Beta-tetrahydro carboline carboxylic acid, its RGD conjugate, their synthesis and medical application

A tetrahydrocarboline carboxylic acid and medical technology, which is applied in the field of β-tetrahydrocarboline carboxylic acid and its RGD conjugates, can solve the problems of poor water solubility and inconvenient biological activity determination, etc.

Inactive Publication Date: 2002-09-25
ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The inventor synthesized tetrahydrocarboline carboxylic acid through the Pictet-Spengler reaction, and found that the water solubility of the compound obtained by conventional methods is extremely poor, and it is inconvenient to carry out various biological activity assays

Method used

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  • Beta-tetrahydro carboline carboxylic acid, its RGD conjugate, their synthesis and medical application
  • Beta-tetrahydro carboline carboxylic acid, its RGD conjugate, their synthesis and medical application
  • Beta-tetrahydro carboline carboxylic acid, its RGD conjugate, their synthesis and medical application

Examples

Experimental program
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Embodiment 1

Embodiment 2

[0015] 25ml of 1N H2SO4, add 5g (24.5mmol) tryptophan while stirring, add 75ml of water, 4ml (45.6mmol) 38% formaldehyde solution, the reaction solution becomes clear, and a large amount of solids are precipitated in about 5Min. After reacting for 4 hours, add dropwise 8ml of concentrated ammonia water, adjust the pH to nearly neutral, let stand overnight, filter with suction, wash the filter cake with a small amount of cold water, drain, and then dry to obtain 5.1g of solid (1) (light yellow powder, yield 96%) MP: 280 -282 C; EI-MS: 217 (M+1); H-NMR (DMSO): δ10.99 (1H, s), 7.44 (1H, d, 7.5), 7.33 (1H, t, 8.0), 7.08 (1H, t, 8.0), 6.99 (1H, t, 7.5), 4.22 (1H, d, 4.8), 3.69 (1H, dd, 10.5, 5.0), 3.14 (1H, dd, 10.5, 2.4), 2.83 ( 1H, ddd, 10.5, 5.0, 2.4) Example 2: Preparation of N-Boc-β-tetrahydrocarbolinecarboxylic acid (2)

Embodiment 3

[0016] Suspend 1.1g (5mmol) of compound 87 in 15ml of DMF, add 1.4ml of triethylamine, stir under ice bath until the suspended particles in the solution are uniform in size, add 1.1g (7.7mmol) Boc-N3 dropwise within 30min, and rise to to 40°C, after 3 days, add 5ml of 20% citric acid aqueous solution, extract with ethyl acetate, organic layer is dried with MgSO4, filtered, the filtrate is distilled to dryness under reduced pressure, and the residue is recrystallized with CHCl3 to obtain the title compound 0.9g (56% )mp165-170 TOF-MS: 317[M+1] + , 339[M+Na] + , 355[M+K] 1 H-NMR (DMSO-d 6 ).1.46(s, 9H, -Boc), 3.25~3.34(m, 2H, 4-H), 4.29~4.75(m, 2H, 1-H), 5.02~5.14(m, 1H, 3-H) , 6.92~7.41 (m, 4H, Ar-H (5, 6, 7, 8)), 10.87 (s, 1H, 9-H), 12.77 (s, 1H, -COOH) Example 3: β-four Preparation of Hydrocarboline Carboxylic Acid Nanoparticles (1)

[0017] Add 0.05ML concentrated H2SO4 to 10ML deionized water, add 1G L-tryptophan while stirring, then add 20ML toluene, 0.02ML TWEEN80, s...

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Abstract

The present invention relates to the synthesis of beta-tetrahydro carboline carboxylic acid and its nanoparticle preparation; liquid phase process of gradually grafting peptide to obtain protected tetrapeptide intermediate, which, after eliminating its Boc, is condensated with N-Boc-beta-tetrahydro carboline carboxylic acid and further HF treated to eliminate its protection to obtain the said compound; the nanoparticle of tetrahydro carboline carboxylic acid and the in-vitro and in-vivo activity of said compound in-vitro and in-vivo experiments show that the compound of the present invention has excellent activity of resisting blood platelet aggregation, effect of resisting cell adhesion and effect of resisting thrombus.

Description

field of invention [0001] The present invention relates to β-tetrahydrocarboline carboxylic acid and its RGD conjugates, their synthesis and their application in medicine. technical background [0002] Platelet aggregation plays an important role in thrombus formation. Normal platelets are activated by prothrombin, adenosine diphosphate, or collagen to release arachidonic acid (AA). AA is catalyzed by cyclooxygenase to generate endoperoxide (PGH2). PGH2 generates thromboxane A2 (TXA2) under the action of isomerase, causing platelet aggregation and adhesion. After platelet activation, surface glycoprotein IIb / IIIa (GP IIb / IIIa) receptors are exposed, undergo a conformational change, and bind to fibrinogen, leading to thrombus formation. [0003] In the process of studying the combination of GP IIb / IIIa receptors with fibrin α chain and γ chain, it was found that the RGD sequence in fibrin is the key sequence that mediates its own combination with GP IIb / IIIa (SamanenJ., et...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07K5/10
Inventor 彭师奇赵明王超琳娜吴国锋
Owner ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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