CN104804051B - A kind of Acegastrodine derivative and preparation method thereof, preparation and application - Google Patents
A kind of Acegastrodine derivative and preparation method thereof, preparation and application Download PDFInfo
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
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- 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
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
Abstract
The invention discloses a kind of Acegastrodine derivative and preparation method thereof, preparation and application, described Acegastrodine derivative is the derivative with formula I：（Ⅰ）In formula：R represents alkyl, carbonyls.Described preparation method is that condensation reaction occurs and obtains object by raw material and Acegastrodine of ethyl-para-hydroxybenzoate, parahydroxyben-zaldehyde, vanillic aldehyde, nicotinic acid, triacetyl gallic acid, cinnamic acid, acetylsalicylic acid, succinic anhydride or 4 hydroxybutyric acid potassium.Described preparation adds tablet, capsule, parenteral solution or the freeze drying powder injection of pharmaceutically acceptable auxiliary material preparation for described Acegastrodine derivative.Described application is described Acegastrodine derivative in the application in preparing anticoagulation medicine and the application in prevention and/or treatment cardiovascular and cerebrovascular diseases medicament is prepared.The preparation method of Acegastrodine derivative of the present invention is simple and easy, and favorable reproducibility, environmental pollution is small, available for formulaA large amount of preparations of shown compound.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of Acegastrodine derivative and preparation method thereof,
Preparation and application.
Background technology
Cardiovascular and cerebrovascular disease is a kind of serious threat mankind, and particularly the common disease of the elderly's health, the whole world are annual
The number for dying from cardiovascular and cerebrovascular disease is up to 25,000,000 people, and it is the first to occupy the various causes of the death.At present, China's Patients with Cardiovascular/Cerebrovascular Diseases has been
Through more than 3.4 hundred million people, China dies from nearly 4,000,000 people of cardiovascular and cerebrovascular disease every year, account for China every year total Death causes 48%.The heart
Cranial vascular disease turns into human death's cause of disease highest number one killer, and " the noiseless demon " of health of people.
Thromboembolism is one of an important factor for causing cardiovascular and cerebrovascular disease, and coronary artery disease and its corresponding ischemic are simultaneously
Hair disease can cause various clinical syndrome, and such as apoplexy, miocardial infarction or peripheral arterial disease, Etiological is exactly shape in the artery
Into thrombus block blood vessel, cause severe ischemic.Thrombotic disease using coronary artery thrombosis and cerebral thrombus as core exists
Also there are very high morbidity and mortality in China, it is therefore prevented that thrombus is also just the warmmest into current cardiovascular and cerebrovascular disease field
One of research topic of door.Be used clinically for treatment of thrombotic disorders at present mainly has anticoagulation, platelet aggregation inhibitor
Formed with Thrombolytic Drugs three major types.The first-line treatment kind of this few class medicine is primarily present Hemorrhage risk, purification technique will
The deficiencies of high is asked, in order to overcome the shortcomings of said medicine, develops new, efficient, less toxic cardiovascular and cerebrovascular diseases medicine
Thing is still the focus of drug research.China's natural resources of Chinese medicinal materials enriches, and being screened from traditional blood-activating and stasis-removing has anti-heart and brain blood
The composition of pipe disease activity carries out reasonable medicine using Modern Pharmaceutical Chemistry research principle as lead compound to lead compound
Thing design, synthesis, therefrom filter out the treatment thromboembolism that better efficacy, few side effects, bioavilability are high, half-life period is longer
Property disease medicament has important theory significance and clinical value.
The content of the invention
The first object of the present invention is to provide a kind of Acegastrodine derivative；Second purpose is to provide the acetyl
The preparation method of gastrodin derivative；3rd purpose is the preparation for providing the Acegastrodine derivative；4th purpose exists
In the application for providing the Acegastrodine derivative.
The first object of the present invention is achieved in that described Acegastrodine derivative is the derivative with formula I
Thing and its salt：
（Ⅰ）
In formula：R represents alkyl, carbonyls.
The second object of the present invention is achieved in that with ethyl-para-hydroxybenzoate, parahydroxyben-zaldehyde, chinese cymbidium
Element, nicotinic acid, triacetyl gallic acid, cinnamic acid, acetylsalicylic acid, succinic anhydride or 4 hydroxybutyric acid potassium are raw material and acetyl day
Numb element occurs condensation reaction and obtains object.
It is pharmaceutically acceptable that the third object of the present invention is achieved in that described Acegastrodine derivative adds
Tablet, capsule, parenteral solution or freeze drying powder injection prepared by auxiliary material.
The fourth object of the present invention is achieved in that described Acegastrodine derivative in anticoagulation medicine is prepared
Application；Application of the described Acegastrodine derivative in prevention and/or treatment cardiovascular and cerebrovascular diseases medicament is prepared.
Acegastrodine, molecular formula C21H26O11, molecular weight 454.4, chemical structural formula is：
。
Modern pharmacology research shows that Acegastrodine has preferably calm and soporific function compared with Gastrodin, to nerve
Weak, insomnia, headache syndromes have mitigation.Gastrodia elata can treat dizziness, extremity numbness, frightened pain and twitch.Clinically acetyl
Gastrodin is mainly used in treating the diseases such as VBI, vestibular neuronitis, vertigo.
