WO2019109935A1 - 一种肾外髓质分泌钾通道抑制剂的晶型及其制备方法 - Google Patents

一种肾外髓质分泌钾通道抑制剂的晶型及其制备方法 Download PDF

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WO2019109935A1
WO2019109935A1 PCT/CN2018/119310 CN2018119310W WO2019109935A1 WO 2019109935 A1 WO2019109935 A1 WO 2019109935A1 CN 2018119310 W CN2018119310 W CN 2018119310W WO 2019109935 A1 WO2019109935 A1 WO 2019109935A1
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solvent
crystal form
iii
sulfoxide
crystallization
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PCT/CN2018/119310
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English (en)
French (fr)
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武乖利
张全良
卢韵
姚飞
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江苏恒瑞医药股份有限公司
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Priority to AU2018380171A priority Critical patent/AU2018380171A1/en
Priority to JP2020531026A priority patent/JP2021505602A/ja
Priority to US16/770,129 priority patent/US20200347039A1/en
Priority to KR1020207019240A priority patent/KR20200096802A/ko
Priority to CA3084848A priority patent/CA3084848A1/en
Priority to RU2020122014A priority patent/RU2020122014A/ru
Application filed by 江苏恒瑞医药股份有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to CN201880075469.8A priority patent/CN111372929B/zh
Priority to EP18886529.9A priority patent/EP3722293A4/en
Priority to MX2020005930A priority patent/MX2020005930A/es
Priority to BR112020011161-9A priority patent/BR112020011161A2/pt
Publication of WO2019109935A1 publication Critical patent/WO2019109935A1/zh
Priority to ZA2020/04017A priority patent/ZA202004017B/en

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    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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 invention relates to a crystal form of a renal extra-medullary medulla secretion potassium channel inhibitor and a preparation method thereof.
  • the renal outer medullary potassium channel is also called inward-rectifying potassium channel 1.1 (Kir1.1).
  • Ion channels may ROMK thick ascending limb segment (the TAL) conductance through apical membrane of renal medullary loop, and Na + -K + -2Cl - cotransporter NKCC2 (responsible for transport of NaCl) synergy regulation of Na + reabsorption.
  • TAL ascending limb segment
  • NKCC2 Na + -K + -2Cl - cotransportergy regulation of Na + reabsorption.
  • the study found that ROMK is directly associated with the secretory pathway of the kidney, knocking out the ROMK gene, missing the 35-pS ion channel and other TAL K + ion channels of mouse TAL and CCD.
  • Batter syndrome is an autosomal recessive hereditary disease characterized by massive loss of salt in the kidneys, hypokalemia, and low blood pressure.
  • Paramyelocytic hyperplasia is mainly caused by mutation of ROMK or Na + -K + -2Cl - cotransporter, except that hypokalemia caused by rotaside cell hyperplasia caused by ROMK mutation is better than Na + -K + - Parathyroid cell hyperplasia induced by 2Cl - cotransporter mutations is greatly alleviated.
  • ROMK suppression function may without causing hypokalemia, effective to inhibit Na + -K + -2Cl - transporter salt reabsorption promoting excretion of urine, functions as a diuretic antihypertensive efficacy.
  • WO2016091042A1 discloses an extrarenal medullary secretory potassium channel (ROMK) inhibitor having the chemical name (R)-5-cyano-N-(1-(2-hydroxy-2-() 4-methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide relative to other ROMK inhibitors
  • ROMK extrarenal medullary secretory potassium channel
  • the compound increases the polar group, reduces the ClogP on the basis of maintaining the activity of the ROMK inhibitor, improves the selectivity of hERG, and increases the safety, and the structure is as shown in formula (II):
  • the crystal structure of the pharmaceutically active ingredient often affects the chemical and physical stability of the drug, and the difference in crystallization conditions and storage conditions may cause changes in the crystal structure of the compound, sometimes accompanied by the formation of other forms of crystal form.
  • amorphous pharmaceutical products have no regular crystal structure and often have other defects, such as poor product stability, difficulty in filtration, easy agglomeration, and poor fluidity. Therefore, it is necessary to improve various aspects of the compound of the formula (II).
  • the technical problem to be solved by the present invention is to provide a (R)-5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisophenyl) a crystal form of a furan-5-yl)ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide tartrate (as shown in formula (I)) and a process for preparing the same Good stability.
