CN101659640A - Ozagrel tromethamine, compound, preparation method and application thereof - Google Patents
Ozagrel tromethamine, compound, preparation method and application thereof Download PDFInfo
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Abstract
The invention provides an ozagrel salt which is stable, has functions of inhibiting platelet aggregation and removing blood-vessel convulsion, has good water solubility, and is prepared into a compound suitable for clinical application. The new compound is ozagrel tromethamine; and the ozagrel and the tromethamine are prepared by reaction in a solvent. The compound has good water solubility, strong and long-term stability, and the functions of inhibiting platelet aggregation and removing blood-vessel convulsion.
Description
Technical field
The present invention relates to a kind of medicine, be specifically related to a kind of ozagrel salt, more specifically relate to Ozagrel tromethamine and composition thereof with anti-platelet aggregation effect, and the preparation method of this salt.Belong to pharmaceutical chemistry and field of pharmaceutical preparations.
Background technology
Ozagrel is a kind of thromboxane synthetase inhibitor, can specific inhibition thromboxane synthetase, have platelet aggregation-against and vasospasmolytic effect, can suppress cerebral thrombosis and cerebral vasospasm, can be used for the improvement of subarachnoid hemorrhage operation back symptoms of cerebral ischemia.
Because ozagrel is water-soluble relatively poor, therefore at present using more clinically is the injection liquid of ozagrel sodium salt, but ozagrel is unstable in the aqueous solution, but generate cis imidazoles tolyl acrylic acid after the isomerization, and the ozagrel sodium water solution can produce insoluble foreign matter (Jpn.J.Pharm.HealthCare Sci.2005 medium-term and long-term placement of Glass Containers, 31 (9), 761-767.
Patent application CN200610046977.2 discloses a kind of novel cpd Ozagrel lysine, and molecular formula is C
6H
14N
2O
2C
13H
12N
2O
2, molecular weight is 374.44.In 30% aqueous ethanolic solution, be carried out to reactant salt by ozagrel and L-Methionin and obtain, have antiplatelet aggregative activity.With the Ozagrel lysine is that activeconstituents and corresponding medicinal dressing combination can be made into the preparation of using for intravenously administrable, be used for the treatment of the dyskinesia that acute thrombotic cerebral infarction and cerebral infarction are followed, and improve the postoperative cerebral vasospasm of subarachnoid hemorrhage and shrink and concurrent symptoms of cerebral ischemia.
Patent application CN200610082246.3 discloses a kind of ozagrel ornithine salt, and it is used to prepare dyskinesia that cerebral vasospasm behind the treatment spider nethike embrane bleed bottom and the empty mass formed by blood stasis of following of brain and brain during acute thrombosis bring and the medicine of the bronchial asthma that formed by thromboxane.It is after being reacted in water by water-insoluble ozagrel and ornithine, obtain the infusion solution that is used for intravenously administrable that it is made by the ozagrel ornithine salt and can add to 5% glucose injection or injection liquid, solvent crystal packing powder pin and lyophilized powder pin that 0.9% sodium chloride injection is used through concentrate drying or after adding insoluble organic solvent crystallization or lyophilize.
Though above-mentioned ozagrel salt is in the stability that has improved ozagrel salt, but long-term shelf-stability descends, and the aspects such as purity of water-soluble, ozagrel salt are defectiveness also, above-mentioned defective at prior art, a kind of new ozagrel salt that has platelet aggregation-against and remove the effect of blood vessel spasm that the present invention proposes, i.e. Ozagrel tromethamine.
Summary of the invention
It is Ozagrel tromethamine that first purpose of the present invention is to provide a kind of compound, this compound has platelet aggregation-against and vasospasmolytic effect, and good water solubility is placed the strong advantage of its stability for a long time, and this compound prepares easily, its purity height, yield height.
Another object of the present invention is to provide a kind of stable preparation method with platelet aggregation-against and water-soluble good Ozagrel tromethamine of removing the effect of blood vessel spasm, this method reaction conditions gentleness, and preparation section is simple, the starting material cheap and simple.
