CN101070338A - Tanshinone IIA potassium sulfonate for preparing medicine for preventing and treating myocardial ischemia and cerebral ischemia and anoxia - Google Patents
Tanshinone IIA potassium sulfonate for preparing medicine for preventing and treating myocardial ischemia and cerebral ischemia and anoxia Download PDFInfo
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- CN101070338A CN101070338A CN 200710011736 CN200710011736A CN101070338A CN 101070338 A CN101070338 A CN 101070338A CN 200710011736 CN200710011736 CN 200710011736 CN 200710011736 A CN200710011736 A CN 200710011736A CN 101070338 A CN101070338 A CN 101070338A
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- tanshinone
- potassium sulfonate
- ischemia
- formula
- cerebral ischemia
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 title claims abstract description 68
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 title claims abstract description 67
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- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000009602 toxicology test Methods 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 230000001515 vagal effect Effects 0.000 description 1
- 208000021331 vascular occlusion disease Diseases 0.000 description 1
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Abstract
The invention relates to a synthesis process, a preparation and a new medical application of a novel water-soluble derivative tanshinone IIA potassium sulfonate (PTS) of tanshinone IIA. In particular to application of tanshinone IIA potassium sulfonate in preparing medicaments for preventing and treating myocardial ischemia and anoxia, cerebral ischemia and anoxia, improving microcirculation, enhancing memory and related diseases (cerebral thrombosis, acute cerebral ischemia, coronary heart disease, angina pectoris and myocardial infarction).
Description
Technical field
The present invention relates to the new soluble derivative Tanshinone II A potassium sulfonate of Tanshinone II A (potassium tanshinone IIAsulfonate, synthesis technique PTS), preparation and new medicinal use.Specific design Tanshinone II A potassium sulfonate is used for the purposes of preparation prevention and treatment myocardial ischemia-anoxemia, cerebral ischemia/anoxia, microcirculation improvement, hypermnesis and relative disease (cerebral thrombosis, acute cerebral ischemia, coronary heart disease, stenocardia, myocardial infarction) medicine.
Technical background
Cerebro-vascular diseases is the general name of the cerebrovascular disease that causes of the various causes of disease.Cerebro-vascular diseases and heart trouble, malignant tumour constitute three big fatal diseases of many countries jointly.
Cerebral ischemia is because cerebral blood supply insufficiency that a variety of causes causes or function stop make the neurone metabolic disturbance and stop, nerve cell death, and permanent lesion appears in pallium and vital center, and therefore produces various serious clinical symptom.
Cerebral ischemia (cerebral ischemia) is the healthy class disease of serious harm the elderly, its sickness rate height, disability rate height, also high as untimely processing mortality ratio.The generation of cerebral ischemia and thrombosis and cerebral vascular resistance increase closely related, and prevention thrombosis and cerebral blood flow increasing amount are the current important clinically methods of preventing and treating cerebral ischemia.
The drug main of treatment ischemic cerebrovascular disease will divide following a few class:
1, anti-freezing and thrombolytic drug
2, platelet aggregation inhibitor
3, vasodilator and calcium channel blocker
4, blood thinners
5, dewatering agent
6, cerebral protective agent
The mode of action of the medicaments for resisting myocardial ischemia of using clinically mainly contains following approach at present:
1, reduces myocardial consumption of oxygen: can realize by vasodilator, reducing heart rate and reduction left ventricular end diastolic volume;
2, increase the supply of myocardium oxygen; The supply of diastole coronary artery, promotion collateral circulation and the myocardium oxygen of promotion blood redistribution all can increasing;
3, improve myocardial metabolism; Realize by promoting metabolism of fat to be converted into sugar.
In addition, still can be by suppressing tonin, Na
+-H
+Exchange and link such as reducing heart rate and produce the effect that resists myocardial ischemia.
The red sage root is the dry root and rhizome of the labiate red sage root (Salvia miltiorrhiza Bunge), the property hardship, is slightly cold the thoughts of returning home, Liver Channel.As traditional Chinese medicine, in clinical side's medicine, be widely used.Be mainly used in stasis-dispelling and pain-killing, promoting blood circulation to restore menstrual flow, relieving restlessness etc. clears away heart-fire.Tanshinone II A (tanshinone IIA) is one of red sage root main component [Okumura, Y., et al., Bull.Chem.Soc. (Japan) 1961,34,895].The Tanshinone II A potassium sulfonate is the water-soluble cpds that this project obtains through the Tanshinone II A derivatize.Up to the present, yet there are no any report of relevant Tanshinone II A potassium sulfonate, and the report that is used to prevent and treat myocardial ischemia-anoxemia, cerebral ischemia/anoxia and relative disease with the Tanshinone II A potassium sulfonate.
Summary of the invention
The purpose of this invention is to provide a kind of application that is used to prevent and treat myocardial ischemia-anoxemia, cerebral ischemia/anoxia and relative disease suc as formula the Tanshinone II A potassium sulfonate shown in the I or its chemical composition in manufacturing.
