CN103330708B - Application of 5-(3', 5'-dimethoxybenzylidene)-2-sulfo-imidazole-4-one to preparation of drug for treating cerebrovascular disease - Google Patents
Application of 5-(3', 5'-dimethoxybenzylidene)-2-sulfo-imidazole-4-one to preparation of drug for treating cerebrovascular disease Download PDFInfo
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- CN103330708B CN103330708B CN201310310564.0A CN201310310564A CN103330708B CN 103330708 B CN103330708 B CN 103330708B CN 201310310564 A CN201310310564 A CN 201310310564A CN 103330708 B CN103330708 B CN 103330708B
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Abstract
The invention discloses application of 5-(3', 5'-dimethoxybenzylidene)-2-sulfo-imidazole-4-one to preparation of drugs for treating cerebrovascular diseases. According to relevant researches disclosed by the invention, the compound has a remarkable cerebral nerve protection effect, can obviously reduce the volume of cerebral infarction of a focal cerebral ischemia rat and can obviously improve neurological signs; and moreover, the protection effect of an IV4 compound to cerebral ischemic injuries is related to the inhibition of the activation of lysosomal enzyme cathepsin B, so that the compound can be used for preparing drugs for preventing or treating diseases such as ischemic brain injuries, cerebral hemorrhage, cerebral thrombosis, cerebral embolism, cerebral infarction, cerebral stroke, lacunar infarction, transient ischemia attacks, cerebral arteriosclerosis and diabetic cardiovascular complications.
Description
Technical field
The present invention relates to drug world, be specifically related to the application of 5-(3 ', 5 '-dimethoxy benzene methylene base)-2-sulfo--imidazol-4-one in the medicine of preparation treatment mammal cerebrovascular disease.
Background technology
Apoplexy is one group and damages the disease of symptom as main clinical manifestation taking cerebral tissue ischemia and hemorrhagic, claims again apoplexy or cerebrovascular accident.This disease morbidity is anxious, has high disability rate and higher mortality rate, is one of topmost disease of harm humans health in the world today.Apoplexy is mainly divided into hemorrhagic cerebral apoplexy (cerebral hemorrhage or subarachnoid hemorrhage) and ischemia apoplexy (ischemic brain injury comprises cerebral infarction, cerebral thrombosis) two large classes, wherein common with ischemia apoplexy.
At present clinically the treatment of ischemia apoplexy is mainly adopted to Drug therapy, comprise thrombolytic, expand blood vessel and antiplatelet aggregation etc.The common feature of above-mentioned treatment ischemia apoplexy medicine is: with strong points, action target spot is clear and definite, but curative effect is single, and the protective effect of part can only be provided, and clinical efficacy is less, and has toxic and side effects in various degree.Play effectiveness as, thrombolytic drug is difficult to enter impaired cerebral tissue by blood brain barrier, thereby curative effect is not certainly, and has and cause that Reperfusion injury injures hemorrhage side effect; Medicament for expanding vascellum can make the vasodilation of normal position, causes the blood flow of diseased region to normal cerebral tissue, produces so-called " robber's blood " phenomenon.Therefore, the pathophysiological mechanism of further investigation ischemia apoplexy, finds the pharmaceutically-active novel targets of ischemia resisting apoplexy, and the new drug of researching and developing treatment ischemia apoplexy with this is a job of urgently exploring.
Lysosome breaks and hydrolytic enzyme is discharged into cytoplasmic amount and affects the destiny of cell death: lysosome incomplete rupture causes apoptosis, and burst is broken and caused necrocytosis.Lysosomal enzyme is made up of much different types of protease, and wherein a representative class lysosomal enzyme is cathepsins, wherein in neuron, is rich in cathepsin B, L and D.Research shows: cathepsins B participates in cerebral ischemia neuronal death, cathepsin B is middle cerebral artery occlusion 2 hours, then pours in 2 hours, and its expression and activating all increases, intracerebroventricular injection cathepsin B inhibitor stefin A, can effectively reduce rat cerebral infarction volume.Therefore, cathepsin B may become the potential treatment target spot of control ischemic brain injury medicine.
