CN110066310A - Tanshinone IIA thiophene pyridine compounds and their and its preparation method and application - Google Patents
Tanshinone IIA thiophene pyridine compounds and their and its preparation method and application Download PDFInfo
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- CN110066310A CN110066310A CN201810056743.9A CN201810056743A CN110066310A CN 110066310 A CN110066310 A CN 110066310A CN 201810056743 A CN201810056743 A CN 201810056743A CN 110066310 A CN110066310 A CN 110066310A
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Abstract
The present invention provides a kind of tanshinone IIA thiophene pyridine compounds and their with structure shown in Formulas I, experiments have shown that such compound can effectively inhibit the expression, combination and its activity of platelet membrane adp receptor, it can be used for treating the disease mediated by ADP, especially cardiovascular and cerebrovascular disease.The application in cardiovascular medicament is prevented and treated the present invention also provides the preparation method of such inhibitor and in preparation.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to a kind of tanshinone IIA thiophene pyridines with cardiovascular and cerebrovascular activity
Compound and its pharmaceutically acceptable salt and/or hydrate.The invention further relates to the preparation method of these compounds and this
A little compounds peripheral blood vessel relevant to platelet aggregation, internal organ, liver and the renal blood vessels of the mankind or other mammals,
Purposes in the treatment and/or prevention of cardiovascular and cerebrovascular disease or illness as adp receptor antagonist.
Background technique
Cardiovascular and cerebrovascular disease is the first cause of disease killer for causing human death all the time, has disease incidence height, disability rate
Feature more than high, death rate height, high recurrence rate and complication.Currently, the whole world is every year because of about 17,000,000 people of cardiovascular and cerebrovascular diseases death,
And China dies of nearly 3,000,000 people of cardiovascular and cerebrovascular disease every year, account for China every year total Death causes 51%, having become China is
One of the great public health problem faced to the whole world.In recent years, with the rapid hair of genomics, molecule and cell biology
Exhibition, it has been found that although cardiovascular and cerebrovascular disease has complicated pathogenic mechanism, it is clear that, atherosclerotic plaque
Thrombosis after rupture or erosion is the deciding factor of such Occurrence and development of disease, and platelet aggregation and coagulation factor
Cascade starting pivotal player (P. Libby. Mechanisms of acute is then played in thrombosis
coronary syndromes and their implications for therapy. N. Engl. J. Med. 2013,368, 2004-2013).Correspondingly, antiatherosclerosis, platelet aggregation-against and it is anticoagulant be antithrombotic heart and brain all the time
The important directions of blood vessel drug eluting research.
However, existing antithrombotic cardiovascular medicament or using platelet aggregation-against as main mechanism (such as aspirin, chlorine pyrrole
Gray, tirofiban etc.) or (such as warfarin, Eliquis, up to pyrrole adds group ester at heparin using anticoagulation as main mechanism
Deng), but rarely have while having the drug of antiatherosclerosis, anticoagulation and/or antiplatelet aggregative activity mechanism.And facing
On bed, in order to reach better thrombus disease therapeutic effect, often need to by Antiatherosclerosis medicine, anticoagulation medicine and/or
Medicament for resisting platelet aggregation be used in combination (Hao Sufang, Xia Yun injection Urinary kallidinogenase and bisulfate clopidogrel combination treat into
Malleability cerebral infarction observation of curative effect [J].Chinese medicine science2012,2, 64-65；Lan Hao warfarin joint clopidogrel exists
Coronary heart disease merge atrial fibrillation patients in application value [J]. Preventing and treating cardiovascular disease knowledge. 2017, 5, 61-62；Yao Jun
Enlightening, the such as Shen Bin Atorvastatin to Anticoagulation in Warfarin influence [J]. Naval medicine magazine. 2011, 32, 377-
380.), but due to the difference that existing drug-drug interactions and drug individual are metabolized, this drug combination is often
Very big security risk is brought to patient.Therefore, it for the demand of further satisfaction thrombus disease clinical treatment drug, opens
It sends out with more mechanism pathways, more preferably antithrombotic reagent will have important research and application value to combined therapy effect.
Chinese medicine has always a unique advantage to the treatment of complex disease, and the day to find from traditional blood-activating and stasis-removing
Cardiovascular medicament is developed based on right active constituent, also becomes the important shortcut of China's modern times new drug initiative.Among these, Radix Salviae Miltiorrhizae
The discovery of ketone IIA and its sodium sulfonate analog is just important research and represents.Tanshinone IIA is red from traditional blood-activating and stasis-removing
The fat-soluble Diterpene quinone active component found in ginseng, accounts for about the 0.35% of medicinal material content.The study found that tanshinone IIA has extensively
General pharmacological action is for example anti-inflammatory, antiatherosclerosis, expansion of coronary artery and adjusts immune response etc., but due to liposoluble
Property strong and poorly water-soluble the shortcomings that, cause its oral bioavailability extremely low, it is difficult to directly apply to clinic.In order to solve tanshinone
The problem of IIA dissolubility difference, early stage people have obtained tanshinone IIA sodium sulfonate by sulfonated reaction, have greatly improved pellet
Join the water solubility of ketone IIA, and is successfully applied to the adjuvant treatment of clinical coronary heart diseases and angina pectoris and myocardial infarction.However, sulfonic group
Presence although improve the water solubility of tanshinone IIA, but also limit the diversity of its Clinical Dosage Form, while also leading to it only
Some injection pH value of solution are relatively low, and irritation is big and the safety issue of poor chemical stability.In addition, prior, tanshinone
Although IIA sodium sulfonate is clinically widely applied, its mechanism of action is still not clear enough, and action target spot is also unintelligible,
To seriously affect the reasonability and safety of its clinical application, and then it is auxiliary currently as cardiovascular and cerebrovascular disease to also result in it
Help the clinical orientation of medication.
