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GRPAK/tetrahydroglyoxaline/RGD ternary conjugate as well as preparation method and application thereof

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

Inactive Publication Date: 2013-01-16
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 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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  • GRPAK/tetrahydroglyoxaline/RGD ternary conjugate as well as preparation method and application thereof
  • GRPAK/tetrahydroglyoxaline/RGD ternary conjugate as well as preparation method and application thereof
  • GRPAK/tetrahydroglyoxaline/RGD ternary conjugate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1 prepares 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] Embodiment 2 prepares 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°C. ...

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 invention discloses a GRPAK / tetrahydroglyoxaline / RGD ternary conjugate as well as a preparation method and application of the GRPAK / tetrahydroglyoxaline / RGD ternary conjugate. According to the preparation method, L-Lys is served as a link arm, and 1, 3-dioxo-2-[(4-peracetic acid) phenyl]-4, 4, 5, 5-tetramethyl tetrahydroglyoxaline, the GRPAK pentapeptide with a thrombolytic effect, and RGD tetrapeptide with an antithrombosis effect are integrally linked, thus obtaining the GRPAK / tetrahydroglyoxaline / RGD ternary conjugate as shown in formula I. The GRPAK / tetrahydroglyoxaline / RGD ternary conjugate disclosed by the invention has high activity on removing NO free radical, excellent thrombolytic activity and antithrombosis activity; as in-vivo apoplexy activity shown, the GRPAK / tetrahydroglyoxaline / RGD ternary conjugate can effectively protect the neurologic function of a rat subjected to apoplexy, and reduces the brain infarct volume of the rat subjected to apoplexy, and has high apoplexy resisting activity, and can be prepared into a clinical medicine for treating apoplexy or cerebral infarction.

Description

technical field [0001] The present invention relates to ternary conjugates, in particular to 1-(4-oxoacetyl-phenyl)-3,3,4,4-tetramethyl-imidazoline, GRPAK pentapeptide 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 GRPAK / 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 po...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/02A61K38/08A61P7/02A61P39/06A61P9/10
CPCY02P20/55
Inventor 彭师奇赵明蒋雪云
Owner YONG GUANG PHARMA
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