Organic amine ester derivative drug of 2-(alpha hydroxyl amyl) benzoic acid

A hydroxypentyl, benzoic acid technology, applied in the preparation of organic compounds, the preparation of aminohydroxy compounds, organic chemistry and other directions, can solve the problems of high environmental and pH value requirements, increase production costs, reduce production costs, etc. The method is simple, the production cost is low, and the effect of improving the druggability

Active Publication Date: 2018-10-30
YAOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the potassium salt and sodium salt of 2-(α-hydroxypentyl)benzoic acid and its derivatives have strong hygroscopicity and poor stability (easy to close the ring), and have high requirements on the environment and pH value during the preparation process. , which greatly increases the production cost
So far, there is no 2-(alpha hydroxypentyl) benzoic acid derivative that can overcome these shortcomings. Therefore, developing a kind of benzoic acid derivative with better solubility, lower hygroscopicity, easy preparation of solid preparations and reduced production costs, And 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 brain aggregation are very necessary

Method used

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  • Organic amine ester derivative drug of 2-(alpha hydroxyl amyl) benzoic acid
  • Organic amine ester derivative drug of 2-(alpha hydroxyl amyl) benzoic acid
  • Organic amine ester derivative drug of 2-(alpha hydroxyl amyl) benzoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1. Synthesis of 2-(1-acetoxypentyl)benzoic acid (compound 4).

[0043] Dissolve 1.24g (6.5mmol) butylphthalide in 10 mL methanol, add 10 mL 2mol L -1 Sodium hydroxide solution, refluxed for 0.5h. Evaporate methanol under reduced pressure, add 10 mL of distilled water to dilute, cool to -5°C, and use 0.6 mol L -1 Acidify with dilute hydrochloric acid to pH 2~3, extract the aqueous layer with ether (50 mL×3), dilute the ether solution with 200 mL of dichloromethane, add 2.7 mL (19.6 mmol) of triethylamine and 0.5 g of 4-dimethylamino Pyridine (DMAP), 1.5mL (19.6 mmol) 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

[0044] Example 2. Synthesis of Compound DB-1.

[0045] 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 column purification, to obtain a white solid, adding absolute ethanol HCl solution to form a salt, adding ether to form a white precipitate, filtering, drying to obtain the hydrochloride product, namely compound DB-1 hydrochloride.

[0046] 1 H NMR (400 MHz, D 2 O) δ 7.88 (dd, J = 7.8, 1.3 Hz, 1H), 7.65 – 7.52(m, 2H), 7.39 (ddd, J = 8.0, 7.0, 1.7 Hz, 1H), 6.30 (dd, J = 8.4, 4.8 Hz,1H), 4.70 – 4.55 (m, 2H), 3.60 (t, J = 5.0 Hz, 2H), 2.94 (s, 6H), 2.04 (s,3H), 1.79 (dddd, J = 18.7, 14.2, 11.1, 5.7 Hz, 2H), 1.38 – 1.21 (m, 4H), 0.79(t, J = 7.1 Hz, 3H).

Embodiment 3

[0047] Example 3. Synthesis of Compound DB-2.

[0048] Weigh 0.5g of 2-(1-acetoxypentyl)benzoic acid, add 50ml of dichloromethane, 0.9g of HATU, 0.8ml of 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

The invention discloses a preparation method and an application of an organic amine derivative drug of 2-(alpha hydroxyl amyl) benzoic acid, and particularly relates to a compound shown as general formula I as shown in the specification, or pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable preparation prepared from the compound or the pharmaceutically acceptable salt of the compound. The compound as shown as the general formula I or the pharmaceutically acceptable salt of the compound has better solubility and lower hygroscopicity in vitro, has significantly higher bioavailability and a brain aggregation concentration and / or an improved drug effect in vivo as compared with an active compound, namely butyphthalide, and is applied in preparation of drugs forpreventing / treating ischemic cardiovascular and cerebral vascular diseases, cardiac and cerebral arterial occlusion diseases, antiparkinsonism drugs 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. Amyl) benzoic acid organic amine derivatives, and their application in the preparation of prevention / treatment of cardio-cerebral ischemic diseases, cardio-cerebrovascular occlusive diseases, and anti-Parkinson's disease and anti-senile dementia drugs. technical background [0002] 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 in addition...

Claims

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Application Information

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Patent Type & Authority Applications(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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