In recent years, people have also carried out a large amount of chemical structure transformation research work to tanshinone IIA, and obtain various structures
The tanshinone IIA analog of type is used for the prevention and treatment of cardiovascular and cerebrovascular disease.For example, a kind of 1. tanshinone IIA phosphoric acid phenol
Ester derivant and preparation method thereof, 103382214 A of CN；2. the synthesis and application of a kind of sulfonamide compounds, CN
104341481 A；3. a kind of synthesis of heterocyclic sulfonic acid derivative and its application in drug therapy, 104341482 A of CN；
4. the synthesis and pharmaceutical applications of a kind of sulfamide derivative, 104341450 A of CN；5. a kind of tanshinone IIA derivative and its system
Standby and application, 104961794 A of CN；6. a kind of tanshinone IIA phosphoric acid derivatives and its synthesis and the application as drug, CN
106478764 A；7. application of the tanshinone IIA derivative in medicine, 105884856 A of CN；8. tanshinone IIA acrylic acid
Or its sodium salt and preparation method and application, 101974068 A of CN；9. a kind of tanshinone compound 17-position ester derivative and
Its preparation process and application, 106810593 A of CN；10. a kind of 15 amide derivatives of tanshinone compound and its preparation
Technique and application, 106831934 A of CN.However, although these analogs are in water-soluble and/or stability and/or bioactivity
It is upper to have a degree of improvement compared to tanshinone IIA, but still have not been changed that its target spot is unintelligible and the indefinite key of mechanism
Problem.In addition to this, the preparation route of such compound is longer, and yield is lower, seriously constrains the subsequent of them and deeply opens
Send out progress.Therefore, the Rational drug design of tanshinone IIA how is directed to by carrying out, discovery mechanism of action is clear, effect
Target spot is clearly and the tanshinone cardiovascular medicament of new generation of bioavilability raising causes the concern of the present inventor.
ADP, that is, adenosine diphosphate (ADP), the nucleotide compound being made of the phosphate radical that a molecule adenosine is connected with two, and so far
It is found that earliest and most important induced platelet aggregation substance until the present.Human platelet includes three kinds of different ADP
Receptor: P2Y1、P2Y12、P2X1。P2X1 It is ligand-gated ion channel, P2Y1、P2Y12It is to be coupled with two different G-proteins
Receptor, wherein P2Y in quantity on blood platelet12>P2Y1, and P2Y12It is also existing clinical adp receptor retarding agent clopidogrel
With prasugrel and ticagrelor main function target spot --- it is small by the inhibition adenosine diphosphate (ADP) (ADP) and its blood of selectivity
Plate receptor P2Y12Combination and the activation of glycoprotein GPIIb/IIIa compound that mediates of secondary ADP, to inhibit blood platelet
Aggregation.Although they still have many curative effects and peace however, existing ADP retarding agent is clinically widely applied
Deficiency in all directions, such as there are 4 ~ 31% clopidogrel Resistants for clopidogrel, have seriously affected the performance of its curative effect.For another example,
Although prasugrel has a faster more longlasting antiplatelet aggregative activity, the risk of bleeding is also with respect to clopidogrel
Increase (the thrombotic diseases medicament for resisting platelet aggregation progress such as Han CongfanChinese Journal of New Drugs. 2016, 12,
1363-1369).Based on above-mentioned analysis, in conjunction with Chinese medicine in the treatment advantage of the complex diseases such as cardiovascular and cerebrovascular, the present inventor passes through
Creativeness invention, provides class I tanshinone IIA thiophene pyridine compounds and their for the first time.It studies on this basis and specifies such
Compound is to the inhibiting effect of the ADP platelet aggregation induced, before showing the excellent treatment for cardiovascular and cerebrovascular occlusion disease
Scape.
Summary of the invention
The object of the present invention is to provide class I tanshinone IIA thiophene pyridine compounds.
It is a further object of the present invention to provide for prevent and/or treat cardiovascular and cerebrovascular disease containing such compound medicine
Compositions.
Another object of the present invention is to provide the preparation method of such compound.
The present invention relates to class I tanshinone IIA thiophene pyridine compounds, such compound is in molecular cell level on pair
Treatment cardiovascular and cerebrovascular disease effect in the inhibiting effect of ADP and in vivo animal level, has and prevents and/or treat heart and brain blood
The purposes of pipe disease.
The present invention provides class I tanshinone IIA thiophene pyridine compounds and its officinal salt, these compounds have general formula I
Shown in structure:
In formula, R1To be selected from the group group: H, formic acid C1~C6Alkyl ester group, C1~C6Linear or branched alkyl group, C3~C6Naphthenic base or
Cycloalkenyl, C1~C6Linear chain or branched chain alkanoyl, C3~C6Cycloalkanoyl, C2~C10Linear chain or branched chain alkenyl, C2~C10Linear chain or branched chain
Alkynyl, cyano, aromatic radical, aralkyl, heterocycle, heteroaryl.Wherein R1Concretely-H ,-COOH ,-COOCH3、-
COOCH2CH3、-CH3、-CH2CH3、-CH(CH3)2、-CH2CH2CH3、-COCH3、-COCH2CH3、-COCHCH2CH2、-Ph、-Ph
(2-Cl)、-Ph(2-F)、-Ph(2-OMe)、-Ph(2-CF3) and R1Preferably H ,-COOCH3。
R2Selected from following any structure group: H, OR3.Wherein R3For C1~C6Alkanoyl, C1~C6Oxygen acyl group, cinnamoyl,
Aromaticacyl radical, miscellaneous aromaticacyl radical；R3Described in aryl in cinnamoyl and aromaticacyl radical be phenyl or be selected from halogen by 1-4
Element, hydroxyl, nitro, cyano, trifluoromethyl, carboxyl, C1~C6Alkyl, C1~C6Phenyl replaced group in alkoxy；R3In
The miscellaneous aromaticacyl radical is the heteroatomic C that O, N, S are selected from 1-35-C10Miscellaneous aromaticacyl radical.Wherein R2Concretely-
COCH3、-COCH2CH3、-COCH(CH3)2、-COCHCH2CH2、-COCHCHPh、-COCHCHPh(3,4-OMe)、-COPh、-
COPh(4-F)、-COPh(4-OMe)、 -COPh(3,4-OMe)、-COPh(4-NO2)。
Dotted line is chemical bond or is not present.
The preferred tanshinone IIA thiophene pyridine compounds and their in part of the invention is as follows.It is only right that these implementations enumerate
The present invention is described further, and it is not intended to limit the scope of the present invention in any way.
Wherein it is known that any stereocenter of any of the above-described compound enumerated can be absolutely when not expressing
(R)-or (S)-configuration is also possible to its raceme mixture.
The present invention also provides the above-mentioned pharmaceutical salt of tanshinone IIA thiophene pyridine compounds and their.The pharmaceutical salt of the present invention
It standardization program well known in the art can be used to obtain, i.e., reacted by tanshinone IIA thiophene pyridine compounds and their with suitable acid
The salt arrived, such as the hydrochloride of tanshinone IIA thiophene pyridine compounds, sulfate, phosphate, acetate, citrate, oxalic acid
Salt, malonate, salicylate, malate, fumarate, succinate, ascorbate, maleate, tartrate,
Citrate, mesylate or isethionate.