Said Tanshinone II A potassium sulfonate of the present invention or its chemical composition can be used for following aspect
1. be used for the treatment of the cerebral ischemia/anoxia that cerebral thrombosis acute phase causes;
2. be used for the cerebral ischemia/anoxia that acute cerebral infarction causes;
3. being used for the prevention of brain thrombus takes place;
4. be used for the myocardial ischemia-anoxemia that Acute Myocardial Infarction causes;
5. be used for the treatment of the myocardial ischemia-anoxemia that coronary heart disease, stenocardia cause;
6. be used to prevent coronary heart disease, myocardial infarction, stenocardia;
8. be used for the cerebral ischemia/anoxia that the anxious thrombus sequela of prevention of brain causes;
The structural formula of the said Tanshinone II A potassium sulfonate of the present invention is suc as formula shown in the I.
Formula I
The inventor finds after deliberation, Tanshinone II A potassium sulfonate of the present invention enters in the blood, the peroxidatic reaction of lipid that can suppress cytolemma effectively, stabilizing cell membrane, particularly more obvious to the neuron operation of grey matter west structure, the damage that is caused when effectively alleviating cerebral ischemia reaches and eliminates oedema and remove the free radical effect.Show that the Tanshinone II A potassium sulfonate has prevention and treatment cerebral ischemia, reaches the good prospect with the cerebral ischemia relative disease
The present invention tests by animal pharmacology, determines that Tanshinone II A potassium sulfonate energy significant prolongation acute cerebral ischemia mouse and normal pressure are the survival time of anoxic mouse, simultaneously can significant prolongation NaNO
2The survival time of poisoning mice and ligation of carotid mouse, point out it can become the active drug that is used for myocardial ischemia-anoxemia, cerebral ischemia/anoxia and relative disease.
Cerebral blood supply interrupted after mouse breaked end, and caused acute cerebral ischemia, because interior original blood of cerebral tissue and nutritive substance still can make brain function keep blink, mouse demonstrates and clocklike dehisces to breathe, when energy consumes extremely to a certain degree activity end.With the time of breathing is that index can be observed the provide protection of medicine to cerebral ischemia, and all medicines that the brain oxygen consumption is reduced all can prolong breathing the time of mouse.Experimental result show the Tanshinone II A potassium sulfonate can significant prolongation decapitated mice breathe the time, point out this medical instrument that the effect of anti-acute cerebral ischemia, the power consumption of reduction brain oxygen consumption is arranged.The branch that coincide is arranged between the encephalic cerebrovascular of mouse, and symptoms of cerebral ischemia does not appear in the ligation bilateral common carotid arteries separately, and when with vagus nerve and arteria carotis communis ligation together, then the vagal stimulation blood pressure drops can cause cerebral ischemia.The Tanshinone II A potassium sulfonate can the significant prolongation mouse Carotid survival time of ligation.NaNO
2The model of being poisoned to death belongs to the extracellular fluid anoxic, and it can make the ferrohemoglobin in the peripheral blood be oxidized to the high price oxyphorase, and the oxygen content of blood is reduced, and causes histanoxia.The Tanshinone II A potassium sulfonate can make NaNO
2Poisoning mice survival time significant prolongation.Above-mentioned experimental result shows that the Tanshinone II A potassium sulfonate can prolong the survival time of anoxic animal due to the multiple reason, may utilize ability and relevant to the anoxybiotic tolerance to hypoxemia with its raising body.
In addition, this medicine mouse memory obstacle due to can antagonism Scopolamine, effect with hypermnesis.This medicine may be relevant with the effect of its expansion of cerebral vascular to the promoter action of study, memory.
The pathophysiological basis of myocardial ischemia is that the blood oxygen supply of cardiac muscle is unbalance, and the most basic prophylactico-therapeutic measures is to improve the blood confession, reduces the oxygen consumption, by remove or the antagonism objectionable impurities to the detrimentally affect of cardiac muscle to protect cardiac muscle.Often the experiment of mouse normal pressure anti-hypoxia is used as a kind of prescreening method of myocardial ischemic antagonist in China.Experimental result shows the survival time of inducing acute myocardial anoxia model mice under the Tanshinone II A potassium sulfonate energy significant prolongation normal pressure hypoxia tolerance condition with Racemic isoproterenol, pointing out this medicine is that the blood coefficient of oxygen utilization that improves body is arranged, reduce the body oxygen-consumption, increase heart the tolerance under the anoxic condition.And can resist effectively that Racemic isoproterenol causes that myocardial consumption of oxygen increases and the myocardial ischemia-anoxemia that causes improves heart function.As everyone knows, Pituitrin can shrink coronary artery, causes deficiency myocardial blood supply, and can shrink the little blood vessel of whole body, causes cardiac load to increase the weight of, and shows as the change of myocardial ischemia on electrocardiogram(ECG, alarms or low flat, heart disorder etc. as the T wave height.Experimental result shows that the Tanshinone II A potassium sulfonate has function of resisting myocardial ischemia preferably, can resist the ST section that Pit causes and move and decreased heart rate, and its effect is relevant with dosage.Yet its definite mechanism of action is still waiting further research.
During myocardial ischemia, hematoblastic gathering and release reaction strengthen, and there is platelet activation in prompting.The activated thrombocyte can discharge a large amount of ADP, TXA2 and the 5-HT isoreactivity factor further to bring out platelet aggregation.Thrombocyte is constantly assembled like snowball formula ground, and forms thrombus under the fellowship of zymoplasm etc., causes artery blood flow sharply to reduce or interrupts causing cerebral ischemia fully.This shows that platelet function is hyperfunction to be the major reason of cerebral ischemia morbidity, so medicament for resisting platelet aggregation has vital role at the prevention of brain ischemic.
