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TRGD peptide-modified carbolino-hexahydropyrazine-1,4-diketones and their preparation method, antithrombotic effect and use

A technology of hexahydropyrazine and antithrombotic activity, which is applied in the field of biomedicine and can solve the problems of no antithrombotic compounds

Inactive Publication Date: 2013-12-18
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although inhibition of insoluble P-selectin expression and cleavage to soluble P-selectin is considered an important target for the design of antithrombotic drugs, few antithrombotic compounds have been linked to this target

Method used

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  • TRGD peptide-modified carbolino-hexahydropyrazine-1,4-diketones and their preparation method, antithrombotic effect and use
  • TRGD peptide-modified carbolino-hexahydropyrazine-1,4-diketones and their preparation method, antithrombotic effect and use
  • TRGD peptide-modified carbolino-hexahydropyrazine-1,4-diketones and their preparation method, antithrombotic effect and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 Preparation of (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (1)

[0029] Put 400ml of water in a 500ml eggplant bottle, and slowly add 0.2ml of concentrated sulfuric acid. Add 5.0 g (24.5 mmol) of L-tryptophan to the obtained dilute sulfuric acid aqueous solution, and ultrasonically shake until the L-tryptophan is completely dissolved. 7.5 ml of 40% formaldehyde solution was added to the solution, and the reaction mixture was stirred at room temperature for 6 hours. The disappearance of L-tryptophan was detected by thin-layer chromatography, and the reaction was terminated. Concentrated ammonia water was slowly added dropwise to the reaction solution, the pH of the reaction mixture was adjusted to 6, and the reaction mixture was allowed to stand for 0.5 hours. Suction filtration under reduced pressure, the obtained precipitate was washed with water, and the filtered colorless solid was spread on a petri dish, and air-dried to obtain 5.14 g (97%) of t...

Embodiment 2

[0030] Example 2 Preparation of (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid methyl ester (2)

[0031] Add 50ml of methanol to a 100ml eggplant bottle, cool to below 0°C with an ice-salt bath, add 6ml (87mmol) SOCl dropwise under stirring 2 10 minutes after the dropwise addition, 5.0 g (23.1 mmol) (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid was added, the ice bath was removed, and the mixture was stirred overnight at room temperature. Stop the reaction after TLC monitors that the raw materials basically disappear, and the water pump depressurizes to extract methanol and excess SOCl 2 , the residue was dissolved in methanol, and the circulating water vacuum pump was used for three times (10ml×3). The residue was added with diethyl ether, and the circulating water was vacuum pumped, and repeated three times (10ml×3). Add 20ml of water and 20ml of ethyl acetate to the residue, and add saturated NaHCO 3 Adjust the pH of the solution to 7-8, separate the layers...

Embodiment 3

[0032] Example 3 Preparation of (3S)-N-[Boc-Asp(OBzl)]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid methyl ester (3)

[0033] Dissolve 1.61g (5mmol) Boc-Asp (OBzl) in 50ml of anhydrous dichloromethane, add 742mg (6mmol) HOBt and 1.42g (6mmol) DCC under ice-cooling, stir for 5-10 minutes and the reaction solution becomes turbid, add 1.15 g (5 mmol) (3S)-methyl 1,2,3,4-tetrahydro-β-carboline-3-carboxylate, the ice bath was removed after 30 minutes. After reacting at room temperature for 12 hours, TLC showed that the starting point disappeared, the reaction was stopped, DCU was filtered off, the filtrate was concentrated to dryness at 30°C under reduced pressure, and the residue was dissolved in ethyl acetate. Then successively washed three times with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, 5% aqueous potassium hydrogensulfate solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride soluti...

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Abstract

The invention discloses TRGD peptide-modified carbolino-hexahydropyrazine-1,4-diketones, which are three novel conjugates of carbolino-hexahydropyrazine-1,4-diketone and TRGD peptide and are shown in the general formula I. In the general formula I, R represents Thr-Arg-Gly-Asp-Val, Thr-Arg-Gly-Asp-Phe or Thr-Arg-Gly-Asp-Ser. The invention also discloses heterocyclic nucleuses of the novel conjugates, wherein R represents OH. The invention also discloses a preparation method and in-vitro anti-platelet aggregation effects of the novel conjugates, and also discloses an antithrombotic use of the novel conjugates in a rat thrombus formation model. A result shows that the three novel conjugates of carbolino-hexahydropyrazine-1,4-diketone and TRGD peptide (wherein R represents Thr-Arg-Gly-Asp-Val, Thr-Arg-Gly-Asp-Phe or Thr-Arg-Gly-Asp-Ser) and their heterocyclic nucleuses (wherein R represents OH) have good antithrombotic activity and clear application prospects in antithrombotic agent preparation.

Description

technical field [0001] The present invention relates to (R represents Thr-Arg-Gly-Asp-Val, Thr-Arg-Gly-Asp-Phe and Thr-Arg-Gly-Asp-Ser) carboline hexahydropyrazine-1 represented by general formula 1 , three novel conjugates of 4-diketones and RGD peptides, and their heterocyclic nuclei (R represents OH), their preparation methods, their in vitro antiplatelet aggregation, and their in vitro Antithrombotic effect on a thrombosis model. The results show that (R represents Thr-Arg-Gly-Asp-Val, Thr-Arg-Gly-Asp-Phe and Thr-Arg-Gly-Asp-Ser) carboline hexahydropyrazine of general formula 1 of the present invention Three novel conjugates of -1,4-diketones and RGD peptides and their heterocyclic cores (R represents OH) have good antithrombotic activity and have clear application prospects in the preparation of antithrombotic agents. The invention belongs to the field of biomedicine. [0002] Background technique [0003] Globally, the morbidity and mortality of thrombotic diseas...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07D471/14A61K38/08A61K31/4985A61P7/02
Inventor 赵明彭师奇王玉记吴建辉韩爽
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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