An organic amine ester derivative drug of 2-(α-hydroxypentyl)benzoic acid

A technology of hydroxypentyl and benzoic acid, which is applied in the preparation of organic compounds, the preparation of aminohydroxyl compounds, and drug combinations, etc., which can solve the problems of high environmental and pH requirements, reduce production costs, increase production costs, etc., and achieve connection The method is simple, the druggability is improved, and the production cost is low

Active Publication Date: 2020-03-24
YAOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the potassium salt and sodium salt of 2-(α-hydroxypentyl)benzoic acid and its derivatives have strong hygroscopicity, poor stability (easy to close the ring), and have high requirements for the environment and pH value in the process of preparation preparation. , which greatly increases the production cost
So far, there is not a kind of 2-(alpha hydroxypentyl) benzoic acid derivative that can overcome these shortcomings, therefore, develop a kind of solubility that has better, lower hygroscopicity, be easy to prepare solid preparation and reduce production cost, And it is very necessary to have 2-(α-hydroxypentyl)benzoic acid derivatives with significantly higher bioavailability than the original drug, which can be rapidly degraded into the original drug in the body and increase the concentration of the brain.

Method used

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  • An organic amine ester derivative drug of 2-(α-hydroxypentyl)benzoic acid
  • An organic amine ester derivative drug of 2-(α-hydroxypentyl)benzoic acid
  • An organic amine ester derivative drug of 2-(α-hydroxypentyl)benzoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1. Synthesis of 2-(1-acetoxypentyl)benzoic acid (Compound 4).

[0044] Dissolve 1.24g (6.5mmol) butylphthalide in 10mL methanol, add 10mL 2mol·L -1 Sodium hydroxide solution, refluxed for 0.5h. Evaporate methanol under reduced pressure, add 10mL distilled water to dilute, cool to -5°C, and use 0.6mol L -1 Acidify with dilute hydrochloric acid to pH 2~3, extract the aqueous layer with ether (50mL×3), dilute the ether solution with 200mL dichloromethane, add 2.7mL (19.6mmol) triethylamine, 0.5g 4-dimethylaminopyridine (DMAP), 1.5mL (19.6mmol) acetyl chloride was added dropwise at -5°C, and the reaction was stirred at -5°C for 5h after the drop was completed. Add 10 mL of water, stir at room temperature for 0.5 h, separate the organic layer, and dry over anhydrous sodium sulfate. Filtrate and concentrate to obtain a waxy solid, and recrystallize from n-hexane to obtain white needle-like crystals.

Embodiment 2

[0045] Example 2. Synthesis of compound DB-1.

[0046] Weigh 0.5g of 2-(1-acetoxypentyl)benzoic acid, add 50ml of dichloromethane, 0.9g of HATU, 0.6ml of N,N-dimethylethanolamine, stir and react overnight, extract with water three times, dichloromethane / Methanol = 80:1 was purified by column to obtain a white solid, which was formed by adding absolute ethanol HCl to form a salt, and diethyl ether was added to form a white precipitate, which was filtered and dried to obtain the hydrochloride product, namely compound DB-1 hydrochloride.

[0047] 1 H NMR (400MHz,D 2 O)δ7.88(dd,J=7.8,1.3Hz,1H),7.65–7.52(m,2H),7.39 (ddd,J=8.0,7.0,1.7Hz,1H),6.30(dd,J=8.4 ,4.8Hz,1H),4.70–4.55(m,2H),3.60(t,J=5.0Hz,2H),2.94(s,6H),2.04(s,3H),1.79(dddd,J=18.7, 14.2, 11.1, 5.7Hz, 2H), 1.38–1.21 (m, 4H), 0.79 (t, J = 7.1Hz, 3H).

Embodiment 3

[0048] Example 3. Synthesis of compound DB-2.

[0049] Weigh 0.5g 2-(1-acetoxypentyl)benzoic acid, add 50ml dichloromethane, 0.9g HATU, 0.8ml 1-(2-hydroxyethyl)piperidine, stir and react overnight, extract with water three times, two Chloromethane / methanol=80:1 column purification, to obtain a white solid, add absolute ethanol HCl solution to form a salt, add ether to form a white precipitate, filter, dry, and obtain the hydrochloride product, namely compound DB-2 hydrochloride .

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PUM

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Abstract

General formula = The present invention discloses a preparation method and application of 2‑(α-hydroxypentyl) benzoic acid organic amine derivative drug. Specifically, it relates to a compound of the general formula or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable preparation prepared from the compound or a pharmaceutically acceptable salt thereof. The compound of the general formula or a pharmaceutically acceptable salt thereof has better solubility and lower hygroscopicity in vitro, and has significantly higher bioavailability and brain concentration and / or increased bioavailability than the original drug butylphthalide in vivo The effect of the drug, and its application in the preparation of prevention / treatment of cardio-cerebral ischemic disease, cardio-cerebral arterial obstructive disease and anti-Parkinson's disease and anti-senile dementia drugs.

Description

technical field [0001] The present invention relates to the field of medicine, and more specifically relates to a 2-(alpha hydroxyl) with good solubility, low hygroscopicity, simple preparation process, high bioavailability and increased concentration in the brain. Pentyl)benzoic acid organic amine derivatives, and their application in the preparation of prevention / treatment of cardio-cerebral ischemic diseases, cardio-cerebral arterial occlusive diseases, and anti-Parkinson's disease and anti-senile dementia drugs. [0002] technical background [0003] Butylphthalide, whose chemical name is racemic 3-n-butyl-1(3H)-isobenzofuranone (dl-3-n-butylphthalide, NBP, 1), is extracted from the natural edible plant celery seed It is a class of new drug for the prevention and treatment of ischemic stroke developed by our country with independent intellectual property rights. A pathological link, has a strong anti-ischemic effect. Experimental studies in recent years have found that ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C219/14C07C213/06C07D295/088A61K31/235A61K31/4453A61P9/10A61P25/16A61P25/28
CPCA61P9/10A61P25/16A61P25/28C07C219/14C07D295/088C07C229/38C07D211/14
Inventor 张凌李建波张志荣林箐
Owner YAOPHARMA CO LTD
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