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Acylated derivatives of ornithine and aspartic acid dipeptide compounds and their application

A technology of peptide compound and aspartic acid, which is applied in the field of medicine, can solve the problems of undisclosed use, undisclosed ornithine and aspartic acid dipeptide compound acylated derivatives, etc.

Active Publication Date: 2020-08-28
NANJING YOUKE BIOLOGICAL MEDICAL RES +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The prior art does not disclose acylated derivatives of ornithine and aspartic acid dipeptide compounds, nor does it disclose its use in the preparation of drugs for the prevention or treatment of hyperammonemia or liver disease, especially hepatic encephalopathy

Method used

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  • Acylated derivatives of ornithine and aspartic acid dipeptide compounds and their application
  • Acylated derivatives of ornithine and aspartic acid dipeptide compounds and their application
  • Acylated derivatives of ornithine and aspartic acid dipeptide compounds and their application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1 Preparation of intermediate 1a

[0032] Under ice-cooling, 10.892g (0.08mol) of phenylacetic acid and 9.66g (0.084mol, 1.05eq) of NHS were dissolved in 100ml of tetrahydrofuran. Another 20 g (0.097 mol, 1.2 eq) of DCC was weighed and dissolved in 100 ml of tetrahydrofuran, and added dropwise to the reaction flask. Stir the reaction for 1 hour. After the reaction is complete as monitored by TLC, add 10ml of distilled water to the reaction solution and stir for 20 minutes to quench excess DCC; filter with suction to remove insoluble matter, and the filtrate is set aside.

[0033] Weigh N-δ-Boc-L-ornithine 19.2g (0.083mol, 1.03eq) and sodium bicarbonate 13.44g (0.160mol, 2.0eq), disperse in 100ml distilled water, then add 50ml THF wherein; The filtrate obtained in the previous step was added dropwise to the reaction solution, and stirred at room temperature for 4 hours; after the completion of the reaction monitored by TLC, the pH was adjusted to pH 7 with 2N HC...

Embodiment 2

[0034] Example 2 Preparation of intermediate 1b

[0035] Weigh 12.697g (0.077mol) of phenylbutyric acid and 8.87g (0.077mol, 1.0eq) of NHS, dissolve it in 100ml of tetrahydrofuran, and stir in an ice bath. Another 18g (0.087mol, 1.1eq) of DCC was weighed and dissolved in 100ml of tetrahydrofuran, and added dropwise to the reaction flask. Stir the reaction for 1 hour. After the reaction is complete as monitored by TLC, add 10ml of distilled water to the reaction solution and stir for 20 minutes to quench excess DCC; filter with suction to remove insoluble matter, and the filtrate is set aside.

[0036] Weigh 19.2g (0.083mol, 1.07eq) of N-δ-Boc-L-ornithine and 13.44g (0.160mol, 2.1eq) of sodium bicarbonate, and disperse them in 100ml of distilled water, then add 50ml of THF; The filtrate obtained in the previous step was added dropwise to the reaction solution, and stirred at room temperature for 4 hours; after the completion of the reaction monitored by TLC, the pH was adjuste...

Embodiment 3

[0037] Example 3 Preparation of intermediate 2a

[0038] Weigh 7.36g (0.021mol) of intermediate 1a and 2.53g (0.022mol, 1.05eq) of NHS and dissolve in 100ml tetrahydrofuran, and stir under ice bath. Another 4.97g (0.024mol, 1.15eq) of DCC was weighed and dissolved in 100ml of tetrahydrofuran, and added dropwise to the reaction flask. Stir the reaction for 1 hour. When there is unreacted intermediate 1a in the TLC monitoring system, add an appropriate amount of DCC. When the monitoring reaction is complete, add 10ml of distilled water to the reaction solution and stir for 20 minutes to quench the excess DCC; Insoluble matter, the filtrate was set aside.

[0039] Weigh 2.942g (0.022mol, 1.05eq) of L-Asp and 7.06g (0.084mol, 4.0eq) of sodium bicarbonate and dissolve them in 150ml of distilled water. Bubbles are generated during dissolution; Stir overnight; after the reaction is monitored by TLC, adjust the pH to pH7 with 2N HCl solution, remove THF by rotary evaporation at 45°C...

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PUM

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Abstract

The invention provides an acylated derivative for an ornithine and aspartate dipeptide compound or an officinal salt thereof, a preparation method thereof, a medicine composition containing the derivative or the officinal salt thereof, and the application of the derivative or the officinal salt thereof for preparing medicines for preventing or curing hyperammonemia or liver diseases, particularlyhepatic encephalopathy. Experimental results definitely indicate that the concentration of blood ammonia can be obviously reduced after administration for the acylated derivative for the ornithine andaspartate dipeptide compound, the acylated derivative takes effect quickly by preferably compared with LOLA, subsequent dysmnesia after TAA-induced rat liver injury can be obviously improved, and theacylated derivative for the dipeptide has a certain treatment effect on hyperammonemia or liver diseases, particularly hepatic encephalopathy.

Description

technical field [0001] The present invention belongs to the field of medicine, and in particular relates to an acylated derivative of ornithine and aspartic acid dipeptide compound, a preparation method thereof, a pharmaceutical composition containing the derivative, and the preparation of the derivative in the preparation of prophylaxis or Use in medicine for treating hyperammonemia or liver disease, especially hepatic encephalopathy. Background technique [0002] Hepatic encephalopathy (HE) is a complex neuropsychiatric disorder that occurs in a variety of clinical conditions such as acute or chronic liver disease and spontaneous portosystemic shunts. In the early stages of hepatic encephalopathy, subtle mental changes such as difficulty concentrating, confusion, and disorientation occur. In severe cases, hepatic encephalopathy can lead to stupor, coma, swelling of the brain (cerebral edema), and death. Accumulation of ammonia is thought to play an important role in the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/068A61K38/05A61P1/16A61P25/00A61P3/00
Inventor 张峰朱素华聂鑫张建华薛峪泉刘春猛
Owner NANJING YOUKE BIOLOGICAL MEDICAL RES
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