CN110711189B

CN110711189B - Application of compound in medicine

Info

Publication number: CN110711189B
Application number: CN201911042608.XA
Authority: CN
Inventors: 占卓; 雷绍南; 单世斌; 张靖; 王佩忠
Original assignee: Fujian Sanan Sino Science Photobiotech Co Ltd
Current assignee: Fujian Sanan Sino Science Photobiotech Co Ltd
Priority date: 2019-10-30
Filing date: 2019-10-30
Publication date: 2022-07-19
Anticipated expiration: 2039-10-30
Also published as: CN110711189A

Abstract

The invention discloses a compound, a preparation method and application thereof, wherein the molecular formula of the compound is C₂₇H₂₂O₁₀The molecular weight is 506. The compound obtained by the preparation method has high purity which reaches 98 percent, good stability and good biological activity. Through an in vitro blood coagulation activity experiment method, the compound is found to have stronger inhibitory activity on platelet aggregation activated by thrombin, and has the potential of developing anticoagulants or antithrombotic drugs and medical devices.

Description

Application of compound in medicine

Technical Field

The invention belongs to the technical field of natural product chemistry, and particularly relates to a compound separated from Clinopodium polycephalum herba Clinopodii, a preparation method and medical application thereof, wherein the molecular formula of the compound is C₂₇H₂₂O₁₀And the molecular weight is 506.

Background

There are more than 20 plants in Clinopodium Linn of Clinopodium of Labiatae (Labiatae) worldwide, and the plants are mainly distributed in Europe, Central Asia and east Asia. Clinopodium polycephalum herba Clinopodii and Clinopodium polycephalum herba Clinopodii are recorded in 2010 edition of Chinese pharmacopoeia, have effects of astringing and stopping bleeding, and are mainly used for treating hemorrhage such as metrorrhagia, hematuria, epistaxis, gingival hemorrhage, traumatic hemorrhage, etc., and diseases such as simple purpura and idiopathic thrombocytopenic purpura. China has rich medical plant resources and a long medical history among people, and has wide development and utilization prospects.

Herba Clinopodii is dry aerial part of calyx Seu fructus Physalis (Clinopodium polycephalum herba Clinopodii) and herba Sonchi Oleracei of Clinopodiaceae. The traditional Chinese medicine composition is slightly bitter and astringent in taste, is cool in nature, enters liver channel, has the efficacy of astringing to stop bleeding, is used for metrorrhagia and metrostaxis, hematuria, epistaxis, gingival bleeding and traumatic bleeding, is suitable for various hemorrhagic diseases in clinic, and particularly has better curative effect on gynecological hemorrhagic diseases. Clinopodium polycephalum is a folk traditional medicine, and modern researches find that clinopodium polycephalum contains various chemical components such as triterpenes, saponins, flavonoids, volatile oil, phenylpropanoids and the like, and has pharmacological effects of stopping bleeding, resisting bacteria, reducing blood sugar, resisting oxidation, resisting inflammation and the like.

At present, the medicinal plants in the genus of Clinopodium contain flavone, triterpene and saponin thereof, volatile oil, phenylpropanoid and other ingredients, wherein the flavone and the saponin are main active ingredients of the plants. Flavonoids are one of the main components of the plants in the genus Clinopodium, and more than 20 compounds are obtained in the plants at present. The flavonoid mother nucleus in the windlass plants is mainly in the structure of flavone and flavanone, is mostly substituted by hydroxyl at 3, 5, 7, 3 'and 4' positions, exists in the form of 7-O-glucoside, mainly comprises monoglycoside and diglycoside, and the connected glycosyl is mostly glucose and rhamnose. Triterpenes and saponins thereof are another important active ingredient of the plants of the genus Clinopodium. Triterpenes and saponins thereof in the plants mainly have 2 structural skeletons: (1) oleanane (Oleanolic acid) and (2) saikosaponin type (containing 13, 28-oxolane).

Clinopodium polycephalum and cape jasmine in Clinopodium plants are used for stopping bleeding. It is reported that the research on the medicinal materials mainly focuses on the procoagulant or hemostatic effects of the medicinal materials, and less research on the anticoagulant active ingredients in the medicinal materials.

