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Synthesis, activity and application for 1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-GRGDV

A dimethylol, -gly-arg-gly-asp-val technology, applied in the field of biomedicine, can solve the problems of no anti-venous thrombosis activity, ineffective venous thrombosis, bleeding side effects and the like

Active Publication Date: 2019-01-04
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The second point is that although the introduction of a methyl group at the 1-position of the carboline can reduce the oral effective dose to 0.01 μmol / kg, such compounds only exhibit anti-arterial thrombosis activity and have no anti-venous thrombosis activity
Because existing anti-venous thrombosis drugs, such as warfarin, can cause fatal bleeding side effects
In addition, because venous thrombosis and arterial thrombosis have completely different mechanisms, compounds that are effective against arterial thrombosis tend to be ineffective against venous thrombosis

Method used

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  • Synthesis, activity and application for 1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-GRGDV
  • Synthesis, activity and application for 1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-GRGDV
  • Synthesis, activity and application for 1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-GRGDV

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1 Preparation of (3S)-1,1-dimethylol-tetrahydro-β-carboline-3-carboxylic acid (1)

[0023] Suspend 6.12 g (30 mmol) of L-tryptophan in 100 mL of distilled water. Under an ice bath, slowly add concentrated sulfuric acid dropwise until the L-tryptophan is completely dissolved. Add 3.24 g (36 mmol) of 1,3-dihydroxyacetone to the solution, and react at room temperature for 72 hours. TLC (ethyl acetate / water / glacial acetic acid, 10 / 1 / 2) showed that the reaction was complete. Filtration and the filter cake was rinsed with ice water to afford 6.13 g (74%) of the title compound as a yellow powder.

Embodiment 2

[0024] Example 2 Preparation of (3S)-1,1-dimethylol-tetrahydro-β-carboline-3-carboxylic acid methyl ester (2)

[0025] Slowly add 5.2 mL of thionyl chloride dropwise to 55 mL of methanol in an ice-salt bath, and stir for 30 minutes. 5.52 g (20 mmol) of (3S)-1,1-dimethylol-tetrahydro-β-carboline-3-carboxylic acid (1) was added to the solution, and stirred until completely dissolved. Stir at room temperature for 12 hours. TLC (dichloromethane / methanol, 20:1) showed the reaction was complete. Concentrate under reduced pressure, and the residue is triturated with ethyl acetate to obtain a brown-yellow solid. The solid was dissolved with 200 mL of ethyl acetate, and the resulting solution was successively washed with saturated NaHCO 3 Wash with aqueous solution (30 mL×3) and saturated NaCl aqueous solution (30 mL×3), and dry over anhydrous sodium sulfate for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded 5.34 g (92%) of the title compound...

Embodiment 3

[0026] Example 3 Preparation of (3S)-1,1-bis(tert-butyldimethylsilyloxy)methyl-tetrahydro-β-carboline-3-carboxylic acid methyl ester (3)

[0027] Mix 5.22g (18mmol) (3S)-1,1-dimethylol-tetrahydro-β-carboline-3-carboxylic acid methyl ester (2) with 50mL of anhydrous N,N-dimethylformamide ( DMF) was stirred until completely dissolved. Under ice cooling, add 4.4 g (64.8 mmol) imidazole to the solution and stir until completely dissolved. Add 8.15 g of tert-butyldimethylsilyl chloride (TBDMSCl) to the solution, and stir at room temperature for 12 hours. TLC (petroleum ether / ethyl acetate, 20 / 1) showed that the reaction was complete. Under ice-cooling, 350 mL of saturated NaCl aqueous solution was first added to the solution, and then extracted three times with ethyl acetate. The ethyl acetate layer was sequentially washed with saturated NaHCO 3 Wash with aqueous solution (40mL×3) and saturated NaCl aqueous solution (40mL×3), and dry over anhydrous sodium sulfate for 12 hours. ...

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Abstract

The invention discloses a (3S) -1, 1-Dihydroxymethyl-Tetrahydro-Beta-Carboline-3-Formyl-Gly-Arg-Gly-Asp-Val, discloses a preparation method thereof, discloses the anti-arterial thrombosis activity, discloses the anti-venous thrombosis activity, discloses the activity of inhibiting the GPIIb / IIIa expression, and discloses the activity of inhibiting the P-selectin expressionin vivo. Therefore, the invention discloses the application in preparing anti-arterial thrombosis medicine, the application in preparing the anti-venous thrombosis medicine, the application in preparing the GPIIb / IIIa antagonist and the application in preparing P-selectin antagonist. The formulas are shown in the decription.

Description

technical field [0001] The present invention relates to (3S)-1,1-dimethylol-tetrahydro-β-carboline-3-formyl-Gly-Arg-Gly-Asp-Val, to its preparation method, to its anti-arterial Thrombotic activity, related to its anti-venous thrombosis activity, related to its activity of inhibiting the expression of GPIIb / IIIa, related to its activity of inhibiting the expression of P-selectin in vivo. Therefore, the present invention relates to its application in the preparation of anti-arterial thrombosis drug, its application in the preparation of anti-venous thrombosis drug, its application in the preparation of GPIIb / IIIa antagonist and its application in the preparation of P-selectin antagonist. The invention belongs to the field of biomedicine. Background technique [0002] Thrombosis is the leading cause of myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, and other cardiovascular diseases, and is a major cause of morbidity and mortality worldwide. Although ...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/02A61K38/08A61P7/02
CPCC07K7/06A61K38/00
Inventor 赵明彭师奇王玉记吴建辉张筱宜刘山
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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