CN104411691B - ACT-064992 crystal and preparation method thereof, its pharmaceutical composition and purposes - Google Patents

ACT-064992 crystal and preparation method thereof, its pharmaceutical composition and purposes Download PDF

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CN104411691B
CN104411691B CN201480001614.XA CN201480001614A CN104411691B CN 104411691 B CN104411691 B CN 104411691B CN 201480001614 A CN201480001614 A CN 201480001614A CN 104411691 B CN104411691 B CN 104411691B
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劳海萍
盛晓霞
盛晓红
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HANGZHOU PUSHA PHARMACEUTICAL TECHNOLOGY Co Ltd
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The present invention relates to the novel crystal forms of ACT-064992, described novel crystal forms has dominance aspect solubility. The preparation method, its pharmaceutical composition who the invention still further relates to described novel crystal forms with and purposes in the medicine for the preparation for the treatment of hypertension, pulmonary hypertension.

Description

ACT-064992 crystal and preparation method thereof, its pharmaceutical composition and purposes
Technical field
The application relates to pharmaceutical chemistry crystallization technique field. More specifically, the application relates to ACT-064992Novel crystal forms, comprises ACT-064992 crystal form II, ACT-064992 methylate crystal, ACT-064992 nitromethaneCompound crystal and ACT-064992 methyl tertbutyl etherate crystal, with and its production and use.
Background technology
On October 18th, 2013, the approval U.S. of FDA (Food and Drug Adminstration) (FDA) is liked can ACE Semi(Actelion) the new drug ACT-064992 (trade name Opsumit) of drugmaker is used for the treatment of pulmonary hypertension(PAH) adult patient. PAH is a kind of pulmonary hypertension (PH) of particular type, belongs to world health groupKnitting (WHO) classification I level to PH, is a kind of serious, gradual and life-threatening lung bloodGuard system disease, is characterized in that the abnormal increasing of smooth muscle cell in vessel retraction extremely and pulmonary arterial wallRaw. ACT-064992 is a kind of two-way (ETA/ETB) endothelin-receptor antagonists, to vascular smooth muscleShrink and breeder reaction bring into play inhibitory action, can delay PAH PD, PD comprise death,Vein or hypodermic injection prostacyclin class medicine or PAH severity of symptoms (comprise 6 minutes walking distances decline,The PAH symptom worsening and the symptom that needs other PAH medicines to treat). Opsumit is that 10mg is oralTablet, approval dosage is 10mg/ day.
ACT-064992, English name is Macitentan, chemical name is N-[5-(4-bromophenyl)-6-[2-[(5-Bromo-2-pyrimidine radicals) oxygen base] ethyoxyl]-4-pyrimidine radicals]-N '-sulfonyl propyl amine, it has following structural formula:
Patent documentation US7,094,781 has described structural formula and the synthetic method thereof of ACT-064992. DocumentJ.Med.Chem.2012, mentions the ACT-064992 product fusing point that crystallization obtains in methyl alcohol in 55,7849 and is135-136 DEG C, for convenient, below is called the crystal formation in the document " crystal formation I ".
The inventor finds that crystal formation I is hydrophobic under study for action, solubility extreme difference in water, its tablet strippingSpeed is slow, and these character may limit oral rear active component and reach concentration and the speed in patient's blood flow,Affect drug effect.
Therefore, the novel crystal forms of ACT-064992 need to be developed in this area.
Summary of the invention
The object of this invention is to provide the novel crystal forms of ACT-064992, solve the problem that known crystal formation exists,And provide preparation method, its pharmaceutical composition and the purposes of described novel crystal forms.
The novel crystal forms of ACT-064992 provided by the invention, comprises ACT-064992 crystal form II, ACT-064992 methyl alcoholCompound crystal, ACT-064992 nitromethane compound crystal and ACT-064992 methyl tertbutyl etherate crystal.Compare known crystal formation, described novel crystal forms has at least one following favourable character: higher degree of crystallinity,Larger solubility, dissolution rate faster, particle shape is good, is difficult for occurring polymorphic inversion, calorificsCompressibility and table with good mechanical stability, agent of low hygroscopicity, better mobility, suitable formulations applicationSee that density, storage stability are good, low-residual solvent etc.
According to object of the present invention, the invention provides ACT-064992 crystal form II (hereinafter referred to as " crystal form II ") andIts preparation method.
Use Cu-K α radiation, the X-ray powder diffraction of described crystal form II the angle of diffraction 2 θ be 8.9 ± 0.2 °,Locate characteristic peak for 11.5 ± 0.2 °, 14.1 ± 0.2 °, 18.7 ± 0.2 °, 19.6 ± 0.2 ° and 25.4 ± 0.2 °.
Typically, the X-ray powder diffraction of described crystal form II the angle of diffraction 2 θ be 8.9 ± 0.2 °,11.5±0.2°、12.4±0.2°、14.1±0.2°、15.2±0.2°、17.8±0.2°、18.7±0.2°、19.6±0.2°、Locate characteristic peak for 20.2 ± 0.2 °, 21.4 ± 0.2 °, 24.1 ± 0.2 ° and 25.4 ± 0.2 °.
Preferably, the X-ray powder diffraction of described crystal form II have at the following angle of diffraction 2 θ places characteristic peak andIts relative intensity:
Without limitation, described crystal form II representative instance has X-ray powder diffraction pattern as shown in Figure 3.
Described crystal form II has at least one following characteristic:
The poor formula scanning amount thermal map (DSC) of crystal form II shows: fusing point is 106 DEG C;
Thermogravimetric analysis (TGA) collection of illustrative plates of crystal form II shows: before 130 DEG C, substantially without weightless, be anhydride,Decomposition temperature is 150 DEG C;
The dynamic moisture content absorption figure of crystal form II shows: the changes in weight within the scope of 20%～80% relative humidity is1.5%, be difficult for moisture absorption.
Described crystal form II has following beneficial property:
(1), compared with known ACT-064992 crystal formation I, adding Surfactant SDSOr in the situation of Tween-80 (Tween-80), the solubility of crystal form II in water is much larger than known (SDS)The solubility of crystal formation I in water;
(2) in the situation that prescription is consistent, the tablet of crystal form II of the present invention is than the tablet stripping of known crystal formation ISpeed is fast;
(3) crystal form II is lower than the fusing point of crystal formation I, is applicable to hot-melt extruded method;
(4) crystal form II is difficult for moisture absorption;
The above-mentioned character of crystal form II shows: compared with known ACT-064992 crystal formation I, and Ma Xi of the present inventionThere is better solubilizing effect, higher solubility and dissolution rate faster for smooth crystal form II, suchCharacter makes formulation application more effective, can improve bioavilability the positive influences of active component and liveThe pharmacokinetic property of property composition, can reach maximum plasma concentration after oral quickly, brings into play at needsPosition onset more quickly in the body of its effect; The fusing point of crystal form II is low, is more suitable for hot-melt extruded method; BrilliantType II has the hygroscopicity of being difficult for, and can resist better in the processes such as medicine manufacture and/or storage and be wet by environmentDegree causes the problems such as the inhomogeneous and purity reduction of the content of active component, reduces the curative effect brought thusDownside risk and security risk, and be conducive to accurate quantitative analysis in unit formulation preparation and the transport in later stage andStore.
