CN106831904A - A kind of compound and preparation method thereof, preparation and application - Google Patents
A kind of compound and preparation method thereof, preparation and application Download PDFInfo
- Publication number
- CN106831904A CN106831904A CN201710052217.0A CN201710052217A CN106831904A CN 106831904 A CN106831904 A CN 106831904A CN 201710052217 A CN201710052217 A CN 201710052217A CN 106831904 A CN106831904 A CN 106831904A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- present
- application
- blood
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a kind of compound and preparation method thereof, preparation and application.The structure of described compound is as follows：
Description
Technical field
The invention belongs to field of medicine preparing technology, and in particular to a kind of compound and preparation method thereof, preparation and application.
Background technology
Cardiovascular and cerebrovascular disease is a kind of serious threat mankind, the particularly common diseases of the elderly's health, and the whole world is annual
The number for dying from cardiovascular and cerebrovascular disease is up to 15,000,000 people, occupies the various causes of the death the first.At present, China's Patients with Cardiovascular/Cerebrovascular Diseases has been
Through more than 2.7 hundred million people, China dies from nearly 3,000,000 people of cardiovascular and cerebrovascular disease every year, the 51% of the annual total Death causes of China is accounted for.The heart
Cranial vascular disease has turned into human death's cause of disease highest number one killer, is also " the noiseless demon " of health of people.Cardiovascular and cerebrovascular
Disease have " incidence of disease is high, disability rate is high, the death rate is high, high recurrence rate, and complication is more ", i.e., " more than four high one " the characteristics of.I.e.
Make to apply treatment means most advanced, perfect at present, the cerebrovas-cularaccident survivor life that can still have more than 50% can not completely certainly
Reason, and the different degrees of disability of patient 75% for surviving, 40% weight are residual, thus caused family, medical treatment and economy
Burden has turned into the social concern that can not be despised.Therefore more cardiovascular and cerebrovascular diseases medicines evident in efficacy, safe are developed
It is extremely urgent thing.
One of main to residual and lethal cause of disease in Chinese thrombotic diseases have become various diseases.These
Disease includes：Acute coronary syndrome：Including UA and myocardial infarction, cardiac sudden death, peripheral arterial occlusion, ischemic
Property apoplexy, DVT (DVT), pulmonary embolism etc..Although at present to the treatment means and medicine of above thrombotic diseases
On have a significant progress, but because these medicines have different degrees of defect, such as anti thrombotic action is not strong or because complete
Block the anticoagulant mechanism of body and trigger internal haemorrhage phenomenon.Therefore the treatment means and medicine still ten that can clinically select
Divide limited, be badly in need of more effective and security antithrombotic new drug higher to substitute existing treatment method, to meet current day
The clinical demand that benefit increases.
The forming process of thrombus mainly has platelet aggregation activation and blood clotting anti-in molecular pathology research display body
The two big mechanism that stress live are participated in.The governing loop that two mechanism is had nothing in common with each other.Aspirin and Lei Bi Grays are that strong blood is small
Plate agglutination inhibitor, is clinically usually used in thrombus prevention and cure.And liquaemin, fondaparin and Fa Hualin then belong to anti-coagulants, make
For blood coagulation path, the prevention and treatment of various thrombotic diseases are clinically also widely used in.But above-mentioned two is big normal
A major side effects for advising antithrombotic reagent are exactly to trigger internal haemorrhage after some patientss use.
Platelet activation and being gathered in the formation of thrombus is played an important role, therefore Antiplatelet therapy is still clinical
The important means of upper prevention and treatment thrombotic diseases.
Platelet activation is assembled to form thrombus and be divided into 3 stages：Intravascular christmas factor (vWF) mediates sugared egg first
White GPIb-IX compounds are by platelet adhesion reaction under blood vessel endothelium；Platelet deposition is simultaneously attached in damaged vessel walls, and discharge
Go out the physiologic platelet active factorses such as a series of thromboxane A2s (TXA2), adenosine diphosphate (ADP) (ADP) and further activate blood
Platelet, and the numerous adhesion receptors occurred conformations transformation on platelet membrane based on GPIIb/IIIa compounds is caused, expose
Binding site, being acted on by " bridging " of fibrinogen makes platelet aggregation, and then causes the formation of early stage thrombus；By blood
The releasing product of platelet, can further cause vessel retraction, stimulate leucocyte, endothelial cell injury to promote blood clotting, cause
Thrombosis.
Blood platelet can be by a series of plasma activities factor activators and aggregation, such as AA, 5-HT, fibrin ferment.Blood coagulation and blood are small
Plate aggregation collectively promotes thrombosis.We are intended to filter out the sample for suppressing platelet activation aggregation, reduce thrombotic way
Footpath.Experiment uses turbidimetry for Determination platelet aggregation rate, and its principle is that centrifugation prepares PPP and PRP, by the printing opacity measured by PPP
The light transmittance that rate is considered as 100%, PRP is considered as 0%.PRP is placed in colorimetric cylinder, derivant is added, under conditions of stirring, induction
Agent and the interphase interaction of platelet membrane acceptor, cause blood platelet gradually to be assembled, and blood plasma turbidity reduction, light transmittance increases, photoelectricity
Pond is rapid to be converted to electric signal by the signal of light turbidity, and platelet aggregation instrument automatically enters Mobile state measurement and records, so as to retouch
Draw curve of platelet aggregation.This method can more easily obtain platelet aggregation situation using platelet aggregation instrument, so that
Evaluate hematoblastic aggregation capability.
Thrombus can betide each position of the circulatory system, such as vein, artery, the chambers of the heart and microcirculation, and it is by fiber egg
White and haemocyte composition.In thrombosis, platelet activation plays an important roll with coagulation system activation, Liang Zhe
It is closely connected in vivo, the fibrin ferment produced after coagulation system activation is a strong platelet activating factor, and blood platelet is lived
To promote coagulation process again after change.Antithrombotic treatments are referred to as anti-freezing and control mainly for two links of blood coagulation system and blood platelet
Treat and Antiplatelet therapy.
