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Compound with thrombus dissolving activity, as well as preparation and use thereof

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

Inactive Publication Date: 2009-08-05
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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  • Compound with thrombus dissolving activity, as well as preparation and use thereof
  • Compound with thrombus dissolving activity, as well as preparation and use thereof
  • Compound with thrombus dissolving activity, as well as preparation and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

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

[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 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.

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

[0046] 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) DCC was added under ice cooling. The...

Embodiment 3

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

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

[0052] 2.099g (2.5mmol) Boc-Arg (NO 2 )-Pro-Ala-Lys(Z)-OBzl and the mixture of 15ml hydrogen chloride-ethyl acetate solution (4N) were 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.

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

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

Embodiment 4

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

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

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

[0061] 2.025g (2.3mmol) HCl Arg (NO 2 )-Pro-Ala-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 (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 fi...

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Abstract

The invention discloses a compound with thrombolytic activity as well as a preparation method and an application as the thrombolytic agent thereof. The 2-nitrogen or the 3-carboxyl of cyclized dopa is respectively coupled or latticed 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 to obtain the compound. The thrombolytic activity of the compound is evaluated by adopting the model of artery-vein bypass cannula thrombus in rats, and the experimental result shows that the compound has the excellent thrombolytic activity and can be clinically used as the thrombolytic agent. The therapeutic action of the compound to the cerebral infarction is further evaluated by adopting the model of cerebral thrombus in rats, and the experimental result shows that the compound has the excellent brain tissue protection action and can be clinically used as the thrombolytic agent.

Description

technical field [0001] 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 [0002] 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 research and development of new drugs. Thrombolytic drugs occupy the most important position in the treatment of cerebral thrombosis. In the treatment of cerebral thrombosis, thrombolytic drugs degrade the fibrin components in the thrombus, s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K5/117A61K38/07A61K38/08A61P7/02
Inventor 彭师奇赵明崔国辉杨斌
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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