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Piperlongumine-ligustrazine heterocomplex, preparation method and medical application

A technology of uses and compounds, applied in the fields of medicinal chemistry and pharmacotherapeutics, can solve the problems of changing pharmacokinetic properties, increasing toxic and side effects, and accumulating toxicity, achieving excellent anti-proliferative and metastatic activities of colon cancer cells, excellent effects, The effect of increasing ROS levels

Inactive Publication Date: 2017-11-24
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, ligustrazine requires high doses to achieve the desired efficacy, which may lead to cumulative toxicity
In addition, ligustrazine generally needs to be used in combination with chemotherapeutic drugs when it is anti-tumor, so it may change the pharmacokinetic properties and increase the toxicity and side effects.

Method used

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  • Piperlongumine-ligustrazine heterocomplex, preparation method and medical application
  • Piperlongumine-ligustrazine heterocomplex, preparation method and medical application
  • Piperlongumine-ligustrazine heterocomplex, preparation method and medical application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: (E)-1-{3-[2-(3,5,6-trimethylpyrazine)]acryloyl}-5,6-dihydropyridine-2(1H)-one (I 1 )

[0054] Intermediate V (0.5mmol) was dissolved in 20mL of anhydrous tetrahydrofuran, triethylamine (0.6mL) was added dropwise thereto, and pivaloyl chloride (0.6mL) was added dropwise to the reaction solution at -20°C, followed by reaction for 45 minutes At the same time, dissolve the intermediate VI (0.5mmol) in 20mL of anhydrous tetrahydrofuran, add n-butyllithium (2.9mL) at -70°C, and then stir for about 45 minutes, then directly add the reaction solution in the previous step to In this reaction, following reaction for 1 hour, the reaction was monitored by TLC. Add 10 mL of saturated ammonium chloride aqueous solution to the reaction liquid, quench the n-butyllithium in the reaction, extract, wash the aqueous phase with ethyl acetate (20 mL × 3), combine the organic phases and wash with saturated brine (30 mL × 3 ), dried over anhydrous sodium sulfate, concentrated to g...

Embodiment 2

[0056] Example 2: (E)-3-chloro-1-{3-[2-(3,5,6-trimethylpyrazine)]acryloyl}-5,6-dihydropyridine-2(1H) - Keto (I 2 )

[0057] Reference compound I 1 The synthetic method of obtaining pure product pale yellow solid (I 2 ) 236 mg. Yield 56%; mp 111-114°C. 1 H NMR (300MHz, CDCl 3 ), δ(ppm): 2.49(s, 6H, 2×CH 3 ),2.54~2.56(m,2H,NCH 2 CH 2 ),2.59(s,3H,CH 3 ),4.06(t,J=6.0Hz,2H,N CH 2 CH 2 ), 7.06(t, J=4.5Hz, 1H, COClC= CH ),7.82~7.95(m,2H,CH=CH); 13 C NMR (75MHz, CDCl 3 ):δ21.0,21.9,22.2,25.5,42.0,126.2,128.3,138.4,141.3,143.2,149.3,150.1,152.6,161.4,168.8; ESI-MS:328.1[M+Na] + ; HRMS calculated for C 15 h 16 N 3 o 2 ClNa[M+Na] + 328.0829, found 328.0835, ppm error 1.8.

Embodiment 3

[0058] Example 3: (E)-3-bromo-1-{3-[2-(3,5,6-trimethylpyrazine)]acryloyl}-5,6-dihydropyridine-2(1H) - Keto (I 3 )

[0059] Reference compound I 1 The synthetic method of obtaining pure product pale yellow solid (I 3 ). Yield 43%; mp 109-113°C. 1 HNMR (300MHz, CDCl 3 ), δ(ppm):2.44~2.59(m,11H,NCH 2 CH 2 and 3×CH 3 ), 4.06(t, J=7.5Hz, 2H, N CH 2 CH 2 ), 7.06(t, J=4.5Hz, 1H, COClC= CH ),7.83~7.93(m,2H,CH=CH); 13 C NMR (75MHz, CDCl 3 ):δ21.0,21.9,22.2,26.9,42.1,113.2,126.3,138.3,143.3,147.3,149.3,150.1,152.6,161.3,169.0; ESI-MS:372.0[M+Na] + ; HRMS calculated for C 15 h 16 N 3 o 2 BrNa[M+Na] + 372.0368, found 372.0371, ppm error 0.8.

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Abstract

The invention discloses a piperlongumine-ligustrazine heterocomplex, a preparation method and a medical application. The piperlongumine-ligustrazine heterocomplex is a compound, isomer or pharmaceutically acceptable salt as shown in the specific formula (I), wherein R1, R3 or R4 is independently selected from C1-3 alkyl groups or C1-3 alkoxygroups; R2 is selected from the hydrogen (H) or halogen. The compound has good water solubility, is higher in proliferation inhibition activity for 4 colon cancer cells than that of piperlongumine. The compound, the isomer or the pharmaceutically acceptable salt can be applied to respects of medicines for treating or preventing tumors, or applies to respects of medicines relevant to metastatic cancer, and can be applied to relevant diseases including but not limited to brain gliomas, colon cancer, metastatic colon cancer, cell lung cancer, myoblastosis and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and pharmacotherapeutics, and specifically relates to a class of pyrimamide-tetramethylmethylpyrazine hybrids or pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions containing these compounds, and their pharmaceutical preparations. use Background technique [0002] Piperlongumine (piperlongumine, PL), also known as piperlongumine (piplartine), belongs to alkaloid compounds. It was originally isolated from the root of Piper longum, and also found in the roots of P. sylvaticum Roxb. and P. tuberculatum Jacq., etc. [0003] Perylene amide has a variety of pharmacological effects, can regulate blood lipid metabolism in hyperlipidemic rats, has anti-platelet aggregation, analgesic, anti-fungal and many other pharmacological activities, and is a chemical substance with great medicinal value. In recent years, studies have found that Piperamide can inhibit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06A61K31/497A61P35/02A61P35/00
CPCC07D401/06
Inventor 张奕华黄张建彭司勋
Owner CHINA PHARM UNIV
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