CN103202832A - Application of acylated tanshinol derivant in prevention and treatment of cardiovascular disease and complication thereof - Google Patents
Application of acylated tanshinol derivant in prevention and treatment of cardiovascular disease and complication thereof Download PDFInfo
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- CN103202832A CN103202832A CN2013101521872A CN201310152187A CN103202832A CN 103202832 A CN103202832 A CN 103202832A CN 2013101521872 A CN2013101521872 A CN 2013101521872A CN 201310152187 A CN201310152187 A CN 201310152187A CN 103202832 A CN103202832 A CN 103202832A
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Abstract
The invention discloses application of a compound shown in a structural general formula (I) in the specification in prevention and treatment of a cardiovascular disease and complication thereof, wherein R1, R2 and R3 are independently selected from hydrogen, benzoyl or C2-C6 acyl, but not H at the same time; and M is H<+>, Na<+> or K<+>. Tanshinol is taken as a material; and a plurality of acylated tanshinol derivants are prepared by acylation reaction. Therefore, not only is easily oxidized hydroxyl protected, but also the lipid solubility and the transmembrane transport capacity are also increased; and an experiment proves that acylated tanshinol has significant protection effect on rat myocardium with ischemia reperfusion injury.
Description
Technical field
The present invention relates to a kind of acyl group Danshensu derivatives of preventing and treating cardiovascular disease and complication thereof, belong to medical technical field.
Background technology
Coronary heart disease, angina pectoris, myocardial infarction etc. have become the principal disease that influences human health.Wherein coronary heart disease is one of the highest disease of global mortality rate, and according to World Health Organization's report in 2011, the coronary heart disease death number of China has been listed as the second place of the world.
Chinese medicine is the treasure-house of motherland's medicine, and Radix Salviae Miltiorrhizae is to use one of more Chinese medicine clinically, has effects such as blood circulation promoting and blood stasis dispelling, very early Radix Salviae Miltiorrhizae is used for the treatment of diseases such as angina pectoris in China, is the natural Chinese medicine that a kind of safety is treated cardiovascular disease again reliably.With the Radix Salviae Miltiorrhizae be the curative effect of medication of main component definite, be widely used, for example, DANHONG ZHUSHEYE, FUFANG DANSHEN DIWAN etc., the latter has become one of leading brand on the domestic cardiovascular market.
Danshensu is the water soluble ingredient of Radix Salviae Miltiorrhizae, is one of Radix Salviae Miltiorrhizae main active.A large amount of domestic and foreign literatures report that it has protective effect to heart, for further development and application in the clinical important theory foundation that provides.But danshensu belongs to the free radical scavenger of Polyphenols, contains phenolic hydroxyl group in its structure, is very easy to oxidation deterioration takes place, for it has brought certain degree of difficulty as new drug development.
Summary of the invention
The purpose of this invention is to provide the acyl group danshensu of preventing and treating cardiovascular disease and complication thereof, compare with danshensu, the acyl group danshensu has advantages such as increasing fat-soluble, change absorbent properties, increase stability, raising drug effect.
Implementation procedure of the present invention is as follows:
Chemical compound shown in the general structure (I) is prevented and treated application in cardiovascular disease and the complication medicine thereof in preparation,
R
1, R
2And R
3Be independently selected from hydrogen, benzoyl, C
2～C
6Acyl group, but be not H simultaneously,
M is H
+, Na
+Or K
+
Described cardiovascular disease and complication thereof comprise arrhythmia, ventricle fibrosis, myocardial infarction, coronary heart disease, angina pectoris, heart failure, congestive heart failure, myocardial ischemia, myocardial ischemia/perfusion again, myocarditis, atherosclerosis, peripheral tissues's organ or limb ischemia, shock, ischemia or pour into histoorgan acute and chronic trauma, imbalance or the indirect sequelae that causes again.
Said medicine contains the chemical compound shown in the general structure (I) and pharmaceutically acceptable carrier, and medicine is injection, tablet, capsule, powder, pill, suppository, aerosol, effervescent tablet, drop, drop pill, granule or Emulsion.
Chemical compound shown in the general structure (I) is to be raw material with the danshensu, its phenolic hydroxyl group and alcoholic extract hydroxyl group are carried out the acyl group protection and obtains, and further reacts with sodium hydroxide or potassium hydroxide to obtain corresponding salt.
Representative acyl group Danshensu derivatives has:
The present invention has measured the protective effect of different acyl Danshensu derivatives (compd A, B, C, D, E, F are representative) to heart; experimental result is found; these Danshensu derivatives all have biological activity in various degree, and wherein compd A is suitable to the DANHONG ZHUSHEYE effect of the protective effect of heart and clinical use.