So taking cathepsin B as treatment target spot, the active novel ischemia resisting apoplexy medicine strong, that toxic and side effects is little of research and development has important practical significance.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of new purposes of compound, the above-mentioned defect existing to solve existing cerebrovascular disease therapy medicine.
To achieve the above object of the invention, the technical solution used in the present invention is: the application of a kind of compound in the medicine of preparation treatment cerebrovascular disease, described compound is 5-(3 ', 5 '-dimethoxy benzene methylene base)-2-sulfo--imidazol-4-one, and its structural formula is:
。
This compound is hereinafter referred to as compound IV
4.
At open source literature " Zheng Liling; Ao Guizhen; Li Zhenqing. the synthetic and sign of 3,5-dimethoxy styrene cyclic ketones compounds. chemical research and application, 2007,19(9): 1051-1055 " in, prepare this compound, but without any the report about pharmacologically active.
Pharmacological evaluation shows, compound IV
4there is significant neuroprotection effect, can obviously reduce rat focal cerebral ischemia infarct volume and significantly improve its nervous symptoms; Meanwhile, IV
4can suppress the neuronal cell line HT of hypoxic-ischemic induction
22the activation of cell cathepsin B.Therefore, IV
4can be used for the medicine of preparation treatment cerebrovascular disease.
Preferably, described cerebrovascular disease is ischemic brain injury.
Described ischemic brain injury is apoplexy, cerebral thrombosis, cerebral embolism, cerebral infarction, transient ischemic attack or lacunar infarction, cerebral arteriosclerosis or diabetes cerebrovascular complication.
Compound of the present invention can be made preparation administration separately or with more than one acceptable carrier combination agent.
Because technique scheme is used, the present invention compared with prior art has following advantages:
The invention provides a kind of compound IV
4new purposes, this compound has significant neuroprotection effect, can obviously reduce rat focal cerebral ischemia infarct volume and significantly improve nervous symptoms, its neuroprotective is relevant with the activation that suppresses cathepsin B.This compound can be used for preparation prevention or treats the medicine of the diseases such as ischemic brain injury, cerebral thrombosis, cerebral embolism, cerebral infarction, apoplexy, lacunar infarction, transient ischemic attack, cerebral arteriosclerosis, diabetes cerebrovascular complication.
Brief description of the drawings
Fig. 1 is compound alone IV in embodiment 1
4to HT
22cell lactic acid dehydrogenase (LDH) spills the figure that affects of rate;
Fig. 2 is compound IV in embodiment 1
4suppress to lack the HT of sugared anoxia (OGD) induction
22the rate that the spills figure of LDH;
Fig. 3 is compound IV in embodiment 2
4reduce the nervous symptoms scoring figure of rats with cerebral ischemia;
Fig. 4 is compound IV in embodiment 2
4improve the grip figure of rats with cerebral ischemia;
Fig. 5 is compound IV in embodiment 2
4reduce the cerebral infarct volume figure of rat;
Fig. 6 is compound IV in embodiment 3
4suppress to lack the HT of sugared hypoxia inducible
22the increase figure that the cathepsin B activating in cell expresses.
Detailed description of the invention
Below in conjunction with drawings and Examples, the invention will be further described:
embodiment 1:
Compound
to the neuronal cell line HT of In vitro culture
22the protective effect of cellular sugar deficiency anoxia-induced apoptosis.This compound is hereinafter referred to as IV
4.
