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Optically active butylphthalide open-ring derivative, preparation method and medical application

An optically active, butylphthalide technology, used in pharmaceutical formulations, organic active ingredients, active ingredients of heterocyclic compounds, etc.

Inactive Publication Date: 2013-07-10
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to literature reports, (S)-NBP and (R)-NBP differ in various biological activities

Method used

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  • Optically active butylphthalide open-ring derivative, preparation method and medical application
  • Optically active butylphthalide open-ring derivative, preparation method and medical application
  • Optically active butylphthalide open-ring derivative, preparation method and medical application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Preparation of 2-[(S)-(-)-1-hydroxy-n-pentyl]benzoic acid (II)

[0101] Dissolve 1.24g (6.5mmol) (S)-butylphthalide in 10mL of methanol, add 10mL of 2M NaOH aqueous solution, reflux and stir for 0.5 hours, evaporate methanol under reduced pressure, add 10mL of distilled water to dilute, cool to -5°C, and vigorously Under stirring, it was acidified to pH 2-3 with 5% dilute hydrochloric acid, extracted with diethyl ether (15 mL×3), and the combined organic layers were directly subjected to the next reaction without any purification.

Embodiment 2

[0103] Preparation of 2-[(S)-(-)-1-acetyl n-pentyl]benzoic acid (III)

[0104] Dilute the ether solution containing II above with 200mL of dichloromethane, add 2.7mL (19.6mmol) of triethylamine and 0.5g of DMAP respectively, add 1.4mL (19.6mmol) of acetyl chloride dropwise at -15°C, and drop to - Stir at 15°C for 5 hours, add 10 mL of water, stir at room temperature for 0.5 hours, separate the organic layer, Na 2 SO 4 Dry, filter, and concentrate to give a waxy solid, recrystallize from n-hexane to give 1.06 g of white needle-like crystals, yield 65%, mp65-66°C. (c1.00CHCl 3 ).MS(ESI): m / z249.1[M-H] - .IR(cm -1 , KBr): v max 1412, 1691, 1734, 2958, 3450. 1 H NMR (300Hz, CDCl 3 ): δ0.93(t, 3H, CH 3 , J=8.5Hz), 1.37-1.42(m, 4H, 2×CH 2 ), 1.88-1.91 (m, 2H, CH 2 ), 2.13-2.33 (m, 3H, COCH 3 ), 6.61-6.72 (m, 1H, OCHCH 2), 7.37-7.40 (m, 1H, ArH), 7.56-7.62 (m, 2H, ArH), 8.05 (d, 1H, ArH, J=8.1Hz), 10.98 (brs, 1H, COOH). 13 C NMR (75Hz, CDCl 3 ): δ172.0, 166.5, 140.8, 1...

Embodiment 3

[0106] Preparation of 2-[(S)-(-)-1-acetylchloro-n-pentyl]benzoic acid (IV)

[0107] Dilute the ether solution containing II above with 200mL of dichloromethane, add 2.7mL (19.6mmol) of triethylamine and 0.5g of DMAP respectively, and add 1.7mL (19.6mmol) of chloroacetyl chloride dropwise at -15°C. Stir at -15°C for 5 hours, add 10 mL of water, stir at room temperature for 0.5 hours, separate the organic layer, Na 2 SO 4 Dry, filter, and concentrate to give a waxy solid, which is recrystallized from n-hexane to give 1.11 g of white needle-like crystals, yield 60%, m.p.67-68°C. (c1.00CHCl 3 ).MS(ESI): m / z283[M-H] - .IR(cm -1 , KBr): v max 1412, 1691, 1734, 2958, 3450. 1 H NMR (300Hz, CDCl 3 ): δ0.93(t, 3H, CH 3 , J=4.2Hz), 1.37-1.42(m, 4H, 2×CH 2 ), 1.88-1.91 (m, 2H, CH 2 ), 4.11 (m, 2H, COCH 2 Cl), 6.78 (m, 1H, OC H CH 2 ), 7.36-7.42 (m, 1H, ArH), 7.56-7.62 (m, 2H, ArH), 8.08 (d, 1H, ArH, J=8.1Hz), 10.89 (brs, 1H, COOH). 13 C NMR (300Hz, CDCl 3 ): δ172.0, 166.5,...

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Abstract

The present invention relates to the field of pharmaceutical chemistry and therapeutics, and particularly relates to an optically active butylphthalide open-ring derivative as shown in the general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, preparation methods thereof, pharmaceutical compositions containing the compounds, and medical application thereof, especially application in medicines for prevention and treatment of cardiovascular and cerebrovascular and improvement of heart and brain circulatory disturbance, antiplatelet aggregation medicines, antithrombotic medicines, anti-ischemic medicines, anti-dementia medicines, anti-atherosclerotic medicines, and medicines for anti-diabetes and complications thereof. Pharmacological experimental results show that the compounds have good anti-platelet aggregation activity, anti-thrombotic activity, anti-ischemic activity and neuroprotective effects, and are clinically useful for the preparation of medicines for preventing or treating diseases associated with platelet aggregation.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to an optically active ring-opened derivative of butylphthalide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, their preparation method, and a drug containing these compounds. Compositions and their medical uses, especially in the prevention and treatment of cardio-cerebral ischemic diseases and drugs for improving cardio-cerebral circulation disorders, anti-platelet aggregation drugs, anti-thrombotic drugs, anti-cerebral ischemic drugs, anti-dementia drugs, anti-arterial Application in atherosclerosis drugs, anti-diabetes and its complications drugs. Background technique [0002] Platelets play an important role in the pathogenesis of arterial thrombotic diseases. Blocking platelet deposition on atherosclerotic plaques and subsequent thrombus formation is the main purpose of antiplatelet drugs. Clinical studies ...

Claims

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Application Information

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IPC IPC(8): C07D493/04A61K31/34A61K31/4025A61K31/5377A61K31/496A61P9/00A61P9/10A61P7/02A61P25/28A61P3/10A61P9/06
Inventor 张奕华王晓丽黄张建王琳娜赖宜生季晖徐进宜彭司勋
Owner CHINA PHARM UNIV
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