CN109045027A - The drug and application for preventing and treating ischemic heart disease or ischemic cerebral disease or thrombosis - Google Patents
The drug and application for preventing and treating ischemic heart disease or ischemic cerebral disease or thrombosis Download PDFInfo
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Abstract
The invention discloses prevention and treatment ischemic heart disease or the drug and application of ischemic cerebral disease or thrombosis, the drug includes indole-3-carbinol and its derivative or di-indole methyl hydride and its derivative；The drug further includes its pharmaceutically acceptable carrier, and the carrier includes beverage or food；The drug can be used for treating and preventing coronary atherosclerotic heart disease, the ischemic heart disease because caused by inflammation thrombus, embolism or damage lead to luminal stenosis or occlusion, thrombosis and cerebral infarction, ischemia apoplexy, cerebral thrombosis, cerebral embolism, lacunar ischemia apoplexy, multiple ischemia apoplexy and cockleshell.
Description
Technical field
The present invention relates to pharmaceutical technology field, specifically a kind of prevention and treatment ischemic heart disease or ischemic cerebral disease or thrombus shape
At drug and application.
Background technique
In recent years, as the change of socio-economic development, eating habit and environment, the aggravation of rhythm of life and population are old
The morbidity and mortality of the acceleration of age process, cardiovascular and cerebrovascular disease in worldwide, coronary heart disease and headstroke show
The trend risen year by year.Coronary atherosclerotic heart disease number of patients is calculated according to " Chinese cardiovascular disease report 2016 "
Reach 11,000,000.Ischemic heart disease, also known as coronary heart disease, including coronary artery occur atherosclerotic lesion and cause
Lumen of vessels stenosis or occlusion causes heart disease caused by myocardial ischemia, anoxic or necrosis.Other diseases include inflammation, embolism
Etc. may also lead to luminal stenosis or occlusion, and cause ischemic myocardium sick.Ischemic cerebral disease refers to cerebrovascular stenosis or occlusion, leads to brain
Bloodstream blocking and make brain tissue occur hypoxic-ischemic, softening even necrosis, cause cerebrovascular function obstacle, cause related symptoms.
Ischemic cerebral disease includes in ischemia apoplexy, cerebral thrombosis, cerebral embolism, lacunar ischemia apoplexy and multiple ischemic brain
Wind and cockleshell.
Although very big progress is had been achieved on therapeutic strategy and means at present, ischemic heart disease or ischemic brain
The prognosis of patient is still poor.What therefore searching was new can prevent and treat thrombosis, reduce hypoxic-ischemic cardiac muscle cell or brain
Cell death, so that reducing the drug of myocardial infarction area and cerebral infarction area has important clinical significance.
Indole-3-carbinol (INDOLE-3-CARBINOL；INDOLE-3-METHANOL；I3C) in most of Cruciferae
Content in vegetables is relatively high, can extract and obtain from brassicaceous vegetable (such as broccoli, radish and cauliflower).Indoles-
3- methanol has a variety of promising biological characteristics, has anticancer, anti-oxidant and anti-inflammatory activity.In the past research shows that indoles-
3- methanol is able to suppress the occurrence and development of the kinds of tumors such as head-neck carcinoma, cutaneum carcinoma, liver cancer, breast cancer.Due to indoles -3- first
Alcohol derives from food, almost without side-effects, has great development prospect.
Have not yet to see the report in relation to being applied in prevention and treatment ischemic heart disease or ischemic cerebral disease with indole-3-carbinol
Road.
Summary of the invention
The purpose of the present invention is to provide the drug for preventing and treating ischemic heart disease or ischemic cerebral disease or thrombosis and answer
With to solve the problems mentioned in the above background technology.
To achieve the above object, the invention provides the following technical scheme:
The drug of ischemic heart disease or ischemic cerebral disease or thrombosis is prevented and treated, the drug includes indole-3-carbinol
And its derivative or di-indole methyl hydride and its derivative.
One kind with following structural formula (I) indole-3-carbinol and its derivative preparation prevention and treatment ischemic heart disease or
Application in ischemic cerebral disease or thrombosis drug,
Wherein, Rl, R2, R4, R5, R6, R7 are respectively H, phenyl, benzoyl, Cl-C1O acyl group, halogenic substituent, nitre
One of base, Cl-C1O alkyl, Cl-C1O alkoxy.