Human body intravascular coagulation system and anticoagulation system are in a state for dynamic equilibrium, and excessive blood coagulation can cause myocardium stalk
Extremely, the serious disease such as cerebral thrombus.Blood clotting needs endogenous and exogenous two coagulation pathways are simultaneously participated in.APTT and
PT is two parameters the most frequently used during clinical coagulation function is detected.Wherein APTT mainly for detection of body intrinsic coagulation
Reflection prothrombin, the plasma activities of V, VIII, X, XI and VII are reduced or increased respectively for system, its extension or shortening.PT
The extrinsic coagulation system of body is then detected, its extension or shortening reflect factor I, the blood plasma of II, V, VII and X respectively
Activity is reduced or increased.
Blood clotting is the process that liquid condition blood becomes solid gel or grumeleuse.Its main mechanism can for fibrin ferment
Soluble fiber proteinogen is converted into insoluble hinge shape fiber protein yarn, and this is last during complicated coagulation cascade reacts
Step.Fibrin ferment is mainly formed by two activation pathways：1st, endogenous path：Trigger in the activation of the factor 12 (XIIa)；
2nd, exogenous path：Trigger in the combination of the tissue factor and the factor seven for being distributed in blood vessel cell surface.Factor Xa
(Factor Xa, Xa factor, FXa), is a kind of serine protease also known as the factor of blood coagulation ten, positioned at blood coagulation cascade
Upstream, is in the center of connection endogenous and exogenous activated pathway co-channel, and it can block endogenous and coagulate
Blood can also suppress the generation of extrinsic coagulation, be the newest target spot of current antithrombotic reagent research.Research shows logical in aggegation
The Lu Zhongyi Xa of molecule can be activated and be produced the fibrin ferment of hundreds of molecules, therefore Anti-Xa activity is a kind of more solidifying than suppression
Hemase more effectively prevents the means that fibrin is formed.Existing substantial amounts of In vitroandin vivotrial evidence shows that Xa suppresses to resistance
Only fibrinous formation is eager to excel than the effect for suppressing fibrin ferment, and the duration is much longer.In addition Xa specificity suppresses
Agent is acted on fibrin ferment unrestraint, thus does not interfere with the activity of the fibrin ferment for having been formed, and is used so as to reduce patient
Potential internal haemorrhage risk afterwards.Therefore the research for Xa inhibitor has become the generally acknowledged tide of contemporary antithrombotic new drug research
Stream.Such as 2008 listing razaxaban, 2011 listing according to Du sand patch and 2012 listing Eliquis.Other
New Xa factor inhibitor such as letaxaban, darexaban, eribaxaban LY517717 etc. has subsequently entered not same order
The experiment of section.
Gastrodin (Gastrodin), alias 4- hydroxymethyl phenyl-β-D- glucopyanosides, molecular formula is C13H18O7, point
Son amount is 286, and chemical structural formula is：
。
Gastrodin extracts isolated in the dry root block of orchid rhizoma Gastrodiae.Modern pharmacology research shows, rhizoma Gastrodiae
Element has preferably calm and soporific function, has mitigation to neurasthenia, insomnia, headache syndromes.Gastrodia elata can be treated
Pain dizziness, extremity numbness, frightened pain are twitched.Clinical Gastrodin is mainly used in treatment vertebra one basilar artery insufficiency, vestibular nerve
The diseases such as first inflammation, vertigo.
Yin Shu is all et al. to report a series of derivatives done around the helicidum with Gastrodin with identical carbon skeleton,
And their purposes (conjunctions of the such as Chen Huafeng, Chen Huawen, Yin Shufan helicidums-pyrazoline derivative in terms of tranquilizing soporific
Into and sedative activity research.Organic chemistry .2011 (02)).The Chinese patent of Application No. CN200710027503.8 equally encloses
A series of derivative is carried out around helicidum, and has protected its purposes in terms of senile dementia is treated.But at present around
Gastrodin aglycon carries out structural modification, and medicine of the exploitation with treating cardiac and cerebral vascular diseases purposes is but rarely reported.
The content of the invention
The first object of the present invention is to provide a kind of compound；Second purpose is the preparation side of described compound
Method；3rd purpose is the preparation of the compound described in offer；4th purpose is the application of the compound described in offer.
The first object of the present invention is achieved in that the structure of described compound is as follows：
Wherein：X is halogen, and R is other compounds residues.
The second object of the present invention is achieved in that with chloro- 4 hydroxy benzaldehydes of 2- or bromo- 4 hydroxy benzaldehydes of 2-
There is Schmidt reactions in raw material and four acetyl glucosamine tri- chloroacetimidates, then reacted with NaBH4 or DAST
Target compound.
The third object of the present invention adds pharmaceutically acceptable auxiliary material to prepare in being achieved in that described compound
Piece agent, capsule, injection or freeze drying powder injection.
The fourth object of the present invention is achieved in that application of the described compound in anticoagulation medicine is prepared.
Compound of the present invention is the compound of brand new, with obvious blood coagulation resisting function, is used as
Potential lead compound, is preparing treatment DVT and pulmonary thromboembolism, cardiovascular and cerebrovascular disease, apoplexy and other and blood
Used in the medicine of the related disease of liquid aggegation；The preparation method of compound is simple and easy to apply shown in of the invention, favorable reproducibility, environment
Pollution is small, can be used for a large amount of preparations of shown compound.
Specific embodiment
With reference to embodiment, the present invention is further illustrated, but the present invention is any limitation as never in any form,
Based on present invention teach that any conversion or replacement made, belong to protection scope of the present invention.
The structure of compound of the present invention is as follows：
Wherein：X is halogen, and R is other compounds residues.
Described compound, X is F, Cl or Br, and R is CHO, CH2OH,CHF2Or CH2F。
The preparation method of compound of the present invention, is to be with chloro- 4 hydroxy benzaldehydes of 2- or bromo- 4 hydroxy benzaldehydes of 2-
There is Schmidt reactions in raw material and four acetyl glucosamine tri- chloroacetimidates, then reacted with NaBH4 or DAST
Target compound.