The 3rd purpose of the present invention has been to provide a kind of Ozagrel tromethamine has been prepared into the pharmaceutical composition that is suitable for clinical application, and the formulation of this pharmaceutical composition can be little liquid drugs injection, infusion solutions, injection freeze-dried powder or sterile powder for injection pin.
The 4th purpose of the present invention is to provide a kind of Ozagrel tromethamine or the application of Ozagrel tromethamine composition on preparation platelet aggregation-against and releasing blood vessel spasm medicine.
For realizing first purpose of the present invention, a kind of Ozagrel tromethamine is provided, its skeleton symbol is:
The molecular formula of this compound is C
13H
12N
2O
2C
4H
11NO
3, its fusing point is 172-176 ℃.This compound is water-soluble, and performance steady in a long-term is good.
This compound is to be reacted and made by ozagrel and Trometamol, from the Trometamol structural analysis, contain three hydroxyls, wetting ability is very strong, the solubility property of the Ozagrel tromethamine that ozagrel and Trometamol are combined into improves greatly, has solved the problem of ozagrel poorly water-soluble.In the Ozagrel tromethamine structure, this structure is very stable, and the long-time placement of its injection liquid does not produce visible foreign matters, thereby has avoided in the clinical use some may introduce the link of pollution.
The synthesis material Trometamol that the present invention uses is applicable to acidaemia, there are some researches show between hyperuricemia and the cerebro-vascular diseases and have linear relationship, hyperuricemia causes the mechanism of cerebro-vascular diseases not clear and definite fully as yet, because ozagrel and Trometamol are treated synergy each other, so Ozagrel tromethamine of the present invention has stronger platelet aggregation-against and removes the effect of blood vessel spasm.
Formula (I) expression medical compounds Ozagrel tromethamine, it has platelet aggregation-against and vasospasmolytic effect, ozagrel trihydroxybutane provided by the invention is guaranteeing that drug effect is constant even better under the prerequisite, its good water solubility, long-term advantage such as stable strong of placing.This compound is to be reacted in solvent by ozagrel and Trometamol to make.This raw material that reacts used is cheap and easy, the degree height that the reaction between the reactant is carried out, and the reaction conditions gentleness, yield is very high, and obtains the purity height of Ozagrel tromethamine, can reach 99.8%.
For realizing second purpose of the present invention, a kind of preparation method of Ozagrel tromethamine is provided, comprise ozagrel and Trometamol are dissolved in the solvent that stirring makes it to react completely, remove and desolvate or crystallisation by cooling, obtain Ozagrel tromethamine.
Reaction process is as follows:
Concrete, above-mentioned preparation method comprises following steps:
(1) Trometamol is dissolved in the solvent, under 0～80 ℃ of temperature, agitation condition, adds ozagrel again, insulation reaction 1.5～5 hours; Solution after reaction finishes is through crystallisation by cooling, suction filtration, and filtration cakes torrefaction obtains the Ozagrel tromethamine crude product;
(2) the Ozagrel tromethamine highly finished product will be got behind the above-mentioned crude product refining.
Step (2) obtains the Ozagrel tromethamine highly finished product with the Ozagrel tromethamine crude product with organic solvent washing described refining comprising, described organic solvent can be ethanol, ethyl acetate or acetone etc.
The described solvent of step (1) is water and/or alcohol, and described alcohol is C
1～C
4Alcohol, preferred alcohols is C
1～C
4Monohydroxy-alcohol.
Above-mentioned solvent is preferably with C
1～C
4Monohydroxy-alcohol and the arbitrary proportion blended mixed solvent of water, it is 30%～60% aqueous ethanolic solution that the arbitrary proportion blended aqueous ethanolic solution of its preferred alcohol and water, described aqueous ethanolic solution more preferably contain ethanol.
Preferred 25～50 ℃ of temperature of reaction, further preferred 35～45 ℃.
