WO2018010622A1 - 化合物的晶型及其制备方法、组合物和应用 - Google Patents

化合物的晶型及其制备方法、组合物和应用 Download PDF

Info

Publication number
WO2018010622A1
WO2018010622A1 PCT/CN2017/092416 CN2017092416W WO2018010622A1 WO 2018010622 A1 WO2018010622 A1 WO 2018010622A1 CN 2017092416 W CN2017092416 W CN 2017092416W WO 2018010622 A1 WO2018010622 A1 WO 2018010622A1
Authority
WO
WIPO (PCT)
Prior art keywords
solvent
mixed solution
compound
formula
ray powder
Prior art date
Application number
PCT/CN2017/092416
Other languages
English (en)
French (fr)
Inventor
雷四军
方祥
陈永凯
冯伟
王朝东
Original Assignee
武汉朗来科技发展有限公司
武汉启瑞药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 武汉朗来科技发展有限公司, 武汉启瑞药业有限公司 filed Critical 武汉朗来科技发展有限公司
Priority to US16/301,027 priority Critical patent/US10611757B2/en
Priority to EP17826958.5A priority patent/EP3461822B1/en
Publication of WO2018010622A1 publication Critical patent/WO2018010622A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a crystalline form of a compound, a preparation method, composition and use thereof.
  • Hypertension is the most common cardiovascular disease and a major risk factor for congestive heart failure, stroke, coronary heart disease, renal failure, and increased morbidity and mortality in aortic aneurysms.
  • Antihypertensive drugs play a key role in the treatment and prevention of hypertension. With the deepening of the understanding of the pathogenesis of hypertension, many antihypertensive drugs with better curative effects, such as diuretics, ⁇ -blockers, calcium channel antagonists, angiotensin converting enzyme inhibitors (ACEI, Angiotensin II, an AT1 receptor antagonist (ARB, sartan), has been continuously discovered and successfully applied in clinical practice.
  • ACEI angiotensin converting enzyme inhibitors
  • ARB AT1 receptor antagonist
  • statin of the AT1 receptor antagonist has stable blood pressure, good curative effect, long duration of action, and good patient tolerance, especially in preventing stroke, delaying diabetes and non-diabetic nephropathy. It has many advantages in improving left ventricular hypertrophy and protection against target organs, and does not affect bradykinin degradation and prostaglandin synthesis, thus causing dry cough and angioedema, and has become a global antihypertensive drug market. Mainstream varieties.
  • the anti-hypertensive drug of sartan has a blood pressure lowering efficiency of only about 50-60% and has a certain degree of adverse reactions. Therefore, the development of a small-dose long-acting antihypertensive drug with stronger antihypertensive effect, less adverse reactions and better protection of target organs has become a hot research direction.
  • the above compound is a sartan compound coupled with ligustrazine, and is a prodrug of angiotensin II receptor antagonist azisartan (TAK-536), which releases hydroxy oxazine in vivo and thus Effective synergy of Shatan It enhances the antihypertensive effect, has a certain heart rate reduction effect, reduces adverse reactions, and has an ideal protective effect on patients' heart and kidney.
  • TAK-536 angiotensin II receptor antagonist azisartan
  • the potassium salt of the compound of formula (B), ie the compound of formula (A) below has better solubility, higher bioavailability, and a more potent and longer-lasting antihypertensive effect.
  • the effect has a more obvious and lasting effect of lowering the heart rate, and has high safety, and has an ideal protective effect on the heart and kidney function of the patient, and can be used for preventing and/or treating hypertension, chronic heart failure, diabetic nephropathy, etc.
  • the present invention provides a crystalline form of the compound of formula (A):
  • It comprises a crystalline form I, a crystalline form II, a crystalline form III, a crystalline form IV or a mixture thereof in any ratio selected from the group consisting of:
  • the X-ray powder diffraction pattern of Form I has a characteristic peak at a position where the diffraction angle 2 ⁇ is 5.3 ⁇ 0.2, 8.6 ⁇ 0.2 degrees; preferably, the X-ray powder diffraction pattern of Form I is further at a diffraction angle 2 ⁇ of 13.3 ⁇ 0.2, A characteristic peak is present at a position of 20.1 ⁇ 0.2 degrees; further preferably, the X-ray powder diffraction pattern of the crystal form I further has a characteristic peak at a position where the diffraction angle 2 ⁇ is 6.3 ⁇ 0.2, 10.6 ⁇ 0.2, and 26.3 ⁇ 0.2 degrees; more preferably, the crystal form
  • the X-ray powder diffraction pattern of I further has a characteristic peak at a position where the diffraction angle 2 ⁇ is 12.7 ⁇ 0.2 degrees; most preferably, the X-ray powder diffraction pattern of Form I is substantially as shown in FIG.
  • the X-ray powder diffraction pattern of Form II has a characteristic peak at a position where the diffraction angle 2 ⁇ is 4.7 ⁇ 0.2 degrees; preferably, the X-ray powder diffraction pattern of Form II is further 7.3 ⁇ 0.2, 9.6 ⁇ 0.2 at a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of the crystal form II further has a characteristic peak at a position where the diffraction angle 2 ⁇ is 11.8 ⁇ 0.2, 24.6 ⁇ 0.2 degrees; more preferably, the crystal form
  • the X-ray powder diffraction pattern of II further has a characteristic peak at a position where the diffraction angle 2 ⁇ is 22.6 ⁇ 0.2 degrees; most preferably, the X-ray powder diffraction pattern of Form II is substantially as shown in FIG. 2 .
  • the X-ray powder diffraction pattern of Form III has a characteristic peak at a position where the diffraction angle 2 ⁇ is 5.2 ⁇ 0.2, 8.0 ⁇ 0.2 degrees; preferably, the X-ray powder diffraction pattern of Form III is further at a diffraction angle 2 ⁇ of 12.4 ⁇ 0.2, There is a characteristic peak at a position of 13.6 ⁇ 0.2 degrees; further preferably, the X-ray powder diffraction pattern of the crystal form III further has a characteristic peak at a position where the diffraction angle 2 ⁇ is 19.2 ⁇ 0.2 degrees; more preferably, the X-ray powder diffraction pattern of the crystal form III Further, there are characteristic peaks at positions where the diffraction angle 2 ⁇ is 10.3 ⁇ 0.2, 12.2 ⁇ 0.2, and 21.4 ⁇ 0.2 degrees; most preferably, the X-ray powder diffraction pattern of Form III is substantially as shown in FIG.
  • the X-ray powder diffraction pattern of Form IV has a characteristic peak at a diffraction angle 2 ⁇ of 7.4 ⁇ 0.2, 14.7 ⁇ 0.2, and 16.0 ⁇ 0.2 degrees; preferably, the X-ray powder diffraction pattern of Form IV is further at a diffraction angle 2 ⁇ . 8.4 ⁇ 0.2, 22.6 ⁇ 0.2, 23.2 ⁇ 0.2, 29.7 ⁇ 0.2 degrees have characteristic peaks; more preferably, the X-ray powder diffraction pattern of Form IV further has characteristic peaks at a diffraction angle 2 ⁇ of 24.0 ⁇ 0.2 degrees; Preferably, the X-ray powder diffraction pattern of Form IV is substantially as shown in FIG.
  • the DSC spectrum of Form I shows a melting point of 184 ⁇ 5 ° C;
  • the DSC spectrum of Form II shows a melting point of 145 ⁇ 5 ° C;
  • the DSC spectrum of Form III shows a melting point of 187 ⁇ 5 ° C;
  • the decomposition temperature of the TGA spectrum of Form I is 180 ⁇ 5 ° C;
  • the decomposition temperature of the TGA spectrum of Form II is 148 ⁇ 5 ° C;
  • the decomposition temperature of the TGA spectrum of Form III is 183 ⁇ 5 ° C;
  • the decomposition temperature of the TGA pattern of Form IV was 149 ⁇ 5 °C.
  • Form I has a DSC-TGA map substantially as shown in Figure 10;
  • Form II has a DSC-TGA pattern substantially as shown in Figure 11;
  • Form III has a DSC-TGA pattern substantially as shown in Figure 12;
  • Form IV has a DSC-TGA pattern substantially as shown in FIG.
  • composition or mixture comprising any one of Forms I, II, III, IV, a mixture of two or more of any ratio.
  • the composition or mixture contains Form I and Form II in any ratio, more preferably, a mixture of Form I and Form II in any ratio.
  • the ratio of Form I and Form II in the mixture of Form I and Form II is not particularly limited.
  • the weight ratio of Form I to Form II may range from 1:99 to 99:1, such as from 5:95 to 95:5.
  • the weight ratio of Form I to Form II can be 1:9 to 9:1, 2:8 to 8:2, 3:7 to 7:3, 4:6 to 6:4, or 5:5. .
  • the invention also provides processes for the preparation of Forms I, II, III and IV.
  • Compounds of formula (B) can be prepared by methods known in the art, such as those disclosed in CN 103709154 A, where CN 103709154 A is incorporated in its entirety.
  • Compounds of formula (A) can be prepared by reacting a compound of formula (B) with a potassium salt reagent.
  • the method for preparing the crystalline form I of the present invention can be carried out by stirring a suspension of the compound of the formula (A), adding an antisolvent to the solution of the compound of the formula (A), cooling the solution of the compound of the formula (A), and formulating the formula (A).
  • the compound is diffused and crystallized in a solvent atmosphere, or a suspension of the crystalline form III and/or the crystalline form IV of the compound of the formula (A) is obtained.
  • a compound of the formula (A) is added, and a solvent is added to obtain a suspension, which is stirred to obtain a crystal form I.
  • the solvent is an ethanol/isopropyl ether mixed solution, an ethanol/n-heptane mixed solution, an isopropanol/n-heptane mixed solution, or a tetrahydrofuran/n-heptane mixed solution; more preferably, the volume of the two solvents in the mixed solution
