CN105777774A - Crystal form X of Tipidogrel free alkali and preparation method and application thereof - Google Patents

Crystal form X of Tipidogrel free alkali and preparation method and application thereof Download PDF

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Publication number
CN105777774A
CN105777774A CN201610118735.3A CN201610118735A CN105777774A CN 105777774 A CN105777774 A CN 105777774A CN 201610118735 A CN201610118735 A CN 201610118735A CN 105777774 A CN105777774 A CN 105777774A
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crystal formation
pharmaceutical composition
preparation
present
injection
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刘登科
刘颖
刘冰妮
樊梦林
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Tianjin Institute of Pharmaceutical Research Co Ltd
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Tianjin Institute of Pharmaceutical Research Co Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13Crystalline forms, e.g. polymorphs

Abstract

The invention belongs to the technical field of medicine and particularly provides a crystal form X of (5-(2-cyanobenzy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)acetate.The invention further provides a preparation method of the crystal form and application of the crystal form in preparation of anti-platelet aggregation pharmaceutical compositions.(Please see the chemical formula in the description.).

Description

For crystal formation Ⅹ than free base and its production and use
Technical field
The invention belongs to pharmaceutical technology field, more precisely, relate to a kind of (5-with antiplatelet aggregative activity (2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetas crystal formation Ⅹ and preparation method thereof and Application.
Background technology
The formation of thrombosis may result in the heart, brain, the pulmonary circulation illness such as acute myocardial infarction, apoplexy, pulmonary infarction, serious threat people The health and lives of class, be also factor inaccessible again after complication common in surgical operation and interventional angioplasty it One.
Cause thrombotic a lot because have, the adhesion on the blood vessel wall surface of damage of the such as platelet and gathering, Blood stream stasis, the activation of thrombin promote the formation of thrombin, antiplasmin activity low inferior.In above-mentioned factor, platelet is Thrombotic required material, therefore suppressing hematoblastic gathering is one of prevention and the important means treating thrombus disease.
The present inventor once have submitted with regard to " the thienopyridine esters derivative of a class nitrile group-containing, Preparation Method And The Use " Chinese invention patent application (publication number: CN102241690).A kind of chemical structural formula change as shown in formula I of this disclosure of the invention Compound: (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetas (hereinafter referred to as formula I Compound).
Above invention discloses compound (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2- Base) acetas is effective for the treatment disease that causes because of platelet aggregation of the mankind, such as thrombotic disease.
The most above-mentioned patent " the thienopyridine esters derivative of a class nitrile group-containing, Preparation Method And The Use " is also disclosed The preparation method of (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetas:
Equipped with stirring, condenser, thermometer reaction bulb in add 2.7g intermediate1, with 10mL dichloromethane by it Dissolving, stirring is lower adds sodium hydroxide 1.2g.Reaction system is cooled to-20 DEG C, 1.02g acetic anhydride is dividedly in some parts reactant System.Add, continue stirring reaction 1h (flaggy display reaction is completely) at room temperature.Wash reactant liquor with 3 × 15mL water, divide and take two Chloromethanes layer, the driest with anhydrous sodium sulfate, to filter, dichloromethane to the greatest extent is steamed in decompression, and post separates, obtains white solid product (HPLC:99.6%).Rf=0.58 [single-point, developing solvent: v (petroleum ether): v (ethyl acetate)=4:1].1H NMR(DMSO- D6,400MHz) δ: 2.253 (s, 3H), 2.700 (s, 2H), 2.767~2.780 (d, 2H), 3.402 (s, 2H), 3.816 (s, 2H), 6.421 (s, 1H), 7.452~7.489 (t, 1H), 7.606~7.625 (d, 1H), 7.660~7.697 (t, 1H), 7.803~7.822 (d, 1H).MS, m/Z:312.0 (M).
In research afterwards, repeating above-mentioned preparation method, the product fusing point obtained is 85 DEG C-85.5 DEG C, and it uses X- Powder diffraction characterizes, such as accompanying drawing 1 (hereinafter referred to as patent CN102241690 crystal formation).
Inventor finds in research process, has obtained a kind of being different from the new of above-mentioned white solid product with refining methanol Crystal formation.This crystal formation has embodied the technical advantage being better than prior art CN102241690 crystal formation, has the most also applied for that novel crystal forms is special Profit.
