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Racemate alkannin oxime amino acid ester derivatives and preparation method and applications thereof

A technology of racemate and amino acid ester, applied in the field of medicine, can solve the problems of disappearance of anti-tumor activity and reduced activity of target substances, and achieve the effects of simple preparation method, improved permeability and good prospect of new drug development

Active Publication Date: 2019-08-16
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the previous research, we introduced phosphate ester and glycoside structural fragments on the side chain hydroxyl of the derivatives of shikonin naphthalene oxyalkylated carbonyl oximation, and the water solubility of the target substance was significantly improved, but its The anti-tumor activity disappears; the introduction of compounds containing carboxyl or amino structures at the hydroxyl site of the oxime also reduces the activity of the target

Method used

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  • Racemate alkannin oxime amino acid ester derivatives and preparation method and applications thereof
  • Racemate alkannin oxime amino acid ester derivatives and preparation method and applications thereof
  • Racemate alkannin oxime amino acid ester derivatives and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041]This embodiment relates to a kind of 2-[1-(2-hydroxyethoxy)-4-methyl-3-pentenyl]-1,4,5,8-tetramethoxy with structural formula (VII) The preparation method of naphthalene (VII-1, n=1), such as figure 1 shown, including the following steps:

[0042] Step 1: Dissolve 2-bromoethanol in anhydrous dichloromethane, add a catalytic amount of p-toluenesulfonic acid or pyridine p-toluenesulfonic acid, then add 1.5 times the equivalent of 3,4-dihydro-2H-pyran , Stir at room temperature for 5h. The reaction was quenched by adding saturated aqueous sodium bicarbonate, CH 2 Cl 2 Extract and combine the organic layers. The organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to obtain 2-(2-bromoethoxy)-tetrahydropyran (IV-1, n=1) . The product was a colorless oil with a yield of 75%. 1 H NMR (300MHz, CDCl 3 ):δ4.67(m,1H),4.01(dt,J=12.3,6.3Hz,1H),3.88(m,1H),3.76(...

Embodiment 2

[0045] This embodiment relates to a kind of 2-[1-(4-hydroxybutoxy)-4-methyl-3-pentenyl]-1,4,5,8-tetramethoxy with structural formula (VII) The preparation method of naphthalene (VII-2, n=2), such as figure 1 shown, including the following steps:

[0046] The steps of this example are the same as the steps of Example 1, in Step 1, 2-bromoethanol is replaced by 4-bromo-1-butanol. Product C was in the form of a light brown oil, with a yield of 82%. 1 H NMR (300MHz, CDCl 3 ):δ6.91(s,1H,H-3),6.75(s,2H,H-6,7),5.18(t,1H,H-3'),4.90(t,1H,H-1' ),3.90(s,6H,ArOCH 3 ),3.84(s,3H,ArOCH 3 ),3.66(s,3H,ArOCH 3 ),3.51(t,2H,CH 2 OH),3.21(2H,m,OCH 2 ),2.42(2H,m,H-2'),1.59(3H,s,CH 3 ),1.46(3H,s,CH 3 ),1.20-1.40(4H,m,CH 2 OH).

Embodiment 3

[0048] This embodiment relates to a kind of 2-[1-(6-hydroxyhexyloxy)-4-methyl-3-pentenyl]-1,4,5,8-tetramethoxy with structural formula (VII) The preparation method of naphthalene (VII-3, n=3), such as figure 1 shown, including the following steps:

[0049] The steps of this example are the same as the steps of Example 1, in Step 1, 2-bromoethanol is replaced by 6-bromo-1-hexanol. The product C was in the form of a light brown oil with a yield of 75%. 1 H NMR (300MHz, CDCl 3 ):δ6.95(s,1H,H-3),6.81(2H,s,H-6,7),5.22(1H,t,H-3'),4.96(1H,t,H-1' ),3.92(6H,s,ArOCH 3 ),3.82(3H,s,ArOCH 3 ),3.72(3H,s,ArOCH 3 ),3.47(2H,t,CH 2 OH),3.25(2H,m,OCH 2 ),2.45(2H,m,H-2'),1.64(3H,s,CH 3 ),1.52(3H,s,CH 3 ),1.20-1.40(8H,m,CH 2 ).

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Abstract

The invention discloses racemate alkannin oxime amino acid ester derivatives and a preparation method and applications thereof. The structure of the derivatives is represented by the formula (I), wherein R represents a group, which is formed by removing one hydrogen atom from the carbon terminal of straight chain alkyl alcohol of natural amino acid esters that contain C2-C8 straight chain alkyl alcohols and physiologically acceptable salts thereof. The preparation method is simple and convenient, the yield is high, and the raw materials are easily available. The prepared racemate alkannin oxime amino acid ester derivatives have a naphthazarine core and a hydroxyl methylated oximated side chain; the structure is novel, and the water solubility is high. The results of in-vitro antitumor activity experiments show that the antitumor activity of the compounds is high.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a racemic shikonin oxime amino acid ester derivative and its preparation method and application; more specifically, it relates to a racemic shikonin naphthalene naphthalene parent nucleus hydroxymethylated carbonyl oxime Amino acid ester derivatives with side chains 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 healin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C249/04C07C251/46A61P35/00
CPCA61P35/00C07C251/46Y02P20/55
Inventor 李绍顺崔家华
Owner SHANGHAI JIAO TONG UNIV
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