Cardiovascular and cerebrovascular thrombotic diseases are common diseases. The average incidence rate of the myocardial infarction in China is about 42 in every 10 ten thousand, and the incidence rate is in an increasing trend along with the improvement of the nutritional status. China is also a high-incidence area of cerebral thrombosis patients, the number of sick people is over 1000 thousands at present, about 150 thousands of new cases occur every year, and more than 100 thousands of death patients occur every year. Of the survivors, about 25% lose labor capacity to varying degrees with severe disability as high as over 40%. More importantly, in recent years, the incidence of thromboembolic diseases such as coronary thrombosis and cerebral thrombosis is on the rise, and the health of human beings is seriously harmed. Therefore, research on the prevention and treatment of such diseases is very important.

Disclosure of Invention

The invention aims to provide a compound which is separated from Clinopodium chinense and has the anticoagulant or antithrombotic effect.

It is another object of the present invention to provide a process for preparing the compound.

The invention also aims to provide the application of the compound in preparing anticoagulant or antithrombotic medicines and medical devices.

In view of the above, it is an object of the present invention to obtain a compound which can be used for the preparation of an anticoagulant or antithrombotic agent, which compound is obtainable from the blood stream of Clinopodium polycephalum.

The technical scheme adopted by the invention for realizing the purpose is as follows:

a compound having the structural formula (I):

the chemical formula name of the compound is:

Benzo[a]naphthacene-2-carboxylicacid,5,6,8,13-tetrahydro-1,6,9,14-tetrahydroxy-3-(2-hydroxypropyl)-7-methoxy-8,13-dioxo-(9CI)。

correspondingly, the invention also provides a preparation method of the compound, which comprises the following steps:

(1) extracting herba Clinopodii with alcohol or alcohol solution, and concentrating to obtain extract;

(2) adding water into the extract, sequentially using different organic solvents for respective extraction, and concentrating to obtain a medium-polarity organic solvent component;

(3) subjecting the medium-polarity organic solvent component to resin column chromatography, and sequentially and respectively performing gradient elution by using different low-concentration to high-concentration alcohol/water solutions as eluents to obtain a first-stage component of the target compound;

(4) taking the first-stage component to carry out chromatography on a silica gel column, sequentially and respectively carrying out gradient elution by taking different two-phase organic solvents from low concentration to high concentration as an elution machine, and combining eluents containing similar components to obtain a second-stage component containing a target compound;

(5) subjecting the second-stage component to reversed-phase C18 column chromatography, eluting with different low-concentration to high-concentration alcohol/water (v/v) solutions as eluents, and mixing eluents containing similar components to obtain third-stage component of the target compound;

(6) and (4) separating and purifying the third-level component by preparative chromatography to obtain the pure target compound shown in the formula (I).

In order to better implement the invention, the organic solvent in the step (2) is selected from petroleum ether, chloroform, dichloromethane, acetone and n-butanol, the medium polar solvent is n-butanol, and the organic phase is: water phase 4: extraction at a ratio of 1 (v/v).

To better practice the invention, two-phase organic solvents include, but are not limited to, methylene chloride/methanol equivalent polarity organic solvents, combined with eluents containing similar components.

In order to better implement the invention, in the step (1), (3) or (5), the alcohol in the alcohol/water solution is methanol or ethanol.

In order to better implement the invention, the high performance liquid chromatography separation and purification in the step (6) adopts: the mobile phase is 15-45% acetonitrile/water (v/v), and the chromatographic column is waters Xbridge BEH C18OBD^TMAnd (3) a chromatographic column, wherein the detection wavelength is 200-280 nm, and the flow rate is 2 mL/min.

In order to better implement the invention, the high performance liquid chromatography separation and purification in the step (6) adopts: the mobile phase is 35% acetonitrile/water (v/v), the chromatographic column is a C18 chromatographic column, and the detection wavelength is 210 nm.

According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention, which may be formulated into a pharmaceutical composition suitable for clinical use by adding a pharmaceutically acceptable carrier or excipient or optionally other ingredients.

According to a further aspect of the present invention, there is provided a use of the compound of the present invention for preparing a medicament for promoting blood circulation to remove blood stasis, which has an effect of inhibiting platelet aggregation.

According to a further aspect of the present invention there is provided the use of a compound of the invention in a medicament for the treatment of cardiovascular disorders which has the effect of inhibiting thrombin-activated platelet aggregation.

In order to better implement the invention, the compound is used for preparing a medicament for inhibiting the platelet aggregation activated by the adenosine diphosphate.

