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Cinnamic acid derivative with aldose reductase inhibitory activity as well as preparation method and application thereof

A cinnamic acid derivative and a technology for inhibiting activity are used in the preparation of medicines for treating diabetic complications and diseases caused by oxidative stress. exact question

Active Publication Date: 2017-08-22
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

Problems solved by technology

Among them, asrestat and sobinil were announced to be discontinued due to their severe side effects, and ponastat was announced to be discontinued due to inaccurate curative effect; torristat was announced to be discontinued in 1997 due to severe liver toxicity and death

Method used

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  • Cinnamic acid derivative with aldose reductase inhibitory activity as well as preparation method and application thereof
  • Cinnamic acid derivative with aldose reductase inhibitory activity as well as preparation method and application thereof
  • Cinnamic acid derivative with aldose reductase inhibitory activity as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1: Preparation of novel cinnamic acid derivatives with aldose reductase inhibitory activity

[0077] 1.1. Preparation of 3-N-(N-acetyl-O-benzyl-D-seryl)-α-cyano-3,4-dihydroxycinnamoylpropylenediamide

[0078] Include the following five steps:

[0079] (1) Synthesis of compound α-cyano-3,4-dihydroxybenzoic acid: Weigh 138mg (1.0mmol) of 3,4-dihydroxybenzaldehyde in a dry 50mL round bottom flask, add cyanoacetic acid 85mg ( 1.0mmol), ammonium acetate 15.4mg (0.2mmol), syringe weighed glacial acetic acid 48mg (0.8mmol) into the reaction system, then added 10mL of toluene as a solvent, the reaction bottle was connected to a small water separator, condenser tube, drying tube. Stir and reflux the reaction in an oil bath at 120°C for 18h. After the reaction was completed, it was lowered to room temperature, then stood at low temperature, filtered, and the filter cake was washed three times with dichloromethane (DCM) to obtain a yellow solid with a yield of 93.2%. 1 ...

Embodiment 2

[0158] Embodiment 2: the inhibitory activity of the synthetic compound of embodiment 1 to aldose reductase enzyme

[0159] In this example, aldose reductase (AR), reduced coenzyme II (NADPH), and DL-glyceraldehyde were purchased from Sigma; Epalrestat was purchased from Tokyo Chemical Industry Co., Ltd.

[0160] Experimental procedure: the enzyme reaction system was carried out on a 96-well plate, and the reaction system included: 100 μL of PBS buffer (pH=6.2), 20 μL of 1.5 mmol / L NADPH, 20 μL of 100 mmol / L DL-glyceraldehyde, different concentrations (Epalrestat or tested sample) solution 20 μL, AR diluent 20 μL, distilled water 20 μL. The experimental setup blank photo group, standard control group and enzyme metabolism group are shown in Table 2-1.

[0161] Table 2-1. Table of grouping and administration

[0162]

[0163] Note: All volume units above are in μL.

[0164] After incubating the above liquid at 37°C for 5 minutes, except for the blank solvent group, each gr...

Embodiment 3

[0172] Embodiment 3: the in vitro antioxidant activity of the compound synthesized in embodiment 1

[0173] In this example, Trolox (6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid); 1,1-diphenyl-2-picrylhydrazyl (DPPH) were purchased from Sigma.

[0174] Experimental procedure: the reaction system was carried out on a 96-well plate, 40 μL of each test solution was added into the 96-well plate, and then 160 μL of DPPH solution was added in parallel to each well. At the same time, a control group (40 μL methanol + 160 μL DPPH) and a blank group (40 μL test substance + 160 μL methanol) were set up. Shake for 1 min to make it evenly mixed, place the 96-well plate in the dark for 0.5 h, and quickly put the plate into a microplate reader with a detection wavelength of 517 nm. The final absorbance (A) value was measured, each sample was detected three times in parallel, and the average value was taken. The formula for calculating the clearance rate is as follows:

[0175] ...

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Abstract

The invention discloses a cinnamic acid derivative with aldose reductase inhibitory activity, a preparation method thereof and an application of the cinnamic acid derivative in preparation of a medicine used for treating diabetic complications and diseases caused by oxidative stress. The structure of the compound is shown in a formula I. The preparation method comprises the following steps: firstly reacting substituted benzaldehyde with substituted acetic acid or acid anhydride thereof to obtain substituted cinnamic acid, then reacting with a diamine compound protected by N-tertiary butoxy acyl to obtain substituted cinnamoyl diamide protected by N-tertiary butoxy acyl; and carrying out tertiary butoxy acyl deprotection on the substituted cinnamoyl diamide protected by N-tertiary butoxy acyl, and then reacting with natural or non-natural N-acyl alpha-amino acid, so that the cinnamic acid derivative is obtained. The cinnamic acid derivative compound disclosed by the invention has excellent inhibitory activity on aldose reductase and excellent antioxidant activity and can be applied to preparation of a medicine used for treating the diabetic complications, especially diabetic retinopathy, senile dementia due to diabetes and nerve ending disturbance, as well as diseases caused by the oxidative stress.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to a cinnamic acid derivative with aldose reductase inhibitory activity and a preparation method thereof, and the application of the cinnamic acid derivative in the preparation of medicines for treating diabetic complications and diseases caused by oxidative stress . Background technique [0002] Diabetes Mellitus (DM) is an endocrine-metabolic syndrome characterized by hyperglycemia and glycosuria caused by insufficient insulin secretion or insulin resistance. According to statistics from the International Diabetes Federation (IDF) in 2013, the number of people with diabetes worldwide is about 382 million, and this number is expected to increase to 592 million by 2035. my country is one of the countries with the largest number of diabetic patients. There are about 98 million patients aged 20 to 79, and it is expected to increase to 143 million by 2035. Therefore, the drug tre...

Claims

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Application Information

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IPC IPC(8): C07C255/41C07C253/30C07D207/16C07C237/22C07C231/14A61K31/165A61K31/277A61K31/40A61P3/10
CPCC07C231/14C07C237/22C07C253/30C07C255/41C07D207/16
Inventor 陈河如袁盛李艳冰李怡芳何蓉蓉
Owner 广州药本君安医药科技股份有限公司
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