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Compounds with thrombolytic activities and preparation methods and applications thereof

A compound, the technology of suppository activity, applied in the field of medicinal chemistry

Inactive Publication Date: 2011-11-16
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, streptokinase, urokinase, and tissue plasminogen activator, which are currently used in the treatment of embolic diseases, generally have bleeding tendency and immunogenic reactions, and there have always been safety issues

Method used

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  • Compounds with thrombolytic activities and preparation methods and applications thereof
  • Compounds with thrombolytic activities and preparation methods and applications thereof
  • Compounds with thrombolytic activities and preparation methods and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0042] Example 2 Boc-Arg(NO 2 )-Pro-Ala-Lys(Z)-OBzl preparation

[0043] 1) Preparation of HCl·Pro-Ala-Lys(Z)-OBzl

[0044] A mixture of 1.596g (2.5mmol) Boc-Pro-Ala-Lys(Z)-OBzl and 15ml of hydrogen chloride-ethyl acetate solution (4N) was stirred at room temperature for 3 hours, TLC (developing solvent chloroform: methanol = 10:1) showed Boc-Pro-Ala-Lys(Z)-OBzl disappeared. The reaction solution was drained by a water pump, ethyl acetate was added, and the reaction solution was drained by a water pump. Repeat 5 times. The residue was soaked and washed with anhydrous ether, and the reaction solution was drained again with a water pump, repeated 5 times. The obtained title compound was directly used in the next reaction.

[0045] 2) Preparation of Boc-Arg(NO 2 )-Pro-Ala-Lys(Z)-OBzl

[0046] Add 798mg (2.5mmol) Boc-Arg(NO 2 )-OH was dissolved in 10ml anhydrous THF, and 10ml 338mg (2.5mmol) HOBt and 619mg (3mmol) DCC in anhydrous THF were added to it under ice bath. The reaction mixt...

Embodiment 3

[0050] Example 3 Boc-Ala-Arg(NO 2 )-Pro-Ala-Lys(Z)-OBzl preparation

[0051] 1) Preparation of HClArg(NO 2 )-Pro-Ala-Lys(Z)-OBzl

[0052] Add 2.099g (2.5mmol) Boc-Arg(NO 2 )-Pro-Ala-Lys(Z)-OBzl and 15ml hydrogen chloride-ethyl acetate (4N) mixture was stirred at room temperature for 3 hours, TLC (developing solvent chloroform: methanol = 10:1) showed 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, washed with a plastic spatula, and the anhydrous ether was poured out, repeated 5 times. The obtained title compound was directly used in the next reaction.

[0053] 2) Preparation of Boc-Ala-Arg(NO 2 )-Pro-Ala-Lys(Z)-OBzl

[0054] Dissolve 473 mg (2.5 mmol) of Boc-Ala-OH in 10 ml of anhydrous THF, and add 10 ml of an anhydrous THF solution of 338 mg (2.5 mmol) HOBt and 619 mg (3 mmol) DCC in ...

Embodiment 4

[0058] Example 4 Boc-Gly-Arg(NO 2 )-Pro-Ala-Lys(Z)-OBzl preparation

[0059] 1) Preparation of Boc-Gly-Arg(NO 2 )-Pro-Ala-Lys(Z)-OBzl

[0060] Dissolve 438 mg (2.5 mmol) of Boc-Gly-OH in 10 ml of anhydrous THF, and add 10 ml of an anhydrous THF solution of 338 mg (2.5 mmol) HOBt and 619 mg (3 mmol) DCC under ice bath. The reaction mixture was stirred in an ice bath for 20 minutes to obtain the corresponding active ester solution, which was set aside.

[0061] Add 2.025g (2.3mmol) HCl·Arg(NO 2 )-Pro-Ala-Lys(Z)-OBzl and 232mg (2.3mmol) of N-methylmorpholine are first miscible with 6ml of anhydrous THF, and then miscible with the active ester solution to be used above. The resulting reaction mixture was reacted at room temperature for 24 hours. TLC (developer chloroform: methanol = 10:1) showed HCl·Arg(NO 2 )-Pro-Ala-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 wa...

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Abstract

The invention discloses compounds with thrombolytic activities, preparation methods thereof and applications of the compounds as thrombolytic agents. The compounds disclosed by the invention are prepared by coupling or conjugating the 2 nitrogen of cyclized dopa respectively with H-Ala-Arg-Pro-Ala-Lys-OH, H-Pro-Ala-Lys-OH, H-Arg-Pro-Ala-Lys-OH, H-Gly-Arg-Pro-Ala-Lys-OH or H-Gln-Arg-Pro-Ala-Lys-OH. The thrombolytic activities of the compounds disclosed by the invention are evaluated by a rat model with carotid artery and jugular vein bypass catheter thrombosis, and shown by experimental results, the compounds disclosed by the invention have excellent thrombolytic activities and can be applied as thrombolytic agents clinically. The therapeutic actions of the compounds disclosed by the invention on cerebral infarction are further evaluated by a rat model with cerebral thrombosis, and shown by experimental results, the compounds disclosed by the invention all have excellent protective actions on brain tissues and can be applied as cerebral thrombolytic agents clinically.

Description

[0001] This case is a divisional application with the application number "200810057220.2", the application date "January 30, 2008", and the invention title "Compounds with thrombolytic activity, their preparation methods, and their applications". Technical field [0002] The present invention relates to a class of heterocyclic compounds, in particular to a compound having thrombolytic activity obtained by conjugating or coupling with P6A or its analogue after dopa cyclization, and a preparation method of the compound. This aspect also relates to The compound is used as a thrombolytic agent, especially as a therapeutic agent for cerebral thrombosis, and belongs to the field of medicinal chemistry. Background technique [0003] Cerebral thrombosis is characterized by high incidence, high disability and high death. Drug therapy is the main method of clinical treatment of cerebral thrombosis. The development of safe and effective drugs for cerebral thrombosis is one of the hot spots ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K5/097C07K5/11C07K1/107A61K38/06A61K38/07A61K38/08A61P7/02
CPCY02P20/55
Inventor 彭师奇赵明崔国辉杨斌
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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