Nitrogen-substituted podophyllin derivatives with anti-tumor activity, preparation method and use thereof

Abstract

The invention discloses nitrogen substitution podophyllum type derivatives with antitumor activity and a preparation method and application thereof. The nitrogen substitution podophyllum type derivatives (as formula V) with fine antitumor activity are prepared by introducing 1-(3-amino propyl) imidazole, benzimidazole, 2-thienylmethylamine or trihydroxymethyl aminomethane to C ring 4-position activated by 4-demethylation surface podophyllotoxin. The nitrogen substitution podophyllum type derivatives can act on tumor cells with multiple paths and multiple target points, and accordingly better antitumor curative effect is achieved. Antitumor activity of the derivatives is evidently increased compared with that of the 4-demethylation surface podophyllotoxin. The derivatives can be prepared into antitumor drugs to apply to antitumor therapies.

Description

technical field

[0001] The present invention relates to podophyllotoxin derivatives, in particular to nitrogen-substituted podophyllotoxin derivatives obtained by substituting the 4-position of the C ring of 4'-desmethyl epipodophyllotoxin and a preparation method thereof. The present invention also relates to said The use of nitrogen-substituted podophyllotoxin derivatives in the preparation of antitumor drugs belongs to the field of preparation and application of podophyllotoxin derivatives. Background technique

[0002] Podophyllotoxin and 4′-Demethylepipodophyllotoxin (4′-Demethylepipodophyllotoxin) are extracted from podophyllum plants (for example: Berberidaceae plants Taoerqi, mountain lotus leaf, star anise lotus, etc.) The obtained natural active lead compound with unique antitumor activity. However, Podophyllotoxin or 4'-desmethylepipodophyllotoxin has defects such as low anti-tumor activity to varying degrees, which severely limits their clinical use. Contents ...

Examples

Embodiment 1

[0039] Example 1 Synthesis and purification of 4-N-(1-(3-aminopropyl)imidazole-1)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound (1))

[0040] (1) Synthesis of 4-N-(1-(3-aminopropyl)imidazole-1)-4-deoxy-4′-demethyl epipodophyllotoxin: Weigh 1mol 4′-demethyl epipodophyllotoxin The activated product of the 4-position of the C ring of phyllotoxin (prepared in Preliminary Example 1) was vacuum-dried at 45° C. for 2 hours; Method) into a four-neck flask, add the activated product of the 4-position of the C ring of 4′-desmethyl epipodophyllotoxin and 3mol 1-(3-aminopropyl)imidazole, and stir and react at 80°C for 48 hours. After the reaction solution was spin-dried, the crude product of 4-N-(1-(3-aminopropyl)imidazole-1)-4-deoxy-4'-desmethyl epipodophyllotoxin was obtained.

[0041] (2) Isolation and purification of 4-N-(1-(3-aminopropyl)imidazole-1)-4-deoxy-4'-desmethyl epipodophyllotoxin:

[0042] Separation and purification using silica gel column chromatography and gel colu...

Embodiment 2

[0046] Example 2 Synthesis and purification of 4-N-(benzimidazole)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound (2))

[0047] (1) Synthesis of 4-N-(benzimidazole)-4-deoxy-4'-desmethyl epipodophyllotoxin: Weigh 1 mol of 4'-desmethyl epipodophyllotoxin C-ring 4-activated product (prepared in Preliminary Example 1), vacuum-dry at 45°C for 2 hours; under nitrogen protection, add dried acetonitrile (the drying method is the same as that of dichloromethane in Preparatory Example 1) into a four-necked bottle, and add the dried The activated product of 4'-desmethyl epipodophyllotoxin C-ring 4 and 3mol benzimidazole were stirred and reacted at 80°C for 48 hours; after the reaction was completed, the reaction solution was spin-dried, dissolved in 50ml ethyl acetate and cleaned with ultrasonic waves Ultrasonic instrument for 5 minutes, there will be insoluble matter at this time, and the insoluble matter obtained after filtering with filter paper is the crude product of 4-N-(benzimi...