The preparation method of the crystal form II of ACT-064992, comprises the following steps: ACT-064992 is suspended in to methyl alcoholMiddle formation suspension, carries out stirring and crystallizing, then the solid of separating out is separated, is greater than at 60 DEG C dry,Obtain the crystal form II of described ACT-064992.
Preferably, the consumption of described ACT-064992 is that every ml methanol adds 10-250mg ACT-064992; MorePreferred every ml methanol adds 10-100mg ACT-064992.
Preferably, described recrystallization temperature is room temperature to 60 DEG C; More preferably room temperature.
Preferably, the described crystallization time is 1-14 days; More preferably 1-7 days.
Preferably, described baking temperature is 70 DEG C-120 DEG C; More preferably 70 DEG C-100 DEG C.
Preferably, be 1-72 hour described drying time; More preferably 1-24 hour.
According to object of the present invention, the invention provides the methylate crystal of ACT-064992 (hereinafter referred to as " methyl alcoholCompound crystal ") and preparation method thereof.
In ACT-064992 methylate crystal provided by the invention, per molecule ACT-064992 band has an appointment 1/2～1Individual methanol molecules, for example, be: per molecule ACT-064992 band 2/3 methanol molecules of having an appointment.
Use Cu-K α radiation, the X-ray powder diffraction of described methylate crystal at the angle of diffraction 2 θ isLocate characteristic peak for 8.9 ± 0.2 °, 11.3 ± 0.2 °, 13.9 ± 0.2 °, 18.6 ± 0.2 °, 19.3 ± 0.2 ° and 25.3 ± 0.2 °.
Typically, the X-ray powder diffraction of described methylate crystal the angle of diffraction 2 θ be 8.9 ± 0.2 °,11.3±0.2°、12.4±0.2°、13.9±0.2°、15.2±0.2°、18.6±0.2°、18.9±0.2°、19.3±0.2°、Locate characteristic peak for 20.1 ± 0.2 °, 21.2 ± 0.2 °, 24.0 ± 0.2 ° and 25.3 ± 0.2 °.
Preferably, the X-ray powder diffraction of described methylate crystal has spy at the following angle of diffraction 2 θ placesLevy peak and relative intensity thereof:
Without limitation, described methylate crystal representative instance has X-ray as shown in Figure 8Powder diagram.
Compared with known ACT-064992 crystal formation I, described methylate crystal has following beneficial property:
(1) in the situation that adding surfactant SDS or Tween-80, methylate crystal is in waterSolubility is the solubility in water much larger than known crystal formation I.
(2) methylate crystal there is good granule-morphology and particle larger.
The above-mentioned character of methylate crystal shows: compared with known ACT-064992 crystal formation I, of the present inventionACT-064992 methylate crystal has better solubilizing effect, higher solubility, can improve activityThe bioavilability of composition, makes formulation application more effective; Granule-morphology, is convenient to bulk drug preferablyIsolated by filtration, preparation processing in the operation such as sieve, enhance productivity, batch good stability. ?Large particle has better preparation machinability, can be used for direct powder compression, has avoided wet granulationThe impact of solvent on bulk drug, is conducive to the control of the quality of the pharmaceutical preparations, improves batch stability.
The preparation method of the methylate crystal of ACT-064992, comprises the following steps: ACT-064992 is suspendedIn methyl alcohol, form suspension, carry out stirring and crystallizing, then the solid of separating out is separated, room temperature vacuum is dryDry, obtain the methylate crystal of described ACT-064992.
Preferably, the consumption of described ACT-064992 is that every ml methanol adds 10-250mg ACT-064992; MorePreferred every ml methanol adds 10-100mg ACT-064992.
Preferably, described recrystallization temperature is room temperature to 60 DEG C; More preferably room temperature.
Preferably, the described crystallization time is 1-14 days; More preferably 1-7 days.
Preferably, be 1-72 hour described drying time; More preferably 1-24 hour.
According to object of the present invention, the invention provides ACT-064992 nitromethane compound crystal (hereinafter referred to as" nitromethane compound crystal ") and preparation method thereof.
In ACT-064992 nitromethane compound crystal provided by the invention, per molecule ACT-064992 band has an appointment 1/2Individual nitromethane molecule.
Use Cu-K α radiation, the X-ray powder diffraction of described nitromethane compound crystal is at the angle of diffraction 2 θBe 11.5 ± 0.2 °, 14.0 ± 0.2 °, 15.3 ± 0.2 °, 18.6 ± 0.2 °, 21.2 ± 0.2 ° and 25.5 ± 0.2 ° and located spyLevy peak.
Typically, the X-ray powder diffraction of described nitromethane compound crystal at the angle of diffraction 2 θ is8.9±0.2°、11.5±0.2°、12.4±0.2°、14.0±0.2°、15.3±0.2°、18.6±0.2°、19.0±0.2°、Locate characteristic peak for 19.5 ± 0.2 °, 20.1 ± 0.2 °, 21.2 ± 0.2 °, 24.2 ± 0.2 ° and 25.5 ± 0.2 °.
Preferably, the X-ray powder diffraction of described nitromethane compound crystal is at the following angle of diffraction 2 θ place toolsThere are characteristic peak and relative intensity thereof:
Without limitation, a representative instance of described nitromethane compound crystal has as shown in figure 10X-ray powder diffraction pattern.
Described nitromethane compound crystal has following beneficial property:
(1) compared with known ACT-064992 crystal formation I, adding surfactant SDS or Tween-80In situation, the solubility of nitromethane compound crystal in water is the solubility in water much larger than known crystal formation I.
(2) in nitromethane compound crystal, do not contain ethanol, be suitable for the crowd of ethanol allergy to use.
The above-mentioned character of nitromethane compound crystal shows: compared with known ACT-064992 crystal formation I, thisBright ACT-064992 nitromethane compound crystal has better solubilizing effect, higher solubility, Ke YitiThe bioavilability of high activity composition, makes formulation application more effective. And nitromethane compound crystalIn containing ethanol, be well-adapted for the patient of ethanol allergy.
The preparation method of the nitromethane compound crystal of ACT-064992, comprises the following steps: by ACT-064992Be suspended in the water saturation solution of nitromethane and form suspension, carry out stirring and crystallizing, then will separate outSolid separates, is dried, and obtains the nitromethane compound crystal of described ACT-064992.
Preferably, in the water saturation solution that the consumption of described ACT-064992 is every milliliter of nitromethane, add1-100mg ACT-064992; More preferably in the water saturation solution of every milliliter of nitromethane, add 1-50mg Ma XiFor smooth.
Preferably, described recrystallization temperature is room temperature to 60 DEG C; More preferably room temperature.
Preferably, the described crystallization time is 1-14 days; More preferably 1-7 days.
Preferably, described baking temperature is room temperature to 80 DEG C; More preferably 40 DEG C.
Preferably, the described dry time is 1-48 hour; More preferably 1-24 hour.