The preferred version that the present invention prepares Ozagrel tromethamine is:
(1) Trometamol is dissolved in the aqueous ethanolic solution that contains ethanol 30%～60%, under being 35～45 ℃, agitation condition, temperature adds ozagrel, after the insulation reaction 1.5～5 hours, through cooling crystallization, suction filtration, obtain the Ozagrel tromethamine crude product through the solution after the reaction end behind the filtration cakes torrefaction;
(2) get the Ozagrel tromethamine highly finished product behind the crude product refining.
In the above-mentioned preparation process, ozagrel is 1: 1～2 with the amount of substance ratio of Trometamol, be preferably 1: 1.05～and 1.65, more preferably 1: 1.05.
The Ozagrel tromethamine that makes by preparation method of the present invention has platelet aggregation-against and vasospasmolytic effect, good water solubility, and stability is strong.
The synthetic method of Ozagrel tromethamine of the present invention, it is simple to operate, and raw material is easy to get, and reaction conditions gentleness, reaction process are not used to human body, to the serious deleterious solvent of environment, and reaction yield reaches 87.5%, and the finished product purity reaches 99.8%.
For realizing the 3rd purpose of the present invention, the Ozagrel tromethamine pharmaceutical composition also is provided, said composition comprises the Ozagrel tromethamine activeconstituents shown in the formula (I), and injection formulations pharmaceutical excipient commonly used.Described auxiliary material includes but not limited to N.F,USP MANNITOL, Xylitol, lactose, sodium-chlor, S-WAT, Sodium Pyrosulfite, Sodium octoate etc.Said composition can be prepared into injection formulationss such as little liquid drugs injection, infusion solutions, injection freeze-dried powder or sterile powder for injection pin with the pharmacy field routine techniques.
In the above-mentioned composition preparation, the Ozagrel tromethamine shown in 20～150mg formula (I), preferred 25～120mg are contained in each preparation unit.
Ozagrel tromethamine of the present invention or Ozagrel tromethamine composition can be in the application on preparation platelet aggregation-against and the releasing blood vessel spasm medicine.
Than prior art, Ozagrel tromethamine of the present invention and preparation method thereof etc. have following advantage:
1, the good water solubility of Ozagrel tromethamine of the present invention, long-term shelf-stability height, because synergy, Ozagrel tromethamine has higher platelet aggregation-against and removes the effect of blood vessel spasm.
2, Ozagrel tromethamine is raw materials used is easy to get in preparation, and synthesis technique is simple, stable reaction conditions, gentleness, and the yield height of product, the purity height does not have serious three-waste pollution in reaction process.
3, Ozagrel tromethamine of the present invention can prepare various injection formulationss, for example frozen powder for injection pin, aseptic powder injection or infusion solutions etc.
Embodiment
Embodiment 1
The preparation of Ozagrel tromethamine
Trometamol 250.7g (2.072mol) is dissolved among the distilled water 1125ml, is 45 ℃ in temperature, adds ozagrel 450g (1.974mol) under stirring, finish insulation reaction 2 hours.Be chilled to room temperature, separate out a large amount of crystal, filter, get crude product.Crude product is added dehydrated alcohol 1125ml, reflux 3 hours, stopped reaction stirred 6 hours under the condition of 5 ℃ of temperature, suction filtration, dehydrated alcohol drip washing is dried, and gets white powder 598g, yield 86.8%, content 99.8%, mp:175-176 ℃ (decomposing during fusion).Ultimate analysis measured value % (theoretical value %): C58.41 (58.44), H 6.65 (6.64), N12.02 (12.03%).
1H-NMR (600MHz, DMSO-d
6) δ: 3.41 (6H, s, 3 * CH
2), 5.17 (2H, s, CH
2), 6.39～6.42 (1H, d ,-CH=CHCOOH), 6.89 (1H, s ,-N=CH-N), 7.18 (1H, s, N-CH=CH-N-CH
2), 7.22～7.23 (2H, d, ph-2H), 7.35～7.38 (1H, d ,-CH=CHCOOH), 7.57～7.59 (2H, d, ph-2H), 7.78 (1H, s, N-CH=CH-N-CH
2), by mass spectroscopy, obtain the molecular weight 349.18 of product.Infrared signature absorption peak: 1690cm
-1, 1640cm
-1, 1520cm
-1, 1440cm
-1, 3200cm
-1, 3460cm
-1, 1030cm
-1
Embodiment 2
The preparation of Ozagrel tromethamine
Trometamol 145.2g (1.2mol) is dissolved among the distilled water 570ml, is to add ozagrel 228g (1mol) under 35 ℃ of stirrings in temperature, finishes insulation reaction 2 hours.Cooling crystallization, suction filtration gets crude product.Crude product is added dehydrated alcohol 600ml, and reflux 3 hours is to stir 6 hours under 10 ℃ the condition in temperature, suction filtration, and a small amount of absolute ethanol washing, drying obtains white powder 305.3g, yield 87.5%, content 99.6%.