According to the second aspect of the invention, a kind of pharmaceutical composition for treating cardiovascular and cerebrovascular disease is provided, wherein containing controlling
A effective amount of at least one compound selected from Formulas I and its pharmaceutical salt compound are treated as medicament.For example, as can carry out
The form of the pharmaceutical composition of enteral or parenteral administration.
Described pharmaceutical composition can further comprise pharmaceutical carrier, excipient, adjuvant and/or auxiliary material.The carrier,
Excipient, adjuvant and/or auxiliary material can be in a manner of known to any technical staff in this field (for example, see Remington, The
Science and Practice of Pharmacy, 21st Edition (2005), Part 5, " Pharmaceutical
Manufacturing " [published by Lippincott Williams&Wilkins]) it is produced comprising by institute
The compound for the Formulas I stated and its pharmaceutically acceptable salt optionally combine other substances for having therapeutic value, together with it is applicable,
Nontoxic, inert, treatment biocompatible solid or liquid carrier materials and the common drug adjuvant selected as needed are made
Galenical form.
A kind of embodiment according to the present invention, pharmaceutical composition of the invention can further comprise therapeutically effective amount
Other pharmaceutical therapeutic agents form compound preparation as active constituent.
According to the third aspect of the invention we, above-mentioned tanshinone IIA thiophene pyridine compounds and their or its pharmaceutical salt are provided
Preparation method, this method includes the preparation of following method.
The preparation of compound of formula I
Abbreviation is applied in the whole instruction and embodiment below:
AcOH acetic acid
ADP adenosine diphosphate
BSA bovine serum albumin(BSA)
DMSO dimethyl sulfoxide
DMF N,NDimethylformamide
Dpm decays per minute
LC-MS liquid chromatography-mass spectrography
Ph- phenyl
RT room temperature
SDS lauryl sodium sulfate
TLC thin-layer chromatography
V liquor capacity
Formula Compound I can be prepared according to following universal method:
。
R of the invention2When substituent group is H or O, structural formula can be directly obtained by method single step reaction shown in above formula method a)
The target compound of I-a.Mannich occurs under Lewis acid catalysis and reacts with aldehyde and thiophene pyridine is replaced for tanshinone IIA, obtains
To tanshinone IIA thiophene pyridine compounds (I-a).
R2Substituent group is OR3When, the targeted of structural formula I-b can be obtained through three-step reaction by method shown in above formula method b)
Close object.Using the pyridine thienone of trityl as protecting group as starting material, alkali effect under with R3X occurs acylation and obtains intermediate-
1, key intermediate -2 then is obtained through sour selective hydrolysis, finally again with tanshinone IIA and substitution aldehyde under Lewis acid catalysis
Mannich reaction occurs, obtains tanshinone IIA thiophene pyridine compounds (I-b).
Preferably, in the method according to the invention, solvent for use in Mannich reaction step in method a) and method b)
It can be but not limited to C1-C4Alcohol, chloroform, methylene chloride, ethyl acetate, methyl acetate,N,NDimethylformamide, dimethyl
Sulfoxide, ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, acetonitrile, chlorobenzene, dimethylbenzene, toluene, formic acid, acetic acid or they two-by-two mix
Close solution etc.；Reaction temperature is generally in RT ~ 120 oC, reaction temperature depend on the reactivity situation of particular compound.
Preferably, in the method according to the invention, acylated bases reaction reagent used can be in method b) step 1
But it is not limited to sodium hydride, triethylamine, diisopropyl ethylenediamine, and acylating agent can be acyl chlorides or acid anhydrides.
Preferably, in the method according to the invention, acids reaction reagent used is hydrolyzed in method b) step 2 can be
But it is not limited to hydrochloric acid or p-methyl benzenesulfonic acid.
Preferably, in the method according to the invention, method a) and b) in step Mannich react Lewis acid used can
Think Bronsted acid, or metal Lewis acid；Preferably metal Lewis acid such as transition metal and lanthanide metal salt.
Preferably, in the method according to the invention, solvent for use can be water, C in method c) salt-forming steps1-C4Alcohol, two
Methyl sulfoxide, dimethylformamide, acetone, acetonitrile, chloroform, methylene chloride, methyl tertiary butyl ether(MTBE) or their mixing two-by-two are molten
Liquid, reaction temperature are RT ~ 60 oC；Sour HA used can be hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, water
Poplar acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, tartaric acid, citric acid, methanesulfonic acid or isethionic acid；N table
Show the number in conjunction with acid, n=0~2, concretely 0.5,1,1.5,2.
Specifically, according to the method for the present invention, using tanshinone IIA as substrate, with the thiophene pyridine for replacing aldehyde and derivatization
The serial tanshinone IIA thiophene pyridines chemical combination of Formulas I-a and Formulas I-b is directly obtained through Mannich reaction under Lewis acid catalysis
Object.Reacting finisheding degree is usually detected with TLC and LC-MS, after completion of the reaction generally with methyl tertiary butyl ether(MTBE), ethyl acetate or
The extraction of methylene chloride equal solvent, is successively washed with saturated sodium bicarbonate, water and saturated common salt, through anhydrous sodium sulfate or magnesium sulfate
It is dry, solvent is removed under low-temperature reduced-pressure.Intermediate product and final product nuclear magnetic resonance and Mass Spectrometer Method confirmation.
According to the fourth aspect of the invention, the compound of Formulas I is adp receptor antagonist.Correspondingly, they can be used for treating
(including combination therapy) cardiovascular and cerebrovascular occlusion disease, wherein they are widely used as platelet activation, aggregation and the inhibition of threshing
Agent, promotor as platelet disaggregation or as antithrombotic agents.I.e. the present invention also provides above-mentioned tanshinone IIA thiophene pyridines
Answering in the drug of compound or its pharmaceutical salt cardiovascular and cerebrovascular disease caused by preparation prevention or treatment platelet aggregation
With.The cardiovascular and cerebrovascular disease be coronary heart disease, myocardial infarction, the heart twist pain, thrombolytic therapy or percutaneous coronary it is intracavitary at
The related acute vascular closure of shape art, transient ischemic attack, apoplexy, intermittent claudication or coronal or peripheral arterial bypass move
Plant art, lumen of vessels narrows, the restenosis after coronary artery or venous angioplasty, Patients in Hemodialysis vascular access are logical
Smooth maintenance and pulmonary thromboembolism.
