(3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid kyrine conjugate, preparation method and application thereof

A tetrahydroisoquinoline, -aa1-aa2-arg technology, applied in the field of conjugates and antithrombotic agents, can solve the problems of low water solubility and low bioavailability

Inactive Publication Date: 2010-12-01
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
View PDF0 Cites 19 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Although (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid has antithrombotic activity, but has defects such as low water solubility and low bioavailability, the present invention uses (3S)-1 , The structure of 2,3,4-tetrahydroisoquinoline-3-carboxylic acid is modified to improve (3S)-1,2,3,4-tetrahydroisoquinoline under the premise of ensuring its antithrombotic activity - Absorption of 3-carboxylic acids, increasing the bioavailability of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid kyrine conjugate, preparation method and application thereof
  • (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid kyrine conjugate, preparation method and application thereof
  • (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid kyrine conjugate, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 Preparation of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

[0027] To 4.0 g (24.2 mmol) of L-phenylalanine, 21.6 ml of formaldehyde was first added dropwise, and then 36 ml of 35% concentrated hydrochloric acid was added dropwise. The obtained suspension was heated in an oil bath to 90-100°C and stirred for 2 hours to completely dissolve the phenylalanine. After 2.5 hours of reaction, a white precipitate began to form. After 7 hours of reaction, TLC (CHCl 3 / CH 3OH=5 / 1) showed the disappearance of L-phenylalanine, suction filtered to obtain 4.2g light yellow solid, which was dried, and then the gained egg yellow solid was added to 86ml of ethanol (80%) and heated in an oil bath at 80°C to The colorless solid was dissolved, cooled to room temperature, and 2mol / ml NaOH potassium hydroxide solution was slowly added dropwise, and a colorless precipitate was precipitated. When the precipitate reached the maximum, 4.17 g (97.5%) of the title compound was...

Embodiment 2

[0028] Example 2 Preparation of (3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

[0029] Dissolve 2.49g (62.15mmol) sodium hydroxide into 62.2ml water under ice bath, then add 10g (56.49mmol) (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid to prepare suspension. Dissolve 14.8g (67.8mmol) (Boc) in 40ml tetrahydrofuran 2 O, added to the suspension. The reaction mixture was stirred for 24 hours, and the CO produced by the reaction was continuously removed during the reaction. 2 , when the solution became clear, TLC (methanol / chloroform: 1:10) showed that (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid disappeared, and the reaction was stopped. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran, and the resulting oil was dissolved in ethyl acetate. The resulting solution was sequentially washed with 5% KHSO 4 Wash with saturated NaCl aqueous solution. The organic layer was dried over anhydrous sodium sulfate, filter...

Embodiment 3

[0030] Example 3 Preparation of N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl]-glycine methyl ester

[0031] Add 0.151g (1.109mmol ) N-hydroxybenzotriazole (HOBt), after stirring for 10 minutes, add 0.228g (1.08mmol) dicyclohexylcarbodiimide (DCC) to obtain the reaction solution (I). Suspend 0.136g (0.102mmol) of HCl·Gly-OMe in 4ml of anhydrous THF, add 1ml of N-methylmorpholine (NMM) to adjust the pH value to 8-9, and stir to obtain the reaction solution (II). Add (I) into (II), stir at room temperature for 12h, TLC (ethyl acetate / petroleum ether, 1:3) showed that (3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline- 3-Carboxylic acid disappears. Dicyclohexylurea (DCU) was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was dissolved in 50 ml of ethyl acetate. The resulting solution was sequentially washed with 5% NaHCO 3 Wash 3 times with aqueous solution, 3 times with saturated NaCl aqueous solution, 5% KHSO 4 Wash 3 times wi...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
particle diameteraaaaaaaaaa
Login to view more

Abstract

The invention discloses a (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid kyrine conjugate, a preparation method and application thereof. The preparation method of the conjugate comprises the following steps of: preparing N-[(3S)-N-Boc-1,2,3,4- tetrahydroisoquinoline-3-formoxyl]-AA1-AA2-Arg (NO2)-OBzl by coupling N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formoxyl]-AA1 and AA2-Arg (NO2)-OBzl; and detracting a protecting group, wherein AAl is selected from Gly, Asp or Gln, and AA2 is selected from Gly, Asp or Gln. The conjugate has excellent antithrombotic activity, can be clinically used as an antithrombotic agent, can be automatically assembled into nano particles in a water solution and is stable in the water solution; and the particle diameter is mostly from 200nm to 600nm.

Description

field of invention [0001] The present invention relates to a class of conjugates with antithrombotic activity, in particular to conjugates obtained by coupling (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid with tripeptide , the present invention also relates to the preparation method of the conjugate and the application of the conjugate as an antithrombotic agent, belonging to the field of biomedicine. Background technique [0002] Vascular embolism is most responsible for the high mortality rate of cardiovascular and cerebrovascular diseases. Thrombosis is the most important etiology of vascular embolism disease. Finding antithrombotic drugs is one of the hot spots in new drug research. The inventors have noticed that 1,2,3,4-tetrahydro-β-carboline-3-S-carboxylic acid is a component in the traditional Chinese medicine Allium, which has anti-platelet aggregation activity (Yao Xinsheng et al., Chinese Journal of Medicinal Chemistry, 1995, 5, 134). The inventors be...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/083C07K5/093C07K1/06A61K38/06A61P7/02
CPCY02P20/55
Inventor 赵明彭师奇张建伟姜南
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap