Salts prepared from 2-(1-acyloxy-n-amyl)benzoic acid and basic amino acid or aminoguanidine, and preparation method and application thereof

A technology of aminoguanidine benzoate and acetoxy-n-pentyl, applied in the fields of medicinal chemistry and pharmacotherapeutics, can solve problems such as poor chemical stability, achieve excellent water solubility, excellent pharmacokinetic properties, and enhance therapeutic effect of effect

Active Publication Date: 2019-04-26
JIANGSU KANION PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have shown that AHPB has excellent water solubility, and its anti-platelet aggregation, anti-cerebral ischemia and neuroprotective activities are better than equimolar NBP, but its chemical stability is not good.

Method used

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  • Salts prepared from 2-(1-acyloxy-n-amyl)benzoic acid and basic amino acid or aminoguanidine, and preparation method and application thereof
  • Salts prepared from 2-(1-acyloxy-n-amyl)benzoic acid and basic amino acid or aminoguanidine, and preparation method and application thereof
  • Salts prepared from 2-(1-acyloxy-n-amyl)benzoic acid and basic amino acid or aminoguanidine, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Embodiment 1: (R / S)-2-(1-acetoxy n-pentyl) benzoic acid L-arginine salt (I 1 ) preparation

[0068] Under the condition of -30~-5℃, to the ether (300mL) solution containing 10.9g (52.6mmol) (R / S)-2-(1-hydroxy-n-pentyl)benzoic acid (II), add 21.8mL (157.8mmol) of triethylamine, 0.6g (5.2mol) of DMAP, then slowly dropwise added 11.1mL (157.8mmol) of acetyl chloride, and stirred for 5 hours. After the reaction, add about 35mL10% hydrochloric acid, acidify to pH 2–3, stir for 2 hours, separate the organic layer, anhydrous Na 2 SO 4 Drying, filtration, concentration under reduced pressure, and column chromatography [petroleum ether: ethyl acetate (v:v) = 10:1] gave 9.96 g of (R / S)-2-(1-acetoxy) in the form of white needle crystals n-pentyl)benzoic acid, yield 76%, mp:65–66°C; MS(m / z):249[M 1 –H] - ; 1 H NMR (300MHz, CDCl 3 ):δ(ppm):0.97(t, 3H,CH 3 , J=6.9Hz), 1.38–1.52 (m, 4H, C H 2 C H 2 CH 3 ), 1.84–1.99 (m, 2H, CHC H 2 CH 2 ),2.17(s,3H,CHOCOC H 3 ),6.69...

Embodiment 2

[0070] Embodiment 2: (R / S)-2-(1-propionyloxy-n-pentyl) benzoic acid L-arginine salt (I 2 ) preparation

[0071] Under the condition of -30~-5℃, to the ether (300mL) solution containing 9.96g (39.8mmol) (R / S)-2-(1-hydroxy-n-pentyl)benzoic acid (II), add 21.8ml (157.8mmol) of triethylamine, 0.6g (5.2mmol) of DMAP, then slowly dropwise added 13.1mL (157.8mmol) of propionyl chloride, and stirred for 5 hours. After the reaction, add about 35mL10% hydrochloric acid, acidify to pH 2–3, stir for 2 hours, separate the organic layer, anhydrous Na 2 SO 4Dry, filter, concentrate under reduced pressure, and then go through column chromatography [petroleum ether: ethyl acetate (v:v) = 10:1] to obtain 9.0 g of oily (R / S)-2-(1-propionyloxynormal Amyl) benzoic acid, yield 65%; MS (m / z): 263 [M 1 –H] - ; 1 H NMR (300MHz, CDCl 3 ):δ(ppm):0.96(t,3H,CH 2 CH 2 C H 3 ,J=6.9Hz), 1.21(t,3H,COCH 2 C H 3 ,J=7.8Hz),1.32–1.51(m,4H,C H 2 C H 2 CH 3 ),1.80–1.98(m,2H, CHC H 2 CH 2 ),2.4...