After this shows cerebral infarction, thrombocyte is activated, secretory nerve toxicant or increase the weight of the damage of microcirculation disturbance and ischemic rat brain by platelet aggregation.Platelet aggregation test is the result show: the Tanshinone II A potassium sulfonate can significantly suppress AA inductive platelet aggregation, thereby suppresses hematoblastic activation, thereby the Tanshinone II A potassium sulfonate is prevented and treated the generation of cerebral ischemia should be with to suppress biologically active pdgf relevant.
Artery thrombosis and cerebral infarction are the main reasons that causes cerebral ischemia to take place.Cerebrovascular tension force increases, and the destruction of vessel wall itself is most important, the most direct factor that cerebral ischemia takes place.As everyone knows, in case blood vessel endothelium is impaired, not only the subendothelial layer of Bao Luing can make platelet adhesion reaction, gathering, thrombosis, and activated endogenous and extrinsic soagulation process, quicken thrombosis.The result of these combined factors effects has overcome the antithrombotic protection mechanism of blood vessel endothelium, so a thrombus that constantly increases causes the outbreak of vascular occlusion the most at last, causes ischemic generation.Given this; the this patent subject study Tanshinone II A potassium sulfonate to the thrombotic effect of rabbit arteria carotis communis; the result shows that the Tanshinone II A potassium sulfonate can significantly suppress the Carotid thrombosis of rabbit, and prompting Tanshinone II A potassium sulfonate has significant protective effect to the cerebral ischemia that artery thrombosis causes.
The present invention also provides a kind of medicine that is used to prevent and treat myocardial ischemia-anoxemia, cerebral ischemia/anoxia, wherein contains the Tanshinone II A potassium sulfonate shown in the formula I, and pharmaceutically acceptable auxiliary.This medicine can be made into the form of injection, tablet, pill, capsule, solution, suspensoid, emulsion.That the route of administration of this medicine can be is oral, through skin, vein or muscle.
The present invention tests by animal toxicology, and acute toxicity test shows that this medicine toxicity is very low, give maximum tolerated dose after mouse all survive, survivor's outward appearance, action are no abnormal, fail to measure LD
50Determine that Tanshinone I I A potassium sulfonate has no side effect the medicine that can take for a long time in the dose therapeutically effective scope.
Embodiment
Below the present invention will be further described by example.
Embodiment 1: the extraction of Tanshinone II A, separation and purifying in the red sage root
Dry red sage root 1kg, with 95% ethanol extracting 3 times, each 24 hours, extract was evaporated to 500mL, added 500mL water then, divide four extractions with the 1000mL trichloromethane, the extraction liquid concentrating under reduced pressure, column chromatography for separation, silica gel is 100～200 orders, elutriant is the petrol ether/ethyl acetate mixing solutions that contains 1%～10% ethyl acetate, carries out gradient elution.Can get the about 0.85g of Tanshinone II A.
Synthesizing of embodiment 2 Tanshinone II A potassium sulfonates
The synthesis technique of Tanshinone II A potassium sulfonate: get Tanshinone II A (purity is more than 20%) 50 grams, add 200 milliliters of aceticanhydrides, place three-necked bottle, under agitation dripped the 100 milliliters of vitriol oil-Glacial acetic acid (1: 1 in 10～15 ℃, V/V) mixed solution after dropwising, at room temperature stirred one hour, impouring isopyknic distilled water then blows slowly reaction solution, add saturated Repone K (chemical pure) aqueous solution of 1 liter at once, promptly have thick Tanshinone II A potassium sulfonate to separate out, centrifugal, throw out is washed twice with saturated potassium chloride solution, with an amount of washing once, make solids pH=5.6 again, solids is got in worry in water-bath, steamed to dry, solids refluxed 3 hours with chloroform earlier, remove the oil-soluble impurities of unsulfonated, reflux with dehydrated alcohol and remove remaining sodium-chlor, ethanol liquid concentrates, promptly there is red Tanshinone II A potassium sulfonate coarse crystallization to separate out, use recrystallizing methanol twice again, promptly get orange red needle crystal, after thorough drying, 194～196 ℃ of fusing points obtain about 10 grams of pure product.
Embodiment 3: Tanshinone II A potassium sulfonate toxicological test
Acute toxicity test in mice: test animal is healthy male mice in kunming.The test of employing intravenous methods.The full 100mg/kg of dosage (having reached maximum).Experiment back in 20 ± 1 ℃ freely drink water and the feed condition under breeding observing 7d, observation mouse survival condition and outward appearance show.
The result: mouse all survives after the administration, survivor's outward appearance, the action no abnormal, fail to measure LD
50Determine that the Tanshinone II A potassium sulfonate has no side effect in the dose therapeutically effective scope, the medicine that can take for a long time.
30 days toxicity tests of mouse: test animal is healthy male mice in kunming.The test of employing intravenous methods.Dosage is 50mg/kg/day, continuous 30 days.Test shows, is tried mouse and does not have death, grows, hemopoietic function, biochemical indicator etc. all do not have tangible ANOMALOUS VARIATIONS or toxic reaction the dissection inspection of vitals and organize microscopy not find pathological change.
Embodiment 4: the Tanshinone II A potassium sulfonate is in the test of animal (rat) interior medicine dynamics
Animal for research is healthy male rat.The test of employing intravenous methods.Give Tanshinone II A potassium sulfonate and sodium tanshinone IIA sulfate respectively, dosage 10,20,50mg/kg regularly take blood after the administration, use methanol extraction albumen, use HPLC and detect, and curve is similar substantially during both medicines, and pharmacokinetic parameter does not have significant difference.
Embodiment 5: the Tanshinone II A potassium sulfonate is to the test of the influence of acute cerebral ischemia mouse
Test animal is healthy male mice in kunming.The test of employing intravenous methods.With the mouse random packet, every group 11, respectively with physiological saline control group, positive drug sodium tanshinone IIA sulfate (sodium tanshinone IIA sulfonate, STS) control group (10mg/kg), basic, normal, high three the dosage groups of Tanshinone II A potassium sulfonate (PTS) (5,10,20mg/kg), every day 1 time, for three days on end.After the last administration 10 minutes, break end fast from the mouse ear rear portion, record begins once to breathe the time to the end (min) from broken end.Each organizes data, and (X ± SD) expression, its significance is judged in the t check between experimental result work group with means standard deviation.
The Tanshinone II A potassium sulfonate sees Table 1 to the provide protection measurement result of chmice acute hypoxic-ischemic.
Table 1 Tanshinone II A potassium sulfonate is to decapitated mice breathe influence (n=11, the Mean ± SD) of time
| Group | Persistent time(s) | Extended rate(％) |
| Dosage group PTS high dose group among the Saline STS PTS low dose group PTS | 19.09±2.39 23.07±2.08 *25.85±2.19 **26.30±2.81 **27.69±3.56 *** | --- 20.85 27.93 29.29 37.57 |
*P＜0.05,
*P＜0.01,
* *P＜0.001 is compared with physiological saline
By above experimental result as can be seen, basic, normal, high three the dosage groups of Tanshinone II A potassium sulfonate all have significant provide protection to the chmice acute hypoxic-ischemic, and its effect is relevant with dosage.Compare with the sodium tanshinone IIA sulfate of same dose, the effect of chmice acute hypoxic-ischemic is better than sodium tanshinone IIA sulfate.
This test is studied this medicine in pharmacological action aspect anti-cerebral ischemia, the anoxic with the chmice acute cerebral ischemic model.Behind the mouse broken end, cerebral blood supply stops, and at short notice, original blood and nutritive substance still can make brain function keep blink in the brain, and mouse demonstrates and clocklike dehisces to breathe, and is that index can be observed the provide protection of medicine to cerebral ischemia with the time of breathing.All medicines that the brain oxygen consumption is reduced all can prolong breathing the time of mouse.Experimental result Tanshinone II A potassium sulfonate can the significant prolongation decapitated mice be breathed the time, points out this medical instrument that the effect of anti-acute cerebral ischemia, the power consumption of reduction brain oxygen consumption is arranged.
Embodiment 6: Tanshinone I I A potassium sulfonate is to the experiment of normal pressure hypoxia tolerance mouse influence
Test animal is healthy male mice in kunming.The test of employing intravenous methods.90 of mouse, body weight 20 ± 2g, male and female half and half are divided into 9 groups at random.The physiological saline group, basic, normal, high three dosage groups of Tanshinone II A potassium sulfonate (5,10,20mg/kg) and sodium tanshinone IIA sulfate control group (10mg/kg).Every day 1 time, for three days on end.After the last administration 10 minutes, respectively mouse is moved into the bottom and fill in the 150ml wide-necked bottle of the fresh sodica calx of 10g, seal.Observing its survival time, is dead indication with breath stopped.It is the same that other gets 4 groups of mouse, give in physiological saline and sodium tanshinone IIA sulfate control group (10mg/kg), the Tanshinone I I A potassium sulfonate dosage group (10mg/kg) administration respectively after 10 minutes, difference abdominal injection Vapo-Iso 2mg/kg, and put into the wide-necked bottle sealing immediately.Observational technique is the same.
And calculate prolonged survival period rate (%) according to following formula:
Experimental result shows, the survival time of 10mg/kg and 20mg/kg energy significant prolongation normal pressure hypoxia tolerance mouse; Simultaneously 20mg/kg dosage group also can obviously prolong and gives the Racemic isoproterenol mouse normal pressure hypoxia tolerance survival time, and prompting has and reduces the effect that Racemic isoproterenol increases myocardial consumption of oxygen.The results are shown in Table 2.
Table 2 Tanshinone II A potassium sulfonate to the influence of mouse survival time of normal pressure hypoxia tolerance (Mean ± SD, n=10)
| Group | Dose (mg/kg) | No. animals | of Persistent tine (min) | Extended Rate(％) |
| NS PTS STS | - 50 50 | 10 10 10 | 13.1±3.3 16.2±2.9 * 19.6±3.8 *** | - 41.6 49.6 |
Embodiment 6 Tanshinone II A potassium sulfonates are to the effect of rat layer neuronal damage due to the anoxic
The rat of conceived 17-19d is taken off neck execution, and aseptic condition takes out the tire mouse down, takes out tire mouse brain before the super clean bench, places the DMEM nutrient solution of ice bath, carefully rejects pia mater and blood vessel, the separation pallium.Isolating pallium is shredded, in 37 ℃ of water-baths, digest 5min with 0.25% pancreatin, it is centrifugal that (1000r 5min) abandons supernatant liquor, blows and beats gently with IMDM nutrient solution (containing 10% foetal calf serum) and is dispersed into cell suspension, cell suspension filters, the adjustment cell concn is 1 * 106cellmL-1, with cell inoculation in 96 well culture plates that covered with 0.01% poly-lysine in advance, every hole 100 μ L, put 37 ℃, 5%CO
2Hatch in the incubator.Renew the bright IMDM nutrient solution that is added with 1 ‰ cytosine arabinosides behind the 18-22h, behind 24h, change 50% again and contain serum I MDM nutrient solution.Later on change the fresh serum I MDM nutrient solution that contains 1 time every 1d, cell cultures is to 5-6d.
Experiment is divided into blank, model group and STS, KTS different concns group.Each group all is changed to the IMDM nutrient solution of serum-free during experiment, and the administration group adds different concns Tanshinone II A potassium sulfonate, sodium tanshinone IIA sulfate places 5%CO
2Incubator is hatched, and the blank group is changed to Earle ' the s liquid that contains glucose behind the 24h, and the anoxia model group is changed to Earle ' the s liquid that does not contain glucose, then culture plate is placed in the anoxic jar, feeds 95%N2 and 5%CO
2Mixed gas 20min.Behind the 24h, every hole adds MTT solution 10 μ l, 37 ℃ of 5%CO
2Incubator is hatched 4h, sucking-off stoste, and every hole adds DMSO solution 100 μ l again, and the 10min that vibrates slightly measures optical density value with microplate reader 492nm wavelength.
Experimental data adopts the SPSS13.0 statistical software to analyze, and each organizes data, and (X ± SE) expression adopts One-Way ANOVA to estimate globality difference, and relatively, P＜0.05 is for there being significant difference between organizing with LSD with the mean value standard error.
Influence sees Table 3 to normal neurons, and neuronic influence sees Table 4 to anoxic.
Table 3 PTS is to normal neuronic influence (Mean ± SD)
| Group | Concentration(μM) | OD |
| Control STS PTS | 0 0.1 0.1 | 100.00±9.37 110.49±7.21 134.43±3.47 |
Table 4 PTS is to the neuronic influence of anoxic (Mean ± SD)
| Group | Concentration(μM) | OD |
| control Model STS PTS | 0 0 0.1 0.1 | 100.0±9.37 45.25±7.38# 104.92±15.96 * 123.93±7.68 ** |
#P＜0.05，##P＜0.01，###P＜0.001，compared with the control group；
*P＜0.05，
**P＜0.01，
***P＜0.001，compared with the model group
Experimental result shows, the basic, normal, high dosage group of STS, PTS neurone surviving rate all is significantly higher than the blank group of model, PTS is neurone surviving rate and the blank significant difference of having compared of organizing of STS model under same dose, especially low dose group, prompting: under the same conditions, use the Tanshinone II A potassium sulfonate of relative low dosage can reach the curative effect of sodium tanshinone IIA sulfate high dosage, like this, can reduce consumption accordingly, reduce toxic side effect, use safer.
Embodiment 7 mouse bilateral common carotid arteries and vagus nerve ligature experiment
According to the method for embodiment 5 grouping administration, the survival time of observing mouse was dead index with breath stopped with No. 0 silk thread ligation bilateral common carotid arteries and vagus nerve in 10 minutes after the administration.
Experimental result shows, the survival time of 10mg/kg and 20mg/kg energy significant prolongation bilateral common carotid arteries and vagus nerve ligation mouse, relatively have significant difference (being respectively P＜0.05 and P＜0.01) with the physiological saline control group, sodium tanshinone IIA sulfate also can the significant prolongation bilateral common carotid arteries and survival time (P＜0.01) of vagus nerve ligation mouse.The results are shown in Table 5.
Table 5 PTS to bilateral common carotid arteries and the influence of vagus nerve ligation mouse survival time (Mean ± SD, n=10)
| Group | Dose(mg/k g) | No.of animals | Persistent tine (min) | Extended Rate (％) |
| NS PTS | - 10 | 10 10 | 1.7±0.8 3.3±1.0 ** | - 94.1 |
Compare with NS
*P＜0.05
*P＜0.01
Embodiment 8 mouse NaNO
2Poison and test
According to the method grouping administration of embodiment 5,10 minutes ip.NaNO after the administration
2800mg/kg, the survival time of observing mouse is dead index with breath stopped.
Experimental result shows that 10mg/kg can significant prolongation NaNO
2The survival time of poisoning mice relatively has significant difference (P＜0.01) with the physiological saline control group, and nimodipine also can significant prolongation NaNO
2The survival time of poisoning mice (P＜0.01).The results are shown in Table 6.