Embodiment 3
The preparation of Ozagrel tromethamine
Trometamol 12.7g (0.105mol) is dissolved among the distilled water 32ml, is to add ozagrel 22.8g (0.1mol) under 40 ℃ of stirrings in temperature, finishes insulation reaction 2 hours.Cooling crystallization, suction filtration gets crude product.Crude product is added among the acetone 80ml, and 50～60 ℃ were stirred 5 hours, and cooling continues crystallization below 10 ℃, suction filtration, and small amount of acetone filter wash cake, drying obtains white powder 30.3g, yield 86.9%, content 99.7%.
Embodiment 4
The preparation of Ozagrel tromethamine
Trometamol 12.7g (0.105mol) being dissolved among 30% the aqueous ethanolic solution 50ml, is 45 ℃ in temperature, stirs to add ozagrel 22.8g (0.1mol) down, finishes insulation reaction 3 hours.Cooling crystallization, suction filtration gets crude product.Crude product is added dehydrated alcohol 60ml backflow stirred 3 hours, stir cooling 5 hours below 10 ℃, suction filtration, a small amount of absolute ethanol washing, drying obtains white powder 29.4g, yield 84.3%, content 99.8%.
Embodiment 5
The preparation of Ozagrel tromethamine
Trometamol 12.7g (0.2mol) being dissolved among 60% the aqueous propanol solution 50ml, is 25 ℃ in temperature, stirs to add ozagrel 22.8g (0.1mol) down, finishes insulation reaction 5 hours.Cooling crystallization, suction filtration gets crude product.Crude product is added dehydrated alcohol 60ml backflow stirred 3 hours, stir cooling 5 hours below 10 ℃, suction filtration, a small amount of absolute ethanol washing, drying obtains white powder 28.72g, yield 82.3%, content 99.5%.
Embodiment 6
The preparation of Ozagrel tromethamine
Trometamol 12.7g (0.15mol) is dissolved among the 50% methanol aqueous solution 80ml, is 50 ℃ in temperature, stirs down to add ozagrel 22.8g (0.1mol), finishes insulation reaction 3 hours.Cooling crystallization, suction filtration gets crude product.Crude product is added among the acetone 80ml, and 55～60 ℃ were stirred 5 hours, and cooling continues crystallization below 10 ℃, suction filtration, and small amount of acetone filter wash cake, drying obtains white powder 29.7g, yield 85.1%, content 99.2%.
The fusing point of the Ozagrel tromethamine that embodiment 2-6 is obtained, ultimate analysis,
1H-NMR and infrared signature absorption peak characterize, and the analytical results of result and embodiment 1 is same or similar.
Embodiment 7
The preparation of Ozagrel tromethamine injection liquid
Prescription:
Ozagrel tromethamine 56g
Water for injection 2000ml
?????????????????????????????????
Make 1000 altogether
Preparation technology: get Ozagrel tromethamine 56g, add injection water dissolving, add 1% gac room temperature and stirred 30 minutes, filter carbon removal, filtrate adds water to full dose, crosses 0.2 μ m filter membrane, divides to be filled to the 2ml ampoule, and 121 ℃ of pressure sterilizings 30 minutes promptly.
Embodiment 8
The preparation of Ozagrel tromethamine injection liquid
Prescription:
Ozagrel tromethamine 56g
N.F,USP MANNITOL 2.5g
Water for injection 2000ml
????????????????????????????