Neuronal cell line HT
22cell culture 24 hours, is divided into non-scarce sugared anoxia matched group, lacks sugared anoxia (OGD) group, non-scarce sugared anoxia (non-OGD)+IV
40.1,1,10,50,100 μ M group and OGD+IV
40.1,1,10,50 or 100 μ M groups.Lack sugared anoxia after 12 hours, adopt lactic acid dehydrogenase (LDH) method to detect cell injury degree.Spill rate=A culture fluid/(A culture fluid+A cell homogenates liquid) × 100% by formula LDH.
Accompanying drawing 1 is compound alone IV
40.1,1,10,50,100 μ M are to HT
22cell LDH spills the figure that affects of rate, mean ± SD, n=6.
Fig. 1 shows: with matched group ratio, alone IV
40.1,1,10,50,100 μ M spill rate to LDH and have no significant effect, and the IV of above dosage is described
4to HT
22cell free of toxic effects.
Accompanying drawing 2 is compound IV
4suppress the HT of OGD induction
22lDH spills rate figure, mean ± SD, n=6; Compare ## p <0.01 with matched group (non-OGD group); OGD organizes relatively with (lacking sugared anoxia), * p <0.05, * * p <0.01.
Fig. 2 shows: with matched group ratio, OGD group LDH spills rate significantly to be increased, and IV
41,10,50 μ M can obviously suppress the HT of OGD induction
22lDH spills rate to be increased, and IV is described
4to the neuronal cell line HT of In vitro culture
22cellular sugar deficiency anoxia-induced apoptosis has protective effect.
embodiment 2:compound IV
4to the protective effect of the permanent Focal Ischemic Cerebral Injury of rat.
Male SD rat, is divided into matched group (sham operated rats), model group, IV at random
4high, in and low dose group (10mg/kg
-1, 5mg/kg
-1and 1mg/kg
-1), 10 every group.Adopt line bolt legal system to make the permanent middle cerebral artery occlusion of rat (MCAO) model.3 hours intravenous injection IV after ischemia
4, with the administration of variable concentrations isometric(al).After ischemia 24 h, adopt 5 points of point systems.Mark higher, function of nervous system's defect is more obvious.Grip method is carried out the mensuration of function of nervous system, observes IV with TTC staining
4on the impact of cerebral infarction volume.
Accompanying drawing 3 is compound IV
4reduce the nervous symptoms scoring figure of rats with cerebral ischemia, mean ± SD, n=10; With model group comparison, * p <0.05.
Accompanying drawing 4 is compound IV
4improve the grip figure of rats with cerebral ischemia, mean ± SD, n=10; With matched group comparison
##p <0.01; With model group comparison, * p<0.05.
Accompanying drawing 5 is compound IV
4reduce the cerebral infarct volume figure of rat, mean ± SD, n=10; With model group comparison, * p<0.05.
Fig. 3 shows with Fig. 4: compared with sham-operation, ischemia model group rat shows obvious neuromotor dysfunction.Within after ischemia 3 hours, give IV
4, IV
4rat function of nervous system defect is all improved significantly, and muscular strength obviously increases, and difference has significance (P<0.05) compared with model group; Fig. 5 shows: compared with model group, and IV
4also can significantly reduce the cerebral infarct volume of rat.Above results suggest IV
4to rat permanent focal cerebral ischemia, damage has protective effect.
embodiment 3:neuronal cell line HT
22cell culture 24 hours, is divided into non-scarce sugared anoxia matched group (non-OGD group), lacks sugared anoxia (OGD) group, non-scarce sugared anoxia IV
40.1,1,10,50,100 μ M group and OGD+IV
40.1,1,10,50 or 100 μ M groups.Lack sugared anoxia after 6 hours, adopt Western Blotting method to detect the expression of cathepsin B.
Accompanying drawing 6 is for lacking the neuronal cell line HT of sugared hypoxia inducible
22the expression figure of cathepsin B in cell.Fig. 6 A is representational Western Blotting figure; Fig. 6 B is Western Blotting cartogram; Mean ± SD, n=3; With matched group comparison
##p <0.01; With model group comparison, * * p<0.01.