Patent " crystal formation of (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfides also [3_2-c] pyridine-2-base) acetas " (CN104098586) (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetic acid is disclosed in A kind of crystal formation of ester:
Monoclinic system, P21/n space group, the molecular number in structure cell is 4,
A=14.174 (3) A, alpha=90deg.,
B=5.9321 (12) A, beta=99.06 (3) deg.,
C=18.796 (4) A, gamma=90deg.,
Unit cell volume 1560.7 (5)
Packing of molecules in structure cell is shown in accompanying drawing 2.
It characterizes with X-powder diffraction, such as accompanying drawing 3.
The preparation method of crystal, it is characterised in that: type I compound is added in the methanol of 8 times (w/vs), stir Mixing and be heated to 60 DEG C, after being completely dissolved, filter, filtrate room temperature is placed 20-24 hour, separates out crystallization.Leach this crystallization, through indoor It is dried to obtain.Purity (HPLC:99.0%), fusing point: 91.1-91.8 DEG C.
It is referred to as polytropism, it is known that it is present in many organic with the ability that different crystal forms compound structure exists In compound.These different crystal formations are referred to as " polymorph ", and the accumulation mode of its crystalline solid state, geometry arrangement and its His descriptive nature aspect and different.Different polymorphs has different lattice energies, and thus it illustrates not when solid-state Same physical property, such as shape, color density, hardness, deformability, stability and dissolubility etc..
To this end, present inventors studied 5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfides also [3,2-c] pyridine-2-base) The polymorphism of acetas, and wish to find the crystal habit with excellent physicochemical property, thus provide more for medicine manufacture Material choice.
Summary of the invention
It is an object of the invention to the defect overcoming the known crystal formation of both the above to exist, it is provided that the one of formula I compound Kind of novel crystal forms, this crystal formation has stable apparent condition and good long-term storing stability, can be stably supplied prepare former Material medicine.Present invention also offers the preparation method and application of this crystal formation.
A further object of the invention is, it is provided that formula I compound is as the application in terms of antiplatelet drug, special It not for preparing prevention or treating the coronary syndrome caused because of platelet aggregation, myocardial infarction, myocardial ischemia Deng the purposes in terms of cardiovascular and cerebrovascular diseases medicament.
Present invention relates particularly to the crystal formation of the compound of structure shown in formula I:
The i.e. crystal formation Ⅹ of (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfides also [3,2-c] pyridine-2-base) acetas, It is characterized in that:
Measuring with D/Max-2500 type x-ray diffractometer, condition determination: CuKa, 40KV, 100mA, its collection of illustrative plates has The angle of diffraction (2 θ), as shown in Figure 4, the error of 2 θ is ± 0.2 for interplanar distance (d value) and intensity (%).
According to the crystal formation of the present invention, wherein, the fusing point of this crystal formation can be 89.8-90.4 DEG C.It addition, the purity of this crystal formation Can be 99.0% or more than.
According to the crystal formation of the present invention, wherein, the X powder diffraction of this crystal formation can be as shown in Figure 4.
Present invention also offers the method for preparing above-mentioned crystal formation, the method comprises the following steps:
The crystal formation Ⅹ of type I compound is to crystallize to obtain in the mixed liquor of petroleum ether acetonitrile.The usage amount of mixed liquor is 2~8 times (volume-mass ratio, mL/g) of type I compound quality, the most preferably 5 times.
Acetonitrile accounts for the 10%~40% of mixed liquor cumulative volume;Preferably 20%.
Temperature during dissolving is 30 DEG C~65 DEG C, preferably 45 DEG C.Then it is naturally cooling to room temperature, places 2~10 hours, excellent Choosing is placed 6 hours;I.e. obtain novel crystal forms Ⅹ type of type I compound.
Specific operation process is:
Take a certain amount of type I compound, add petroleum ether acetonitrile mixture, heated and stirred, after dissolving, naturally cool to Room temperature.Separate out solid, filter, obtain type I compound crystal formation Ⅹ.
Purity (HPLC:99.8%), fusing point: 89.8-90.4 DEG C.