  • the present invention provides a crystal form of III of the compound of the formula (I), characterized in that an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ angle is obtained using Cu-K ⁇ radiation, which is 3.88, 7.54, 14.76, There are characteristic peaks at 18.64 and 22.21.
  • the Form III has characteristic peaks at 3.88, 7.54, 11.22, 14.76, 17.29, 18.64, 20.28, 22.21, 23.79, 25.34 and 27.09.
  • the III crystal forms are 3.88, 7.54, 11.22, 11.61, 12.26, 12.73, 13.35, 13.64, 14.76, 15.98, 16.47, 17.07, 17.29, 18.64, 20.28, 20.62, 22.21, 23.16, 23.79, 24.14, There are characteristic peaks at 24.85, 25.34, 26.08, 26.85, 27.09, 28.77, 29.74, 32.22, 33.66, 34.50, 35.60, 37.42 and 39.27.
  • the invention also provides a method of preparing a crystalline form of III, the method being selected from the group consisting of:
  • the method (1) reacts the free state of the compound represented by the formula (I) with L-tartaric acid in a solvent or a mixed solvent, stirs, crystallizes, filters, and dries to obtain a target III crystal form;
  • the solvent is selected from the group consisting of a sulfone solvent, an amide solvent or an alcohol solvent, wherein the mixed solvent is selected from a mixed solvent of a sulfoxide solvent and an alcohol solvent or a mixed solvent of an amide solvent and an alcohol solvent; and the sulfoxide solvent is preferably dimethyl
  • the sulfoxide is preferably N,N-dimethylformamide or N,N-dimethylacetamide
  • the alcohol solvent is preferably methanol, ethanol, n-propanol, isopropanol or n-butyl alcohol;
  • Method (2) Dissolving the compound of the formula (I) in a solvent or a mixed solvent, crystallization, filtering, and drying to obtain a target crystal form;
  • the crystallization method is selected from room temperature crystallization, cooling and precipitation Crystallization, crystallization of a volatile solvent or addition of a seed crystal to induce crystallization, the temperature of the cooling crystallization is selected from -10 ° C to 25 ° C, preferably room temperature crystallization;
  • the solvent is selected from a sulfoxide solvent, an amide solvent or an alcohol a solvent-like solvent selected from the group consisting of a mixed solvent of a sulfoxide solvent and an alcohol solvent or a mixed solvent of an amide solvent and an alcohol solvent;
  • the sulfoxide solvent is preferably dimethyl sulfoxide, and the amide solvent N,N-dimethylformamide or N,N-dimethylacetamide is preferred, and the alcohol solvent is preferably methanol, ethanol, n-propanol, is
  • the invention further relates to a pharmaceutical composition of the III crystalline form comprising a crystalline form of III and a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention further relates to a process for the preparation of a pharmaceutical composition
  • a process for the preparation of a pharmaceutical composition comprising the step of mixing the Form III of the above described formula with a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention further relates to the use of a pharmaceutical composition of Form III, Form III, in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition associated with a renal extra-medullary medullary potassium channel (ROMK) inhibitor,
  • ROMK renal extra-medullary medullary potassium channel
  • the condition is preferably hypertension or heart failure.
  • bioavailability and wettability of the III crystal form of the compound of the formula (I) are improved relative to the aforementioned free base form: bioavailability of the III crystal form in a mouse experiment (5 mg/kg) From the free base of 9283 ng / mL ⁇ h to 12618 ng / mL ⁇ h, it can be seen that the in vivo bioavailability of the III crystal form is significantly better than the free base; on the other hand, relative to the free base, the III crystal form is at 0% RH -80% RH, with a weight change of only 0.93%, has a clear advantage.
  • the crystal form of the III crystal form of the obtained compound of the formula (I) was examined by X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC).
  • the method of crystal recrystallization of III is not particularly limited and can be carried out by a usual recrystallization operation method.
  • the compound of the formula (I) can be dissolved in an organic solvent and then added to an anti-solvent to crystallize. After the crystallization is completed, it can be dried by filtration to obtain a desired crystal.
  • the method for crystallization of the present invention includes volatile crystallization, room temperature crystallization, cooling crystallization, seed crystal induced crystallization, and the like.
  • the starting material used in the method for preparing a crystal form of the present invention may be any compound of the formula (I), and the specific forms include, but are not limited to, amorphous, arbitrary crystal forms and the like.
  • C 1-6 alkyl group of the present invention means a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl.
