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Phenylacrylate derivative and application thereof as neuroprotective drug

A technology of phenylacrylate and phenylacrylic acid, which is applied in the field of phenylacrylate derivatives, can solve the problems of low oral bioavailability, only injection administration, unstable physical and chemical properties, etc., and achieve high neuroprotective activity and acute toxicity Low, ideal effect of pharmacokinetic characteristics

Active Publication Date: 2019-04-19
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, as a neuroprotective agent, Edaravone has unstable physical and chemical properties, low oral bioavailability, and can only be administered by injection for clinical use.

Method used

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  • Phenylacrylate derivative and application thereof as neuroprotective drug
  • Phenylacrylate derivative and application thereof as neuroprotective drug
  • Phenylacrylate derivative and application thereof as neuroprotective drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The preparation of embodiment 1 (E)-3-methyl-1-phenyl-1H-pyrazole-5-(3-(4-hydroxyphenyl)) acrylate (T-1)

[0038] 4-Hydroxyphenylacrylic acid (5 mmol, 1.0 eq) was dissolved in 40 mL of dichloromethane at room temperature. Oxalyl chloride (6.5 mmol, 1.3 eq) was slowly added dropwise to the solution at 0-5°C. After the dropwise addition was completed, it was moved to room temperature for 8h. After the reaction, vacuum-dry to obtain 4-hydroxyphenylacryloyl chloride.

[0039]Dissolve phenylhydrazine hydrochloride (7.5mmol, 1.0eq) and triethylamine (11.3mmol, 1.5eq) in 20mL absolute ethanol at room temperature. The reaction solution was heated to 50° C., and ethyl acetoacetate (7.5 mmol, 1.0 eq) was slowly added dropwise. After the addition was complete, the reaction was refluxed for 24 hours. After completion of the reaction, vacuum-dry to obtain 3-methyl-1-phenyl-2-pyrazolin-5-one.

[0040] 3-Methyl-1-phenyl-2-pyrazolin-5-one (7.5 mmol, 1.5 eq) was dissolved in 30 mL ...

Embodiment 2

[0042] Embodiment 2 (E)-3-methyl-1-phenyl-1H-pyrazole-5-(3-(4-hydroxyl-3-methoxyphenyl)) acrylate (T-2) and its salt preparation

[0043] 4-Hydroxy-3-methoxyphenylacrylic acid (5 mmol, 1.0 eq) was dissolved in 40 mL of dichloromethane at room temperature. Oxalyl chloride (6.5 mmol, 1.3 eq) was slowly added dropwise to the solution at 0-5°C. After the dropwise addition was completed, it was moved to room temperature for 8h. After the reaction, vacuum-dry to obtain 4-hydroxy-3-methoxyphenylacryloyl chloride.

[0044] Dissolve phenylhydrazine hydrochloride (7.5mmol, 1.0eq) and triethylamine (11.3mmol, 1.5eq) in 20mL absolute ethanol at room temperature. The reaction solution was heated to 50° C., and ethyl acetoacetate (7.5 mmol, 1.0 eq) was slowly added dropwise. After the addition was complete, the reaction was refluxed for 24 hours. After completion of the reaction, vacuum-dry to obtain 3-methyl-1-phenyl-2-pyrazolin-5-one.

[0045] 3-Methyl-1-phenyl-2-pyrazolin-5-one (7....

Embodiment 3

[0055] Example 3 Preparation of (E)-3-methyl-1-phenyl-1H-pyrazole-5-(3-(4-methoxyphenyl))acrylate (T-3) and its salts

[0056] 4-Methoxyphenylacrylic acid (5 mmol, 1.0 eq) was dissolved in 40 mL of dichloromethane at room temperature. Oxalyl chloride (6.5 mmol, 1.3 eq) was slowly added dropwise to the solution at 0-5°C. After the dropwise addition was completed, it was moved to room temperature for 8h. After the reaction, vacuum-dry to obtain 4-methoxyphenylacryloyl chloride.

[0057] Dissolve phenylhydrazine hydrochloride (7.5mmol, 1.0eq) and triethylamine (11.3mmol, 1.5eq) in 20mL absolute ethanol at room temperature. The reaction solution was heated to 50° C., and ethyl acetoacetate (7.5 mmol, 1.0 eq) was slowly added dropwise. After the addition was complete, the reaction was refluxed for 24 hours. After completion of the reaction, vacuum-dry to obtain 3-methyl-1-phenyl-2-pyrazolin-5-one.

[0058] 3-Methyl-1-phenyl-2-pyrazolin-5-one (7.5 mmol, 1.5 eq) was dissolved in...

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Abstract

The invention discloses a phenylacrylate derivative and application thereof as a neuroprotective drug, the phenylacrylate derivative and a medicinal preparation thereof have a good curative treating effect on cranial nerve injury diseases such as cerebral apoplexy and related diseases, are low in acute toxicity and do not have the potential heart toxicity risk, and have a prominent technical effect and a substantial scientific progress compared with existing medicines. The phenylacrylate derivative is a compound represented by a general formula i or a salt thereof as shown in the specification.

Description

technical field [0001] The present invention relates to phenylacrylate derivatives and applications thereof. Background technique [0002] Nerve cell injury has the characteristics of multiple factors, multiple pathways, and multiple links, and the therapeutic effect of only intervening in one link or a single pathway is not significant. In recent years, traditional Chinese medicine has been widely used in the treatment of neurological diseases and exerts neuroprotective effects. Traditional Chinese medicine has the advantage of multi-target synergy in the treatment of nerve injury diseases, and can intervene in the pathological process of nerve cell injury from multiple channels. [0003] The inventors found that in traditional Chinese medicine, many monomers or active ingredients with neuroprotective effect contain phenylacrylic acid (ester) structure, for example: scrophroside A 1 , B 1 , B 2 、C 1 It is a natural neuroprotectant against the damage of glutamate to ner...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/22C07D231/34A61K31/415A61P9/10A61P7/02A61P25/00
CPCC07D231/22C07D231/34
Inventor 李建其张庆伟李洋周超
Owner SHANGHAI INST OF PHARMA IND
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