Further, in the structure formula (I), R1 be one of phenyl, benzoyl, Cl-C1O acyl group, R2, R4,
R5, R6, R7 are hydrogen.
Further, in the structure formula (I), R5 be hydroxyl, methoxyl group, halogenic substituent, nitro, Cl-C1O alkyl,
One of Cl-C1O acyl group, R1, R2, R4, R6, R7 are hydrogen.
Further, in the structure formula (I), R1 is one of phenyl, benzoyl, Cl-C1O acyl group, and R5 is hydroxyl
One of base, methoxyl group, halogenic substituent, nitro, Cl-C1O alkyl, Cl-C1O alkoxy, Cl-C1O acyl group, R2, R4,
R6, R7 are hydrogen.
Further, in the structure formula (I), R1 is phenyl, benzoyl, halogenic substituent, nitro, Cl-C1O alkane
One of base, Cl-C1O alkoxy, Cl-C1O acyl group, R5 be one of hydroxyl, methoxyl group, Cl-C1O acyl group, R2, R4,
R6, R7 are hydrogen.
One kind with following structural formula (II) di-indole methyl hydride and its derivative preparation prevention and treatment ischemic heart disease or
Application in ischemic cerebral disease or thrombosis drug,
Wherein, Rl, R2, R4, R5, R6, R7, Rl ', R2 ', R4 ', R5 ', R6 ', R7 ' be respectively H, phenyl, benzoyl,
One of halogenic substituent, nitro, Cl-C1O alkyl, Cl-C1O alkoxy, Cl-C1O acyl group.
Further, in the structure formula (II), R1 and Rl ' are one of phenyl, benzoyl, Cl-C1O acyl group,
R2, R4, R5, R6, R7, R2 ', R4 ', R5 ', R6 ', R7 ' be hydrogen.
Further, in the structure formula (II), R5 and R5 ' be simultaneously hydroxyl, methoxyl group, halogenic substituent, nitro,
One of Cl-C1O alkyl, Cl-C1O acyl group, R1, R2, R4, R6, R7, Rl ', R2 ', R4 ', R6 ', R7 ' be hydrogen.
Further, in the structure formula (II), R1 and Rl ' are one of phenyl, benzoyl, Cl-C1O acyl group,
R5 and R5 ' is hydroxyl, methoxyl group, halogenic substituent, nitro, Cl-C1O alkyl, Cl-C1O alkoxy, one in Cl-C1O acyl group
Kind, R2, R4, R6, R7, R2 ', R4 ', R6 ', R7 ' be hydrogen.
Further, in the structure formula (II), R1 and Rl ' are phenyl, benzoyl, halogenic substituent, nitro, Cl-
One of C1O alkyl, Cl-C1O alkoxy, Cl-C1O acyl group, R5 and R5 ' be hydroxyl, methoxyl group, Cl-C1O acyl group, R2,
R4, R6, R7, R2 ', R4 ', R6 ', R7 ' be hydrogen.
Compared with prior art, the beneficial effects of the present invention are:
1) present invention has carried out experiment of the indole-3-carbinol to the survival rate of hypoxic-ischemic damaged cardiomyocytes, ties
Fruit shows that the survival rate of hypoxic-ischemic damaged cardiomyocytes can be improved in indole-3-carbinol, improves hypoxic-ischemic cardiac muscle cell's
ROS value (levels of reactive oxygen species) can significantly improve total SOD vigor, the lipid peroxidation of inhibitory activity oxygen induction, table
Bright indole-3-carbinol can prevent myocardial damage heart disease.
2) present invention is tested by external myocardial cells culture, the results show that hypoxic-ischemic can be improved in indole-3-carbinol
The survival rate of damaged cardiomyocytes；It is horizontal active with superoxide dismutase (SOD) to improve active oxygen (ROS)；Inhibit lipid mistake
Oxidation.
3) in experiment of the invention, toy Heart Brightness Mode inspection finds left systolic heart between experimental animal each group
Difference；Indole-3-carbinol significantly improves the heart function of ischemic myocardial rat model；Model group is obviously increased compared with negative control group
The ratio of H/BW, I3-C 20mg/kg, I3-C 50mg/kg can be substantially reduced the ratio of H/BW caused by ISO
Increase；SD rat oral gavage prevention administration is given within continuous 7 days, I3C low dose group (20mg/kg) and I3C high dose group (50mg/kg) are dead
Rat quantity is died considerably less than model group (P < 0.05), the results showed that I3C is in low dosage (20mg/kg) and I3C high dose
There is prevention and treatment mortality risk effect when (50mg/kg).The I3C can be used as therapeutic agent and be applied to treatment Atherosclerosis
Change.