  • the ratio is 1:8-8:1, most preferably 1:5-5:1.
  • the mixture is stirred at room temperature for 0.5 to 3 days, most preferably at room temperature for 1-2 days.
  • the compound of the formula (A) is dissolved in a good solvent to obtain a clear solution, and an anti-solvent is added under stirring to obtain a crystal form I.
  • the good solvent is methanol, ethanol or n-butanol
  • the antisolvent is isopropyl ether, methyl tert-butyl ether or methylcyclohexane.
  • the solvent is an ethanol/isopropyl ether mixed solution, an ethanol/ethyl acetate mixed solution, an ethanol/methyl tert-butyl ether mixed solution, an ethanol/n-heptane mixed solution, an ethanol/methylcyclohexane mixed solution, or A n-butanol/n-heptane mixed solution; more preferably, the volume ratio of the two solvents in the mixed solution is 1:8-8:1, and most preferably 1:5-5:1.
  • it is heated to a temperature of from 40 to 90, most preferably, to a temperature of from 50 to 70 °C.
  • the solvent to be added is selected from an ester solvent such as acetic acid B. Ester, isopropyl acetate or a mixture thereof.
  • the method for preparing the crystalline form II of the present invention can be carried out by volatilizing a solution of the compound of the formula (A), stirring a solution of the compound of the formula (A), a saturated solution, a supersaturated solution or a suspension, and a solution of the compound of the formula (A). An anti-solvent is added thereto, the solution of the compound of the formula (A) is cooled, a saturated solution of the compound of the formula (A) is diffused in a solvent atmosphere, or a compound of the formula (A) is diffused and crystallized in a solvent atmosphere.
  • a compound of the formula (A) is dissolved in a solvent to obtain a clear solution, which is evaporated to dryness at room temperature to give a crystal form II.
  • the solvent is an ethanol/ethyl acetate mixed solution, an acetone/ethyl acetate mixed solution, an acetone/isopropyl ether mixed solution, or an acetone/n-heptane mixed solution; more preferably, the volume ratio of the two solvents in the mixed solution is 1:8-8:1, most preferably 1:5-5:1.
  • a compound of the formula (A) is added, and a solvent is added to obtain a clear solution, a saturated solution, a supersaturated solution or a suspension, and stirred to obtain a crystal form II.
  • the solvent is isopropanol, sec-butanol, ethyl acetate, toluene, isopropyl acetate or ethanol/ethyl acetate mixed solution, ethanol/isopropyl acetate mixed solution, ethanol/toluene mixed solution, acetone/gengeng a mixed solution of an alkane or a mixed solution of 1,4-dioxane/n-heptane; more preferably, the volume ratio of the two solvents in the mixed solution is 1:8-8:1, most preferably 1:5-5:1 .
  • the mixture is stirred at room temperature for 10 minutes to 5 days, most preferably at room temperature for 3 hours to 3 days.
  • the compound of the formula (A) is dissolved in a good solvent to obtain a clear solution, and an anti-solvent is added under stirring to obtain a crystal form II.
  • the good solvent is methyl ethyl ketone, dimethyl sulfoxide or 1,4-dioxane
  • the anti-solvent is n-heptane, isopropyl ether or isopropyl acetate.
  • the compound of the formula (A) is dissolved in a solvent under heating to obtain a clear solution, and the crystal is cooled to obtain a crystal form II.
  • the solvent is sec-butanol, nitromethane, acetone, or tetrahydrofuran.
  • it is heated to a temperature of from 40 to 90, most preferably, to a temperature of from 50 to 70 °C.
  • the method for producing the crystal form III of the present invention can be obtained by stirring a suspension of the compound of the formula (A) or by diffusion-crystallization of a saturated solution of the compound of the formula (A) in a solvent atmosphere. Specifically, one or two methods selected from the following may be included:
  • a compound of the formula (A) is added, and tetrahydrofuran is added to obtain a suspension, which is stirred to obtain a crystal form III.
  • the mixture is stirred at room temperature for 12 hours to 5 days, most preferably at room temperature for 1-3 days.
  • the process for preparing Form IV of the present invention can be obtained by adding an antisolvent crystallization to a solution of the compound of the formula (A). Specifically:
  • the compound of formula (A) is dissolved in n-butanol to give a clear solution, and n-heptane is added with stirring to obtain crystal form IV.
  • the method for preparing a mixture (or mixed crystal) of Form I and Form II of the present invention can be obtained by stirring and crystallizing a suspension of Form II at room temperature or elevated temperature. Specifically, one or more methods selected from the group consisting of:
  • the crystal form II is taken, and isopropyl acetate is added to obtain a suspension, which is stirred at 50 to 90 ° C to obtain a mixture of the crystal form I and the crystal form II.
  • Crystal form II is taken, and a solvent is added to obtain a suspension, which is stirred at room temperature to obtain a mixture of Form I and Form II.
  • the solvent is methyl tert-butyl ether or a mixed solution of ethanol/methylcyclohexane; more preferably, the volume ratio of the two solvents in the mixed solution is 1:8-8:1, most preferably 1:6-5 :1.
  • the stirring is for 3 hours to 3 days, most preferably, stirring for 1-3 days.
  • the crystalline form I of the present invention can also be used as a starting material for the preparation of Form II; preferably, Form I is suspended in an ester solvent such as ethyl acetate, isopropyl acetate or a mixture thereof. Liquid, stirred at room temperature overnight to obtain Form II;
  • an ester solvent such as ethyl acetate, isopropyl acetate or a mixture thereof. Liquid, stirred at room temperature overnight to obtain Form II;
  • the crystalline form III of the present invention can also be used as a starting material for the preparation of Form II; preferably, Form III is formed into a suspension in an ester solvent such as ethyl acetate, isopropyl acetate or a mixture thereof. Stirring at room temperature overnight to obtain Form II;
  • an ester solvent such as ethyl acetate, isopropyl acetate or a mixture thereof.
  • Form III of the present invention can also be used as a starting material for the preparation of Form I; preferably, Form III forms a suspension in an ester solvent such as ethyl acetate, isopropyl acetate or a mixture thereof. Stirring at room temperature overnight to obtain Form I;
  • an ester solvent such as ethyl acetate, isopropyl acetate or a mixture thereof.
  • Form IV of the present invention can also be used as a starting material for the preparation of Form I; preferably, Form IV is dried overnight at room temperature to obtain Form I.
  • a pharmaceutical composition comprising a therapeutically effective amount of any one of the crystalline forms I, II, III, IV of the invention, a mixture of any two or more, in any ratio, And a pharmaceutically acceptable carrier.
  • the pharmaceutical composition contains a therapeutically effective amount of a mixture of Forms I, II of the present invention or any ratio thereof, and a pharmaceutically acceptable carrier. More preferably, the weight ratio of Form I to Form II is from 1:99 to 99:1.
  • the pharmaceutical composition of the present invention can be formulated into powders for oral administration, tablets, (including various coated tablets, sustained release or controlled release tablets), troches, capsules (including soft capsules and hard capsules), Granules, pills, dispersible powders, aqueous or oily suspensions, aqueous or oily solutions, milk Agents, elixirs, syrups, etc.; powders or liquid aerosols suitable for inhalation; creams, ointments, gels, aqueous or oily solutions, aqueous or oily suspensions, etc. suitable for topical use, etc.
  • Pharmaceutically acceptable carriers include, but are not limited to, excipients, lubricants, binders, disintegrants, water soluble polymers, inorganic salts, solvents, dissolution aids, suspending agents, isotonic agents, buffers, preservatives Agents, antioxidants, colorants, sweeteners, sour agents, foaming agents and flavoring agents, and the like.
  • the pharmaceutical composition of the present invention may further comprise other active ingredients, such as other active ingredients for preventing and/or treating hypertension, such as calcium ion antagonists (dihydropyridines, aralkylamines, phenylthiazide). Leather and triphenyl piperazine).
  • the term "effective amount” or “therapeutically effective amount” refers to any one of the crystalline forms I, II, III, IV of the present invention, two of which are sufficient to achieve the intended application, including but not limited to disease treatment as defined below.
  • the amount of the mixture in any ratio or more.
  • the therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, etc. It is readily determined by one of ordinary skill in the art.
  • the particular dosage will vary depending on the particular compound selected, the dosage regimen upon which it is administered, whether it is administered in combination with other compounds, the timing of administration, the tissue to be administered, and the physical delivery system carried.