Table 6 PTS is to NaNO
2The influence of poisoning mice (Mean ± SD, n=10)
| Group | Dose (mg/kg) | No.of animals | Persistent tine (min) | Extended Rate(％) |
| NS PTS | - 10 | 10 10 | 6.6±0.8 8.7±1.8 ** | - 31.8 |
Compare with NS
*P＜0.05,
*P＜0.01
The experiment of embodiment 9 learning and memories
Mouse is divided into 3 groups at random, 15 every group, be male, be respectively blank 1, blank 2, positive controls and administration group, begin training behind the tail intravenously administrable 3d, train 10 every every day, trains 3d continuously.30min after the last administration, blank 2, positive controls and administration group be abdominal injection Scopolamine (1ml/kg) respectively, begins test after 30 minutes, surveys 5 times the record mouse wrong times for every.Carry out group difference relatively with the t method of inspection.
The diving tower errors number of blank 1 control group, positive controls and 20mg/kg, 10mg/kg, 5mg/kg dosage group mouse all obviously reduces.The results are shown in Table 7.
Table 7 PTS is to the influence of learning and memory of little mouse (Mean ± SD)
| Group | dose(mg/k g) | No.of animals | No.oferrors in testing |
| NS Model PTS | - - 10 | 10 10 10 | 0.75±0.46 ** 3.14±1.77 0.67±0.87 ** |
Compare with NS,
*P＜0.01
The myocardial ischemia experiment
Embodiment 10 Tanshinone II A potassium sulfonates are to the influence of rat heart muscle ischemic due to the Pituitrin
Get body weight and be 40 of the healthy SD rats of 180～220g, male and female are not limit, be divided into 4 groups at random: physiological saline (NS) group, basic, normal, high three the dosage groups of Tanshinone II A potassium sulfonate (5,10,20mg/kg), after 25% urethane 1g/kg ip. anesthesia, face upward the position and be fixed on the mouse platform, sting in four limbs subcutaneously with No. 6 syringe needles, and link to each other with electrocardiograph limb leads electrode.Electrocardiograph choice criteria voltage 1mv=10mm, chart speed 50mm/s.What each organized tail vein iv. respective concentration respectively is subjected to reagent thing 5ml/kg, and administration was annotated in hypogloeeis iv. Pituitrin (Pit) 0.8U/kg, 5s after 10 minutes.With the ECG that reaches injection back 15s, 30s, 45s, 60s, 90s and 3min, 5min, 8min before the electrocardiograph record injection Pit.Observing the T wave height changes and changes in heart rate.T wave height and heart rate are each time point and survey 5 waveforms continuously, get its mean value.No matter the T wave height raises or reduces, and gets the absolute value of variation.Its significance is judged in the t check between experimental result work group.
Result: to the experimental result that influences of rat heart muscle ischemic due to the Pituitrin
1, the T wave height changes
Behind the NS control rats iv.Pit, electrocardio takes place obviously to change, and the first phase, (0～30s) tangible S-T section occurs raised and T wave height towering (P＜0.01); The second phase (after the 30s) presents tangible S-T section and moves down, the low flat or inversion (P＜0.05 or P＜0.01) of T ripple.Low dosage and middle dosage can significantly resist ∑ ST rising or the reduction that Pit causes at some time point; High dosage then can significantly resist ∑ ST rising or the reduction that Pit causes at each time point.The results are shown in Table 8.
Table 8 Tanshinone II A potassium sulfonate to the influence of the T ripple of rats with myocardial ischemia due to the Pituitrin (Mean ± SD, n=10)
Compare with pre-pit
*P＜0.05
*P＜0.01
2, changes in heart rate
Behind the NS group rat iv.Pit, the rat heart rate is obviously slowed down, not recover yet to 8 minutes.Low dosage and middle dosage (30mg/kg and 60mg/kg) have the tendency of alleviating decreased heart rate due to the Pit at the part-time point.High dosage (120mg/kg) is all obviously alleviated decreased heart rate due to the Pit at each time point.The results are shown in Table 9.
Table 9 Tanshinone II A potassium sulfonate to the influence of the rats with myocardial ischemia rhythm of the heart due to the Pituitrin (Mean ± SD, n=10)
Compare with pre-pit
*P＜0.05
*P＜0.01
Embodiment 11 external platelet aggregation-against experiments (turbidimetry)
Rabbit is divided 5 groups at random, 6 every group.Ear edge vein exploitating blood 4.5mL, with 3.8% Sodium Citrate anti-freezing (blood and antithrombotics volume ratio are 9: 1), centrifugal under the room temperature (800kg 3min), gets supernatant liquor and prepares platelet rich plasma (PRP).After isolating PRP, centrifugal again (2000kg 10min) gets supernatant liquor and prepares platelet poor plasma (PPP), and regulating transmittance with PPP is 100%.Get PRP 200 μ L and place in the opacity tube, add respectively different concns the Tanshinone II A potassium sulfonate (5,10,20mg/ml) or acetylsalicylic acid (control group adds isometric(al) NS for ASP, 100mg/ml) 20 μ L.Behind the incubation 5 minutes, (AA) is inductor with arachidonic acid, traces 10 minutes and assembles curve, measures maximum aggregation intensity.
Calculate the anticoagulant percentage according to following formula:
The result: experimental result shows that PTS has obvious restraining effect external to AA inductive rabbit platelet aggregation.Along with dosage increases, effect strengthens, and presents the dose-effect dependency.Each dosage group and NS control group relatively all have significant difference (P＜0.05, P＜0.01 or P＜0.001).The ASP group also has obvious suppression effect (P＜0.01) to the external rabbit platelet aggregation of AA inductive.The results are shown in Table 10.
