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Indole podophyllotoxin derivatives, preparation method, pharmaceutical composition and application thereof

A technology of podophyllotoxin and indole, which is applied in drug combination, antineoplastic drugs, organic chemistry, etc., can solve the problems of side effects, myelosuppression of gastrointestinal tract, and narrow tumor inhibition spectrum, and achieve the goal of preparation method and post-processing Ease of application, good tumor cell inhibitory activity, and good market development prospects

Active Publication Date: 2017-09-15
SHANGHAI INST OF PHARMA IND CO LTD +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 Indole podophyllotoxin derivatives, preparation method, pharmaceutical composition and application thereof

Method used

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  • Indole podophyllotoxin derivatives, preparation method, pharmaceutical composition and application thereof
  • Indole podophyllotoxin derivatives, preparation method, pharmaceutical composition and application thereof
  • Indole podophyllotoxin derivatives, preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Synthesis of 4β-amino-4'-desmethylepipodophyllotoxin Synthesis of 4β-chloroacetamido-4'-desmethylepipodophyllotoxin

[0033]

[0034]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%.

[0035] ESI-MS: 476 (M+H + ) / 493(M+H 3 o + ).

[0036] 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

[0038] Preparation of 4β-amino-4'-desmethyl epipodophyllotoxin

[0039]

[0040] 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%.

[0041] ESI-MS: 400 (M+H + ).

[0042] 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

[0051] Preparation of 4β-(indole-2-acetoxy)-4-deoxy-4'-desmethyl epipodophyllotoxin (I-1)

[0052] DCM 3mL, indole-2-carboxylic acid (364mg, 2.25mmol) were fed and processed according to Method 2 to obtain 120mg of white solid with a yield of 21.4%.

[0053] ESI-MS: 566 (M+Na +) .

[0054] 1 H NMR (400MHz, DMSO-d 6 )δ11.98(s,1H),7.71(d,J=8Hz,1H),7.50(d,J=8.4Hz,1H),7.30(t,J=7.2Hz,2H),7.11(t,J =8Hz,1H),6.97(s,1H),6.58(s,1H),6.41(s,2H),6.01(d,J=2.8Hz,2H),5.72(s,1H),5.44(d, J=5.6Hz, 1H), 4.78(t, J=3.6Hz, 1H), 4.65(d, J=5.6Hz, 1H), 4.39(t, J=8Hz, 1H), 4, 23(t, J =10.8Hz,1H),3.64(s,6H),3.36(dd,J=5.6Hz,5.6Hz,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 an indole podophyllotoxin derivative, its preparation method, pharmaceutical composition and application. Background technique [0002] Podophyllotoxin compounds have many uses such as antifungal, antiviral, antitumor and so on. Etoposide (VP-16), as the first semi-synthetic podophyllotoxin derivative on the market, is mainly used for the treatment of small cell lung cancer, and also for acute leukemia, malignant lymphoma, bladder cancer, prostate cancer, gastric cancer, ovarian cancer, etc. efficient. The anti-tumor mechanism of podophyllotoxin derivatives mainly includes: (1) Inhibit cell microtubule polymerization, prevent cell mitosis, and make it stagnate in metaphase. (2) Inhibit the activity of topoisomerase II (Topo-II), form a stable DNA-Topo II-drug molecule complex, cause DNA breakage, and cause cell death. (3) Inhibit the uptake of various nucleosides such as thymine, uracil, adenine, and guanine by cells, thereb...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/04A61K31/404A61K31/405A61P35/00A61P35/02
CPCA61K31/365A61K31/4025A61K31/404A61K31/4709C07D493/04
Inventor 肖旭华姚利霞孙亚飞刘全海沈舜义
Owner SHANGHAI INST OF PHARMA IND CO LTD
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