Beneficial effect
The present invention has designed and synthesized a kind of novel tanshinone IIA thiophene pyridine structure class compound, small to the blood of ADP induction
Plate is populated with apparent inhibiting effect.Not only chemical stability is good for such compound, but also water solubility substantially improves, and shows excellent
Different druggability feature, can be used for preparing treatment cardiovascular and cerebrovascular diseases medicament.The compounds of this invention synthesis is simple, easily prepared,
And synthesis material is abundant, has significant industrialization development researching value.
Detailed description of the invention
Fig. 1 is the platelet aggregation activity experiment of tanshinone IIA thiophene pyridine compounds and their of the present invention anti-ADP induction in vitro
As a result.
Fig. 2 tanshinone IIA thiophene pyridine compounds and their of the present invention inhibits rat arteriovenous shunt thrombosis formation effect experiment
As a result.
The present invention is further explained combined with specific embodiments below, but does not limit the present invention.Experiment behaviour of the invention
Make that there is versatility, is not limited to the particular compound mentioned in following embodiment.
In following preparation examples,1H-NMR is measured with Varian Mercury AMX300 type instrument.MS VG ZAB-HS or VG-
7070 types and Esquire 3000Plus-01005 measurement.All reaction dissolvents are passing through re-distillation using preceding, are made
Anhydrous solvent is to be dried to obtain according to standard method.Except explanation is outer, it is all react be under protection of argon gas into
Row is simultaneously tracked with TLC, post-processes Shi Junjing saturated salt solution and anhydrous sodium sulfate drying process.The purifying of product is equal in addition to explanation
It is purified using the column chromatography of silica gel (200-300 mesh).
Route 1
Embodiment 1
By paraformaldehyde (30 mg, 1 mmol), copper acetate (2 mg, 0.01 mmol) and thi ophene hydrochloride pyridine (52 mg, 0.3
Mmol) be added in the mixed solution containing tanshinone IIA (59 mg, 0.2 mmol) dimethyl sulfoxide and glacial acetic acid (v/v=2:
1,2 mL), and in 60oIt reacts under C to complete.After the reaction was completed, filter, gained filtrate decompression be evaporated after through silica gel column chromatography
Purify (VPetroleum ether:VEthyl acetate=10:1 ~ 2:1), obtain 1 compound JNLD-1(68 mg of embodiment, yield 76%).MS-ESI [M+H
]+ 446.1; 1H NMR (300 MHz, CDCl3) δ 7.65–7.52 (m, 2H), 7.09 (d, J = 5.1 Hz,
1H), 6.74 (d, J = 5.1 Hz, 1H), 3.79 (s, 2H), 3.67 (s, 2H), 3.18 (t, J = 6.4
Hz, 2H), 2.98–2.88 (m, 4H), 2.29 (s, 3H), 1.84–1.74 (m, 2H), 1.66–1.61 (m,
2H), 1.30 (s, 6H)。
Embodiment 2 to embodiment 7 preparation reference implementation example 1 operation, pass course 1 obtains, and wherein paraformaldehyde can
Aldehyde such as glyoxalic acid methylester, glyoxylic acid ethyl ester, acetaldehyde cyclopropanone and aromatic aldehyde is replaced to replace by other, acquired results are as follows:
Route 2
Embodiment 6
Preparation step 1: embodiment 6-1 synthesis
Under conditions of ice bath stirring, Xiang Hanyou SM-1(397 mg, 1 mmol) and triethylamine (201 mg, 2 mmol) second
It is slowly added into acetic anhydride (204 mg, 2 mmol) in nitrile solution (2 mL), is then slowly increased to room temperature and the reaction was continued 2 ~ 3 h
To complete.TLC detect after the reaction was completed, add 5 ml of water to be quenched, then be added ethyl acetate (10 mL) extraction, organic phase according to
It is secondary that saturated sodium bicarbonate, brine It is used then to pass through through being concentrated to dryness to obtain white solid after anhydrous sodium sulfate drying
Ethyl alcohol recrystallization obtains embodiment 6-1 compound JNLD-2 (408 mg, 93% yield).MS-ESI [M+H]+ 440.1。
Preparation step 2: embodiment 6-2 synthesis
Under the conditions of ice bath stirring, in the acetone soln (2 ml) of Xiang Hanyou embodiment 6-1 compound (219 mg, 0.5 mmol)
2.5 M HCl acetone solns (2 mL, 5 mmol) are added.Then RT ~ 45 are risen to oC and the reaction was continued 2 ~ 3 h are to complete.Reaction
After the completion, precipitation solid filtering will be precipitated, acetone washing (5 ml) then is dried under reduced pressure to obtain embodiment 6-2 compound (87
mg, 75% yield)。MS-ESI [M+H]+ 198.0; 1H NMR (300 MHz, DMSO-d 6) δ9.76 (brs, 1H),
6.54 (s, 1H), 4.37−3.93 (m, 2H), 3.42−3.28 (m, 2H), 3.05 (t, J = 6.0 Hz, 2H),
2.26 (s, 3H)。
Preparation step 3: embodiment 6 synthesizes
By paraformaldehyde (30 mg, 1 mmol), zinc acetate (2 mg, 0.01 mmol) and embodiment 6-1 compound (70 mg,
0.3 mmol) it is added to containing in tanshinone IIA (59 mg, 0.2 mmol) dimethyl sulphoxide solution (2 mL), and in 60oC
24 h of lower reaction.After the reaction was completed, filter, gained filtrate decompression be evaporated after through silica gel chromatography (VPetroleum ether:VEthyl acetate=10:1