  • the present invention also provides a mixture of any one of the crystalline forms I, II, III, IV, any ratio of two or more, or the pharmaceutical composition of the present invention for preparing an angiotensin II receptor antagonist Use in the preparation, or in the preparation of a medicament for the prevention and/or treatment of hypertension, chronic heart failure, diabetic nephropathy.
  • the present invention also provides a mixture of any one of the crystalline forms I, II, III, IV, any ratio of two or more, or the pharmaceutical composition of the present invention as an angiotensin II receptor antagonist Applications, or for the prevention and/or treatment of hypertension, chronic heart failure, diabetic nephropathy.
  • Forms I, II and III described in this specification have stable chemical properties.
  • the content of impurities generated after they are placed is reduced relative to the amorphous material.
  • the crystal form stability of Forms I, II, and III is superior to Form IV at room temperature.
  • the crystal form of the present invention is relatively stable under tabletting conditions and under high temperature or high humidity conditions with respect to the amorphous material. These characteristics make the crystal form of the present invention more favorable to the quality control and drug-forming properties of the drug.
  • bioavailability of the crystal forms I, II, III and, for example, the mixture of Forms I and II is also improved relative to the amorphous material.
  • the inventors have also found that the crystalline form I of the present invention can be used as a raw material for preparing the crystalline form II, the crystalline form III is used as a raw material for preparing the crystalline form II, and the crystalline form III is used as a raw material for preparing the crystalline form I, and Form IV is used as a raw material for preparing crystal Type I.
  • the present invention provides more options for the preparation of the crystalline form of the compound of formula (A), which allows for the highly selective acquisition of the target crystalline form under milder conditions.
  • crystal refers to a crystalline form of a spatial arrangement of molecules and/or ions that have the same chemical composition but different crystallisation.
  • amorphous refers to a solid form of molecules and/or ions that are not crystalline.
  • the amorphous solid does not exhibit a defined X-ray powder diffraction pattern with a clear maximum.
  • X-ray powder diffraction pattern substantially as shown means at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least of the main peaks shown in the X-ray powder diffraction pattern. 90%, or at least 95%, or at least 99% of the peaks appear in the X-ray powder diffraction pattern; the main peak refers to the highest peak as the reference (the relative intensity of the highest peak is specified as 100%), and the relative intensity is greater than 10% Preferably, a peak greater than 30% is preferred.
  • Figure 1 is an X-ray powder diffraction pattern of Form I
  • Figure 2 is an X-ray powder diffraction pattern of Form II
  • Figure 3 is an X-ray powder diffraction pattern of Form III
  • Figure 4 is an X-ray powder diffraction pattern of Form IV
  • Figure 5 is a 1 H-NMR chart of the compound of formula (A);
  • Figure 6 is an X-ray powder diffraction pattern of the amorphous form of the compound of formula (A);
  • Form 7 is an X-ray powder diffraction pattern before and after drying at room temperature of Form IV (from top to bottom, Form I, Form IV after drying at room temperature, Form IV);
  • Figure 8 is an X-ray powder diffraction pattern of Form II under tabletting conditions (initial sample from top to bottom, sample after 25 kg pressure tableting, sample after 20 kg pressure tableting);
  • Figure 9 is an X-ray powder diffraction pattern of Form II after 10 days under high temperature and high humidity conditions (initial sample from top to bottom, sample at 60 ° C, sample at 85% relative humidity);
  • Figure 10 is a DSC-TGA spectrum of Form I
  • Figure 11 is a DSC-TGA spectrum of Form II
  • Figure 12 is a DSC-TGA spectrum of Form III
  • Figure 13 is a DSC-TGA map of Form IV.
  • the compound of the formula (B) (1.0 g) was dissolved in dichloromethane (5 ml), stirred at room temperature to form a solution, potassium phthalimide (0.27 g) was added to the solution, the reaction was kept for 4 h, and cooled to -50.
  • the solid obtained by spin-drying was dissolved in a solvent of the formula (A) (amorphous).
  • the control group was given 0.5% sodium carboxymethylcellulose (hereinafter referred to as CMC-Na); the compound group of the formula (B) and the compound of the formula (A) were dissolved in 0.5% CMC-Na at a dose of 1 mg/kg.
  • the effective dose of valsartan was administered at a dose of 4 mL/kg, and was administered by intragastric administration.
  • the systolic blood pressure and heart rate of the animals before administration were compared.
  • the systolic blood pressure and heart rate of SHR were compared before and after administration. Change, average three times per time point. The results are shown in Tables 1 and 2 below.
  • the compound group of the formula (A) has a more potent and long-lasting effect of lowering heart rate than the compound group of the formula (B).
  • a mixed solution of ethanol/ethyl acetate (0.1 ml: 0.5 ml), a mixed solution of ethanol/methyl tert-butyl ether (0.2 ml: 0.5 ml), ethanol/n-heptane (0.2 ml: 0.5 ml)
  • the mixed solution, a mixed solution of ethanol/methylcyclohexane (0.2 ml: 0.5 ml), or a mixed solution of n-butanol/n-heptane (0.2 ml: 0.5 ml) was also prepared to obtain crystal form I.
  • Form II 15 mg was taken, and 0.5 ml of methyl t-butyl ether was added to obtain a suspension, which was stirred at room temperature for 3 days, filtered, and dried to obtain a mixture of Form I and Form II.
  • a mixture of Form I and Form II was also prepared in the same manner by mixing a solution of ethanol/methylcyclohexane (1:5 by volume).
  • Form I and Form II samples were mixed well, 0.8 ml of ethyl acetate was added to form a suspension, stirred overnight, XRD detection, and the mixture of Forms I and II was prepared in an equal amount, compared with the overnight sample. It was found that the Form I content was about 5%.
  • the characteristic peak based on the crystal form I has a significant weakening tendency, and it is foreseen that the crystal form I will be completely crystallized into the crystal form II as long as sufficient time is given. It can be seen that the stability of Form II is better than that of Form I at room temperature.
  • Form II and Form III samples were mixed well, and 0.2 ml of ethyl acetate was added to form a suspension, which was stirred overnight, and XRD was found to be Form II. It can be seen that the crystal form III in the mixture is completely crystallized into the crystal form II, so that the crystal form II is better than the crystal form III under room temperature conditions.
  • Form I and Form III samples were mixed well, and 0.2 ml of ethyl acetate was added to form a suspension, which was stirred overnight, and XRD was determined to be Form I. It can be seen that the crystal form III in the mixture is completely crystallized into the crystal form I, so that the crystal form I is better than the crystal form III under room temperature conditions.
  • Crystalline Form III and Form IV samples were taken separately and dried overnight at room temperature. XRD detection showed that Form III was converted to Form I only by no more than 30%. However, the crystal form IV is all crystallized into the crystal form I, and the stability is poor. It can be seen from the above experiments that the stability of Forms I, II and III is superior to that of Form IV at room temperature.
  • Tableting method 50 mg of Form II was taken, and 20 kg and 25 kg of pressure tablets were placed under a single punching machine.
  • Example 12 Comparative pharmacokinetic test
  • the test sample in this study is the crystalline form I, crystalline form II, mixed crystal of the compound of formula (A) of the invention (a mixture of crystalline form I and crystalline form II, wherein Form I and Form II are The weight ratio is 1:3), the crystal form III and the amorphous type, the purity of the sample starting material is 99% or more, and the sodium carboxymethyl cellulose is a pharmaceutical grade auxiliary material.
  • Test animals SD rats were randomly divided into 6 groups of 6 animals each, half male and half female.
  • Drug preparation An appropriate volume of 0.5% (w/v) sodium carboxymethylcellulose aqueous solution was added according to the weight of each sample to make the final concentration of the drug 0.15 mg/ml, and the mixture was stirred under a magnetic stirrer for use.
  • Each test article was intragastrically administered to a fasted SD rat at a dose of 10 ml/kg. Collect 0.3 ml of blood into the anti-coagulation tube of EDTA-K2 at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h and 24 h after administration, and centrifuge at 3000 g for 10 min at 4 ° C. To -80 ° C to be tested.
  • the crystal form or the crystal form mixture of the present invention has good bioavailability and is superior to amorphous.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

