RPAK/imidazolidine/RGD ternary conjugate, preparation method and uses thereof

A technology of tetramethylimidazoline and compounds, applied in the field of RPAK/imidazoline/RGD ternary conjugates and their preparation and application, can solve the problem of inability to effectively cross the blood-brain barrier, complex, and limited curative effect in patients with cerebral infarction to achieve excellent anti-stroke activity, protect neurological function, and reduce the volume of cerebral infarction

Inactive Publication Date: 2013-01-30
YONG GUANG PHARMA
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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 blood-brain barrier, so that the curat

Method used

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  • RPAK/imidazolidine/RGD ternary conjugate, preparation method and uses thereof
  • RPAK/imidazolidine/RGD ternary conjugate, preparation method and uses thereof
  • RPAK/imidazolidine/RGD ternary conjugate, preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Preparation of 2,3-dimethyl-2,3-dinitrobutane

[0037] 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

[0038] Example 2 Preparation of 2,3-dimethyl-2,3-dihydroxyaminobutane

[0039] 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

[0040] Example 3 Preparation of 1,3-dihydroxy-2-(4'-hydroxyphenyl)-4,4,5,5-tetramethylimidazolidine

[0041] 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 an RPAK/imidazolidine/RGD ternary 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, an RPAK tetrapeptide having a thrombolysis effect, and a RGD tetrapeptide having an anti-thrombosis effect to obtain the RPAK/imidazolidine/RGD ternary conjugate represented by a formula I, wherein the RPAK/imidazolidine/RGD ternary conjugate integrally has effects of BBB crossing, thrombolysis and NO removing. The RPAK/imidazolidine/RGD ternary conjugate has high NO free radical clearance activity, excellent thrombolysis activity and excellent anti-thrombosis activity. In vivo anti-stroke activity test results show that: with the RPAK/imidazolidine/RGD ternary conjugate, nerve functions of stroke rats can be effectively protected, brain infarct volume of the stroke rats can be reduced, anti-stroke activity is provided, and the RPAK/imidazolidine/RGD ternary conjugate can be adopted as a clinical drug for brain infarction treatment.

Description

technical field [0001] The present invention relates to ternary conjugates, in particular to 1-(4-oxoacetyl-phenyl)-3,3,4,4-tetramethyl-imidazoline, RPAK tripeptide and RGD tetrapeptide via L- The ternary conjugate obtained by linking Lys together, the present invention also relates to the preparation method of the ternary conjugate, and the present invention further relates to the use of the ternary conjugate in removing NO, antithrombosis, thrombolysis and cerebral infarction treatment The medical use of the invention belongs to the field of RPAK / imidazoline / RGD ternary conjugates and their 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 positi...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06A61K38/08A61P7/02A61P39/06A61P9/10
Inventor 彭师奇赵明蒋雪云
Owner YONG GUANG PHARMA
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