CN103450087B - Preparation method of paeonol and ozagrel conjugate - Google Patents
Preparation method of paeonol and ozagrel conjugate Download PDFInfo
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- CN103450087B CN103450087B CN201310419227.5A CN201310419227A CN103450087B CN 103450087 B CN103450087 B CN 103450087B CN 201310419227 A CN201310419227 A CN 201310419227A CN 103450087 B CN103450087 B CN 103450087B
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Abstract
The invention discloses a preparation method of a paeonol and ozagrel conjugate. The structural formula of the paeonol and ozagrel conjugate is shown in the specification. The preparation method comprises the following steps shown in the specification. The conjugate prepared by the preparation method disclosed by the invention has an effect on preventing or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation, especially on preventing diseases of anoxemia cardiovascular disease, cerebral thrombosis disease or thrombotic myocardial infarction and thrombotic cerebral infarction and the like.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to the preparation method of a kind of Paeonol-ozagrel conjugate.
Background technology
Cardiovascular and cerebrovascular diseases is common disease, the frequently-occurring disease of serious harm human health, and along with the aging of social population, sickness rate rises day by day.
Thromboembolism is one of important factor causing cardiovascular and cerebrovascular diseases, coronary artery disease and corresponding ischemic complications thereof can cause various clinical syndrome, as apoplexy, myocardial infarction or peripheral arterial disease, Etiological is exactly the thrombus artery-clogging formed in the artery, causes severe ischemic.Also have very high M & M with the thrombotic disease that coronary artery thrombosis and cerebral thrombosis are core in China, therefore, anti-hemostasis suppository has also just become one of current research topic the most popular in cardiovascular disorder field.Platelet aggregation is a key link in normal coagulation mechanism, and hematoblastic adhesion, gathering and release reaction cause thrombosis, medicament for resisting platelet aggregation refers to and can suppress hematoblastic adhesion and aggregation capability, stop thrombotic medicine.Therefore play a significant role in treatment thrombotic disease.Thromboxane element (TXA2) is the product with very strong physiologically active generated in arachidonic acid metabolism process.TXA2 has regulating effect to antiotasis, can make blood vessel, segmental bronchus and smooth muscle contraction, has strong platelet aggregation, and platelet aggregation can be impelled to form thrombus.Clinical study results shows, the generation of the oversensitive vascular disease of blood is relevant with the too much generation of TXA2.
Ozagrel is specific TXA2 synthetase inhibitors, and its site of action is thrombocyte and vascular endothelial cell.Pharmacological research shows, the potent suppression TXA2 synthase activity of this product energy, thus anticoagulant, reach the effect suppressing cerebral thrombosis and treatment cerebral infarction.Be mainly used in acute cerebral infarction, coronary heart disease and anginal treatment clinically.But pharmacokinetic study shows, after human vein instils, this product blood concentration-time curve meets fixed double chamber bed, plasma half-life very short (t1/2 (β)=0.764h), Plasma Concentration can measure to the greatest extent 3h after drug withdrawal, and after drug withdrawal 24h, almost all medicine excretes through urine.Because after ozagrel sodium injection administration, medicine is eliminated very fast from blood, therefore this product can only adopt continuous intravenous infusion administration clinically, causes patient medication poor compliance, and this product aqueous solution is unstable in addition, meet light easily to decompose, its clinical application is restricted further.
China's natural resources of Chinese medicinal materials enriches, from traditional blood-activating and stasis-removing, screening has the composition of anticoagulant effect as lead compound, Modern Pharmaceutical Chemistry research principle is utilized to carry out Rational drug design to lead compound, thus filter out better efficacy, few side effects, bioavailability are high, the medicine of the treatment thrombotic disease that the transformation period is longer has important theory significance and clinical value.
Natural product Paeonol is the effective constituent in Chinese medicine, has the effects such as antipyretic, analgesia, antibacterial, anti-inflammatory, spasmolysis, step-down.In recent years, along with the exploitation to traditional Chinese medicine novelty teabag, find that Paeonol not only shows in the conciliation to heart muscular strength, frequency and blood pressure to the pharmacological action of cardiovascular systems, but also show by anticoagulant and Anti-lipoid peroxide to the damage of tunica intima reach shoulder thrombosis and atherosclerosis.The antiplatelet aggregative activity of Paeonol is by suppressing cyclooxygenase reaction, is that the synthesis minimizing of thromboxane A2 realizes.Paeonol shows and reduces whole blood apparent viscosity, and pcv is reduced, and reduces erythrocyte aggregation and Adherence of Platelet simultaneously, erythrocytic modification ability is significantly strengthened.