The water saturation solution of described nitromethane, concrete compound method is: get 10-20ml water, add 10-20mlNitromethane, stirs 10-24 hour under room temperature, leaves standstill water intaking layer after 0.5-2 hour.
According to object of the present invention, the methyl tertbutyl etherate crystal that the invention provides ACT-064992 is (followingBe called " methyl tertbutyl etherate crystal ") and preparation method thereof.
In ACT-064992 methyl tertbutyl etherate crystal provided by the invention, per molecule ACT-064992 withApproximately 1/3～1/2 methyl tertiary butyl ether(MTBE) molecule, for example per molecule ACT-064992 is with 1/3 methyl tertbutylEther molecule.
Use Cu-K α radiation, the X-ray powder diffraction of described methyl tertbutyl etherate crystal is at diffractionAngle 2 θ are 5.7 ± 0.2 °, 6.9 ± 0.2 °, 9.7 ± 0.2 °, 16.7 ± 0.2 ° and 25.3 ± 0.2 ° and have located characteristic peak.
Typically, the X-ray powder diffraction of described methyl tertbutyl etherate crystal at the angle of diffraction 2 θ is5.7±0.2°、6.9±0.2°、9.7±0.2°、11.6±0.2°、14.0±0.2°、16.0±0.2°、16.7±0.2°、Locate characteristic peak for 19.3 ± 0.2 °, 19.8 ± 0.2 °, 20.6 ± 0.2 °, 23.3 ± 0.2 ° and 25.3 ± 0.2 °.
Preferably, the X-ray powder diffraction of described methyl tertbutyl etherate crystal is at the following angle of diffraction 2 θPlace has characteristic peak and relative intensity thereof:
Without limitation, a representative instance of described methyl tertbutyl etherate crystal has the institute as Figure 11Show X-ray powder diffraction pattern.
Compared with known ACT-064992 crystal formation I, described methyl tertbutyl etherate crystal has following usefulCharacter:
(1) in the situation that adding surfactant SDS or Tween-80, methyl tertbutyl etherate crystalSolubility in water is the solubility in water much larger than known crystal formation I.
(2) in methyl tertbutyl etherate crystal, do not contain ethanol, be suitable for the crowd of ethanol allergy to use.
The above-mentioned character of methyl tertbutyl etherate shows: compared with known ACT-064992 crystal formation I, thisThe methyl tertbutyl etherate crystal of bright ACT-064992 has better solubilizing effect, higher solubility,Can improve the bioavilability of active component, make formulation application more effective. And methyl tertbutylIn etherate crystal, not containing ethanol, be well-adapted for the patient of ethanol allergy.
The preparation method of the methyl tertbutyl etherate crystal of ACT-064992, comprises the following steps: by Ma XiForm solution for smooth being dissolved in methyl tertiary butyl ether(MTBE), leave standstill crystallization, then by the crystal separation of separating out,Room temperature vacuum drying, obtains described ACT-064992 methyl tertbutyl etherate crystal.
Preferably, the consumption of described ACT-064992 is that every milliliter of methyl tertiary butyl ether(MTBE) dissolving 1-3mg Ma Xi replacesSmooth; More preferably every milliliter of methyl tertiary butyl ether(MTBE) dissolves 1-2mg ACT-064992.
Preferably, described recrystallization temperature is room temperature to 40 DEG C; More preferably room temperature.
Preferably, the described crystallization time is 1-14 days; More preferably 1-2 days.
Preferably, be 1-72 hour described drying time; More preferably 1-24 hour.
ACT-064992 crystal form II of the present invention, ACT-064992 methylate crystal, ACT-064992 nitromethaneIn the above-mentioned preparation method of compound crystal, ACT-064992 methyl tertbutyl etherate crystal:
Described " stirring " can adopt the conventional method of this area to carry out, and for example magnetic agitation, machinery stirMix etc. Stir speed (S.S.) is 50～1800 revs/min, is preferably 300～900 revs/min;
Described " separation " can adopt the conventional method example of this area to carry out, for example filtration, centrifugal; CrossThe concrete operations of filter are: the sample that wish is separated is placed on filter paper, decompress filter; Centrifugal concrete operationsFor: the sample that wish is separated is placed in centrifuge tube, and High Rotation Speed is until solid is all sink to centrifuge tube afterwardsBottom, for example 6000 revs/min of centrifugation rates;
Described " room temperature " operation refers to the condition identical or approaching with the temperature of room or fume hood that operate inUnder carry out. Conventionally this temperature is from 15 to 25 DEG C, for example 17 DEG C, or 22 DEG C.
The present invention prepares ACT-064992 crystal form II, ACT-064992 methylate crystal, ACT-064992 nitro firstIn the method for alkide crystal and ACT-064992 methyl tertbutyl etherate crystal, the initial substance of use canTo be any crystal or the amorphous form of ACT-064992 material, for example, according to patent documentation US7,094,781The ACT-064992 that the preparation method who describes obtains, or according to document J.Med.Chem.2012,55,7849 describePreparation method obtain ACT-064992 crystal formation I.
The crystallization mode adopting in the present invention comprises magma and volatilization.
Magma is sample to be formed in dicyandiamide solution to supersaturated solution (to have undissolved solid to exist, be suspendedLiquid), then stirring and crystallizing, normally 1 day to 2 time-of-weeks.
Volatilization is that sample settled solution is placed in open-top receptacle, for example, in 5mL vial, specificUnder temperature conditions, (be generally room temperature) and volatilize. Can use the method that nitrogen blows or directly under room temperature, volatilize.
ACT-064992 crystal formation of the present invention, comprise ACT-064992 crystal form II, ACT-064992 methylate crystal,ACT-064992 nitromethane compound crystal and ACT-064992 methyl tertbutyl etherate crystal are pure, singleOne, do not mix any other crystal formation. Particularly crystal form II does not mix any other crystal formation substantially. ?In the present invention, " substantially not having ", in the time being used to refer to ACT-064992 novel crystal forms, refers to other horse that this crystal formation containsWest is less than 20% (weight) for smooth crystal formation, especially refers to be less than 10% (weight), more refers to be less than 5% (weight),Or more refer to be less than 1% (weight). Described " single crystal form " refers to that it is single detecting through X-ray powder diffractionThe ACT-064992 crystal formation of crystal formation.
In the present invention, " crystal " or " crystal formation " can exchange use, all refer to by shown in X ray powderThe signs such as end diffraction pattern confirm. Experimental error wherein depend on instrument condition, sample preparation andThe purity of sample. Conventionally, X-ray powder diffraction figure can change to some extent along with the condition of instrument. EspeciallyIt is to be noted that the relative intensity of X-ray powder diffraction figure also may become along with the variation of experiment conditionChange, so the strong order in peak should not be considered. In addition, the experimental error of peak angle conventionally 5% or moreFew, conventionally allow ± error of 0.2 °. Thereby, be understandable that the X of a crystal formation in the present inventionRay powder diffraction pattern needn't with embodiment in X-ray powder diffraction figure in full accord, any have andThe crystal formation of the basic identical or similar collection of illustrative plates of these collection of illustrative plates is all within category of the present invention.