For the present invention using Acegastrodine as lead compound, design has synthesized Acegastrodine derivative, and finds its tool
There is the features such as efficient, less toxic, selectivity is high.Acegastrodine derivative of the present invention is the compound of brand new, is had
The effect of obvious expansion blood vessel, anticoagulation and anti-ischemical reperfusion injury, available for preparation prevention or treatment cardiovascular and cerebrovascular disease
Medicine and anticoagulation medicine.The preparation method of Acegastrodine derivative of the present invention is simple and easy, favorable reproducibility, environmental pollution
It is small, available for formulaA large amount of preparations of shown compound.
Brief description of the drawings
Fig. 1 is Acegastrodine parahydroxyben-zaldehyde etherate1H-NMR collection of illustrative plates；
Fig. 2 is Acegastrodine ethylparaben etherate1H-NMR collection of illustrative plates；
Fig. 3 is Acegastrodine vanillic aldehyde etherate1H-NMR collection of illustrative plates；
Fig. 4 is Acegastrodine butyrolactone carboxylate1H-NMR collection of illustrative plates；
Fig. 5 is Acegastrodine nicotinic acid carboxylate1H-NMR collection of illustrative plates；
Fig. 6 is Acegastrodine acetyl gallic acid carboxylate1H-NMR collection of illustrative plates；
Fig. 7 is Acegastrodine acetylsalicylic acid carboxylate1H-NMR collection of illustrative plates；
Fig. 8 is Acegastrodine cinnamate compound1H-NMR collection of illustrative plates；
Fig. 9 is Acegastrodine succinate compound1H-NMR collection of illustrative plates.
Embodiment
The present invention is further illustrated below in conjunction with the accompanying drawings, but the present invention is not any limitation as in any way, base
In present invention teach that any conversion or replacement made, belong to protection scope of the present invention.
Acegastrodine derivative of the present invention is derivative and its salt with formula I：
（Ⅰ）
In formula：R represents alkyl, carbonyls.
R is ethyl-para-hydroxybenzoate, parahydroxyben-zaldehyde, vanillic aldehyde, nicotinic acid, triacetyl gallic acid, cinnamic acid, second
One kind in acyl salicylic acid, succinic anhydride or 4 hydroxybutyric acid potassium, its structural formula are respectively：
、、 、、
、、、Or
The preparation method of Acegastrodine derivative of the present invention, it is with ethyl-para-hydroxybenzoate, para hydroxybenzene
Formaldehyde, vanillic aldehyde, nicotinic acid, triacetyl gallic acid, cinnamic acid, acetylsalicylic acid, succinic anhydride or 4 hydroxybutyric acid potassium are original
Material occurs condensation reaction with Acegastrodine and obtains object.
Wherein, R is
、、 、、
、、、Or
The condensation reaction specifically includes：
The first kind：
Step 1, compound shown in formula II is dissolved in organic solvent, and ice bath stirring is lower to be added dropwise thionyl chloride, and stirring reaction obtains
Compound shown in formula III, it is standby to add organic solvent；
Step 2, ethyl-para-hydroxybenzoate, parahydroxyben-zaldehyde, 4 hydroxybutyric acid potassium, vanillic aldehyde in base catalyst and have
In the presence of solvent, with step 1 made from organic solvent dissolving formula III shown in compound heating response productionShown chemical combination
Thing.
Ⅱ Ⅲ
Second class：
Step 1, compound shown in formula IV is dissolved in organic solvent, and ice bath stirring is lower to be added dropwise thionyl chloride, and stirring reaction obtains
Compound shown in formula V, it is standby to add organic solvent；
Step 2, Acegastrodine is in the presence of base catalyst and organic solvent, with step 1 made from organic solvent dissolve
Formula V shown in compound shown in compound heating response production I；
Ⅳ Ⅴ
Wherein R1For
、、Or。
3rd class：
Acegastrodine is in the presence of base catalyst and organic solvent, with shownization of succinic anhydride heating response production I
Compound.
Described organic solvent is the organic compound that can dissolve material not soluble in water comprising carbon atom, is alkane
In hydrocarbon, alkene, alcohol, aldehyde, amine, ester, ether, ketone, aromatic hydrocarbon, hydrogenate hydrocarbon, terpene hydrocarbon, halogenated hydrocarbons, heterocyclic compound or sulphur compound
One kind.
Described organic solvent is one kind in tetrahydrofuran, acetone or dichloromethane.
Described base catalyst is inorganic base or organic base；Described inorganic base be potassium carbonate, saleratus, sodium carbonate,
One kind in sodium acid carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide or sodium hydrogen；Described organic base is 4- dimethylamino pyrroles
One kind in pyridine, triethylamine, sodium alkoxide or ammoniacal liquor.
The preparation of Acegastrodine derivative of the present invention adds for described Acegastrodine derivative pharmaceutically may be used
Tablet, capsule, parenteral solution or freeze drying powder injection prepared by the auxiliary material of receiving.
The application of the present invention is application of the described Acegastrodine derivative in anticoagulation medicine is prepared.