提供如式（A）所示的化合物的晶型，其制备方法、组合物以及其在制备血管紧张素II受体拮抗剂中的应用，或者在制备用于预防和/或治疗高血压、慢性心衰、糖尿病肾病的药物中的应用。

Description

化合物的晶型及其制备方法、组合物和应用 技术领域
本发明涉及药物化学领域，具体涉及一种化合物的晶型及其制备方法、组合物和应用。
背景技术
高血压(Hypertension)是最常见的心血管疾病，也是导致充血性心力衰竭、脑卒中、冠心病、肾功能衰竭、主动脉瘤的发病率和病死率升高的主要危险因素。抗高血压药物在高血压的治疗与防治中起着关键作用。随着对高血压发病机制认识的不断深入，许多具有较佳疗效的抗高血压药物，比如利尿剂、β-受体阻滞剂、钙通道拮抗剂、血管紧张素转化酶抑制剂(ACEI，普利类)、血管紧张素II AT1受体拮抗剂(ARB，沙坦类)，不断被发现并成功应用于临床。经过多年的临床实践，确证AT1受体拮抗剂沙坦类药物由于其降血压平稳、疗效佳、作用时间长、患者耐受性好，尤其在预防卒中、延缓糖尿病和非糖尿病肾病的肾功能不全、改善左心室肥厚、对靶器官的保护作用等方面具有较多优势，且不影响缓激肽降解和前列腺素合成，从而不引起干咳和血管神经性水肿，现已成为全球抗高血压药物市场的主流品种。但是沙坦类抗高血压药物的降血压有效率仅约为50-60％，且具有一定程度的不良反应。因此，开发降压效果更强、不良反应更少，并对靶器官有较佳保护作用的小剂量长效降压药已成为一个热门的研究方向。
公开号为CN103709154A的中国专利申请首次公开了结构如下式(B)所示的化合物:
Figure PCTCN2017092416-appb-000001
上述化合物是偶联了川芎嗪的沙坦类药物，是血管紧张素II受体拮抗剂阿齐沙坦(TAK-536)的前药，该化合物在体内释放出羟基川芎嗪，从而与阿齐沙坦发生有效的协同 作用，增强抗高血压疗效，具有一定的降心率作用，减少不良反应，对患者心肾也具有较理想的保护作用。
申请人在进一步的研究中发现式(B)化合物的钾盐，即如下式(A)所示的化合物，溶解性能更好，生物利用度更高，具有更强效和更长效的降压效果，同时具有更明显且持久的降心率效果，且安全性高，对患者心肾功能具有较理想的保护作用，能够用于预防和/或治疗高血压、慢性心衰、糖尿病肾病等，
Figure PCTCN2017092416-appb-000002
然而，现有技术对于继续开发上述化合物更适宜的形式仍存在着需求。
发明内容
本发明提供式(A)所示化合物的晶型：
Figure PCTCN2017092416-appb-000003
其包括选自下列的晶型I、晶型II、晶型III、晶型IV或它们任意比例的混合物：
晶型I的X-射线粉末衍射图在衍射角2θ为5.3±0.2、8.6±0.2度位置有特征峰；优选，晶型I的X-射线粉末衍射图进一步在衍射角2θ为13.3±0.2、20.1±0.2度位置有特征峰；进一步优选，晶型I的X-射线粉末衍射图进一步在衍射角2θ为6.3±0.2、10.6±0.2、26.3±0.2度位置有特征峰；更优选，晶型I的X-射线粉末衍射图进一步在衍射角2θ为12.7±0.2度位置有特征峰；最优选，晶型I的X-射线粉末衍射图基本上如图1所示。
晶型II的X-射线粉末衍射图在衍射角2θ为4.7±0.2度位置有特征峰；优选，晶型II的X-射线粉末衍射图进一步在衍射角2θ为7.3±0.2、9.6±0.2、15.2±0.2、26.3±0.2度位置有特征峰；进一步优选，晶型II的X-射线粉末衍射图进一步在衍射角2θ为11.8±0.2、24.6±0.2度位置有特征峰；更优选，晶型II的X-射线粉末衍射图进一步在衍射角2θ为22.6±0.2度位置有特征峰；最优选，晶型II的X-射线粉末衍射图基本上如图2所示。
晶型III的X-射线粉末衍射图在衍射角2θ为5.2±0.2、8.0±0.2度位置有特征峰；优选，晶型III的X-射线粉末衍射图进一步在衍射角2θ为12.4±0.2、13.6±0.2度位置有特征峰；进一步优选，晶型III的X-射线粉末衍射图进一步在衍射角2θ为19.2±0.2度位置有特征峰；更优选，晶型III的X-射线粉末衍射图进一步在衍射角2θ为10.3±0.2、12.2±0.2、21.4±0.2度位置有特征峰；最优选，晶型III的X-射线粉末衍射图基本上如图3所示。
晶型IV的X-射线粉末衍射图在衍射角2θ为7.4±0.2、14.7±0.2、16.0±0.2度位置有特征峰；优选，晶型IV的X-射线粉末衍射图进一步在衍射角2θ为8.4±0.2、22.6±0.2、23.2±0.2、29.7±0.2度位置有特征峰；更优选，晶型IV的X-射线粉末衍射图进一步在衍射角2θ为24.0±0.2度位置有特征峰；最优选，晶型IV的X-射线粉末衍射图基本上如图4所示。
根据本发明的晶型，优选地，
晶型I的DSC图谱显示熔点为184±5℃；
晶型II的DSC图谱显示熔点为145±5℃；
晶型III的DSC图谱显示熔点为187±5℃；
晶型IV的DSC图谱显示熔点为145±5℃。
根据本发明的晶型，优选地，
晶型I的TGA图谱的分解温度为180±5℃；
晶型II的TGA图谱的分解温度为148±5℃；
晶型III的TGA图谱的分解温度为183±5℃；
晶型IV的TGA图谱的分解温度为149±5℃。
根据本发明的晶型，优选地，
晶型I具有基本如图10所示的DSC-TGA图谱；
晶型II具有基本如图11所示的DSC-TGA图谱；
晶型III具有基本如图12所示的DSC-TGA图谱；
晶型IV具有基本如图13所示的DSC-TGA图谱。
根据本发明的实施方案，还提供一种组合物或混合物，其含有晶型I、II、III、IV中的任一种、两种或更多种的任意比例的混合物。
优选，所述组合物或混合物含有任意比例的晶型I和晶型II，更优选，为晶型I和晶型II的任意比例的混合物。
由于晶型I和晶型II在一些条件下可以互相转化，本领域技术人员可以理解，对于晶型I和晶型II的混合物中晶型I和晶型II的比例没有特别限制。例如，晶型I和晶型II的重量比可以为1:99～99:1，如5:95～95:5。作为实例，晶型I和晶型II的重量比可以为1:9～9:1，2:8～8:2、3:7～7:3、4:6～6:4或5:5。
本发明还提供晶型I、II、III和IV的制备方法。
式(B)化合物可以通过本领域已知的方法，例如CN103709154A中公开的方法制备得到，在此将CN103709154A全文引入。式(A)化合物可以通过将式(B)化合物与钾盐试剂反应制备得到。
本发明制备晶型I的方法可以通过将式(A)化合物的悬浊液搅拌、在式(A)化合物的溶液中加入抗溶剂、将式(A)化合物的溶液冷却、将式(A)化合物在溶剂气氛中扩散结晶，或将式(A)化合物晶型III和/或晶型IV的悬浊液搅拌得到。具体来说，可以包括选自下列的一种或多种方法：
(1)取式(A)化合物，加入溶剂，得悬浊液，搅拌，得到晶型I。优选，溶剂为乙醇/异丙醚混合溶液、乙醇/正庚烷混合溶液、异丙醇/正庚烷混合溶液、或四氢呋喃/正庚烷混合溶液；更优选，混合溶液中两种溶剂的体积比为1:8-8:1，最优选1:5-5:1。优选，室温搅拌0.5-3天，最优选，室温搅拌1-2天。
(2)将式(A)化合物溶于良溶剂中，得澄清溶液，搅拌下加入抗溶剂，得到晶型I。优选，良溶剂为甲醇、乙醇、或正丁醇，抗溶剂为异丙醚、甲基叔丁基醚、或甲基环己烷。
(3)将式(A)化合物在加热条件下溶于溶剂中，得澄清溶液，冷却结晶，得到晶型I。优选，溶剂为乙醇/异丙醚混合溶液、乙醇/乙酸乙酯混合溶液、乙醇/甲基叔丁基醚混合溶液、乙醇/正庚烷混合溶液、乙醇/甲基环己烷混合溶液、或正丁醇/正庚烷混合溶液；更优选，混合溶液中两种溶剂的体积比为1:8-8:1，最优选1:5-5:1。优选，加热至温度为40-90，最优选，加热至温度为50-70℃。
(4)将式(A)化合物置于乙醇的溶剂气氛中扩散1-3天，得到晶型I。
(5)将式(A)化合物晶型III和/或晶型IV加入溶剂，形成悬浊液，搅拌，干燥，得到晶型I；优选地，加入的溶剂选自酯类溶剂，例如乙酸乙酯，乙酸异丙酯或其混合物。
本发明制备晶型II的方法可以通过将式(A)化合物的溶液挥发干、将式(A)化合物的溶液、饱和溶液、过饱和溶液或悬浊液搅拌、在式(A)化合物的溶液中加入抗溶剂、将式(A)化合物的溶液冷却、将式(A)化合物的饱和溶液在溶剂气氛中扩散、或将式(A)化合物在溶剂气氛中扩散结晶得到。具体来说，可以包括选自下列的一种或多种方法：
(1)将式(A)化合物溶于溶剂中，得澄清溶液，室温挥发干，得到晶型II。优选，溶剂为乙醇/乙酸乙酯混合溶液、丙酮/乙酸乙酯混合溶液、丙酮/异丙醚混合溶液、或丙酮/正庚烷混合溶液；更优选，混合溶液中两种溶剂的体积比为1:8-8:1，最优选1:5-5:1。
(2)取式(A)化合物，加入溶剂，得澄清溶液、饱和溶液、过饱和溶液或悬浊液，搅拌，得到晶型II。优选，溶剂为异丙醇、仲丁醇、乙酸乙酯、甲苯、乙酸异丙酯或者乙醇/乙酸乙酯混合溶液、乙醇/乙酸异丙酯混合溶液、乙醇/甲苯混合溶液、丙酮/正庚烷混合溶液、或1,4-二氧六环/正庚烷混合溶液；更优选，混合溶液中两种溶剂的体积比为1:8-8:1，最优选1:5-5:1。优选，室温搅拌10分钟-5天，最优选，室温搅拌3小时-3天。
(3)将式(A)化合物溶于良溶剂中，得澄清溶液，搅拌下加入抗溶剂，得到晶型II。优选，良溶剂为丁酮、二甲基亚砜、或1,4-二氧六环，抗溶剂为正庚烷、异丙醚、或乙酸异丙酯。
(4)将式(A)化合物在加热条件下溶于溶剂中，得澄清溶液，冷却结晶，得到晶型II。优选，溶剂为仲丁醇、硝基甲烷、丙酮、或四氢呋喃。优选，加热至温度为40-90，最优选，加热至温度为50-70℃。
(5)将式(A)化合物的乙醇饱和溶液，置于异丙醚或乙酸异丙酯的溶剂气氛中扩散，直至析出固体，得到晶型II。
