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Isoquinolinium compounds with antithrombotic activity, preparation method and application thereof

A technology of antithrombotic drugs and compounds, applied in the field of biomedicine

Inactive Publication Date: 2008-12-10
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by the present invention at first is to overcome the existing L-amino acid is introduced into 3S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, there is L-amino acid metabolism in vivo or Defects that are easy to degrade, provide a new isoquinoline compound, the L-amino acid introduced in the isoquinoline compound is relatively stable, and is not easy to metabolize in vivo

Method used

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  • Isoquinolinium compounds with antithrombotic activity, preparation method and application thereof
  • Isoquinolinium compounds with antithrombotic activity, preparation method and application thereof
  • Isoquinolinium compounds with antithrombotic activity, preparation method and application thereof

Examples

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Effect test

Embodiment 13

[0023] Example 13 Preparation of S-1,2,3,4-tetrahydroisoline-3-carboxylic acid hydrochloride (1)

[0024] 1.65 g (10 mmol) of L-phenylalanine was dissolved in 90 mL of concentrated hydrochloric acid, and 35 mL of formaldehyde solution with a concentration of 35% was added to the obtained solution. The reaction mixture was reacted at 90°C for 8-9 hours, and the disappearance of L-phenylalanine was monitored by thin layer chromatography to terminate the reaction. The reaction was cooled to room temperature, and colorless crystals were precipitated, which was filtered, and the filter cake was washed with acetone to obtain 1.92 g (95.4%) of the title compound as a colorless solid. ESI / MS: 178[M+H]+;

Embodiment 23

[0025]Example 23 Preparation of S-N-Boc-1,2,3,4-tetrahydroisoline-3-carboxylic acid (2)

[0026] 4.0 g (18.7 mmol) of 3S-1,2,3,4-tetrahydroisoline-3-carboxylic acid hydrochloride (1) were dissolved in 40 ml of DMF. To this suspension was added 5.2 g (23.9 mmol) of Boc with stirring in an ice bath 2 O. Triethylamine was added to adjust the pH of the reaction mixture to 10, the reaction mixture was stirred at room temperature for 48 hours, monitored by thin layer chromatography until the disappearance of the raw materials, and the reaction was terminated. Pour the reaction solution into a watch glass and blow it under a fan for about 24 hours to dry. The dried oil was dissolved in 200 mL of ethyl acetate, and then placed in a 250 mL separatory funnel, and KHSO was added to the solution. 4 (5%) aqueous solution (20 mL x 3). Separate the combined ethyl acetate layers, add anhydrous sodium sulfate to a 250 mL conical flask, dry for 0.5 h, and filter at normal pressure. The fil...

Embodiment 33

[0027] Example 33 Preparation of S-N-Boc-1,2,3,4-tetrahydroisoline-3-formyl-L-leucine methyl ester (3a)

[0028] Under ice bath cooling, 2.00 g (7.22 mmol) of 3S-N-Boc-1,2,3,4-tetrahydroisoline-3-carboxylic acid, 0.97 g (7.19 mmol) of N- Hydroxybenzotriazole (HOBt) and 1.37g (7.55mmol) of L-leucine methyl ester hydrochloride and 70ml of anhydrous tetrahydrofuran (THF) were added dropwise to 1.70g (8.25mmol) of dicyclohexylcarbonyldiimide. (DCC) and 5 mL of anhydrous THF. The resulting solution was adjusted to pH 8 by dropwise addition of a solution of NMM and THF. The reaction mixture was stirred at 0°C for 2 hours, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure using a rotary evaporator. The obtained residue was dissolved in 150 mL of ethyl acetate, placed in a 250 mL separatory funnel, washed three times with saturated aqueous sodium bicarbonate solution (30 mL each time), washed three times with saturated aqueous sodium chloride...

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Abstract

The invention discloses compounds with anti-thrombus activity shown in a formula I, a preparation method thereof and an application of the compounds as antithrombotic agents. A rat thrombus model is adopted to evaluate the anti-thrombus activity of the compounds shown in the formula I. Experiment results show that: the compounds shown in the formula I have excellent anti-thrombus activity, and can be used as the antithrombotic agent clinically.

Description

technical field [0001] The present invention relates to tricyclic compounds, in particular to isoquinoline compounds with antithrombotic activity, and a preparation method thereof. The present invention also relates to the application of the isoquinoline compounds as antithrombotic agents, belonging to the field of biomedicine. Background technique [0002] Vasoembolic disease is the most important responsible for the high mortality of cardiovascular and cerebrovascular diseases. Thrombosis is the most important etiology of vascular thromboembolic disease. Searching for antithrombotic drugs is one of the hotspots in new drug research. Platelet aggregation is related to Ca ion concentration. Intracytoplasmic Ca ion concentration increased, platelet activation and aggregation. Intracytoplasmic Ca ion concentration decreased, platelet inhibition. Most of the tetrahydroisoquinoline compounds have calcium antagonism and platelet aggregation inhibition activity. In addition, ...

Claims

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Application Information

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IPC IPC(8): C07D235/02C07D403/06A61K31/4184A61P7/02
Inventor 彭师奇赵明崔国辉澎乐
Owner PEKING UNIV
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