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Nitric oxide donor type beta-elemene derivative and preparation method and application thereof

A technology of nitric oxide and elemene, applied in the direction of organic chemistry, drug combination, pharmaceutical formula, etc.

Active Publication Date: 2017-06-20
YUAN INT GROUP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is worth noting that there are no related reports in the prior art that combine NO donors with β-elemene to prepare derivatives

Method used

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  • Nitric oxide donor type beta-elemene derivative and preparation method and application thereof
  • Nitric oxide donor type beta-elemene derivative and preparation method and application thereof
  • Nitric oxide donor type beta-elemene derivative and preparation method and application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0073] Preparation of intermediate 13-β-elemenol

[0074] Dissolve 100mmol of β-elemene in 20mL of dichloromethane and acetic acid mixed solution (V:V=2:1), and slowly drop into sodium hypochlorite solution containing 180mmol of active chlorine under ice-bath conditions, react in ice-bath for 4h and then separate the liquids. The aqueous layer was extracted 3 times with dichloromethane, and the combined dichloromethane was concentrated to obtain a light yellow liquid crude product. The liquid crude product was dissolved in 15 mL of anhydrous N,N-dimethylformamide (DMF), and 200 mmol of anhydrous sodium acetate was added under stirring. , and reacted at 100°C for 7 hours; the reaction liquid was filtered with 200 mesh silica gel, 15 mL of saturated saline was added to the filtrate, and then extracted three times with petroleum ether, combined and concentrated petroleum ether to obtain a yellow liquid, mixed solution of 8 mL of methanol and 8 mL of chloroform Dissolve the yellow...

Embodiment 1

[0079]

[0080] Preparation method of 13-O-(4-oxobutanoic acid-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide-4-oxy)ethyl ester)-β-elemene as follows:

[0081] 1) Preparation of 3,4-diphenylsulfonyl-1,2,5-oxadiazole-2-oxide (intermediate 1)

[0082] Add thiophenol (50ml, 0.50mol) into a reaction flask equipped with mechanical stirring, add 200mL of 5M NaOH aqueous solution under stirring at room temperature, add chloroacetic acid (53g, 0.55mol) after 15min, a large amount of white precipitates are precipitated in the reaction solution; After reaching 140°C, heat and reflux for 2 hours, the reaction solution becomes clear, and turns into a white paste after cooling; slowly add 6N HCl dropwise in an ice bath to adjust the pH to 1, filter, and dry to obtain a crude product, which is washed with H 2 O was recrystallized to obtain 68 g of white solid (97% yield): mp.60-62°C.

[0083] 2) Preparation of 3-benzenesulfonyl-4-hydroxyethyl ether-1,2,5-oxadiazole-2-oxide (formula (Ⅲ)) ...

Embodiment 2

[0094]

[0095] Preparation method of 13-O-(4-oxobutanoic acid-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide-4-oxo)butyl ester)-β-elemene Basically the same as Example 1, the difference is that the ethylene glycol in step 2) of Example 1 is replaced by Butanediol.

[0096] In this example, a colorless liquid product was obtained with a yield of 85%.

[0097] The 13-O-(4-oxobutanoic acid-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide-4-oxygen) butyl ester)-β-elemene The structural characterization results are as follows:

[0098] 1 H NMR (300MHz, CDCl 3 )δ8.12–8.01(m,2H),7.77(dd,J=10.7,4.3Hz,1H),7.63(t,J=7.7Hz,2H),5.81(dd,J=17.8,10.5Hz,1H ),5.05(s,1H),5.01(s,1H),4.93(d,J=3.4Hz,1H),4.88(d,J=1.0Hz,1H),4.82(s,1H),4.61(s ,2H),4.58(s,1H),4.46(t,J=6.2Hz,2H),4.20(t,J=6.2Hz,2H),2.76–2.62(m,4H),2.08–1.91(m, 4H),1.90–1.75(m,3H),1.71(s,3H),1.69–1.55(m,3H),1.53–1.41(m,3H),1.00(s,3H).

[0099] 13 C NMR (75MHz, CDCl 3 )δ171.77,171.52,158.42,149.50,147.72,146.88,137.52,135.16,129.20,12...

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Abstract

The invention belongs to the technical field of the preparation of beta-elemene derivatives, and specifically discloses a nitric oxide donor type beta-elemene derivative and a preparation method and application thereof. The beta-elemene derivative and pharmaceutical salts thereof have a general formula M, wherein X is O or radical simultaneously containing ester group and amido; R1 represents C1-10 alkyl, C6-12 cycloalkyl, C6-12 aryl, C2-10 alkenyl, C2-10 alkynyl or C2-10 ether group, each not containing or optionally containing one to three substituents; R2 represents C1-10 alkyl, C6-12 cycloalkyl, C6-12 aryl, C2-10 alkenyl, C2-10 alkynyl or C4-22 ether group, each not containing or optionally containing one to three substituents. The nitric oxide donor type beta-elemene derivative and the pharmaceutical salts thereof can be used for preparing anti-tumor drugs.

Description

technical field [0001] The invention belongs to the technical field of preparation of beta-elemene derivatives, and in particular relates to nitric oxide donor type beta-elemene derivatives and a preparation method and application thereof. Background technique [0002] β-Elemene is a sesquiterpene compound with anti-tumor activity isolated from the rhizome of C. Wenchowensis, and its molecular formula is C 15 h 24 , the structural formula is as follows (1): [0003] [0004] The emulsion with β-elemene as the main component has been approved by the Ministry of Health in 2008 as a national second-class anti-cancer new drug and has entered the second phase of clinical research. This new anti-tumor natural product has gradually shown strong performance in various tumors clinical therapeutic effect. At present, it is mainly used in the chemotherapy of malignant serous cavity effusion, lung cancer, digestive tract tumor, brain tumor and other superficial tumors, and has cer...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/08C07D413/12A61K31/4245A61P35/00
CPCC07D271/08C07D413/12
Inventor 徐进宜陈继超王天雨许海王若研许婷陈晓彤
Owner YUAN INT GROUP
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