~ 2:1), obtain 6 compound JNLD-2 of embodiment (90 mg, yield 89%).MS-ESI [M+H]+ 504.1; 1H NMR (300
MHz, CDCl3) δ7.66–7.52 (m, 2H), 6.27 (s, 1H), 3.80–3.65 (m, 4H), 3.17 (t, J =
6.4 Hz, 2H), 2.98–2.89 (m, 4H), 2.28 (s, 3H), 2.25 (s, 3H), 1.82–1.73 (m,
2H), 1.67–1.62 (m, 2H), 1.30 (s, 6H)。
Embodiment 7
According to the preparation method in embodiment 6, pass course 2, wherein using propionic andydride substitution acetic anhydride as raw material in preparation step 1,
Obtain 7 compound JNLD-3(89 mg of embodiment, yield 86%).MS-ESI [M+H]+ 518.3; 1H NMR (300 MHz,
CDCl3) δ7.65–7.52 (m, 2H), 6.26 (s, 1H), 3.81–3.65 (m, 2H), 3.16 (t, J = 6.4
Hz, 2H), 2.98–2.88 (m, 4H), 2.55 (q, 2 H, J = 7.4 Hz), 2.28 (s, 3H), 1.82–
1.75 (m, 2H), 1.66–1.60 (m, 2H), 1.29 (s, 6H), 1.23 (t, 3 H, J = 7.4 Hz)。
Embodiment 8
According to the preparation method in embodiment 6, pass course 2 is wherein original with isobutyryl chloride substitution acetic anhydride in preparation step 1
Material, obtains 8 compound JNLD-4(84 mg of embodiment, yield 79%).MS-ESI [M+H]+ 532.3; 1H NMR (300 MHz,
CDCl3) δ7.66–7.52 (m, 2H), 6.26 (s, 1H), 3.80–3.65 (m, 4H), 3.17 (t, J = 6.4
Hz, 2H), 2.97–2.88 (m, 4H), 2.70–2.63 (m, 1H), 2.28 (s, 3H), 1.82–1.74 (m,
2H), 1.66–1.61 (m, 2H), 1.30 (s, 6H), 1.27 (d, J = 2.1 Hz, 3H), 1.24 (d, J =
2.1 Hz, 3H)。
Embodiment 9
According to the preparation method in embodiment 6, pass course 2 is wherein original with chlorobenzoyl chloride substitution acetic anhydride in preparation step 1
Material, obtains 9 compound JNLD-5(104 mg of embodiment, yield 92%).MS-ESI [M+H]+ 566.3; 1H NMR (300 MHz,
CDCl3) δ8.17 (d, J = 8.1 Hz, 2H), 7.72–7.52 (m, 5H), 6.42 (s, 1H), 3.79–3.64
(m, 4H), 3.17 (t, J = 6.3 Hz, 2H), 2.97–2.89 (m, 4H), 2.27 (s, 3H), 1.82–1.75
(m, 2H), 1.65–1.60 (m, 2H), 1.29 (s, 6H)。
Embodiment 10
According to the preparation method in embodiment 6, pass course 2, wherein with 3,4- dimethoxy-benzoyl chloride substitution in preparation step 1
Acetic anhydride is raw material, obtains 10 compound JNLD-6(109 mg of embodiment, yield 87%).MS-ESI [M+H]+ 626.3; 1H
NMR (300 MHz, CDCl3) δ7.86 (dd, J = 8.4, 1.7 Hz, 1H), 7.70 (d, J = 1.7 Hz,
1H), 7.66–7.53 (m, 2H), 6.95 (d, J = 8.4 Hz, 1H), 6.39 (s, 1H), 3.85 (s, 6H),
3.81–3.65 (m, 4H), 3.17 (t, J = 6.4 Hz, 2H), 2.97–2.88 (m, 4H), 2.28 (s, 3H),
1.82–1.74 (m, 2H), 1.66–1.60 (m, 2H), 1.30 (s, 6H)。
Embodiment 11
According to the preparation method in embodiment 6, pass course 2 is wherein original with methylchloroformate substitution acetic anhydride in preparation step 1
Material, obtains 11 compound JNLD-7(89 mg of embodiment, yield 86%).MS-ESI [M+H]+ 520.3; 1H NMR (300 MHz,
CDCl3) δ 7.66–7.52 (m, 2H), 6.40 (s, 1H), 3.90 (s, 3H), 3.80–3.64 (m, 4H),
3.18 (t, J = 6.4 Hz, 2H), 2.98–2.88 (m, 4H), 2.28 (s, 3H), 1.81–1.59 (m, 4H),
1.30 (s, 6H)。
Embodiment 12
According to the preparation method in embodiment 6, pass course 2 is wherein with 4- fluorobenzoyl chloride substitution acetic anhydride in preparation step 1
Raw material obtains 12 compound JNLD-8(94 mg of embodiment, yield 81%).MS-ESI [M+H]+ 584.3; 1H NMR (300
MHz, CDCl3) δ8.18 (d, J = 8.4 Hz, 2H), 7.67–7.58 (m, 4H), 6.42 (s, 1H), 3.79–
3.66 (m, 4H), 3.18 (t, J = 6.4 Hz, 2H), 2.99–2.89 (m, 4H), 2.28 (s, 3H),
1.82–1.75 (m, 2H), 1.66–1.60 (m, 2H), 1.30 (s, 6H)。
Embodiment 13
According to the preparation method in embodiment 6, pass course 2 is wherein original with cinnamoyl chloride substitution acetic anhydride in preparation step 1
Material, obtains 13 compound JNLD-9(76 mg of embodiment, yield 64%).MS-ESI [M+H]+ 592.1; 1H NMR (300 MHz,
CDCl3) δ7.85 (d, J =15.9 Hz, 1H), 7.71–7.33 (m, 7H), 6.56 (d, J = 15.9 Hz,
1H), 6.40 (s, 1H), 3.81–3.64 (m, 4H), 3.18 (t, J = 6.3 Hz, 2H), 2.97–2.89 (m,
4H), 2.28 (s, 3H), 1.81–1.73 (m, 2H), 1.66–1.60 (m, 2H), 1.30 (s, 6H)。
Embodiment 14
According to the preparation method in embodiment 6, pass course 2, wherein using nicotinoyl chlorine substitution acetic anhydride as raw material in preparation step 1,
Obtain 14 compound JNLD-10(88 mg of embodiment, yield 78%).MS-ESI [M+H]+ 567.1; 1H NMR (300 MHz,
CDCl3) δ 9.34 (m, 1 H), 8.84−8.83 (m, 1 H), 8.41−8.38 (m, 1 H), 7.69–7.53 (m,
3H), 6.42 (s, 1H), 3.82–3.66 (m, 4H), 3.17 (t, J = 6.3 Hz, 2H), 2.97–2.87 (m,
4H), 2.28 (s, 3H), 1.82–1.74 (m, 2H), 1.66–1.60 (m, 2H), 1.29 (s, 6H)。
Embodiment 15
According to the preparation method in embodiment 6, pass course 2, wherein preparation step 3 substitutes paraformaldehyde with para-acetaldehyde, obtains reality
Apply 15 compound JNLD-11(12 mg of example, yield 11%).MS-ESI [M+H]+ 518.3; 1H NMR (300 MHz,
CDCl3) δ7.66–7.52 (m, 2H), 6.27 (s, 1H), 4.72–4.66 (m, 1H), 3.68 (s, 2H),
3.17 (t, J = 6.4 Hz, 2H), 2.97–2.88 (m, 4H), 2.28 (s, 3H), 2.26 (s, 3H),
1.82–1.61 (m, 7H), 1.31 (s, 3H), 1.30 (s, 3H)。
Embodiment 16
According to the preparation method in embodiment 6, pass course 2, wherein preparation step 3 substitutes paraformaldehyde with propionic aldehyde, obtains embodiment