For finding the medicine of better antiplatelet aggregative activity, the present invention carries out split with Paeonol and ozagrel, design and synthesis Paeonol of the present invention-ozagrel conjugate.It is longer that Paeonol of the present invention-ozagrel conjugate has good stability, transformation period, the features such as bioavailability is high, better efficacy.
Summary of the invention
For prior art, the invention provides a kind of preparation method that can be used for treating cardiovascular and cerebrovascular diseases Paeonol and the ozagrel conjugate caused by platelet aggregation.
For achieving the above object, the invention provides the preparation method of a kind of Paeonol and ozagrel conjugate, the structural formula of described Paeonol and ozagrel conjugate is as follows:
described preparation method comprises the following steps:
The compound prepared according to preparation method of the present invention can add pharmaceutically acceptable carrier and make common medicinal preparations, as tablet, capsule, pulvis, syrup, liquor, suspension agent, injection, the pharmaceutically acceptable pharmaceutical excipients such as spices, sweeting agent, liquid or solid filler or thinner can be added.Compound of the present invention administering mode clinically can adopt the modes such as oral, injection.Pharmacological testing proves, compound of the present invention has the effect of cardiovascular and cerebrovascular diseases that prevention or treatment platelet aggregation cause, and particularly can treat the diseases such as the thrombotic heart, the ischemic of brain or infarct.
Embodiment
In order to make object of the present invention, technical scheme and advantage clearly understand, below in conjunction with embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
Compound of the present invention---Paeonol and ozagrel conjugate, its structural formula is as follows:
Its chemistry is by name: (E)-2-ethanoyl-5-p-methoxy-phenyl-3-(4-((1H-imidazolyl-1-base) methyl) phenyl) acrylate
The preparation method of compound of the present invention is as follows:
Compound of the present invention can add pharmaceutically acceptable carrier and make common medicinal preparations, as tablet, capsule, pulvis, syrup, liquor, suspension agent, injection, the pharmaceutically acceptable pharmaceutical excipients such as spices, sweeting agent, liquid or solid filler or thinner can be added.
Compound of the present invention administering mode clinically can adopt the modes such as oral, injection.
Pharmacological testing proves, compound of the present invention has the effect of cardiovascular and cerebrovascular diseases that prevention or treatment platelet aggregation cause, and particularly can treat the diseases such as the thrombotic heart, the ischemic of brain or infarct.
Here is pharmacological testing and the result of the compounds of this invention:
Laboratory animal: New Zealand's white big ear rabbit, weight 2.0 ± 0.5kg.
Experiment grouping: New Zealand's large ear rabbit, every rabbit establishes 13 medicine groups, i.e. blank dimethyl sulfoxide (DMSO) group, the basic, normal, high concentration group of acetylsalicylic acid, the basic, normal, high concentration group of Paeonol, the basic, normal, high concentration group of ozagrel acid, the basic, normal, high concentration group of ozagrel-Paeonol conjugates.Each medicine is all dissolved in dimethyl sulfoxide (DMSO), and after adding PRP opacity tube, medicine group final concentration is 5 × 10 respectively
-5molL
-1, 1 × 10
-4molL
-1with 2 × 10
-4molL
-1.
Test method: after rabbit fasting 12h, 3% Nembutal sodium solution anaesthetizes (dosage 1mL/kg) through auricular vein, abdominal aortic blood.Blood 3.8% Sodium Citrate (1: 9) anti-freezing, with the centrifugal 10min of 3000r/min, prepares platelet rich plasma (Platelet-rich plasma, PRP).Residual blood continues centrifugal, and the centrifugal 10min of 3000r/min, prepares platelet poor plasma (Platelet-poor plasma, PPP).
With PPP, blood pool instrument is returned to zero, get 200 μ lPRP in opacity tube, each drug component does not add corresponding medicine 1 μ l, blank adds 1 μ l dimethyl sulfoxide (DMSO), after putting into that blood pool instrument bottoming hole 37 DEG C is static and hatching 3min, add ADP induced platelet aggregation, measure maximum platelet aggregation rate with MPG-3E multipotency two channels blood pool instrument.
Calculate thrombocyte inhibiting rate by following formula: inhibiting rate (100%)=[(blank group MA-administration group MA)/blank group MA] × 100%, by t inspection between result group, data see the following form.