The reaction equation of the reaction is：
In embodiment, the reaction is specially 2- chloro-4-hydroxyl benzaldehydes, the bromo- 4- hydroxy benzaldehydes of 2- etc. and four acetyl Portugals
There is Schmidt reactions in grape sugar tri- chloroacetimidate, under conditions of organic solvent and catalyst then with NaBH4, DAST
Described compound is obtained final product etc. react.
Organic solvent refers to the class organic compound that can dissolve water insoluble material comprising carbon atom in solvent, bag
Include alkane, alkene, alcohol, aldehyde, amine, ester, ether, ketone, aromatic hydrocarbon, hydrogenate hydrocarbon, terpene hydrocarbon, halogenated hydrocarbons, heterocycle compound, nitrogenous chemical combination
The multiclass material such as thing and sulfur-containing compound, is in a liquid state at normal temperatures and pressures, molten in course of dissolution with larger volatility
The property of matter and solvent is without change.
Wherein, preferably, organic solvent described in preparation method of the present invention is dichloromethane, methyl alcohol, ethanol, tertiary fourth
One kind in ylmethyl ether or tetrahydrofuran.
Catalyst refers to that can improve chemical reaction rate, and this body structure does not occur the material for forever sexually revising, the present invention
The preparation method is using BFEE as catalyst.
In the embodiment of the present invention, gastrodin derivative shown in the test present invention induces rabbit extracorporeal platelet aggregation to ADP
The influence of inhibiting rate, the influence and the influence to APTT of the anticoagulin xa activity that AT-III is relied on.
The preparation of compound of the present invention is to add pharmaceutically acceptable auxiliary material to be prepared into described compound
Tablet, capsule, injection or freeze drying powder injection.
Compound of the present invention can with conventional auxiliary material combination be made treatment DVT and pulmonary thromboembolism,
The medicine of cardiovascular and cerebrovascular disease, apoplexy and other diseases related to blood coagulation, including oral liquid, granule, tablet, ball
Agent, powder, capsule and pill etc..
Present invention also offers a kind of pharmaceutical preparation, including therapeutically effective amount compound of the present invention（Gastrodin spreads out
It is biological）With pharmaceutically acceptable auxiliary material.Those skilled in the art can be by the compound（Gastrodin derivative）Directly or
Connect addition and prepare pharmaceutically acceptable various conventional auxiliary materials required during different dosage forms, such as filler, disintegrant, lubricant,
Adhesive etc., in traditional drug formulations method, is made common dosage forms such as tablet, capsule, parenteral solution, oral liquid, granule, ball
Agent, powder and pill etc..Wherein, filler such as starch, lactose, sucrose, glucose, mannitol and silicic acid；Disintegrant such as fine jade
Fat, calcium carbonate, potato starch or tapioca, alginic acid, some silicate and sodium carbonate, low-substituted hydroxypropyl cellulose；Profit
Lubrication prescription such as talcum powder, calcium stearate, magnesium stearate, solid polyethylene glycol, Sodium Laurylsulfate；Adhesive such as carboxymethylcellulose calcium,
Alginates, gelatin, polyvinyl pyrrolidone, sucrose and Arabic gum.
The application of compound of the present invention is application of the described compound in anticoagulation medicine is prepared.
Application of the described compound in prevention and/or treatment cardiovascular and cerebrovascular diseases medicament is prepared.
In sum, compound shown in the present invention has obvious anticoagulant effect, is used as potential guide
Compound, is preparing treatment DVT and pulmonary thromboembolism, cardiovascular and cerebrovascular disease, apoplexy and other are related to blood coagulation
Disease medicine in use.
Compound shown in of the invention is the compound of brand new, with obvious blood coagulation resisting function, is used as diving
Lead compound, prepare treatment DVT and pulmonary thromboembolism, cardiovascular and cerebrovascular disease, apoplexy and other and blood
Used in the medicine of the related disease of aggegation.The preparation method of compound is simple and easy to apply shown in of the invention, favorable reproducibility, and environment is dirty
Dye is small, can be used for a large amount of preparations of compound shown in the present invention.
The embodiment of the invention discloses a kind of gastrodin derivative of class containing naphthalene nucleus and preparation method and application.This area skill
Art personnel can use for reference present disclosure, be suitably modified technological parameter realization.In particular, all similar replacements and
Change apparent to those skilled in the art, they are considered as being included in the present invention.Product of the invention, side
Method and application have been described by preferred embodiment, related personnel substantially can not depart from present invention, spirit and
In the range of to product as herein described, method and application be modified or suitably change with combine realize and apply the present invention
Technology.
So that case is embodied, the present invention will be further described below：
Embodiment 1
The preparation of KPC-4000020：
Add compound 1 (400mg, 1.99 mmol, 1.0 eq), compound 2 (1.76 in a twoport flask of 25 ml
G, 3.58 mmol, 1.8 eq）And molecular sieve（3.0 g, 4A）.Displacement nitrogen.Dichloromethane (5 is sequentially added toward flask
ML), flask is placed in ice bath, is stirred 30 minutes.Etherate of trifluoroboron (0.28 mL, 2.19 are slowly instilled with syringe
Mmol, 1.1 eq).Continue to stir 30 minutes after completion of dropping.Then ice bath is removed, makes reaction solution warm naturally to room temperature
（20℃）.Detected with TLC and reacted into 8 journeys, until raw material disappears（2 hours）.Reaction solution is slowly poured into one and fills trash ice（20
g）Beaker be quenched.Treat that ice cube melts completely, the water of the mixed liquor to generating is extracted with ethyl acetate（20 mL ×
3）.Organic phase is merged, anhydrous sodium sulfate drying is used.Mixture is filtered.Solvent is removed in revolving.With silicagel column to thick product
Thing is purified.Wash-out liquid proportional：Ethyl acetate/petroleum ether=30%.Obtain the mg of white solid 183, yield：60 %.
