CN104983731B - (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 - Google Patents
(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 Download PDFInfo
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- CN104983731B CN104983731B CN201510445254.9A CN201510445254A CN104983731B CN 104983731 B CN104983731 B CN 104983731B CN 201510445254 A CN201510445254 A CN 201510445254A CN 104983731 B CN104983731 B CN 104983731B
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Abstract
The invention discloses application of the ketone of (Z) 2 imino group 5 (3,5 dimethoxy benzene methylene base) 1 methylimidazole alkane 4 in cardiovascular drugs is prepared.Specifically, compound of the invention has significant myocardial ischemia/reperfusion injury protective effect, can significantly reduce rats with myocardial ischemia left ventricle infarct volume, is suitable for preparing for preventing and/or treating angiocardiopathy（The particularly illness such as ischemic cardiomyopathy, myocardial ischemia/reperfusion injury）Medicine.
Description
Technical field
The present invention relates to drug field, is related to (Z) -2- imino groups -5- (3,5- dimethoxy benzene methylene base) -1- methyl miaows
Oxazolidine -4- ketone is preparing the application in being used to prevent and/or treat the medicine of angiocardiopathy.
Background technology
Is with the progress of shock treatment and artery bypass art, thrombolytic therapy, percutaneous intracavitary coronary artery angiopoiesis in recent years
The foundation and popularization and application of the methods of art, department of cardiac surgery's extracorporal circulatory system, CPCR, the replantation of a severed limb and organ transplant, makes to be permitted
More histoorgans can retrieve blood reperfusion after ischemic.As a rule, postischemic reperfusion can make organizer
Official's function is restored, and damaged structure is repaired, and conditions of patients is taken a turn for the better.But postischemic reperfusion can not only make sometimes
Tissue, organ dysfunction recover, and aggravate tissue, the dysfunction and structural damage of organ on the contrary.It is this to recover on the basis of ischemic
Tissue damage aggravates on the contrary after blood flow, or even the phenomenon of generation irreversible damage is referred to as ischemia/reperfusion injury
（Ischemia-Reperfusion injury）.
Myocardial ischemia/reperfusion injury is shown as after making the Reperfu- sion of ischemic myocardium acquisition blood by treatment, is damaged
The function of cardiac muscle is not restored, and degree of injury aggravates on the contrary, or even the irreversible damages such as Infarction volume expansion occurs.Cardiac muscle
Ischemia/reperfusion injury is easily caused heart failure after generation heart infarction, has compared with high mortality.
With the treatment technology means for myocardial ischemia raising and be widely used, preventing and treating Ischemic/reperfusion damage
The medicine of wound turns into important research direction, including suppresses intracellular calcium overload, scavenging activated oxygen and antioxidant, anti-inflammatory
Reaction, cardiac metabolism protective agent etc..It is above-mentioned resist myocardial ischemia/common feature of reperfusion injury medicine is：With strong points, effect
Target spot is clear and definite, but curative effect is single, can only provide the protective effect of part, and clinical efficacy is smaller, and has different degrees of poison is secondary to make
With.Such as, oxygen free radical scavenger vitamin E is fat-soluble antioxidant, it is necessary to which largely could orally reach in cardiac muscle has for a long time
The anti reperfusion injury concentration of effect, clinically still lack objective science evaluation.
Therefore, the pathophysiological mechanism of myocardial ischemia/reperfusion injury is furtherd investigate, searching resists myocardial ischemia/filled again
The novel targets of damage medicine effect are noted, being one with this new drug for researching and developing treatment myocardial ischemia/reperfusion injury urgently explores
Work.Therefore, research and development activity is strong, toxic side effect is small it is new resist myocardial ischemia/reperfusion injury medicine have it is important
Realistic meaning.
The content of the invention
For the above situation, it is an object of the invention to provide a kind of imidazolidine compound comprising multiple substituents to make
Application in standby cardiovascular drugs, to solve the defects of present in existing medicine.
In order to reach foregoing invention purpose, the present invention adopts the following technical scheme that：A kind of compound is being prepared for preventing
And/or the application in the medicine for the treatment of angiocardiopathy, the compound is (Z) -2- imino groups -5- (3,5- dimethoxy benzenes
Methylene base) -1- methylimidazole alkane -4- ketone（(Z)-2-imino-5-(3,5-dimethoxybenzylidene)-1-
methylimidazolidin-4-one）, its structural formula is shown in formula I：
；
The compound is hereinafter referred to as compound IV5.
Pharmacological evaluation shows that compound IV5 has significant myocardium protecting action, can significantly reduce myocardial ischemia/again
Perfusion injury rat left ventricle infarct volume.Therefore, compound IV5, which is applied to prepare, is used to prevent and/or treat cardiovascular disease
The medicine of disease.
Preferably, the angiocardiopathy is ischemic cardiomyopathy or myocardial ischemia/reperfusion injury；It is furthermore preferred that institute
State myocardial ischemia/reperfusion injury and be in early stage, with Refractory Arrhythmias, serious cardiac muscle cell infringement and heart function
The ill symptomses such as decline.
