1R-methyl-beta-tetrahydrocarbolineacyl-K(QRPAK)-RGDV, and synthesis, activity and application thereof

A -arg-gly-asp-val, methyl technology, applied in 1R-methyl-β-tetrahydrocarbolinyl-K(QRPAK)-RGDV, its synthesis, activity and application fields, can solve the difficulty of preservation , sensitive to reducing environment, difficult preparation and other problems

Inactive Publication Date: 2018-12-07
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

That is, the free radicals of 1,3-dioximidazoline are sensitive to the reducing environment, which is not only difficult to prepare, but also difficult to store

Method used

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  • 1R-methyl-beta-tetrahydrocarbolineacyl-K(QRPAK)-RGDV, and synthesis, activity and application thereof
  • 1R-methyl-beta-tetrahydrocarbolineacyl-K(QRPAK)-RGDV, and synthesis, activity and application thereof
  • 1R-methyl-beta-tetrahydrocarbolineacyl-K(QRPAK)-RGDV, and synthesis, activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Example 1 Preparation of 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid benzyl ester

[0017] At 60° C., 1 mL of 98% concentrated sulfuric acid was added dropwise to 800 mL of distilled water, and after stirring, 10.0 g (34 mmol) of L-Trp-OBzl was added in three times. Stir for five minutes to fully suspend L-Trp-OBzl and sulfuric acid aqueous solution. After that, 10 mL of 40% acetaldehyde aqueous solution was added dropwise to the suspension. The reaction mixture was first stirred at 60°C for 12 hours, and then 3 mL of concentrated ammonia was added dropwise to adjust the pH of the reaction solution to 8. The reaction compound is allowed to stand for 1 hour, and the product is fully analyzed. The solid was filtered and dried to obtain 9.84 g (90%) of a pale yellow solid, which was 1R-methyl-1,2,3,4-tetrahydro-β-carboline-3S-carboxylic acid benzyl ester and 1S-methyl -A mixture of 1,2,3,4-tetrahydro-β-carboline-3S-carboxylic acid benzyl ester. ESI-MS(m / e):3...

Embodiment 2

[0018] Example 2 Preparation of N-Boc-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid benzyl ester (1)

[0019] The 9.84 g (30.8 mmol) 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid benzyl ester obtained in Example 1 was used with 20 mL of N,N-dimethylformamide ( DMF) dissolved. Add 6.98g (32.0mmol) Boc to the solution at 0℃ 2 O. The resulting solution was adjusted to pH 12 with triethylamine and stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was dissolved with 100 mL ethyl acetate. The obtained ethyl acetate solution was washed with 5% potassium hydrogen sulfate aqueous solution (50 mL×3) and saturated sodium chloride aqueous solution (50 mL×3) successively. The separated ethyl acetate layer was dried over anhydrous sodium sulfate for 12 h, filtered, and the filtrate was concentrated under reduced pressure to obtain an oily substance. The oil was separated with a silica g...

Embodiment 3

[0022] Example 3 Preparation of Boc-1R-methyl-1,2,3,4-tetrahydro-β-carboline-3S-carboxylic acid (2)

[0023] Add 100mg Pd / C to 1g (2.38mmol) N-Boc-1R-methyl-1,2,3,4-tetrahydro-β-carboline-3S-benzyl carboxylate and 40mL anhydrous tetrahydrofuran , Stir to make a uniform suspension. The air in the reaction system was evacuated under reduced pressure, hydrogen was introduced, and stirred at room temperature for 10 hours. TLC (dichloromethane / methanol, 40 / 1) showed N-Boc-1R-methyl-1,2,3,4-tetrahydro- β-carboline-3S-carboxylic acid benzyl ester disappeared completely. Pd / C was removed by filtration, and the filtrate was concentrated under reduced pressure. The ESI-MS (m / e) of the colorless powder obtained was 329[M-H] - .

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Abstract

The invention discloses 1R-methyl-1,2,3,4-tetrahydro-beta-carboline-3S-acyl-Lys(Gln-Arg-Pro-Ala-Lys)-Arg-Gly-Asp-Val, a preparation method, antithrombotic activity and thrombolytic activity thereof, and application of the compound in treating rats with a 24-hour stroke. Thus the invention discloses application of the compound in preparation of antithrombotic drugs, thrombolytic drugs and drugs fortreatment of ischemic strokes. The compound has a formula shown in the description.

Description

Technical field [0001] The present invention relates to 1R-methyl-1,2,3,4-tetrahydro-β-carboline-3S-acyl-Lys(Gln-Arg-Pro-Ala-Lys)-Arg-Gly-Asp-Val, to Its preparation method relates to its antithrombotic activity, relates to its thrombolytic activity and relates to its treatment of stroke in rats for 24 hours, so the present invention relates to its preparation of antithrombotic drugs, thrombolytic drugs and treatment of ischemic stroke Application in medicine. The invention belongs to the field of biomedicine. Background technique [0002] Ischemic stroke is a relatively common and serious cerebrovascular disease, which is characterized by high morbidity, mortality, disability and recurrence. At present, the clinical treatment of ischemic stroke is facing the reality that there is no effective drug, especially the patients with stroke more than 4 hours are either dead or disabled. It is an important clinical need to invent effective drugs for patients with strokes for more tha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/60A61K38/12A61P7/02
CPCA61K38/00C07K7/60
Inventor 彭师奇赵明王玉记吴建辉张筱宜桂林王晓珍
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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