Make 1000 altogether
Preparation technology: get Ozagrel tromethamine 56g, N.F,USP MANNITOL 2.5g, add the dissolving of injection water, the gac room temperature of adding 1% stirred 30 minutes, filter carbon removal, filtrate adds water to full dose, crosses 0.2 μ m filter membrane, divide to be filled to the 2ml ampoule, 121 ℃ of pressure sterilizings 30 minutes promptly.
Embodiment 9
The preparation of Ozagrel tromethamine injection liquid
Prescription:
Ozagrel tromethamine 112g
Water for injection 5000ml
?????????????????????????????
Make 1000 altogether
Preparation technology: get Ozagrel tromethamine 112g, add injection water dissolving, add 1% gac room temperature and stirred 30 minutes, filter carbon removal, filtrate adds water to full dose, crosses 0.2 μ m filter membrane, divides to be filled to the 5ml ampoule, and 121 ℃ of pressure sterilizings 35 minutes promptly.
Embodiment 10
The preparation of Ozagrel tromethamine sodium chloride injection
Prescription:
Ozagrel tromethamine 112g
Sodium-chlor 900g
Water for injection 100000ml
?????????????????????????????????
Make 1000 altogether
Preparation technology: get Ozagrel tromethamine 112g, sodium-chlor 900g, add the dissolving of injection water, the gac room temperature of adding 1% stirred 30 minutes, filter carbon removal, filtrate adds water to full dose, crosses 0.2 μ m filter membrane, divide to be filled to the 100ml infusion bottle, 121 ℃ of pressure sterilizings 45 minutes promptly.
Embodiment 11
The preparation of Ozagrel tromethamine freeze-dried powder
Prescription:
Ozagrel tromethamine 56g
N.F,USP MANNITOL 11.5g
Water for injection 2000ml
????????????????????????????????
Make 1000 altogether
Preparation technology: get Ozagrel tromethamine 56g, N.F,USP MANNITOL 11.5g, add the dissolving of injection water, the gac room temperature of adding 1% stirred 30 minutes, filter carbon removal, filtrate adds water to full dose, crosses 0.2 μ m filter membrane, divide to be filled to the 2ml ampoule, after lyophilize, obtain Ozagrel tromethamine powder pin.
Embodiment 12
The preparation of Ozagrel tromethamine injection liquid: the 3.0g Ozagrel tromethamine is dissolved with proper amount of water for injection, the sodium hydroxide that adds 0.1mol/L, and then, adjust full dose to 100ml with water for injection with the hydrochloric acid bar PH to 7.5 of 0.1mol/L, stirring and evenly mixing is made injection liquid.
Experimental example 1
This experimental example is that the Ozagrel tromethamine (B) of the present invention's preparation and the stability of Ozagrel lysine (A) are compared experiment, wherein Ozagrel lysine is that method according to the disclosed embodiment 1 of patent application CN200610046977.2 is prepared from, above-mentioned two kinds of ozagrel salt of equivalent are dissolved in respectively in the water for injection of equivalent, get trial-product, 40 ℃ ± 2 ℃ of temperature, under the condition of relative humidity 75% ± 5%, respectively at the 1st, 2,3,6,9 sampling at the end of month once, observe outward appearance, content, the result is as shown in table 1:
Table 1 Ozagrel tromethamine (B) and Ozagrel lysine (A) stability experiment result
Can show that from the experimental result of table 1 ozagrel trihydroxybutane of the present invention is placed for a long time, its stability is still fine, and Ozagrel lysine is very stable in a short time, but after long-term the placement, has insolubles and occur, and content sharply descends.