Unless stated otherwise, in the present invention, " anhydride " refers to ACT-064992 crystal formation and contains through TGA measurementNo more than 1.5% (weight ratio), or the water of no more than 1% (weight ratio).
According to object of the present invention, the invention provides a kind of pharmaceutical composition, it comprises treatment effective doseACT-064992 crystal form II of the present invention, ACT-064992 methylate crystal, ACT-064992 nitromethane compoundCrystal, ACT-064992 methyl tertbutyl etherate crystal or its combination, and at least one pharmaceutically can connectThe carrier being subject to.
Pharmaceutical composition of the present invention can be solid-state or liquid. If this pharmaceutical composition is liquid, above-mentioned horseReplace for smooth crystal form II, ACT-064992 methylate crystal, ACT-064992 nitromethane compound crystal and Ma Xi in westSmooth methyl tertbutyl etherate crystal remains solid in this fluid composition, for example, as suspension.
Pharmaceutically acceptable carrier of the present invention includes but not limited to: diluent, for example starch, pre-Gelling starch, lactose, powdered cellulose, microcrystalline cellulose, calcium monohydrogen phosphate, tricalcium phosphate, sweet mellow wine,Sorbierite, sugar etc.; Adhesive, for example Arabic gum, guar gum, gelatin, polyvinylpyrrolidone,Hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol etc.; Disintegrant, for example starch, hydroxylAmylcose acetate sodium, pregelatinized starch, PVPP, Ac-Di-Sol, colloid titanium dioxideSilicon etc.; Lubricant, such as stearic acid, dolomol, zinc stearate, Sodium Benzoate, sodium acetate etc.;Glidant, such as cataloid etc.; Compound forming agent, the cyclodextrin of for example various ranks and treeFat; Rate of release controlling agent, for example hydroxypropyl cellulose, CMC, hydroxypropyl methyl fiberElement, ethyl cellulose, methylcellulose, methyl methacrylate, wax etc. Available other pharmaceuticallyAcceptable carrier include but not limited to film forming agent, plasticizer, colouring agent, flavor enhancement, viscosity modifier,Anticorrisive agent, antioxidant etc.
ACT-064992 crystal form II of the present invention, ACT-064992 methylate crystal, ACT-064992 nitromethaneCompound crystal, ACT-064992 methyl tertbutyl etherate crystal or its combination are suitable for being prepared into various formulations.For example can be mixed with: oral formulations, comprise solid oral dosage form as tablet, capsule, granule, pill,Powder etc. can be the systems of conventional, dispersible, masticable, Orally dissolving or rapid meltingAgent, liquid oral dosage form is as syrup, supensoid agent, dispersant, emulsion etc.; Ejection preparation as solution,The composition of dispersant and freeze-drying. Formula can be suitable for quick release, delayed release or the adjusting of active componentDischarge. That the method for administration of described pharmaceutical composition comprises is oral, intravenous injection, hypodermic injection, transdermal toMedicine, rectally, intranasal administration, eye drip administration etc. Preferably, described pharmaceutical composition is oral systemAgent or ejection preparation; More preferably, described pharmaceutical composition is solid orally ingestible, comprises tablet, glueWafer, granule, pill and powder.
Described pharmaceutical composition can be with well known to a person skilled in the art method system in prior artStandby. In the preparation, ACT-064992 crystal form II of the present invention, ACT-064992 methylate crystal, Ma Xi replaceSmooth nitromethane compound crystal, ACT-064992 methyl tertbutyl etherate crystal or its combination are with a kind of or manyPlant pharmaceutically acceptable carrier, other active components of optional one or more mix mutually. Solid systemAgent can be prepared by techniques such as mixing, granulations.
According to object of the present invention, the invention provides described ACT-064992 crystal form II, ACT-064992 methylateCrystal, ACT-064992 nitromethane compound crystal, ACT-064992 methyl tertbutyl etherate crystal and described medicineCompositions for the preparation for the treatment of caused by Endothelin increase with vessel retraction, cell proliferation, inflammation phaseThe disease of closing, for example hypertension, pulmonary hypertension, HPVD, coronary heart disease, heart failure, kidney andMyocardial atrophy, kidney failure, cerebral ischemia, cerebral angiospasm, dementia, antimigraine, subarachnoid hemorrhage,The ISR of thunder Na Shi syndrome, portal hypertension, arteriosclerosis, postangioplasty, cancer,Purposes in the medicine of the diseases such as asthma.
According to object of the present invention, the invention still further relates to treatment hypertension, pulmonary hypertension, HPVD,Coronary heart disease, heart failure, kidney and myocardial atrophy, kidney failure, cerebral ischemia, cerebral angiospasm, dementia, inclined to one sideHeadache, subarachnoid hemorrhage, thunder Na Shi syndrome, portal hypertension, arteriosclerosis, blood vessel becomeThe method of the diseases such as ISR that shape is postoperative, cancer, asthma, comprises described patient is treated to effective doseACT-064992 crystal form II of the present invention, ACT-064992 methylate crystal, ACT-064992 nitromethaneThing crystal, ACT-064992 methyl tertbutyl etherate crystal or its combination or its pharmaceutical composition. Described troublePerson refers to mammal, particularly the mankind. The consumption of medicine depends on type, the patient of active componentAge and demand and using method, the scope of consumption is that per kilogram human body weight uses every day conventionally0.1～50 milligram.
Brief description of the drawings
The XRPD collection of illustrative plates of Fig. 1 ACT-064992 crystal formation I.
The DSC collection of illustrative plates of Fig. 2 ACT-064992 crystal formation I.
The XRPD collection of illustrative plates of Fig. 3 ACT-064992 crystal form II.
The PLM collection of illustrative plates of Fig. 4 ACT-064992 crystal form II.
The DSC collection of illustrative plates of Fig. 5 ACT-064992 crystal form II.
The TGA collection of illustrative plates of Fig. 6 ACT-064992 crystal form II.
The dynamic moisture content absorption figure of Fig. 7 ACT-064992 crystal form II.
The XRPD collection of illustrative plates of Fig. 8 ACT-064992 methylate crystal.
The PLM collection of illustrative plates of Fig. 9 ACT-064992 methylate crystal.
The XRPD collection of illustrative plates of Figure 10 ACT-064992 nitromethane compound crystal.
The XRPD collection of illustrative plates of Figure 11 ACT-064992 methyl tertbutyl etherate crystal.
Figure 12 ACT-064992 crystal form II carries out stability by embodiment 13 and places the XRPD collection of illustrative plates of front and back(sample while being successively from top to bottom preparation and the sample of room temperature placement after 3 months in cillin bottle).
Figure 13 ACT-064992 crystal formation I carries out the XRPD figure of stable crystal form compressing tablet experiment by embodiment 24Spectrum (sample is from top to bottom crystal formation I successively, by the auxiliary material of table 4 tablet formulation physical mixed, by enforcementThe crystal formation I tablet that example 24 prepares).