Application of the present invention is that described Acegastrodine derivative is preparing prevention and/or treatment cardiovascular and cerebrovascular disease
Application in medicine.
Fibrinogen can be changed into fibrin, thrombin time in the presence of fibrin ferment（thrombin
Time, TT）It is that reflection fibrin ferment makes fibrinogen be changed into the fibrinous time, is usually used in detecting medicine for exogenous
The influence of blood coagulation system.In a specific embodiment, the present invention investigates this with reference to Markwardt fibrin ferment titration method
Invent influence of the compound to thrombin time.As a result when display is not added with medicine, fibrinogen and thrombin action, about
25s solidifies, and adds heparin（Heparin, 0.725mg/mL) after, fibrinogen occurs with thrombin action about 40.5s
Solidification.And compound of the present invention is in each concentration（0.725 mg/mL, 1.25 mg/mL and 2.5mg/mL）Can significantly it extend
The setting time of fibrinogen（p<0.05）.Show that influence of the compound of the present invention for extrinsic coagulation system shows
Write, there is obvious blood coagulation resisting function.Therefore the application the invention provides the compound in anticoagulation medicine is prepared.
In a specific embodiment, tested, found by the diastole function influence to Contraction of Aortic ring caused by KCl
Compound of the present invention can be in the vascular circle that dose dependent diastole is shunk as caused by KCl, wherein in Acegastrodine fourth
Ester carboxylate（KPC-3000139）Medium effective concentration EC50Far below positive control drug ligustrazine medium effective concentration.Show this
Invent the compound especially Acegastrodine butyrolactone carboxylate（KPC-3000139）To Contraction of Aortic ring caused by KCl
Diastole effect be better than ligustrazine, there is obvious expansion blood vessel function.
During myocardial ischemia-reperfusion injury, hypoxic-ischemic promotes Endothelin（ET）A large amount of releases, cause coronary artery to continue
And acutely shrink, or even cause coronary blood flow to stop.ET can promote cardiac muscle and vascular smooth muscle synthesis release angiotensinⅡ
（AngⅡ）, and Ang II can act on blood vessel or heart endothelial cell, increase ET releases.When plasma A ng II is raised, blood flow can be hindered
Smoothness, lower cardiac output and regional tissue perfusion, and regulate and control endochylema Ca2+Concentration and protein kinase C, promote proto-oncogene c-
Fos, c-myc are expressed, and make growth and proliferation of cell, cause myocardial hypertrophy and vascular remodeling, and then aggravate the damage of cardiovascular system.
On the other hand, during myocardial ischemia-reperfusion injury, arterial endothelium is damaged, and makes to occur mainly with coronary blood endothelial cell
Prostacyclin (PGI2) synthesis is disturbed, platelet adhesion reaction is in subendothelial collagen tissue, and further release is with thromboxane (TXA2) be
Main vaso-excitor material.TXA2Ca can be used as2+Carrier directly facilitates Ca2+Interior stream and dense tubular system Ca2+Release, so as to promote
Enter platelet aggregation and local vasoconstriction, aggravate endothelial injuries.Therefore, TXA2With PGI2Dysequilibrium be probably cardiac muscle lack
One of the main reason for blood or myocardial necrosis.
In another embodiment, the present invention determines ischemical reperfusion injury rat by radio immunoassay
Blood plasma ET, Ang II, PGI2And TXA2It is horizontal.As a result compound acetyl Gastrodin butyrolactone carboxylate of the present invention is shown
（KPC-3000139）Myocardial Ischemia-Reperfusion rat plasma ET and Ang II release can be significantly reduced, reduces the heart
The blood plasma TXA of myocardial ischemia reperfusion injury rat2Level, increase blood plasma PGI2Horizontal and PGI2/TXA2Ratio, improve TXA2/
PGI2The poised state of system, mitigate the damage of cardiac muscle cell, show compound acetyl Gastrodin butyrolactone ester of the present invention
Compound（KPC-3000139）There is obvious anti-ischemical reperfusion injury.
Compound of the present invention can mitigate myocardial ischemia-reperfusion injury, by reducing ET release, improve TXA2/
PGI2The poised state of system, mitigate the damage of cardiac muscle cell, there is obvious anti-ischemical reperfusion injury.
In summary, formula of the present inventionShown compound has obvious expansion blood vessel, anticoagulation and anti-Ischemia Reperfusion
The effect of damage is noted, available for preventing or treat cardiovascular and cerebrovascular disease, therefore present invention also offers formulaShown compound is being made
It is standby to prevent and/or treat the application in cardiovascular and cerebrovascular diseases medicament.
Formula of the present inventionAnticoagulation medicine, while the present invention can be made in shown compound with the auxiliary material combination of routine
The formulaPrevention and/or treatment cardiovascular and cerebrovascular diseases medicament can also be made in shown compound with the auxiliary material combination of routine, including
Oral liquid, granule, tablet, pill, powder, capsule and pill etc..
