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Podophyllotoxin derivative, and preparation method, medicine composition and application thereof

A technology of podophyllotoxin and derivatives, applied in the field of podophyllotoxin derivatives, which can solve the problems of bone marrow suppression in the gastrointestinal tract, narrow anti-tumor spectrum, side effects, etc.

Active Publication Date: 2015-11-11
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The technical problem to be solved by the present invention is to solve the problem that the existing podophyllotoxin derivatives have a relatively narrow antitumor spectrum, severe bone marrow suppression and gastrointestinal side effects, etc., and provide a completely different from the prior art Podophyllotoxin derivative, its preparation method, pharmaceutical composition and application

Method used

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  • Podophyllotoxin derivative, and preparation method, medicine composition and application thereof
  • Podophyllotoxin derivative, and preparation method, medicine composition and application thereof
  • Podophyllotoxin derivative, and preparation method, medicine composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Synthesis of 4β-amino-4'-desmethylepipodophyllotoxin Synthesis of 4β-chloroacetamido-4'-desmethylepipodophyllotoxin

[0041]

[0042] At room temperature, add 4'-desmethyl epipodophyllotoxin (10g, 25mmol) to chloroacetonitrile (15mL, 250mmol), add 0.15mL 98% concentrated sulfuric acid dropwise, and stir. It can be seen that the insoluble matter dissolves and quickly turns white A solid is formed, add 50 mL of isopropanol to dilute the solid, filter with suction, continue to wash the filter cake twice with 100 mL of isopropanol, and then wash with water until neutral. Place in a vacuum oven to dry at 40°C for 4 hours to obtain 10 g of white solid powder, yield: 84%.

[0043] ESI-MS: 476 (M+H + ) / 493(M+H 3 o + ).

[0044] 1 HNMR (DMSO-d 6 ): 8.60 (1H, dd, NH), 8.20 (1H, d, OH heavy water exchange), 6.89 (1H, d, 5H), 6.52 (1H, d, 8H), 6.23 (2H, s, H-2′ ,6′),6.00(2H,d,-OCH 2 O), 5.19 (1H, dd, H-4), 4.5 (1H, d, H-1), 4.34 (1H, t, H-11α), 3.79 (1H, t, H-11β), 4.19 ...

Embodiment 2

[0046] Preparation of 4β-amino-4'-desmethyl epipodophyllotoxin

[0047]

[0048] Add 4β-chloroacetyl-4'-desmethyl epipodophyllotoxin (10g, 21mmol) into 50mL of glacial acetic acid, raise the temperature to 80°C, add thiourea (2.4g, 31mmol), and it can be seen within about 10min When the reaction liquid turns turbid to clear, keep stirring at 80°C for 2.5 hours, a white solid is formed, stop the reaction until the precipitate no longer forms, continue to add 50mL of glacial acetic acid, dilute the solid, filter with suction, and filter the cake with 150mL of anhydrous diethyl ether Washed three times, transferred to a vacuum drying oven to dry, 4β-amino-4'-desmethyl epipodophyllotoxin hydrochloride 6.85g yield: 84%.

[0049] ESI-MS: 400 (M+H + ).

[0050] 1 HNMR (DMSO-d 6 ): 8.60 (2H,s,-NH 2 Heavy water exchange disappears), 8.20 (1H, s, OH heavy water exchange disappears), 7.20 (1H, d, 5H), 6.80 (1H, d, 8H), 6.19 (2H, s, H-2′, 6′), 6.00 (2H,d,-OCH 2 O), 4.78(1H,d,H-4...

Embodiment 3

[0068] Preparation of 4β-(2-pyrroleformyloxy)-4-deoxy-4'-desmethyl epipodophyllotoxin (Compound I-1)

[0069] DCM 5mL, 2-pyrrolecarboxylic acid (206mg, 1.875mmol), DMEP (500mg, 1.25mmol), and the rest of the operation and material ratio refer to method 4 to prepare I-1 to obtain 128mg of white solid, yield: 20.8%.

[0070] ESI-MS: 516 (M+Na + )

[0071] 1 HNMR (400MHz, DMSO-d 6 )δ11.93(s,1H),7.08(d,J=0.8Hz,1H),6.95(s,1H),6.92(d,J=8.4Hz,1H),6.54(s,1H),6.36( s,2H),6.23(s,1H),5.98(d,J=2.4Hz,2H),5.49(d,J=6Hz,1H),4.78(dd,3.6Hz,4Hz,1H),4.61(d ,J=5.6Hz,1H),4.37(t,J=15.6Hz,1H),4.21(m,1H),3.60(s,6H),3.39–3.30(m,2H),2.87–2.81(m, 1H).

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Abstract

Disclosed in the present invention is a podophyllotoxin derivative, and a preparation method, pharmaceutical composition and use thereof. The preparation method disclosed in the present invention comprises the following step: in an organic solvent, in the presence of a base, carrying out a condensation reaction between the compound as shown in formula II and the compound as shown in formula III under the action of a condensating agent. The pharmaceutical composition disclosed in the present invention comprises the podophyllotoxin derivative as shown in formula I and a pharmaceutically acceptable excipient. Also disclosed in the present invention is the use of the podophyllotoxin derivative as shown in formula I in the preparation of a drug for treating a cancer. The podophyllotoxin derivative of the present invention has a good tumour cell inhibitory activity, and the preparation method and post-treatment thereof are simple, with good prospects for market development.

Description

technical field [0001] The invention relates to a podophyllotoxin derivative, its preparation method, pharmaceutical composition and application. Background technique [0002] Etoposide (VP-16) and teniposide (VM-26) are podophyllotoxin derivatives clinically used to treat tumors. Etoposide is often used in combination with cisplatin to treat lung cancer and testicular cancer. Cancer, curative effect is better, also used in the treatment of lymphoma. Teniposide mainly treats Hodgkin's and non-Hodgkin's lymphoma and has obvious effects, and it also has a therapeutic effect on brain tumors and childhood lymphocytic leukemia. However, the above-mentioned anti-tumor drugs have a relatively narrow anti-tumor spectrum, accompanied by severe bone marrow suppression and gastrointestinal side effects. Therefore, there is an urgent need in the field for a podophyllotoxin derivative with a broad anti-tumor spectrum, no obvious bone marrow suppression and gastrointestinal side effects...

Claims

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Application Information

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IPC IPC(8): C07D493/04A61K31/365A61K31/4025A61K31/4709A61K31/381A61K31/4178A61K31/4155A61K31/416A61P35/00A61P35/02
CPCA61K31/365A61K31/4025A61K31/404A61K31/4709C07D493/04
Inventor 肖旭华孙亚飞姚利霞刘全海沈舜义
Owner SHANGHAI INST OF PHARMA IND
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