Figure 14 ACT-064992 crystal form II carries out the XRPD figure of stable crystal form compressing tablet experiment by embodiment 24Spectrum (sample is from top to bottom crystal form II successively, by the auxiliary material of table 4 tablet formulation physical mixed, by realityExecute the crystal form II tablet that example 24 prepares).
Detailed description of the invention
The application is with further reference to following examples, described embodiment DETAILED DESCRIPTION The present application compound andIts crystal or crystal formation, its preparation method and application. It is right to it will be apparent for a person skilled in the art thatCan in the situation that not departing from the application's scope, implement in both many changes of materials and methods.
Test instrument used
The instrument that X-ray powder diffraction detection (XRPD) is used is BrukerD8AdvanceDiffractometer, adopts the K α X-ray that copper target wavelength is 1.54nm, the behaviour of 40kV and 40mADo under condition, θ-2 θ angular instrument, Mo monochromator, Lynxeye detector. Instrument is used Buddha's warrior attendant before useSand detects. Acquisition software is DiffracPlusXRDCommander. Sample is tested at ambient temperature,Sample is placed on SiP sheet. Testing conditions is as follows: angular range: 3-40 ° of 2 θ, and step-length: 0.02 ° of 2 θ,Speed: 0.2 second step-1。
Polarization microscope (PLM) collection of illustrative plates picks up from XP-500E polarization microscope (the rectangular light in ShanghaiLearn Instrument Ltd.). The powder sample that takes a morsel is placed on slide, drips a small amount of mineral oil with betterGround dispersion powders sample, covered, is then placed on sample on objective table, selects suitable puttingThe pattern of large multiple observing samples is also taken pictures.
Differential thermal analysis (DSC) data acquisition is certainly in TAInstrumentsQ200MDSC, and instrument control is softPart is ThermalAdvantage, and analysis software is UniversalAnalysis. Conventionally get 1-10 milligramSample is positioned in aluminium crucible, is dried N with the programming rate of 10 DEG C/min at 40mL/min2Protection underSample is risen to 250 DEG C from room temperature.
Thermogravimetric analysis (TGA) data acquisition is from TAInstrumentsQ500TGA, instrument control softwareBe ThermalAdvantage, analysis software is UniversalAnalysis. Conventionally getting 5-15mg sample putsBe placed in platinum crucible, adopt the mode of segmentation high resolution detection, exist with the programming rate of 10 DEG C/min40mL/min is dried N2Protection under sample is risen to 300 DEG C from room temperature, simultaneously TA software records sampleChanges in weight in temperature-rise period.
Isothermal adsorption is analyzed (DVS) data acquisition certainly in TAInstrumentsQ5000TGA, instrument controlSoftware is ThermalAdvantage, and analysis software is UniversalAnalysis. Conventionally get 1-10mg sampleProduct are positioned in platinum crucible, and TA software records sample is in relative humidity from 0% to 90% to 0% variationChanges in weight in process. Concrete condition per sample, also can adopt different absorption and de-to sampleAdsorption step.
Nucleus magnetic hydrogen spectrum data (1HNMR) pick up from BrukerAvanceIIDMX400MHZ nuclear-magnetism altogetherSpectrometer shakes. Weigh 1-5mg sample, with 0.5mL deuterochloroform (CDCl3) dissolve, be made intoThe solution of 2mg/mL-10mg/mL.
High performance liquid chromatography (HPLC) is analyzed data acquisition certainly in Agilent1260, and B.04 chem workstation is.Relevant parameter is as follows: chromatographic column EclipstXDB-C18,5 μ m, 4.6 × 250mm, H-005#, column temperature25 DEG C, flow velocity 0.3mL/min, mobile phase 97% acetonitrile and 3% water, wavelength 254nm, sample size 10ulWith 20 minutes running times.
Preparation example 1
Reference literature J.Med.Chem.2012,55,7849 methods of describing are prepared N-[5-(4-bromobenzeneBase) the bromo-2-pyrimidine radicals of-6-[2-[(5-) oxygen base]-ethyoxyl]-4-pyrimidine radicals]-N '-sulfonyl propyl amine (ACT-064992)Crystal formation I. Be specially:
10mL n-hexane washed twice for sodium hydride (55% content is in mineral oil for 1.67g, 69.6mmol), justHexane solution abandons, and the sodium hydride after washing is dissolved in 200mL oxolane, adds N-[5-(4-bromobenzene in batchesBase)-6-[2-[(hydroxyl-oxethyl)-4-pyrimidine radicals]-N '-sulfonyl propyl amine (10.0g, 23.2mmol), mixture stirs15 minutes, add 400mLDMF dilution, finally add 5-bromo-2-chlorine pyrimidine (5.38g, 27.8mmol),Reactant liquor is warmed up to 60 DEG C, is incubated 2 hours, and reaction completes. Reactant liquor is poured the citric acid of 250mL10% intoIn the aqueous solution, add ethyl acetate extracting twice, each 300mL ethyl acetate, merges organic phase, waterWash 2 times, each 200mL water, organic phase adds dried over mgso, filters, and filtrate decompression is concentrated, thickProduct obtain target product white powder 11.9g, molar yield 88% by 100mL recrystallizing methanol.
XRPD collection of illustrative plates as shown in Figure 1.
1HNMR(CDCl3)：8.51(s，2H)，8.49(s，1H)，7.58-7.61(m，2H)，7.16-7.19(m，2H)，5.61(t，J＝6.2Hz，1H)，4.73-4.76(m，2H)，4.62-4.65(m，2H)，2.98(q，J＝6.8Hz，2H)，1.58-1.62 (m, 2H), 0.96 (t, J=7.4Hz, 3H); Be shown as ACT-064992.
DSC collection of illustrative plates as shown in Figure 2, shows: 135 DEG C of fusing points, and document Med.Chem.2012,55,7849In the fusing point (135-136 DEG C) of ACT-064992 crystal formation (crystal formation I) consistent.
Embodiment 1
Get 9.8mg ACT-064992 in 5mL vial, add 0.9mL methyl alcohol, form suspension,At 60 DEG C, stir 1 day, separate out white crystal, isolated by filtration, with methyl alcohol drip washing 2 times, room temperature vacuum is dryDry 1 hour, obtain ACT-064992 methylate crystal. Output 8.6mg, productive rate 85%.
XRPD collection of illustrative plates as shown in Figure 8.
1HNMR(CDCl3)：8.52(s，2H)，8.50(s，1H)，7.59-7.61(m，2H)，7.17-7.19(m，2H)，5.65(t，J＝6.2Hz，1H)，4.73-4.76(m，2H)，4.63-4.65(m，2H)，3.52(s，2H)，2.98(q，J=6.8Hz, 2H), 1.58-1.63 (m, 2H), 1.30-1.52 (m, 7H), 0.97 (t, J=7.4Hz, 3H). Show: withACT-064992 crystal formation I prepared by preparation example 1 compares, and in ACT-064992 methylate crystal, contains methyl alcohol, andPer molecule ACT-064992 is approximately containing 2/3 methanol molecules.
PLM collection of illustrative plates as shown in Figure 9, shows that it has good pattern.
