CN106478608A - The crystalline polymorph of the husky sulfate of Walla handkerchief - Google Patents
The crystalline polymorph of the husky sulfate of Walla handkerchief Download PDFInfo
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- CN106478608A CN106478608A CN201510551080.4A CN201510551080A CN106478608A CN 106478608 A CN106478608 A CN 106478608A CN 201510551080 A CN201510551080 A CN 201510551080A CN 106478608 A CN106478608 A CN 106478608A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention provides a kind of crystalline polymorph A of the husky sulfate of Walla handkerchief, shows the powder x ray diffraction pattern of the characteristic peak locations with 12.1,15.5,19.3 and 20.8 degree of 2 θ.The stability of crystal form is good, long-term placement, seldom produces degradation impurity.Present invention also offers the preparation method of above-mentioned crystal formation and the purposes in medicine is prepared.The preparation method is easy to operate, and technology stability is good, and the product purity of preparation is high, is suitable for industrialized production.
Description
Technical field
The present invention relates to the crystalline polymorph of the husky sulfate of Walla handkerchief, and the preparation method and application of crystalline polymorph.
Background technology
Walla handkerchief is husky（English name：Vorapaxar, trade name：Zontivity）It is a kind of novel protease activated receptor 1（PAR-1）Antagonist, can suppress coagulation process.PAR-1 be a kind of can be by the acceptor of thrombin activation, and fibrin ferment is a kind of effective platelet activating agent.Walla handkerchief sand can suppress blood platelet PAR-1 acceptor, so as to suppress the platelet aggregation of thrombin induction.
WO03089428 discloses the husky structure having as shown in Formula Il of Walla handkerchief,
,
Compound II shows good thrombin receptor antagonist activity and selectivity, and dares to quality thrombosis, other cardiovascular and non-cardiovascular conditions.2014.05.08 by FDA approval listing, there is the patient of blocking for the patient that had a heart attack or leg arteries, to reduce further heart attack, apoplexy, cardiovascular death and need the risk of operation.
The numerous patents such as WO2008005348, WO2009055416 and WO2006076564 disclose the husky synthetic method of Walla handkerchief.
Report at present with regard to the crystal formation research of husky or its sulfate of Walla handkerchief is fewer, only WO2005070923 discloses Walla handkerchief sand sulfate and has the structure shown in following formula I, and disclose the crystalline polymorph 1 and 2 of the sulfate, point out in the document that polymorphic Form 2 is unstable, and over time changes into the crystalline texture of form I
.
Research compound I crystalline polymorph, prepares stable crystal form be beneficial, and for exploitation be suitable for preparation process requirement（As good stability, moisture absorption is difficult, is more suitable for making tablet）There is provided more crystal formations select be also significantly.
Content of the invention
The invention provides a kind of crystalline polymorphs A of following formula: compound I：
,
Which shows the powder x ray diffraction pattern of the characteristic peak locations with 12.1,15.5,19.3 and 20.8 degree of 2 θ.
It is highly preferred that the powder x ray diffraction pattern of the crystalline polymorph A has the characteristic peak locations of 12.1,15.5,19.3,19.7,20.8,24.0,24.4 and 25.8 degree of 2 θ.
In another embodiment, the invention provides the crystalline polymorph A of compound I, the powder x ray diffraction pattern shown in its powder x ray diffraction pattern and Fig. 1 is essentially identical.
In another embodiment, present invention also offers the crystalline polymorph A of compound I, which shows the means of differential scanning calorimetry pattern essentially identical with the means of differential scanning calorimetry pattern of display in Fig. 2.
In another embodiment, the invention provides a kind of preparation method of the crystalline polymorph A of compound I,
,
Which includes,
a）Compound II is dissolved in stirring in acetonitrile and forms mixture；
b）Heating mixture is to 50 DEG C ~ 70 DEG C；
c）Sulfuric acid is added in the mixture of heating；
d）System temperature is down to 0 DEG C ~ 20 DEG C, is added crystal seed and stirs, separate out crystal.
Preferably, in said method, c）Sulfuric acid be with the form of mixtures with acetonitrile；It is highly preferred that d）The crystal of precipitation is filtered, after filter cake is washed with acetonitrile, gained solid precipitation 2 hours at 40 DEG C, and then it is vacuum dried 12 hours then at 80 DEG C, obtains the polymorph A for crystallizing.
Wherein, the crystal seed can be prepared using following methods：By compound I（1.0 g）5.0 ml acetonitriles are dissolved in, stirring is simultaneously heated to 50 DEG C ~ 70 DEG C through solution, treat that system is molten clear, then by system precipitation, dry, gained white solid grind into powder, this powder are used as the crystal seed for preparing novel crystal forms.
