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Butylphthalide-telmisartan hybrid compound and its preparation method and use

A technology of telmisartan and butylphthalide, applied in the field of butylphthalide-telmisartan hybrid and its preparation and application

Active Publication Date: 2019-02-01
GUANGDONG LONGFU MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, when PHPB is taken orally, the bioavailability of NBP converted into NBP in the body is nearly doubled compared with direct oral NBP, which completely overcomes the disadvantage of poor water solubility of NBP

Method used

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  • Butylphthalide-telmisartan hybrid compound and its preparation method and use
  • Butylphthalide-telmisartan hybrid compound and its preparation method and use
  • Butylphthalide-telmisartan hybrid compound and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] Synthesis of 2-(1-hydroxy-n-pentyl)benzoic acid (III):

[0104] Dissolve 1.24g (6.5mmol) NBP in 10mL of methanol, add 10mL of 2M NaOH solution, reflux and stir for 0.5h, distill methanol off under reduced pressure, add 10mL of distilled water to dilute, cool to -5°C, and use 5% dilute hydrochloric acid under vigorous stirring Acidify to pH 2-3, extract with ether (15mL×3), and directly put into the next reaction without any purification.

Embodiment 2

[0106] Synthesis of 2-(1-acetyl n-pentyl)benzoic acid:

[0107] Dilute the ether solution containing III 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 -10°C, and drop to -10 Stir at ℃ for 5h, add 10mL of water, stir at room temperature for 0.5h, separate the organic layer, Na 2 SO 4 Dry, filter, and concentrate to obtain a waxy solid, which is recrystallized from n-hexane to obtain 1.06 g of white needle-like crystals, with a yield of 65%. mp 65-66℃.MS(ESI):m / z 249.1[M-H]-. 1 H NMR (300MHz, 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 (75MHz, CDCl 3 ): δ172.0, 166.5, 140.8, 133.1, 130.3, 130.0, 127.1, 125.7, 74.8, 41.0, 36.3, 27.8, 22.4, 13.8.

Embodiment 3

[0109] A representative intermediate V for the coupling of diols based on 2-(1-acetyl-n-pentyl)benzoic acid 1 Synthesis:

[0110] Dissolve 2-(1-acetyl n-pentyl)benzoic acid (2.50g, 10.0mmol) in anhydrous dichloromethane (50mL), add EDAC (2.29g, 12.0mmol) and a catalytic amount of DMAP, stir at room temperature for 0.5 h, then added ethylene glycol (0.62g, 10.0mmol), stirred at room temperature for 5h, filtered, concentrated under reduced pressure, and obtained oily substance 1.71 through column chromatography [petroleum ether: ethyl acetate (v:v) = 30:1] g, yield 58%. MS(ESI):m / z 317.1[M+Na] + . 1 H NMR (300MHz, CDCl 3 ):δ0.807(t,3H,CH 3 ,J=7.0Hz), 1.181-1.356(m, 4H, 2×CH 2 ),1.730-1.777(m,2H,CH 2 ),1.965(s,3H,COCH 3 ),3.823-3.862(m,2H,CH 2 ),4.269-4.474(m,2H,CH 2 ), 5.206(s, 1H, OH), 6.452(t, 1H, COOCH, J=6.7Hz), 7.197-7.265(m, 1H, ArH), 7.441-7.444(m, 2H, ArH), 7.750-7.777 (m,1H,ArH). 13 CNMR (75MHz, CDCl 3 ): δ170.90, 167.51, 142.37, 132.15, 129.94, 129.34, 127...

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Abstract

The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to an optically active ring-opening butylphthalide-telmisartan hybrid or a pharmaceutically acceptable salt or ester thereof, their preparation method, containing these Pharmaceutical compositions of compounds and their medical use, especially in the prevention and treatment of diseases associated with neuroinflammation, including ischemic stroke, Alzheimer's disease, traumatic brain injury, Parkinson's disease, multiple sclerosis and Applications in depression etc.

Description

technical field [0001] The present invention relates to a butylphthalide-telmisartan hybrid, in particular to an optically active ring-opening butylphthalide-telmisartan hybrid or a pharmaceutically acceptable salt or ester thereof. Preparation methods, pharmaceutical compositions containing these compounds and their medical use, especially in the prevention and treatment of diseases related to neuroinflammation, including ischemic stroke, Alzheimer's disease, traumatic brain injury, Parkinson's disease , multiple sclerosis, depression and other aspects of the application, belongs to the field of pharmaceutical technology. Background technique [0002] Microglia in the central nervous system (CNS) play a key role in mediating various immune-related functional diseases, which are divided into pro-inflammatory type (M1 classic type) and anti-inflammatory type (M2 alternative activated type). M1 microglia highly express oxidative metabolites (such as superoxide and nitric oxid...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D235/18A61K31/4184A61P9/10A61P25/00A61P29/00A61P25/28A61P25/16A61P25/24
CPCC07D235/18A61P9/10A61P25/00A61P29/00A61P25/16C07D403/04C07D257/04C07D403/10
Inventor 黄张建庞涛黄云张陆勇王云杰张奕华
Owner GUANGDONG LONGFU MEDICINE CO LTD
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