  • n-butyl isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3 -methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, and the like.
  • the "alcohol solvent” as used in the present invention means a group derived from one or more "hydroxyl groups” substituted with one or more hydrogen atoms on a "C 1-6 alkyl group", said “C 1-6 alkane”
  • the bases are as defined above, and specific examples include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, n-butanol, isoamyl alcohol or trifluoroethanol.
  • sulfoxide solvent refers to a compound in which a sulfinyl group (-SO-) is bonded to a hydrocarbon group, and specific examples include, but are not limited to, dimethyl sulfoxide, diethyl sulfoxide or benzyl. Sulfoxide.
  • amide solvent refers to a liquid compound in which a hydroxyl group in a carboxyl group of a carboxylic acid molecule is substituted with an amino group or a hydrocarbon amino group (-NHR or -NR 2 ); it can also be regarded as an ammonia or an amine molecule.
  • a liquid compound in which hydrogen on a nitrogen atom is substituted with an acyl group include, but are not limited to, N,N-dimethylformamide, N,N-dimethylacetamide.
  • the “mixed solvent” as used in the present invention refers to a solvent in which one or more different kinds of organic solvents are mixed in a certain ratio; the mixed solvent is preferably a mixed solvent of sulfoxides and alcohols, an amide and an alcohol. a mixed solvent; the sulfoxide solvent is preferably dimethyl sulfoxide, and the amide solvent is preferably N,N-dimethylformamide or N,N-dimethylacetamide, and the alcohol solvent is preferably methanol.
  • a certain ratio of alcohol, dimethyl sulfoxide / n-butanol, N, N-dimethylformamide / ethanol or N, N - dimethyl acetamide / ethanol may be volume ratio or mass ratio, volume ratio From 0.05:1 to 1:0.05, preferably 1:1, 1:2, 2:1, 4:1, 5:1 or 10:1, the mass ratio is selected from 10:1 to 1:10, preferably 5: 1, 2: 1, 1: 2 or 1.6: 1;
  • the "differential scanning calorimetry or DSC” as used in the present invention refers to measuring the temperature difference and heat flow difference between a sample and a reference during temperature rise or constant temperature of the sample to characterize all physical changes and chemistry related to thermal effects. Change to get the phase change information of the sample.
  • the "2 ⁇ or 2 ⁇ angle" as used in the present invention means a diffraction angle, ⁇ is a Bragg angle, and the unit is ° or degree, and the error range of 2 ⁇ is ⁇ 0.1 to ⁇ 0.5, preferably ⁇ 0.1 to ⁇ 0.3, more preferably ⁇ 0.2.
  • the "plane spacing or interplanar spacing (d value)" means that the spatial lattice selects three unit vectors a, b, c which are not parallel to each other and adjacent two lattice points, and they point the points.
  • the parallelepiped unit which is divided into juxtapositions, is called the interplanar spacing.
  • the spatial lattice is divided according to the determined parallelepiped unit lines, and a set of linear grids is obtained, which is called a space lattice or a lattice.
  • the lattice and the lattice reflect the periodicity of the crystal structure by geometric points and lines, respectively, and the interplanar spacing (ie, the distance between two adjacent parallel crystal planes) is different; Or ang.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form of the compound of formula (I), and optionally one or more pharmaceutically acceptable carriers and/or diluents.
  • the pharmaceutical composition can be formulated into any of the pharmaceutically acceptable dosage forms.
  • the III crystal form or pharmaceutical preparation of the compound of the formula (I) of the present invention can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, Sterile powder for injection and concentrated solution for injection), suppository, inhalation or spray.
  • the pharmaceutical compositions of the present invention may also be administered to a patient or subject in need of such treatment by any suitable mode of administration, such as oral, parenteral, rectal, pulmonary or topical administration.
  • the pharmaceutical composition can be formulated into an oral preparation such as an oral solid preparation such as a tablet, a capsule, a pill, a granule or the like; or an oral liquid preparation such as an oral solution or an oral mixture. Suspension, syrup, and the like.
  • the pharmaceutical preparation may further contain a suitable filler, binder, disintegrant, lubricant, and the like.
  • the pharmaceutical preparation When used for parenteral administration, the pharmaceutical preparation can be prepared as an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection.
  • the pharmaceutical composition When formulated as an injection, the pharmaceutical composition can be produced by a conventional method in the existing pharmaceutical field.