Chemical compound of the present invention can be used for preparation prevention or treatment cardiovascular disease and complication thereof, comprises arrhythmia, ventricle fibrosis, myocardial infarction, coronary heart disease, angina pectoris, heart failure, congestive heart failure, myocardial ischemia, myocardial ischemia/perfusion again, myocarditis, atherosclerosis, peripheral tissues's organ or limb ischemia, shock, ischemia or pours into histoorgan acute and chronic trauma, imbalance or the indirect sequelae etc. that cause again.
The present invention is raw material with the danshensu; make multiple acyl group Danshensu derivatives through acylation reaction; not only protected the hydroxyl of easy oxidation; also increased fat-soluble and the transmembrane transport ability, the present invention experimental results show that the acyl group danshensu has significant protective effect to the rat heart muscle of ischemical reperfusion injury.
Description of drawings
Fig. 1 for respectively organize after the rat different disposal myocardial infarction area (
,N=8), Sham: sham operated rats; MI/R: myocardial ischemia/perfusion group again; A, B, C, D, E, F: different acyl Danshensu derivatives; DHI: DANHONG ZHUSHEYE.
# P＜0.05 compares * with Sham group
P＜0.05 compares with MI/R group;
Fig. 2 be external survival rate after the myocardial cell different disposal mensuration (
, n=5), Control: matched group; SI/R: simulation ischemia/reperfusion group; A, B, C, D, E, F: different acyl Danshensu derivatives; DHI: DANHONG ZHUSHEYE.
## P＜0.01 compares with Control group; *
P＜0.05, * *
P＜0.01 compares with SI/R group;
Fig. 3 be cell conditioned medium LDH after the myocardial cell different disposal mensuration (
, n=5), Control: matched group; SI/R: simulation ischemia/reperfusion group; A, B, C, D, E, F: different acyl Danshensu derivatives; DHI: DANHONG ZHUSHEYE.
## P＜0.01 compares with Control group; *
P＜0.05, * *
P＜0.01 compares with SI/R group.
The specific embodiment
Synthesizing of acetyl danshensu
With 2.97 g(15 mmol) danshensu and 60 mL acetic anhydride add in the 250 mL flasks, add catalytic amount perchloric acid stirring reaction 2.5 h, thin layer chromatography (TLC) monitoring reaction.Question response in reactant liquor impouring trash ice, is used ethyl acetate extraction, successively water and saturated common salt water washing organic layer after finishing, anhydrous sodium sulfate drying, steam desolventize glassy yellow grease, dissolve with dichloromethane again, rapid column chromatography gets water white transparency wax 4.29 g, productive rate 88%.R
1, R
2And R
3The chemical compound of different substituents all can obtain by adjusting raw material and ratio by similar approach.
Embodiment 1: the protective effect of compd A, B, C, D, E, the rat myocardial ischemia and reperfusion of F (MI/R) damage
(1) test material
72 of male and healthy SD rats, quality 250-270 g is available from The Fourth Military Medical University's animal center.Animal sub-cage rearing (24 ℃ of ambient temperatures, humidity 60%-70%), the preceding 1 h fasting of art is freely drunk water.
Positive drug: DANHONG ZHUSHEYE (DHI), specification 10ml(Heze Buchang Pharma Co., Ltd., lot number: 12051067); Creatine kinase isozyme (CK-MB) (west, Shanghai Tang bio tech ltd); Lactic acid dehydrogenase (LDH) and Coomassie brilliant blue protein quantification test kit (bio-engineering research institute is built up in Nanjing); 2,3,5-triphenyltetrazolium chloride indigo plant (TTC) stain (Shanghai chemical reagents corporation of Chinese Medicine group); Azovan blue (EB) (U.S. Sigma-Aldrich company).
HX-100E toy respirator (Chengdu TME Technology Co., Ltd.); BL-420S polygraph (Chengdu TME Technology Co., Ltd.); 5417 type low-temperature and high-speed centrifuges (Eppendorf company); COOLPIX S1 type photographing unit (Nikon company, Japan); 680 type microplate reader (BIO-RAD company).