Experimental example 2
This experimental example is that the stability to the embodiment of the invention 7 preparation Ozagrel tromethamine injection liquids (B) and the injection liquid (C) of self-control Sodium Ozagrel compares experiment, wherein the prescription of ozagrel sodium injection is identical with embodiment 7 Ozagrel tromethamines, get trial-product, 25 ℃ ± 2 ℃ of temperature, under the condition of relative humidity 60% ± 10%, respectively at the 1st, 3,6 sampling at the end of month once, observe outward appearance, content, the result is as shown in table 2:
Table 2 Ozagrel tromethamine (B) and Sodium Ozagrel (C) stability experiment result
Table 3 is that the stability to the embodiment of the invention 7 preparation Ozagrel tromethamine injection liquids (B) and the injection liquid (C) of self-control Sodium Ozagrel compares experiment, wherein the prescription of ozagrel sodium injection is identical with embodiment 7 Ozagrel tromethamines, get trial-product, 40 ℃ ± 2 ℃ of temperature, under the condition of relative humidity 75% ± 5%, respectively at the 1st, 2,3,6,9 sampling at the end of month once, observe outward appearance, content.
Table 3 Ozagrel tromethamine (B) and Sodium Ozagrel (C) accelerated stability experimental result
This experimental example of table 4 is that the stability to the embodiment of the invention 9 preparation Ozagrel tromethamine injection liquids (B) and the injection liquid (C) of self-control Sodium Ozagrel compares experiment, wherein the prescription of ozagrel sodium injection is identical with embodiment 7 Ozagrel tromethamines, get trial-product, 25 ℃ ± 2 ℃ of temperature, under the condition of relative humidity 60% ± 10%, respectively at the 1st, 3,6 sampling at the end of month once, observe outward appearance, content.
Table 4 Ozagrel tromethamine (B) and Sodium Ozagrel (C) stability experiment result
Table 5 is that the stability to the embodiment of the invention 9 preparation Ozagrel tromethamine injection liquids (B) and the injection liquid (C) of self-control Sodium Ozagrel compares experiment, wherein the prescription of ozagrel sodium injection is identical with embodiment 7 Ozagrel tromethamines, get trial-product, 40 ℃ ± 2 ℃ of temperature, under the condition of relative humidity 75% ± 5%, respectively at the 1st, 2,3,6,9 sampling at the end of month once, observe outward appearance, content.
Table 5 Ozagrel tromethamine (B) and Sodium Ozagrel (C) accelerated stability experimental result
From the interpretation of table 2-5, the ozagrel trihydroxybutane is compared with Sodium Ozagrel, and apparently higher than Sodium Ozagrel, solution still is colourless clear liquid in long-term stability of placing the ozagrel trihydroxybutane.
Experimental example 3
This experimental example is that Ozagrel tromethamine and Sodium Ozagrel, the ozagrel ornithine solvability of embodiment 1 compares, Sodium Ozagrel is the commercially available prod, the ozagrel ornithine is that the inventor adopts the method for patent application CN200610082246.3 experimental example 1 to be prepared from, experiment condition is: at ambient temperature, solvent is a water, is determined at solvability in the different acid-basicity solution.See Table 6.
The solvability of table 6 Ozagrel tromethamine, Sodium Ozagrel and ozagrel ornithine relatively
| The pH value | Ozagrel tromethamine | Sodium Ozagrel | The ozagrel ornithine |
| ??pH6 | ??57.6g/L | ??34g/L | ??46.2g/L |
| ??pH7 | ??78.4g/L | ??44g/L | ??60.7g/L |
| ??pH8 | ??99.6g/L | ??46.9g/L | ??81g/L |
| ??pH9 | ??123.8g/L | ??53g/L | ??99.2g/L |
Draw from table 6 interpretation, the solubility property of Ozagrel tromethamine improves greatly.