1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 8.08 (s, 1H), 7.80 (d, J =
8.1 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 5.27 (ddd, J = 33.6, 31.6, 8.0 Hz,
4H), 4.25 – 3.88 (m, 3H), 2.07 (d, J = 13.3 Hz, 12H).。
Embodiment 2
The preparation of KPC-4000021：
Compound K PC-4000020 (300 mg, 0.56 mmol, 1.0 eq) is dissolved in 2.0 mL methyl alcohol, under nitrogen protection
0 DEG C is cooled to, sodium borohydride (21 mg, 0.56 mmol, 1.0 eq) is dividedly in some parts.Then ice bath is removed, reaction solution is made certainly
So it is warming up to room temperature（20 ℃）.Reaction process is detected with TLC, until raw material disappears（1 hour）.Reaction solution is slowly poured into
In the saturated solution of NH4Cl (20 mL).The water of the mixed liquor to generating is extracted with ethyl acetate（10 mL × 3）.
Organic phase is merged, anhydrous sodium sulfate drying is used.Mixture is filtered.Solvent is removed in revolving.With silicagel column to crude product
Purified.Wash-out liquid proportional：Ethyl acetate/petroleum ether=60 %.Obtain the mg of white solid 221, yield：73 %.
1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.24 (s, 1H), 7.14 (d, J =
8.4 Hz, 1H), 5.42 – 5.33 (m, 1H), 5.29 (t, J = 9.2 Hz, 1H), 5.18 (t, J = 9.5
Hz, 1H), 5.00 (d, J = 7.7 Hz, 1H), 4.64 (s, 2H), 4.29 (dd, J = 12.2, 5.2 Hz,
1H), 4.23 – 4.16 (m, 1H), 3.85 (dd, J = 9.9, 2.7 Hz, 1H), 2.14 – 2.01 (m,
12H)。
Embodiment 3
The preparation of KPC-4000022
Compound K PC-4000021 (150 mg, 0.28 mmol, 1.0 eq) is dissolved in 2.0 mL dichloromethane, nitrogen is protected
0 DEG C is cooled under shield, diethylin sulfur trifluoride (68 mg, 0.42mmol, 1.5 eq) is slowly instilled with syringe.Then
Ice bath is removed, makes reaction solution warm naturally to room temperature（20 ℃）.Reaction process is detected with TLC, until raw material disappears（3 hours）.
Reaction solution is slowly poured into the saturated solution of NaHCO3 (20 mL).The water of the mixed liquor to generating is carried out with ethyl acetate
Extraction（10 mL × 3）.Organic phase is merged, anhydrous sodium sulfate drying is used.Mixture is filtered.Solvent is removed in revolving.
Crude product is purified with silicagel column.Wash-out liquid proportional：Ethyl acetate/petroleum ether=30 %.The mg of white solid 72 is obtained,
Yield：48 %.
1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.27 (d, J = 8.3 Hz, 1H),
7.15 (d, J = 8.4 Hz, 1H), 5.41-5.33 (m, 2H), 5.30 (t, J = 9.3 Hz, 1H), 5.20
(dd, J = 19.2, 9.5 Hz, 2H), 5.02 (d, J = 7.7 Hz, 1H), 4.29 (dd, J = 12.3, 5.2
Hz, 1H), 4.20 (dd, J = 12.3, 2.4 Hz, 1H), 3.87 (ddd, J = 9.9, 5.2, 2.4 Hz,
1H), 2.12 – 2.02 (m, 12H)。
Embodiment 4
The preparation of KPC-40000023：
Compound K PC-4000020 (50 mg, 0.09 mmol, 1.0 eq) is dissolved in 2.0 mL dichloromethane, nitrogen is protected
0 DEG C is cooled under shield, diethylin sulfur trifluoride (38 mg, 0.23mmol, 2.5 eq) is slowly instilled with syringe.Then
Ice bath is removed, makes reaction solution warm naturally to room temperature（20 ℃）.Reaction process is detected with TLC, until raw material disappears（3 hours）.
Reaction solution is slowly poured into the saturated solution of NaHCO3 (20 mL).The water of the mixed liquor to generating is carried out with ethyl acetate
Extraction（10 mL × 3）.Organic phase is merged, anhydrous sodium sulfate drying is used.Mixture is filtered.Solvent is removed in revolving.
Crude product is purified with silicagel column.Wash-out liquid proportional：Ethyl acetate/petroleum ether=40 %.The mg of white solid 24 is obtained,
Yield：48 %.
1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H),
7.17 (t, J = 12.8 Hz, 1H), 6.56 (dd, J = 69.0, 43.6 Hz, 1H), 5.43 – 5.35 (m,
1H), 5.30 (t, J = 9.3 Hz, 1H), 5.19 (t, J = 9.6 Hz, 1H), 5.06 (d, J = 7.7 Hz,
1H), 4.25 (ddd, J = 28.5, 12.3, 7.8 Hz, 2H), 3.93 – 3.83 (m, 1H), 2.11 – 2.02
(m, 12H)。
Embodiment 5
The preparation of KPC-40000024：
Compound 3 (1.200 mg, 7.66 mmol, 1.0 eq), compound 2 are added in a twoport flask of 25 mL
(4.530 g, 9.20 mmol, 1.2 eq）And molecular sieve（3.0 g, 4A）.Displacement nitrogen.Dichloromethane is sequentially added toward flask
Alkane (40 mL), flask is placed in ice bath, is stirred 30 minutes.Etherate of trifluoroboron (1.06 is slowly instilled with syringe
ML, 8.43 mmol, 1.1 eq).Continue to stir 30 minutes after completion of dropping.Then ice bath is removed, makes reaction solution rise naturally
Warm to room temperature（20 ℃）.Reaction process is detected with TLC, until raw material disappears（2 hours）.Reaction solution is slowly poured into a Sheng
There is trash ice（20 g）Beaker be quenched.Treat that ice cube melts completely, the water of the mixed liquor to generating is extracted with ethyl acetate
（20 mL × 3）.Organic phase is merged, anhydrous sodium sulfate drying is used.Mixture is filtered.Solvent is removed in revolving.Use silicon
Glue post is purified to crude product.Wash-out liquid proportional：Ethyl acetate/petroleum ether=40%.The g of white solid 1.870 is obtained, is produced
Rate：50 %.
