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Podophyllotoxin derivative tubulin inhibitor as well as preparation method and medical application thereof

A technology of podophyllotoxin and derivatives, which is applied in the field of preparation of podophyllotoxin derivatives, and can solve problems such as toxic side effects, limitations, and poor selectivity

Pending Publication Date: 2022-05-27
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, podophyllotoxin has obvious toxic and side effects such as poor water solubility, narrow anticancer spectrum, and severe bone marrow suppression and gastrointestinal reactions, which limit its clinical application.
Researchers at home and abroad have made a lot of structural modifications and transformations. Although the obtained derivatives etoposide (VP-16) and teniposide (VM-26) have been used in clinical anti-tumor applications, these drugs are still There are problems such as multidrug resistance, poor selectivity and toxic side effects, which greatly limit its clinical application

Method used

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  • Podophyllotoxin derivative tubulin inhibitor as well as preparation method and medical application thereof
  • Podophyllotoxin derivative tubulin inhibitor as well as preparation method and medical application thereof
  • Podophyllotoxin derivative tubulin inhibitor as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Step 1: Preparation of compound 4a

[0053] Using levodopa (compound 1, 10 g, 50 mmol) as the starting material, it was dissolved in methanol (200 ml), thionyl chloride (150 mmol) was added dropwise, the reaction was carried out at room temperature for 6 hours, and concentrated under reduced pressure to obtain compound 2. Yellow solid, 98% yield.

[0054] Compound 2 (10.5g, 50mmol) was placed in 1,4-dioxane (70ml), 1M aqueous sodium hydroxide solution (70ml) was slowly added, followed by di-tert-butyl carbonate (16g, 1.5eq), 80 The reaction was refluxed at °C for 8 h, and hydrochloric acid was added to adjust the pH to 5, extracted with ethyl acetate three times, the ethyl acetate layers were combined, and the water was removed with anhydrous sodium sulfate to obtain an oil (compound 3), which was directly used in the next step. Compound 3 (73.3 mmol) was dissolved in acetonitrile, potassium carbonate (20.7 g, 150 mmol) and dimethyl sulfate (10.4 ml, 110 mmol) were add...

Embodiment 2

[0059] (5R,9aS)-8-ethyl-5-(3,4,5-trimethoxyphenyl)-9a,10-dihydro-[1,3]dioxacyclo[4,5-g] Imidazo[1,5-b]isoquinoline-7,9(5H,8H)-dione (Compound I 2 ) preparation

[0060]

[0061] The preparation method is the same as in Example 1, except that the dimethyl sulfate used in the preparation of compound 4a is replaced by diiodomethane (to obtain compound 4b, R 1 , R 2 Connect to each other and form dioxane together with benzene ring), other conditions are constant, obtain compound I 2 , white solid, 68% yield. 1 H NMR (600MHz, CDCl 3 )δ6.68(s,1H),6.46(s,2H),6.45(s,1H),6.03(s,1H),5.96(d,J=1.0Hz,1H),5.94(d,J=1.0 Hz,1H),4.14(dd,J=11.4,5.2Hz,1H),3.83(s,3H),3.80(s,6H),3.56(qd,J=13.8,7.2Hz,2H),3.23(dd , J=15.8, 5.2Hz, 1H), 2.84 (dd, J=15.8, 11.5Hz, 1H), 1.21 (t, J=7.2Hz, 3H). 13 C NMR (151MHz, CDCl 3)δ173.05,154.93,153.79,147.64,147.35,138.17,137.77,127.18,125.12,108.81,108.57,105.94,101.70,61.17,56.59,55.54,52.63,34.14,30.94,13.86.HRMS(ESI)m / z:463.1474 ,calcd for:C 23 H 24 ...

Embodiment 3

[0063] (6R,10aS)-9-ethyl-6-(3,4,5-trimethoxyphenyl)-2,3,10a,11-tetrahydro-[1,4]dioxane[2, 3-g]imidazo[1,5-b]isoquinoline-8,10(6H,9H)-dione (Compound I 3 ) preparation

[0064]

[0065] The preparation method is the same as in Example 1, except that the dimethyl sulfate used in the preparation of compound 4a is replaced by 1,2-dibromoethane (to obtain compound 4c, R 1 , R 2 Connect to each other and form dioxane together with benzene ring), other conditions are unchanged, obtain compound I 3 , a colorless solid, 73% yield. 1 H NMR (500MHz, CDCl 3 )δ6.73(s,1H),6.51(s,1H),6.45(s,2H),6.01(s,1H),4.23(dd,J=14.0,4.3Hz,4H),4.14(dd,J =11.6,5.1Hz,1H),3.56(dq,J=13.7,7.2Hz,2H),3.21(dd,J=15.8,5.1Hz,1H),2.81(dd,J=15.6,11.6Hz,1H) ,1.20(t,J=7.2Hz,3H). 13 C NMR (126MHz, CDCl 3 )δ172.67,154.61,153.28,142.97,142.64,137.74,137.52,126.60,124.30,116.83,116.80,105.57,64.28,64.20,60.67,56.14,54.78,52.54,33.64,29.95,13.36.HRMS(ESI)m / z :477.1634,calcd for:C 24 H 26 N 2 O 7 Na[M+Na] + 4...

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Abstract

The invention discloses a podophyllotoxin derivative with a structure as shown in a formula I or a pharmaceutically acceptable salt or solvate. The invention further discloses application of the podophyllotoxin derivative or the pharmaceutically acceptable salt or solvate in preparation of a tubulin inhibitor, proliferation of tumor cells can be inhibited on the cellular level, growth of transplanted tumors in nude mice can be inhibited on the animal level, and the podophyllotoxin derivative or the pharmaceutically acceptable salt or solvate can be used for treating various cancers. And the podophyllotoxin derivative has low toxic and side effects, almost has no obvious toxicity to normal cells, and improves the safety.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of a class of podophyllotoxin derivatives and its medicinal use. As tubulin inhibitors, the compounds can inhibit the proliferation of tumor cells at the cellular level, and inhibit the growth of transplanted tumors in nude mice at the animal level, and can be used to treat various tumors or cancers and other diseases. Background technique [0002] Currently, malignant tumors are a serious threat to human life and health, and the mortality rate remains high. Today, chemotherapy for cancer is considered one of the most effective treatments. However, clinically, more and more tumors have multidrug resistance (MDR) problems, which directly lead to the failure of drug chemotherapy. [0003] Microtubules are widely found in eukaryotic cells. In the early stage of tumor cell mitosis, microtubules are in a dynamic balance of depolymerization and repolymerization...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D491/147C07D498/14A61P35/00A61P35/02A61K31/4745
CPCC07D471/04C07D491/147C07D498/14A61P35/00A61P35/02
Inventor 孔令义殷勇夏元铮冷加富
Owner CHINA PHARM UNIV
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