4) present invention has studied the pharmacological action that indole-3-carbinol treats ischemic cerebral disease in rat model, as a result shows
Show, the indole-3-carbinol can be used as therapeutic agent and be applied to the ischemic cerebral diseases such as treatment cerebral infarction.
5) present invention has studied indole-3-carbinol to external people rich in adenosine diphosphate (ADP) in the blood plasma (PRP) of blood platelet
(ADP) influence of the platelet aggregation induced, discovery I3C can dose-dependently inhibit the blood platelet that ADP is induced in people PRP
Aggregation.The indole-3-carbinol can inhibit platelet aggregation.
6) indole-3-carbinol described in has significant protective effect to Ischemic Heart and brain tissue, can prepare prevention and treatment and lack
The drug of hemorrhagic heart disease or ischemic cerebral disease or thrombosis.
Detailed description of the invention
Fig. 1 is influence of the I3C to the survival rate of hypoxic-ischemic damaged cardiomyocytes.
Fig. 2 is influence of the I3C to active oxygen (ROS) level in hypoxic-ischemic damaged cardiomyocytes.
Fig. 3 is influence of the I3C to superoxide dismutase (SOD) in hypoxic-ischemic damaged cardiomyocytes.
Fig. 4 is influence of the I3C to hypoxic-ischemic damaged cardiomyocytes inner lipid peroxidating.
Fig. 5 is influence of the I3C to ischemic myocardial rat model death.
Fig. 6 is the Heart function test that I3C improves ischemic myocardial rat model, rat left chamber's ejection fraction of each experimental group
(LVEF) value.
Fig. 7 is the Heart function test that I3C improves ischemic myocardial rat model, and score shortens in the rat left chamber of each experimental group
(LVFS) value.
Fig. 8 is cardiac weight/weight ratio that I3C significantly reduces ischemic myocardial rat model.
Fig. 9 is that I3C reduces the postoperative Infarction volume of intraluminal middle cerebral artery occlusion in rats occlusion.
Figure 10 is influence of the I3C to people rich in the platelet aggregation of ADP induction in the blood plasma of blood platelet.
Specific embodiment
The technical solution of the patent is explained in further detail With reference to embodiment.
Embodiment 1
One kind with following structural formula (I) indole-3-carbinol and its derivative preparation prevention and treatment ischemic heart disease or
Application in ischemic cerebral disease or thrombosis drug,
Wherein, Rl, R2, R4, R5, R6, R7 are respectively H, phenyl, benzoyl, Cl-C1O acyl group, halogenic substituent, nitre
One of base, Cl-C1O alkyl, Cl-C1O alkoxy.
Embodiment 2
On the basis of embodiment.In the structure formula (I), R1 is phenyl, benzoyl, one in Cl-C1O acyl group
Kind, R2, R4, R5, R6, R7 are hydrogen.
Embodiment 3
On the basis of embodiment 1.In the structure formula (I), R5 is hydroxyl, methoxyl group, halogenic substituent, nitro, Cl-
One of C1O alkyl, Cl-C1O acyl group, R1, R2, R4, R6, R7 are hydrogen.
Embodiment 4
On the basis of embodiment 1.In the structure formula (I), R1 is phenyl, benzoyl, one in Cl-C1O acyl group
Kind, R5 is hydroxyl, methoxyl group, halogenic substituent, nitro, Cl-C1O alkyl, Cl-C1O alkoxy, one in Cl-C1O acyl group
Kind, R2, R4, R6, R7 are hydrogen.
Embodiment 5
On the basis of embodiment 1.In the structure formula (I), R1 be phenyl, benzoyl, halogenic substituent, nitro,
One of Cl-C1O alkyl, Cl-C1O alkoxy, Cl-C1O acyl group, R5 are hydroxyl, methoxyl group, one in Cl-C1O acyl group
Kind, R2, R4, R6, R7 are hydrogen.
Embodiment 6
One kind with following structural formula (II) di-indole methyl hydride and its derivative preparation prevention and treatment ischemic heart disease or
Application in ischemic cerebral disease or thrombosis drug,
Wherein, Rl, R2, R4, R5, R6, R7, Rl ', R2 ', R4 ', R5 ', R6 ', R7 ' be respectively H, phenyl, benzoyl,
One of halogenic substituent, nitro, Cl-C1O alkyl, Cl-C1O alkoxy, Cl-C1O acyl group.
