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1-o-acetyl inulalide spiroaryl isoxazoline derivatives and their medicinal uses

A technology of inula inula, isoxazoline, applied in the field of medicine

Active Publication Date: 2021-08-17
上海坤元天成医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the only anti-asthma drug based on the inhibition of leukotriene production in the world is Zileuton (English name, Zileuton), which has not yet been approved for marketing in my country

Method used

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  • 1-o-acetyl inulalide spiroaryl isoxazoline derivatives and their medicinal uses
  • 1-o-acetyl inulalide spiroaryl isoxazoline derivatives and their medicinal uses
  • 1-o-acetyl inulalide spiroaryl isoxazoline derivatives and their medicinal uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Embodiment 1: the preparation method of compound 1a-1j

[0016] A certain volume of acetonitrile and water (V / V=1:1) dispersed the aromatic aldehyde in the reaction flask, and added hydroxylamine hydrochloride (1.1 equivalents) into the reaction flask at room temperature. The reaction solution was stirred at room temperature and monitored by TLC until the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate without purification, which was directly carried out in subsequent reactions. The intermediate obtained in the above reaction was dissolved in DMF at 40°C and stirred, and 1 equivalent of N-chlorosuccinimide (NCS) was added in batches, and the reaction solution was stirred at 40°C under heat preservation conditions, and TLC was monitored until the reaction was complete. 20 times the amount of EtOAc was added to the solution to dilute the reaction solution, the reaction solution was washed with water (5×2...

Embodiment 2

[0017] Embodiment 2: the preparation method of compound 2a-2j

[0018] Use 0.75 mL of CH 2 Cl 2 Disperse intermediate 1a-1j (0.16mmol) in a reaction flask, add 0.13mmol of triethylamine (Et3N) with stirring at room temperature, use 0.75mL of CH 2 Cl 2 Dissolve 1-O-acetyl inulalide (0.1 mmol), add the solution into the reaction flask, and stir for reaction. After 16 hours of reaction, TLC monitors that the reaction is complete, and directly concentrates the reaction solution under reduced pressure to obtain a crude product. 2a-2j were obtained by silica gel column chromatography (300-400 mesh, PE:EA=6:1-3:1, V / V).

[0019] 2.1 Synthesis of Compound 2a

[0020] 2a, colorless oil, yield 44.7%. 1 H NMR (400MHz, CDCl 3 ): δ7.69(d, J=7.4Hz, 1.4Hz, 2H), 7.40-7.47(m, 3H), 5.17(m, 1H), 4.13(s, 1H), 4.01(t, J=6.3Hz , 2H), 3.63(s, 2H), 2.93(dd, J=5.9Hz, 2.0Hz, 1H), 2.72-2.77(m, 2H), 2.48-2.53(m, 1H), 2.01(s, 3H) , 1.78(s, 3H), 1.42-1.57(m, 2H), 1.19-1.40(m, 2H), 1.13(d, J=7.0Hz, ...

Embodiment 3

[0039] Embodiment 3: the preparation method of compound 3a-3j

[0040] Use 3 mL of anhydrous dichloromethane (freshly prepared) to dissolve DMAP (1.1 equivalents) and acetic anhydride (1.5 equivalents) in a reaction flask, and 3 mL of dichloromethane to dissolve 1-O-acetyl inulalide (1 equivalents ), the solution was added to the reaction bottle, and transferred to room temperature for reaction. After 20 minutes, TLC monitored the reaction to be complete, and the reaction was stopped. 10 mL of ice water was added to the reaction bottle and stirred for 20 minutes. The reaction liquid was extracted with dichloromethane (15 mL×3), anhydrous MgSO 4 Dry, filter, and concentrate under reduced pressure to obtain crude 1,6-O,O-acetyl inulalide. The crude product was purified by silica gel column chromatography to obtain a pure product for subsequent reactions. Use 0.3 mL of CH 2 Cl 2 Disperse intermediate 1a-1j (0.16mmol) in the reaction bottle, stir at room temperature and add 0.1...

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Abstract

The invention provides a 1-O-acetyl inulalide spiroaryl isoxazoline derivative and its medical use, belonging to the technical field of medicine. It specifically relates to the compound represented by formula I and the pharmacological effect of inhibiting the production of leukotrienes. The results of pharmacological experiments showed that 1‑O‑acetyl inulalide spiroarylisoxazoline derivatives can inhibit mast cell leukotriene C 4 Generation, and then exert anti-inflammatory and anti-asthma pharmacological effects through this mechanism of action.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to 1-O-acetyl inulalide spiroaryl isoxazoline derivatives and their medical application. Background technique [0002] Inula japonica Thunb (Inula japonica Thunb / Inula britannica L.) is a traditional Chinese herbal medicine of the genus Inula japonica Thunb in the family Compositae. , slightly warm; returns to the lung, spleen, stomach, and large intestine meridians; has the effects of lowering qi, eliminating phlegm, promoting water flow, and stopping vomiting; mainly treats wind-cold cough, accumulation of phlegm and retention, tightness in the chest and diaphragm, wheezing and coughing, excessive phlegm, and vomiting , hard heart (National Pharmacopoeia Committee. Pharmacopoeia of the People's Republic of China [M]. Part One. Beijing: China Medical Science and Technology Press, 2015: 326). The dried roots and leaves of Inula inula are used as traditional Chinese herb...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/10A61K31/424A61K31/4439A61P29/00A61P11/06
CPCA61P11/06A61P29/00C07D498/10C07D495/04
Inventor 秦楠金美花段宏泉魏晓鹏纪宁
Owner 上海坤元天成医药科技有限公司
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