Present invention also offers the formula of the present invention of a kind of pharmaceutical preparation, including therapeutically effective amountShown compound and
Pharmaceutically acceptable auxiliary material.Those skilled in the art can be by the formulaIt is different that shown compound directly or indirectly adds preparation
Required pharmaceutically acceptable various conventional auxiliary materials, such as filler, disintegrant, lubricant, adhesive, with routine during formulation
Drug formulation process, common dosage forms such as tablet, capsule, parenteral solution, oral liquid, granule, pill, powder and pill is made
Deng.Wherein, filler such as starch, lactose, sucrose, glucose, mannitol and silicic acid；Disintegrant such as agar, calcium carbonate, potato form sediment
Powder or tapioca, alginic acid, some silicate and sodium carbonate, low-substituted hydroxypropyl cellulose；Lubricant such as talcum powder, it is stearic
Sour calcium, magnesium stearate, solid polyethylene glycol, Sodium Laurylsulfate；Adhesive such as carboxymethyl cellulose, alginates, gelatin, polyethylene
Pyrrolones, sucrose and Arabic gum.In a particular embodiment, pharmaceutical preparation of the present invention is tablet, capsule, parenteral solution
Or freeze drying powder injection, it is deep due to easy to use to be favored by clinical patients.
Formula of the present inventionShown compound is the compound of brand new, have obvious expansion blood vessel, anticoagulation and
The effect of anti-ischemical reperfusion injury, available for preparation prevention and/or treatment cardiovascular and cerebrovascular diseases medicament and anticoagulation medicine.This
Invention formulaThe preparation method of shown compound is simple and easy, and favorable reproducibility, environmental pollution is small, available for formulaShown compound
It is a large amount of to prepare.
For a further understanding of the present invention, the present invention is further described with reference to embodiment：
Embodiment 1
The preparation of Acegastrodine parahydroxyben-zaldehyde etherate:
A. the preparation of intermediate acetyl Gastrodin benzyl chloride
In reaction bulb, Acegastrodine is added（4.55g 0.01mol）, dichloromethane 20ml, ice bath stirring is lower to be added dropwise
Thionyl chloride（2ml, 0.028mol）.2h is reacted at 0-25 DEG C, decompression steams solvent and remaining thionyl chloride, and it is solid to obtain white
Body 4.8g, yield are：98%.
B. the preparation of Acegastrodine parahydroxyben-zaldehyde etherate
In reaction bulb, parahydroxyben-zaldehyde is added（1.22g 0.01mol）, acetone 20ml, potassium carbonate（3g,
0.02mol）.50 DEG C of stirring 30min, are added dropwise Acegastrodine benzyl chloride（4.8g, 0.01mol）Acetone soln, 70 DEG C reaction
5h.It is filtered to remove potassium carbonate, filtrate decompression concentration.Dichloromethane 50ml is added, it is anhydrous successively with water, saturated common salt water washing
Magnesium sulfate is dried.Remove dichloromethane under reduced pressure and obtain light yellow solid, white solid acetyl rhizoma Gastrodiae is obtained with 70% ethyl alcohol recrystallization
Plain parahydroxyben-zaldehyde etherate 4.4g, yield are：78%.
Compound nuclear magnetic resonance identification is as follows：
1H-NMR（500MHz,CDCl3,δppm）：δ9.89（S, 1H）, δ 7.84（D, 2H）, δ 7.37（D, 2H）, δ 7.07（D,
2H）, δ 7.03（D, 2H）, δ 5.29（M, 2H）, δ 5.17（T, 1H）, δ 5.10（D, 3H）, δ 4.29（M, 1H）, δ 4.17（D, 1H）, δ
3.86（M, 1H）, δ 2.05（M, 12H）.Structural formula is shown in Table 1.
Embodiment 2
The preparation of Acegastrodine ethylparaben etherate：
The preparation reference implementation example 1 of the compounds of this invention Acegastrodine ethylparaben etherate, is prepared white
Solid Acegastrodine ethylparaben etherate 4g, yield 66%.
Compound nuclear magnetic resonance identification is as follows：
1H-NMR（500MHz,CDCl3,δppm）：δ7.99（D, 2H）, δ 7.36（D, 2H）, δ 7.01（D, 2H）, δ 6.96（D,
2H）, δ 5.29（M, 2H）, δ 5.17（T, 1H）, δ 5.09（D, 1H）, δ 5.05（S, 2H）, δ 4.31（M, 3H）, δ 4.16（D, 1H）, δ
3.86（M, 1H）, δ 2.05（M, 12H）, δ 1.37（T, 3H）.Structural formula is shown in Table 1.
Embodiment 3
The preparation of Acegastrodine vanillic aldehyde etherate：
The preparation reference implementation example 1 of the compounds of this invention Acegastrodine vanillic aldehyde etherate, is prepared white solid
Acegastrodine vanillic aldehyde etherate 4.7g, yield 80%.
Compound nuclear magnetic resonance identification is as follows：
1H-NMR（500MHz,CDCl3,δppm）：δ9.84（S, 1H）, δ 7.42（D, 2H）, δ 7.39（D, 2H）, δ 6.99（M,
3H）, δ 5.28（M, 2H）, δ 5.17（M, 3H）, δ 5.08（D, 1H）, δ 4.29（M, 1H）, δ 4.16（D, 1H）, δ 3.93（S, 3H）, δ
3.85（M, 1H）, δ 2.06（M, 12H）.Structural formula is shown in Table 1.