In order to better realize the invention, the compound can be used as an active ingredient, and can be prepared into a pharmaceutical preparation or a medical appliance by adding auxiliary materials.

In a further aspect of the invention there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a derivative thereof.

To better implement the invention, the content of the compound or derivative thereof according to claim 1 in the pharmaceutical composition is more than 60%, in particular more than 95%.

The beneficial effects of the invention are:

1. the invention designs the extraction and separation process of the active site of the Clinopodium chinense Pursh on the basis of the preliminary prediction of chemical components by a PDA detector of HPLC, and obtains the compound of formula (I). The compound is an alcohol extract of the Clinopodium polycephalum herba Clinopodii, and has the effects of stopping bleeding with small dose and promoting blood circulation with large dose. The blood activating component is flavanone component with good water solubility and capable of showing anticoagulant effect only by using a large amount of the compound shown in the formula (I).

2. The compound of formula (I) obtained by the preparation method has high purity, high stability and good biological activity, and the purity reaches 98%. By the method of in vitro coagulation activity experiments, the compound can be used as anticoagulant or antithrombotic agent, has stronger inhibitory activity on platelet aggregation activated by thrombin, and particularly has better curative effect on thrombus, cardiovascular diseases and the like.

Drawings

FIG. 1 shows the nuclear magnetic resonance two-dimensional HMBC and of the compounds obtained according to the invention¹H-¹H COSY spectrogram;

FIG. 2 shows a high resolution mass spectrum (HR-ESI-MS, negative ion scan) of a compound obtained according to the present invention;

FIG. 3 shows a high resolution mass spectrum (HR-ESI-MS, positive ion scan) of a compound obtained according to the present invention;

FIG. 4 shows the preparation of the compounds obtained according to the invention¹³C NMR spectrum;

FIG. 5 shows the preparation of compounds obtained according to the invention¹H NMAn R spectrogram;

FIG. 6 shows the preparation of compounds obtained according to the invention¹H-¹H COSY spectrogram;

FIG. 7 shows HSQC spectra of the compounds obtained for the present invention;

FIG. 8 shows HMBC spectra of the compounds obtained according to the present invention;

FIG. 9 shows a chromatographic overlay of a compound prepared using the method described in example 2;

FIG. 10 shows the maximum aggregation rate of platelets (adenosine diphosphate is the inducer) after the addition of the compound obtained by the present invention;

FIG. 11 shows the maximum aggregation rate of platelets (thrombin is an inducer) after the addition of the compound obtained by the present invention;

fig. 12 shows the maximum aggregation rate of platelets after adding the compound obtained by the present invention and aspirin, respectively.

Detailed Description

The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto, and various substitutions and alterations can be made without departing from the technical idea of the present invention as described above, according to the common technical knowledge and the conventional means in the field, and the present invention is included in the scope of the present invention.

The invention takes clinopodium polycephalum as a raw material, and obtains a new compound through the processes of extraction, column chromatography separation, concentration and the like, and the structural formula of the new compound is shown as formula 1:

the present invention will be further described with reference to the following examples.

Example 1

A method of preparing a compound comprising the steps of:

material sources are as follows: clinopodium chinense is purchased from green source biotechnology limited, and specimen samples of the medicinal materials are preserved in pharmacy of drug development center of Fujian Zhongke biology limited.

(1) Taking the aerial parts of Clinopodium polycephalum herba Clinopodii as raw materials, drying, pulverizing to obtain 10kg coarse powder, extracting the coarse powder with 100L of 60% ethanol water solution, and rotary evaporating the obtained extractive solution to dryness to obtain 980g crude extract;

(2) dissolving the extract with pure water to obtain water solution with concentration of 50mg/mL, sequentially extracting with chloroform and n-butanol, specifically according to organic phase: water phase 4: extracting according to a ratio of 1(v/v), shaking for 15min by adopting an amplitude of 120rpm of an oscillator, standing for 4 hours, and extracting for three times to obtain 300g of n-butyl alcohol extract;

(3) subjecting 260g of n-butanol extract to D101 macroporous adsorbent resin column chromatography, and sequentially and respectively subjecting to gradient elution with 0%, 10%, 30%, 60%, and 100% (v/v) ethanol/water solution as eluent to obtain 58g of first-stage component containing target compound

