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Thrombolysis oligopeptide-imidazolidine binary conjugate, preparation method and uses thereof

A technology of tetramethylimidazoline and compounds, applied in the field of RPAK or PAK through L, GRPAK, K, can solve the problems of limited curative effect and complexity in patients with cerebral infarction, achieve excellent anti-stroke activity, protect neurological function, and excellent thrombolysis active effect

Inactive Publication Date: 2013-01-30
SHANGHAI LUMOSA THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the problems faced by the treatment of cerebral infarction are more complicated
For example, none of the existing thrombolytic drugs can effectively cross the m-brain barrier, so that the curative effect of intravenous thrombolytic drugs on patients with cerebral infarction is extremely / limited
Another example is that there is currently no suitable operation to treat patients with cerebral infarction

Method used

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  • Thrombolysis oligopeptide-imidazolidine binary conjugate, preparation method and uses thereof
  • Thrombolysis oligopeptide-imidazolidine binary conjugate, preparation method and uses thereof
  • Thrombolysis oligopeptide-imidazolidine binary conjugate, preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1 Preparation of 2,3-dimethyl-2,3-dinitrobutane

[0038] 69g (0.78mol) of 2-nitropropane was added to 130ml of NaOH (6N) aqueous solution, and 20ml (0.38mol) of Br 2 , Added dropwise within 1 hour, then added 240ml of ethanol, refluxed at 90°C for 3h, poured the reaction solution into 800ml of ice water while heating, and filtered 55g (81%) of the title compound as colorless flaky crystals, Mp110-112°C.

Embodiment 2

[0039] Example 2 Preparation of 2,3-dimethyl-2,3 dihydroxyaminobutane

[0040] 7g (40mmol) 2,3-dimethyl-2,3-dinitrobutane and 4g NH 4 Cl was suspended in 80ml ethanol aqueous solution (50%), stirred under ice bath, and 16g zinc powder was added within 3h. After the zinc powder was added, the ice bath was removed, and the stirring reaction at room temperature was continued for 3 h, and then the reaction liquid was suction-filtered. The filter cake was washed repeatedly with aqueous ethanol (50%), the filtrate and washings were combined, adjusted to pH = 2 with concentrated hydrochloric acid, and steamed under reduced pressure until it became a slurry. Add an appropriate amount of potassium carbonate, mix well, use a Soxhlet extractor, use chloroform as the extractant, and extract for 6 hours. The extract is concentrated under reduced pressure to a small amount. After adding petroleum ether, 2.60 g (44%) of the title compound is precipitated as colorless crystals . Mp157-159°...

Embodiment 3

[0041] Example 3 Preparation of 1,3---Hydroxy-2-(4'-hydroxyphenyl)-4,4,5,5-tetramethylimidazolidine

[0042] 1.22g (10mmol) of p-hydroxybenzaldehyde and 1.48g (10mmol) of 2,3-dimethyl-2,3-dihydroxyaminobutane were dissolved in 10ml of methanol. After stirring at room temperature for 8h, TLC showed that the raw material point disappeared. Filtration with suction gave 1.29 g (51%) of the title compound as colorless crystals. EI-MS(m / z)252[M] + . 1 H-NMR (DMSO-d 6 )δ (ppm) = 1.03 (s, 6H), 1.05 (s, 6H), 4.39 (s, 1H), 6.70 (d, J = 6.9Hz, 2H), 7.23 (d, J = 6.9Hz, 2H) , 7.63(s, 1H), 7.85(s, 2H).

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Abstract

The present invention discloses a thrombolysis oligopeptide-imidazolidine binary conjugate, a preparation method and uses thereof. According to the present invention, L-Lys is adopted as a linking arm to link 1,3-dioxy-2-[(4-oxyacetic acid)phenyl]-4,4,5,5-tetramethylimidazoline, ARPAK having a thrombolysis effect, GRPAK, RPAK or PAK to obtain the thrombolysis oligopeptide-imidazolidine binary conjugate represented by a formula I or II, wherein the thrombolysis oligopeptide-imidazolidine binary conjugate integrally has characteristics of nanometer structure, BBB crossing, thrombolysis and NO removing. The thrombolysis oligopeptide-imidazolidine binary conjugate has high NO free radical clearance activity, excellent thrombolysis activity and excellent antithrombosis activity. In vivo anti-stroke activity test results show that: with the thrombolysis oligopeptide-imidazolidine binary conjugate, nerve functions of stroke rats can be effectively protected, brain infarct volume of the stroke rats can be reduced, excellent anti-stroke activity is provided, and the thrombolysis oligopeptide-imidazolidine binary conjugate can be prepared into a clinical drug for brain infarction treatment.

Description

technical field [0001] The present invention relates to binary conjugates, in particular to 1-(4-oxoacetyl-phenyl)-3,3,4,4-tetramethyl-imidazoline and ARPAK, GRPAK, RPAK with thrombolytic effect Or the binary conjugate obtained by linking together PAK through L-Lys, the present invention also relates to the preparation method of the binary conjugate, and the present invention further relates to the use of the binary conjugate in removing NO, thrombolysis and cerebral infarction The medical use in treatment belongs to the field of thrombolytic oligopeptide-imidazoline binary conjugate and its medical use. Background technique [0002] Globally, thrombotic disease is the leading cause of morbidity and mortality. Coronary thrombosis, leading to myocardial infarction. Cerebrovascular embolism, leading to cerebral infarction. Patients with myocardial infarction can either receive intravenous thrombolytic drugs or undergo bypass surgery. It must be pointed out that the positiv...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K5/107C07K5/117C07K1/06A61K38/08A61K38/07A61P7/02A61P39/06A61P9/10
Inventor 彭师奇赵明蒋雪云
Owner SHANGHAI LUMOSA THERAPEUTICS
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