4-amino oxadiazole epipodophyllotoxin derivative and preparation method and application thereof

A technology of aminooxadiazole epipodophyllotoxin, which is applied in the application field of 4-aminooxadiazole epipodophyllotoxin derivatives, can solve the problems of poor water solubility and poor oral effect, and achieve good cytotoxicity, Improvement of water solubility, reduction of normal cytotoxicity

Inactive Publication Date: 2012-05-02
CHANGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

With the widespread clinical application of etoposide and teniposide, their drug resistance, poor water solubility, severe bone marrow suppression, and poor oral effect have become problems.

Method used

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  • 4-amino oxadiazole epipodophyllotoxin derivative and preparation method and application thereof
  • 4-amino oxadiazole epipodophyllotoxin derivative and preparation method and application thereof
  • 4-amino oxadiazole epipodophyllotoxin derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 Compound 2 preparation of

[0029] Add podophyllotoxin (830mg, 2mmol), sodium azide (650mg, 10mmol), chloroform 20mL, and trifluoroacetic acid 4mL sequentially in a 100mL round-bottom flask under ice-bath conditions, and stir at room temperature for 6h. TLC detects that the reaction is over, adding saturated sodium carbonate solution (20mL), separating the organic layer, washing the organic layer with water (20mL) and saturated brine (20mL) respectively, and extracting the aqueous layer with ethyl acetate (2×20mL) Wash with water (20mL) and saturated brine (20mL), combine the organic layers, wash with anhydrous MgSO 4 After drying, the desiccant was filtered off, the filtrate was evaporated to dryness under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 (volume ratio)) to obtain the target product. 1 H NMR (CDCl 3 , 500MHz): δ2.91-2.98 (1H, m, 3-H), 3.18 (1H, dd, J=5.0Hz, 2-H), 3.74 (6H, s, 3′, 5′-...

Embodiment 2

[0030] Example 2 Compound 3 preparation of

[0031] Azidopodophyllotoxin (826 mg, 2 mmol), 15 ml of methanol, and 80 mg of 10% Pd / C were sequentially added to a 50 mL round bottom flask, and stirred overnight at room temperature under a hydrogen atmosphere. After the reaction was detected by TLC, the Pd / C was filtered off, the filtrate was evaporated to dryness under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2 (volume ratio)), and the target product was obtained. 1 HNMR (CDCl 3, 500MHz): δ2.81-2.88 (1H, m, 3-H), 3.30 (1H, dd, J=5.5Hz, 2-H), 3.74 (6H, s, 3′, 5′-OCH 3 ), 3.79 (3H, s, 4'-OCH 3 ), 4.21 (1H, d, J = 4.0Hz, 4-H), 4.27-4.33 (2H, m, 11-H), 4.56 (1H, d, J = 5.0Hz, 1-H), 5.96 (1H , s, OCHO), 5.97 (1H, s, OCHO), 6.30 (2H, s, 2′, 6′-H), 6.49 (1H, s, 8-H), 6.82 (1H, s, 5-H ); 13 C NMR (CDCl 3 , 500MHz): δ38.15 (3-C), 40.20 (2-C), 43.98 (1-C), 48.95 (4'-OCH 3 ), 56.28 (3',5'-OCH 3 ), 60.75(4-C), 68.18(11...

Embodiment 3

[0032] Example 3 Compound 4 preparation of

[0033] Add aminoepipodophyllotoxin (206mg, 0.5mmol), anhydrous THF 4mL, Et 3 N (3.5equiv, 0.24mL), cooled to 0°C, dissolved CS in 1mL of anhydrous THF 2 (0.05mL) was added slowly, and the ice bath was removed after the dropwise addition, and stirred at room temperature for 1.5h. After cooling to 0°C, MsCl (0.043 mL, 1.1 equiv) was added, the ice bath was removed after the addition, and the mixture was stirred at room temperature for 1 h. After the reaction was detected by TLC, 20 mL of ethyl acetate was added, washed with 1N HCl (2×20 mL), water (20 mL), saturated brine (20 mL), and washed with anhydrous MgSO 4 Dry and filter to remove the desiccant, evaporate the filtrate to dryness under reduced pressure, and separate by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 (volume ratio)) to obtain the target product. MS (ESI, m / z): [M+Na] + 478.1; 1 H NMR (CDCl 3 , 500MHz): δ2.88-2.95 (1H, m, 3-H), 3.13 ...

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Abstract

The invention discloses a 4-amino oxadiazole epipodophyllotoxin derivative and a preparation method and application thereof. The 4-amino oxadiazole epipodophyllotoxin derivative has a structure shown as a Formula (1), wherein R1 represents hydrogen or methyl, and R2 represents hydrogen, alkyl, aryl, heteroaryl or heteroaryl alkyl. The derivative is prepared according to the following steps of: firstly, subjecting podophyllotoxin serving as a raw material to azido reaction, reduction, addition and elimination to obtain isothiocyanate epipodophyllotoxin; secondly, reacting an isothiocyanate epipodophyllotoxin intermediate with a hydrazide compound to obtain a thiosemicarbazide derivative; and finally, subjecting to cyclization, and thus obtaining a corresponding 4-amino oxadiazole derivative. The preparation method is simple and is easy to operate. Initial in-vitro screening tests show that the toxicity of the derivative on normal cells is obviously reduced, meanwhile, certain compounds have better anti-tumor activity, and high-efficiency and low-toxicity anti-tumor drugs can be expected to be prepared.

Description

Technical field: [0001] The invention relates to a class of 4-aminooxadiazole epipodophyllotoxin derivatives and a preparation method thereof, as well as pharmaceutical compositions containing them and the application of the 4-aminooxadiazole epipodophyllotoxin derivatives. Background technique: [0002] Podophyllotoxin, also called podophyllotoxin, podophyllotoxin, podophyllotoxin, belongs to cyclolignan lactone in lignan compounds, and is a natural product with antitumor activity. Although podophyllotoxin can inhibit mitosis in the middle stage, its toxic and side effects are relatively large, especially for the gastrointestinal tract, so it cannot be directly used clinically. Since the early 1950s, a large number of derivatives have been synthesized and screened using it as a parent, and some derivatives with high activity and low toxicity have been obtained and are expected to be used in clinical tumor treatment. At present, podophyllotoxin compounds have been well appl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04A61K31/4245A61K31/4439A61P35/00
Inventor 胡昆吴琳任杰陈新辛文群
Owner CHANGZHOU UNIV
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