In another embodiment, present invention also offers the pharmaceutical composition of the crystalline polymorph A of inclusion compound I, the crystalline polymorph A of its inclusion compound I and at least one excipient or carrier.Inert pharmaceutical acceptable carrier can be solid or liquid.Solid form preparations include powder, tablet, dispersible particle, capsule and suppository.Powder and tablet can include 0.1 ~ about 95% active component.Suitable solid carrier is known in the art, as microcrystalline cellulose, sugar or lactose.Tablet, powder and capsule can serve as being suitable to the solid dosage forms of oral administration.The production method of pharmaceutically useful Examples of carriers and numerous compositions can part A. Gennaro (ed.), The Science and Practice of Pharmacy, 20th
Edition, Lippincott Williams &Wilkins, Baltimore, MD, (2000).
The preparation of liquid form includes solution, suspension and emulsion.Can be mentioned that for parenteral injection water or water-propylene glycol solution as example or count sweetener and opacifier for oral solutions, suspension and emulsion.Liquid form preparation can also include solutions for intranasal administration.Also include the aerosol preparations for being suitable to suck, the preparation of solid form, its will be closed on using forward chemical conversion liquid form again for oral or parenteral administration, and such liquid form includes solution, suspension and emulsion.
In other embodiments, it is preferable that the pharmaceutical composition oral administration that the present invention is provided.Preferably, pharmaceutical preparation is unit formulation.It is further preferred that described pharmaceutical composition is tablet or capsule.
Pharmaceutically acceptable excipient or carrier include flavor enhancement, pharmaceutical grade dyes or pigment, solvent, cosolvent, buffer system, surfactant, preservative, sweetening agent, filler, lubricant, glidant, disintegrant adhesive etc..The pharmaceutical composition of the present invention generally comprises about 0.1% ~ 99.9% solvent.Preferred solvent is water.Preferred cosolvent includes ethanol, glycerine, propane diols, polyethylene glycol etc..The pharmaceutical composition of the present invention can include about 0% ~ 50% cosolvent.Preferred buffer system is comprising acetic acid, boric acid, carbonic acid, phosphoric acid, butanedioic acid, malic acid, tartaric acid, citric acid, acetic acid, benzoic acid, lactic acid, glyceric acid, gluconic acid, glutaric acid and glutamic acid and their sodium, potassium and ammonium salt.The pharmaceutical composition of the present invention generally comprises about 0% ~ 5% buffer solution.Preferred surfactant is comprising polyoxyethylene sorbitan fatty acid ester, polyoxyethylene monoalkyl ethers, sucrose monoester and lanolin ester and ether, the alkyl sulfate of aliphatic acid and sodium, potassium and ammonium salt.The pharmaceutical composition of the present invention generally comprises about 0% ~ 2% surfactant.Preferred preservative is comprising phenol, the Arrcostab of P-hydroxybenzoic acid, o-phenylphenol benzoic acid and its salt, boric acid and its salt, sorbic acid and its salt etc..Pharmaceutical composition of the present invention generally comprises about 0% ~ 2% preservative.Sweetener includes but is not limited to sucrose, glucose.Saccharin, mannitol and Aspartame, the pharmaceutical composition of the present invention generally comprise 0% ~ 5% sweetener.Filler includes but is not limited to lactose, mannitol, D-sorbite, tertiary calcium phosphate, secondary calcium phosphate, starch, compressible sugar, microcrystalline cellulose.The pharmaceutical composition of the present invention generally comprises about 0% ~ 90% filler.Lubricants/glidants include but is not limited to magnesium stearate, stearic acid and talcum powder.The pharmaceutical composition of the present invention generally comprises about 0% ~ 7%, preferably 1% ~ 5% lubricants/glidants.Disintegrant includes but is not limited to starch, sodium starch glycollate, polyvinylpyrrolidone and Ac-Di-Sol and microcrystalline cellulose.The pharmaceutical composition of the present invention generally comprises about 0% ~ 20%, preferably 4% ~ 15% disintegrant.
Generally comprise the active component of about 0.1% ~ 99.9% (weight or volume meter) in pharmaceutical composition, preferably from about 5% ~ 95%, more there is the active component of choosing about 20% ~ 80%.
In other embodiments, the invention provides the method for suppression thrombin receptor, which includes that the mammal to the such treatment of needs applies the crystalline polymorph A of the compound I of effective dose.