16 compound JNLD-12(10 mg, yield 9%).MS-ESI [M+H]+ 532.3; 1H NMR (300 MHz, CDCl3) δ
7.65–7.53 (m, 2H), 6.27 (s, 1H), 4.53–4.37 (m, 1H), 3.67 (s, 2H), 3.17 (t, J
= 6.3 Hz, 2H), 2.98–2.89 (m, 4H), 2.28 (s, 3H), 2.25 (s, 3H), 1.82–1.74 (m,
6H), 1.30 (s, 3H), 1.29 (s, 3H), 1.05–0.96 (m, 3H)。
Embodiment 17
According to the preparation method in embodiment 6, pass course 2, wherein preparation step 3 substitutes paraformaldehyde with pyroracemic aldehyde, must implement
17 compound JNLD-13(79 mg of example, yield 73%).MS-ESI [M+H]+ 546.3; 1H NMR (300 MHz, CDCl3)δ7.66–7.52 (m, 2H), 6.27–5.39 (m, 2H), 3.70 (s, 2H), 3.19 (t, J = 6.3 Hz,
2H), 2.99–2.89 (m, 4H), 2.28 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H), 1.82–1.61
(m, 4H), 1.30 (s, 3H), 1.29 (s, 3H)。
Embodiment 18
According to the preparation method in embodiment 6, pass course 2 wherein substitutes poly first in preparation step 3 with 2- cyclopropyl pyroracemic aldehyde
Aldehyde obtains 18 compound JNLD-14(78 mg of embodiment, yield 68%).MS-ESI [M+H]+ 572.3; 1H NMR (300
MHz, CDCl3) δ7.66–7.52 (m, 2H), 6.27–5.42 (m, 2H), 3.70 (s, 2H), 3.19 (t, J =
6.3 Hz, 2H), 2.99–2.87 (m, 4H), 2.37–2.35 (m, 1H), 2.28 (s, 3H), 2.26 (s,
3H), 1.84–1.73 (m, 2H), 1.67–1.60 (m, 2H), 1.31 (s, 3H), 1.30 (s, 3H), 1.15–
1.09 (m, 2H), 1.00–0.92 (m, 2H)。
Embodiment 19
According to the preparation method in embodiment 6, pass course 2, wherein preparation step 3 substitutes paraformaldehyde with glyoxalic acid methylester, obtains
19 compound JNLD-15(93 mg of embodiment, yield 83%).MS-ESI [M+H]+ 562.2; 1H NMR (300 MHz,
CDCl3) δ7.66–7.52 (m, 2H), 6.27–5.41 (m, 2H), 3.73 (s, 3H), 3.67 (s, 2H),
3.19 (t, J = 6.3 Hz, 2H), 2.98–2.88 (m, 4H), 2.28 (s, 3H), 2.26 (s, 3H),
1.82–1.73 (m, 2H), 1.67–1.61 (m, 2H), 1.30 (s, 3H), 1.29 (s, 3H)。
Route 3
Embodiment 20
Under nitrogen protection, compound JNLD-14(57 mg, 0.1 mmol) is dissolved in 1 ml ethanol solution, is then added 0.5
10% HCL aqueous solution of ml and in stirring 2 days under room temperature to fully reacting.After the reaction was completed, ethyl acetate (5 ml) is added
It is extracted with saturated salt solution (3 ml), through silica gel chromatography (V after gained organic phase evaporated under reduced pressurePetroleum ether:VEthyl acetate=6:1~1:
1) 20 compound JNLD-20 of embodiment (41 mg, yield 78%), is obtained.MS-ESI [M+H]+ 530.1; 1H NMR (300
MHz, CDCl3) δ 7.66–7.53 (m, 2H), 6.03 (s, 1H), 5.51 (s, 1H), 4.16–3.93 (m
3H), 3.25–2.31 (m, 6H), 2.28 (s, 3H), 1.93–1.62 (m, 5H), 1.31 (s, 3H), 1.30
(s, 3H), 1.15–1.09 (m, 2H), 1.00–0.92 (m, 2H)。
Embodiment 21
According to the preparation method in embodiment 20, pass course 3 obtains 21 compound JNLD-21 of embodiment using JNLD-15 as raw material
(39 mg, yield 75%).MS-ESI [M+H]+ 520.2; 1H NMR (300 MHz, CDCl3) δ7.67–7.52 (m,
2H), 6.04 (s, 1H), 5.42 (s, 1H), 4.18–3.92 (m 3H), 3.75 (s, 3H), 3.25–2.38
(m, 6H), 2.29 (s, 3H), 1.93–1.63 (m, 4H), 1.32 (s, 3H), 1.31 (s, 3H)。
Embodiment 22
According to the preparation method in embodiment 20, pass course 3 obtains 22 compound JNLD-22 of embodiment using JNLD-2 as raw material
(39 mg, yield 75%).MS-ESI [M+H]+ 462.1; 1H NMR (300 MHz, CDCl3) δ 7.65–7.53 (m,
2H), 6.05 (s, 1H), 4.17–3.92 (m, 2H), 3.80 (s, 2H), 3.65–2.32 (m, 6H), 2.28
(s, 3H), 1.93–1.61 (m, 5H), 1.30 (s, 6H)。
The preparation of 23 compound JNLD-15 sulfate of embodiment
Will be dissolved with embodiment 19 compound JNLD-15(56 mg, 0.1 mmol) ethanol solution, be slowly added to 12 at room temperature
ml 0.005 M H2SO4Solution, and stir to dissolution；Then gained red solution is concentrated under reduced pressure into 3 ml, placed at room temperature
Cooling crystallization, filtering, ice water washing obtain JNLD-15 sulfate red solid (42 mg, yield 75%).MS-ESI [M+H]+
562.2; 1H NMR (300 MHz, CD3OD) δ7.86–7.65 (m, 2H), 6.96–5.68 (m, 2H), 4.93–
4.68 (m, 5H), 3.80–3.17 (m, 6H), 2.42 (s, 3H), 2.38 (s, 3H), 1.88–1.62 (m,
4H), 1.35 (s, 3H), 1.32 (s, 3H)。
The preparation of 24 compound JNLD-1 hydrochloride of embodiment
22 will be slowly added at room temperature dissolved with the ethanol solution of 1 compound JNLD-1 of embodiment (45 mg, 0.1 mmol)
0.005 M HCl solution of ml, and stir to dissolution；Then gained red solution is concentrated under reduced pressure into 2 ml, placed cold at room temperature
But crystallization, filtering, ice water washing obtain JNLD-1 hydrochloride red solid (41 mg, yield 69%).MS-ESI [M+H]+
446.1; 1H NMR (300 MHz, CD3OD) δ 7.81–7.67 (m, 2H), 7.45–7.40 (m, 1H), 6.94
(d, J = 5.2 Hz, 1H), 4.85–4.60 (m, 4H), 3.68–3.14 (m, 6H), 2.39 (s, 3H),
1.84–1.66 (m, 4H), 1.35 (s, 3H), 1.33 (s, 3H)。
The water-soluble Journal of Sex Research of embodiment 25
Fat-soluble strong water-soluble difference is one of the main reason for tanshinone IIA druggability is poor.For clear present invention gained Radix Salviae Miltiorrhizae
