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Chalcone derivatives containing allyl structures, and application of chalcone derivatives

A technology of chalcone derivatives and allyl groups, which is applied in the direction of medical preparations containing active ingredients, organic chemistry, drug combinations, etc., can solve problems such as unavoidable side effects, and achieve a good inhibitory effect

Active Publication Date: 2019-03-22
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Then if the PTP1B inhibitor cannot achieve high selectivity for subtypes, it will be difficult to avoid side effects

Method used

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  • Chalcone derivatives containing allyl structures, and application of chalcone derivatives
  • Chalcone derivatives containing allyl structures, and application of chalcone derivatives
  • Chalcone derivatives containing allyl structures, and application of chalcone derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1～39

[0027] The synthesis of embodiment 1~39 compound:

[0028] The method for the chalcone derivatives containing allyl structure prepared by the present invention, the synthetic general route is as follows formula a:

[0029]

[0030]

[0031] Synthetic steps (steps a-e) of compounds (1,3-8,10-30) in type I:

[0032] Step a Synthesis of 2a: Potassium carbonate (68.1 g, 0.48 mol) was slowly added to 4-hydroxy-2-methoxybenzaldehyde (1a; 25.0 g, 0.16 mol) and 3-bromoprop-1-ene (38.1 g , 0.32mol) in acetone solution, the reaction mixture was refluxed for 6 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was then dissolved in ethyl acetate (50 mL), washed with water (50 mL) and brine (50 mL). MgSO for organic layer 4 Dry, filter, and concentrate under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 2a (27.95 g, 91%) as a pale yellow liquid.

[0033] Step b Synthesis ...

Embodiment 29

[0078] The chemical structure characterization data of compound 2 synthesized in Example 29

[0079] Compound 2: (E)-3-{5-allyl-2-methoxy-4-[(tetrahydro-2H-pyran-2-yl)oxy]phenyl}-1-(4- (E)-3-{5-Allyl-2-methoxy-4-[(tetrahydro-2H-pyran-2-yl)oxy]phenyl}-1- (4-hyd roxyphenyl)prop-2-en-1-on. Yellow liquid, yield 45.3%, 1 H NMR (500MHz, acetone--d 6 )δ (ppm): 8.98 (s, 1H), 8.71 (s, 1H), 7.90 (d, J = 15.7Hz, 1H), 7.88 (d, J = 8.6Hz, 2H), 7.50 (d, J = 15.6Hz, 1H), 7.47(s, 1H), 6.8(d, J=8.5Hz, 1H), 6.47(s, 1H), 5.90(ddt, J=16.7, 10.1, 6.5Hz, 1H), 5.76( m,1H),4.93(dd, J=17.1,1.7Hz,1H),4.87(d,J=8.9Hz,1H),3.74(s,3H),3.60(t,J=8.6Hz, 2H), 3.22(d, J=6.5Hz, 2H), 2.22(m, 2H), 1.93(m, 2H), 1.71(m, 2H). 13 C-NMR (125MHz, acetone-d 6 )δ (ppm): 188.4, 162.3, 159.7, 159.2, 139.2, 138.1, 131.7, 131.5×2, 131.4, 120.1, 119.5, 116.6, 116.0×2, 102.3, 115.4, 99.9, 62.4, 56.0, 34.2, 24.6. ESI-MS m / z:395.18(M+H) + , calcd for C 24 h 26 o 5 :394.18.

[0080] Compound 9: (E)-3-{5-allyl-2-methoxy-...

Embodiment 40

[0098] Example 40 Activity Test

[0099] With p-nitrophenyl phosphate (pNPP) as a substrate, the inhibitory activity of the compounds prepared in Examples 1 to 39 of the present invention on PTP1B was determined, and the results are summarized in figure 1middle. A known PTP1B inhibitor, ursolic acid (IC50 = 3.1 M), was used as a positive control. Except compounds 4, 9, 27 and 37, all synthetic compounds dose-dependently inhibited PTP1B activity with IC50 values ​​ranging from 0.5 to 24.8 μM. Most of these compounds showed better activity than licochalcone. Among them, compound 1 showed twice the inhibitory activity compared with licochalcone A. Compound 7 (IC50=5.3×M), 8 (IC50=5.4×M) and 11 (IC50=5.8×M), compared with compound 1, the inhibitory activity increased about 2 times. As the length of 4-hydroxyl substitution increases, it shows proportionally increased inhibitory potency against PTP1B (especially compound 12 with isoprenyl group), exhibiting particularly good act...

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Abstract

The invention discloses chalcone derivatives containing allyl structures, and application of the chalcone derivatives. 39 novel allyl-progeny steranes, based on licochalcone A and E used as pre-molecules are synthesized. As a PTP1B inhibitor, the chalcone derivatives can improve the treatment of common diabetes mellitus type 2. Most synthetic compounds show potent inhibition on PTP1B.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to the design and synthesis, biological evaluation and molecular docking research of an allyl-reverse chalcone derivative PTP1B inhibitor. Background technique [0002] Diabetes is a progressive metabolic disease. Under the condition that the current medical level cannot be cured, diabetic patients need to use anti-diabetic regulating drugs for life. With the in-depth research on the pathogenesis of diabetes, the research on diabetes drugs has also transitioned from the traditional mechanism to the research on new targets and new mechanisms of action. Unfortunately, although a large number of studies have shown that insulin resistance is the main pathological mechanism of T2M, only biguanides and thiazolidinediones are currently used clinically as insulin sensitizers. Therefore, new insulin sensitizers are the focus of research and development of drugs for the treatmen...

Claims

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Application Information

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IPC IPC(8): C07C49/84C07D295/116C07D231/12C07C225/22C07C311/08C07C69/78C07C69/76C07C69/708C07D317/66A61P3/04A61P3/10A61P5/50A61K31/12A61K31/4453A61K31/5375A61K31/136A61K31/415A61K31/235A61K31/22
CPCA61P3/04A61P3/10A61P5/50C07C49/84C07C69/708C07C69/76C07C69/78C07C225/22C07C311/08C07D231/12C07D295/116C07D317/66
Inventor 张婷婷郑素清钱建畅邹鹏刘志国梁广
Owner WENZHOU MEDICAL UNIV
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