Embodiment 4
The preparation of Acegastrodine butyrolactone carboxylate：
The preparation reference implementation example 1 of the compounds of this invention Acegastrodine butyrolactone carboxylate, is prepared white solid
Acegastrodine butyrolactone carboxylate 4.0g, yield 74%.
Compound nuclear magnetic resonance identification is as follows：
1H-NMR（500MHz,CDCl3,δppm）：δ7.29（D, 2H）, δ 6.97（D, 2H）, δ 5.28（M, 2H）, δ 5.16（T,
1H）, δ 5.07（M, 3H）, δ 4.28（M, 1H）, δ 4.16（M, 1H）, δ 3.86（M, 1H）, δ 3.69（T, 2H）, δ 2.46（T, 2H）, δ
2.05（M, 12H）, δ 1.88（M, 2H）.Structural formula is shown in Table 1.
Embodiment 5
The synthesis of Acegastrodine nicotinic acid carboxylate：
A. the preparation of intermediate nicotinoyl chlorine
In reaction bulb, nicotinic acid is added（1.3g, 0.01mol）, 20mL acetone, ice bath stirring is lower to be added dropwise thionyl chloride
（2mL, 0.025mol）, it is heated to reflux 2 hours, decompression steams solvent and thionyl chloride, obtains nicotinoyl chlorine 1.4g, yield is
98%。
B. the preparation of Acegastrodine nicotinic acid carboxylate
In reaction bulb, Acegastrodine is sequentially added（4.55gg 0.01mol）, dichloromethane 20ml, triethylamine
（3ml, 0.02mol）.Ice bath stirring is lower to be added dropwise nicotinoyl chlorine（1.5g, 0.106mol）Dichloromethane solution.Reacted at 60 DEG C
2h, it is filtered to remove triethylamine hydrochloride.Reaction solution is dried with water, saturated common salt water washing, anhydrous magnesium sulfate successively, and decompression steams
Solvent obtains light yellow oil, and white solid Acegastrodine nicotinic acid carboxylate 4.2g, yield are obtained with 70% ethyl alcohol recrystallization
For 75%.
Compound nuclear magnetic resonance identification is as follows：
1H-NMR（500MHz,CDCl3,δppm）：δ9.23（S, 1H）, δ 8.78（S, 1H）, δ 8.32（S, 1H）, δ 7.40（D,
3H）, δ 7.01（D, 2H）δ5.33（S, 2H）, δ 5.28（M, 2H）, δ 5.17（M, 1H）, δ 5.09（M, 1H）, δ 4.29（M, 1H）, δ
4.17（M, 1H）, δ 3.86（M, 1H）, δ 2.05（M, 12H）.Structural formula is shown in Table 1.
Embodiment 6
The preparation of Acegastrodine acetyl gallic acid carboxylate：
The preparation reference implementation example 5 of the compounds of this invention Acegastrodine acetyl gallic acid carboxylate, is prepared white
Color solid Acegastrodine acetyl gallic acid carboxylate 4.75g, yield 65%.
Compound nuclear magnetic resonance identification is as follows：
1H-NMR（500MHz,CDCl3,δppm）：δ7.79（S, 2H）, δ 7.36（D, 2H）, δ 7.00（D, 2H）, δ 5.29（M,
4H）, δ 5.18（D, 1H）, δ 5.09（M, 1H）, δ 4.29（M, 1H）, δ 4.17（M, 1H）, δ 3.87（M, 1H）, δ 2.30（D, 9H）, δ
2.06（M, 12H）.Structural formula is shown in Table 1.
Embodiment 7
The preparation of Acegastrodine acetylsalicylic acid carboxylate：
The preparation reference implementation example 5 of the compounds of this invention Acegastrodine acetylsalicylic acid carboxylate, is prepared white
Solid Acegastrodine acetylsalicylic acid carboxylate 4g, yield 65%.
Compound nuclear magnetic resonance identification is as follows：
1H-NMR（500MHz,CDCl3,δppm）：δ8.03（D, 1H）, δ 7.56（T, 1H）, δ 7.36（D, 2H）, δ 7.30（T,
1H）, δ 7.09（D, 1H）, δ 7.00（D, 2H）, δ 5.29（M, 2H）, δ 5.25（S, 2H）, δ 5.17（T, 1H）, δ 5.08（D, 1H）, δ
4.29（M, 1H）, δ 4.17（D, 1H）, δ 3.86（M, 1H）, δ 2.16（S, 3H）, δ 2.06（M, 12H）.Structural formula is shown in Table 1.
Embodiment 8
The preparation of Acegastrodine cinnamate compound：
The preparation reference implementation example 5 of the compounds of this invention Acegastrodine cinnamate compound, is prepared white solid
Acegastrodine cinnamate compound 3.7g, yield 71%.
Compound nuclear magnetic resonance identification is as follows：
1H-NMR（500MHz,CDCl3,δppm）：δ7.70（D, 1H）, δ 7.51（M, 2H）, δ 7.37（M, 5H）, δ 6.99（D,
2H）, δ 6.45（D, 1H）, δ 5.28（M, 2H）, δ 5.17（M, 3H）, δ 5.08（D, 1H）, δ 4.28（M, 1H）, δ 4.16（D, 1H）, δ
3.86（M, 1H）, δ 2.05（M, 12H）.Structural formula is shown in Table 1.