Table 10 KTS to the influence of arachidonic acid-induction extracorporeal platelet aggregation (Mean ± SD, n=6)
| Group | Con.(mg/mL) | platelet aggregation rat(％) | inhibition (％) |
| NS PTS ASP | - 5 10 20 100 | 43.5±9.1 40.1±11.0 * 31.2±8.7 ** 24.9±6.5 *** 26.8±7.4 ** | - 7.8 28.3 42.8 38.4 |
Compare with NS,
*P＜0.05,
*P＜0.01,
* *P＜0.001
Platelet aggregation-against experiment (turbidimetry) in embodiment 12 bodies
Rabbit is respectively from basic, normal, high three the dosage groups of auricular vein iv. Tanshinone II A potassium sulfonate (5,10,20mg/kg), or ASP 80mg/kg, control group iv. isometric(al) NS.10min carries out the preparation of PRP and PPP from another auricular vein bloodletting respectively by the in vitro tests method after the administration, makes inductor with AA, investigates the influence of medicine to platelet aggregation.
The result: experimental result shows (iv.) AA inductive rabbit platelet aggregation is had obvious restraining effect.And along with dosage increase effect strengthens, dosage is relevant with effect.Each dosage group and control group relatively all have significant difference (P＜0.05, P＜0.01 or P＜0.001).The ASP group also has obvious suppression effect (P＜0.01) to AA inductive rabbit platelet aggregation.The results are shown in Table 11.
Table 11 PTS to the influence of platelet aggregation in the arachidonic acid-induction rabbit body (Mean ± SD, n=6)
| Group | Dose(mg/kg) | platelet aggregation rat (％) | inhibition(％) |
| NS PTS ASP | - 5 10 15 80 | 50.6±7.4 47.1±8.9 * 39.6±9.5 ** 27.2±10.5 *** 35.8±11.7 ** | - 6.9 21.7 46.2 29.2 |
Compare with NS,
*P＜0.05,
*P＜0.01,
* *P＜0.001
13 pairs of thrombotic influences of rabbit arteria carotis communis of embodiment
Rabbit is divided into 5 groups at random, 8 every group.Press 60mg/kg auricular vein injecting anesthetic with 3% talamo, the back of the body
The position is fixing, separate a side arteria carotis communis, at a distance of about 4cm place blood vessel is being clamped with bulldog clamp in two ends, get thin sewing-needle No. 12, connect the fine rule of one one end knotting, penetrate arteria carotis communis from proximal part, along blood vessel traveling 3cm, pass from distal end, cut off fine rule after other end is also tied a knot, slowly unclamp bulldog clamp then.Respectively from opposite side auricular vein iv. physiological saline, basic, normal, high three the dosage groups of Tanshinone II A potassium sulfonate (5,10,20mg/kg), and ASP 80mg/kg.Recover behind the blood flow 2h this section arteria carotis communis of each group rabbit to be cut, vertically cut, take out fine rule, put on the filter paper, inhale and remove surplus blood, and weigh rapidly, deduct the fine rule own wt, promptly get wet weight of thrombus.Calculate the thrombosis inhibiting rate according to following formula:
Experimental result shows that (iv.) PTS has obvious restraining effect to rabbit arteria carotis communis thrombosis, and is the dose-effect dependency.Along with dosage strengthens, wet weight of thrombus alleviates, and with control group significant difference (P＜0.05, P＜0.01 or P＜0.001) is arranged relatively.The ASP group also has obvious suppression effect (P＜0.01) to rabbit arteria carotis communis thrombosis.The results are shown in Table 12.
Table 12 PTS to the influence of rabbit arteria carotis communis wet weight of thrombus (Mean ± SD, n=8)
| Group | Dose(mg/kg) | No.of animals | wet weight of thrombosis(mg) | inhibition (％) |
| NS PTS | - 15 30 60 | 8 8 8 8 | 19.0±2.3 17.2±4.7 * 15.6±3.2 ** 13.1±4.0 *** | - 4.2 17.9 31.1 |
| ASP | 80 | 8 | 14.4±6.3 ** | 24.2 |
Compare with NS,
*P＜0.05,
*P＜0.01,
* *P＜0.001
Practicality pharmaceutically
Above-mentioned experiment of the present invention shows:
(1) tanshinone IIA shows on chmice acute cerebral ischemia, the anti-anoxic of normal pressure, Rats Exposed To Hypoxia neuron and on the experiment of the impact of Rabbit Myocardium and thrombus: the time-to-live that the tanshinone IIA potassium sulfonate can significant prolongation hypoxic-ischemic mouse, myocardial ischemia-anoxemia is improved significantly, and can improve mouse memory power.
(2) point out this compound and the Chemical composition that thereof can be for the preparation of the cerebral hypoxia ischemia that causes for the treatment of cerebral thrombosis acute phase, the cerebral hypoxia ischemia that Patients With Acute Cerebral Infarction causes, the myocardial ischemia-anoxemia that acute myocardial infarction causes, the myocardial ischemia-anoxemia that coronary heart diseases and angina pectoris causes; The generation of prevention cerebral thrombus, prevention coronary heart disease, miocardial infarction, angina pectoris, the cerebral hypoxia ischemia that the anxious thrombus sequela of prevention brain causes.