1H NMR (400 MHz, CDCl3) δ 9.90 (d, J = 12.7 Hz, 1H), 7.90 (d, J = 1.9
Hz, 1H), 7.75 (dd, J = 8.5, 1.9 Hz, 1H), 7.30–7.20 (m, 1H), 5.39 (dd, J =
9.4, 7.6 Hz, 1H), 5.31 (dd, J = 11.8, 6.7 Hz, 1H), 5.19 (dd, J = 11.6, 7.4
Hz, 1H), 5.13 (d, J = 7.6 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.92 (ddd, J =
9.9, 5.2, 2.5 Hz, 1H), 2.05 (dd, J = 7.9, 4.3 Hz, 12H)。
Embodiment 6
The preparation of KPC-40000025：
It is dissolved in 2.0 mL methyl alcohol by compound K PC-400024 (200 mg, 0.41 mmol, 1.0 eq), nitrogen protection
Under be cooled to 0 DEG C, be dividedly in some parts sodium borohydride (16 mg, 0.41 mmol, 1.0 eq).Then ice bath is removed, reaction solution is made
Warm naturally to room temperature（20 ℃）.Reaction process is detected with TLC, until raw material disappears（1 hour）.Reaction solution is slowly poured into
In the saturated solution of NH4Cl (20 mL).The water of the mixed liquor to generating is extracted with ethyl acetate（10 mL × 3）.
Organic phase is merged, anhydrous sodium sulfate drying is used.Mixture is filtered.Solvent is removed in revolving.With silicagel column to crude product
Purified.Wash-out liquid proportional：Ethyl acetate/petroleum ether=50 %.Obtain the mg of white solid 120, yield：60 %.
1H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 7.22–7.10 (m, 2H), 5.34- 5.23
(m, 2H), 5.15 (t, J = 9.4 Hz, 1H), 4.95 (d, J = 7.6 Hz, 1H), 4.61 (s, 2H),
4.29 – 4.14 (m, 2H), 3.82 (ddd, J = 9.8, 5.0, 2.4 Hz, 1H), 2.05 (dd, J =
18.0, 2.7 Hz, 12H)。
Embodiment 7
The preparation of KPC-40000026：
Compound K PC-400025 (80 mg, 0.16 mmol, 1.0 eq) is dissolved in 1.0 ml dichloromethane, nitrogen protection
Under be cooled to 0 DEG C, diethylin sulfur trifluoride (32 mg, 0.20mmol, 1.2 eq) is slowly instilled with syringe.Then remove
Ice bath is removed, makes reaction solution warm naturally to room temperature（20 ℃）.Reaction process is detected with TLC, until raw material disappears（3 hours）.Will
Reaction solution is slowly poured into the saturated solution of NaHCO3 (20 mL).The water of the mixed liquor to generating is extracted with ethyl acetate
Take（10 mL × 3）.Organic phase is merged, anhydrous sodium sulfate drying is used.Mixture is filtered.Solvent is removed in revolving.With
Silicagel column is purified to crude product.Wash-out liquid proportional：Ethyl acetate/petroleum ether=50 %.The mg of white solid 57 is obtained, is produced
Rate：71 %.
1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.24 – 7.16 (m, 2H), 5.39 –
5.22 (m, 5H), 5.18 (dd, J = 12.2, 6.7 Hz, 1H), 5.00 (d, J = 7.6 Hz, 1H), 4.28
(dd, J = 12.3, 5.2 Hz, 1H), 4.20 (dd, J = 12.3, 2.4 Hz, 1H), 3.85 (ddd, J =
9.9, 5.1, 2.4 Hz, 1H), 2.09 – 2.04 (m, 12H)。
Embodiment 8
The preparation of KPC-40000027：
It is dissolved in 2.0 mL dichloromethane, nitrogen by compound K PC-400027 (100 mg, 0.20 mmol, 1.0 eq)
0 DEG C is cooled under protection, diethylin sulfur trifluoride (83 mg, 0.51mmol, 2.5 eq) is slowly instilled with syringe.So
Ice bath is removed in recession, makes reaction solution warm naturally to room temperature（20 ℃）.Reaction process is detected with TLC, until raw material disappears（3 is small
When）.Reaction solution is slowly poured into the saturated solution of NaHCO3 (20 mL).The water of the mixed liquor to generating mutually uses ethyl acetate
Extracted（10 mL × 3）.Organic phase is merged, anhydrous sodium sulfate drying is used.Mixture is filtered.Removed in revolving
Solvent.Crude product is purified with silicagel column.Wash-out liquid proportional：Ethyl acetate/petroleum ether=40 %.Obtain white solid 75
Mg, yield：72 %.
1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.36 (d, J = 8.3 Hz, 1H),
7.23 (d, J = 8.2 Hz, 1H), 6.58 (t, J = 56.2 Hz, 1H), 5.38 – 5.17 (m, 3H),
5.04 (d, J = 7.5 Hz, 1H), 4.23 (dd, J = 19.0, 9.9 Hz, 2H), 3.89 (s, 1H), 2.09
–2.03 (m, 12H)。
Compound is shown in Table 1 obtained in above-described embodiment：
Compound obtained in the embodiment 1 ~ 8 of table 1
Embodiment 9
Gastrodin derivative shown in the present invention induces ADP the measure of rabbit extracorporeal platelet aggregation inhibiting rate
Experiment reagent：Ethanol disinfection liquid (lot number 160406), Yunnan Xiangshan medical material Co., Ltd；ADP (lot number 3449),
It is U.S.'s Chronolog Products；Ticagrelor (Ticagrelor, lot number：20151126), Guan Dong biotechnologies in Shanghai have
Limit company.
Experimental animal：Japan large ear rabbit, credit number：SCXK (river) 2013-24, has purchased from Chengdu up to large biotechnology
Limit company.
Apparatus and equipment：Chronolog-700 type platelet aggregation instruments, disposable cuvette (lot number 416022), stirrer
(lot number 072312), is U.S.'s Chronolog Products；5804R type low speed refrigerated centrifuges, eppendorf；Once
Property 4ml sodium citrate anti-freezings vacuum test tube (lot number 20150618), Zhiyuan Medical Science and Technology Co., Ltd., Wuhan；It is medical once
Property blood taking needle (lot number 20150420), Jiangxi Hongda Medical Equipment Group Corp., Ltd.；VORTEX-5 swirl mixing devices, Jiang Suhai
Its woods Bel's instrument manufacturing Co., Ltd of retail sales；METTLER TOLEDO XS105 type electronic balances, Switzerland plum Teller-Tuo Li
It is many；Liquid-transfering gun, eppendorfresearch plus, German Ai Bende.
