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Andrographolide derivatives and application of the same in pharmacy

A technology of andrographolide, derivatives, applied in antipyretic, antibacterial, antitumor and other directions

Inactive Publication Date: 2008-02-20
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no single mechanism is sufficient to explain its antitumor activity and perhaps each of them plays a role

Method used

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  • Andrographolide derivatives and application of the same in pharmacy
  • Andrographolide derivatives and application of the same in pharmacy
  • Andrographolide derivatives and application of the same in pharmacy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0122] Example 1. Preparation of 3,19-isopropylidene andrographolide 1

[0123] Dissolve andrographolide (150 mg, 0.43 mmol) in a mixed solution containing 2,2-dimethoxypropane (0.2 mL), pyridinium p-toluenesulfonate (3 mg) and toluene / DMSO (3 mL / 0.4 mL) , stirred at 80° C. for 1 hour, after the reaction was complete, cooled to room temperature, and quenched the reaction mixture with triethylamine (0.1 mL). The reaction mixture was diluted with toluene (20 mL), washed with water (3×5 mL), and the organic layer was washed with anhydrous Na 2 SO 4 After drying and concentration, the resulting white solid was washed with ether and filtered to obtain compound 1 (130 mg, 78%) (Srinivas et al., Bioorg. Med. Chem. Lett. 2004, 14, 4711-4717).

Embodiment 2

[0124] Example 2. Preparation of 14-lipoyl-3,19-isopropylidene andrographolide 2

[0125] Add ethyl chloroformate (0.11 mL) to α-lipoic acid (214 mg) CH 2 Cl 2 (8 mL) solution, add 0.21 mL of triethylamine, and stir at 0° C. for 1 h under the protection of nitrogen. Compound 1 (100 mg) was dissolved in CH 2 Cl 2 (8 mL), was added to the mixture, and stirred at room temperature for 2 days. Add CH after reaction 2 Cl 2 (30mL) diluted with NaHCO 3 Aqueous solution and water wash. Anhydrous NaSO for organic layer 4 Dry and concentrate in vacuo. The mixture was separated on a silica gel column to obtain compound 2 (90 mg, 61%) as a yellow crystalline powder. 1 H NMR (CDCl 3 , 400MHz): δ7.03(t, 1H, J=5.20Hz), 5.90(d, 1H, J=6.50Hz), 4.90(s, 1H), 4.20(dd, 1H, J=7.20, 17.20Hz) , 3.90 (d, 1H, J=11.99Hz), 1.42 (s, 3H), 1.37 (s, 3H), 1.21 (s, 3H), 0.81 (s, 3H). MS(ESI)[M+H] + m / z 578.

Embodiment 3

[0126] Example 3. Preparation of 14-lipoyl-3,19-dihydroxy-andrographolide AL-1

[0127] Compound 2 (100mg) was added into acidic aqueous solution (AcOH / H 2 O=7 / 3, 3 mL), stirred at room temperature for 1 h. The reaction mixture was added with water and NaHCO 3 In, use CH 2 Cl 2 (3 x 20 mL) extraction. Anhydrous NaSO for organic layer 4 Dry and concentrate in vacuo. The mixture was separated on a silica gel column to obtain compound AL-1 (42 mg, 45%) as a yellow crystalline powder. 1 H NMR (CDCl 3 , 400MHz): 7.03(t, 1H, J=5.20Hz), 5.93(d, 1H, J=6.50Hz), 4.88(s, H), 4.50(s, 1H), 4.24-4.17(dd, 1H, J=6.80, 18.40Hz), 3.34-3.32(d, 1H, J=10.79Hz), 1.34(s, 6H). HRMS[M] + m / z 538.2417, (calcd 538.2408).

[0128] Its synthetic reaction formula is as follows:

[0129]

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PUM

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Abstract

The invention relates to an andrographolide derivative, which has the structure as shown in a general formula I: wherein, R1, R2 and R3 are the same or different hydrogen, substituted or non-substituted organic acid radical, inorganic acid radical, alkyl, aryl or heteroaryl, while at least one of R1, R2 and R3 is R-lipoic acid or S-lipoic acid or the mixture of R-lipoic acid and S-lipoic acid or the corresponding dihydrolipoic acid or acetylcysteine radical of R-lipoic acid or S-lipoic acid; the derivative has good anti-tumor effect, and the derivative can cause apoptosis of tumor cells, directly eliminate gram positive bacteria, staphylococcus aureus and sensitivities MRSA5676 and MRSA5677, inhibit the QS system of gram negative bacteria and pseudomonas aeruginosa and inhibit and damage the formation of the bio-film of pseudomonas aeruginosa; the product has prominent hypoplycemic effect and is suitable for the preparation of the medicines that can cure cancers, inflammations, diabetes mellitus and bacterial and viral infection.

Description

technical field [0001] The present invention relates to new andrographolide derivatives and their application in pharmacy. Background technique [0002] Andrographolide (Andrographolide) is the main active ingredient in the traditional Chinese medicine Andrographis paniculata. Andrographis paniculata is widely used in Asian countries, including China, India, Japan, Korea, etc., to treat inflammatory diseases, including rheumatoid arthritis, pharyngitis, diarrhea, bacterial and viral infections (Zhao and Fang, Chin. Med. J. (Engl) 1991, 104, 770-775; Puri et al., J.Nat.Prod.1993, 56, 995-999; Zhang and Tan, Clin.Exp.Pharmacol.Physiol.1996, 23, 675-678; Zhang and Tan, Clin. Exp. Pharmacol. Physiol. 2000, 27, 358-363; Shen et al., Br. J. Pharmacol. 2002, 35, 399-406). Recently, studies have shown that andrographolide has broad-spectrum anticancer effects and good therapeutic effects (Rajagopal et al., J.Exp.Ther.Oncol.2003, 3, 147-158; Satyanarayana et al.Science 2003, 299, ...

Claims

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Application Information

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IPC IPC(8): C07D409/12C07D307/58A61K31/365A61K31/385A61P35/00A61P29/00A61P3/10A61P31/00
CPCC07D307/58C07D409/12C07D307/60A61P29/00A61P31/00A61P31/04A61P31/10A61P31/12A61P35/00A61P35/02A61P3/10
Inventor 王玉强江晓间蒋杰张在军杨兆琪于沛
Owner JINAN UNIVERSITY
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