The external impact on Rabbit Blood Platelets MA of table 1 different concns Paeonol-ozagrel conjugate difficult to understand
Note: compare with blank group,
★p<0.05,
★ ★p<0.01; Compare with acetylsalicylic acid,
#p<0.05; Compare with Paeonol,
▲ ▲p<0.01.
Result shows, and 2 × 10
-4molL
-1with 1 × 10
-4molL
-1the Paeonol of concentration-ozagrel conjugate can remarkable (P<0.01) platelet aggregation of suppressing ADP to induce, and presents concentration according to patience.2 × 10
-4molL
-1paeonol-ozagrel conjugate to platelet aggregation-against effect, comparatively acetylsalicylic acid and Paeonol are strong, demonstrate good Development volue.
Compound of the present invention obtains through chlorination, step of esterification.Case study on implementation understanding the present invention that those skilled in the art can be made deep below, but do not limit the present invention in any way.
Embodiment 1:
The synthesis of 1.1 (E)-3-(4-((1H-imidazolyl-1-base) methyl) phenyl) acrylate chloride
Reaction formula:
Reactions steps:
By ozagrel (6.84g, 0.03mol), CH
2cl
2(60ml) mix, add 5 DMF, under stirring at room temperature, drip SOCl
2(15ml) at CH
2cl
2(30ml) solution in, about drips off half an hour, and after dripping off, outer temperature is heated to 70 degrees Celsius, refluxes 2.5 hours.By reaction solution evaporated under reduced pressure removing SOCl
2, CH
2cl
2, resistates adds CH
2cl
2(20ml) pull an oar, suction filtration, obtains faint yellow solid 7.51g, yield 88.5%.
The synthesis of 1.2 (E)-2-ethanoyl-5-p-methoxy-phenyl-3-(4-((1H-imidazolyl-1-base) methyl) phenyl) acrylate
Reaction formula:
Reactions steps:
By Paeonol (3.67g, 0.022mol), CH
2cl
2(60ml) with triethylamine (7.5ml) mixing, ice bath slowly adds step product (7.51g, 0.027mol) under stirring, and finishes, removes ice bath, stirring at room temperature 2.5 hours, adds 90ml washing, aqueous phase CH
2cl
2extract 3 times, merge organic phase, anhydrous Na
2sO
4after drying, evaporated under reduced pressure, obtains dark brown oil liquid.Column chromatography (eluent: ethyl acetate) obtains off-white color yellowish solid 4.86g, yield: 58.46%, m.p.74-76 DEG C.1H-NMR(CDCl
3,ppm):δ2.52(s,3H),3.87(s,3H),5.17(s,2H),6.65-7.89(m,12H);EI-MS:376[M]。
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.
Claims (1)
1. the preparation method of Paeonol and ozagrel conjugate, is characterized in that, described Paeonol and ozagrel conjugate structural formula as follows:
described preparation method comprises the following steps:
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| CN103450087B true CN103450087B (en) | 2015-07-01 |
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| CN107823649B (en) * | 2017-11-10 | 2021-07-27 | 安徽中医药大学 | Paeonol-ozagrel conjugate brain-targeted liposome and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1106790A (en) * | 1994-07-25 | 1995-08-16 | 华西医科大学药学院 | Acetylsalicylate deriv. |
| CN101219994A (en) * | 2007-01-10 | 2008-07-16 | 王立峰 | Ozagrel ester, composition and production method thereof |
| WO2009007679A2 (en) * | 2007-07-11 | 2009-01-15 | Cardoz Ab | Combination for use in the treatment of atherosclerosis comprising a mast cell inhibitor and a thromboxane a2 antagonist |
| CN102079703A (en) * | 2010-12-16 | 2011-06-01 | 苏州大学 | Method for preparing novel nonsteroidal anti-inflammatory drug and anti-inflammatory and analgesic effects thereof |
-
2013
- 2013-09-13 CN CN201310419227.5A patent/CN103450087B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1106790A (en) * | 1994-07-25 | 1995-08-16 | 华西医科大学药学院 | Acetylsalicylate deriv. |
| CN101219994A (en) * | 2007-01-10 | 2008-07-16 | 王立峰 | Ozagrel ester, composition and production method thereof |
| WO2009007679A2 (en) * | 2007-07-11 | 2009-01-15 | Cardoz Ab | Combination for use in the treatment of atherosclerosis comprising a mast cell inhibitor and a thromboxane a2 antagonist |
| CN102079703A (en) * | 2010-12-16 | 2011-06-01 | 苏州大学 | Method for preparing novel nonsteroidal anti-inflammatory drug and anti-inflammatory and analgesic effects thereof |
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