In other embodiments, the invention provides the method for the treatment of thrombosis, atherosclerotic, ISR, hypertension, angina pectoris, heart failure, myocardial infarction, glomerulonephritis, tbrombotic stroke, peripheral artery disease, inflammatory conditions, cerebral ischemia or cancer, which includes that the mammal to the such treatment of needs applies the crystalline polymorph A of the compound I of effective dose.
In other embodiments, the invention provides treatment thrombosis, atherosclerotic, ISR, hypertension, angina pectoris, heart failure, myocardial infarction, glomerulonephritis, tbrombotic stroke, peripheral artery disease, inflammatory conditions, cerebral ischemia or the method for cancer, which includes that the mammal in conjunction to the such treatment of needs applies the crystalline polymorph A of the compound I of effective dose and at least one extra Cardiovascular agents, at least one extra Cardiovascular agents are preferably thromboxane A2 biosynthesis inhibitor, GP IIb/IIa antagonist, thromboxane antagonist, adenosine diphosphate inhibitor, inhibitors of cyclooxygenases, angiotensin antagonist, endothelium contracting blood vessel element antagonist, ACEI, anti-coagulants, diuretics and RA233 etc..It is highly preferred that at least one extra Cardiovascular agents are aspirin or clopidogrel hydrogenesulphate.
In pharmaceutical composition of the present invention, the daily dose of the crystalline polymorph A of inclusion compound I is for about 0.001 ~ 100mg/kg body weight/day, preferably from about 0.001 ~ 10mg/kg body weight/day.For the average weight of 70kg, therefore dosage level is for about 0.1 ~ 700mg medicine/day, with single dose or 2 ~ 4 separate administration.In unit dose preparation, the amount of the crystalline polymorph A of compound I can be adjusted according to concrete application, for about 0.01mg ~ 4000mg, preferably from about 0.02mg ~ 2000mg, more preferably from about 0.03mg ~ 1000mg even more preferably 0.04mg ~ 500mg, most preferably 0.05mg ~ 250mg.The general recommended of oral administration about 0.02mg ~ 2000mg/ days, with twice or four separate agent time.Its amount of application and frequency are adjusted according to the judgement of attending clinicians, it is considered to the factor such as seriousness at age, situation and size and the symptom that is just treating of factor such as patient.
The powder x-ray diffraction of the crystalline polymorph A of heretofore described compound I（XRPD）The curve map of pattern is to use Panalytical（PANalytical）The EMPYREAN of company
Type X x ray diffractometer x.Will be evenly laid out on monocrystal silicon sample disk for about 10 milligrams of samples, XRPD test is carried out with table 1 below characterising parameter.
Table 1：XRPD sweep parameter
.
Walla handkerchief sand sulfate of the present invention, compound I refer to the compound with following structure：
.
Polymorphism can be characterized as compound and different crystal forms are crystallized into, while keeping the ability of identical chemical formula.Other crystalline polymorphs any of the crystalline polymorphs story drug substance of given drug substance are identical in chemistry, show as them and contain the same atoms be combineding with each other in the same manner, but crystal form is different, this can affect one or more physical property, such as stability, dissolubility, fusing point, bulk density, flowing property, bioavilability etc..
Compound I can be present including hydrate forms with unsolvated and solvate form thereof.In the present invention, generally, with medicinal solvent, such as water, ethanol equal solvent solvate form are equal to unsolvated form.
Term " polymorph " refers to the material of crystal form, but its total identical chemical formula different from another kind of crystal form." excipient " refer to as diluent or when preparation produce the substantially inert material of proterties or denseness." effective " or " therapeutically effective amount " is intended to describe effective antagonizing thrombin acceptor and thereby generation is so the compound of the present invention or the amount of composition of the treatment, improvement, suppression or the preventive effect that are.
The XRPD peak position of the crystalline polymorph A of compound I is as shown in table 2：
.
The measurement of the XRPD peak position of the given crystal form of identical compound well known by persons skilled in the art will the interior variation of error span again.With instrument to collect the collimation technique of these data within the scope of industrial standard, but need not be as so strict in art technology state.The fact that can change in view of sample preparation technology and can measure peak position with other analytical instrument, so the error span of about ± 0.5 degree of 2 θ of data above.Standard sample technology of preparing, same analysis instrument use and the instrument high precision calibration can increase repeatable to about ± 0.3 degree of 2 θ or less.
DSC collection of illustrative plates is gathered on TA Q200 differential scanning calorimeter, and test parameters is as shown in table 3 below.
Table 3：DSC test parameters
.