(2) experimental program and result
The preparation of rat MI/R damage model
Rat is divided into 9 groups at random: sham operated rats (Sham), model group (MI/R), administration group (compd A, B, C, D, E, F, 30 mg/kg), DANHONG positive controls (DHI concentrates back 8 ml/kg).Each group is carried out MI/R model preparation back, and (Sham group rat is except not ligation anterior descending coronary blood vessel, other operation techniques are identical with model preparation group), in pouring at once the medicine of injecting normal saline or corresponding dosage (dosage is determined according to the beneficial effect curve of package insert and new drug) respectively again.After rat is weighed, 2 mL/kg lumbar injections, 3% pentobarbital sodium, dorsal position is fixed, and connects electrocardiogram monitoring, and tracheal intubation also connects respirator (frequency: 75 times/min; Tidal volume: 8-9 mL; Inhale: exhale=1:2), the other longitudinal incision 3-5 of left border of sternum intercostal is done and is walked crosswise otch, cut off and provoke pericardium, expose heart, with ramus descendens anterior arteriae coronariae sinistrae (the Left anterior descending coronary aery of left auricle and pulmonary conus intersection, LAD) be sign, in 1-2 mm place, left auricle below inserting needle, threading (across ramus descendens anterior arteriae coronariae sinistrae), a little silica gel tube is penetrated from the silk thread two ends, stablize ligation behind 10 min, behind ischemia 30 min, pour into 3 h again and finish.The success standard: the electrocardiogram II ST section of leading the back of a bow occurs and upwards raises behind the ligation LAD, and the T wave height is alarmmed to wait and is the ischemia success; After loosening ligature, the ST section of raising descends more than 1/2 to pouring into successfully again.
After pouring into 3 h again, the rat ramus descendens anterior arteriae coronariae sinistrae is respectively organized in ligation again, injects 3% EB solution, 2 mL rapidly from carotid artery, treats to extract heart rapidly after rat lip and extremity tip skin indigo plant are dyed, and filter paper is absorbed remaining dye liquor in the ventricular chamber, and-20 ℃ freeze to hardening.Take out the back from the apex of the heart entad the parallel coronary sulcus direction in the end be cut into 5 of equal thickness, 2% TTC solution (pH=7.4) is hatched 10 min for 37 ℃, 4% paraformaldehyde fixedly spends the night.Dyeing back white represent infarcted region, and (area of necrosis AN), redly represent ischemia but infarcted region not, and blue representative is normally distinguished, and (area at risk AAR) is redness and white area sum in the hazardous area.Adopt Image-Pro Plus 6.0 image analysis software to analyze.The infarction degree adopts the ratio value representation of infarcted region area (AN) and dangerous area (AAR).After rat ischemia 30 min poured into 3 h again, tangible infarction appearred in the model group animal cardiac muscle, and the infarcted region area is (42.1 ± 5.5) % with the ratio of dangerous area.With sham group relatively, model group animal cardiac muscle infarct size significantly increase (
P＜0.05), prompting MI/R damage model is made successfully.Compare with model group, give compd A, can obviously reduce after the B treatment rat MI/R damage back myocardial infarction area (
P＜0.05), and with the therapeutic effect of positive control drug quite (
P＞0.05), C, D, E, F group reduces infarct size degree and model than no significant difference, sees Fig. 1.
After pouring into 3 h again, abdominal aortic blood, centrifugal (4000 r/min) 12 min, separation of serum, test kit detects the activity of CK-MB and LDH, to specifications operation.Compare with sham operated rats, model group rat blood serum CK-MB and LDH level obviously increase (
P＜0.05).A, B treatment group rat blood serum CK-MB and LDH level obviously descend, compared with model group significant difference (
P＜0.05), other groups no significant difference of comparing with model sees Table 1.
Embodiment 2: the protective effect of compd A, B, C, D, E, the rat of F myocardial cell of former generation simulation ischemia/reperfusion (SI/R) damage
(1) test material
The newborn SD rat, male and female are regardless of, and 1-2 days, are provided by The Fourth Military Medical University's Experimental Animal Center.
Main medicine and reagent
Lactic acid dehydrogenase (LDH) quantification kit (bio-engineering research institute is built up in Nanjing); DMEM culture medium (U.S. Gibco company), tetramethyl azo azoles indigo plant (MTT), 5-bromouracil deoxyribose (BrdU), trypsin, calf serum (U.S. Sigma-Aldrich company).
Superclean bench (Suzhou cleaning equipment company); Inverted microscope (Olympus, Japan); The cell culture incubator (Hera, USA); 5417 type low-temperature and high-speed centrifuges (Eppendorf company); C680 type microplate reader (BIO-RAD company).
(2) experimental program and result
1. myocardial cell former is commissioned to train foster
Take out and give birth to 1-2 days SD neonatal rats for experiment, the sterilization back moves into superclean bench.Cut off thoracic wall along left border of sternum and take out heart, with putting into culture dish behind the residual blood of the PBS washing removal of sterilization.Shred cardiac muscular tissue, add 0.125% tryptic digestive juice, 37 ℃ of water-baths digest 5 min, abandon supernatant, add Digestive system again, repeat aforesaid operations 5 times.Add the DMEM culture medium contain serum and stop digestion, abandon supernatant after centrifugal, it is resuspended to add the DMEM culture medium that contains 10% calf serum, behind the mix homogeneously cell kind is gone in the culture plate, differential adherent method purification myocardial cell adds an amount of BrdU, making its final concentration is 0.01 mM, 37 ℃ of CO
2Cultivate in the incubator.Change culture medium behind 24 h.