Embodiment 3

[0053] Example 3 Synthesis and purification of 4-N-(2-thienylamine)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound (3))

[0054] (1) Synthesis of 4-N-(2-thiophenemethylamine)-4-deoxy-4′-desmethyl epipodophyllotoxin: Weigh 1 mol of 4′-desmethyl epipodophyllotoxin C ring 4 activation The product (prepared in Preliminary Example 1) was vacuum-dried at 45°C for 2 hours; under nitrogen protection, the dried acetonitrile (drying method was the same as that of dichloromethane in Preparatory Example 1) was added to the four-necked flask, and dried A good 4'-demethyl epipodophyllotoxin C ring 4-activated product and 3mol thiophene-2-methylamine (80°C stirred for 48 hours, and the reaction solution was spin-dried to get the crude product

[0055] (2) Separation and purification:

[0056] Separation and purification using silica gel column chromatography and gel column chromatography:

[0057](A) Use a normal phase silica gel column (normal phase silica gel: China Qingdao Ocean Chem...

technical field

[0001] The present invention relates to podophyllotoxin derivatives, in particular to nitrogen-substituted podophyllotoxin derivatives obtained by substituting the 4-position of the C ring of 4'-desmethyl epipodophyllotoxin and a preparation method thereof. The present invention also relates to said The use of nitrogen-substituted podophyllotoxin derivatives in the preparation of antitumor drugs belongs to the field of preparation and application of podophyllotoxin derivatives. Background technique

[0002] Podophyllotoxin and 4′-Demethylepipodophyllotoxin (4′-Demethylepipodophyllotoxin) are extracted from podophyllum plants (for example: Berberidaceae plants Taoerqi, mountain lotus leaf, star anise lotus, etc.) The obtained natural active lead compound with unique antitumor activity. However, Podophyllotoxin or 4'-desmethylepipodophyllotoxin has defects such as low anti-tumor activity to varying degrees, which severely limits their clinical use. Contents ...

Examples

Embodiment 1

[0039] Example 1 Synthesis and purification of 4-N-(1-(3-aminopropyl)imidazole-1)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound (1))

[0040] (1) Synthesis of 4-N-(1-(3-aminopropyl)imidazole-1)-4-deoxy-4′-demethyl epipodophyllotoxin: Weigh 1mol 4′-demethyl epipodophyllotoxin The activated product of the 4-position of the C ring of phyllotoxin (prepared in Preliminary Example 1) was vacuum-dried at 45° C. for 2 hours; Method) into a four-neck flask, add the activated product of the 4-position of the C ring of 4′-desmethyl epipodophyllotoxin and 3mol 1-(3-aminopropyl)imidazole, and stir and react at 80°C for 48 hours. After the reaction solution was spin-dried, the crude product of 4-N-(1-(3-aminopropyl)imidazole-1)-4-deoxy-4'-desmethyl epipodophyllotoxin was obtained.

[0041] (2) Isolation and purification of 4-N-(1-(3-aminopropyl)imidazole-1)-4-deoxy-4'-desmethyl epipodophyllotoxin:

[0042] Separation and purification using silica gel column chromatography and gel colu...

Embodiment 2

[0046] Example 2 Synthesis and purification of 4-N-(benzimidazole)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound (2))

[0047] (1) Synthesis of 4-N-(benzimidazole)-4-deoxy-4'-desmethyl epipodophyllotoxin: Weigh 1 mol of 4'-desmethyl epipodophyllotoxin C-ring 4-activated product (prepared in Preliminary Example 1), vacuum-dry at 45°C for 2 hours; under nitrogen protection, add dried acetonitrile (the drying method is the same as that of dichloromethane in Preparatory Example 1) into a four-necked bottle, and add the dried The activated product of 4'-desmethyl epipodophyllotoxin C-ring 4 and 3mol benzimidazole were stirred and reacted at 80°C for 48 hours; after the reaction was completed, the reaction solution was spin-dried, dissolved in 50ml ethyl acetate and cleaned with ultrasonic waves Ultrasonic instrument for 5 minutes, there will be insoluble matter at this time, and the insoluble matter obtained after filtering with filter paper is the crude product of 4-N-(benzimi...

Embodiment 3

[0053] Example 3 Synthesis and purification of 4-N-(2-thienylamine)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound (3))

[0054] (1) Synthesis of 4-N-(2-thiophenemethylamine)-4-deoxy-4′-desmethyl epipodophyllotoxin: Weigh 1 mol of 4′-desmethyl epipodophyllotoxin C ring 4 activation The product (prepared in Preliminary Example 1) was vacuum-dried at 45°C for 2 hours; under nitrogen protection, the dried acetonitrile (drying method was the same as that of dichloromethane in Preparatory Example 1) was added to the four-necked flask, and dried A good 4'-demethyl epipodophyllotoxin C ring 4-activated product and 3mol thiophene-2-methylamine (80°C stirred for 48 hours, and the reaction solution was spin-dried to get the crude product

[0055] (2) Separation and purification:

[0056] Separation and purification using silica gel column chromatography and gel column chromatography:

[0057](A) Use a normal phase silica gel column (normal phase silica gel: China Qingdao Ocean Chem...

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