Report in CN101899039B that the use using isopropanol, acetone, acetonitrile, ethyl acetate, isopropyl acetate and tetrahydrofuran as the solvent in said method all produces the crystalline polymorph of form 1.The invention provides a kind of preparation method of the new crystalline polymorphic form A and crystalline polymorph A of compound I.Inventor passes through multiple batches of verification experimental verification, finds the good stability of crystalline polymorph A, and reproducibility is good, crystalline polymorph A in tablet manufacture, good fluidity, it is easier to be molded.The preparation method of the crystalline polymorph A that the present invention is provided is simple, it is easy to operate, low cost, process stabilizing, and the product purity that produces is high, quality controllable.
Description of the drawings
Fig. 1 shows the powder x-ray diffraction of the crystalline polymorph A of compound I prepared by embodiment method 1 on time（XRPD）The curve map of pattern.
Fig. 2 shows the differential scanning calorimetry of the crystalline polymorph A of compound I prepared by embodiment method 1 on time（DSC）Differential thermogram.
Fig. 3 shows the HPLC spectrogram of the crystalline polymorph A of compound I prepared by 1 method of embodiment on time.
Fig. 4 shows the curve map of the XRPD pattern of the crystalline polymorph A of compound I prepared by 2 method of embodiment on time.
Fig. 5 shows that the polymorph A for preparing embodiment 1 is carried out after stability study, the HPLC spectrogram of measure.
Fig. 6 shows that the polymorph A for preparing embodiment 1 is carried out after stability study, the curve map of the XRPD pattern of measure.
Specific embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are only illustrative of the invention and is not intended to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, generally according to normal condition or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise all of percentage, ratio, ratio or number be by weight.
Unless otherwise defined, all specialties used in text are identical with meaning familiar to one skilled in the art institute with scientific words.Additionally, any method similar or impartial to described content and material are all can be applicable in the inventive method.Preferable implementation described in text is only presented a demonstration with material and is used.
Embodiment
1
Compound
I
Crystalline polymorph
A
Preparation
By compound II（1.0g）5.0ml acetonitrile is dissolved in, stirring is simultaneously heated to 50 DEG C ~ 70 DEG C through solution, and 1.2ml 2N H is added at a temperature of this in solution2SO4/ acetonitrile, then 15 DEG C ~ 20 DEG C are down to system temperature, appropriate crystal seed being added in system and stirring 2h, the solid for separating out is filtered, filter cake is washed twice with 2.5ml acetonitrile, obtain white solid, white solid is placed in precipitation 2 hours at 40 DEG C, is then vacuum dried at 80 DEG C, obtains 0.83 g of white solid, yield 69.3%, HPLC：99.94%.Its powder x-ray diffraction spectrogram is as shown in figure 1, dsc endothermic curve is as shown in Fig. 2 its HPLC spectrogram is as shown in Figure 3.
Wherein, HPLC peak data is as shown in table 4 below, and powder x-ray diffraction spectrum peak position is as shown in table 5.
Table 4：HPLC peak data
.
Table 5：XRPD peak position
.
Embodiment
2
Compound
I
Crystalline polymorph
A
Preparation
By compound II（1.0g）5.0ml acetonitrile is dissolved in, stirring is simultaneously heated to 60 DEG C ~ 70 DEG C through solution, and 1.2ml 2N H is added at a temperature of this in solution2SO4/ acetonitrile, then 10 DEG C ~ 15 DEG C are down to system temperature, appropriate crystal seed being added in system and stirring 2h, the solid for separating out is filtered, filter cake is washed twice with 2.5ml acetonitrile, obtain white solid, white solid is placed in precipitation 2 hours at 40 DEG C, is then vacuum dried at 80 DEG C, obtains 0.83 g of white solid, yield 69.3%, HPLC：99.8%.Its powder x-ray diffraction spectrogram is as shown in Figure 4.
Embodiment
3
Stability test
Polymorph A prepared by embodiment 1 was placed in 0 DEG C ~ 5 DEG C sealing avoid light places after 6 months, and detection is not degraded substantially, and its HPLC purity is that 99.92%, HPLC spectrogram is as shown in Figure 5；Its HPLC peak data is as shown in table 6 below：
Table 6：HPLC peak data
.
Taking the sample carries out crystal formation detection, and the XRPD spectrogram that its powder x-ray diffraction spectrogram shows with embodiment 1 is determined is basically identical, concrete as shown in fig. 6, its XRPD main peak position is as shown in table 7：
Table 7：XRPD main peak position
.
Embodiment
4
Compound
I
Crystalline polymorph
A
Preparation
By compound II（1.0g）5.0ml acetonitrile is dissolved in, stirring is simultaneously heated to 60 DEG C ~ 70 DEG C through solution, and 1.2ml 2N H is added at a temperature of this in solution2SO4/ acetonitrile, then 5 DEG C ~ 10 DEG C are down to system temperature, appropriate crystal seed being added in system and stirring 2h, the solid for separating out is filtered, filter cake is washed twice with 2.5ml acetonitrile, obtain white solid, white solid is placed in precipitation 2 hours at 40 DEG C, is then vacuum dried at 80 DEG C, obtains 0.83 g of white solid, yield 75.4%, HPLC：99.95%.