The water-soluble improvement situation of ketone IIA thiophene pyridine compounds and their, the representative tanshinone IIA of this experiment Primary Study
Thiophene pyridiniujm JNLD-1(hydrochloride) and JNLD-15(sulfate) dissolution implementations (see Table 1) in water.Experimental result table
Bright, tanshinone IIA thiophene pyridine compounds water solubility significantly improves.
1. tanshinone IIA of table is compared with representative tanshinone IIA thiophene pyridinium compound water solubility
26 stability study of embodiment
Stability is one of important attribute of drug, to this this experiment using HPLC to tanshinone IIA thiophene pyridine compounds and their
And its chemical stability of salt is studied.Specific experiment method: JNLD-1 and its hydrochloride are configured to centainly at 25 DEG C
The aqueous solution of concentration (0.1 mg/mL), detected respectively with HPLC later they 0,2,4,6,8,12 and 24 hour when 254 wave bands
Peak area variation.Experimental result is as shown in table 2, and JNLD-1 and its hydrochloride have excellent chemical stability in the solution.
The stability of 2. JNLD-1 of table and its salt
Pharmacological experiment
The Platelet Aggregation in Rabbits inhibiting effect research to ADP induction in vitro of embodiment 27
Drug and preparation: test-compound is dissolved in few (fixed) amount DMSO, then pipettes lμL is added 100 ~ 300μL deionized water
In be made into 10μG/ml, it is spare after 37 DEG C of heating water bath dissolutions.
ADP, Sigma, the U.S.
Animal: male scientific research rabbit, 2.0-2.5 Kg, Shandong University's Experimental Animal Center
Instrument: platelet aggregation instrument (560 Ca), CHRONO-LOG, the U.S.
Test method: male 24 h of scientific research rabbit fasting, weighing, 5% chloral hydrate anesthesia, neck arteries, which are intubated, takes blood, and 109
Mmol/l liquor sodii citratis and blood are anticoagulant with the ratio of 9:1, are collected in 10 ml plastic centrifuge tubes.Under room temperature,
900 rpm are centrifuged 10 min, and Aspirate supernatant obtains PRP；Blood is centrifuged 10 min with 3500 rpm more than Retained, and Aspirate supernatant obtains
PPP.Adjustment PRP makes platelet count 4 ~ 5 × 1012A/ml；Taking out test cup adds rotor, and l is addedμL test sample, 300μ
ADP is added into test cup, measures and records maximum aggregation rate after 37 DEG C of constant temperature 5 min, PPP zeroings by l PRP.By BORN ratio
Turbid method is measured platelet aggregation percentage with platelet aggregation instrument, is examined with t- and carry out statistics comparison.Platelet aggregation inhibitor
Rate is calculated as follows: L-Arginine (%)=[1- (delivery tube assembles percentage/control tube and assembles percentage)] ×
100%.
Experimental result: showing as shown in Fig. 1, and test-compound has certain blood platelet for inhibiting ADP induction in vitro
Aggregation activity (**P < 0.01vsBlank control,*P < 0.05vsBlank control).
The inhibiting effect research that 28 rat arteriovenous shunt thrombosis of embodiment is formed
Drug and preparation: positive drug is clopidogrel sulfate.Positive drug and test-compound are with 0.5% CMC-Na(carboxymethyl
Sodium cellulosate) suspension is made into for animal administrable.
Experimental animal: male SD rat, 200-350 g, are provided totally by Shandong University's Experimental Animal Center by 50.
Test method: the production of bypass modeling pipe: the polyethylene of two 6.5 cm long internal diameter, 1 mm is taken to mould pipe, centre penetrates one
The silk thread of 6 cm of root long, wherein 3 centimeters of the length in a modeling pipe both ends, the polyethylene modeling pipe of about 0.8 mm of internal diameter is connected, Ling Yigen
For use, stand-by full of 50 U/ml heparin sodium physiological saline in pipe.Experiment selects weight 250-350g male SD rat to be randomly divided into
5 dosage groups.Rat 40 mg/kg intraperitoneal injection of anesthesia of yellow Jackets, anesthetized rat, which is lain on the back, is fixed on rat dissection plate
On, oesophagus is ligatured, right carotid and left side vena jugularis externa are separated.From 50 U/kg heparin sodium physiology of rat vena femoralis injection
Salt water is anticoagulant, then right carotid is inserted at first plastic union pipe both ends respectively and left side vena jugularis externa forms side
Road.Artery clamp is opened when 60 min after gastric infusion, blood is flowed into outside the neck of left side from right carotid by bypass modeling pipe
Vein, middle clinopodium polycephalum takes out rapidly the silk thread with thrombus in modeling pipe after decontroling 15 min of blood flow, siphons away excess blood, claims silk thread wet
It is again 60 min thrombosis amounts.Thrombus when the ratio between blank control group silk thread weight in wet base and administration group silk thread weight in wet base are found out 60 min
It is formed and inhibits percentage and carry out statistical disposition.