  • an additional agent may be added to the pharmaceutical preparation, and a suitable additional agent may be added depending on the nature of the drug.
  • the pharmaceutical preparation When used for rectal administration, can be formulated into a suppository or the like.
  • the pharmaceutical preparation For pulmonary administration, the pharmaceutical preparation can be formulated as an inhalant or a spray.
  • the Form III of the compound of Formula (I) of the present invention is present in a pharmaceutical composition or medicament in a therapeutically and/or prophylactically effective amount.
  • the Form III of the compound of Formula (I) of the present invention is present in a pharmaceutical composition or medicament in unit dosage form.
  • a compound of formula (I) according to the invention for the manufacture of a medicament for the treatment of a disease or condition associated with a renal extra-medullary medullary potassium channel (ROMK) inhibitor.
  • the present application also relates to the use of the crystalline form III of the compound of the formula (I) of the present invention for the preparation of a medicament for the treatment of a disease associated with a renal extra-medullary medullary potassium channel (ROMK) inhibitor. the use of.
  • the present application relates to a method of inhibiting a disease associated with a renal extra-medullary medullary potassium channel (ROMK) inhibitor, comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of the present invention Form III of the compound of formula (I), or a pharmaceutical composition of the invention.
  • ROMK renal extra-medullary medullary potassium channel
  • the disease is a disease associated with an extrarenal medullary secretory potassium channel (ROMK) inhibitor selected from the group consisting of hypertension or heart failure.
  • ROMK extrarenal medullary secretory potassium channel
  • III crystal form of the compound of the formula (I) prepared by the present invention has good solubility and high purity, and the crystal form is not changed by XRPD under high temperature, high humidity and light conditions, and the crystal form is stable.
  • the crystal form of the compound of the formula (I) obtained by the technical scheme of the present invention can meet the pharmaceutical requirements for production transportation and storage, and the production process is stable, reproducible and controllable, and can be adapted to industrial production.
  • Figure 1 is an XRPD pattern of the crystalline form of Compound III of formula (I).
  • Figure 2 is a DSC chart of the crystalline form of Compound III of formula (I).
  • Figure 3 is an XRPD pattern of the crystalline form of Compound I of formula (I).
  • Figure 4 is an XRPD pattern of the crystalline form of Compound II of formula (I).
  • the compound of the formula (II) (free state) is prepared by the method of the patent application WO2016091042A1 (publication date 2016.06.16).
  • XRPD pattern The X-ray powder diffraction spectrum (XRPD pattern) of the crystal sample is shown in Fig. 1, the DSC spectrum is shown in Fig. 2, and the sharp melting endothermic peak is obtained at 227.60 ° C, and the crystal form is defined as the III crystal form, and the 2 ⁇ characteristic peak thereof is obtained.
  • the location is shown in the following table:
  • the sulfoxide is heated to 70 ° C to dissolve, and (0.4 g, 2.66 mmol) of L-tartaric acid is added to the reaction flask B, 20 mL of absolute ethanol is added, and the mixture is heated to 70 ° C to dissolve, and the solution in the reaction bottle B is added.
  • the reaction was carried out at 70 ° C for 4 h, cooled to room temperature, and stirred overnight. The mixture was filtered under suction and dried to give 1.13 g of solid.
  • the X-ray powder diffraction spectrum and the DSC pattern were compared by study to confirm that the product was a crystal form III.
  • N-dimethylformamide heated to 70 ° C heat solution, take (0.4g, 2.66mmol) L-tartaric acid added to the reaction bottle B, add 20mL of absolute ethanol, heated to 70 B dissolved, the reaction bottle B The solution was added to the reaction flask A, reacted at 70 ° C for 4 h, cooled to room temperature, and stirred overnight. The mixture was suction filtered and dried to give a solid, 1.10 g, and a yield of 82.7%. The X-ray powder diffraction spectrum and the DSC pattern were compared by study to confirm that the product was a crystal form III.
  • the crystal form of the compound of the formula (I) obtained in Example 1 and the crystal form of the crystal form I and the crystal form obtained in the comparative example 2 were separately placed in an open position, and the light was irradiated (4,500 Lux) and heated. (40 ° C, 60 ° C), high humidity (75% RH, 90% RH) conditions of the stability of the sample. The sampling time was 5 days and 10 days, and the purity was determined by HPLC.
  • the crystal form of the III obtained in Example 1 was subjected to grinding, heating and tableting to examine the stability of the sample.
