14-chloro-beta-elemene nitric oxide donor type derivative as well as preparation and application thereof

A nitric oxide and elemene technology is applied in organic chemistry, drug combination, medical preparations containing active ingredients, etc. It can solve the problems of poor stability of compounds, death of animals administered with drugs, and high safety risks, etc., and achieve good results. Therapeutic activity, improving in vivo stability, and improving the effect of antitumor activity

Active Publication Date: 2021-12-17
HANGZHOU NORMAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, 13-β-elemenal has strong cytotoxicity, and long-term administration of medium and high doses can directly cause the death of animals administered with it. Therefore, long-term administration has a greater safety risk and is not suitable for use in humans.
In

Method used

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  • 14-chloro-beta-elemene nitric oxide donor type derivative as well as preparation and application thereof
  • 14-chloro-beta-elemene nitric oxide donor type derivative as well as preparation and application thereof
  • 14-chloro-beta-elemene nitric oxide donor type derivative as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0042] (1) Preparation of Intermediate 4

[0043] like figure 2 As shown, at 0 °C, to a mixed solution of β-elemene (1.02 g, 5 mmol) in dichloromethane (8 mL) and tetrahydrofuran (2 mL), were added NCS (1.34 g, 20 mmol), trifluoro Ytterbium methanesulfonate (310 mg, 0.5 mmol) and trimethylchlorosilane (54 mg, 0.5 mmol) were reacted at 0° C. for 8 h. At the end of the reaction, the solvent was distilled off under reduced pressure, diluted with water (15 mL), extracted with ethyl acetate (4 mL×3), the organic phases were combined, washed with water (20 mL×2) and saturated brine (20 mL×2) in turn, After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (pure petroleum ether) to obtain a colorless liquid compound, namely Intermediate 4, with a yield of 45%.

[0044] 1 H NMR (400MHz, CDCl 3 )δ5.85–5.72(m,1H),5.28(s,1H),5.18(s,1H),5.04(s,1H),4.98–4.89(m,3H),4.15–4.05(m,3H...

Embodiment 1

[0083]

[0084] 4-(2-((4-(2-((2-((1R,3R,4S)-3-(3-chloroprop-1-en-2-yl)-4-methyl-4-ethene cyclohexyl)))(methyl)amino)ethoxy)-4-oxobutyryl)oxy)ethoxy)-3-(benzenesulfonyl)-1,2,5-oxadiazole 2- Preparation of oxides.

[0085] To a solution of intermediate 5 (26 mg, 0.084 mmol) in dichloromethane (1.5 mL), intermediate 14a (39 mg, 0.101 mmol), DMAP (1 mg, 0.008 mmol), EDCI (24 mg, 0.126 mmol) were added sequentially, Stir at room temperature for 8h. Dichloromethane (5 mL) was added to dilute, washed with water (10 mL×2) and saturated brine (10 mL×2) in turn, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane). Methane:methanol volume ratio 400:1), pale yellow liquid, yield 69%.

[0086] 1 H NMR (400MHz, CDCl 3 )δ8.07(d,J=7.8Hz,2H),7.75(d,J=7.5Hz,1H),7.63(t,J=7.8Hz,2H),5.78(dd,J=17.8,10.4Hz, 1H), 5.26 (s, 1H), 5.02–4.87 (m, 5H), 4.65–4.59 (m, 2H), 4.57–4...

Embodiment 2

[0088]

[0089] 4-(2-((5-(2-((2-((1R,3R,4S)-3-(3-chloroprop-1-en-2-yl)-4-methyl-4-ethene cyclohexyl)allyl)(methyl)amino)ethoxy)-5-oxopentanoyl)oxy)ethoxy)-3-(benzenesulfonyl)-1,2,5-oxadi The preparation method of oxazole 2-oxide is basically the same as that in Example 1, the difference is that the succinic anhydride in (3) is replaced with glutaric anhydride.

[0090] In this example, a yellow waxy liquid was prepared with a yield of 71%.

[0091] 1 H NMR (400MHz, CDCl 3 )δ8.06(d,J=8.5Hz,2H),7.76(t,J=7.5Hz,1H),7.63(t,J=7.9Hz,2H),5.87–5.71(m,1H),5.26( s, 1H), 5.01–4.86 (m, 5H), 4.67–4.60 (m, 2H), 4.53–4.46 (m, 2H), 4.17 (t, J=5.7Hz, 2H), 4.09 (d, J= 11.6Hz, 1H), 3.96 (d, J=11.7Hz, 1H), 2.95 (s, 2H), 2.57 (t, J=5.1Hz, 2H), 2.43 (dt, J=17.0, 7.3Hz, 4H) ,2.28(dd,J=11.9,4.0Hz,1H),2.16-2.07(m,1H),2.02-1.93(m,2H),1.65-1.35(m,6H),0.96(s,3H). 13 CNMR (100MHz, CDCl 3 )δ173.0,172.8,158.8,151.4,149.4,147.8,138.1,135.8,129.8,128.7,116.3,110.9,110.5,69.0,63.3,62.5,61.2,55.4,51.1,...

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Abstract

The invention discloses a 14-chloro-beta-elemene nitric oxide donor type derivative as well as preparation and application thereof in preparation of an anti-tumor drug. The 14-chloro-beta-elemene nitric oxide donor type derivative has the following general formula (I) shown in the description, wherein in the formula (I), R1 is a straight-chain or cyclic alcohol amine structure containing nitrogen and oxygen atoms, R2 and R3 are respectively and independently selected from C1-10 chain alkyl, C3-12 cycloalkyl, C6-12 aryl, 5-10 membered ring heteroaryl, C2-10 alkenyl, C2-10 alkynyl or C2-10 alkoxy. According to the present invention, the design strategy of the derivative is superior to the previous beta-elemene nitric oxide donor type derivative, the alcohol amine structure capable of improving the in-vivo anti-tumor activity is introduced as the connecting arm, the in-vivo stability is improved, and the good treatment activity on the malignant brain glioma lacking the effective treatment drug clinically is provided.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of 14-chloro-beta-elemene nitric oxide donor derivatives and their preparation and application. Background technique [0002] Elemene is a sesquiterpene natural product isolated from Curcuma curcuma and has broad antitumor activity. In 1994, elemene oral emulsion and injection were approved by the China Food and Drug Administration (CFDA) as a broad-spectrum anticancer drug for the treatment of lung, liver, esophageal, nasopharyngeal and brain cancers. treat. [0003] In the elemene extract mixture, β-elemene has the highest content and is also the most important antitumor active ingredient. However, the structure of β-elemene only contains two elements, hydrocarbons, which leads to its high fat solubility, poor water solubility, and low bioavailability. Taking β-elemene injection as an example, large-dose injections are often required during the treatment process of...

Claims

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Application Information

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IPC IPC(8): C07D271/08C07D413/12A61K31/4245A61K31/454A61K31/496A61P35/00
CPCC07D271/08C07D413/12A61P35/00Y02P20/55
Inventor 谢恬白仁仁叶向阳朱俊龙白自强
Owner HANGZHOU NORMAL UNIVERSITY
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