(4) Performing column chromatography on 53g of the first-stage component on silica gel, performing gradient elution by respectively using 3%, 10%, 20%, 40% and 100% (v/v) dichloromethane/methanol solution as eluent, and combining eluents containing similar components to obtain 12g of a second-stage component containing the target compound;

(5) performing reversed phase C18 column chromatography on 10g of the second-stage component, sequentially performing gradient elution with 25%, 40%, 60%, 75%, and 100% (v/v) methanol/water solution as eluents, respectively, tracking according to thin layer, and mixing eluents containing similar components to obtain 210mg of third-stage component containing the target compound;

(6) separating and purifying the third fraction 180mg by preparative high performance liquid chromatography using waters XBidge BEH C18OBD as column^TMThe size specification of the chromatographic column is 10 x 250mm, the particle size of the filler is 5 microns, the temperature of the chromatographic column is room temperature when the chromatographic column is used, gradient elution with 25% acetonitrile/water (v/v) as a mobile phase is selected, a PDA detector is adopted, the detection wavelength is 254nm, the flow rate is 2mL/min, a target peak eluent is collected according to ultraviolet absorption spectrum, and the target compound 82mg is obtained by rotary evaporation and concentration to dryness.

(7) The structure of the target compound is analyzed, and finally the structure of the compound is comprehensively identified through data (shown in table 1 and figures 1-8) such as mass spectrum, nuclear magnetic resonance spectrogram, specific optical rotation and the like, and is shown in a formula (I). The compound is a yellow-brown colloidal solidAn optical rotation of

(c 1.0 MeOH), high resolution Mass Spectrometry (HR-ESI-MS) M/z [ M-H [ ]]^-＝505.1067,[M+Na]⁺＝529.1101,[M+H]⁺507.1291, NMR one-dimensional hydrogen and carbon spectra data shown in attached Table 1, NMR two-dimensional HMBC and¹H-¹the related signals of the H COSY spectrogram are shown in the attached figure 1.

TABLE 1 assignment of nuclear magnetic hydrogen (1H NMR 600MHz DMSO) and nuclear magnetic carbon (13C NMR 215MHz DMSO) spectra for compounds

Example 2

A method of preparing a compound comprising the steps of:

(1) taking the aerial part of Clinopodium polycephalum herba Clinopodii as raw material, pulverizing dried sample to obtain 5kg, extracting with 50L 60% methanol water solution, and rotary evaporating the extractive solution to dryness to obtain 480g crude extract;

(2) taking 450g of crude extract, preparing an aqueous solution with the concentration of 100mg/mL by using pure water, sequentially using chloroform and n-butyl alcohol for respective extraction, and specifically according to the organic phase: water phase 4: extracting at a ratio of 1(v/v), shaking for 15min at an amplitude of 120rpm of an oscillator, standing for 4 hours, and extracting for three times to obtain 145g of n-butanol extract;

(3) taking 130g of n-butanol extract, performing column chromatography by using D101 macroporous adsorption resin, and performing gradient elution by using 0%, 20%, 45%, 70% and 100% (v/v) ethanol/water solution as eluent in sequence to obtain 23g of a first-stage component containing a target compound;

(4) taking 20g of the first-stage component, adopting silica gel column chromatography, sequentially using 6%, 15%, 30%, 50% and 100% (v/v) dichloromethane/methanol solution as eluent to carry out gradient elution, tracking according to a thin layer, and combining the eluents containing similar components to obtain 4g of a second-stage component containing the target compound;

(5) taking 3.5g of the second-level component, adopting reversed-phase C18 column chromatography, sequentially using 30%, 50%, 65%, 80%, 100% (v/v) methanol/water solution as eluent to carry out gradient elution, and combining the eluents containing similar components according to thin-layer tracing to obtain 78mg of a third-level component containing the target compound;

(6) collecting three components 60mg, and respectively separating and purifying by high performance liquid chromatography with waters XBidge BEH C18OBD as chromatographic column^TMThe size specification of the chromatographic column is 10 x 250mm, the particle size of a filler is 5 microns, the temperature of the chromatographic column is room temperature when the chromatographic column is used, gradient elution with 35% acetonitrile/water (v/v) as a mobile phase is selected, a PDA detector is used as the detector, the detection wavelength is 210nm, the flow rate is 2mL/min, a target peak eluent is collected according to ultraviolet absorption spectrum, rotary evaporation and concentration are carried out until the eluent is dried, target compounds S1, S2, S3, S4, S5 and S6 are obtained, and the target compounds prepared by six parts have the average purity>98％，RSD<0.2% yield>91 percent. FIG. 9 shows a chromatographic overlay of the target compounds S1, S2, S3, S4, S5, S6.