Present invention also offers a kind of pharmaceutical composition, described pharmaceutical composition comprises above-mentioned crystal formation and the one of effective dose Or multiple pharmaceutically acceptable adjuvant.Described pharmaceutically acceptable adjuvant can be to maintain the substrate of pharmaceutical dosage form or auxiliary Material, by selecting according to different medicaments or be applied in combination, is optionally included with carrier, excipient, diluent, filling Agent, binding agent, disintegrating agent, lubricant, fluidizer, effervescent, correctives, preservative, coating material etc..Excipient includes such as Microcrystalline Cellulose, lactose, pregelatinized Starch, starch, dextrin, calcium phosphate, sucrose, dextran, mannitol, sorbitol, Fructus Vitis viniferae The compositions of one or more in sugar, fructose, water, Polyethylene Glycol, propylene glycol, glycerol, cyclodextrin, cyclodextrin derivative.Fill out Fill agent and include such as lactose, sucrose, dextrin, starch, pregelatinized Starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, carbonic acid Calcium, the compositions of one or more of microcrystalline Cellulose.Binding agent includes such as sucrose, starch, polyvidone, carboxymethyl cellulose Sodium, carboxylic the third methylcellulose, carboxylic the third cellulose, methylcellulose, Polyethylene Glycol, medicinal alcohol, the combination of one or more of water Thing.Disintegrating agent includes such as starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxylic first fibre Dimension element sodium, the compositions of one or more of gas-producing disintegrant.
According to the pharmaceutical composition of the present invention, wherein, described pharmaceutical composition can be solid orally ingestible, liquid port Formulation or injection.Preferably, described solid orally ingestible include dispersible tablet, enteric coatel tablets, chewable tablet, oral cavity disintegration tablet, capsule or Granule;Described liquid oral medicine includes oral solution;Described injection includes injection liquid drugs injection, injection lyophilized powder Pin, infusion solutions or primary infusion.
Present invention also offers above-mentioned crystal formation or the crystal formation prepared according to the said method of the present invention is being prepared for anti-blood Purposes in the pharmaceutical composition that platelet is assembled.It addition, present invention also offers above-mentioned crystal formation or the above-mentioned side according to the present invention Crystal formation prepared by method preparation for treatment cause because of antiplatelet aggregation coronary syndrome, myocardial infarction, cardiac muscle Ischemia, cardiovascular and cerebrovascular disease pharmaceutical composition in purposes.The present inventor is by assembling inhibitory action to mouse platelets It is experimentally confirmed that the crystal formation of the formula I compound of the present invention has the platelet aggregation that obvious anti-ADP induces, therefore it can Be used for preventing or treat cause because of platelet aggregation coronary syndrome, myocardial infarction, the heart and brain blood such as myocardial ischemia Pipe disease.
The crystal formation of the present invention is effective in comparatively wide dosage range.The dosage that such as every day takes is about at 10mg- In the range of 500mg, it is divided into once or is administered for several times.The actual dosage taking crystal formation of the present invention can be by doctor according to relevant situation Determine.These situations include: the condition of patient, route of administration, age, body weight, individual reaction to medicine, disease The order of severity etc. of shape.
White solid product phase with the formula I compound obtained by direct solvent evaporated (such as dichloromethane) mode Ratio, the crystal formation prepared by the present invention has good appearance stability and repeatability between batch.Such as, the present inventor is by real Issuing after examination and approval existing, this crystal formation is in the range of the batch of preparation 7 batches continuously, and its outward appearance is stable, is all normally white solid, and warp Measuring every batch is all stable crystal formation (test result is as shown in table 1).
Table 1 stability of crystal form is tested
Additionally, the crystal formation of the present invention also has good long-term storing stability.Such as, the present inventor is tested by experiment Card, this crystal formation schedules to last trimestral in light, heat, wet stability experiment, and its impurity is not significantly increased, thus has more Good long term storage stability.
Based on features described above, the crystal formation of the present invention can be more suitable for as the stable supplying source of formula I raw materials of compound medicine Industrialized production.
Meanwhile, in view of the crystal formation of the present invention has preferable long-time stability, can affirm, the system prepared for raw material with it Agent should have the longer limited time limit, and the requirement to preservation condition is the lowest simultaneously.
Accompanying drawing explanation
Hereinafter, describe embodiment of the present invention in detail in conjunction with accompanying drawing, wherein:
Fig. 1 shows the X-ray powder diffraction pattern being prepared crystal formation by patent CN102241690 method;
Fig. 2 shows the structure cell packing of molecules figure being prepared crystal formation by patent CN104098586 method;
Fig. 3 shows the X-ray powder diffraction pattern being prepared crystal formation by patent CN104098586 method;
Fig. 4 shows the X-ray powder diffraction pattern of crystal formation Ⅹ.
Detailed description of the invention
The present invention is further illustrated below by specific embodiment, it should be understood, however, that, these embodiments are only It is used for specifically describing in more detail, and is not to be construed as limiting in any form the present invention.
