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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: 2014-02-19
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 tendencies 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 2B

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

[0042] 1) Preparation of HCl Pro-Ala-Lys(Z)-OBzl

[0043] A mixture of 1.596g (2.5mmol) Boc-Pro-Ala-Lys(Z)-OBzl and 15ml hydrogen chloride-ethyl acetate solution (4N) was stirred at room temperature for 3 hours, TLC (developing agent chloroform:methanol=10:1) showed Boc-Pro-Ala-Lys(Z)-OBzl disappears. Drain the reaction solution with a water pump, add ethyl acetate, and drain the reaction solution with 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, and this was repeated 5 times. The obtained title compound was directly used in the next reaction.

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

[0045] 798mg (2.5mmol) Boc-Arg (NO 2 )-OH was dissolved in 10ml of anhydrous THF, and 10ml of 338mg (2.5mmol) HOBt and 619mg (3mmol) of DCC in anhydrous THF were added under ice cooling. The re...

Embodiment 3B

[0049] Embodiment 3Boc-Ala-Arg (NO 2 Preparation of )-Pro-Ala-Lys(Z)-OBzl

[0050] 1) Preparation of HCl Arg (NO 2 )-Pro-Ala-Lys(Z)-OBzl

[0051] 2.099g (2.5mmol) Boc-Arg (NO 2 )-Pro-Ala-Lys(Z)-OBzl and 15ml hydrogen chloride-ethyl acetate solution (4N) was stirred at room temperature for 3 hours, TLC (developing agent chloroform:methanol=10:1) showed 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.

[0052] 2) Preparation of Boc-Ala-Arg (NO 2 )-Pro-Ala-Lys(Z)-OBzl

[0053] Dissolve 473mg (2.5mmol) of Boc-Ala-OH in 10ml of anhydrous THF, and add 10ml of anhydrous THF solution of 338mg (2.5mmol) of HOBt and 619mg (3mmol) ...

Embodiment 4B

[0057] Embodiment 4Boc-Gly-Arg (NO 2 Preparation of )-Pro-Ala-Lys(Z)-OBzl

[0058] 1) Preparation of Boc-Gly-Arg (NO 2 )-Pro-Ala-Lys(Z)-OBzl

[0059] Dissolve 438mg (2.5mmol) of Boc-Gly-OH in 10ml of anhydrous THF, add 10ml of 338mg (2.5mmol) of HOBt and 619mg (3mmol) of DCC in anhydrous THF under ice cooling. The reaction mixture was stirred in an ice bath for 20 minutes to obtain the corresponding active ester solution for use.

[0060] 2.025g (2.3mmol) HCl Arg (NO 2 )-Pro-Ala-Lys(Z)-OBzl and 232 mg (2.3 mmol) of N-methylmorpholine were first miscible with 6 ml 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 (developing agent chloroform:methanol=10:1) shows that 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 was filtered...

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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 filing date is "January 30, 2008", and the invention title is "compound with thrombolytic activity, its preparation method, and its application". technical field [0002] The present invention relates to a class of heterocyclic compounds, in particular to a compound with thrombolytic activity obtained by conjugating or coupling P6A or its analogs after dopa cyclization and a preparation method for the compound. This aspect also relates to The application of the compound as a thrombolytic agent, especially as a therapeutic agent for cerebral thrombosis, belongs to the field of medicinal chemistry. Background technique [0003] Cerebral thrombosis is characterized by high morbidity, disability and death. Drug therapy is the main means of clinical treatment of cerebral thrombosis. The development of safe and effective drugs against cerebral thrombosis is one of the hot spots in the r...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06
CPCY02P20/55
Inventor 彭师奇赵明崔国辉杨斌
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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