  • the temperature is from 10 to 90% at 25 ° C, the step is 10%, and the mass change within the 10000 min is less than 0.01%, and the cycle is two cycles.
  • the sample of the crystal form of the compound of the formula (I) of the present invention has an increase in water absorption with an increase in humidity between 10.0% RH and 80.0% RH at 25 ° C, and the weight change is 0.9332%. , less than 15% but not less than 2%, the sample is slightly hygroscopic; during the humidity change of 0%-85%, the desorption process of the sample substantially coincides with the adsorption process.
  • SD rats were used as test animals.
  • the LC-MS/MS method was used to determine the concentration of the drug in the plasma of the rats of the formula (I) by intragastric administration of the compound of formula (I) and the plasma concentration at different times after the free state.
  • the pharmacokinetic behavior of the crystalline form and free form of the compound shown in SD rats, and its pharmacokinetic characteristics were evaluated.
  • Test sample Form III of the compound of the formula (I) (the preparation method thereof is shown in Example 1) and the free state (the preparation method can be prepared by referring to the method in the patent application WO2016091042A1).
  • Test animals 8 healthy SD rats, male and female, divided into 2 groups, purchased from Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number SCXK (Shanghai) 2008-0016.
  • Drug preparation 0.5% CMC-Na, sonicated to make a uniform suspension, prepared at a concentration of 0.5 mg / mL, for oral administration.
  • T 1/2 is the half-life
  • AUC last is the area under the curve of the drug 0 ⁇ t
  • Cl/F is the clearance rate
  • Vz/F is the apparent volume of distribution.

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Abstract

一种肾外髓质分泌钾通道抑制剂的晶型及其制备方法。具体而言，一种肾外髓质分泌钾通道(ROMK)抑制剂的L-酒石酸盐的III晶型(I)及其制备方法。该III晶型具备良好的化学稳定性和晶型稳定性，并且所用结晶溶剂低毒低残留，可更好地用于临床治疗。

Description

一种肾外髓质分泌钾通道抑制剂的晶型及其制备方法
本申请要求申请日为2017年12月6日的中国专利申请CN201711273099.2的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及肾外髓质分泌钾通道抑制剂的晶型及其制备方法。
背景技术