This part to the present invention test used in material and test method carry out general description.Although it is Realize many materials that the object of the invention used and operational approach is to it is known in the art that but the present invention still uses up at this May describe in detail.It will be apparent to those skilled in the art that within a context, if not specified, material therefor of the present invention and behaviour It is well known in the art as method.
With the following Examples, the present invention is as follows to the condition determination of crystal formation:
Measuring with D/Max-2500 type x-ray diffractometer, condition determination: CuKa, 40KV, 100mA, its collection of illustrative plates has The angle of diffraction (2 θ), as shown in Figure 3, the error of 2 θ is 0.2 for interplanar distance (d value) and intensity (%).
Fusing point test:
Instrument: YTR-3 type melting point apparatus (purchased from Precision Instrument Factory, Tianjin Univ.)
High performance liquid chromatography (HPLC) condition:
Chromatographic column: C18, 150mm × 4.6mm, 5um
Flowing phase: methanol: water: acetic acid=70:30:0.25
Wavelength: 230nm
Flow velocity: 0.8ml/min
Sample size: 10uL
Column temperature: 35 DEG C
Instrument:
General analysis general L6 chromatograph of liquid
Hitachi's L-7250 automatic sampler
General analysis general LC Win chromatographic work station
Embodiment 1
The present embodiment is for illustrating (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyrrole of the present invention Pyridine-2-base) crystal formation of acetas and preparation process thereof.
Preparation (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetas is as former Material.Its preparation process is referred to the open reaction process described in CN102241690 of Chinese invention patent.Such as, its reaction Flow process can be:
Intermediate1Preparation:
Equipped with stirring, condenser, thermometer reaction bulb in add 5,6,7,7a-Tetramethylene sulfide also [3,2-c] pyridine- 2 (4H)-one 19.2g, is dissolved with 70mL acetonitrile, is cooled to-10 DEG C under stirring, adds Anhydrous potassium carbonate 41.5g.By 2-cyanogen Bromide benzyl 19.6g is dividedly in some parts in reaction system, finishes and is warming up to 45 DEG C of continuation reaction 4h (flaggy display reaction is completely).Cross Filter, filtrate solvent evaporated acetonitrile, add 50mL dichloromethane, wash reactant liquor with 3 × 50mL water, divide and take dichloromethane layer, use Anhydrous sodium sulfate is the driest, filters, and dichloromethane to the greatest extent is steamed in decompression, obtains yellow oil product 22.6g (HPLC:97.2%). Rf=0.47 [single-point, developing solvent: v (petroleum ether): v (ethyl acetate)=1: 2].MS, m/Z:270.0 (M).
Formula (I) compound ((5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetic acid Ester) preparation:
Equipped with stirring, condenser, thermometer reaction bulb in add the above-mentioned prepared intermediate of 2.7g1, with 10mL bis- Chloromethanes is dissolved, and stirring is lower adds sodium hydroxide 1.2g.Reaction system is cooled to-20 DEG C, by 1.02g acetic anhydride in batches Add reaction system.Add, continue stirring reaction 1h (flaggy display reaction is completely) at room temperature.Anti-with the washing of 3 × 15mL water Answer liquid, divide and take dichloromethane layer, the driest with anhydrous sodium sulfate, to filter, dichloromethane to the greatest extent, post separation are steamed in decompression, obtain white Color solid product (HPLC:99.6%).Rf=0.58 [single-point, developing solvent: v (petroleum ether): v (ethyl acetate)=4:1].1H NMR (DMSO-d6,400MHz) δ: 2.253 (s, 3H), 2.700 (s, 2H), 2.767~2.780 (d, 2H), 3.402 (s, 2H), 3.816 (s, 2H), 6.421 (s, 1H), 7.452~7.489 (t, 1H), 7.606~7.625 (d, 1H), 7.660~7.697 (t, 1H), 7.803~7.822 (d, 1H).MS, m/Z:312.0 (M).
White solid product (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyrrole to above-mentioned gained Pyridine-2-base) acetas carry out X-ray powder diffraction (PXRD) characterize, its PXRD collection of illustrative plates is as shown in Figure 1.Repeat above-mentioned preparation side Method, the fusing point of the white solid product measuring gained is 85-85.5 DEG C.