Experimental example 4
Pharmacological toxicology
Animal experiment shows that this medicine intravenously administrable can reduce blood plasma TXB2 level, and 6-Keto-PGF1 α/TXB2 ratio descends, and platelet aggregation due to the different inductors is all had restraining effect, the rat mesencephalic arteries is blocked the cerebral infarction that causes be plugged with prophylactic effect.This medicine is lower to the half-inhibition concentration IC50 of human platelet aggregation, is 4nM.The test of injecting the subarachnoid hemorrhage model with self blood shows, continues to inject vein, has effect such as TXB2 concentration and cerebrovascular contracture in the blood of inhibition.Acute toxicity LD50 (mg/kg): the quiet notes of mouse are 2708 (heros), 2206 (female); Oral is 5305 (heros), 5026 (female); Subcutaneous is 3420 (heros), 2932 (female).The quiet notes of rat are 1605 (heros), 1815 (female); Oral is 8237 (heros), 7958 (female); Subcutaneous is 3211 (heros), 3141 (female).The quiet notes of dog are 1023 (heros).Subacute, chronic toxicity: intravenous injection this product, the rat high dose group does not see that other are unusual except that finding that slight urine electrolyte drainage is risen.Maximum tolerated dose rat 175mg/kg, dog 14-17mg/kg.Other toxicity: rat, rabbit reproductive toxicity test result, taking place during this product high dosage to suppress the close relative is signs of toxicity such as the weight of animals, embryo, the young death of tire, the young growth of tire suppressed phenomenons such as new cub's death.In addition, find in rat Seg II test that high dose group has the unusual and unusual abnormal litter size of bone of internal organ slightly to increase, antigenicity, variability and local irritation are tested all negative.With the subarachnoid hemorrhage postoperative patient is object, begins to give this product 10-14 days after surgery in early days, carries out double blind trial in high dose group (558mg every day), low dose group (112mg every day) and the prazepam control group of this medicine.Efficient and the curative effect of low dose group, high dose group all obviously is better than control group as a result.In addition, high dose group cerebrovascular contracture occurrence frequency is also obviously low than control group.
Pharmacokinetics
This medicine of people's single intravenous injection, it is very fast to disappear in blood.Main component also has its β-Yang Hua body and goes back substance except that the free form of this medicine in the blood.This drug metabolite does not almost have pharmacologically active.Vein is annotated when thanking continuously, reaches the blood concentration steady state in 2 hours.This medicine major part was drained in 24 hours.Animal experiment does not find that this product has the property of accumulating and toxicity.After this product intravenous drip, Plasma Concentration one time curve meets two Room open models, and t1/2 β is 1.22 ± 0.44 hours, and Vd is 2.32 ± 0.62L/kg, and AUC is 0.47 ± 0.08ug hour/nl.Cl is 3.25 ± 0.82L/ hour/g, and experimenter's transformation period is the longest to be 1.93 hours, and Plasma Concentration can measure after the drug withdrawal 3 hours.Drug withdrawal 24 hours, almost all medicine excretes through urine.
To the functional study of Ozagrel tromethamine vivo medicine-feeding of the present invention to ADP inductive rabbit platelet aggregation.
Get New Zealand and plant 40 of White Rabbits, male and female half and half are divided into 4 groups at random, 10 every group, are respectively the blank group, the Ozagrel tromethamine group.Difference auricular vein injecting normal saline, Ozagrel tromethamine, auricular vein is got blood 3.6ml after 2 minutes, add in the plastics tubing of 0.42% liquor sodii citratis that is placed with 0.4ml in advance, with blood and antithrombotics mixing gently, with speed is centrifugal 5 minutes of 800rpm, the yellow suspension in sucking-off upper strata is a platelet rich plasma, and then is centrifugal 10 minutes of 2000rpm with speed, and the sucking-off supernatant liquor is a platelet poor plasma.Measure medicine to the influence of ADP (phosphate buffered saline buffer with PH7.2 is made into 1mmol/l) induced platelet accumulative, the results are shown in Table 7:
Table 7 Ozagrel tromethamine to the influence of platelet aggregation in the rabbit body (X ± SD, n=10)
| Group | Dosage (mg/kg) | Size of animal | Platelet aggregation rate (%) | Inhibiting rate (%) |
| Control group | ??- | ??10 | ??59.07±5.96 | ??- |
| Experimental group 1 | ??7.0 | ??10 | ??39.67±1.98 * | ??32.84 |
| Experimental group 2 | ??20 | ??10 | ??29.75±2.59 * | ??49.63 |
| Experimental group 3 | ??62.1 | ??10 | ??21.56±4.34 ** | ??63.50 |
Compare with blank
*P＜0.05;
*P＜0.01
Find out that from the test-results of table 7 Ozagrel tromethamine has tangible antiplatelet aggregative activity, evident difference is relatively arranged with the blank group.
