Andrographolide derivative and preparation method and application thereof

Abstract

The invention discloses an andrographolide derivative and a preparation method and application thereof. The derivative has a structure expressed by the formula (1), wherein R1 is C1 to C11 chain hydrocarbon or C1 to C11 chain hydrocarbon with terminals substituted by ternary to heptabasic ring groups; and R2 and R3 are hydrogen, organic acid radical, inorganic acid radical, alkyl or acryl. The andrographolide derivative can be made into tablets, capsules, granules, fine granules, powder, pills, patches, oral liquid or injection.

Description

technical field

[0001] The invention belongs to the technical field of traditional Chinese medicines, and in particular relates to an andrographolide derivative and a preparation method and application thereof. Background technique

[0002] Andrographolide (Andro) is one of the main active ingredients in Andrographis paniculata of the Acanthaceae plant, which has antipyretic and anti-inflammatory effects, including rheumatoid arthritis, pharyngitis, diarrhea, bacterial and viral infections. Recently, studies have shown that andrographolide has broad-spectrum anticancer effects, and the therapeutic effect is good. In India and Malaysia, andrographolide is widely used in the treatment of diabetes. In the past 30 years, andrographolide has been widely used clinically in China.

[0003]

[0004] A study of the antibacterial activity of andrographolide. Andrographis paniculata extract was used to treat acute upper respiratory tract infection combined with sinusitis. The res...

Examples

Embodiment 1

[0066] Synthesis of Example 1 Compound 2

[0067] Andrographolide 1 (150mg, 0.43mmol) was dissolved in 2,2-dimethoxypropane (0.2ml, 0.85mmol), pyridinium p-toluenesulfonate (3mg, 0.88mmol) and toluene / DMSO (3ml / 0.4ml) of the mixed solution, stirred at 80°C for 1 hour, after the reaction was complete, cooled to room temperature, and the reaction mixture was terminated with triethylamine (0.1ml). The reaction mixture was diluted with toluene (20ml), washed with water (15ml), 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 2 (130 mg, 78%).

Embodiment 2

[0068] Example 2 Synthesis of compound AC-002 (synthetic route diagram as figure 1 shown)

[0069] Ethyl chloroformate (0.33ml, 3.4mmol) was added to 5-cyclopentylpentanoic acid (350mg, 2.0mmol) CH 2 Cl 2 (16ml) solution, add 0.63mL of triethylamine, and stir in an ice-water bath under nitrogen protection for 1h. Compound 2 (200 mg, 0.5 mmol) was dissolved in CH 2 Cl 2 (20ml), was added dropwise to the mixture, and stirred at room temperature for 40h. Add CH after reaction 2 Cl 2 (50ml) 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 (PE:EA=2:1) ​​to obtain compound AC-001 as a colorless viscous liquid (132 mg, 47.6%).

[0070] Compound AC-001 was added to acidic aqueous solution (AcOH / H 2 O=7 / 3, 10ml), stirred at room temperature within 30min. The reaction mixture was added with water and NaHCO 3 , with a large amount of CH 2 Cl 2 extraction....

Embodiment 3

[0073] Embodiment 3. the synthesis of compound AC-004 (synthetic route figure such as figure 1 shown)

[0074] Ethyl chloroformate (0.33ml, 3.4mmol) was added to 3-furanoacrylic acid (283mg, 2.0mmol) CH 2 Cl 2 (16ml) solution, add 0.63mL of triethylamine, and stir in an ice-water bath under nitrogen protection for 1h. Compound 2 (200 mg, 0.5 mmol) was dissolved in CH 2 Cl 2 (20ml), was added dropwise to the mixture, and stirred at room temperature for 40h. Add CH after reaction 2 Cl 2 (50ml) 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 (PE:EA=2:1) ​​to obtain compound AC-003 as a colorless viscous liquid (112.3 mg, 43%).

[0075] Compound AC-003 was added to acidic aqueous solution (AcOH / H 2 O=7 / 3, 10ml), stirred at room temperature within 30min. The reaction mixture was added with water and NaHCO 3 , with a large amount of CH 2 Cl 2 extrac...

technical field

[0001] The invention belongs to the technical field of traditional Chinese medicines, and in particular relates to an andrographolide derivative and a preparation method and application thereof. Background technique

[0002] Andrographolide (Andro) is one of the main active ingredients in Andrographis paniculata of the Acanthaceae plant, which has antipyretic and anti-inflammatory effects, including rheumatoid arthritis, pharyngitis, diarrhea, bacterial and viral infections. Recently, studies have shown that andrographolide has broad-spectrum anticancer effects, and the therapeutic effect is good. In India and Malaysia, andrographolide is widely used in the treatment of diabetes. In the past 30 years, andrographolide has been widely used clinically in China.

[0003]

[0004] A study of the antibacterial activity of andrographolide. Andrographis paniculata extract was used to treat acute upper respiratory tract infection combined with sinusitis. The res...

Examples

Embodiment 1

[0066] Synthesis of Example 1 Compound 2

[0067] Andrographolide 1 (150mg, 0.43mmol) was dissolved in 2,2-dimethoxypropane (0.2ml, 0.85mmol), pyridinium p-toluenesulfonate (3mg, 0.88mmol) and toluene / DMSO (3ml / 0.4ml) of the mixed solution, stirred at 80°C for 1 hour, after the reaction was complete, cooled to room temperature, and the reaction mixture was terminated with triethylamine (0.1ml). The reaction mixture was diluted with toluene (20ml), washed with water (15ml), 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 2 (130 mg, 78%).

Embodiment 2

[0068] Example 2 Synthesis of compound AC-002 (synthetic route diagram as figure 1 shown)

[0069] Ethyl chloroformate (0.33ml, 3.4mmol) was added to 5-cyclopentylpentanoic acid (350mg, 2.0mmol) CH 2 Cl 2 (16ml) solution, add 0.63mL of triethylamine, and stir in an ice-water bath under nitrogen protection for 1h. Compound 2 (200 mg, 0.5 mmol) was dissolved in CH 2 Cl 2 (20ml), was added dropwise to the mixture, and stirred at room temperature for 40h. Add CH after reaction 2 Cl 2 (50ml) 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 (PE:EA=2:1) ​​to obtain compound AC-001 as a colorless viscous liquid (132 mg, 47.6%).

[0070] Compound AC-001 was added to acidic aqueous solution (AcOH / H 2 O=7 / 3, 10ml), stirred at room temperature within 30min. The reaction mixture was added with water and NaHCO 3 , with a large amount of CH 2 Cl 2 extraction....

Embodiment 3

[0073] Embodiment 3. the synthesis of compound AC-004 (synthetic route figure such as figure 1 shown)

[0074] Ethyl chloroformate (0.33ml, 3.4mmol) was added to 3-furanoacrylic acid (283mg, 2.0mmol) CH 2 Cl 2 (16ml) solution, add 0.63mL of triethylamine, and stir in an ice-water bath under nitrogen protection for 1h. Compound 2 (200 mg, 0.5 mmol) was dissolved in CH 2 Cl 2 (20ml), was added dropwise to the mixture, and stirred at room temperature for 40h. Add CH after reaction 2 Cl 2 (50ml) 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 (PE:EA=2:1) ​​to obtain compound AC-003 as a colorless viscous liquid (112.3 mg, 43%).

[0075] Compound AC-003 was added to acidic aqueous solution (AcOH / H 2 O=7 / 3, 10ml), stirred at room temperature within 30min. The reaction mixture was added with water and NaHCO 3 , with a large amount of CH 2 Cl 2 extrac...

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