Embodiment 7
On the basis of embodiment 6.In the structure formula (II), R1 and Rl ' are phenyl, benzoyl, Cl-C1O acyl group
One of, R2, R4, R5, R6, R7, R2 ', R4 ', R5 ', R6 ', R7 ' be hydrogen.
Embodiment 8
On the basis of embodiment 6.In the structure formula (II), R5 and R5 ' are hydroxyl, methoxyl group, halogen substitution simultaneously
One of base, nitro, Cl-C1O alkyl, Cl-C1O acyl group, R1, R2, R4, R6, R7, Rl ', R2 ', R4 ', R6 ', R7 ' be
Hydrogen.
Embodiment 9
On the basis of embodiment 6.In the structure formula (II), R1 and Rl ' are phenyl, benzoyl, Cl-C1O acyl group
One of, R5 and R5 ' they are hydroxyl, methoxyl group, halogenic substituent, nitro, Cl-C1O alkyl, Cl-C1O alkoxy, Cl-C1O
One of acyl group, R2, R4, R6, R7, R2 ', R4 ', R6 ', R7 ' be hydrogen.
Embodiment 10
On the basis of embodiment 6.In the structure formula (II), R1 and Rl ' be phenyl, benzoyl, halogenic substituent,
One of nitro, Cl-C1O alkyl, Cl-C1O alkoxy, Cl-C1O acyl group, R5 and R5 ' are hydroxyl, methoxyl group, Cl-C1O acyl
Base, R2, R4, R6, R7, R2 ', R4 ', R6 ', R7 ' be hydrogen.
Embodiment 11
On the basis of embodiment 1.The drug further includes indole-3-carbinol and its pharmaceutically acceptable load of derivative
Body.The carrier includes beverage or food.
The drug of embodiment 1-11 can be used for preparing the medicine of prevention and treatment ischemic heart disease or ischemic cerebral disease or thrombosis
Object, the ischemic heart disease include: coronary atherosclerotic heart disease, because inflammation thrombus, embolism or damage cause
Ischemic heart disease caused by luminal stenosis or occlusion；The ischemic cerebral disease includes: cerebral infarction, ischemia apoplexy, brain blood
Bolt, cerebral embolism, lacunar ischemia apoplexy, multiple ischemia apoplexy and cockleshell；The thrombosis includes: quiet
Thrombosis when thrombosis, hemodialysis shunt thrombosis formation, arrhythmia cordis when arteries and veins thrombosis, cardiopulmonary bypass surgery.
1 indole-3-carbinol of experimental example (I3C) improves cell viability experiment
It establishes experimental model: taking 1-3 age in days SD suckling mouse, aseptic condition coring is dirty, cleans in PBS, shreds, and moves into 5ml
Containing 15% pancreatin centrifuge tube, room temperature digests 5 minutes, while gently being blown and beaten with pasteur pipet 2-3 minutes, receives after digestion every time
Collect supernatant, appropriate serum stops digestion, repeats 6-8 times, until 4 DEG C, 1400 turns, being centrifuged 10mn without precipitating.Collect cell precipitation
Adjusting cell density is 10-6.With the DMEM/F-12 culture medium culture containing 10% fetal calf serum, third day is for testing.Research
It is divided into negative control group, hypoxic-ischemic model group (not giving pharmaceutical intervention, 5%CO2 peacefulness packet hypoxic-ischemic 6h), low dose of I3C
Measure (100nm/ml) group, I3C middle dosage (200nm/ml) group, I3C high dose group (400nm/ml).Negative control group, which uses, to be contained
The DMEM/F-12 culture of 10% fetal calf serum is based on the culture of common CO 2 incubator.Low dose of hypoxic-ischemic model group, I3C
Amount group, middle dose group, high dose group use the DMEM sugar-free culture-medium culture of serum-free.I3C low dose group, middle dose group, height
After dosage group handles cell with the I3C that concentration is 100nm/ml, 200nm/ml, 400nm/ml respectively, it is placed in anaerobism bag, anaerobism
Bag, which is placed in 37 DEG C of incubator, to be cultivated 6 hours.Hypoxic-ischemic treated cell is used as experiment detection.
