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Shikonin oxime derivative containing nitrogen hetero side chain and its preparation method and medical use

A derivative, shikonin technology, applied in the field of medicine, can solve the problems of reduced anti-tumor activity and great influence of anti-tumor activity

Active Publication Date: 2020-11-17
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In our previous work, we introduced a nitrogen-containing heterocycle to the oxime hydroxyl group of the shikonin derivatives oxyalkylated with naphthalene nucleoside, and the water solubility of the compound was improved but the antitumor activity was significantly reduced. The results show that the position of introducing nitrogen-containing heterocycle has a great influence on the antitumor activity of this class of compounds

Method used

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  • Shikonin oxime derivative containing nitrogen hetero side chain and its preparation method and medical use
  • Shikonin oxime derivative containing nitrogen hetero side chain and its preparation method and medical use
  • Shikonin oxime derivative containing nitrogen hetero side chain and its preparation method and medical use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065]

[0066] This example relates to a 2-[1-(8-hydroxyoctyloxy)-4-methyl-3-pentenyl]-1,4,5,8-tetra The preparation method of methoxynaphthalene, such as figure 1 shown, including the following steps:

[0067] Dissolve 2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene (X) in anhydrous N,N'-dimethylformamide , cooled to 0°C, added 2 times the equivalent of sodium hydride, stirred for 30 minutes, then added 2 times the equivalent of 2-(8-bromooctyloxy)-tetrahydropyran, the reaction solution was heated to 50°C and stirred for 24 Hour. The reaction was quenched by adding ice water, extracted with ethyl acetate, and a light brown oil was obtained after silica gel column chromatography. The oil was dissolved in methanol, 1 ml of concentrated hydrochloric acid was added dropwise, and stirred overnight at room temperature. The reaction solution was concentrated to a small volume under reduced pressure, and extracted with ethyl acetate. The organic layer was w...

Embodiment 2

[0069]

[0070] This embodiment relates to a kind of (R)-2-[1-(8-hydroxyoctyloxy)-4-methyl-3-pentenyl]-1 having the above structural formula ((R)-XII-1) , the preparation method of 4,5,8-tetramethoxynaphthalene, such as figure 1 shown, including the following steps:

[0071] The steps of this example are the same as those of Example 1. In step one, (R)-2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxy Naphthalene ((R)-X) instead of 2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene (X). The product was brown oil with a yield of 71%. 1 H NMR (400MHz, CDCl 3 )δ6.95(s,1H),6.76–6.66(m,2H),5.21–5.13(m,1H),4.87–4.76(m,1H),3.88(s,3H),3.71(s,3H) ,3.79(s,3H),3.65(s,3H),3.49–3.41(m,2H),3.28–3.16(m,2H),2.82–2.75(m,1H),2.48–2.33(m,2H) ,1.56(s,3H),1.45(s,3H),1.46–1.34(m,2H),1.30–1.10(m,10H).

Embodiment 3

[0073]

[0074] This example relates to a (S)-2-[1-(8-hydroxyoctyloxy)-4-methyl-3-pentenyl]-1 having the above structural formula ((S)-XII-1) , the preparation method of 4,5,8-tetramethoxynaphthalene, such as figure 1 shown, including the following steps:

[0075] The steps of this example are the same as those of Example 1. In step one, (S)-2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxy 2-(1-Hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene (X) is replaced by substituted naphthalene ((S)-X). The product was brown oil with a yield of 75%. 1 H NMR (400MHz, CDCl 3 )δ6.91(s,1H),6.76–6.66(m,2H),5.21–5.13(m,1H),4.85–4.76(m,1H),3.89(s,3H),3.71(s,3H) ,3.79(s,3H),3.65(s,3H),3.49–3.41(m,2H),3.26–3.16(m,2H),2.81–2.75(m,1H),2.48–2.33(m,2H) ,1.56(s,3H),1.45(s,3H),1.45–1.34(m,2H),1.28–1.10(m,10H).

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Abstract

The invention discloses a shikonin oxime derivative containing an aza-side chain, a preparation method and medical application thereof. The structure of the derivative is shown in a formula (I), the formula (I) is shown in the description, wherein R represents a nitrogen-containing heterocyclic ring; the nitrogen-containing heterocyclic ring comprises a substituent-containing pyridine, pyrimidine,pyrazine, pyridazine, thiazole, benzazole, morpholine, piperidine, piperazine, N-methylene-N-hydroxyethyl piperazine, N-methylene-N-hydroxybutyl piperazine and a physiologically acceptable salt thereof; n is any positive integer ranging from 1 to 4. A compound disclosed by the invention is simple in preparation method, mild in reaction condition, and relatively high in yield. The prepared shikonin naphthazarin parent nucleus hydroxymethylated carbonyl oxime derivative containing the aza-side chain has the advantages of novel structure and good water solubility. Experimental studies on in-vitro metabolism and antitumor activity show that the compound plays a role through a prodrug mechanism and is relatively strong in antitumor activity.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a shikonin oxime derivative containing an aza side chain, a preparation method thereof and a medical application thereof, in particular to a shikonin, akanin and its external elimination containing an aza side chain Spiral oxime derivatives and their preparation methods and medical applications. Background technique [0002] Comfrey is a commonly used clinical traditional Chinese medicine recorded in the Pharmacopoeia of the People's Republic of China. Comfrey can be divided into hard comfrey (also known as northeast comfrey, Lithospermum erythrohizon) and soft comfrey (also known as Xinjiang comfrey, A.euchroma Johnst). The main active ingredients in hard comfrey are shikonin and its derivatives, and soft comfrey contains arcanin and its derivatives. Shikonin and Akanin are enantiomers of each other, which have been proven to have anti-inflammatory, wound healing, antibacterial, antivira...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C43/243C07C41/01C07D213/79C07D213/803C07D295/15C07D211/62C07D241/24C07D239/28C07D237/24C07D277/56A61P35/00
CPCA61P35/00C07C43/243C07D211/62C07D213/79C07D213/803C07D237/24C07D239/28C07D241/24C07D277/56C07D295/15Y02P20/55
Inventor 李绍顺张启景崔家华
Owner SHANGHAI JIAO TONG UNIV
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