Embodiment 9
The synthesis of Acegastrodine succinate compound：
Acegastrodine is added in reaction bulb（4.5g, 0.01mol）, succinic anhydride（1.2g, 0.012mol）, 4- diformazan ammonia
Yl pyridines（0.2g）, 50mL tetrahydrofurans, 48h is reacted at 70 DEG C.Decompression steams solvent, adds dichloromethane 50mL, is washed with water
Wash, decompression steams solvent and obtains white solid, and white solid 3.9g, yield 70% are obtained with ethyl alcohol recrystallization.
Compound nuclear magnetic resonance identification is as follows：
1H-NMR（500MHz,CDCl3,δppm）：δ7.29（D, 2H）, δ 6.97（D, 2H）, δ 5.28（M, 2H）, δ 5.17（T,
1H）, δ 5.09（T, 3H）, δ 4.28（M, 1H）, δ 4.17（M, 1H）, δ 3.86（M, 1H）, δ 2.67（M, 4H）, δ 2.06（M, 12H）.
Structural formula is shown in Table 1.
Compound made from the embodiment 1 ~ 9 of table 1
Test example 1
The compound prepared below with embodiment 1 ~ 9 makees following experiment：
First, to the influence of thrombin time：
Thrombin time is that reflection fibrin ferment makes fibrinogen be changed into fibrinous experiment, compound of the invention
The measure influenceed on thrombin time is carried out with reference to Markwardt fibrin ferment titration method.Specific method is small in ELISA Plate
200 μ L are added in hole, 0.5% human fibrinogen, add 1 μ L sample liquid, are fully mixed.5 μ L are drawn with microsyringe to coagulate
Hemase solution（100U/mL）It is rapid to mix simultaneously timing, the time that record fibrinogen solidifies, it the results are shown in Table 2.
Table 2 is to thrombin time（TT）Influence
Note：All results are the average value of 3 result of the tests
From the result of table 2, when being not added with medicine, fibrinogen and thrombin action, about 25s solidify, and add liver
Element（Heparin, 0.725mg/mL) after, fibrinogen solidifies with thrombin action about 40.5s.And the chemical combination of the present invention
Thing is in each concentration（0.725 mg/mL, 1.25 mg/mL and 2.5mg/mL）It can significantly extend the setting time of fibrinogen
（p<0.05）.
2nd, to diastolic blood vessel activity evaluation study：
Male SD rat, cervical dislocation, thoracic cavity is cut off, takes out thoracic aorta strips rapidly, be positioned in 4 DEG C of K-H liquid, carefully
Peel off the fat and connective tissue for being attached to aorta pectoralis, the crosscutting vascular circle into 3mm length.Vascular circle is hung on into preset 5mL K-
In the bath of H liquid, 37.0 ± 0.2 DEG C of temperature is constant, is continually fed into 95%O2And 5%CO2Mixed gas.One end of sample is fixed,
The other end connects ALC-M in vitro tissue organ experimental systems through tonotransducer, records the change of tension force in experimentation.It is stable
Process is first started with 0g tension force, is adjusted its basal tension to 1g after maintaining 30min, is balanced 1h, during which changed once every 15min
K-H liquid.After aortic annulus is stable, KCl is used（60mmol/L）Stimulate, eluted after shrinkage amplitude is stable with K-H liquid, to excite most
Shrink greatly and make vessel retraction state more stable.With 10 μm of ol/L diastoles sustainers more than 70% of Ach, it is believed that endothelium is complete.
Diastole effect to Contraction of Aortic ring caused by KCl
After vascular circle detection endothelium, vascular circle is set to reach maximum collapse with final concentration of 60mmol/L KCl solution, with list
The compound of the invention of concentration gradient is added in secondary administration normal direction bath ware, records aortic annulus tension force, it is soft by GraphPad
Part calculates maximum diastole effect and medium effective concentration, the results are shown in Table 3.
Diastole effect of the table 3 to Contraction of Aortic ring caused by KCl
The compound of the result of the table 3 display present invention can be in the vascular circle that dose dependent diastole is shunk as caused by KCl, its
Acegastrodine butyrolactone carboxylate made from middle embodiment 4（KPC-3000139）Medium effective concentration EC50It is right far below positive
According to medicine ligustrazine medium effective concentration.Show compound of the present invention especially Acegastrodine butyrolactone carboxylate（KPC-
3000139）Diastole effect to Contraction of Aortic ring caused by KCl is better than ligustrazine.
3rd, to the influence of ischemical reperfusion injury：
Male Wistar rat 60,340 ± 20g of body weight, is provided by Kunming Medical University's Experimental Animal Center（Experiment is dynamic
Thing production licence number：SCXK（Yunnan）2005-2008）.Rearing conditions：Room temperature is 22 ± 2 DEG C, relative humidity 60 ~ 70%.