(6)将式(A)化合物置于甲苯、异丙醇、四氢呋喃、或乙酸乙酯的溶剂气氛中扩散1-3天，得到晶型II。
本发明制备晶型III的方法可以通过将式(A)化合物的悬浊液搅拌、或将式(A)化合物的饱和溶液在溶剂气氛中扩散结晶得到。具体来说，可以包括选自下列的一种或两种方法：
(1)取式(A)化合物，加入四氢呋喃，得悬浊液，搅拌，得到晶型III。优选，室温搅拌12小时至5天，最优选，室温搅拌1-3天。
(2)将式(A)化合物的四氢呋喃饱和溶液，置于异丙醚的溶剂气氛中扩散，直至析出固体，得到晶型III。
本发明制备晶型IV的方法可以通过在式(A)化合物的溶液中加入抗溶剂结晶得到。具体来说：
将式(A)化合物溶于正丁醇中，得澄清溶液，搅拌下加入正庚烷，得到晶型IV。
本发明制备晶型I和晶型II的混合物(或者混晶)的方法可以通过将晶型II的悬浊液在室温或高温条件下搅拌结晶得到。具体来说，可以包括选自下列的一种或多种方法：
(1)取晶型II，加入乙酸异丙酯，得悬浊液，50-90℃下搅拌，得到晶型I和晶型II的混合物。优选，50-90℃下搅拌3小时至3天，最优选，60-90℃下搅拌5小时至1天；
(2)取晶型II湿品，粉碎过筛后，于40～60℃(如50℃)真空烘料，优选真空烘料3小时至3天，例如24h；
(3)取晶型II湿品，于40～60℃(如50℃)真空烘料3小时至3天后微粉化，优选真空烘料24小时后微粉化；
(4)取晶型II，加入溶剂，得悬浊液，室温搅拌，得到晶型I和晶型II的混合物。优选，溶剂为甲基叔丁基醚、或乙醇/甲基环己烷混合溶液；更优选，混合溶液中两种溶剂的体积比为1:8-8:1，最优选1:6-5:1。优选，搅拌3小时至3天，最优选，搅拌1-3天。
作为选择，还可以将本发明的晶型I作为原料用于制备晶型II；优选地，将晶型I在酯类溶剂(例如乙酸乙酯、乙酸异丙酯或其混合物)中形成悬浊液，室温搅拌过夜获得晶型II；
或者，还可以将本发明的晶型III作为原料用于制备晶型II；优选地，将晶型III在酯类溶剂(例如乙酸乙酯、乙酸异丙酯或其混合物)中形成悬浊液，室温搅拌过夜获得晶型II；
或者，还可以将本发明的晶型III作为原料用于制备晶型I；优选地，晶型III在酯类溶剂(例如乙酸乙酯、乙酸异丙酯或其混合物)中形成悬浊液，室温搅拌过夜获得晶型I；
或者，还可以将本发明的晶型IV作为原料用于制备晶型I；优选地，晶型IV在室温下干燥过夜获得晶型I。
本发明的另一个方面，提供了一种药物组合物，含有治疗有效量的本发明的晶型I、II、III、IV中的任一种、两种或更多种的任意比例的混合物，以及药学上可接受的载体。优选，药物组合物中含有治疗有效量的本发明的晶型I、II或其任意比例的混合物，以及药学上可接受的载体。更优选，晶型I和晶型II的重量比为1:99-99:1。本发明的药物组合物可以制成用于口服的散剂、片剂、(包括各种包衣片剂、缓释或控释片剂)、锭剂、胶囊剂(包括软胶囊和硬胶囊)、颗粒剂、丸剂、可分散粉末、水性或油性混悬剂、水性或油性溶液剂、乳 剂、酏剂、糖浆剂等等；适于吸入使用的粉末或液体气雾剂；适于局部使用的霜剂、软膏剂、凝胶、水性或油性溶液剂、水性或油性混悬剂等等；适于经胃肠外给药的静脉内、皮下或肌内注射用无菌水性或油性的注射剂或冻干粉针剂、栓剂等等。药学上可接受的载体包括但不限于赋形剂、润滑剂、粘合剂、崩解剂、水溶性聚合物、无机盐、溶剂、溶解助剂、悬浮剂、等渗剂、缓冲液、防腐剂、抗氧剂、着色剂、甜味剂、酸味剂、起泡剂和调味剂等等。
本发明的药物组合物中还可以进一步含有其他活性成分，例如其他用于预防和/或治疗高血压的活性成分，如钙离子拮抗剂(二氢吡啶类、芳烷基胺类、苯硫氮革类和三苯哌嗪类)。
本领域技术人员根据常规方法能够确定药物组合物中晶型I、II、III、IV中的任一种、两种或更多种的任意比例的混合物以及各种药学上可接受的载体和/或其他活性成分的合适的量。术语“有效量”或者“治疗有效量”是指足以实现预期应用(包括但不限于如下定义的疾病治疗)的本发明所述晶型I、II、III、IV中的任一种、两种或更多种的任意比例的混合物的量。治疗有效量可以因以下因素而改变：预期应用(体外或者体内)，或者所治疗的受试者和疾病病症如受试者的重量和年龄、疾病病症的严重性和给药方式等，其可以由本领域普通技术人员容易地确定。具体剂量将取决于以下因素而改变：所选择的特定化合物、所依据的给药方案、是否与其它化合物联合给药、给药的时间安排、所给药的组织和所承载的物理递送系统。
本发明还提供所述晶型I、II、III、IV中的任一种、两种或更多种的任意比例的混合物，或本发明所述药物组合物在制备血管紧张素II受体拮抗剂中的应用，或者在制备用于预防和/或治疗高血压、慢性心衰、糖尿病肾病的药物中的应用。
本发明还提供所述晶型I、II、III、IV中的任一种、两种或更多种的任意比例的混合物，或本发明所述药物组合物作为血管紧张素II受体拮抗剂的应用，或者用于预防和/或治疗高血压、慢性心衰、糖尿病肾病的应用。
本发明的有益效果
发明人发现，本说明书描述的晶型I、II和III具有稳定的化学性质。相对于无定型物，它们放置后所产生杂质的含量均得以降低。并且，在室温条件下，晶型I、II、III的晶型稳定性均优于晶型IV。并且，相对于无定型物，本发明的晶型在压片条件下以及高温或高湿条件下晶型较稳定。这些特性使得本发明的晶型更有利于药物的质量控制及成药性。进一步地，相对于无定型物，晶型I、II、III以及例如晶型I和II的混合物的生物利用度也均得到改善。
并且，发明人还发现，可以将本发明的晶型I作为原料用于制备晶型II，晶型III作为原料用于制备晶型II，晶型III作为原料用于制备晶型I，以及将晶型IV作为原料用于制备晶 型I。从而，本发明为式(A)化合物晶型的制备方法提供更多选择，可以实现在更为温和的条件下，高选择性地获得目标晶型。
术语解释
术语“晶体”指具有相同化学组成但有不同的形成结晶的分子和/或离子的空间排布的晶型。
术语“无定型”指不是结晶的分子和/或离子的固体形式。无定型固体不显示确定的具有清晰最大值的X-射线粉末衍射图形。
术语“X-射线粉末衍射图基本上如图所示”是指X-射线粉末衍射图所示的主要峰中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰出现在X-射线粉末衍射图中；其主要峰指以最高峰作为参照(最高峰的相对强度指定为100％)，相对强度大于10％、优选大于30％的峰。
附图说明
图1为晶型I的X-射线粉末衍射图；
图2为晶型II的X-射线粉末衍射图；
图3为晶型III的X-射线粉末衍射图；
图4为晶型IV的X-射线粉末衍射图；
图5为式(A)化合物的1H-NMR图谱；
图6为式(A)化合物无定型形式的X-射线粉末衍射图谱；
图7为晶型IV室温干燥前后X-射线粉末衍射图谱(从上到下依次为晶型I、晶型IV室温干燥后、晶型IV)；
图8为晶型II在压片条件下的X-射线粉末衍射图(从上到下依次为初始样品、25公斤压力压片后的样品、20公斤压力压片后的样品)；
图9为晶型II在高温高湿条件下10天后的X-射线粉末衍射图(从上到下依次为初始样品、60℃条件下的样品、85％相对湿度下的样品)；
图10为晶型I的DSC-TGA图谱；
图11为晶型II的DSC-TGA图谱；
图12为晶型III的DSC-TGA图谱；
图13为晶型IV的DSC-TGA图谱。
具体实施方式
下面将结合具体实施例对本发明做更进一步的详细说明。本领域技术人员可以借鉴本文内容，适当更改工艺参数实现。特别需要指出的是，所有类似的替换和改动均应被视为包括在本发明的保护范围内。本发明的产品已经通过较佳实施例进行了描述，相关人员能在不脱离本发明内容、精神和范围内对本文所述的产品进行改动或适当变更与组合，来实现和应用本技术。
实施例1：式(A)化合物的制备
将式(B)化合物(1.0g)溶于二氯甲烷(5ml)中，室温搅拌形成溶液，往溶液中加入邻苯二甲酰亚胺钾(0.27g)，保温反应4h，冷却至-50℃，过滤，溶剂旋干所得固体为式(A)化合物(无定型)。
熔点：135-145℃。
MS/HRMS m/z：717[M+H]+；677[M-K]-。
1H-NMR(400MHz,DMSO-d6)δ：1.44(t，3H)，1.46(t，3H)，2.38(s，3H)，2.41(s，3H)，2.44(s，3H)，4.64(q，2H)，5.29(d，1H)，5.32(d，1H)，5.52(d，1H)，5.56(d，1H)，6.86(q，1H)，6.90(d，2H)，7.18(m，2H)，7.22(d，2H)，7.33(m，1H)，7.36(m，1H)，7.46(d，1H)，7.52(dd，1H)，7.75(d，1H)。
1H-NMR图谱和X射线粉末衍射图谱分别见图5和图6。
实施例2：式(A)化合物在自发性高血压大鼠上的抗高血压药效试验
取12周龄的自发性高血压大鼠(以下简称SHR，购自北京维通利华实验动物技术有限公司)，以2.5％的戊巴比妥钠进行腹腔注射麻醉，将血压植入子的血压感应导管插入腹主动脉，植入子固定于腹壁，缝合后进行术后日常看护。选取收缩压超过160mm Hg的动物进入分组，每组8只动物，共3组。对照组给予0.5％的羧甲基纤维素钠(下称CMC-Na)；式(B)化合物组和式(A)化合物组采用0.5％CMC-Na溶解，给药剂量均以1mg/kg阿齐沙坦有效剂量计，给药体积为4mL/kg，均灌胃给药，以给药前动物的收缩压和心率为基准值，比较给药前、后各时间点SHR的收缩压和心率变化，每个时间点测三次取平均值。结果见下表1和表2。
表1.式(B)化合物、式(A)化合物口服给药前、后各时间点收缩压变化(平均值(mmHg)±标准误差)
Figure PCTCN2017092416-appb-000004
*P<0.01(相对于对照组)。