Embodiment
5
Compound
I
Crystalline polymorph
A
Preparation
By compound II（1.0g）5.0ml acetonitrile is dissolved in, stirring is simultaneously heated to 60 DEG C ~ 70 DEG C through solution, and 1.2ml 2N H is added at a temperature of this in solution2SO4/ acetonitrile, then 0 DEG C ~ 5 DEG C are down to system temperature, appropriate crystal seed being added in system and stirring 2h, the solid for separating out is filtered, filter cake is washed twice with 2.5ml acetonitrile, obtain white solid, white solid is placed in precipitation 2 hours at 40 DEG C, is then vacuum dried at 80 DEG C, obtains 0.83 g of white solid, yield 75.4%, HPLC：99.91%.
It will be appreciated by those skilled in the art that can be changed the embodiment above without departing from inventive concept.Thus, it will be appreciated that the invention is not restricted to above-mentioned specific embodiment, and it is intended to cover the modification in spirit and scope of the invention, as limited by the word of claims below.
Claims (8)
1. the crystalline polymorphs A of following formula: compound I：
,
Which shows the powder x ray diffraction pattern of the characteristic peak locations with 12.1,15.5,19.3 and 20.8 degree of 2 θ.
2. the crystalline polymorphs A of compound I according to claim 1, which shows the powder x ray diffraction pattern of the characteristic peak locations with 12.1,15.5,19.3,19.7,20.8,24.0,24.4 and 25.8 degree of 2 θ.
3. the crystalline polymorphs A of compound I according to claim 1, its show the powder x ray diffraction pattern essentially identical with the powder x ray diffraction pattern that shows in Fig. 1.
4. the crystalline polymorphs A of following formula: compound I：
,
Which shows the means of differential scanning calorimetry pattern essentially identical with the means of differential scanning calorimetry pattern of display in Fig. 2.
5. the preparation method of the crystalline polymorphs A of compound I described in a kind of claim 1,
,
Which includes：
a）Compound II is dissolved in stirring in acetonitrile and forms mixture；
b）Heating mixture is to 50 DEG C ~ 70 DEG C；
c）Sulfuric acid is added in the mixture of heating；
d）System temperature is down to 0 DEG C ~ 20 DEG C, is added crystal seed and stirs, separate out crystal.
6. method, wherein c according to claim 5）Sulfuric acid be with the form of mixtures with acetonitrile.
7. method, wherein d according to claim 5）The crystal of precipitation is filtered, and after filter cake wash with acetonitrile, gained solid precipitation at 40 DEG C, after 2 hours, is vacuum dried 12 hours then at 80 DEG C, obtains the polymorph A of crystallization.
8. the pharmaceutical composition of the crystalline polymorph A of compound I described in claim 1 is included, and wherein described pharmaceutical composition is tablet or capsule.
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| CN201510551080.4A CN106478608A (en) | 2015-09-01 | 2015-09-01 | The crystalline polymorph of the husky sulfate of Walla handkerchief |
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| CN201510551080.4A CN106478608A (en) | 2015-09-01 | 2015-09-01 | The crystalline polymorph of the husky sulfate of Walla handkerchief |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003089428A1 (en) * | 2002-04-16 | 2003-10-30 | Schering Corporation | Tricyclic thrombin receptor antagonists |
| CN1910176A (en) * | 2004-01-09 | 2007-02-07 | 先灵公司 | Crystalline polymorph of a bisulfate salt of a thrombin receptor antagonist |
| CN101137647A (en) * | 2005-01-14 | 2008-03-05 | 先灵公司 | Synthesis of himbacine analogs |
-
2015
- 2015-09-01 CN CN201510551080.4A patent/CN106478608A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003089428A1 (en) * | 2002-04-16 | 2003-10-30 | Schering Corporation | Tricyclic thrombin receptor antagonists |
| CN1910176A (en) * | 2004-01-09 | 2007-02-07 | 先灵公司 | Crystalline polymorph of a bisulfate salt of a thrombin receptor antagonist |
| CN101137647A (en) * | 2005-01-14 | 2008-03-05 | 先灵公司 | Synthesis of himbacine analogs |
Non-Patent Citations (1)
| Title |
|---|
| 倪坤仪: "《药物分析学》", 31 March 2000, 长春出版社 * |
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Application publication date: 20170308 |