Example 3

A method of preparing a compound comprising the steps of:

(1) taking the overground part of a clinopodium polycephalum medicinal material (Clinopodium polycephalum herba Clinopodii) as a raw material, crushing a dried sample to obtain 5kg of coarse powder, extracting with 70% ethanol water solution, and rotatably evaporating the obtained extracting solution to dryness to obtain 430g of crude extract;

(2) preparing 410g of crude extract into aqueous solution with the concentration of 100mg/mL by using pure water, and then sequentially extracting by using chloroform and n-butanol respectively, wherein the organic phase is as follows: water phase 4: extracting at a ratio of 1(v/v), shaking for 15min at an amplitude of 120rpm of an oscillator, standing for 4 hours, and extracting for three times to obtain 135g of n-butanol extract;

(3) taking 125g of n-butanol extract, performing column chromatography by using D101 macroporous adsorption resin, and performing gradient elution by using 0%, 30%, 60%, 85% and 100% (v/v) ethanol/water solution as eluent in sequence to obtain 21g of a first-stage component containing a target compound;

(4) taking 18g of the first-stage component, adopting silica gel column chromatography, sequentially carrying out gradient elution by using 10%, 20%, 40%, 60% and 100% (v/v) dichloromethane/methanol solution as eluent, and combining the eluents containing similar components to obtain 3.6g of a second-stage component containing the target compound;

(5) taking 3g of the secondary component, adopting reversed-phase C18 column chromatography, sequentially performing gradient elution by using 40%, 60%, 75%, 90% and 100% (v/v) methanol/water solution as eluents, combining eluents containing similar components according to thin layer tracking to obtain 69mg of a tertiary component containing a target compound;

(6) separating and purifying the third fraction 60mg by high performance liquid chromatography with waters XBidge BEH C18OBD as chromatographic column^TMThe size specification of the chromatographic column is 10 x 250mm, the particle size of the filler is 5 microns, the temperature of the chromatographic column is room temperature when the chromatographic column is used, gradient elution with a mobile phase of 45% acetonitrile/water (v/v) is selected, the detector is a PDA detector, the detection wavelength is 280nm, the flow rate is 2mL/min, a target peak eluent is collected according to ultraviolet absorption spectrum, and the target compound is obtained by rotary evaporation and concentration to be dry, wherein the target compound is 31 mg.

EXAMPLE 4 biological assay and analysis of anticoagulant or antithrombotic Effect of Compound (I)

1, material of

Plasma: blood purchased from hospitals was indicated as platelet-rich blood, and purchased at 300CC at one time.

Reagent: 15mg of the compound represented by the formula (I).

2, method

Experiment one:

platelet Poor Plasma (PPP) was obtained as a relative control for platelet aggregation by collecting the supernatant as Platelet Rich Plasma (PRP) by centrifugation at 200g centrifugal force and washing other components (including thrombomin and fibrinogen) from the plasma with the benchtop B solution. Adding a compound shown in a formula (I), using Adenosine Diphosphate (ADP) as an inducer for a platelet aggregation experiment, carrying out the experiment by using a platelet aggregation instrument, carrying out blood coagulation activity detection according to the requirements of a kit, repeating the concentration of each sample for three times, and taking the average value of the platelet aggregation rate. The control group was a group of platelet-rich plasma (PRP) to which no compound solvent was added, and the results are shown in fig. 10.

The experimental results are as follows: using the blood coagulation index platelet aggregation rate as an index, as shown in FIG. 10, it was found that the maximum platelet aggregation rate decreased with the increase in the concentration of the compound represented by formula (I), and it differed from the control group in the case where the concentration of the compound represented by formula (I) was higher. The anticoagulant activity of the compound shown in the formula (I) is gradually enhanced along with the increase of the concentration, and the maximum aggregation rate of the blood platelets is related to the concentration of the compound shown in the formula (I), so that the anticoagulant activity of the compound is shown.