Cell changes the culture of the DMEF/F-12 containing appropriate CCK-8 reagent into after hypoxic-ischemic is handled, by culture solution
Liquid.37 DEG C are then incubated for 2 hours, detect absorbance in 450nm with microplate reader, are used as detection cell viability.As a result such as Fig. 1 institute
Show, hypoxic-ischemic model group survival rate is significantly lower than negative control group, and each concentration of indole-3-carbinol can significantly improve cell and deposit
Motility rate, one-way analysis of variance P < 0.05.
ROS value (the water of reactive oxygen species of 2 indole-3-carbinol of experimental example (I3C) raising hypoxic-ischemic cardiac muscle cell
It is flat) experiment
It is used according to the method in experimental example 1 and establishes experimental model.Intracellular reactive is detected using DCFH-DA fluorescence probe
Oxygen level.Primary cardiomyocytes kind reaches 80% or so in 96 orifice plates, third day cardiac muscle cell's density.It is said according to ROS kit
Bright book detects intracellular reactive oxygen level with fluorescence microplate reader, as a result as shown in Fig. 2, hypoxic-ischemic model group intracellular reactive
Oxygen level is significantly lower than negative control group, and each concentration of indole-3-carbinol can significantly improve intracellular reactive oxygen level, single factor test
Variance analysis P < 0.05.
3 indole-3-carbinol of experimental example (I3C) improves SOD activity experiment
It is used according to the method in experimental example 1 and establishes experimental model.Superoxide dismutase (SOD) to the oxidation of body with
Anti-oxidant balance plays a crucial role.This enzyme can remove ultra-oxygen anion free radical, protect cells from damage.Using
Xanthine oxidase (hydroxylamine assay) measures SOD vigor, every milligram of histone in 1ml reaction solution inhibiting rate up to 50% when institute
Corresponding SOD amount is a SOD unit of activity (U).As a result as shown in figure 3, hypoxic-ischemic model group total SOD vigor is bright into the cell
It is aobvious to be lower than negative control group, and total SOD vigor significantly increases each concentration group of indole-3-carbinol compared with hypoxic-ischemic model group into the cell
(P<0.05)。
The experiment of experimental example 4 indole-3-carbinol (I3C) anti-lipid peroxidation
It is used according to the method in experimental example 1 and establishes experimental model.Body generates oxygen certainly by enzyme system and non-enzyme system
By base, the latter can attack the polyunsaturated fatty acid (PUFA) in biomembrane, cause lipid peroxidation, and therefore form lipid mistake
Oxide malonaldehyde (MDA).MDA can be condensed with thio barbital, form red product, there is maximum absorption band at 532nm.Knot
Fruit is as shown in figure 4, hypoxic-ischemic model group cytolipin peroxidating is apparently higher than negative control group, and indole-3-carbinol is each dense
Degree can be substantially reduced lipid within endothelial cells levels of peroxide (P < 0.05), show that indole-3-carbinol can inhibit active oxygen induction
Lipid peroxidation.
5 indole-3-carbinol of experimental example (I3C) significantly improves the heart function of ischemic myocardial rat model, reduces heart weight
Amount/weight ratio and reduction death rate experiment
By Sprague-Dawley (SD) rat 60, it is randomly divided into 4 groups, every group 12, comprising: saline control
Group, hypoxic-ischemic model group, I3C low dose group (20mg/kg), I3C high dose group (50mg/kg).I3C low dose group (20mg/
Kg), I3C high dose group (50mg/kg) is continuously given before isoprel (ISO) prepares ischemic myocardial rat model
I3C gastric infusion 7 days, carry out prevention administration；Then ISO 5mg/kg/ days, while stomach-filling I3C is subcutaneously injected, carries out one daily
It is secondary, continue 7 days；Independent I3C gastric infusion 15 days again.Saline control group rat is not given without ISO, whole process is subcutaneously injected
Give I3C stomach-filling.ISO 5mg/kg/ days is subcutaneously injected in hypoxic-ischemic model group rats, continues 7 days, and whole process does not give I3C stomach-filling.
Influence of the I3C to each group surviving rats is observed, carries out rat heart ultrasound diagnosis before finally putting to death rat.Rat is finally put to death, is stayed
Coring is dirty, heart weighing is carried out, for illustrating cardiac hypertrophy situation.