Test sample is prepared by the following method：
Sample solution is prepared：Sample accurately weighs 8 samples such as KPC-4000020, plus DMSO dissolvings, is configured to 30 mg/ml molten
Liquid is standby.
Test solution is prepared：Adenosine diphosphate (ADP) (ADP) test solution by specification method is configured to concentration 1mmol/L solution, by 100 μ
Refrigeration (- 80 DEG C) is standby after the packing of l/ pipes；It is standby that Ticagrelor (Ticagrelor) DMSO dissolvings are configured to 0.5mg/ml solution
With.
It is prepared by PRP and PPP：After Japan large ear rabbit ear center is wiped with ethanol disinfection liquid, disposable medical blood taking needle is used
Blood (sodium citrate vacuum anticoagulant blood-collecting pipe, whole blood are extracted through ear central artery:Sodium citrate is 9:1) blood sampling, is gently overturned
Pipe makes blood and anti-coagulants well mixed for several times.
Gained anticoagulation is centrifuged (200 × g, 10min), and collection supernatant is platelet rich plasma (PRP)；Remaining blood
Liquid is centrifuged (2400 × g, 20min) again, and collection supernatant is platelet poor plasma (PPP), in terms of PPP tune PRP blood platelets
Number is 500 × 109/L [1-3].
The anti-ADP inductions Platelet Aggregation in Rabbits experiment of given the test agent
Cuvette with stirrer is respectively placed in platelet aggregation instrument pre-temperature hole, 37 DEG C of pre-temperatures with the cuvette without stirrer
10min.To 250 μ lPRP are added in the good cuvette with stirrer of pre-temperature, while adding 2.5 μ l given the test agent；Without stirring
250 μ l PPP are added in the cuvette of son, while adding 2.5 μ l given the test agent dissolving solvent used.Then proceed to pre-temperature
After 5min, two cuvettes are respectively put into PRP test positions and PPP tests position.Adjust the baseline of recording curve, the agent as shown in table 2
Amount adds derivant, records curve of platelet aggregation and calculates MA, while calculate given the test agent induces rabbit to ADP
The inhibiting rate of platelet aggregation.
Experimental result：Influence of the given the test agent to ADP induction Platelet Aggregation in Rabbits is as shown in table 2.
8 samples such as table 2.KPC-400020 induce ADP the influence of Platelet Aggregation in Rabbits（n=3）
Note：Compare with CON., * P<0.05, * * P<0.01, * * * P< 0.001
Embodiment 10
The anticoagulin xa activity detection that gastrodin derivative AT-III shown in the present invention is relied on
Experiment reagent：BIOPHEN Heparin Anti-Xa kits：HYPHEN BioMed companies produce, lot number：
F1500031。
Laboratory apparatus：ELIASA：Thermo Products, model MULTISKAN FC
Sample solution is prepared：With appropriate DMSO sample dissolutions (30 mg/mL), then with 0.02M, the Tris-HCl of pH7.4 is buffered
Liquid（Containing 5% Tween80）By Sample Dilution to concentration to be measured (1 mg/mL).
Testing inspection：Reference reagent box specification method is detected.Using 96 orifice plates, each hole is separately added into series concentration
30 μ l by after test sample solution or reference substance solution, adding 30 μ l R1 (1 IU/ml AT), vibration plate mixing, 37 DEG C are incubated 1
min；It is subsequently adding 30 μ l R2 (8 μ g/ml FXa solution), vibration plate mixing, 37 DEG C of 1 min of accurate incubation；It is eventually adding 30
The R3 (1.2 mM FXa specificity chromogenic substrate) of μ l preheatings；Negative control hole separately is set, it is with 0.02M, the Tris- of pH7.4
HCl buffer solutions（Containing 5% Tween80,3.33%DMSO）Isometric solution replaces test sample to add reaction system.In ELIASA
After mixing light absorption value (OD405) at 405nm, 7.5 min of continuous detection, the rate of change table of enzyme activity light absorption value are read every 30s
Show.
Positive control：Heparin（Heparin, Sigma company, Lot:119K1581）.
Blank（Solvent control）：The Tris-HCl buffer solutions of 0.02M, pH7.4（Containing 5% Tween80,3.33%
DMSO）.
Testing result：The anticoagulin xa activity that sample is relied on AT-III（Single concentration screening）：With the change of light absorption value
Rate (OD405/min) represents the activity of enzyme, the inhibiting rate=(solvent of the anticoagulin xa activity that sample is relied on AT-III
Control (OD405/min)-sample (OD405/min))/solvent control (OD405/min) × 100%.The results are shown in Table 3.
The influence of the anticoagulin xa activity that 8 samples such as KPC-4000020 of table 3. are relied on AT-III（n=2）
Compare with Con：*** P< 0.001, **P< 0.01, *P<0.05
Embodiment 11
The influence of gastrodin derivative shown in the present invention to APTT
Experiment reagent：
Blood coagulation Quality Control blood plasma：German TECO companies production, lot number：047B-E1371A
APTT test solutions：German TECO companies production, lot number：11265637
CaCl2：German TECO companies production, lot number：11239717
Tris-HCl：Amresco companies of the U.S., lot number 20160118
Laboratory apparatus：German Megtron MC-4000 coagulo meters
With reference to embodiment, the present invention is expanded on further：
Sample solution is prepared：Sample DMSO is dissolved into 100mM, then (contains 5% with pH7.4 0.02M Tris-HCl again
Tween80) it is diluted to 10mM.
Positive control：Enoxaparin (LMWH, GlaxoSmithKline PLC, lot number 4SH69)
Blank：Sample solvent (0.02M Tris-HCl, containing 5% Tween80 and 10% DMSO).
