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Oligopeptide with thrombolysis activity, preparation method and application thereof

An active and thrombolytic technology, applied in the treatment of cerebral thrombosis and in the field of clinical treatment of cerebral thrombosis, oligopeptides, can solve the problems of eNOS and nNOS activity increase and expression upregulation

Inactive Publication Date: 2009-12-02
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At this time, not only the expression of eNOS and nNOS is up-regulated, but also the activity of eNOS and nNOS is increased.

Method used

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  • Oligopeptide with thrombolysis activity, preparation method and application thereof
  • Oligopeptide with thrombolysis activity, preparation method and application thereof
  • Oligopeptide with thrombolysis activity, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 14

[0032] Embodiment 14,4,5, the preparation of 5-tetramethyl-1,3-dioxyimidazolin-2-ylbenzene-4'-yloxyacetic acid

[0033] 1) Preparation of 2,3-dimethyl-2,3-dinitrobutane

[0034] 69g (0.78mol, 70ml) of 2-nitropropane was added to 130ml of NaOH (6mol / l) aqueous solution. Under stirring conditions in an ice-salt bath, 20ml (0.38mol) of Br was added dropwise 2 , Add dropwise within 1hr. Then 240ml of ethanol was added. The reaction mixture was stirred at reflux at 90°C for 3 hr, and flake insoluble matter appeared. The reaction mixture was poured into 800 ml of ice water while heating. After suction filtration, 55 g (81%) of white flaky crystals were obtained, mp 110-112°C.

[0035] 2) Preparation of 2,3-dimethyl-2,3-dihydroxyaminobutane

[0036] 7.0g (40mmol) 2,3-dimethyl-2,3-dinitrobutane and 4.0g NH 4 Cl was suspended in 80ml ethanol (50%) solution. Stir under ice bath. 16.0 g zinc powder was added within 3 hrs. After the zinc powder was added, the ice bath was remove...

Embodiment 2B

[0045] The preparation of embodiment 2Boc-Pro-Ala-Lys(Z)-OBzl

[0046] 1) Preparation of Boc-Ala-Lys(Z)-OBzl

[0047] Dissolve 473mg (2.5mmol) Boc-Ala-OH in 10ml anhydrous tetrahydrofuran (THF), add 10ml 338mg (2.5mmol) N-hydroxybenzotriazole (HOBt) and 619mg (3.0mmol) dicyclohexyl Carbonyldiimide (DCC) in anhydrous THF. The reaction mixture was stirred in an ice bath for 20 minutes to obtain the corresponding active ester solution for use.

[0048] 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 chloroform:methanol=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 successively ...

Embodiment 3B

[0056] The preparation of embodiment 3Boc-Arg(Tos)-Pro-Ala-Lys(Z)-OBzl

[0057] 1) Preparation of HCl Pro-Ala-Lys(Z)-OBzl

[0058] 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.

[0059] 2) Preparation of Boc-Arg(Tos)-Pro-Ala-Lys(Z)-OBzl

[0060] Dissolve 1.073g (2.5mmol) Boc-Arg(Tos)-OH in 10ml of anhydrous THF, and add 10ml of anhydrous THF solution of 338mg (2.5mmol) HOBt and 619mg (3mmol) DCC under ice cooling. The reaction mixtu...

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Abstract

The invention discloses an oligopeptide modified by 4, 4, 5, 5-tetramethyl-1, 3-dioxy imidazoline-2-benzene-4'-oxygen acetyl and a preparation method thereof and also discloses the application thereof in treating cerebral thrombosis. The preparation method comprises the following step: respectively coupling Ala-Arg-Pro-Ala-Lys, Pro-Ala-Lys, Arg-Pro-Ala-Lys, Gly-Arg-Pro-Ala-Lys or Gln-Arg-Pro-Ala-Lys with the 4, 4, 5, 5-tetramethyl-1, 3-dioxy imidazoline-2-benzene-4'-oxygen acetyl, thus obtaining the compound of the invention. On a rat carotid and jugular bypass cannula thrombosis model, the compound of the invention shows excellent thrombolysis activity. On a rat cerebral thrombosis model, the compound of the invention shows excellent therapeutic effect on cerebral infarction.

Description

technical field [0001] The present invention relates to oligopeptides, in particular to 4,4,5,5-tetramethyl-1,3-dioxyimidazolin-2-ylphenyl-4'-yloxyacetyl modified lysates with thrombolytic activity Thrombus oligopeptides and preparation methods thereof, the present invention further relates to their activity in treating cerebral thrombosis and their clinical use as therapeutic agents for cerebral thrombosis, which belong to the field of biomedicine. 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, so ...

Claims

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Application Information

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IPC IPC(8): C07K5/08C07K5/10C07K7/06A61K38/06A61K38/07A61K38/08A61P7/02
CPCY02P20/55
Inventor 彭师奇赵明钟晓青
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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