Alpha-cyano-4-hydroxy cinnamic acid derivative and preparation method and application thereof

A technology of hydroxycinnamic acid and derivatives, which is applied in the field of pharmaceutical compounds and their preparation, can solve the problems of death, large toxic and side effects, inaccurate curative effect and the like, and achieves the effects of simple preparation process and excellent curative effect.

Active Publication Date: 2015-03-25
广州药本君安医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This new substance can effectively reduce excessive blood sugar levels by reducing glycemic hormones called deoxygluconate (also known as pyranone) that help regulate insulin production during pregnancy or adolescence. It also helps prevent certain types of cancer from growing at high risk due to increased uptake of free radicals caused by radiation exposure.

Problems solved by technology

This patented technical problem addressed in this patents relating to improving treatment strategies against diabesis associated diseases like renal failure, stroke, peripheral vascular syndrome, macrosome degeneration, etc., which involve increased production of advanced oxidant substances called ALDH. These agents can cause changes that affect protein structure and behavior leading to impairment of important functions including calcium regulation, neuron signaling, inflammations, apoptosis, cancer growth, cerebral vasculature malfunctions, obstructive sleep apnea, ocular conditions, arterial slip attacks on organs involved in the management therapy process, and even comorbities from various medicines commonly prescribed during long term medical practicals.

Method used

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  • Alpha-cyano-4-hydroxy cinnamic acid derivative and preparation method and application thereof
  • Alpha-cyano-4-hydroxy cinnamic acid derivative and preparation method and application thereof
  • Alpha-cyano-4-hydroxy cinnamic acid derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Preparation of α-cyano-4-hydroxycinnamic acid derivatives with aldose reductase inhibitory activity

[0045] 1.1.2-N-(N-acetyl-O-benzyl-D-seryl)-α-cyano-4-hydroxycinnamoylethylenediamide preparation

[0046] Include the following four steps.

[0047] (1) Preparation of 2-N-tert-butoxyacyl-α-cyano-4-hydroxycinnamoylethylenediamine: Add 946.0mg (5.0mmol ), add an appropriate amount of DCM / DMF=10:1 (V / V) and stir to dissolve, add 1.15g (6.0mmol) of EDC. mg (6.0 mmol) was added to the reaction flask, and the reaction was stirred at 0°C for 10 min to fully activate the free carboxyl groups. After the carboxyl group is fully activated, measure 0.9mL (5.5mmol) of N-Boc-ethylenediamine and 2.3mL (13.2mmol) of DIPEA into the reaction flask in turn, stir and react at 0°C for about 30min, then slowly rise to room temperature, and continue the reaction 24h. After the reaction was completed, the solvent was removed, and silica gel column chromatography (developing solvent: ethyl...

Embodiment 2

[0081] The synthetic compound of embodiment 1 is to the inhibitory activity of aldose reductase enzyme

[0082] In this example, aldose reductase (AR), NADPH, and DL-glyceraldehyde were all purchased from Wako Pure Chemical Industries, Ltd.; Epalrestat (EPS) was purchased from Tokyo Chemical Industry Co., Ltd.

[0083] Experimental procedure: Add 500 μL of pH 6.2 buffer solution, 100 μL of 1.5 mmol / L NADPH solution and 100 μL of 100 mmol / L DL-glyceraldehyde solution into a 48-well plate, then add 100 μL of sample solutions of different concentrations and 195 μL of distilled water. At the same time, a blank vehicle group (500 μL of pH 6.2 buffer solution, 100 μL of 1.5 mmol / L NADPH solution, 100 μL of 1 / 1000 solvent, 300 μL of distilled water), and an enzyme power group (500 μL of pH 6.2 buffer solution, 100 μL of 1.5 mmol / L NADPH solution, 100 mmol / L L DL-glyceraldehyde solution 100μL, 1 / 1000 vehicle 100μL, distilled water 195μL) and positive drug EPS group (PH6.2 buffer solut...

Embodiment 3

[0095] The in vitro antioxidant activity of the synthetic compound of embodiment 1

[0096] In this example, Trolox (6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) and Fluorescein (FL) (sodium salt) were purchased from Aldrich Company (Milwaukee, WI); 2,2' -Azobis (2-amidino-propane) dihydrochloride (AAPH) was purchased from Wako Pure Chemical Industries, Ltd., Japan.

[0097] Experimental steps:

[0098] Add 20 μL of pH 6.8 phosphate buffer to the 96-well plate, then add 20 μL of samples to be tested at different concentrations, measure 3 wells in parallel for each concentration sample, then add 140 μL of AAPH solution, and set up AAPH absorption holes (40 μL of phosphate buffer, AAPH solution 140 μL), fluorescence control wells (phosphate buffer 180 μL) and Trolox control wells (Trolox standard solution 20 μL, phosphate buffer 20 μL, AAPH solution 140 μL); after adding 20 μl of disodium fluorescein solution to each well to start the reaction, the 96 The orifice pl...

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Abstract

The invention discloses an alpha-cyano-4-hydroxy cinnamic acid derivative with aldose reductase inhibition activity and a preparation method and application thereof. The structure of the compound is as shown in formula I. The preparation method comprises the following steps: firstly reacting alpha-cyano-4-hydroxy cinnamic acid with a diamine compound protected by N-tert-butyloxycarbonyl (Boc) to obtain N-Boc-protected alpha-cyanocinnamic carbamide. After removal of a protective group, namely Boc from the compound, the alpha-cyano-4-hydroxy cinnamic acid derivative is obtained by reaction with N-acyl alpha-amino acid (natural or unnatural). The compound disclosed by the invention has inhibition activity against aldose reductase, and can be applied to preparation of medicaments for treating diabetic complications, such as diabetic retinopathy, diabetic senile dementia, disorders of nerve endings and other diseases.

Description

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Claims

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Application Information

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Owner 广州药本君安医药科技股份有限公司
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