Claims (10)
1, Ozagrel tromethamine salt, its structure is:
2, the preparation method of the described compound of a kind of claim 1 comprises the steps: to comprise ozagrel and Trometamol are added in the solvent, stirs to make it to react completely, and removes and desolvates or crystallisation by cooling, obtains Ozagrel tromethamine;
Reaction process is as follows:
3, preparation method according to claim 2 is characterized in that:
(1) Trometamol is dissolved in the solvent, under 0～80 ℃ of temperature, agitation condition, adds ozagrel again, insulation reaction 1.5～5 hours; Solution after reaction finishes is through crystallisation by cooling, suction filtration, and filtration cakes torrefaction obtains the Ozagrel tromethamine crude product;
(2) the Ozagrel tromethamine highly finished product will be got behind the above-mentioned crude product refining.
4, preparation method according to claim 3, it is characterized in that, step (2) obtains the Ozagrel tromethamine highly finished product with the Ozagrel tromethamine crude product with organic solvent washing described refining comprising, described organic solvent is ethanol, ethyl acetate or acetone.
5, preparation method according to claim 3 is characterized in that, the described solvent of step (1) is water and/or alcohol, and described alcohol is C
1～C
4Alcohol, preferred alcohols is C
1～C
4Monohydroxy-alcohol; Described solvent is preferably with C
1～C
4Monohydroxy-alcohol and the arbitrary proportion blended mixed solvent of water; Described solvent is the arbitrary proportion blended aqueous ethanolic solution of ethanol and water more preferably, and it is 30%～60% aqueous ethanolic solution that described aqueous ethanolic solution more preferably contains ethanol.
6, preparation method according to claim 3 is characterized in that, described temperature of reaction is preferred 25～50 ℃, further preferred 35～45 ℃.
7, preparation method according to claim 3 is characterized in that, in the preparation process, ozagrel is 1: 1～2 with the amount of substance ratio of Trometamol for the amount of substance ratio, be preferably 1: 1.05～and 1.65.
8, a kind of pharmaceutical composition of Ozagrel tromethamine is characterized in that, it comprises the described Ozagrel tromethamine of claim 1.
9, composition according to claim 8, it is characterized in that, said composition is prepared into injection formulationss such as little liquid drugs injection, infusion solutions, injection freeze-dried powder or sterile powder for injection pin, the described Ozagrel tromethamine of 20～150mg claim 1, preferred 25～120mg are contained in its preferred each preparation unit.
10, Ozagrel tromethamine or the Ozagrel tromethamine composition application on preparation platelet aggregation-against and releasing blood vessel spasm medicine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102757403A (en) * | 2011-04-27 | 2012-10-31 | 浙江九洲药业股份有限公司 | Febuxostat derivative and preparation method thereof |
| CN103044333A (en) * | 2013-01-11 | 2013-04-17 | 德州翰华医药化学有限公司 | Preparation method of high-purity sodium ozagrel |
| CN104610153A (en) * | 2015-01-19 | 2015-05-13 | 沈阳中海生物技术开发有限公司 | Ozagrel meglumine salt, as well as composition, preparation method and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1847228B (en) * | 2006-05-15 | 2012-02-15 | 沈阳药科大学 | Ozagrel ornithine salt and its injection form |
| CN100402506C (en) * | 2006-06-20 | 2008-07-16 | 王绍杰 | Ozagrel lysine, preparing method and usage |
-
2009
- 2009-05-27 CN CN2009101437700A patent/CN101659640B/en active Active
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102757403A (en) * | 2011-04-27 | 2012-10-31 | 浙江九洲药业股份有限公司 | Febuxostat derivative and preparation method thereof |
| CN103044333A (en) * | 2013-01-11 | 2013-04-17 | 德州翰华医药化学有限公司 | Preparation method of high-purity sodium ozagrel |
| CN104610153A (en) * | 2015-01-19 | 2015-05-13 | 沈阳中海生物技术开发有限公司 | Ozagrel meglumine salt, as well as composition, preparation method and application thereof |
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