Rat is expert at before Heart Brightness Mode inspection, control group, hypoxic-ischemic model group, I3C low dose group (20mg/kg) and I3C
High dose group (50mg/kg) rat difference dead 0,8,4 and 2.Card side's exact probability examines display I3C low dose group
(20mg/kg) and I3C high dose group (50mg/kg) rat cadavers quantity are considerably less than hypoxic-ischemic model group (P < 0.05).
As a result see that Fig. 5, I3C have prevention and treatment mortality risk effect in low dosage (20mg/kg) and I3C high dose (50mg/kg).
The row Heart Brightness Mode inspection after the end of the experiment of remaining survival rats shortens score with ejection fraction (LVEF) and left room
(LVFS) assessment models Cardiac Function in Rat is horizontal.As a result see Fig. 6-7.Compared with negative control group, hypoxic-ischemic model group, Yin
Diindyl -3- methanol is low, LVEF and LVFS of high dose group rat have different degrees of reduction (P < 0.05), shows that ISO can be damaged
Cardiac Function in Rat.Compared with hypoxic-ischemic model group, indole-3-carbinol is low, LVEF and LVFS of high dose group rat have increasing
Add.Indole-3-carbinol can improve the heart function of ischemic myocardial rat model: ISO effect weakens Cardiac Function in Rat, and I3C makees
With can weaken this damage, and I3C concentration increases, and protective effect increases.The left room contracting of Left Ventricular Ejection Fraction LVEF 55-80%
Short rate LVFS 30% or so.
After completing Heart Brightness Mode inspection, rat is put to death, chest is opened rapidly and takes out rat heart, with the conscientious chamber of normal saline flushing
Residual blood, filter paper blot rear heart weighing.As a result see that Fig. 8, the ratio of hypoxic-ischemic model group rats H/BW are more negative
Property control group obviously increases.I3-C20mg/kg, I3-C50mg/kg group rat heart and the ratio of weight are compared with hypoxic-ischemic model
Group is obviously reduced, it was demonstrated that I3C can be obviously improved cardiac hypertrophy caused by subcutaneous injection ISO.
The above results show that indole-3-carbinol can significantly improve the heart function of ischemic myocardial rat model, reduce heart
Weight/weight ratio and the reduction death rate.
6 indole-3-carbinol of experimental example (I3C) reduces intraluminal middle cerebral artery occlusion in rats and occludes postoperative Infarction volume experiment
Male SD rat is divided into 5 groups (every group 6), is sham-operation group (physiological saline) respectively, model group, low dose of I3C
Amount group (10mg/kg), I3C middle dose group (20mg/kg), I3C high dose group (50mg/kg).It is closed with intracavitary suture block system
Right side arteria cerebri media prepares intraluminal middle cerebral artery occlusion in rats and occludes (MCAO) model.After ischaemic 2 hours or in Reperfu- sion
I3C is given by the way that oral gavage is oral.Treatment continues once a day, to continue 14 days.Rats in sham-operated group after surgical incision,
Arteria cerebri media crosses line but does not ligature closing, and after myometrial suture, normal diet, whole process does not give I3C.MCAO model group rats mouth
Take that gavage is oral to give the solvent without I3C.I3C low dose group, I3C middle dose group and I3C high dose group take orally strong respectively
Feeding is oral to give I3C 10mg/kg, 20mg/kg and 50mg/kg treatment, once a day, continues 14 days.Last time administration 1
After hour, rat is implemented to be euthanized, and collect brain tissue, for measuring infarct volume.By every group of rat brain at -20 DEG C
Freeze 5 minutes and be cut into the coronal section of 2mm thickness.It will be sliced at 37 DEG C in phosphate buffered saline (PBS) (PBS, pH 7.4)
It is incubated 20 minutes in 2% triphenyl tetrazolium chloride (TTC) solution.The color image of these slices is captured, and using suitable
Software calculates the size of infraction.As a result see Fig. 9, sham-operation group is significantly higher than without cerebral infarction, model group cerebral infarct volume up to 30%
Sham-operation group (P < 0.05)；Compared with model group, three I3C dosage groups (10,20 and 50mg/kg) substantially reduce and MCAO
Rat infarct volume (P < 0.05).
7 indole-3-carbinol of experimental example (I3C) dose-dependently inhibits platelet aggregation test
Take healthy volunteer's blood into the plastic injector containing 1000U heparin sodium/ml (0.9% salt water) solution.First 4
1200rpm is centrifuged 5 minutes at DEG C, takes blood plasma, is then centrifuged 10 minutes in 1600rpm, is obtained the blood plasma (PRP) containing blood platelet.