Acegastrodine butyrolactone carboxylate（KPC-3000139）There is provided by Kunming Medicine Group Stock Co., Ltd, it is interior
Pi Su（ET）Put exempt from medicine box, 6- ketone-Prostaglandin F1a (6-keto-PGF1 α) is put and exempts from medicine box and thromboxane B2（TXB2）Put and exempt from medicine
Box is provided by PLA General Hospital East Asia immunological technique research institute, Plasma angiotensin Ⅱ（AngⅡ）Ria-determination box is by north
Capital north immunoreagent research institute provides.
Wistar rats 60 are only randomly divided into 5 groups, every group 12.1st group is sham-operation group：Sublingual vein injects physiology
Salt solution 2mL/kg；2nd group is model group：Sublingual vein injecting normal saline 2mL/kg;3rd ~ 5 group be KPC-3000139 it is small,
In, heavy dose of group：Sublingual vein injection KPC-3000139 is respectively 25,50,100 mg/kg.
The coronary ligation of rat faces upward position and is fixed on operating table, from the intercostal of left side 3 ~ 4 under etherization with reference to pertinent literature
Chest is opened, exposure heart, coronary artery left anterior descending branch is found out between pulmonary conus and atrium sinistrum, is not ligatured except sham-operation group only threads
Outside, remaining each group ligatures coronary artery immediately with No. 0 line, is padded on a tiny emulsion tube between blood vessel and ligature during ligation, will
Heart sends thoracic cavity back to, and extrudes chest intracavity blood and gas, closes thoracic cavity rapidly, opens the chest time and is no more than 30 s.Each group animal
Sublingual vein administration or physiological saline are distinguished when ligaturing 30 min, ligature of then loosening carries out Reperfu- sion.Reperfu- sion 120
After min, with yellow Jackets 30mg/kg intraperitoneal injection of anesthesia, every group of animal surveys endothelin level by radio immunoassay
(ET), Ang II and prostacyclin (PGI2) and thromboxane A2(TXA2) the ketone prostaglandin F 1A (6-Keto- of metabolite 6
) and TXB PGF1A2It is horizontal.Experimental data with± s is represented, is examined with t between group and is carried out statistical analysis.It the results are shown in Table 4 and table 5.
Influence horizontal to ischemical reperfusion injury rat plasma ET and Ang II KPC-3000139 of table 4
Note:Compared with model group,1)P<0.05,2)P<0.01,±s,n=10
The KPC-3000139 of table 5 is to ischemical reperfusion injury rat plasma PGI2And TXA2Horizontal influence
Note:Compared with model group,1)P<0.05,2)P<0.01,±s,n=10
From the result of table 4, the content of model group blood plasma ET and Ang II is apparently higher than sham-operation group (P<0.05 or P<
0.01) with the increase that internal ET and Ang II are horizontal when, showing Acute Myocardial Ischemia in Rats reperfusion injury.KPC-3000139
100 mg/kg groups can obviously reduce the level of Myocardial Ischemia-Reperfusion rat plasma ET and Ang II, compared with model group
Significant difference (P<0.05).
By the visible re-perfusion model group of the result of table 5 compared with sham-operation group, blood plasma TXA2Significantly raised, the PGI of level2It is horizontal
And PGI2/TXA2Ratio substantially reduces (P<0.05 or P<0.01) with intravascular when, showing myocardial ischemia-reperfusion injury
The dysequilibrium of chrotoplast.The mg/kg groups of KPC-3000139 50,100 can obviously reduce myocardial ischemia-reperfusion injury in rats
Blood plasma TXA2Level, increase blood plasma PGI2Horizontal and PGI2/TXA2Ratio, with re-perfusion model group comparing difference significantly (P<0.05
Or P<0.01).
In summary, compound acetyl Gastrodin butyrolactone carboxylate of the present invention（KPC-3000139）Can be obvious
Myocardial Ischemia-Reperfusion rat plasma ET and Ang II release is reduced, reduces myocardial ischemia-reperfusion injury in rats
Blood plasma TXA2Level, increase blood plasma PGI2Horizontal and PGI2/TXA2Ratio, improve TXA2/ PGI2The poised state of system, subtracts
The damage of negligent myocyte, show compound acetyl Gastrodin butyrolactone carboxylate of the present invention（KPC-3000139）Have
The effect of obvious anti-ischemical reperfusion injury.
Compound acetyl Gastrodin parahydroxyben-zaldehyde etherate, Acegastrodine Ni Bo are investigated using above-mentioned experimental method
Golden ethyl ester etherate, Acegastrodine vanillic aldehyde etherate, Acegastrodine acetyl gallic acid carboxylate, Acegastrodine second
Acyl salicylate compound, Acegastrodine nicotinic acid carboxylate, Acegastrodine cinnamate compound, Acegastrodine succinate
Compound, the influence to ischemical reperfusion injury is as a result similar to Acegastrodine butyrolactone carboxylate, can equally significantly reduce
Myocardial Ischemia-Reperfusion rat plasma ET and Ang II release, reduce the blood of myocardial ischemia-reperfusion injury in rats
Starch TXA2Level, increase blood plasma PGI2Horizontal and PGI2/TXA2Ratio, improve TXA2/ PGI2The poised state of system, mitigate the heart
The damage of myocyte, there is obvious anti-ischemical reperfusion injury.
