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Active salt of dipeptide compound of ornithine and aspartic acid as well as application thereof

A peptide compound, aspartic acid technology, applied in the field of medicine, can solve the problems of undisclosed ornithine and aspartic acid dipeptide compound active salts, undisclosed uses, etc.

Active Publication Date: 2018-01-12
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 active salts 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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  • Active salt of dipeptide compound of ornithine and aspartic acid as well as application thereof
  • Active salt of dipeptide compound of ornithine and aspartic acid as well as application thereof
  • Active salt of dipeptide compound of ornithine and aspartic acid as well as application thereof

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Experimental program
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Effect test

Embodiment 1

[0039] The preparation of embodiment 1 intermediate 1

[0040] Add 0.258g (6.45mmol, 3eq) of sodium hydroxide, 10ml of purified water and 0.5g (2.15mmol, 1eq) of N-δ-Boc-L-ornithine into a 100ml reaction flask, and add Boc anhydride at 0-10°C 0.563g (2.58mmol, 1.2eq) / 10ml THF solution, after the dropwise addition, stirred at room temperature. After the reaction was monitored by TLC until the reaction was complete, the temperature was lowered to below 10°C, dilute hydrochloric acid was added dropwise to pH 4-5, the aqueous phase was extracted with ethyl acetate (15ml×2), the ethyl acetate layers were combined, washed once with purified water, organic The phase was dried with anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 0.81 g of intermediate 1 as a foamy solid crude product, and the yield was basically quantitative.

Embodiment 2

[0041] The preparation of embodiment 2 intermediate 1

[0042] Add 11.8g (296.5mmol, 5eq) of sodium hydroxide and 200ml of purified water into a 500ml three-necked flask, cool down to 0°C, add 10g (59.3mmol, 1eq) of L-ornithine hydrochloride, stir to dissolve, 0 A solution of Boc-anhydride (38.8g, 177.9mmol, 3eq) in tetrahydrofuran (200ml) was added dropwise at about ℃, and reacted at room temperature after the addition was complete. After TLC monitoring to the completion of the reaction, concentrate tetrahydrofuran under reduced pressure at 45°C, adjust the aqueous phase to about pH 4-5 with 1N hydrochloric acid, extract with ethyl acetate (100ml×2), combine the ethyl acetate layers, wash twice with purified water, and organic The phase was dried with anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure at 45°C to obtain 20 g of white foamy solid, Intermediate 1, with a quantitative yield.

Embodiment 3

[0043] The preparation of embodiment 3 intermediate 2

[0044] In a 500ml round bottom flask, add intermediate 1 compound 18.0g (54.2mmol, 1eq), add 180ml tetrahydrofuran and stir to dissolve, then add N-hydroxysuccinimide 6.86g (59.6mmol, 1.1eq), stir to The temperature was lowered to about 0°C, and a solution of DCC (12.3g, 59.6mmol, 1.1eq) in tetrahydrofuran (100ml) was slowly added dropwise, and stirred at room temperature after the dropwise addition, solids slowly precipitated at room temperature, monitored by TLC until the reaction was complete , filtered with suction, and the filtrate was kept for use.

[0045] Take another 1000ml three-necked flask, add 7.9g (59.35mmol, 1.1eq) of L-aspartic acid, 200ml of purified water, 18.2g (21.66mmol, 4eq) of sodium bicarbonate and stir until the solid dissolves, then add dropwise at room temperature The remaining filtrate obtained in the previous step (i.e. the prepared activated ester solution), after the dropwise addition, was ...

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Abstract

The invention provides active salt of a dipeptide compound of ornithine and an aspartic acid, a preparation method of the active salt, a pharmaceutical composition including the active salt, and application of the dipeptide compound or the active salt thereof in preparation of medicine for preventing or treating hyperammonemia or liver diseases, in particular to hepatic encephalopathy. A test result clearly indicates that after the dipeptide compound of the ornithine and the aspartic acid and the active salt of the dipeptide compound are administered, the concentration of blood ammonia can beobviously reduced, and secondary memory disorder after TAA(tumor-associated antigen)-induced liver injury in rats can be obviously improved, indicating that the dipeptide compound and the active saltof the dipeptide compound have a certain treatment effect on hyperammonemia or liver diseases, in particular to the hepatic encephalopathy.

Description

technical field [0001] The present invention belongs to the field of medicine, and in particular relates to an active salt of an ornithine and aspartic acid dipeptide compound, a preparation method thereof, a pharmaceutical composition containing the active salt, and the dipeptide compound or its active salt in Use in the preparation of medicines for preventing or 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 ...

Claims

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Application Information

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IPC IPC(8): C07K5/068C07K1/02C07K1/18A61K38/05A61P1/16A61P3/00
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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