加强肾脏的盐重吸收功能，会引发高血压风险。相反，抑制肾脏的重吸收功能，可以促进尿液的排泄，起到利尿降压的功效。常见的利尿剂有噻嗪类利尿药，作为美国一线降压药，主要作用于Na +-Cl转运载体；Loop利尿剂对肾功能受损患者更为有效，主要通过Na +-K +-2Cl -转运蛋白发挥作用。但这两种利尿剂均会引起低血钾症(症状：虚弱、疲劳、肌肉痉挛、便秘和心律问题如心律不齐)，增加心血管疾病的发病率和致死率的风险。
肾外髓质分泌钾通道(renal outer medullary potassium channel,ROMK)也称内向性整流型钾离子通道1.1(inward-rectifying potassium channels 1.1,Kir1.1)。ROMK离子通道可以通过肾脏髓袢升支粗段(TAL)的顶端膜电导，与Na +-K +-2Cl -共转运蛋白NKCC2(负责NaCl转运)协同作用，调节Na +的重吸收。研究发现，ROMK与肾脏的分泌通道有直接的关联，敲除ROMK基因，小鼠TAL和CCD的35-pS离子通道和TAL其它K +离子通道缺失。球旁细胞增生症(Batter syndrome)是一种常染色体隐性遗传性疾病，表现为肾脏大量盐流失，低血钾症，血压较低。球旁细胞增生症主要由ROMK或Na +-K +-2Cl -共转运蛋白的突变引起的，不同的是由ROMK突变引起的球旁细胞增生症的低血钾症较Na +-K +-2Cl -共转运蛋白突变引发的球旁细胞增生症有极大的缓和。综上，抑制ROMK的功能，可以在不引起低血钾症的情况下， 有效抑制Na +-K +-2Cl -转运蛋白的盐重吸收功能，促进尿液的排泄，起到利尿降压的功效。
WO2016091042A1(公开日2016.06.16)公开一种肾外髓质分泌钾通道(ROMK)抑制剂，其化学名为(R)-5-氰基-N-(1-(2-羟基-2-(4-甲基-1-羰基-1,3-二氢异苯并呋喃-5-基)乙基)哌啶-4-基)-4-甲氧基吡啶甲酰胺，相对于其他ROMK抑制剂，该化合物增加了极性基团，在保持ROMK抑制剂活性的基础上，降低了ClogP，提升了hERG选择性，增加了安全性，结构如式(II)所示：
Figure PCTCN2018119310-appb-000001
作为药用活性成分的晶型结构往往影响到该药物的化学和物理稳定性，结晶条件及储存条件的不同有可能导致化合物的晶体结构的变化，有时还会伴随着产生其他形态的晶型。一般来说，无定形的药物产品没有规则的晶体结构，往往具有其它缺陷，比如产物稳定性较差，过滤较难，易结块，流动性差等。因此，改善式(II)所示化合物的各方面性质是很有必要的。
发明内容
本发明要解决的技术问题是提供一种(R)-5-氰基-N-(1-(2-羟基-2-(4-甲基-1-羰基-1,3-二氢异苯并呋喃-5-基)乙基)哌啶-4-基)-4-甲氧基吡啶甲酰胺酒石酸盐(如式(I)所示)的III晶型及其制备方法，该晶型具备良好的稳定性。
本发明的技术方案如下：
本发明提供一种式(I)所示化合物的III晶型，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在3.88、7.54、14.76、18.64和22.21处有特征峰，
Figure PCTCN2018119310-appb-000002
优选的，所述III晶型在3.88、7.54、11.22、14.76、17.29、18.64、20.28、22.21、23.79、25.34和27.09处有特征峰。
更优选的，所述III晶型在3.88、7.54、11.22、11.61、12.26、12.73、13.35、13.64、14.76、15.98、16.47、17.07、17.29、18.64、20.28、20.62、22.21、23.16、23.79、24.14、24.85、25.34、26.08、26.85、27.09、28.77、29.74、32.22、33.66、34.50、35.60、37.42和39.27处有特征峰。
本发明还提供一种制备III晶型的方法，所述方法选自：
方法(1)将式(I)所示化合物的游离态与L-酒石酸在一种溶剂或混合溶剂中反应，搅拌，析晶，过滤，干燥后即得目标III晶型；所述溶剂选自亚砜类溶剂、酰胺类溶剂或醇类溶剂，所述混合溶剂选自亚砜类溶剂与醇类溶剂的混合溶剂或酰胺类溶剂与醇类溶剂的混合溶剂；所述亚砜类溶剂优选二甲基亚砜，所述酰胺类溶剂优选N,N-二甲基甲酰胺或N,N-二甲基乙酰胺，所述醇类溶剂优选甲醇、乙醇、正丙醇、异丙醇或正丁醇；
方法(2)将式(I)所示化合物溶解于一种溶剂或混合溶剂中，析晶，过滤，干燥后即得目标III晶型；所述析晶的方法选自室温析晶、冷却析晶、挥发溶剂析晶或加入晶种诱导析晶，所述冷却析晶的温度选自-10℃～25℃，优选室温析晶；所述溶剂选自亚砜类溶剂、酰胺类溶剂或醇类溶剂，所述混合溶剂选自亚砜类溶剂与醇类溶剂的混合溶剂或酰胺类溶剂与醇类溶剂的混合溶剂；所述亚砜类溶剂优选二甲基亚砜，所述酰胺类溶剂优选N,N-二甲基甲酰胺或N,N-二甲基乙酰胺，所述醇类溶剂优选甲醇、乙醇、正丙醇、异丙醇或正丁醇，所述混合溶剂更优选二甲基亚砜/甲醇、二甲基亚砜/乙醇、二 甲基亚砜/正丙醇、二甲基亚砜/异丙醇、二甲基亚砜/正丁醇、N,N-二甲基甲酰胺/乙醇或N,N-二甲基乙酰胺/乙醇。
