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(3S)-N-(L-aminoacyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, preparation method and uses thereof

An alanyl and glycyl-based technology, applied in the field of biomedicine, can solve the problems of low solubility, poor solubility, complex preparation process, etc., and achieve good thrombolytic activity, good antithrombotic activity, and bioavailability high effect

Inactive Publication Date: 2008-06-18
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

For 1,2,3,4-tetrahydro-β-carboline-3-S-carboxylic acid has low bioavailability caused by poor solubility in polar solvents and non-polar solvents. (3S)-1,2,3,4-Tetrahydro-beta-carboline-3-carboxylic acid introduces L-amino acid to obtain a class of antithrombotic agent, although the obtained above-mentioned antithrombotic agent has good antithrombotic Thrombotic activity, but due to the complex structure of (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid, the antithrombotic agent prepared from this also has a complex structure , the resulting problem is that the preparation process is complicated, which will inevitably increase the production cost
If the pyrrole ring is removed from the (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid structure, one is the resulting (3S)-1,2,3,4- Whether tetrahydroisoquinoline-3-carboxylic acid also has antithrombotic activity is obviously unpredictable, and the second is (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid whether In polar solvents or in non-polar solvents, its solubility is not good, so that the bioavailability is not high

Method used

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  • (3S)-N-(L-aminoacyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1 Preparation of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

[0044]To 5.0g (0.03mmol) L-phenylalanine, first add 27ml formaldehyde dropwise, and then add 45ml concentrated hydrochloric acid dropwise. The resulting suspension was heated in an oil bath to 80-90°C and stirred for 10 h, TLC (CCl 3 :CH 3 OH=10:1) showed the disappearance of phenylalanine. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with water (30ml×3) and then with acetone (30ml×3) to obtain 4.5g (83.9%) of the title compound as a colorless solid. Mp.302-303; ESI-MS (m / e) 178 [M+H] + ; 1 HNMR (CDCl 3 -d) δ / ppm=11.0(s, 1H), 7.0(m, 4H), 3.80(m, 3H), 3.03(d.1H), 2.78(d, 1H), 2.0(s, 1H); 13 C-NMR (CDCl 3 -d) δ / ppm=174.9, 136.2, 134.2, 127.2, 126.0, 57.6, 47.4, 29.4.

Embodiment 2

[0045] Example 2 Preparation of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester

[0046] Add 5.2ml of thionyl chloride dropwise to 20ml of methanol in an ice-salt bath, and stir for 10min after the dropping. Afterwards, 4.27 g (20 mmol) of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid were added. The reaction mixture was stirred at room temperature for 100 h, TLC (CCl 3 :CH 3 OH=5:1) showed the disappearance of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 20 ml of methanol and concentrated under reduced pressure. This operation was repeated 3 times. The residue was dissolved in 20 ml of ether and concentrated under reduced pressure. This operation was repeated 3 times. The residue was crystallized from methanol / ether to afford 4.2 g (92%) of the title compound as a colorless solid. ESI-MS(m / e)192[M+H] + ; 1 HNMR (CDCl 3 -d) δ / ppm=7.0(m, 4H)...

Embodiment 3

[0047] Example 3 Preparation of (3S)-N-(Boc-L-alanyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester (1a) 0.832g (4.4mmol) Boc-Ala-OH was dissolved in 10 ml tetrahydrofuran (THF). To the resulting solution was added 0.594 g (4.4 mmol) of N-hydroxybenzotriazole (HOBt) under ice cooling. Stir. Mix 0.91g (4.0mmol) (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester with 5ml THF first, then adjust the pH to 8-9 with triethylamine, and stir for 30min Then it was mixed with the newly obtained Boc-Ala-OH solution under ice bath, and then 1.071 g (5.2 mmol) of dicyclohexylcarbodiimide (DCC) was added. The reaction mixture was stirred in ice bath for 2 h and at room temperature for 12 h. TLC (ethyl acetate:petroleum ether=1:2) showed that methyl (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate disappeared. Dicyclohexylurea (DCU) was filtered off, and the filtrate was subconcentrated to dryness. The residue was dissolved with 50ml ethyl acetate, and t...

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Abstract

The invention discloses a compound with general formula (I) of anti-thrombus activity. The invention also discloses a preparation method of the compound and the application as the anti-thrombus agent. The invention introduces the amino acid residues into the second N of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid to prepare the compound with general formula (I) of the invention. The compound of the invention not only has the good anti-thrombus activity, but also has the simpler structure and the lower preparation cost by comparing with the anti-thrombus agent prepared by the L-amino acid modification of (3S)-1,2,3,4-tetrahydro-Beta-carboline-3-carboxylic acid. Moreover, whether in the polar solvent or the non-polar solvent, the compound with the general formula (I) of the invention has the good solubility and high bioavailability.

Description

technical field [0001] The present invention relates to heterocyclic compounds, in particular to (3S)-N-(L-aminoacyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, its preparation method and its antithrombotic agent The application belongs 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). For 1,2,3,4-tetrahydro-β-carboline-3-S-carboxylic acid has low bioavailability caused by poor solubility in polar solvents and non-polar solvents. (3S)-1,2...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/06A61K38/05A61P7/02
Inventor 彭师奇赵明崔国辉郑美青
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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