Embodiment 2
Get 50.0mg ACT-064992 in 5mL vial, add 0.5mL methyl alcohol, form suspension,Stirring at room temperature 7 days, separates out white crystal, and isolated by filtration is washed 3 times room temperature vacuum drying 24 with methyl alcoholHour, obtain ACT-064992 methylate crystal, output 48.1mg, productive rate 93%.
Embodiment 3
Get 124.9mg ACT-064992 in 5mL vial, add 0.5mL methyl alcohol, form suspension,Stirring at room temperature 14 days, separates out white crystal, and isolated by filtration is washed 3 times room temperature vacuum drying 72 with methyl alcoholHour, obtain ACT-064992 methylate crystal, output 118.6mg, productive rate 92%.
The sample of embodiment 2,3 has and the same or analogous XRPD collection of illustrative plates of embodiment 1 sample, nuclear-magnetism hydrogenSpectrum and PLM collection of illustrative plates (not shown). The sample that embodiment 2,3 is described is identical with embodiment 1 sampleCrystal.
Embodiment 4
Get 10.0mg ACT-064992 in 5mL vial, add 1mL methyl alcohol, form suspension,At 60 DEG C, stir 1 day, separate out white crystal, isolated by filtration, washes 2 times with methyl alcohol, does in 70 DEG C of vacuumDry 72 hours, obtain ACT-064992 crystal form II. Output 7.5mg, productive rate 75%.
XRPD collection of illustrative plates as shown in Figure 3.
PLM collection of illustrative plates as shown in Figure 4. Show: sheet crystalline state.
DSC collection of illustrative plates as shown in Figure 5, shows: 106 DEG C of fusing points.
TGA collection of illustrative plates as shown in Figure 6. Show: before 130 DEG C, substantially without weightless, decomposition temperature is 150 DEG C.
Dynamically moisture content absorption figure as shown in Figure 7. Show: 20%RH～80%RH changes in weight is 1.5%.
Above-mentioned testing result shows that ACT-064992 crystal form II is anhydride, sheet crystalline state, and it is low to have fusing point(be applicable to hot-melt extruded method) and be difficult for the good physical propertys such as moisture absorption.
Embodiment 5
Get 100.1mg ACT-064992 in 5mL vial, add 1mL methyl alcohol, form suspension,Stirring at room temperature 7 days, separates out white crystal, and isolated by filtration is washed 3 times with methyl alcohol, in 100 DEG C of vacuum drying24 hours, obtain ACT-064992 crystal form II. Output 90.5mg, productive rate 90%.
Embodiment 6
Get 125.0mg ACT-064992 in 5mL vial, add 0.5mL methyl alcohol, form suspension,Stirring at room temperature 14 days, separates out white crystal, and isolated by filtration is washed 3 times with methyl alcohol, does in 120 DEG C of vacuumDry 1 hour, obtain ACT-064992 crystal form II. Output 120.1mg, productive rate 96%.
The sample of embodiment 5,6 has and the same or analogous XRPD collection of illustrative plates of embodiment 4 sample, PLMCollection of illustrative plates, DSC collection of illustrative plates, TGA collection of illustrative plates and dynamic moisture content absorption figure (not shown). Embodiment 5,6 is describedSample and embodiment 4 samples are identical crystal formations.
Embodiment 7
Get 10mL nitromethane and 10mL water and mix, stirring at room temperature 16 hours, leaves standstill and gets after 2 hoursWater layer, is the water saturation solution of following nitromethane.
Get 15.1mg ACT-064992 in 5mL vial, add the water saturation of 0.3mL nitromethane moltenLiquid, forms suspension, stirring at room temperature 7 days, and isolated by filtration, washes 2 times, in 40 DEG C of vacuum drying 24Hour, obtain ACT-064992 nitromethane compound crystal. Output 13.5mg, productive rate 85%.
XRPD collection of illustrative plates as shown in figure 10.
1HNMR(CDCl3)：δ8.52(s，2H)，8.50(s，1H)，7.59-7.61(m，2H)，7.18-7.19(m，2H)，5.65(t，J＝6.2Hz，1H)，4.74-4.75(m，2H)，4.64-4.65(m，2H)，4.35(s，1.5H)，2.99 (q, J=6.8Hz, 2H), 1.59-1.65 (m, 4H), 0.97 (t, J=7.4Hz, 3H). Show: make with preparation example 1Standby crystal formation I compares, and ACT-064992 nitromethane compound crystal contains nitromethane, and per molecule Ma Xi replacesSmooth band 1/2 the nitromethane molecule of having an appointment.
Embodiment 8
Get 50.0mg ACT-064992 in 5mL vial, add the water saturation of 0.2mL nitromethane moltenLiquid, forms suspension, stirring at room temperature 14 days, and isolated by filtration, washes with water 3 times, dry in 80 DEG C of vacuumDry 1 hour, obtain ACT-064992 nitromethane compound crystal. Output 47.4mg, productive rate 90%.
Embodiment 9
Get 1.01mg ACT-064992 in 5mL vial, add the water saturation of 1.0mL nitromethane moltenLiquid, forms suspension, and 60 DEG C are stirred 1 day, and isolated by filtration, washes with water 2 times, in room temperature vacuum drying48 hours, obtain ACT-064992 nitromethane compound crystal. Output 0.45mg, productive rate 42%.
The sample of embodiment 8,9 has and the embodiment same or analogous XRPD collection of illustrative plates of 7 sample and nuclear-magnetism hydrogenSpectrum (not shown). The sample that embodiment 8,9 is described and embodiment 7 samples are identical crystal.
Embodiment 10
Get 9.9mg ACT-064992 in 5mL vial, add 3.3mL methyl tertiary butyl ether(MTBE), form moltenLiquid, with the organic filter membrane filtration of 0.45 μ m, leaves standstill 2 days under filtrate room temperature, separates out white crystal, centrifugal,Room temperature vacuum drying 24 hours, obtains ACT-064992 methyl tertbutyl etherate crystal. Output 8.0mg, producesRate 77%.
XRPD collection of illustrative plates as shown in figure 11.
1HNMR(CDCl3)：δ8.51(s，2H)，8.50(s，1H)，7.60-7.61(m，2H)，7.18-7.19(m，2H)，5.62(t，J＝6.2Hz，1H)，4.74-4.76(m，2H)，4.63-4.65(m，2H)，3.62(s，1H)，2.99(q，J=6.8Hz, 2H), 1.58-1.64 (m, 12H), 1.22 (s, 4H), 0.97 (t, J=7.4Hz, 3H). Show: with preparationCrystal formation I prepared by example 1 compares, and ACT-064992 methyl tertbutyl etherate crystal contains methyl tertiary butyl ether(MTBE),And per molecule ACT-064992 is approximately containing 1/3 methyl tertiary butyl ether(MTBE) molecule.