从表1结果可以看出，给药3小时后各给药组与对照组比较收缩压均显著下降，在给药5-7小时药效达峰，式(A)化合物组具有比式(B)化合物组更强效和长效的降压效果。
表2.式(B)化合物、式(A)化合物口服给药前、后各时间点心率变化(平均值(次/分钟)±标准误差)
Figure PCTCN2017092416-appb-000005
*P<0.05(相对于对照组单因素方差比较)。
从表2结果可以看出，式(A)化合物组具有比式(B)化合物组更强效和长效的降心率效果。
实施例3：晶型I的制备
(1)取15mg式(A)化合物，加入0.2ml乙醇/异丙醚(体积比为1:5)混合溶液，得悬浊液，室温搅拌1天，过滤，干燥，得到晶型I。XRD检测图谱见附图1；DSC：184℃。按照相同的方法，用乙醇/正庚烷(体积比为1:5)混合溶液、异丙醇/正庚烷(体积比为1:5)混合溶液、或四氢呋喃/正庚烷(体积比为1:5)混合溶液同样制备得到了晶型I。
(2)将15mg式(A)化合物溶于0.1ml甲醇中，得澄清溶液，搅拌下加入1.0ml异丙醚，析出固体，继续搅拌，过滤，干燥，得到晶型I。按照相同的方法，用良溶剂乙醇/抗溶剂异丙醚、良溶剂乙醇/抗溶剂甲基叔丁基醚、良溶剂乙醇/抗溶剂甲基环己烷、良溶剂正丁醇/抗溶剂异丙醚同样制备得到了晶型I。
(3)将10mg式(A)化合物在60℃溶于乙醇/异丙醚(0.2ml:0.5ml)混合溶液中，得澄清溶液，冷却结晶，得到晶型I。按照相同的方法，用乙醇/乙酸乙酯(0.1ml:0.5ml)混合溶液、乙醇/甲基叔丁基醚(0.2ml:0.5ml)混合溶液、乙醇/正庚烷(0.2ml:0.5ml)混合溶液、乙醇/甲基环己烷(0.2ml:0.5ml)混合溶液、或正丁醇/正庚烷(0.2ml:0.5ml)混合溶液同样制备得到了晶型I。
(4)将8mg式(A)化合物置于乙醇的溶剂气氛中(即置于装有乙醇的大容器中)扩散1天，干燥，得到晶型I。
(5)将15mg式(A)化合物晶型III样品，加入0.2ml乙酸乙酯形成悬浊液，搅拌过夜，干燥，得到晶型I。
(6)将15mg式(A)化合物晶型IV样品，加入0.2ml乙酸乙酯形成悬浊液，搅拌过夜，室温干燥，得到晶型I。
实施例4：晶型II的制备
(1)取1.1g式(A)化合物，加入10ml乙酸乙酯，得澄清溶液，室温搅拌3小时，过滤，干燥，得到产品0.88g，所得晶型II的XRD检测图谱见附图2；DSC：145.4℃。逐渐减少乙酸乙酯的用量，发现饱和溶液、过饱和溶液、悬浊液室温搅拌均能够得到晶型II。
按照相同的方法，用异丙醇、仲丁醇、乙酸异丙酯、或甲苯，或者乙醇/乙酸乙酯(体积比为1:5)混合溶液、乙醇/乙酸异丙酯(体积比为1:5)混合溶液、乙醇/甲苯(体积比为1:5)混合溶液、丙酮/正庚烷(体积比为1:5)混合溶液、或1,4-二氧六环/正庚烷(体积比为1:5)混合溶液，同样制备得到了晶型II。
(2)将5mg式(A)化合物溶于乙醇/乙酸乙酯(0.2ml:0.5ml)混合溶液中，得澄清溶液，室温挥发干，得到晶型II。按照相同的方法，用丙酮/乙酸乙酯混合溶液(1.0ml:0.5ml)、丙酮/异丙醚混合溶液(2.0ml:0.5ml)、或丙酮/正庚烷混合溶液(2.0ml:0.5ml)同样制备得到了晶型II。
(3)将15mg式(A)化合物溶于0.8ml丁酮中，得澄清溶液，搅拌下加入4.0ml正庚烷，析出固体，过滤，干燥，得到晶型II。按照相同的方法，用良溶剂为丁酮/抗溶剂异丙醚、 良溶剂二甲基亚砜/抗溶剂乙酸异丙酯、或良溶剂1,4-二氧六环/抗溶剂异丙醚同样制备得到了晶型II。
(4)将10mg式(A)化合物在60℃溶于仲丁醇中，得澄清溶液，冷却结晶，得到晶型II。按照相同的方法，用硝基甲烷、丙酮、或四氢呋喃同样制备得到了晶型II。
(5)将5mg式(A)化合物溶于适量乙醇中，得饱和溶液，置于异丙醚的溶剂气氛中(即置于装有异丙醚的大容器中)扩散，直至析出固体，过滤，干燥，得到晶型II。按照相同的方法，置于乙酸异丙酯的溶剂气氛中扩散同样制备得到了晶型II。
(6)将8mg式(A)化合物置于甲苯的溶剂气氛中(即置于装有甲苯的大容器中)扩散3天，干燥，得到晶型II。按照相同的方法，置于异丙醇、四氢呋喃、乙酸乙酯的溶剂气氛中扩散同样制备得到了晶型II。
实施例5：晶型III的制备
(1)取100mg式(A)化合物，加入1.0ml四氢呋喃，得悬浊液，室温搅拌1天，过滤，干燥，所得晶型III的XRD检测图谱见附图3；DSC：187.3℃。
(2)将5mg式(A)化合物溶于适量四氢呋喃中，得饱和溶液，置于异丙醚的溶剂气氛中(即置于装有异丙醚的大容器中)静置，直至析出固体，过滤，干燥，得到晶型III。
实施例6：晶型IV的制备
将50mg式(A)化合物溶于1.0ml正丁醇中，得澄清溶液，搅拌下加入5.0ml正庚烷，析出固体，过滤，所得晶型IV的XRD检测图谱见附图4；DSC熔点：144.7℃。
晶型IV的晶型在室温下干燥会转变为晶型I，详见附图7。
实施例7：晶型I和晶型II的混合物的制备
(1)取100mg晶型II，加入2.5ml乙酸异丙酯，得悬浊液，于80℃水浴中搅拌8小时，过滤，干燥，经XRD检测结果可知，晶型I含量约为95％，晶型II含量约为5％。
(2)取100mg晶型II湿品，粉碎过筛后，于50℃真空烘料24h，经XRD检测结果可知，晶型I含量约为10％，晶型II含量约为90％。
(3)取100g晶型II湿品，于50℃真空烘料24h，微粉机微粉化后，经XRD检测结果可知，晶型I含量约为30％，晶型II含量约为70％。
(4)取15mg晶型II，加入0.5ml甲基叔丁基醚得到悬浊液，在室温下搅拌3天，过滤，干燥，得到晶型I和晶型II的混合物。按照相同的方法，用乙醇/甲基环己烷(体积比为1:5)混合溶液同样制备得到了晶型I和晶型II的混合物。
实施例8：室温竞争试验
(1)晶型I与晶型II的竞争实验
取等量晶型I和晶型II样品混合均匀，加入0.8ml乙酸乙酯形成悬浊液，搅拌过夜，XRD检测，按照等量递增的方式配制晶型I和II的混合物，与过夜样品对比得到，晶型I含量约为5％。基于晶型I的特征峰有明显的减弱趋势，可以预见，只要给予足够的时间，晶型I会完全转晶为晶型II。从而可知室温条件下，晶型II稳定性优于晶型I。
(2)晶型II与晶型III的竞争实验
取等量晶型II和晶型III样品混合均匀，加入0.2ml乙酸乙酯形成悬浊液，搅拌过夜，XRD检测为晶型II。由此可见，混合物中晶型III完全转晶为晶型II，从而可知室温条件下，晶型II稳定性优于晶型III。
(3)晶型I与晶型III的竞争实验
取等量晶型I和晶型III样品混合均匀，加入0.2ml乙酸乙酯形成悬浊液，搅拌过夜，XRD检测为晶型I。由此可见，混合物中晶型III完全转晶为晶型I，从而可知室温条件下，晶型I稳定性优于晶型III。
(4)晶型III与晶型IV稳定性对比实验
分别取晶型III和晶型IV样品，室温干燥过夜，XRD检测显示晶型III仅有不超过30％的量转化为晶型I。然而，晶型IV全部转晶为晶型I，稳定性较差。由上述实验可知，室温条件下，晶型I、II和III的稳定性均优于晶型IV。
实施例9：考察压片对晶型II的影响
压片方法：取50mg的晶型II，于单冲压片机下进行20公斤和25公斤压力压片。
对压片后样品粉末进行XRD检测，与初始样品进行比较，见图8，从上到下依次为初始样品、25公斤压力压片后的样品、20公斤压力压片后的样品，由图中看出压片后晶型保持不变。
实施例10：考察高温和高湿对晶型II的影响
取两份20mg的晶型II，分别在60℃(避光密封)和85％相对湿度下(室温避光敞口)放置，10天后进行XRD检测，与初始样品进行比较，样品晶型未发生改变，详见图9(从上到下依次为初始样品、60℃条件下的样品、85％相对湿度下的样品)。
实施例11：稳定性对比试验
申请人对式(A)化合物的无定型、晶型I和II的混合物和晶型II的稳定性进行了考察，取无定型、晶型I和晶型II的混合物(重量比为1:2)、晶型II和晶型Ⅲ各200mg，采用如下方式进行考察：
包装：内层PVC材质自封袋抽真空，中层铝箔抽真空，外层铝箔干燥剂抽真空充氮气；考察条件：25℃，60％相对湿度。考察指标为总杂质含量，于不同时间点取样检测，每批次取样检测三次，取平均值，取样时间为：0、1、2、3和6个月。试验结果见下表3。
表3：稳定性试验
Figure PCTCN2017092416-appb-000006
结论：从上表可见，晶型I，晶型II，晶型III及晶型I和晶型II的混合物的化学稳定性明显优于无定型，晶型化合物对比无定型更有利于药物的质量控制及成药性。
实施例12：药代动力学对比试验
药品与试剂：本研究中受试样品为本发明式(A)化合物的晶型I、晶型II、混晶(晶型I和晶型II的混合物，其中晶型I和晶型II的重量比为1:3)、晶型III和无定型，样品起始物质纯度为99％以上，羧甲基纤维素钠为药用级辅料。
试验动物：SD大鼠被随机分为6组，每组6只动物，雌雄各半。
药物配制：根据各样品的重量加入适量体积的0.5％(W/V)的羧甲基纤维素钠水溶液，使药物终浓度为0.15mg/ml，置于磁力搅拌器下搅拌备用。
给药和样品采集：将各受试物按10ml/kg的剂量灌胃给予禁食的SD大鼠。在给药后的15min、30min、1h、2h、4h、6h、8h、10h和24h分别收集0.3ml血液至EDTA-K2的抗凝管中，于4℃下3000g离心10min后取上清液保存至-80℃待检。
样品通过LC-MS/MS(AB Sciex,API 3500QTRAP)分析血浆中化合物B和阿齐沙坦。在各时间点取样的动物血浆中检测不到化合物B，给药后各受试物在动物体内会快速转化为阿齐沙坦，给予受试物后动物血浆中阿齐沙坦的药代动力学参数如下表：
Figure PCTCN2017092416-appb-000007
结论：上述实验中，本发明的晶型或晶型混合物的生物利用度良好，优于无定型。