Concentration is added in 500 μ l PRP respectively in I3C low dose group (1 μM), I3C middle dose group (10 μM), I3C high dose group (50 μM)
For 1 μM, 10 μM, 50 μM of I3C, stir and evenly mix, blank control adds the solvent without I3C.After five minutes, each group is at 1200rpm
Stirring, and 10 μM of ADP are added into blood platelet, light transmissive variation in 5 minutes is detected after stimulation.The result is shown in Figure 10, with blank pair
Photograph ratio, I3C dose-dependently inhibit the platelet aggregation (P < 0.05) that ADP is induced in people PRP.
The preferred embodiment of the patent is described in detail above, but this patent is not limited to above-mentioned embodiment party
Formula within the knowledge of one of ordinary skill in the art can also be under the premise of not departing from this patent objective
Various changes can be made.
Claims (11)
1. the drug for preventing and treating ischemic heart disease or ischemic cerebral disease or thrombosis, which is characterized in that the drug includes Yin
Diindyl -3- methanol and its derivative or di-indole methyl hydride and its derivative.
2. indole-3-carbinol and its derivative of the one kind with following structural formula (I) in preparation prevention and treatment ischemic heart disease or lack
Application in hemorrhagic encephalopathy or thrombosis drug,
Wherein, Rl, R2, R4, R5, R6, R7 be respectively H, phenyl, benzoyl, Cl-C1O acyl group, halogenic substituent, nitro,
One of Cl-C1O alkyl, Cl-C1O alkoxy.
3. application according to claim 2, it is characterised in that: in the structure formula (I), R1 be phenyl, benzoyl,
One of Cl-C1O acyl group, R2, R4, R5, R6, R7 are hydrogen.
4. application according to claim 2, it is characterised in that: in the structure formula (I), R5 is hydroxyl, methoxyl group, halogen
One of substituent group, nitro, Cl-C1O alkyl, Cl-C1O acyl group, R1, R2, R4, R6, R7 are hydrogen.
5. application according to claim 2, it is characterised in that: in the structure formula (I), R1 be phenyl, benzoyl,
One of Cl-C1O acyl group, R5 be hydroxyl, methoxyl group, halogenic substituent, nitro, Cl-C1O alkyl, Cl-C1O alkoxy,
One of Cl-C1O acyl group, R2, R4, R6, R7 are hydrogen.
6. application according to claim 2, it is characterised in that: in the structure formula (I), R1 is phenyl, benzoyl, halogen
One of plain substituent group, nitro, Cl-C1O alkyl, Cl-C1O alkoxy, Cl-C1O acyl group, R5 are hydroxyl, methoxyl group, Cl-
One of C1O acyl group, R2, R4, R6, R7 are hydrogen.
7. di-indole methyl hydride and its derivative of the one kind with following structural formula (II) in preparation prevention and treatment ischemic heart disease or lack
Application in hemorrhagic encephalopathy or thrombosis drug,
Wherein, Rl, R2, R4, R5, R6, R7, Rl ', R2 ', R4 ', R5 ', R6 ', R7 ' be respectively H, phenyl, benzoyl, halogen
One of substituent group, nitro, Cl-C1O alkyl, Cl-C1O alkoxy, Cl-C1O acyl group.
8. application according to claim 7, it is characterised in that: in the structure formula (II), R1 and Rl ' are phenyl, benzene first
One of acyl group, Cl-C1O acyl group, R2, R4, R5, R6, R7, R2 ', R4 ', R5 ', R6 ', R7 ' be hydrogen.
9. application according to claim 7, it is characterised in that: in the structure formula (II), R5 and R5 ' be simultaneously hydroxyl,
One of methoxyl group, halogenic substituent, nitro, Cl-C1O alkyl, Cl-C1O acyl group, R1, R2, R4, R6, R7, Rl ', R2 ',
R4 ', R6 ', R7 ' are hydrogen.
10. application according to claim 7, it is characterised in that: in the structure formula (II), R1 and Rl ' are phenyl, benzene first
One of acyl group, Cl-C1O acyl group, R5 and R5 ' are hydroxyl, methoxyl group, halogenic substituent, nitro, Cl-C1O alkyl, Cl-
One of C1O alkoxy, Cl-C1O acyl group, R2, R4, R6, R7, R2 ', R4 ', R6 ', R7 ' be hydrogen.
