CN104983731A - Application of (Z)-2-imino-5-(3,5-dimethoxyphenylmethylene)-1-methylimidazolidinyl-4-one in preparation of cardiovascular drugs - Google Patents
Application of (Z)-2-imino-5-(3,5-dimethoxyphenylmethylene)-1-methylimidazolidinyl-4-one in preparation of cardiovascular drugs Download PDFInfo
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- CN104983731A CN104983731A CN201510445254.9A CN201510445254A CN104983731A CN 104983731 A CN104983731 A CN 104983731A CN 201510445254 A CN201510445254 A CN 201510445254A CN 104983731 A CN104983731 A CN 104983731A
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Abstract
The invention discloses an application of (Z)-2-imino-5-(3,5-dimethoxyphenylmethylene)-1-methylimidazolidinyl-4-one in the preparation of cardiovascular drugs. Specifically, the provided compound has a prominent effect on reducing damage caused by myocardial ischemia/reperfusion; is capable of prominently reducing the infarct volume in left ventricle of myocardial ischemia rats, and is suitable for preparing drugs for preventing and/or treating cardiovascular diseases especially ischemic cardiomyopathy, myocardial ischemia/reperfusion damage, and the like.
Description
Technical field
The present invention relates to drug world, relate to (Z)-2-imino group-5-(3,5-dimethoxy benzene methylene base)-1-Methylimidazole. alkane-4-ketone for the preparation of the application prevented and/or treated in the medicine of cardiovascular disease.
Background technology
In recent years. along with the method such as progress and artery bypass art, thrombolytic therapy, percutaneous intracavity Coronary angioplasty, department of cardiac surgery extracorporeal circulation, cardio-pulmonary-cerebral resuscitation, the replantation of amputated limb and organ transplantation of shock treatment foundation and apply, make many histoorgans again can obtain blood reperfusion after ischemia.As a rule, postischemic reperfusion can make tissue organ function be restored, and damaged structure is repaired, and conditions of patients is taken a turn for the better.But postischemic reperfusion not only can not make tissue, organ dysfunction recover sometimes, add re-organized, the dysfunction of organ and structural damage on the contrary.This on ischemia basis, recover blood flow after tissue injury increase the weight of on the contrary, the phenomenon that irreversible damage even occurs is called as ischemia/reperfusion injury (Ischemia-Reperfusion injury).
After myocardial ischemia/reperfusion injury shows as and makes ischemic myocardium obtain the Reperfu-sion of blood by treatment, the function of damaged myocardium is not restored, and degree of injury increases the weight of on the contrary, even occurs the irreversible damages such as Infarction volume expansion.Myocardial ischemia/reperfusion injury easily causes heart failure after heart infarction occurs, and has comparatively high mortality.
Along with the treatment technology means for myocardial ischemia raising and be widely used; the medicine preventing and treating myocardial ischemia/reperfusion injury has become important research direction, comprises calcium overload in T suppression cell, scavenging activated oxygen and antioxidant, anti-inflammatory response, cardiac metabolism protective agent etc.Above-mentionedly to resist myocardial ischemia/common feature of reperfusion injury medicine is: with strong points, action target spot clear and definite, but curative effect is single, and can only provide the protective effect of part, clinical efficacy is less, and has toxic and side effects in various degree.As, oxygen free radical scavenger vitamin E is fat-soluble antioxidant, needs orally to reach effective anti reperfusion injury concentration at cardiac muscle in a large number for a long time, still lacks objective science evaluation clinically.
Therefore, the pathophysiological mechanism of further investigation myocardial ischemia/reperfusion injury, finds/pharmaceutically-active the novel targets of reperfusion injury that resists myocardial ischemia, and the new drug researching and developing treatment myocardial ischemia/reperfusion injury with this is the work urgently explored.Therefore, little novel of active strong, the toxic and side effects of research and development resist myocardial ischemia/reperfusion injury medicine has important practical significance.
Summary of the invention
For above-mentioned situation, the object of the present invention is to provide and a kind ofly comprise multiple substituent imidazolidine compound and preparing the application in cardiovascular drugs, to solve the defect existing for existing medicine.
In order to reach foregoing invention object, the present invention adopts following technical scheme: a kind of compound is for the preparation of the application prevented and/or treated in the medicine of cardiovascular disease, described compound is (Z)-2-imino group-5-(3,5-dimethoxy benzene methylene base)-1-Methylimidazole. alkane-4-ketone ((Z)-2-imino-5-(3,5-dimethoxybenzylidene)-1-methylimidazolidin-4-one), its structural formula is such as formula shown in I:
；
Hereinafter this compound is called compound IV 5.
Pharmacological evaluation shows, and compound IV 5 has significant myocardium protecting action, obviously can reduce myocardial ischemia/reperfusion injury rat left ventricle infarct volume.Therefore, compound IV 5 is applicable to the medicine for the preparation of preventing and/or treating cardiovascular disease.