Experiment two:

blood purchased from a hospital to which an anticoagulant has been added was centrifuged at 200g to collect the supernatant as platelet-rich plasma (PRP), and the other components (including thrombomin, fibrinogen, etc.) in the plasma were washed off with the desktop B liquid to obtain platelet-poor plasma (PPP) as a relative control for platelet aggregation. Adding a compound shown in a formula (I), using thrombin (thrombin) as an inducer of a platelet aggregation experiment, carrying out an experiment by using a platelet aggregation instrument, carrying out blood coagulation activity detection according to the requirements of a kit, repeating the experiment for three times for each sample concentration, and taking an average value of platelet aggregation rate. The control group was a group of platelet-rich plasma (PRP) to which no compound solvent was added, and the results are shown in fig. 11.

The experimental results are as follows: using the blood coagulation index platelet aggregation rate as an index, it was found that the maximum platelet aggregation rate decreased with the increase in the concentration of the compound represented by formula (i), as shown in fig. 11, showing a decreasing dependence relationship and being significantly different from the control group. The anticoagulant activity of the compound shown in the formula (I) is gradually enhanced along with the increase of the concentration, which shows that the maximum aggregation rate of the blood platelets is related to the concentration of the compound shown in the formula (I) and has negative correlation, and the compound has strong anticoagulant activity.

Experiment three

Blood purchased from a hospital and added with an anticoagulant, supernatant fluid is collected as Platelet Rich Plasma (PRP) by centrifugation with a centrifugal force of 200g, other components (including thrombomin, fibrinogen and the like) in the plasma are washed away by a bench B liquid, Platelet Poor Plasma (PPP) is obtained as a relative control for platelet aggregation, a compound represented by formula (I) is added at a concentration of 66.67ug/ml, and Aspirin (Aspirin) is used as a positive control to prepare 66.7 ug/ml. Thrombin (thrombin) is used as an inducer of a platelet aggregation experiment, a platelet aggregation instrument is used for carrying out experiments, the blood coagulation activity is detected according to the requirements of a kit, each sample concentration is repeated three times, the average value of the platelet aggregation rate is taken, a control group is a platelet-rich plasma (PRP) group without adding a compound solvent, and the result is shown in figure 12.

The experimental results are as follows: the platelet aggregation rate as an index of blood coagulation is adopted, as shown in fig. 12, the compound group of the formula (I) and the aspirin group have difference from the control group, and the compound group of the formula (I) and the aspirin have anticoagulant property for inhibiting platelet aggregation. Compared with the compound group shown in the formula (I), the maximum platelet aggregation rate of the compound group shown in the formula (I) is lower than that of the aspirin group, and the compound group shown in the formula (I) has obvious difference, and the anticoagulant activity of the compound group shown in the formula (I) is better than that of the aspirin.

The experimental result shows that the compound of the formula (I) has strong anticoagulant activity, and the anticoagulant activity of the compound of the formula (I) is superior to that of aspirin.

Although the embodiments have been described, once the basic inventive concept is obtained, other variations and modifications of these embodiments can be made by those skilled in the art, so that the above embodiments are only examples of the present invention, and not intended to limit the scope of the present invention, and all equivalent structures or equivalent processes using the contents of the present specification and drawings, or any other related technical fields, which are directly or indirectly applied thereto, are included in the scope of the present invention.

Claims

1. The application of a compound in medicine is characterized in that the compound of formula (1) is adopted for preparing a pharmaceutical composition for inhibiting platelet aggregation in clinical use, and the structure of the compound of formula (1) is shown as the following formula:

（1）。

2. the use of a compound of claim 1 in medicine, wherein said pharmaceutical composition is a medicament for inhibiting thrombin-activated platelet aggregation.

3. The use of a compound according to claim 1 in medicine, wherein the pharmaceutical composition is a medicament for inhibiting adenosine diphosphate-activated platelet aggregation.

4. The use of a compound of formula (1) in medicine for preparing a clinically used medical device for inhibiting platelet aggregation is characterized in that the structure of the compound of formula (1) is shown as the following formula:

（1）。

5. the use of a compound according to claim 4 in medicine, wherein the medical device is one which inhibits thrombin-activated platelet aggregation.

6. The use of a compound according to claim 4 in medicine, wherein the medical device is one which inhibits adenosine diphosphate-activated platelet aggregation.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (1), the compound of formula (1) having the structure:

（1）。

8. the pharmaceutical composition of claim 7, wherein: the content of the compound of the formula (1) in the pharmaceutical composition is more than 60%.

9. The pharmaceutical composition of claim 8, wherein: the content of the compound of the formula (1) in the pharmaceutical composition is more than 95%.