Embodiment 11
Get 5.1mg ACT-064992 in 5mL vial, add 2.5mL methyl tertiary butyl ether(MTBE), form moltenLiquid, filters with the organic filter membrane of 0.45 μ m, at 40 DEG C of filtrates, leaves standstill 1 day, separates out white crystal, centrifugal,Room temperature vacuum drying 1 hour, obtains ACT-064992 methyl tertbutyl etherate crystal. Output 3.2mg, productive rate60％。
Embodiment 12
Get 14.9mg ACT-064992 in 20mL vial, add 15mL methyl tertiary butyl ether(MTBE), formSolution, with the organic filter membrane filtration of 0.45 μ m, leaves standstill 14 days under filtrate room temperature, separates out white crystal, fromThe heart, room temperature vacuum drying 72 hours, obtains ACT-064992 methyl tertbutyl etherate crystal. Output 12.8mg,Productive rate 82%.
The sample of embodiment 11,12 has and the embodiment same or analogous XRPD collection of illustrative plates of 10 sample and coreMagnetic hydrogen spectrum (not shown). The sample that embodiment 11,12 is described and embodiment 10 samples are identical crystal.
Embodiment 13
Get 10mg ACT-064992 crystal form II and be placed in 10mL cillin bottle and seal, room temperature preservation 3 months,Before and after placing, respectively carry out XRPD sign. XRPD collection of illustrative plates as shown in figure 12, shows: ACT-064992 crystal formationBefore and after II at room temperature places, stable crystal form is constant.
Embodiment 14
ACT-064992 methyl tertbutyl etherate crystal prepared by the present invention, after 40 DEG C of desolventizings, samplesDetect. Its XRPD collection of illustrative plates is similar to Fig. 1, has changed ACT-064992 crystal formation I into after showing its desolventizing.
Embodiment 15
ACT-064992 methylate crystal prepared by the present invention is at 70 DEG C after desolventizing, and sampling detects.Its XRPD collection of illustrative plates is similar to Fig. 3, changes ACT-064992 crystal form II into after showing its desolventizing.
Embodiment 16
ACT-064992 nitromethane compound crystal prepared by the present invention is at 40 DEG C after desolventizing, and sampling is examinedSurvey. After showing its desolventizing, its XRPD collection of illustrative plates changes amorphous article into.
Embodiment 17
Get crystal form II prepared by crystal formation I prepared by preparation example 1 and the present invention and carry out solubility contrast experiment.
Respectively at adding about 10mg sample and 250mL purified water in 500mL vial, respectively ultrasonic(40Khz ultrasonic power) respectively got about 110mL suspension for 15 minutes, 60 minutes and filtered, and gets filtrate determiningHold to 100mL, be placed in round-bottomed flask and be spin-dried for solvent, add a small amount of acetonitrile sample dissolution and be transferred to 10mLIn volumetric flask, and with acetonitrile rinse flask 2 times, then rinse liquid is transferred in same 10mL volumetric flask,Use acetonitrile constant volume, after filtering, directly survey HPLC concentration. The results are shown in Table 1.
Embodiment 18
Get crystal form II prepared by crystal formation I prepared by preparation example 1 and the present invention and carry out solubility contrast experiment.
Respectively at adding in 100mL vial, 60mg sample, 0.2g lauryl sodium sulfate and 50mL are pureChange water, within 15 minutes, 60 minutes, respectively get about 15mL suspension at ultrasonic (40Khz ultrasonic power) respectivelyFilter, get filtrate and be settled to 10mL, be placed in round-bottomed flask and be spin-dried for solvent, add a small amount of acetonitrile sample dissolutionBe transferred in 10mL volumetric flask, and with acetonitrile rinse flask 2 times, then rinse liquid is transferred to same 10mLIn volumetric flask, use acetonitrile constant volume, after filtering, directly survey HPLC concentration. The results are shown in Table 1.
Embodiment 19
Get crystal formation I prepared by preparation example 1, methylate crystal, crystal form II, nitro first prepared by the present inventionAlkide crystal and methyl tertbutyl etherate crystal carry out solubility contrast experiment.
Respectively at adding in 100mL vial, 200mg sample, 1.0g lauryl sodium sulfate and 50mL are pureChange water, within 15 minutes, 60 minutes, respectively get about 15mL suspension at ultrasonic (40Khz ultrasonic power) respectivelyFilter, get filtrate and be settled to 10mL, be placed in round-bottomed flask and be spin-dried for solvent, add a small amount of acetonitrile sample dissolutionBe transferred in 10mL volumetric flask, and with acetonitrile rinse flask 2 times, then rinse liquid is transferred to same 10mLIn volumetric flask, use acetonitrile constant volume, after filtering, directly survey HPLC concentration. The results are shown in Table 1.
Embodiment 20
Get crystal form II prepared by crystal formation I prepared by preparation example 1 and the present invention and carry out solubility contrast experiment.
Respectively at adding 60mg sample, 0.2g Tween-80 and 50mL purified water in 100mL vial, pointWithin 15 minutes, 60 minutes, respectively do not get about 15mL suspension at ultrasonic (40Khz ultrasonic power) and filter, getFiltrate is settled to 10mL, is placed in round-bottomed flask and is spin-dried for solvent, adds a small amount of acetonitrile sample dissolution and is transferred toIn 10mL volumetric flask, and with acetonitrile rinse flask 2 times, then rinse liquid is transferred to same 10mL capacityIn bottle, use acetonitrile constant volume, after filtering, directly survey HPLC concentration. The results are shown in Table 1.
Embodiment 21
Get crystal form II prepared by crystal formation I prepared by preparation example 1 and the present invention and carry out solubility contrast experiment.
Respectively at adding 60mg sample, 1.0g Tween-80 and 50mL purified water in 100mL vial,Within 15 minutes, 60 minutes, respectively get about 15mL suspension at ultrasonic (40Khz ultrasonic power) respectively and filter,Get filtrate constant volume 10mL, be placed in round-bottomed flask and be spin-dried for solvent, add a small amount of acetonitrile sample dissolution and be transferred toIn 10mL volumetric flask, and with acetonitrile rinse flask 2 times, then rinse liquid is transferred to same 10mL capacityIn bottle, use acetonitrile constant volume, after filtering, directly survey HPLC concentration. The results are shown in Table 1.
Table 1 solubility contrast experiment data statistics
From table 1: crystal formation I and crystal form II are almost insoluble in pure water, but adding surfactantIn the situation of lauryl sodium sulfate or Tween-80, the solubility of crystal form II in water exists much larger than crystal formation ISolubility in water, and methylate crystal, nitromethane compound crystal and methyl tertbutyl etherate crystalline substanceAll than crystal formation I and crystal form II, the solubility in water is good for the solubility of body in water.
Embodiment 22
The preparation of tablet. Formula is in table 2, and concrete steps are as follows:
(1) by bulk drug (API, be selected from ACT-064992 crystal form II, ACT-064992 methylate crystal,ACT-064992 nitromethane compound crystal or ACT-064992 methyl tertbutyl etherate crystal) and lactose (Water) mix.
(2) after polyvinylpyrrolidone is dissolved with 50% appropriate ethanol water, join above-mentioned mixedIn compound, cross sieve series wet granular.
(3) by after dry, whole wet granular grain, mix compressing tablet with PVPP and dolomol.