Preferably, described cardiovascular disease is ischemic cardiomyopathy or myocardial ischemia/reperfusion injury; Preferred, described myocardial ischemia/reperfusion injury is in commitment, with ill symptomses such as Refractory Arrhythmias, severe cardiac myocyte infringement and cardiac function declines.
Described compound IV 5 in the present invention both can be individually dosed, again can with one or more pharmaceutically acceptable carrier in combination administrations; Preferably, described pharmaceutically acceptable carrier includes, but is not limited to diluent, filler, coloring agent, correctives, lubricant, pigment etc.
Described compound IV 5 in the present invention both can as drug activity material unique in medicine, again can with one or more for preventing and/or treating the reactive compound combination formulations of cardiovascular disease (particularly ischemic cardiomyopathy, myocardial ischemia/reperfusion injury); Preferably, described reactive compound includes, but is not limited to nifedipine, verapamil, ligustrazine, puerarin, trimetazidine, ulinastatin etc.
Described medicine in the present invention can make corresponding dosage form as tablet, capsule, granule, pill, powder, solution, injection, suppository, liniment etc. according to the method known in pharmaceutical field, be applicable to oral, rectum, locally, oral cavity, Sublingual, subcutaneous, the multiple route of administration such as muscle, vein.In addition, the consumption of the described medicine in the present invention can adjust according to factors such as the order of severity of the physiological feature of patient, disease and concrete dosage forms and revise.
Due to the utilization of technique scheme, the present invention compared with prior art has following advantages:
The invention provides a kind of medical usage of polysubstituted imidazolidine compound; this compound has significant myocardium protecting action; obviously can reducing myocardial ischemia/reperfusion injury rat left ventricle infarct volume, being applicable to the medicine for the preparation of preventing and/or treating cardiovascular disease (particularly the disease such as ischemic cardiomyopathy, myocardial ischemia/reperfusion injury).
Accompanying drawing explanation
Fig. 1 be compound IV 5(0.1 obtained in embodiment 1,1,10 μM) rate (LDH) spills on non-scarce sugared hypoxia/reoxygenation-stimulated myocardial cell lactic acid dehydrogenase affect schematic diagram.
Fig. 2 is that compound IV 5 obtained in embodiment 1 suppresses to lack myocardial cell LDH that sugared hypoxia/reoxygenation-stimulated (OGD/R) induces and spills the effect schematic diagram that rate increases.
Fig. 3 is the effect schematic diagram that compound IV 5 obtained in embodiment 1 reduces the left ventricle infarct volume of myocardial ischemia/reperfusion injury rat.
Detailed description of the invention
Below in conjunction with the accompanying drawings and the specific embodiments further description is made to the present invention.
Embodiment 1:(Z) preparation of-2-imino group-5-(3,5-dimethoxy benzene methylene base)-1-Methylimidazole. alkane-4-ketone (compound IV 5).
By 3,5-dimethoxy benzaldehyde (0.83g, 5mmol), creatinine (0.57g, 5mmol), the sodium acetate (2.05g of melting, 25mmol) under reflux conditions stir 10h with glacial acetic acid (7mL), after being cooled to room temperature, add 5mL water, sucking filtration, washing, adopts DMF and water recrystallization, obtains the deep yellow brown crystal of 1.09g (compound IV 5), yield 84.2%, physical and chemical identification result is as follows:
mp：222~223℃；
IR (KBr, cm
-1): 3287，2999，2842，1703, 1660，1588，1558，1505，1458；
1H-NMR (400MHz, DMSO-d
6): δ (ppm) 3.17 (s, 3H, CH
3), 3.79 (s, 6H, CH
3), 6.139 (s, 1H, =CH), 6.216 (s, 1H, Ar), 7.58 (s, 2H, ArH)；
HR-MS:C
13h
15n
3o
3theoretical value: 261.1113, actual value: 261.1111.
Embodiment 2: the primary cardiomyocytes of compound IV 5 pairs of In vitro culture lacks the protective effect of sugared anoxia/reperfusion injury.
Neonatal Rat Primary Cardiomyocytes is cultivated 72h, be divided into non-scarce sugared hypoxia/reoxygenation-stimulated matched group (being expressed as in Fig. 1 " normally ") at random, non-scarce sugared hypoxia/reoxygenation-stimulated+IV5 group (is expressed as in Fig. 1 " IV5 ", wherein the consumption of IV5 is respectively 0.1,1,10 μM), lack sugared hypoxia/reoxygenation-stimulated group (being expressed as in Fig. 2 " OGD/R ") and lack sugared hypoxia/reoxygenation-stimulated+IV5 group (be expressed as in Fig. 2 " OGD/R+IV5 ", wherein the consumption of IV5 is respectively 0.1,1,10 μM).Lack sugared anoxic treatment 3h, change normal glucose culture medium subsequently and reoxygenation 12h, adopt LDH method to detect cell injury degree, and spill rate (%)=A by following formulae discovery lactic acid dehydrogenase (LDH)
culture fluid/ (A
culture fluid+ A
cell homogenates liquid) × 100%.