The preparation of crystal formation of the present invention:
Take white solid (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyrrole that 3g said method prepares Pyridine-2-base) acetas, add the mixed liquor (acetonitrile accounts for the 40% of mixed liquor cumulative volume) of the petroleum ether-acetonitrile of 6ml, in stirring Under be heated to 65 DEG C so that it is all dissolve, filter, take filtrate;Gained filtrate is at room temperature placed 2h crystallize, knot is collected by filtration Crystalline substance, is dried, obtains the crystal 2.96g of the present invention.
The fusing point recording this crystal formation is 90.0-90.3 DEG C, and the purity using HPLC to record this crystal formation is 99.8%.
Embodiment 2
The present embodiment is for illustrating (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyrrole of the present invention Pyridine-2-base) crystal formation of acetas and preparation process thereof.
Formula (I) compound is prepared as raw material according to method in the same manner as in Example 1.
Take white solid (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyrrole that 3g said method prepares Pyridine-2-base) acetas, add the mixed liquor (acetonitrile accounts for the 20% of mixed liquor cumulative volume) of the petroleum ether-acetonitrile of 15ml, in stirring Under be heated to 45 DEG C so that it is all dissolve, filter, take filtrate;Gained filtrate is at room temperature placed 6h crystallize, knot is collected by filtration Crystalline substance, is dried, obtains the crystal 2.89g of the present invention.
The fusing point recording this crystal formation is 89.9-90.2 DEG C, and the purity using HPLC to record this crystal formation is 99.9%.
Embodiment 3
The present embodiment is for illustrating (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyrrole of the present invention Pyridine-2-base) crystal formation of acetas and preparation process thereof.
Formula (I) compound is prepared as raw material according to method in the same manner as in Example 1.
Take white solid (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyrrole that 3g said method prepares Pyridine-2-base) acetas, add the mixed liquor (acetonitrile accounts for the 40% of mixed liquor cumulative volume) of the petroleum ether-acetonitrile of 24ml, in stirring Under be heated to 30 DEG C so that it is all dissolve, filter, take filtrate;Gained filtrate is at room temperature placed 10h crystallize, is collected by filtration Crystallization, is dried, obtains the crystal 2.85g of the present invention.
The fusing point recording this crystal formation is 90.1-90.4 DEG C, and the purity using HPLC to record this crystal formation is 99.9%.
Embodiment 4
The present embodiment contains the preparation of the tablet of crystal formation of the present invention for explanation.
Sample crystal formation, pregelatinized Starch and microcrystalline Cellulose that embodiment 1 prepares are sieved, are sufficiently mixed with recipe quantity, Add the solution containing recipe quantity polyvinylpyrrolidone, mixing, soft material processed, sieve, wet granular processed, it is dried in 50-60 DEG C;So After Sodium carboxymethyl starch, magnesium stearate and Pulvis Talci are sieved in advance, join in above-mentioned dried granule with recipe quantity, Tabletting, obtains the tablet of the crystal formation containing the present invention.
Embodiment 5
This test example is used for the crystal formation that the present invention the is described inhibitory action to rat platelet aggregation.
1, Experimental agents and reagent:
The crystal formation of embodiment 1 preparation;
ADP:SIGMA Products;
Sodium carboxymethyl cellulose 800-1200: Chemical Reagent Co., Ltd., Sinopharm Group, lot number: F20051103.
2, laboratory animal:
Wistar rat: SPF level, male, Institute of Experimental Animals, Chinese Academy of Medical Sciences provides, credit number SCXK (capital) 2005-0013.
3, experimental apparatus:
PAM-3 type dual pathways platelet aggregation instrument: Danyang, Jiangsu Province radio factory product.
4, experimental technique and result:
Select healthy male Wistar rat, body weight 210-250g, random packet.Every batch is all provided with Normal group and crystal formation Administration group.The dosage of crystal formation administration group is 30mg/kg.Use gastric infusion, be administered volume and be 10mL/kg bw, the most right Giving equivalent 0.5%CMC-Na according to group, 2h after administration, lumbar injection 40mg/kg pentobarbital sodium (1mL/kg) anesthesia, abdomen is actively Arteries and veins is taken a blood sample, and with 3.8% sodium citrate anticoagulant, prepares platelet rich plasma (PRP) and platelet poor plasma (PPP) respectively, PAM-3 type dual pathways platelet aggregation instrument measures the platelet maximum gathering percentage rate that ADP (final concentration: 1.08 μMs) induces.Knot Fruit is shown in Table 2.