(3) use tanshinone IIA potassium sulfonate shown in the formula I of the present invention, the using dosage scope is 10～200mg/ days.
(4) use tanshinone IIA potassium sulfonate shown in the formula I of the present invention, under normal dose, it is safe as medicinal application.
(5) compare with existing clinical treatment cardiovascular medicament commonly used, it is better that compound of the present invention has result for the treatment of, the less and wider characteristics of range of application of side effect.
Claims (8)
- What 1, formula I represented is the Tanshinone II A potassium sulfonate:
Formula I. - 2, the method for the compound of preparation claim I:Synthetic route:
The extraction of Tanshinone II A, separation and purifying in the red sage rootDry red sage root 1kg, with 95% ethanol extracting 3 times, each 24 hours, extract was evaporated to 500mL, added 500mL water then, divide four extractions with the 1000mL trichloromethane, the extraction liquid concentrating under reduced pressure, column chromatography for separation, silica gel is 100～200 orders, elutriant is the petrol ether/ethyl acetate mixing solutions that contains 1%～10% ethyl acetate, carries out gradient elution.Can get the about 0.85g of Tanshinone II A.The concrete synthesis technique flow process of Tanshinone II A potassium sulfonate:The synthesis technique of Tanshinone II A potassium sulfonate: get Tanshinone II A (purity is more than 20%) 50 grams, add 200 milliliters of aceticanhydrides, place three-necked bottle, under agitation dripped the 100 milliliters of vitriol oil-Glacial acetic acid (1: 1 in 10～15 ℃, V/V) mixed solution after dropwising, at room temperature stirred one hour, impouring isopyknic distilled water then blows slowly reaction solution, add saturated Repone K (chemical pure) aqueous solution of 1 liter at once, promptly have thick Tanshinone II A potassium sulfonate to separate out, centrifugal, throw out is washed twice with saturated potassium chloride solution, with an amount of washing once, make solids pH=5.6 again, solids is got in worry in water-bath, steamed to dry, solids refluxed 3 hours with chloroform earlier, remove the oil-soluble impurities of unsulfonated, reflux with dehydrated alcohol and remove remaining sodium-chlor, ethanol liquid concentrates, promptly there is red Tanshinone II A potassium sulfonate coarse crystallization to separate out, use recrystallizing methanol twice again, promptly get orange red needle crystal, after thorough drying, 194～196 ℃ of fusing points obtain about 10 grams of pure product. - 3, in Tanshinone II A potassium sulfonate shown in the formula I or its chemical composition in the application of medicine of prevention and treatment cerebral ischemia/anoxia.
- 4, Tanshinone II A potassium sulfonate shown in the formula I or its chemical composition application in the medicine of prevention and treatment myocardial ischemia-anoxemia.
- 5, be used for the application of the medicine of microcirculation improvement, hypermnesis in Tanshinone II A potassium sulfonate shown in the formula I or its chemical composition in preparation.
- 6, be used to prevent, treat the application of the medicine of the cerebral ischemia/anoxia that cerebral thrombosis and sequela thereof, acute cerebral ischemia cause in Tanshinone II A potassium sulfonate shown in the formula I or its chemical composition in preparation.
- 7, Tanshinone II A potassium sulfonate shown in the formula I or its chemical composition are used to prepare the medicine of the myocardial ischemia-anoxemia that prevention, treatment coronary heart disease, myocardial infarction, stenocardia cause.
- 8, the Tanshinone II A potassium sulfonate shown in the formula I can be made into oral preparations such as injection, freeze-dried powder, primary infusion, tablet, capsule, granule.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102532249A (en) * | 2010-12-24 | 2012-07-04 | 郑州大学 | 1-chloro tanshinone compound and preparation method thereof |
| CN102558287A (en) * | 2010-12-22 | 2012-07-11 | 秦引林 | Dehydro-tanshinone IIA sulfoacid and application thereof |
| CN112999231A (en) * | 2021-03-01 | 2021-06-22 | 杭州百晓生物技术有限公司 | Application of medicine in reducing side effect of anesthetic |
| CN115025103A (en) * | 2021-03-04 | 2022-09-09 | 上海上药第一生化药业有限公司 | Application of tanshinone IIA sodium sulfonate in preparation of medicine |
-
2007
- 2007-06-18 CN CN 200710011736 patent/CN101070338A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558287A (en) * | 2010-12-22 | 2012-07-11 | 秦引林 | Dehydro-tanshinone IIA sulfoacid and application thereof |
| CN102558287B (en) * | 2010-12-22 | 2015-07-01 | 秦引林 | Dehydro-tanshinone IIA sulfoacid and application thereof |
| CN102532249A (en) * | 2010-12-24 | 2012-07-04 | 郑州大学 | 1-chloro tanshinone compound and preparation method thereof |
| CN102532249B (en) * | 2010-12-24 | 2015-08-19 | 郑州大学 | 1-chloro tanshinone compound and preparation method thereof |
| CN112999231A (en) * | 2021-03-01 | 2021-06-22 | 杭州百晓生物技术有限公司 | Application of medicine in reducing side effect of anesthetic |
| CN115025103A (en) * | 2021-03-04 | 2022-09-09 | 上海上药第一生化药业有限公司 | Application of tanshinone IIA sodium sulfonate in preparation of medicine |
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