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(3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives, and synthesis method and application thereof

A technology of tetrahydrocarboline and 4-b, which can be applied in drug combinations, blood diseases, extracellular fluid diseases, etc., and can solve the problems of poor water solubility of antithrombotic active polycyclic nuclei

Inactive Publication Date: 2011-11-09
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The inventors found that (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivative hexahydro-pyrazino-pyrido-indoledione has antithrombotic activity and polycyclic parent Poor nuclear water solubility

Method used

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  • (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives, and synthesis method and application thereof
  • (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives, and synthesis method and application thereof
  • (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives, and synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1 Preparation of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

[0039] Put 400ml of water in a 500ml round bottom 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. 10 ml of 35% 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 reaction mixture was adjusted to pH 6, and left to stand for half an hour. The precipitate obtained by suction filtration under reduced pressure was washed with water, and the filtered colorless solid was spread on a petri dish and air-dried to obtain S-carbolinecarboxylic acid, which was 5.0...

Embodiment 2

[0040] Example 2 Preparation of (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid methyl ester

[0041] 50ml of methanol was cooled to below 0°C with an ice-salt bath, and 10ml (145mmol) of SOCl was added dropwise while 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 checks that the raw materials basically disappear, and evaporate the solvent methanol and excess SOCl under reduced pressure with a water pump 2 , and then entrained with methanol three times (10ml×3). Add 20ml water and 20ml ethyl acetate to the reaction flask, and add NaHCO 3 Adjust the pH to 7-8, extract the aqueous layer with ethyl acetate (20ml×3), combine the organic layers, wash with saturated sodium chloride three times, and anhydrous NaCl 2 SO 4 After drying and filtering, the filtrate was concentrated...

Embodiment 3

[0042] Example 3 Preparation of (3S)-N-[Boc-(Z)lysyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid methyl ester (1)

[0043] Dissolve 798mg (1.05mmol) Boc-(Z) lysine in 4ml of anhydrous THF, add 433mg (2.10mmol) DCC and 270mg (2mmol) HOBt under ice-cooling, stir for 5-10 minutes and the reaction solution becomes turbid, add 460mg ( 3S)-methyl 1,2,3,4-tetrahydro-β-carboline-3-carboxylate, adjust the pH of the reaction solution to 8-9 with NMM, and remove the ice bath 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. Wash successively with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, 5% aqueous potassium hydrogensulfate solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous so...

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Abstract

The invention discloses (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives, and a synthesis method and application thereof. The structural formula of the compounds is shown as a general formula I. Hexa hydro-pyrazino-pyridino-indoldione compounds are structurally modified by natural amino acid, the water solubility and in-vivo absorption are improved and the anti-thrombotic activity is improved. In-vitro and in-vivo anti-thrombotic activity experiments indicate that the compounds in the general formula I have excellent anti-thrombotic activity, and can be prepared into anti-thrombotic medicines.

Description

technical field [0001] The present invention relates to (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives and a synthesis method thereof, in particular to hexahydropyrazino[1',2':1,6] Pyrido[3,4-b]indole-1,4-dione compound and its synthesis method, the present invention also relates to the disclosure of hexahydropyrazino[1',2':1,6]pyrido The application of [3,4-b]indole-1,4-dione derivatives as antithrombotic agents, the present invention belongs to (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Derivatives field. Background technique [0002] Thromboembolic disease is a serious threat to human health and life safety. It is manifested in the blockage of blood vessels by embolism formed in the blood, which can affect various organs and systems of the whole body, and its morbidity, disability and mortality are very high. At present, antithrombotic and thrombolytic drugs commonly used in clinical practice have various shortcomings, such as bleeding, gas...

Claims

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Application Information

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IPC IPC(8): C07D471/14A61K31/4985A61P7/02
Inventor 赵明彭师奇刘菲
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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