The explanation of above example is only intended to help the method and its core concept for understanding the present invention.It should be pointed out that pair
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 (7)
1. a kind of Acegastrodine derivative, it is characterised in that described Acegastrodine derivative is the derivative with formula I
Thing and its salt：
Formula I
In formula：R is、、 、、
、、、Or。
2. the preparation method of Acegastrodine derivative described in a kind of claim 1, it is characterised in that be with P-hydroxybenzoic acid
Ethyl ester, parahydroxyben-zaldehyde, vanillic aldehyde, nicotinic acid, triacetyl gallic acid, cinnamic acid, acetylsalicylic acid, succinic anhydride or 4- hydroxyls
Base potassium butyrate is that raw material obtains object with Acegastrodine generation condensation reaction；Condensation reaction is three classes：
The first kind：
Step 1, Acegastrodine is dissolved in organic solvent, ice bath stirring is lower to be added dropwise thionyl chloride, and stirring reaction obtains acetyl day
The plain benzyl chloride of fiber crops, it is standby to add organic solvent；
Step 2, ethyl-para-hydroxybenzoate, parahydroxyben-zaldehyde, 4 hydroxybutyric acid potassium or vanillic aldehyde are in base catalyst and organic
In the presence of solvent, with compound shown in the Acegastrodine benzyl chloride heating response generation formula I of organic solvent dissolving.
Second class：
Step 1, nicotinic acid, triacetyl gallic acid, cinnamic acid or acetylsalicylic acid are dissolved in organic solvent, and ice bath stirring is lower to be added dropwise two
Chlorine sulfoxide, stirring reaction, it is standby that obtained compound adds organic solvent；
Step 2, Acegastrodine is in the presence of base catalyst and organic solvent, the compound with organic solvent dissolving in step 1
Compound shown in heating response generation formula I；
3rd class：
Acegastrodine is in the presence of base catalyst and organic solvent, with chemical combination shown in succinic anhydride heating response generation formula I
Thing.
3. the preparation method of Acegastrodine derivative according to claim 2, it is characterised in that the organic solvent is four
One kind in hydrogen furans, acetone or dichloromethane.
4. the preparation method of Acegastrodine derivative according to claim 2, it is characterised in that the base catalyst is nothing
Machine alkali or organic base；Described inorganic base be potassium carbonate, saleratus, sodium carbonate, sodium acid carbonate, potassium hydroxide, sodium hydroxide,
One kind in lithium hydroxide or sodium hydride；Described organic base is one in DMAP, triethylamine, sodium alkoxide or ammoniacal liquor
Kind.
A kind of 5. preparation of Acegastrodine derivative described in claim 1, it is characterised in that the Acegastrodine derivative
Add tablet, capsule, parenteral solution or freeze drying powder injection prepared by pharmaceutically acceptable auxiliary material.
A kind of 6. application of the Acegastrodine derivative in anticoagulation medicine is prepared described in claim 1.
7. Acegastrodine derivative described in a kind of claim 1 is in prevention and/or treatment cardiovascular and cerebrovascular diseases medicament is prepared
Application.
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| CN106074580B (en) * | 2016-06-18 | 2018-10-09 | 昆药集团股份有限公司 | A kind of new application of Acegastrodine derivative |
| CN106336442B (en) * | 2016-07-27 | 2018-11-27 | 昆药集团股份有限公司 | Gastrodin derivative, preparation method, its application and pharmaceutical preparation |
| CN108017681B (en) * | 2016-11-04 | 2022-07-19 | 海口凯宝实业有限公司 | O-aryl glycoside derivative, pharmaceutical composition and application thereof |
| CN106619667B (en) * | 2016-11-19 | 2020-02-14 | 昆药集团股份有限公司 | Application of acegastrodine and acegastrodine derivative |
| CN106831904B (en) * | 2017-01-24 | 2019-09-20 | 昆药集团股份有限公司 | A kind of compound and preparation method thereof, preparation and application |
| CN109988204B (en) * | 2018-01-03 | 2023-01-24 | 江西青峰药业有限公司 | O-aryl glycoside derivative, and pharmaceutical composition and application thereof |
| CN109498636A (en) * | 2018-11-29 | 2019-03-22 | 昆明医科大学 | A kind of Gastrodin or Acegastrodine are applied in the pathology damage for improving Protein tau |
| CN112851725B (en) * | 2019-11-12 | 2022-12-09 | 中国海洋大学 | Gastrodin derivative and preparation method and application thereof |
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| CN1737007A (en) * | 2004-08-20 | 2006-02-22 | 昆明制药集团股份有限公司 | Gastrodine derivative, its preparation method, pharmaceutical composition and uses |
| CN102159206A (en) * | 2008-09-19 | 2011-08-17 | 诺瓦提斯公司 | Glucoside derivatives and uses thereof as sglt inhibitors |
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| CN1737007A (en) * | 2004-08-20 | 2006-02-22 | 昆明制药集团股份有限公司 | Gastrodine derivative, its preparation method, pharmaceutical composition and uses |
| CN102159206A (en) * | 2008-09-19 | 2011-08-17 | 诺瓦提斯公司 | Glucoside derivatives and uses thereof as sglt inhibitors |
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