The compound IV 5 being used alone various dose spills rate impact (mean ± SD, n=6) on myocardial cell LDH is shown in Fig. 1.Therefrom known, compared with Normal group, be used alone IV5 and rate is spilt to LDH have no significant effect, compound IV 5 pairs of normal myocardial cells free of toxic effects of above dosage are described.
The myocardial cell LDH showing compound IV 5 pairs of OGD/R inductions in Fig. 2 spills inhibitory action (mean ± SD, the n=6 of rate increase; Compared with OGD/R group, * * p <0.01).Therefrom known; compared with Normal group; in OGD/R group, LDH spills rate significantly increases; after the compound IV 5 using various dose; the myocardial cell LDH of OGD/R induction spills rate increase obviously to be suppressed, and illustrates that the cellular sugar deficiency anoxia-induced apoptosis of IV5 to the Neonatal Rat Primary Cardiomyocytes of In vitro culture has protective effect.
Embodiment 3: the protective effect of compound IV 5 pairs of myocardial ischemia/reperfusion injury in rats.
Male SD rat, be divided at random matched group (sham operated rats is expressed as in Fig. 3 " CON "), model group, height, in and low dosage IV5 group (wherein the consumption of IV5 is respectively 4mg/kg, 2mg/kg and 1mg/kg), often organize 10.Adopt the left anterior descending method of following coronary artery occlusion to make myocardial ischemia in rats model, Reperfu-sion after ischemia 30min, in the Reperfu-sion total intravenous injection IV5 of neck at once, with the administration of various dose isometric(al).IV5 is observed on the impact of left ventricle Infarction volume with TTC staining.
Effect (mean ± SD, n=10 that compound IV 5 reduces rat left ventricle infarct volume is shown in Fig. 3; Compared with model group, * * p<0.01).Therefrom known, compound IV 5 pairs of myocardial ischemia/reperfusion injury in rats have protective effect.
According to above result, compound IV 5 pairs of rats lack sugared anoxia-induced apoptosis and myocardial ischemia/reperfusion injury has certain protective effect, may be used for the prevention and therapy of myocardial ischemia disease.
Claims (10)
1. a compound is for the preparation of the application prevented and/or treated in the medicine of cardiovascular disease, described compound is (Z)-2-imino group-5-(3,5-dimethoxy benzene methylene base)-1-Methylimidazole. alkane-4-ketone, its structural formula is such as formula shown in I:
。
2. application according to claim 1, is characterized in that, described cardiovascular disease is ischemic cardiomyopathy.
3. application according to claim 1, is characterized in that, described cardiovascular disease is myocardial ischemia/reperfusion injury.
4. application according to claim 3, is characterized in that, described myocardial ischemia/reperfusion injury is in commitment.
5. application according to claim 1, is characterized in that, except such as formula except the compound shown in I, described medicine also comprises one or more pharmaceutically acceptable carriers.
6. application according to claim 5, is characterized in that, described pharmaceutically acceptable carrier comprises diluent, filler, coloring agent, correctives, lubricant and pigment.
7. application according to claim 1, is characterized in that, except such as formula except the compound shown in I, described medicine also comprises one or more for preventing and/or treating the reactive compound of cardiovascular disease.
8. application according to claim 7, is characterized in that, described reactive compound comprises nifedipine, verapamil, ligustrazine, puerarin, trimetazidine and ulinastatin.
9. application according to claim 1, is characterized in that, the dosage form of described medicine is tablet, capsule, granule, pill, powder, solution, injection, suppository or liniment.
10. application according to claim 1, is characterized in that, described medicine is applicable to oral, rectally, topical, oral administration, sublingual administration, subcutaneous injection, intramuscular injection or intravenous injection.
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| CN201510445254.9A CN104983731B (en) | 2015-07-27 | 2015-07-27 | (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 |
|---|---|---|---|---|
| CN107510840A (en) * | 2017-07-25 | 2017-12-26 | 广东天普生化医药股份有限公司 | Purposes of the composition containing UTI in skin injury medicine caused by treatment chemicotherapy is prepared |
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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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| 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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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107510840A (en) * | 2017-07-25 | 2017-12-26 | 广东天普生化医药股份有限公司 | Purposes of the composition containing UTI in skin injury medicine caused by treatment chemicotherapy is prepared |
| CN107510840B (en) * | 2017-07-25 | 2018-05-22 | 广东天普生化医药股份有限公司 | Purposes of the composition containing ulinastatin in skin injury drug caused by preparation treatment chemicotherapy |
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