Embodiment 3

[0073] Embodiment 3: (R / S)-2-(1-n-butyryloxy-n-pentyl) benzoic acid L-arginine salt (I 3 ) preparation

[0074] Under the condition of -30~-5℃, to the ether (300mL) solution containing 9.96g (39.8mmol) (R / S)-2-(1-hydroxy-n-pentyl)benzoic acid (II), add 21.8mL (157.8mmol) of triethylamine, 0.6g (5.2mmol) of DMAP, and then slowly dropwise added 15.9mL (157.8mmol) of n-butyryl chloride, and stirred for 5 hours. Add about 35mL10% hydrochloric acid after the reaction, acidify to pH 2–3, stir for 2 hours, separate the organic layer, anhydrous Na 2 SO 4 Drying, filtration, concentration under reduced pressure, and column chromatography [petroleum ether: ethyl acetate (v: v) = 10:1] gave 8.4 g of oily (R / S)-2-(1-n-butyryloxy-n- Pentyl)benzoic acid, yield 58%; MS(m / z): 277[M 1 –H] - ; 1 H NMR (300MHz, CDCl 3 ):δ(ppm):0.89–1.06(m,6H,2×CH 3 ), 1.33–1.51 (m,4H,CH 2 C H 2 C H 2 CH 3 ),1.7-1.78(m,2H,COCH 2 C H 2 CH 3 ),1.85–1.98 (m,2H,CHC H 2 CH 2 ),2.41(t,2H,COC H 2 ...

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Abstract

The invention discloses salts prepared from 2-(1-acyloxy-n-amyl)benzoic acid and basic amino acid or aminoguanidine, a preparation method thereof, a medicinal preparation containing the salts, and application of the salts to preparing of medicines used for preventing or treating ischemic cardiovascular and cerebral vascular diseases, resisting thrombus and relieving cardio-cerebral circulatory disturbance. A compound not only has good water solubility, aqueous solution stability and pharmacokinetics performance, but also has strong activity for resisting platelet aggregation, resisting thrombus, resisting cerebral ischemia and protecting nerves, the effect is superior to that of (S)-butylphthalide and (R / S)-2-(1-hydroxy-n-amyl)potassium benzoate salt (PHPB), acute toxicity of the compoundto mouse intravenous injection dosing is remarkably lower than that of butylphthalide and PHPB, the inhibition ratio of the compound to an hERG potassium channel of a CHO-hERG cell is lower than thatof the (S)-butylphthalide, and a result of a bacterial reverse mutation test (Ames test) is negative.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and pharmacotherapeutics, in particular to salts formed of 2-(1-acyloxy-n-pentyl)benzoic acid and basic amino acids or aminoguanidine, a preparation method thereof, and pharmaceutical combinations containing these salt compounds Drugs and their medical uses, especially in the preparation of drugs for the prevention or treatment of cardio-cerebral ischemic diseases, anti-thrombosis and improvement of cardio-cerebral circulation disorders. Background technique [0002] 3-n-butylphthalide (3-N-butylphthalide, NBP), referred to as butylphthalide, the chemical name is racemic (R / S)-3-n-butyl-1(3H)-isobenzofuranone, It is a drug independently developed and marketed in my country for the treatment of mild and moderate ischemic stroke. Although NBP has certain biological activities such as anti-platelet aggregation, anti-thrombosis, reducing cerebral infarct volume, protecting mitochondrial function, an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/157C07C279/14C07C69/78C07C229/26C07D233/64C07C279/02C07C277/08C07C67/08A61K31/222A61K31/235A61K31/155A61P9/10A61P7/02
CPCA61P7/02A61P9/10C07C67/08C07C69/157C07C69/78C07C229/26C07C277/08C07C279/02C07C279/14C07D233/64C07C69/24C07B2200/07C07C281/16C07C279/12C07C227/26A61K31/192A61K9/0019
Inventor 张奕华黄张建朱嘉熠
Owner JIANGSU KANION PHARMA CO LTD
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