Test preceding 24 h culture medium is replaced with the DMEM culture medium of serum-free, change to fast through 95% N
2-5% CO
2The low sugar serum-free DMEM culture medium that gaseous mixture is saturated, and move into rapidly in the hypoxia device of the abundant balance of this gaseous mixture, put into conventional incubator behind 2 h and hatch 24 h, cause the damage of myocardial cell anoxia _ reoxygenation.It is 9 groups that experiment is divided into: blank group (Control), simulation ischemia/reperfusion group (SI/R), administration group (compd A, B, C, D, E, F) and DANHONG ZHUSHEYE positive controls (DHI).
After former generation, myocardial cell poured into end again, each group added the MTT of 20 μ L 5mg/ml respectively, hatches 4 h, discards culture fluid, adds 150 μ L dimethyl sulfoxide (DMSO) more separately, and abundant dissolving to be crystallized back is detected in 490 nm places with microplate reader.The result as shown in Figure 2, after the simulation ischemical reperfusion injury is handled, the myocardial cell survival rate significantly reduce (
P＜0.01), after giving each 10 μ M of compd A, B, C, D, E, F and handling, compd A, B, D can obviously strengthen myocardial cell survival rate (
P＜0.05 or 0.01), and the DHI of compd A effect and positive control drug 2% quite (
P0.05).
After former generation, myocardial cell poured into end again, each was organized cell and gets the supernatant culture fluid, in strict accordance with the activity of the description operation detection cell conditioned medium LDH of test kit, the result as shown in Figure 3, after ischemical reperfusion injury is handled, myocardial cell LDH burst size significantly increase (
P＜0.01), after giving each 10 μ M of compd A, B, C, D, E, F and handling, can obviously reduce cell conditioned medium LDH content (
P＜0.05 or
P＜0.01), and the DHI of compd A effect and positive control drug 2% quite (
P0.05).
Claims (6)
1. the chemical compound shown in the general structure (I) is prevented and treated application in cardiovascular disease and the complication medicine thereof in preparation,
R
1, R
2And R
3Be independently selected from hydrogen, benzoyl, C
2～C
6Acyl group, but be not H simultaneously,
M is H
+, Na
+Or K
+
2. according to the described application of claim 1, it is characterized in that: R
1, R
2And R
3Be independently selected from C
2～C
6Acyl group.
3. according to the described application of claim 2, it is characterized in that: R
1, R
2And R
3Be acetyl group or propiono.
4. according to the described application of claim 1, it is characterized in that: described cardiovascular disease and complication thereof comprise arrhythmia, ventricle fibrosis, myocardial infarction, coronary heart disease, angina pectoris, heart failure, congestive heart failure, myocardial ischemia, myocardial ischemia/perfusion again, myocarditis, atherosclerosis, peripheral tissues's organ or limb ischemia, shock, ischemia or pour into histoorgan acute and chronic trauma, imbalance or the indirect sequelae that causes again.
5. according to the described application of claim 4, it is characterized in that: described medicine contains the chemical compound shown in the general structure (I) and pharmaceutically acceptable carrier.
6. according to the described application of claim 5, it is characterized in that: medicine is injection, tablet, capsule, powder, pill, suppository, aerosol, effervescent tablet, drop, drop pill, granule or Emulsion.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101521872A CN103202832A (en) | 2013-04-28 | 2013-04-28 | Application of acylated tanshinol derivant in prevention and treatment of cardiovascular disease and complication thereof |
| PCT/CN2013/079153 WO2014176826A1 (en) | 2013-04-28 | 2013-07-10 | Acylated tanshinol derivative, composition comprising same and use thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101521872A CN103202832A (en) | 2013-04-28 | 2013-04-28 | Application of acylated tanshinol derivant in prevention and treatment of cardiovascular disease and complication thereof |
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|---|---|
| CN103202832A true CN103202832A (en) | 2013-07-17 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102718653A (en) * | 2012-01-30 | 2012-10-10 | 中国人民解放军第四军医大学 | Pro-drug for treating cardiovascular and cerebrovascular diseases |
-
2013
- 2013-04-28 CN CN2013101521872A patent/CN103202832A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102718653A (en) * | 2012-01-30 | 2012-10-10 | 中国人民解放军第四军医大学 | Pro-drug for treating cardiovascular and cerebrovascular diseases |
Non-Patent Citations (1)
| Title |
|---|
| 向卓 等: "乙酰丹参素单硝酸异山梨醇酯的合成及对心肌缺血/再灌注大鼠心脏的保护作用", 《第四军医大学学报》 * |
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Application publication date: 20130717 |