 20: 6947-6950] In addition, Mathad et al. conducted oxidation studies on the 3,19-OH of andrographolide , unfortunately the researchers did not test the pharmacological activity of the compounds they synthesized

Method used

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  • Andrographolide-19-amide derivative, preparation method and its use in medicine
  • Andrographolide-19-amide derivative, preparation method and its use in medicine
  • Andrographolide-19-amide derivative, preparation method and its use in medicine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] 3, Preparation of 19-isopropoxy-andrographolide (2)

[0052] Dissolve andrographolide (10.00g, 28.54mmol) in dry toluene / DMSO (200ml / 27ml), add 2,2-dimethoxypropane (14ml), p-toluenesulfonic acid (catalytic amount), 80°C Stir for about 1.5 hours until the reaction is complete, cool to room temperature, add triethylamine (7ml) to quench the catalyst, add toluene (150ml) to the reaction solution and wash with water (3×300ml), separate the organic layer, and dry over anhydrous sodium sulfate. Concentrate the dry organic phase, add diethyl ether (30ml), stir, filter and dry with suction to obtain white solid particles (10.36g, 26.53mmol, yield 93%). mp: 160-161°C. 1 H-NMR (300MHz, CDCl 3 , ppm) δ: 6.96 (1H, t, J=6.4Hz), 5.03 (1H, d, J=5.9Hz), 4.91 (1H, s), 4.63 (1H, s), 4.46 (1H, dd, J =10.4, 6.1Hz), 4.26(1H, dd, J=1.9, 10.4Hz), 3.97(1H, d, J=5.8Hz), 3.50(1H, dd, J=3.4, 8.4Hz), 3.2(dd , 1H), 2.64-2.40(4H, m), 2.05-1.97(2H, m), 1.85-1.72(4H, m), 1.32-1.25(3H, m), 1.42(3H...

Embodiment 2

[0054] Preparation of 14-O-tert-butyldimethylsiloxane-andrographolide (4)

[0055] 3,19-isopropoxy-andrographolide (7.00g, 17.93mmol) was dissolved in dry DMF (50ml), and imidazole (2.32g, 34.06mmol), TBSCl (4.86g, 32.27mmol) were added under ice-cooling ), rose to room temperature after 20 min, and stopped the reaction after 10 hours. The reaction solution was diluted with water (20ml), extracted with ethyl acetate (3X30ml), and the organic layer was separated. The organic phase is directly concentrated without drying, and then the concentrated crude product 3,19-isopropoxy-14-tert-butyldimethylsilyl ether-andrographolide is dissolved in an aqueous solution of acetic acid at room temperature (acetic acid: water = 28ml: 12ml), after the completion of the reaction, add sodium bicarbonate powder and stir until no bubbles overflow, dilute the reaction solution with dichloromethane (80ml), separate the organic layer and successively wash with saturated sodium bicarbonate solution...

Embodiment 3

[0057] Preparation of 14-O-tert-butyldimethylsilyl ether-andrographolide-19-aldehyde (5)

[0058] 14-O-tert-butyldimethylsilyl ether-andrographolide (5.00g, 10.76mmol) was dissolved in dichloromethane (130ml), and TEMPO (0.17g, 1.08mmol) was added successively under ice-cooling, and the pH was Potassium carbonate-sodium bicarbonate buffer solution (130ml), TBAB (0.35g, 1.08mmol) and NCS (2.73g, 20.44mmol) of 8-9 were vigorously stirred for about 9 hours until the reaction was complete. After the reaction was complete, the organic layer was separated, the aqueous layer was extracted with dichloromethane (2×100ml), the organic layer was washed with saturated brine (2×300ml), and dried over anhydrous sodium sulfate. The dried organic phase was concentrated and separated by column chromatography (petroleum ether: ethyl acetate) to finally obtain a white powdery solid (4.53 g, 9.79 mmol, yield 91%). mp: 101-102°C. 1 H-NMR (300MHz, CDCl 3 , ppm) δ: 9.76(1H, s), 6.80(1H, t, J=5.4H...

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Abstract

The invention discloses an andrographolide-19-amide derivative, a preparation method and its use in medicine, which belongs to the pharmaceutical chemistry field. According to the invention, a structural general formula of the andrographolide-19-amide derivative is shown as (A): R1 and R2 are hydrogen, substituted or non-substituted C1-C8 aliphatic acyl, substituted or non-substituted aromatic acyl; and R3 and R4 are hydrogen, substituted or non-substituted C1-C8 alkyl, substituted or non-substituted aromatic group. The invention also discloses the preparation method of the andrographolide-19-amide derivative and an application of the andrographolide-19-amide derivative for preparing antitumor drugs.

Description

technical field [0001] The invention relates to a synthesis method and a medical application of andrographolide derivatives, in particular to a synthesis method of andrographolide-19-amide derivatives and an application in preparing antitumor drugs, belonging to the field of medicinal chemistry. Background technique [0002] Andrographolide (Andro) is one of the main active ingredients of the extract of Andrographis paniculata, a plant of the Acanthaceae family. It is a diterpene lactone compound and is widely used in traditional medical systems in India, China and Southeast Asia. Modern pharmacological studies have shown that andrographolide has antibacterial, anti-inflammatory, hepatoprotective, anti-tumor and immune regulation effects. [Gupta, S.; Choudhry, M.A.; Yadava, J.N.S.; Srivastava, V.; Tandon, J.S. Int. J. Crude Drug Res. 1990, 28, 273.; Babish, J.G.; Howell, T.; , 20020068098, 2002.; Saraswat, B.; Visen, P.K.; Patnaik, G.K.; Dhawan, B.N. Fitoterapia1995, 66, 41...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/60A61P35/00
CPCC07D307/60
Inventor 薛晓文李莉宋雅萍路云龙李嘉宾
Owner CHINA PHARM UNIV
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