Claims (10)

  1. 式(A)所示化合物的晶型：
    Figure PCTCN2017092416-appb-100001
    其包括选自下列的晶型I、晶型II、晶型III、晶型IV或它们任意比例的混合物，其中：
    所述晶型I的X-射线粉末衍射图在衍射角2θ为5.3±0.2、8.6±0.2度位置有特征峰；优选，晶型I的X-射线粉末衍射图进一步在衍射角2θ为13.3±0.2、20.1±0.2度位置有特征峰；进一步优选，晶型I的X-射线粉末衍射图进一步在衍射角2θ为6.3±0.2、10.6±0.2、26.3±0.2度位置有特征峰；更优选，晶型I的X-射线粉末衍射图进一步在衍射角2θ为12.7±0.2度位置有特征峰；最优选，晶型I的X-射线粉末衍射图基本上如图1所示；
    所述晶型II的X-射线粉末衍射图在衍射角2θ为4.7±0.2度位置有特征峰；优选，晶型II的X-射线粉末衍射图进一步在衍射角2θ为7.3±0.2、9.6±0.2、15.2±0.2、26.3±0.2度位置有特征峰；进一步优选，晶型II的X-射线粉末衍射图进一步在衍射角2θ为11.8±0.2、24.6±0.2度位置有特征峰；更优选，晶型II的X-射线粉末衍射图进一步在衍射角2θ为22.6±0.2度位置有特征峰；最优选，晶型II的X-射线粉末衍射图基本上如图2所示；
    所述晶型III的X-射线粉末衍射图在衍射角2θ为5.2±0.2、8.0±0.2度位置有特征峰；优选，晶型III的X-射线粉末衍射图进一步在衍射角2θ为12.4±0.2、13.6±0.2度位置有特征峰；进一步优选，晶型III的X-射线粉末衍射图进一步在衍射角2θ为19.2±0.2度位置有特征峰；更优选，晶型III的X-射线粉末衍射图进一步在衍射角2θ为10.3±0.2、12.2±0.2、21.4±0.2度位置有特征峰；最优选，晶型III的X-射线粉末衍射图基本上如图3所示；
    所述晶型IV的X-射线粉末衍射图在衍射角2θ为7.4±0.2、14.7±0.2、16.0±0.2度位置有特征峰；优选，晶型IV的X-射线粉末衍射图进一步在衍射角2θ为8.4±0.2、22.6±0.2、23.2±0.2、 29.7±0.2度位置有特征峰；更优选，晶型IV的X-射线粉末衍射图进一步在衍射角2θ为24.0±0.2度位置有特征峰；最优选，晶型IV的X-射线粉末衍射图基本上如图4所示。
  2. 如权利要求1所述的晶型，其特征在于，晶型I的DSC图谱显示熔点为184±5℃；晶型II的DSC图谱显示熔点为145±5℃；晶型III的DSC图谱显示熔点为187±5℃；晶型IV的DSC图谱显示熔点为145±5℃。
  3. 如权利要求1或2所述的晶型的制备方法，其特征在于，晶型I的制备方法包括选自下列的一种或多种方法：
    (1)取式(A)化合物，加入溶剂，得悬浊液，搅拌，得到晶型I；优选，溶剂为乙醇/异丙醚混合溶液、乙醇/正庚烷混合溶液、异丙醇/正庚烷混合溶液、或四氢呋喃/正庚烷混合溶液；更优选，混合溶液中两种溶剂的体积比为1:8-8:1，最优选1:5-5:1；优选，室温搅拌0.5-3天，最优选，室温搅拌1-2天；或
    (2)将式(A)化合物溶于良溶剂中，得澄清溶液，搅拌下加入抗溶剂，得到晶型I；优选，良溶剂为甲醇、乙醇、或正丁醇，抗溶剂为异丙醚、甲基叔丁基醚、或甲基环己烷；或
    (3)将式(A)化合物在加热条件下溶于溶剂中，得澄清溶液，冷却结晶，得到晶型I；优选，溶剂为乙醇/异丙醚混合溶液、乙醇/乙酸乙酯混合溶液、乙醇/甲基叔丁基醚混合溶液、乙醇/正庚烷混合溶液、乙醇/甲基环己烷混合溶液、或正丁醇/正庚烷混合溶液；更优选，混合溶液中两种溶剂的体积比为1:8-8:1，最优选1:5-5:1；优选，加热至温度为40-90℃，最优选，加热至温度为50-70℃；或
    (4)将式(A)化合物置于乙醇的溶剂气氛中扩散1-3天，得到晶型I；或
    (5)将式(A)化合物晶型III和/或晶型IV加入溶剂，形成悬浊液，搅拌，干燥，得到晶型I；优选地，加入的溶剂选自酯类溶剂，例如乙酸乙酯，乙酸异丙酯或其混合物。
  4. 如权利要求1或2所述的晶型的制备方法，其特征在于，晶型II的制备方法包括选自下列的一种或多种方法：
    (1)将式(A)化合物溶于溶剂中，得澄清溶液，室温挥发干，得到晶型II；优选，溶剂为乙醇/乙酸乙酯混合溶液、丙酮/乙酸乙酯混合溶液、丙酮/异丙醚混合溶液、或丙酮/正庚烷混合溶液；更优选，混合溶液中两种溶剂的体积比为1:8-8:1，最优选1:5-5:1；或
    (2)取式(A)化合物，加入溶剂，得澄清溶液、饱和溶液、过饱和溶液或悬浊液，搅拌，得到晶型II；优选，溶剂为异丙醇、仲丁醇、乙酸乙酯、甲苯、乙酸异丙酯或者乙醇/乙酸乙酯混合溶液、乙醇/乙酸异丙酯混合溶液、乙醇/甲苯混合溶液、丙酮/正庚烷混合溶液、或1,4-二氧六环/正庚烷混合溶液；更优选，混合溶液中两种溶剂的体积比为1:8-8:1，最优选1:5-5:1；优选，室温搅拌10分钟-5天，最优选，室温搅拌3小时-3天；或
    (3)将式(A)化合物溶于良溶剂中，得澄清溶液，搅拌下加入抗溶剂，得到晶型II；优选，良溶剂为丁酮、二甲基亚砜、或1,4-二氧六环，抗溶剂为正庚烷、异丙醚、或乙酸异丙酯；或
    (4)将式(A)化合物在加热条件下溶于溶剂中，得澄清溶液，冷却结晶，得到晶型II；优选，溶剂为仲丁醇、硝基甲烷、丙酮、或四氢呋喃；优选，加热至温度为40-90，最优选，加热至温度为50-70℃；或
    (5)将式(A)化合物的乙醇饱和溶液，置于异丙醚或乙酸异丙酯的溶剂气氛中扩散，直至析出固体，得到晶型II；或
    (6)将式(A)化合物置于甲苯、异丙醇、四氢呋喃、或乙酸乙酯的溶剂气氛中扩散1-3天，得到晶型II。
  5. 如权利要求1或2所述的晶型的制备方法，其特征在于，晶型III的制备方法包括选自下列的一种或多种方法：
    (1)取式(A)化合物，加入四氢呋喃，得悬浊液，搅拌，得到晶型III；优选，室温搅拌12小时至5天，最优选，室温搅拌1-3天；或
    (2)将式(A)化合物的四氢呋喃饱和溶液，置于异丙醚的溶剂气氛中扩散，直至析出固体，得到晶型III。
  6. 如权利要求1或2所述的晶型的制备方法，其特征在于，晶型IV的制备方法包括将式(A)化合物溶于正丁醇中，得澄清溶液，搅拌下加入正庚烷，得到晶型IV。
  7. 一种组合物，其特征在于，含有如权利要求1或2所述的晶型I、II、III、IV中的任一种、两种或更多种的任意比例的混合物；
    优选，所述组合物含有如权利要求1或2所述的晶型I和晶型II；
    例如，晶型I和晶型II的重量比为1:99-99:1，如5:95～95:5；
    例如，晶型I和晶型II的重量比可以为1:9～9:1，2:8～8:2、3:7～7:3、4:6～6:4或5:5。
  8. 如权利要求7所述的组合物的制备方法，其特征在于包括选自下列的一种或多种方法：
    (1)取晶型II，加入乙酸异丙酯，得悬浊液，50-90℃下搅拌，得到晶型I和晶型II的混合物；优选，50-90℃下搅拌3小时至3天，最优选，60-90℃下搅拌5小时至1天；或
    (2)取晶型II湿品，粉碎过筛后，于40～60℃(如50℃)真空烘料，优选真空烘料3小时至3天，例如24h；或
    (3)取晶型II湿品，于40～60℃(如50℃)真空烘料3小时至3天后微粉化，优选真空烘料24小时后微粉化；或
    (4)取晶型II，加入溶剂，得悬浊液，室温搅拌，得到晶型I和晶型II的混合物；优选，溶剂为甲基叔丁基醚、或乙醇/甲基环己烷混合溶液；更优选，混合溶液中两种溶剂的体积比为1:8-8:1，最优选1:6-5:1；优选，搅拌3小时至3天，最优选，搅拌1-3天。
  9. 一种药物组合物，含有治疗有效量的如权利要求1或2所述晶型中的一种、两种或更多种，以及药学上可接受的载体；或者含有治疗有效量的如权利要求7所述的组合物，以及药学上可接受的载体。
  10. 如权利要求1或2述的晶型中的一种、两种或更多种、权利要求7所述的组合物或者权利要求9所述的药物组合物在制备血管紧张素II受体拮抗剂中的应用，或者在制备用于高血压、慢性心衰、糖尿病肾病的药物中的应用；
    或者，如权利要求1或2述的晶型中的一种、两种或更多种、权利要求7所述的组合物或者权利要求9所述的药物组合物作为血管紧张素II受体拮抗剂的应用，或者用于预防和/或治疗高血压、慢性心衰、糖尿病肾病的应用。
PCT/CN2017/092416 2016-07-11 2017-07-10 化合物的晶型及其制备方法、组合物和应用 WO2018010622A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US16/301,027 US10611757B2 (en) 2016-07-11 2017-07-10 Crystalline form of chemical compound, and preparation method, composition, and application thereof
EP17826958.5A EP3461822B1 (en) 2016-07-11 2017-07-10 Crystalline form of chemical compound, and preparation method, composition, and application thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610539614 2016-07-11
CN201610539614.6 2016-07-11