Testing inspection：5 μ L testing sample solutions or reference substance solution are added in 37 DEG C of pre-temperature cuvettes, is subsequently adding
45 μ L people's Quality Control blood plasma, preheat 2 min at 37 DEG C, add 50 μ L APTT reagents, after 3 min are incubated at 37 DEG C, add 50 μ
The M CaCl2 of L 0.02 (37 DEG C of pre-temperatures), record the clotting time.
Testing result：Sample is shown in Table 4. to APTT test results
Influence of 8 samples such as table 4.KPC-4000020 to APTT（n=3）
Compare with Con：*** P< 0.001, **P< 0.01, *P<0.05
Embodiment 12
The preparation of structure gastrodin derivative tablet shown in of the invention
Take structure gastrodin derivative shown in the present invention to mix with customary adjuvant, conventionally prepare shown in the present invention
Structure gastrodin derivative tablet.
Embodiment 13
The preparation of structure gastrodin derivative oral liquid shown in of the invention
Take structure gastrodin derivative shown in the present invention to mix with customary adjuvant, conventionally prepare shown in the present invention
Structure gastrodin derivative oral liquid.
Embodiment 14
The preparation of structure gastrodin derivative pill shown in of the invention
Take structure gastrodin derivative shown in the present invention to mix with customary adjuvant, conventionally prepare shown in the present invention
Structure gastrodin derivative pill.
Embodiment 15
The preparation of structure gastrodin derivative capsule shown in of the invention
Take structure gastrodin derivative shown in the present invention to mix with customary adjuvant, conventionally prepare shown in the present invention
Structure gastrodin derivative capsule.
Embodiment 16
The preparation of structure gastrodin derivative granule shown in of the invention
Take structure gastrodin derivative shown in the present invention to mix with customary adjuvant, conventionally prepare shown in the present invention
Structure gastrodin derivative granule.
Embodiment 17
The preparation of structure gastrodin derivative paste shown in of the invention
Take structure gastrodin derivative shown in the present invention to mix with customary adjuvant, conventionally prepare shown in the present invention
Structure gastrodin derivative paste.
Embodiment 18
The preparation of structure gastrodin derivative pill shown in of the invention
Take structure gastrodin derivative shown in the present invention to mix with customary adjuvant, conventionally prepare shown in the present invention
Structure gastrodin derivative pill.
Embodiment 19
The preparation of structure gastrodin derivative syrup shown in of the invention
Take structure gastrodin derivative shown in the present invention to mix with customary adjuvant, conventionally prepare shown in the present invention
Structure gastrodin derivative syrup.
Embodiment 20
The preparation of structure gastrodin derivative powder shown in of the invention
Take structure gastrodin derivative shown in the present invention to mix with customary adjuvant, conventionally prepare shown in the present invention
Structure gastrodin derivative powder.
Embodiment 21
The preparation of structure gastrodin derivative electuary shown in of the invention
Take structure gastrodin derivative shown in the present invention to mix with customary adjuvant, conventionally prepare shown in the present invention
Structure gastrodin derivative electuary.
Embodiment 22
The preparation of structure gastrodin derivative tincture shown in of the invention
Take structure gastrodin derivative shown in the present invention to mix with customary adjuvant, conventionally prepare shown in the present invention
Structure gastrodin derivative tincture.
Embodiment 23
The preparation of structure gastrodin derivative powder-injection shown in of the invention
Take structure gastrodin derivative shown in the present invention to mix with customary adjuvant, conventionally prepare shown in the present invention
Structure gastrodin derivative powder-injection.
Embodiment 24
The preparation of structure gastrodin derivative parenteral solution shown in of the invention
Take structure gastrodin derivative shown in the present invention to mix with customary adjuvant, conventionally prepare shown in the present invention
Structure gastrodin derivative parenteral solution.
The explanation of above example is only intended to help and understands the method for the present invention and its core concept.It should be pointed out that right
For those skilled in the art, under the premise without departing from the principles of the invention, the present invention can also be carried out
Some improvement and modification, these are improved and modification is also fallen into the protection domain of the claims in the present invention.
Claims (6)
1. a kind of compound, it is characterised in that the structure of described compound is as follows：
Wherein：X is halogen, and R is other compounds residues.
2. compound according to claim 1, it is characterised in that X is F, Cl or Br, R is CHO, CH2OH,CHF2Or CH2F。
3. the preparation method of the compound described in a kind of claim 1 or 2, it is characterised in that be with chloro- 4 hydroxy benzaldehydes of 2- or
Bromo- 4 hydroxy benzaldehydes of 2- are that raw material and four acetyl glucosamine tri- chloroacetimidates occur Schmidt reactions, then with NaBH4
Or DAST react obtaining target compound.
4. the preparation of the compound described in a kind of claim 1 or 2, it is characterised in that added in described compound and pharmaceutically may be used
The auxiliary material of receiving prepares piece agent, capsule, injection or freeze drying powder injection.
5. the application of the compound described in a kind of claim 1 or 2, it is characterised in that described compound is preparing anticoagulant
Application in thing.