The compound IV5 in the present invention can be both administered alone, again can be pharmaceutically acceptable with one or more
Carrier in combination administration；Preferably, the pharmaceutically acceptable carrier includes（But it is not limited to）Diluent, filler, coloring
Agent, flavouring, lubricant, pigment etc..
The compound IV5 in the present invention can both be used as unique drug activity material in medicine, again can be with one
Kind is a variety of for preventing and/or treating angiocardiopathy（Particularly ischemic cardiomyopathy, myocardial ischemia/reperfusion injury）'s
Reactive compound combination formulations；Preferably, the reactive compound includes（But it is not limited to）Nifedipine, Verapamil, Ligusticum wallichii
Piperazine, Puerarin, Trimetazidine, UTI etc..
Corresponding formulation such as tablet, glue can be made in the medicine in the present invention according to well known method in pharmaceutical field
Wafer, granule, pill, powder, solution, injection, suppository, liniment etc., suitable for oral, rectum, part, oral cavity, tongue
Under, a variety of methods of administration such as subcutaneous, muscle, vein.In addition, the dosage of the medicine in the present invention can be according to the life of patient
Manage the factors such as feature, the order of severity of disease and specific formulation and adjust and change.
Due to the utilization of above-mentioned technical proposal, the present invention has following advantages compared with prior art：
The invention provides a kind of medical usage of polysubstituted imidazolidine compound, there is the compound significant cardiac muscle to protect
Shield acts on, and can significantly reduce myocardial ischemia/reperfusion injury rat left ventricle infarct volume, is used to prevent suitable for preparing
And/or treatment angiocardiopathy（The particularly illness such as ischemic cardiomyopathy, myocardial ischemia/reperfusion injury）Medicine.
Brief description of the drawings
Fig. 1 is obtained compound IV5 in embodiment 1（0.1、1、10μM）To non-scarce sugared hypoxia/reoxygenation-stimulated cardiac muscle cell
Lactic dehydrogenase spills rate（LDH）Influence schematic diagram.
Fig. 2 is that obtained compound IV5 suppresses to lack sugared hypoxia/reoxygenation-stimulated in embodiment 1（OGD/R）The cardiac muscle cell of induction
LDH spills the increased effect diagram of rate.
Fig. 3 is the left ventricle infraction that obtained compound IV5 reduces myocardial ischemia/reperfusion injury rat in embodiment 1
The effect diagram of volume.
Embodiment
Further description is made to the present invention below in conjunction with the accompanying drawings and the specific embodiments.
Embodiment 1：(Z) -2- imino groups -5- (3,5- dimethoxy benzene methylenes base) -1- methylimidazole alkane -4- ketone（Chemical combination
Thing IV5）Preparation.
By 3,5- dimethoxy benzaldehydes（0.83g, 5mmol）, creatinine（0.57g, 5mmol）, melting sodium acetate
（2.05g 25mmol）And glacial acetic acid（7mL）10h is stirred under reflux conditions, after being cooled to room temperature, is added 5mL water, is filtered, water
Wash, recrystallized using DMF and water, obtain the deep yellow brown crystals of 1.09g（Compound IV5）, yield 84.2%, physics and chemistry qualification result
It is as follows：
mp：222~223℃；
IR (KBr, cm-1):3287,2999,2842,1703,1660,1588,1558,1505,1458；
1H-NMR (400MHz, DMSO-d6): δ (ppm) 3.17 (s, 3H, CH3), 3.79 (s, 6H,
CH3), 6.139 (s, 1H, =CH), 6.216 (s, 1H, Ar), 7.58 (s, 2H, ArH)；
HR-MS: C13H15N3O3Theoretical value：261.1113, actual value：261.1111.
Embodiment 2：The protection that compound IV5 lacks sugared anoxic/reperfusion injury to the primary cardiomyocytes of in vitro culture is made
With.
By Neonatal Rat Primary Cardiomyocytes culture 72h, non-scarce sugared hypoxia/reoxygenation-stimulated control group is randomly divided into（It is expressed as in Fig. 1
" normal "）, non-scarce sugared hypoxia/reoxygenation-stimulated+IV5 groups（It is expressed as in Fig. 1 " IV5 ", wherein IV5 dosage is respectively 0.1,1,10 μ
M）, lack sugared hypoxia/reoxygenation-stimulated group（It is expressed as in Fig. 2 " OGD/R "）And lack sugared hypoxia/reoxygenation-stimulated+IV5 groups（It is expressed as in Fig. 2
" OGD/R+IV5 ", wherein IV5 dosage are respectively 0.1,1,10 μM）.Sugared anoxic treatment 3h is lacked, then changes normal glucose culture
Base and reoxygenation 12h, cellular damage degree is detected using LDH methods, and lactic dehydrogenase is calculated by following equation（LDH）Spill rate
（%）=ANutrient solution/（ANutrient solution+ACell homogenates liquid）×100%.
Show that the compound IV5 that various dose is used alone spills the influence of rate to cardiac muscle cell LDH in Fig. 1（mean
± SD, n=6）.It can be seen that compared with Normal group, exclusive use IV5 spills rate to LDH and had no significant effect, more than explanation
The compound IV5 of dosage is free of toxic effects to normal myocardial cells.
Show that compound IV5 spills the increased inhibitory action of rate to the cardiac muscle cell LDH that OGD/R is induced in Fig. 2（mean
± SD, n=6；Compared with OGD/R groups, * * p<0.01）.It can be seen that compared with Normal group, LDH is spilt in OGD/R groups
Rate dramatically increases, and after the compound IV5 using various dose, the cardiac muscle cell LDH of OGD/R inductions spills rate increase and obtained
It is obvious to suppress, illustrate that IV5 has protective effect to the cellular sugar deficiency anoxia-induced apoptosis of the Neonatal Rat Primary Cardiomyocytes of in vitro culture.
Embodiment 3：Protective effects of the compound IV5 to myocardial ischemia/reperfusion injury in rats.
Male SD rat, it is randomly divided into control group（Sham-operation group, it is expressed as " CON " in Fig. 3）, model group, height, in and it is low
Dosage IV5 groups（Wherein IV5 dosage is respectively 4mg/kg, 2mg/kg and 1mg/kg）, every group 10.Using following coronary artery occlusion
The method of left anterior descending branch makes myocardial ischemia in rats model, and Reperfu- sion after ischemic 30min, in Reperfu- sion, neck is always injected intravenously at once
IV5, it is administered with various dose isometric(al).With influences of the TTC decoration methods observation IV5 to left ventricle Infarction volume.
Show that compound IV5 reduces the effect of rat left ventricle infarct volume in Fig. 3（Mean ± SD, n=10；With model
Group is compared, * * p<0.01）.It can be seen that compound IV5 has protective effect to myocardial ischemia/reperfusion injury in rats.
It can be seen from result above, compound IV5 lacks sugared anoxia-induced apoptosis and myocardial ischemia/reperfusion injury tool to rat
There is certain protective effect, can be used for the prevention and treatment of myocardial ischemia disease.
Claims (10)
1. a kind of application of compound in preparation is used to prevent and/or treat the medicine of angiocardiopathy, the compound are
(Z) -2- imino groups -5- (3,5- dimethoxy benzene methylene base) -1- methylimidazole alkane -4- ketone, its structural formula is shown in formula I：
；
The angiocardiopathy is myocardial ischemia/reperfusion injury.
2. application according to claim 1, it is characterised in that the myocardial ischemia/reperfusion injury is in early stage.
3. application according to claim 1, it is characterised in that in addition to compound shown in formula I, the medicine is also
Include one or more pharmaceutically acceptable carriers.
4. application according to claim 3, it is characterised in that the pharmaceutically acceptable carrier is diluent, filling
Agent, colouring agent, flavouring, lubricant or pigment.
5. application according to claim 1, it is characterised in that in addition to compound shown in formula I, the medicine is also
Include one or more reactive compounds for being used to preventing and/or treating angiocardiopathy.
6. application according to claim 5, it is characterised in that the reactive compound is nifedipine, Verapamil, river
Rhizome of chuanxiong piperazine, Puerarin, Trimetazidine or UTI.
7. application according to claim 1, it is characterised in that the formulation of the medicine be tablet, capsule, granule,
Pill, powder, solution, injection, suppository or liniment.
8. application according to claim 1, it is characterised in that the medicine is applied to oral, local administration, subcutaneous note
Penetrate, intramuscular injection or intravenous injection.
9. application according to claim 1, it is characterised in that the medicine is applied to rectally, oral administration.
10. application according to claim 1, it is characterised in that the medicine is applied to sublingual administration.
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Citations (3)
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| CN101234106A (en) * | 2008-03-05 | 2008-08-06 | 中国药科大学 | Use of imidazolone compounds for treating cardiovascular and cerebrovascular diseases |
| CN103330708A (en) * | 2013-07-23 | 2013-10-02 | 苏州大学 | Application of 5-(3', 5'-dimethoxybenzylidene)-2-sulfo-imidazole-4-one to preparation of drug for treating cerebrovascular disease |
| US20140023603A1 (en) * | 2011-02-09 | 2014-01-23 | Pusan National University Industry-University Cooperation Foundation | Novel compound having skin-whitening, anti-oxidizing and ppar activities and medical use therefor |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101234106A (en) * | 2008-03-05 | 2008-08-06 | 中国药科大学 | Use of imidazolone compounds for treating cardiovascular and cerebrovascular diseases |
| US20140023603A1 (en) * | 2011-02-09 | 2014-01-23 | Pusan National University Industry-University Cooperation Foundation | Novel compound having skin-whitening, anti-oxidizing and ppar activities and medical use therefor |
| CN103330708A (en) * | 2013-07-23 | 2013-10-02 | 苏州大学 | Application of 5-(3', 5'-dimethoxybenzylidene)-2-sulfo-imidazole-4-one to preparation of drug for treating cerebrovascular disease |
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