11. application according to claim 7, it is characterised in that: in the structure formula (II), R1 and Rl ' are phenyl, benzene first
One of acyl group, halogenic substituent, nitro, Cl-C1O alkyl, Cl-C1O alkoxy, Cl-C1O acyl group, R5 and R5 ' are hydroxyl
Base, methoxyl group, Cl-C1O acyl group, R2, R4, R6, R7, R2 ', R4 ', R6 ', R7 ' be hydrogen.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
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| CN201811126747.6A CN109045027A (en) | 2018-09-26 | 2018-09-26 | The drug and application for preventing and treating ischemic heart disease or ischemic cerebral disease or thrombosis |
| PCT/CN2019/076751 WO2020062780A1 (en) | 2018-09-26 | 2019-03-01 | Medicament for preventing and treating ischemic heart diseases or ischemic encephalopathy or thrombosis and use thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811126747.6A CN109045027A (en) | 2018-09-26 | 2018-09-26 | The drug and application for preventing and treating ischemic heart disease or ischemic cerebral disease or thrombosis |
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|---|---|---|---|---|
| CN109674787A (en) * | 2019-02-01 | 2019-04-26 | 百迈康生物医药科技(广州)有限公司 | It is a kind of prevent and treat ischemic heart disease drug and its application |
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| WO2021242970A1 (en) * | 2020-05-29 | 2021-12-02 | Boulder Bioscience Llc | Methods for improved endovascular thrombectomy using 3,3'-diindolylmethane |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110301180A1 (en) * | 2010-04-23 | 2011-12-08 | Stanford University | Reducing Platelet Activation, Aggregation and Platelet-Stimulated Thrombosis or Blood Coagulation by Reducing Mitochondrial Respiration |
| CN102389419A (en) * | 2011-10-08 | 2012-03-28 | 合肥博太医药生物技术发展有限公司 | Application of indole-3-carbinol, diindolylmethane and derivatives thereof to preparation of medicine for preventing and controlling atherosclerosis |
| CN106377524A (en) * | 2016-08-16 | 2017-02-08 | 黄晶 | Application of indole-3-carbinol or dimer thereof |
| WO2018065132A1 (en) * | 2016-10-04 | 2018-04-12 | Institut National De La Recherche Agronomique | Use of ahr agonist for the preventive or curative treatment of metabolic syndrome and the associated disorders. |
-
2018
- 2018-09-26 CN CN201811126747.6A patent/CN109045027A/en active Pending
-
2019
- 2019-03-01 WO PCT/CN2019/076751 patent/WO2020062780A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110301180A1 (en) * | 2010-04-23 | 2011-12-08 | Stanford University | Reducing Platelet Activation, Aggregation and Platelet-Stimulated Thrombosis or Blood Coagulation by Reducing Mitochondrial Respiration |
| CN102389419A (en) * | 2011-10-08 | 2012-03-28 | 合肥博太医药生物技术发展有限公司 | Application of indole-3-carbinol, diindolylmethane and derivatives thereof to preparation of medicine for preventing and controlling atherosclerosis |
| CN106377524A (en) * | 2016-08-16 | 2017-02-08 | 黄晶 | Application of indole-3-carbinol or dimer thereof |
| WO2018065132A1 (en) * | 2016-10-04 | 2018-04-12 | Institut National De La Recherche Agronomique | Use of ahr agonist for the preventive or curative treatment of metabolic syndrome and the associated disorders. |
Non-Patent Citations (3)
| Title |
|---|
| BARBARA LICZNERSKA,WANDA BAER-DUBOWSKA: "Indole-3-Carbinol and Its Role in Chronic Diseases", 《ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY》 * |
| KAI LIANG,WEN-HAO QIAN,JING ZONG: "3,3"-Diindolylmethane attenuates cardiomyocyte 3,3"‑Diindolylmethane attenuates cardiomyocyte", 《MOLECULAR MEDICINE REPORTS》 * |
| PANKAJ PALIWAL,GAURAV CHAUHAN，DEEPA GAUTAM, ET AL: "Indole-3-carbinol improves neurobehavioral symptoms in a cerebral ischemic stroke model", 《NAUNYN-SCHMIEDEBERG"S ARCHIVES OF PHARMACOLOGY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109674787A (en) * | 2019-02-01 | 2019-04-26 | 百迈康生物医药科技(广州)有限公司 | It is a kind of prevent and treat ischemic heart disease drug and its application |
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