Publications (1)

Publication Number Publication Date
WO2018010622A1 true WO2018010622A1 (zh) 2018-01-18

Family

ID=60952813

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/092416 WO2018010622A1 (zh) 2016-07-11 2017-07-10 化合物的晶型及其制备方法、组合物和应用

Country Status (4)

Country Link
US (1) US10611757B2 (zh)
EP (1) EP3461822B1 (zh)
CN (1) CN107602546B (zh)
WO (1) WO2018010622A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11096928B2 (en) * 2016-10-08 2021-08-24 Wuhan Ll Science And Technology Development Co., Ltd. Pharmaceutical composition

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107400122B (zh) * 2016-05-20 2020-10-23 武汉朗来科技发展有限公司 化合物及其制备方法、组合物和应用
CN107661302B (zh) * 2016-07-29 2021-08-27 武汉朗来科技发展有限公司 一种口服固体制剂及其应用
WO2022258059A1 (zh) * 2021-06-10 2022-12-15 武汉朗来科技发展有限公司 一种药物组合物、制剂及其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103709154A (zh) * 2012-09-28 2014-04-09 武汉启瑞药业有限公司 苯并咪唑衍生物及其制备方法和医药用途
CN104774196A (zh) * 2014-01-09 2015-07-15 武汉朗来科技发展有限公司 一种苯并咪唑衍生物的制备方法
CN105153141A (zh) * 2013-02-04 2015-12-16 武汉朗来科技发展有限公司 苯并咪唑衍生物及其制备方法和医药用途

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7157584B2 (en) * 2004-02-25 2007-01-02 Takeda Pharmaceutical Company Limited Benzimidazole derivative and use thereof
JP2014530805A (ja) * 2011-09-30 2014-11-20 スンシネ ルアケ プハルマ カンパニー リミテッド アジルサルタンの結晶形並びにその製造及び使用
US9403811B2 (en) * 2012-01-14 2016-08-02 Sunshine Lake Pharma Co., Ltd. Crystalline forms of azilsartan medoxomil potassium and preparation and uses thereof
WO2013114305A1 (en) * 2012-02-02 2013-08-08 Ranbaxy Laboratories Limited Process for the preparation of azilsartan medoxomil or pharmaceutically acceptable salts thereof
US9708306B2 (en) * 2015-03-18 2017-07-18 Wuhan Ll Science And Technology Development Co., Ltd Benzimidazole derivatives and preparation process and pharmaceutical uses thereof
CN107400122B (zh) * 2016-05-20 2020-10-23 武汉朗来科技发展有限公司 化合物及其制备方法、组合物和应用
WO2018005591A1 (en) * 2016-06-29 2018-01-04 Universite De Montreal Biarylmethyl heterocycles
CN107661302B (zh) * 2016-07-29 2021-08-27 武汉朗来科技发展有限公司 一种口服固体制剂及其应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103709154A (zh) * 2012-09-28 2014-04-09 武汉启瑞药业有限公司 苯并咪唑衍生物及其制备方法和医药用途
CN105237527A (zh) * 2012-09-28 2016-01-13 武汉朗来科技发展有限公司 苯并咪唑衍生物及其制备方法和医药用途
CN105153141A (zh) * 2013-02-04 2015-12-16 武汉朗来科技发展有限公司 苯并咪唑衍生物及其制备方法和医药用途
CN104774196A (zh) * 2014-01-09 2015-07-15 武汉朗来科技发展有限公司 一种苯并咪唑衍生物的制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3461822A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11096928B2 (en) * 2016-10-08 2021-08-24 Wuhan Ll Science And Technology Development Co., Ltd. Pharmaceutical composition

Also Published As

Publication number Publication date
EP3461822A4 (en) 2019-10-30
CN107602546A (zh) 2018-01-19
EP3461822B1 (en) 2022-11-02
US20190177312A1 (en) 2019-06-13
US10611757B2 (en) 2020-04-07
CN107602546B (zh) 2022-04-22
EP3461822A1 (en) 2019-04-03

Similar Documents

Publication Publication Date Title
TWI447114B (zh) 阿齊沙坦的新晶型及其製備方法
WO2018010622A1 (zh) 化合物的晶型及其制备方法、组合物和应用
EP2639234B1 (en) Crystalline 6,7-unsaturated-7-carbamoyl morphinane derivative, and method for producing same
TWI718104B (zh) AHU-377結晶型游離酸、半鈣鹽、α-苯乙胺鹽及其製備方法和應用
US11286259B2 (en) Co-crystals of ribociclib and co-crystals of ribociclib monosuccinate, preparation method therefor, compositions thereof, and uses thereof
CN107661302B (zh) 一种口服固体制剂及其应用
EP3447054B1 (en) Compound and preparation method therefor, composition and application thereof
AU2013330603B2 (en) Monohydrate crystal of fimasartan potassium salt, method for preparing same, and pharmacological composition comprising same
EP2817303A2 (en) Solid forms of dabigatran etexilate mesylate and processes for their preparation
EP2800747A1 (en) Polymorphs of perampanel
WO2016155578A1 (zh) 达格列净的新晶型及其制备方法
WO2016155670A1 (zh) 一种cdk抑制剂和mek抑制剂的共晶及其制备方法
WO2019033969A1 (zh) 替米沙坦与氢氯噻嗪的共晶
WO2023193563A1 (zh) 一种噻吩并吡啶化合物的晶型a、制备方法及其药物组合物
US20130059872A1 (en) Polymorphs of alogliptin benzoate
WO2019052470A1 (zh) 一种艾尔骨化醇晶型、药物组合物及制备方法和应用
CN115466252A (zh) 一种Lanifibranor的晶型及其制备方法
WO2023202651A1 (en) Polymorphic forms of glutamine antagonist and uses thereof
WO2022194160A1 (zh) 非索替尼固体形式及其制备方法
KR101423630B1 (ko) 비칼루타미드와 니코틴아미드의 공결정
JP2023532217A (ja) Ｓｈｐ２阻害剤の結晶形、その組成物、その製造方法及び応用
JP5608666B2 (ja) ２種のピノセンブリン、その製造方法、および、医薬組成物の製造におけるその使用
CN117105923A (zh) 具有高生物利用度的鲁拉西酮盐及其制法和应用
AU2010353051A1 (en) Polymorphs of alogliptin benzoate
WO2012105708A1 (en) Novel crystal of tetrahydronaphthalene compound

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17826958

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2017826958

Country of ref document: EP

Effective date: 20181122

NENP Non-entry into the national phase

Ref country code: DE