Hybridized peptide with 3S-tetrahydrochysene-beta-carboline-3-carboxylic acid as connecting arm, preparation method and application thereof

A carboline and carboxylic acid technology, applied in the field of hybrid peptides, can solve problems such as difficulty in detection, and achieve the effect of excellent thrombolytic activity

Inactive Publication Date: 2008-12-10
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] P6A and its analogs as the lead structure of thrombolytic oligopeptides and the metabolites of P6A as the lead structure of thrombolytic oligopeptides have inherent room for improvement, that is, the difficulties in their detection caused by proteins and peptides existing in the body, and LC / MS detection The resulting technical and economic difficulties are subject to improvement

Method used

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  • Hybridized peptide with 3S-tetrahydrochysene-beta-carboline-3-carboxylic acid as connecting arm, preparation method and application thereof
  • Hybridized peptide with 3S-tetrahydrochysene-beta-carboline-3-carboxylic acid as connecting arm, preparation method and application thereof
  • Hybridized peptide with 3S-tetrahydrochysene-beta-carboline-3-carboxylic acid as connecting arm, preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1B

[0026] The preparation of embodiment 1Boc-Pro-Ala-Lys(Z)-OBz

[0027] 1) Preparation of Boc-Ala-Lys(Z)-Obzl

[0028] Dissolve 473mg (2.5mmol) Boc-Ala-OH in 10ml anhydrous tetrahydrofuran (THF), add 10ml 338mg (2.5mmol) N-hydroxybenzotriazole (HOBt) and 619mg (3mmol) dicyclohexyl Anhydrous tetrahydrofuran (THF) solution of carbonyldiimide (DCC). The reaction mixture was stirred in an ice bath for 20 minutes to obtain the corresponding active ester solution for use.

[0029]936mg (2.3mmol) HCl·Lys(Z)-OBzl and 232mg (2.3mmol) N-methylmorpholine were first miscible with 6ml of anhydrous THF, and then with the active ester solution to be used above. The resulting reaction mixture was reacted at room temperature for 24 hours. TLC (developer CHCl3:MeOH=20:1) showed that HCl·Lys(Z)-OBzl disappeared. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed...

Embodiment 2B

[0035] Embodiment 2Boc-Arg (NO 2 Preparation of )-Pro-Ala-Lys(Z)-OBzl

[0036] 1) Preparation of HCl Pro-Ala-Lys(Z)-OBzl

[0037] A mixture of 1.596g (2.5mmol) Boc-Pro-Ala-Lys(Z)-OBzl and 15ml hydrogen chloride-ethyl acetate solution (4N) was stirred for 1 hour under ice-bath conditions, TLC (developing agent CHCl 3 :MeOH=20:1) showed that Boc-Pro-Ala-Lys(Z)-OBzl disappeared. Drain the reaction solution with a water pump, add anhydrous ether, and drain the reaction solution with a water pump again, repeating 5 times. The residue was soaked and washed with anhydrous ether, rubbed with a plastic shovel, and poured out of anhydrous ether, repeated 5 times. The obtained title compound was directly used in the next reaction.

[0038] 2) Preparation of Boc-Arg(NO 2 )-Pro-Ala-Lys(Z)-OBzl

[0039] 798mg (2.5mmol) Boc-Arg (NO 2 )-OH was dissolved in 10ml of anhydrous THF, and 10ml of anhydrous THF solution of 338mg (2.5mmol) HOBt and 619mg (3mmol) of DCC was added under ice cool...

Embodiment 3B

[0041] Embodiment 3Boc-Ala-Arg (NO 2 Preparation of )-Pro-Ala-Lys(Z)-OBzl

[0042] 1) Preparation of HCl Arg (NO 2 )-Pro-Ala-Lys(Z)-OBzl

[0043] 2.099g (2.5mmol) Boc-Arg (NO 2 )-Pro-Ala-Lys(Z)-OBzl and 15ml of hydrogen chloride-ethyl acetate solution (4N) was stirred for 1 hour under ice-bath conditions, TLC (developing agent CHCl 3 : MeOH=10:1) shows that Boc-Arg (NO 2 )-Pro-Ala-Lys(Z)-OBzl disappeared. Drain the reaction solution with a water pump, add anhydrous ether, and drain the reaction solution with a water pump again, repeating 5 times. The residue was soaked and washed with anhydrous ether, rubbed with a plastic shovel, and poured out of anhydrous ether, repeated 5 times. The obtained title compound was directly used in the next reaction.

[0044] 2) Boc-Ala-Arg (NO 2 Preparation of )-Pro-Ala-Lys(Z)-OBzl

[0045] Dissolve 473mg (2.5mmol) of Boc-Ala-OH in 10ml of anhydrous THF, and add 10ml of anhydrous THF solution containing 338mg (2.5mmol) of HOBt and 619...

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Abstract

The invention discloses a general formula I compound and a general formula II compound having thrombus dissolving activity, a preparation method thereof and an application thereof as thrombus dissolving agent. The invention adopts a rat carotid-jugular vein bypass intubation thrombus model to evaluate the thrombus dissolving activity of the general formula I compound and the general formula II compound respectively. Animal experimental results show that: both the general formula I compound and the general formula II compound have excellent thrombus dissolving activity and can be applied to clinical practice as a thrombus dissolving agent.

Description

technical field [0001] The present invention relates to a hybrid peptide, in particular to a hybrid peptide with 3S-tetrahydro-β-carboline-3-carboxylic acid as a linking arm and a preparation method thereof. The present invention also relates to the application of the hybrid peptide as a thrombolytic agent , belonging to the field of medicine. Background technique [0002] Streptokinase, urokinase, recombinant tissue plasminogen activator and other drugs currently used clinically for the treatment of acute thromboembolic diseases generally have systemic hemorrhage tendency and immunogenic reactions. Finding safe and effective thrombolytic drugs is the goal of new drug research. One of the hot spots. The inventors used the fibrin degradation product P6A (ARPAK) as the leading structure, modified the structure through liquid phase synthesis, and obtained a series of oligopeptides (inventors: Peng Shiqi, Zhao Ming, Wang Chao, Tang Chaoshu, Wang Yinye; invention name: Cardiovas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06A61K38/08A61P7/02
CPCY02P20/55
Inventor 彭师奇赵明崔国辉温敏
Owner PEKING UNIV
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