Fig. 6 shows, with the comparison of non-scarce sugared anoxia group, lacks sugared anoxia 6 h and significantly induces HT
22the increase that cytoactive cathepsin B expresses; And with scarce sugared anoxia group comparison, IV
4can obviously suppress the HT of OGD induction
22the increase that cytoactive cathepsin B expresses, illustrates IV
4can suppress the activation of cathepsin B.
Can infer from above result: formula IV
4compound cerebral ischemia is had to certain protective effect, can be for this prevention and treatment of diseases, IV
4compound relevant with the activation that suppresses cathepsin B to the protective effect of cerebral ischemia.
embodiment 4:
5-(3 ', 5 '-dimethoxy benzene methylene base)-2-sulfo--imidazol-4-one (IV
4) preparation
Glycine (2.1g, 27.5mmol), ammonium thiocyanate (1.9g, 25.0mmol), acetic anhydride 14.4mL and glacial acetic acid 1.6mL stir 40min in 100 DEG C of oil baths, cooling, in impouring 150mL water, there is yellow solid to separate out, washing, ethyl alcohol recrystallization, obtains faint yellow flat crystal 1-acetyl thio glycolylurea, yield 71.4%, 175～177 DEG C of mp.
By 3,5-dimethoxy benzaldehyde (0.83g, 5mmol), 1-acetyl thio glycolylurea (0.79g, 5mmol), the sodium acetate (1.44g of melting, 17.5mmol) with 7mL glacial acetic acid return stirring 10 h, be cooled to after room temperature, add 5mL water, sucking filtration, washing, DMF and water recrystallization obtain brown color crystal, yield 91.6%, mp:254 ~ 255 DEG C.
IR?(KBr,?cm
-1):?3268(NH),?2995(CH
3),?1725(C=O),?1649,?1596,?1495;?HR-MS(FAB):?Calcd.?for?C
12H
11SNO
4:?264.0569,?Found:?264.0382;?
1HNMR(400MHz,?DMSO-d
6),δ(ppm):?3.78(s,?6H,?CH
3),?6.54(s,?1H,?ArH),?6.88(s,?2H,?ArH),?7.97(s,?1H,?=CH)。
Claims (2)
1. the application of compound in the medicine of preparation treatment cerebrovascular disease, the structural formula of described compound is:
; Described cerebrovascular disease is ischemic brain injury.
2. application according to claim 1, is characterized in that: described ischemic brain injury is cerebral thrombosis, cerebral embolism, cerebral infarction, transient ischemic attack, cerebral arteriosclerosis or diabetes cerebrovascular complication.
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| CN201310310564.0A CN103330708B (en) | 2013-07-23 | 2013-07-23 | Application of 5-(3', 5'-dimethoxybenzylidene)-2-sulfo-imidazole-4-one to preparation of drug for treating cerebrovascular disease |
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| CN201310310564.0A CN103330708B (en) | 2013-07-23 | 2013-07-23 | Application of 5-(3', 5'-dimethoxybenzylidene)-2-sulfo-imidazole-4-one to preparation of drug for treating cerebrovascular disease |
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| CN103330708B true CN103330708B (en) | 2014-11-26 |
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|---|---|---|---|---|
| WO2023144742A1 (en) * | 2022-01-26 | 2023-08-03 | Universidade De Aveiro | Ionic-liquid-based formulations for the prevention or treatment of neurological diseases |
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|---|---|---|---|---|
| CN104983731B (en) * | 2015-07-27 | 2018-01-19 | 苏州大学 | (Z) application of the ketone of 2 imino group 5 (3,5 dimethoxy benzene methylene base) 1 methylimidazole alkane 4 in cardiovascular drugs is prepared |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023144742A1 (en) * | 2022-01-26 | 2023-08-03 | Universidade De Aveiro | Ionic-liquid-based formulations for the prevention or treatment of neurological diseases |
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