Experimental result: as shown in Fig. 2, compared with blank control, test-compound is to rat arteriovenous shunt thrombosis shape
At with significant inhibiting effect (**P < 0.01vsBlank control).
Claims (10)
1. a kind of tanshinone IIA thiophene pyridine compounds and their of structure shown in Formulas I or its pharmaceutical salt:
In formula, R1To be selected from the group group: H, formic acid C1~C6Alkyl ester group, C1~C6Linear or branched alkyl group, C3~C6Naphthenic base or
Cycloalkenyl, C1~C6Linear chain or branched chain alkanoyl, C3~C6Cycloalkanoyl, C2~C10Linear chain or branched chain alkenyl, C2~C10Linear chain or branched chain
Alkynyl, cyano, aromatic radical, aralkyl, heterocycle, heteroaryl；Wherein R1The aromatic radical be by 1-4 selected from halogen, hydroxyl,
Nitro, cyano, trifluoromethyl, carboxyl, C1~C6Alkyl, C1~C6Phenyl replaced group in alkoxy；R1The heteroaryl
For the heteroatomic C for being selected from O, N, S with 1-35-C10Heteroaryl；
R2For selected from following any structure group: H, OR3；
Wherein R3For C1~C6Alkanoyl, C1~C6Oxygen acyl group, cinnamoyl, aromaticacyl radical, miscellaneous aromaticacyl radical；R3Described in cinnamoyl
Aryl in base and aromaticacyl radical is phenyl or is selected from halogen, hydroxyl, nitro, cyano, trifluoromethyl, carboxyl, C by 1-41
~C6Alkyl, C1~C6Phenyl replaced group in alkoxy；R3Described in miscellaneous aromaticacyl radical be to be selected from O, N, S with 1-3
Heteroatomic C5-C10Miscellaneous aromaticacyl radical；
Dotted line is chemical bond or is not present.
2. tanshinone IIA thiophene pyridine compounds and their according to claim 1, which is characterized in that
R1To be selected from the group group: H, formic acid C1~C6Arrcostab, C1~C6Straight chain alkanoyl, C3~C6Cycloalkanoyl, aromatic radical；Wherein
R1The aromatic radical is phenyl or is selected from halogen, hydroxyl, nitro, cyano, trifluoromethyl, carboxyl, C by 1-41~C6Alkyl,
C1~C6Phenyl replaced group in alkoxy；
R2Selected from following any structure group: H, OR3；
Wherein R3For C1~C6Alkanoyl, C1~C6Oxygen acyl group, cinnamoyl, aromaticacyl radical, miscellaneous aromaticacyl radical；R3Described in cinnamoyl
Aryl in base and aromaticacyl radical is phenyl or is selected from halogen, hydroxyl, nitro, cyano, trifluoromethyl, carboxyl, C by 1-41
~C6Alkyl, C1~C6Phenyl replaced group in alkoxy；R3Described in miscellaneous aromaticacyl radical be the C with 1 N atom6Virtue
Base；
Dotted line is chemical bond or is not present.
3. tanshinone IIA thiophene pyridine compounds and their according to claim 1 or its pharmaceutical salt, which is characterized in that
The compound is including but not limited to the following group compound:
。
4. tanshinone IIA thiophene pyridine compounds and their described in any one of -3 or its pharmaceutical salt according to claim 1,
Wherein the pharmaceutical salt is the salt that the tanshinone IIA thiophene pyridine compounds and their is reacted with acid, such as hydrochloride, sulphur
Hydrochlorate, phosphate, acetate, citrate, oxalates, malonate, salicylate, malate, fumarate, succinic acid
Salt, ascorbate, maleate, tartrate, citrate, mesylate or isethionate.
5. a kind of pharmaceutical composition, it includes the compound of at least one Formulas I as described in one of claim 1-4 or its pharmacy
Acceptable salt and one or more pharmaceutically acceptable carriers, diluent or excipient.
6. a kind of tanshinone IIA thiophene pyridine compounds and their described in any one of -4 according to claim 1 or its is pharmaceutically acceptable
Salt preparation method, obtained by following methods:
A) in compound of formula I, R2When for H or O: using tanshinone IIA as starting material, and with replace aldehyde and thiophene pyridine having
In solvent, Mannich occurs through Lewis acid catalysis and reacts to obtain Formulas I-a compound；
B) in compound of formula I, R2For OR3When: using the pyridine thienone of trityl as protecting group as starting material, under alkali effect
React to obtain intermediate -1 with acylating reagent, then obtain key intermediate -2 through sour water solution, finally again with tanshinone IIA and take
Mannich occurs through Lewis acid catalysis for aldehyde to react to obtain Formulas I-b compound；
C) HA is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, amber
Acid, ascorbic acid, maleic acid, tartaric acid, citric acid, methanesulfonic acid or isethionic acid, n=0~2.
7. tanshinone IIA thiophene pyridine compounds and their described in any one of claim 1-4 or its pharmaceutical salt are being made
Application in the standby drug for preventing or treating the occlusion disease of cardiovascular and cerebrovascular caused by platelet aggregation.
8. a kind of method for treating the occlusion patient of cardiovascular and cerebrovascular caused by platelet aggregation, including award patient in need for the treatment of
Any one of -4 tanshinone IIA thiophene pyridine compounds and their according to claim 1 of therapeutically effective amount or its is pharmaceutically acceptable
Salt.
9. the tanshinone IIA thiophene pyridine compounds and their of any one of the claim 1-4 as platelet aggregation-against therapeutic agent or
Its pharmaceutically acceptable salt.
10. according to the purposes of claim 7,8 or 9, method or tanshinone IIA thiophene pyridine compounds and their, wherein the heart and brain
Ischemic disease is that coronary heart disease, myocardial infarction, heart strand pain, thrombolytic therapy or percutaneous transluminal coronary angioplasty are related
Acute vascular closure, transient ischemic attack, apoplexy, intermittent claudication or coronal or peripheral arterial bypass grafting, blood vessel
Chamber narrows, the restenosis after coronary artery or venous angioplasty, Patients in Hemodialysis vascular access are unobstructed maintenance,
And pulmonary thromboembolism.
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Application publication date: 20190730 |