The table 2 impact on the platelet aggregation that ADP induces
From table 2, compared with Normal group, the crystal formation (30mg/kg) of the present invention has the blood that obvious anti-ADP induces Platelet aggregation.Therefore it may be used for prevention or treats coronary syndrome, the cardiac muscle caused because of platelet aggregation The cardiovascular and cerebrovascular disease such as infarction, myocardial ischemia.
Embodiment 6
The crystal formation of the present invention that embodiment 1 is prepared and patent CN102241690 crystal formation and patent CN104098586 crystal formation Carry out influence factor's test, respectively at illumination (4500 ± 500Lx), high temperature (60 DEG C) and the bar of high humidity (92.5% relative humidity) Place three months under part, compared outward appearance, impurity number and impurity level (measuring with HPLC) with the 0th day.Result of the test is shown in Table respectively 3-5。
Table 3 light durability test data
Table 4 thimble test data
Table 5 high humidity stability test data
From table 3-5, in the stability test under the illumination of 3 months by a definite date, high temperature, super-humid conditions, the present invention is brilliant The long-time stability of type are preferable, are especially better than CN102241690 crystal formation and CN104098586 crystal formation, measured by HPLC simultaneously, Its impurity number and gathering way of total impurities are also considerably slower than CN102241690 crystal formation and CN104098586 crystal formation, it is seen that this The crystal formation of invention has preferable long term storage stability, can be as the stable source of formula (I) raw materials of compound medicine.
Although present invention has been a certain degree of description, it will be apparent that, without departing from the spirit and scope of the present invention Under the conditions of, the suitable change of each condition can be carried out.It is appreciated that and the invention is not restricted to described embodiment, and be attributed to right The scope required, it includes the equivalent of described each factor.

Claims (9)

1. the crystal formation Ⅹ of one kind (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfides also [3,2-c] pyridine-2-base) acetas, It is characterized in that, the X-ray powder diffraction spectrum of described crystal formation is as shown in Figure of description 4.
Crystal formation Ⅹ the most according to claim 1, it is characterised in that the fusing point of this crystal formation is 89.8-90.4 DEG C.
The preparation method of crystal formation Ⅹ the most according to claim 1 and 2, it is characterised in that the method comprises the following steps:
(1) according to 1:2-8 w/v will (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine- 2-yl) acetas adds in petroleum ether acetonitrile mixture, and wherein acetonitrile accounts for the 10%~40% of mixed liquor cumulative volume, in stirring Lower 30 DEG C~65 DEG C of heating for dissolving, filter;
(2) filtrate that step (1) filters gained at room temperature places 2-10h crystallize, collected by filtration, is dried, obtains institute State crystal formation Ⅹ.
Preparation method the most according to claim 3, it is characterised in that in step (1), described w/v is 1:5; In the mixed liquor of petroleum ether acetonitrile, acetonitrile accounts for the 20% of mixed liquor cumulative volume;Preferably, under agitation it is heated to 45 DEG C, analysis Brilliant 6h.
5. a pharmaceutical composition, it is characterised in that described pharmaceutical composition comprises described in the claim 1 or 2 of effective dose Crystal formation Ⅹ and one or more pharmaceutically acceptable adjuvants.
Pharmaceutical composition the most according to claim 5, it is characterised in that described pharmaceutical composition be solid orally ingestible, Liquid oral medicine or injection.
Pharmaceutical composition the most according to claim 6, it is characterised in that described solid orally ingestible includes dispersible tablet, intestinal Molten, chewable tablet, oral cavity disintegration tablet, capsule or granule;Described liquid oral medicine includes oral solution;Described injection includes Injection liquid drugs injection, injection freeze-dried powder, infusion solutions or primary infusion.
8. the crystal formation Ⅹ described in claim 1 or 2 or the crystal formation Ⅹ prepared according to the method described in claim 3 or 4 are in system The purposes being ready for use in the pharmaceutical composition of antiplatelet aggregation.
9. crystal formation Ⅹ described in claim 1 or 2 or the crystal formation Ⅹ prepared according to the method described in claim 3 or 4 are in preparation The coronary syndrome that causes because of antiplatelet aggregation for treatment, myocardial infarction, myocardial ischemia, cardiovascular and cerebrovascular disease Purposes in pharmaceutical composition.
CN201610118735.3A 2016-03-02 2016-03-02 Crystal form X of Tipidogrel free alkali and preparation method and application thereof Pending CN105777774A (en)

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