6. the application of compound according to claim 5, it is characterised in that described compound is preparing prevention and/or controlling
Treat the application in cardiovascular and cerebrovascular diseases medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710052217.0A CN106831904B (en) | 2017-01-24 | 2017-01-24 | A kind of compound and preparation method thereof, preparation and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710052217.0A CN106831904B (en) | 2017-01-24 | 2017-01-24 | A kind of compound and preparation method thereof, preparation and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106831904A true CN106831904A (en) | 2017-06-13 |
| CN106831904B CN106831904B (en) | 2019-09-20 |
Family
ID=59120829
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710052217.0A Active CN106831904B (en) | 2017-01-24 | 2017-01-24 | A kind of compound and preparation method thereof, preparation and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106831904B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019172210A1 (en) * | 2018-03-03 | 2019-09-12 | 国立大学法人 東京大学 | Prodrug-type anticancer agent using cancer-specific enzymatic activity |
| CN112851725A (en) * | 2019-11-12 | 2021-05-28 | 中国海洋大学 | Gastrodin derivative and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104497072A (en) * | 2015-01-15 | 2015-04-08 | 佛山市赛维斯医药科技有限公司 | Derivative containing acrylonitrile and benzene halide O-glucoside structures and preparation method and application thereof |
| CN104530149A (en) * | 2015-01-14 | 2015-04-22 | 佛山市赛维斯医药科技有限公司 | Halogen-substituted phenyl group double-O-glucoside derivant, and preparation method and application thereof |
| CN104804051A (en) * | 2014-01-25 | 2015-07-29 | 昆明制药集团股份有限公司 | Acetagastrodin derivative, preparation method, preparation, and applications thereof |
-
2017
- 2017-01-24 CN CN201710052217.0A patent/CN106831904B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104804051A (en) * | 2014-01-25 | 2015-07-29 | 昆明制药集团股份有限公司 | Acetagastrodin derivative, preparation method, preparation, and applications thereof |
| CN104530149A (en) * | 2015-01-14 | 2015-04-22 | 佛山市赛维斯医药科技有限公司 | Halogen-substituted phenyl group double-O-glucoside derivant, and preparation method and application thereof |
| CN104497072A (en) * | 2015-01-15 | 2015-04-08 | 佛山市赛维斯医药科技有限公司 | Derivative containing acrylonitrile and benzene halide O-glucoside structures and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| ISRAT SULTANA，等: "An expeditious chemo-enzymatic synthesis of dihydronorcapsaicin β-D-glucopyranoside", 《SCIENCE AND TECHNOLOGY OF ADVANCED MATERIALS》 * |
| JIE JACK LI: "《有机人名反应及机理》", 30 September 2003 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019172210A1 (en) * | 2018-03-03 | 2019-09-12 | 国立大学法人 東京大学 | Prodrug-type anticancer agent using cancer-specific enzymatic activity |
| CN111801315A (en) * | 2018-03-03 | 2020-10-20 | 国立大学法人东京大学 | Prodrug-type anticancer agent utilizing cancer-specific enzyme activity |
| JPWO2019172210A1 (en) * | 2018-03-03 | 2021-02-25 | 国立大学法人 東京大学 | Prodrug-type anticancer drug utilizing cancer-specific enzyme activity |
| US11655269B2 (en) | 2018-03-03 | 2023-05-23 | The University Of Tokyo | Prodrug-type anticancer agent using cancer-specific enzymatic activity |
| JP7442192B2 (en) | 2018-03-03 | 2024-03-04 | 国立大学法人 東京大学 | Prodrug-type anticancer drugs that utilize cancer-specific enzyme activity |
| AU2019231422B2 (en) * | 2018-03-03 | 2024-03-07 | The University Of Tokyo | Prodrug-type anticancer agent using cancer-specific enzymatic activity |
| AU2019231422B9 (en) * | 2018-03-03 | 2024-03-21 | The University Of Tokyo | Prodrug-type anticancer agent using cancer-specific enzymatic activity |
| CN112851725A (en) * | 2019-11-12 | 2021-05-28 | 中国海洋大学 | Gastrodin derivative and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106831904B (en) | 2019-09-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Lee et al. | Antiplatelet, anticoagulant, and profibrinolytic activities of baicalin | |
| Kou et al. | Inhibitory effects of ethanol extract from Radix Ophiopogon japonicus on venous thrombosis linked with its endothelium-protective and anti-adhesive activities | |
| CN106831904B (en) | A kind of compound and preparation method thereof, preparation and application | |
| Zhou et al. | Evaluation of the antithrombotic activity of Zhi-Xiong capsules, a traditional Chinese medicinal formula, via the pathway of anti-coagulation, anti-platelet activation and anti-fibrinolysis | |
| JP3963301B2 (en) | Pharmaceutical composition containing a tetrahydroisoquinoline compound | |
| Yan et al. | Therapeutic effects of JLX001 on cerebral ischemia through inhibiting platelet activation and thrombus formation in rats | |
| MATSUDA et al. | Pharmacological study on Panax ginseng CA MEYER. III.: effects of red ginseng on experimental disseminated intravascular coagulation.(2).: effects of ginsenosides on blood coagulative and fibrinolytic systems | |
| CN102209545A (en) | Method for treating or preventing thrombosis using dabigatran etexilate or a salt thereof with improved efficacy over conventional warfarin therapy | |
| US20190023695A1 (en) | Terpene derivative-based par1 inhibitor, preparation method thereof, and use in treatment of thrombotic diseases | |
| JP6695361B2 (en) | Deuterated thienopiperidine derivative, preparation method and use thereof | |
| CN106117173A (en) | A kind of breviscapine B aglycone derivant and preparation method thereof, preparation and application | |
| CN107400131A (en) | Eliquis derivative and its production and use | |
| CN105055476B (en) | A kind of Xuesaitong dispersible tablet and preparation method thereof | |
| Wang et al. | [Retracted] A Cohort Study on the Safety and Efficacy of Warfarin and Rivaroxaban in Anticoagulant Therapy in Patients with Atrial Fibrillation Study | |
| CN112851725B (en) | Gastrodin derivative and preparation method and application thereof | |
| CN101665489B (en) | Dehydrosilybin trialky ether and preparation method and medical application thereof | |
| CN106336442B (en) | Gastrodin derivative, preparation method, its application and pharmaceutical preparation | |
| CA2966249C (en) | Pharmaceutical composition containing ginkgolide b and xa factor inhibitor, preparation method thereof and use thereof | |
| CN101548969B (en) | Use of ethyl malonyl silybin derivant in preparing antioxidant medicine | |
| CN112159439B (en) | Taxocyanum glycoside compound and preparation method and application thereof | |
| CN104974270B (en) | A kind of Sulfation Lachnum exocellular polysaccharide and its purposes in terms of anticoagulation medicine | |
| Murata et al. | Improvement of blood rheology by extract of Asana, Pterocarpus marsupium-Suppression of platelet aggregation activity and pterostilbene, as a main stilbene in the extract | |
| Peng et al. | Systematic investigation of the material basis, effectiveness and safety of Thesium chinense Turcz. and its preparation Bairui Granules against lung inflammation | |
| CN101912386B (en) | Application of quercetin dimer flavone for preparing anti-oxidation medicines | |
| CN104650058A (en) | Rivaroxaban monohydrate compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |