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Beta-elemene derivative containing dihydropyridine structure, and preparation method and purpose thereof

A technology of dihydropyridine and elemene, applied in the field of treatment of glioma, β-elemene derivatives, β-elemene derivatives containing dihydropyridine structure, can solve low bioavailability and side effects , too strong and other issues

Active Publication Date: 2017-09-29
NANJING BRAIN HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These physical and chemical properties lead to certain side effects of elemene in clinical application
Due to the strong lipophilicity and weak hydrophilicity of elemene, it is not easy to be absorbed by the human body, resulting in low bioavailability
However, due to its strong lipophilicity, it cannot penetrate the blood-brain barrier well, nor can it gather in the brain to exert its due drug effect.

Method used

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  • Beta-elemene derivative containing dihydropyridine structure, and preparation method and purpose thereof
  • Beta-elemene derivative containing dihydropyridine structure, and preparation method and purpose thereof
  • Beta-elemene derivative containing dihydropyridine structure, and preparation method and purpose thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 113

[0051] Example 1 Preparation of 13-beta-elemenol

[0052] β-Elemene (2.04g, 10.0mmol) was dissolved in a mixed solution of acetic acid (2mL) and dichloromethane (8mL), and slowly dropped into NaClO solution (1.6M, 11.3mL, 18.0mmol) under ice-cooling conditions , Reacted under ice bath conditions for 6h. The layers were separated, the aqueous layer was extracted with dichloromethane (3×20mL), the dichloromethane layers were combined, and saturated NaHCO 3 solution, H 2 Washed with O and saturated NaCl solution, anhydrous Na 2 SO 4 dry. After concentration, use petroleum ether column chromatography to separate β-elemene, 13-chloro-β-elemene, 14-chloro-β-elemene mixture, and 13,14-dichloro-β-elemene Alkene, the product is a colorless liquid.

[0053] β-elemene, 13-chloro-β-elemene, 14-chloro-β-elemene mixture (3.00g, containing about 13-chloro-β-elemene, 14-chloro-β-elemene Arocene (10.0 mmol) was dissolved in anhydrous DMF (15 mL), anhydrous NaOAc (2.22 g, 30.0 mmol) was ...

Embodiment 2

[0056] The preparation of embodiment 2 compound 1

[0057] Dissolve 13-β-elemenol and dihydropicolinic acid in dichloromethane, add EDCI and DMAP, stir overnight at room temperature, and perform silica gel column chromatography with petroleum ether:ethyl acetate=3:1 (V:V) to obtain Target compound 1, colorless liquid, yield 79%. 1 HNMR (CDCl 3 , 300MHz) δ: 1.04(s, 3H), 1.40-1.62(m, 6H), 1.73(s, 3H), 1.88(d, J=5.4Hz, 3H), 1.93-2.01(m, 2H), 2.84 (m, 2H), 3.42(s, 3H), 4.66(s, 2H), 4.81(s, 1H), 4.89(s, 1H), 4.91(d, J=4.3Hz, 1H), 5.01(s, 1H), 5.09(s, 1H), 5.23(m, 1H), 5.54(s, 1H), 5.87(m, 1H).

Embodiment 3

[0058] The preparation of embodiment 3 compound 2

[0059] Referring to the operation steps of Example 2, the target compound 2 was obtained as a colorless liquid with a yield of 64%. 1 H NMR (CDCl 3 , 300MHz) δ: 1.01(s, 3H), 1.40-1.61(m, 6H), 1.70(s, 3H), 1.82(d, J=5.1Hz, 3H), 1.98-2.01(m, 2H), 2.83 (m, 2H), 3.40(s, 3H), 4.69(s, 2H), 4.80(s, 1H), 4.94(s, 1H), 4.98(d, J=4.3Hz, 1H), 5.03(s, 1H), 5.09(s, 1H), 5.53(m, 1H), 5.64(s, 1H), 5.92(m, 1H).

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Abstract

The invention relates to the field of new medicine research and development and tumor therapy, in particular to a novel beta-elemene derivative containing a dihydropyridine structure, particularly a derivative directly or indirectly introducing the brain-targeted dihydropyridine structure through a connecting arm in a beta-elemene 13 bit. The invention also discloses a preparation method of the beta-elemene derivative with the brain-targeted function, and a purpose of the novel derivative for treating gliomas.

Description

technical field [0001] The present invention relates to the field of new drug research and development and medical technology, in particular to a new class of β-elemene derivatives containing dihydropyridine structure, in particular to β-elemene containing dihydropyridine structure designed through brain targeting mechanism Derivatives, these β-elemene derivatives can better penetrate the blood-brain barrier and release the original drug at the brain tumor site. The invention also discloses the preparation method of these β-elemene derivatives with brain targeting function and the use of these novel derivatives for treating glioma. technical background [0002] Glioma, also known as glioma for short, is the most common primary central nervous system tumor, accounting for about half of all primary intracranial tumors. In a broad sense, it refers to all neuroepithelial-derived tumors. In a narrow sense, it refers to tumors derived from various types of glial cells. Most glio...

Claims

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Application Information

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IPC IPC(8): C07D211/90A61K31/4422A61P35/00
CPCC07D211/90
Inventor 钱春发
Owner NANJING BRAIN HOSPITAL
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