Table 2 tablet formulation
Embodiment 23
The preparation of tablet. Formula is in table 3, and concrete steps are as follows:
(1) API (is selected to ACT-064992 crystal form II, ACT-064992 methylate crystal, ACT-064992 nitreMethylmethane compound crystal or ACT-064992 methyl tertbutyl etherate crystal) and pregelatinized starch mix.
(2) in said mixture, add dolomol, mix, compressing tablet.
Table 3 tablet formulation
Embodiment 24
Get crystal form II prepared by crystal formation I prepared by preparation example 1 and the present invention, carry out stable crystal form compressing tablet realTest.
A) press the tablet formulation consumption of table 4, by API (crystal formation I or crystal form II) and crosslinked polyethylene pyrrolePyrrolidone, lactose monohydrate, dolomol and microcrystalline cellulose mix, 4MPa lower sheeting;
Table 4 tablet formulation
B) by agate mortar grind into fine powder solid gently for tablet, carry out XRPD sign, compare itThe crystal formation of making tablet front and back changes.
XRPD the results are shown in Figure 13 and Figure 14, shows: compared with crystal formation before compressing tablet, and crystal formation I after compressing tabletAll do not change with the crystal formation of crystal form II; The auxiliary material of embodiment 24 tablets and technique are to crystal formation I and crystal formationThe crystal formation of II is all without impact.
Embodiment 25
Get crystal formation I tablet and the crystal form II tablet prepared by embodiment 24 methods, carry out dissolution rate more realTest.
Leaching condition with reference to " Benorilate Tablets " in " Chinese pharmacopoeia " 2010 editions is measured dissolution rate, adoptsOar method, using 1% lauryl sodium sulfate (SDS) aqueous solution of 900mL as dissolution medium, temperature37 DEG C, rotating speed of agitator is 100r/min, during respectively at 10min, 20min, 30min, 60min, samples3mL, the SDS solution with 1% after every sub-sampling is supplied, and HPLC measures the concentration of each time point sample,Calculate stripping percentage. Stripping data result is in table 5.
The stripping data of table 5 crystal formation I tablet, crystal form II tablet
The result of table 5 shows: the stripping percentage of the tablet of crystal form II of the present invention in the time of 30min reachesMore than 95%, and the stripping percentage of the tablet of known crystal formation I in the time of 30min is less than 85%, therefore the present inventionThe dissolution rate of tablet of crystal form II faster than the dissolution rate of the tablet of known crystal formation I. Illustrate in preparationWhen quick releasing formulation, the preparation of crystal form II of the present invention more easily reaches the requirement of product.
All patent documentations of quoting in this description and non-patent publications are all complete with it by referenceThe mode of literary composition is incorporated herein.
The above-mentioned generality to the invention relating in the application is described and to the description of its detailed description of the invention notBeing interpreted as is the restriction that this invention technical scheme is formed. Those skilled in the art are according to the applicationDisclose, can be under the prerequisite of the invention inscape without prejudice to related, to above-mentioned general descriptionOr/and the public technology feature in detailed description of the invention (comprising embodiment) increases, reduces or combine,Formation belongs to other technical scheme of described invention.

Claims (17)

1. the crystal form II of structural formula ACT-064992 as follows,
It is characterized in that, use Cu-K α radiation, the X-ray powder diffraction of described crystal form II is in the angle of diffraction2 θ be 8.9 ± 0.2 °, 11.5 ± 0.2 °, 12.4 ± 0.2 °, 14.1 ± 0.2 °, 15.2 ± 0.2 °, 17.8 ± 0.2 °, 18.7 ± 0.2 °,Locate characteristic peak for 19.6 ± 0.2 °, 20.2 ± 0.2 °, 21.4 ± 0.2 °, 24.1 ± 0.2 ° and 25.4 ± 0.2 °.
2. the crystal form II of ACT-064992 according to claim 1, is characterized in that, described crystal form IIX-ray powder diffraction there is characteristic peak and relative intensity thereof at the following angle of diffraction 2 θ places:
3. the preparation method of the crystal form II of ACT-064992 described in any one in claim 1～2, comprises followingStep: ACT-064992 is suspended in methyl alcohol and forms suspension, carry out stirring and crystallizing, then will separate outSolid separates, and is greater than at 60 DEG C and is dried, and obtains the crystal form II of described ACT-064992.
4. preparation method according to claim 3, is characterized in that, the consumption of described ACT-064992For every ml methanol adds 10-250mg ACT-064992.
5. preparation method according to claim 4, is characterized in that, the consumption of described ACT-064992For every ml methanol adds 10-100mg ACT-064992.
6. preparation method according to claim 3, is characterized in that, described recrystallization temperature is room temperatureTo 60 DEG C.
7. preparation method according to claim 6, is characterized in that, described recrystallization temperature is room temperature.
8. preparation method according to claim 3, is characterized in that, the described crystallization time is 1-14My god.
9. preparation method according to claim 8, is characterized in that, the described crystallization time is 1-7My god.
10. preparation method according to claim 3, is characterized in that, described baking temperature is 70℃-120℃。
11. preparation methods according to claim 10, is characterized in that, described baking temperature is 70℃-100℃。
12. preparation methods according to claim 3, is characterized in that, be 1-72 described drying timeHour.
13. preparation methods according to claim 12, is characterized in that, be 1-24 described drying timeHour.
14. 1 kinds of pharmaceutical compositions, comprise in the claim 1～2 for the treatment of effective dose horse described in any oneWest is for smooth crystal form II, and at least one pharmaceutically acceptable carrier.
15. pharmaceutical compositions according to claim 14, is characterized in that, described pharmaceutical compositionFor oral formulations or ejection preparation.
16. pharmaceutical compositions according to claim 15, is characterized in that, described pharmaceutical compositionFor being selected from the solid orally ingestible of tablet, capsule, granule, pill or powder.
In 17. claims 1～2 described in any one in the crystal form II of ACT-064992 or claim 14-16Pharmaceutical composition described in any one is for the preparation for the treatment of hypertension, HPVD, coronary heart disease, the heartForce failure, kidney and myocardial atrophy, kidney failure, cerebral ischemia, cerebral angiospasm, dementia, antimigraine, spider webFilm lower cavity hemorrhage, thunder Na Shi syndrome, portal hypertension, arteriosclerosis, postangioplasty are againPurposes in the medicine of narrow, cancer, asthma.
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CN106924190A (en) * 2015-12-30 2017-07-07 深圳翰宇药业股份有限公司 A kind of ACT-064992 microballoon and preparation method thereof
WO2018153925A1 (en) * 2017-02-22 2018-08-30 Amneal Pharmaceuticals Company Gmbh Stable pharmaceutical compositions comprising macitentan
TW202103703A (en) * 2019-04-05 2021-02-01 瑞士商艾克泰聯製藥有限公司 Methods for treating portopulmonary hypertension
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AR062501A1 (en) * 2006-08-29 2008-11-12 Actelion Pharmaceuticals Ltd THERAPEUTIC COMPOSITIONS

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CN107868055B (en) * 2016-09-28 2020-02-07 普济生物科技（台州）有限公司 Preparation method of macitentan

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