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

A dimethylol, dihydroxyacetone 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-v

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

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

Embodiment 2

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

[0025] 5.2 mL of thionyl chloride was slowly added dropwise to 55 mL of methanol under an ice-salt bath, and stirred 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 that the reaction was complete. It was concentrated under reduced pressure, and the residue was washed with ethyl acetate to obtain a brown-yellow solid. The solid was dissolved with 200 mL ethyl acetate, and the resulting solution was sequentially used with saturated NaHCO 3 Wash with aqueous solution (30 mL×3) and saturated NaCl aqueous solution (30 mL×3), and dry with anhydrous sodium sulfate for 12 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain 5.34 g (92%)...

Embodiment 3

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

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

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Abstract

The invention discloses a (3S) -1, 1-Dihydroxymethyl-Tetrahydro-Beta-Carboline-3-Formyl-Gly-Arg-Gly-Asp-Ser, 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 expression in vivo. Therefore, theinvention 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-Dihydroxymethyl-tetrahydro-β-carboline-3-formyl-Gly-Arg-Gly-Asp-Ser, its preparation method, and its anti-arterial effect The thrombotic activity relates to its anti-venous thrombotic activity, its activity to inhibit the expression of GPIIb / IIIa, and its activity to inhibit the expression of P-selectin. Therefore, the present invention relates to its application in the preparation of anti-arterial thrombosis drugs, the application in the preparation of anti-venous thrombosis drugs, the application in the preparation of GPIIb / IIIa antagonists and the application in the preparation of P-selectin antagonists. The invention belongs to the field of biomedicine. Background technique [0002] The formation of thrombus is the main cause of myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis and other cardiovascular diseases, and is the main cause of global morbidity and mortality. Although the current...

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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