本发明还涉及III晶型的药物组合物，所述药物组合物包含III晶型与药学上可接受的载体、稀释剂或赋形剂。
本发明还涉及一种制备药物组合物的方法，所述方法包括上述方案中所述的III晶型与药学上可接受的载体、稀释剂或赋形剂混合的步骤。
本发明还涉及III晶型、III晶型的药物组合物在制备治疗和/或预防与肾外髓质分泌钾通道(ROMK)抑制剂有关的疾病或病症的药物中的用途，所述疾病或病症优选高血压或心力衰竭。经研究发现，相对于前述自由碱形式，式(I)所示化合物的III晶型的生物利用度及引湿性均得到改善：III晶型在小鼠实验(5mg/kg)中的生物利用度由自由碱的9283ng/mL×h提升到12618ng/mL×h，可以看出，III晶型的体内生物利用度明显优于自由碱；另一方面相对于自由碱，III晶型在0％RH-80％RH，重量变化仅为0.93％，具有明显优势。
通过X-射线粉末衍射图谱(XRPD)、差示扫描量热分析(DSC)对所得到式(I)所示化合物的III晶型进行结构测定、晶型研究。
III晶型重结晶的方法没有特别限定，可以用通常的重结晶操作方法进行。例如，可以用原料式(I)所示化合物在有机溶剂中溶解后加入反溶剂析晶，结晶完成后，经过滤干燥，即可得到所需要的结晶。
本发明析晶的方法有挥发析晶、室温析晶、冷却析晶、加入晶种诱导析晶等。
本发明晶型制备方法中所用的起始原料可以是任意形式的式(I)所示化合物，具体形式包括但不限于：无定型、任意晶型等。
发明详述
在本申请的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地 理解本发明，下面提供了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。
本发明所述“C 1-6烷基”表示直链或支链的含有1-6个碳原子的烷基，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
本发明所述的“醇类溶剂”是指一个或多个“羟基”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“C 1-6烷基”如前文所定义，具体实例包括但不限于：甲醇、乙醇、异丙醇、正丙醇、正丁醇、异戊醇或三氟乙醇。
本发明所述的“亚砜类溶剂”是指亚硫酰基(-SO-)与烃基结合而成的化合物，具体实例包括但不限于：二甲基亚砜、二乙基亚砜或苄基亚砜。
本发明所述的“酰胺类溶剂”是指羧酸分子中羧基中的羟基被氨基或烃氨基(-NHR或-NR 2)取代而成的液体化合物；也可看作是氨或胺分子中氮原子上的氢被酰基取代而成的液体化合物；具体实例包括但不限于：N,N-二甲基甲酰胺、N,N-二甲基乙酰胺。
本发明所述的“混合溶剂”是指一种或多种不同种类的有机溶剂按照一定比例混合而成的溶剂；所述混合溶剂优选为亚砜类与醇类混合溶剂、酰胺类与醇类混合溶剂；所述亚砜类溶剂优选二甲基亚砜，所述酰胺类溶剂优选N,N-二甲基甲酰胺或N,N-二甲基乙酰胺，所述醇类溶剂优选甲醇、乙醇、正丙醇、异丙醇或正丁醇，更优选二甲基亚砜/甲醇、二甲基亚砜/乙醇、二甲基亚砜/正丙醇、二甲基亚砜/异丙醇、二甲基亚砜/正丁醇、N,N-二甲基甲酰胺/乙醇或N,N-二甲基乙酰胺/乙醇所述一定比例可以是体积比或者质量比，体 积比例选自0.05:1～1:0.05，优选为1:1、1:2、2:1、4:1、5:1或10:1，质量比例选自10:1-1:10，优选5:1、2:1、1:2或1.6:1；。
本发明所述的“X-射线粉末衍射图谱或XRPD”是指根据布拉格公式2d sinθ＝nλ(式中，λ为X射线的波长，
Figure PCTCN2018119310-appb-000003
衍射的级数n为任何正整数，一般取一级衍射峰，n＝1)，当X射线以掠射角θ(入射角的余角，又称为布拉格角)入射到晶体或部分晶体样品的某一具有d点阵平面间距的原子面上时，就能满足布拉格方程，从而测得了这组X射线粉末衍射图。
本发明所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本发明所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度，2θ的误差范围为±0.1～±0.5，优选±0.1～±0.3，更优选±0.2。
本发明所述的“晶面间距或晶面间距(d值)”是指空间点阵选择3个不相平行的连结相邻两个点阵点的单位矢量a，b，c，它们将点阵划分成并置的平行六面体单位，称为晶面间距。空间点阵按照确定的平行六面体单位连线划分，获得一套直线网格，称为空间格子或晶格。点阵和晶格是分别用几何的点和线反映晶体结构的周期性，不同的晶面，其面间距(即相邻的两个平行晶面之间的距离)各不相同；单位为
Figure PCTCN2018119310-appb-000004
或埃。
本发明还涉及，包括式(I)所示的化合物的III晶型，以及任选的一种或多种药用载体和/或稀释剂的药物组合物。所述药物组合物可以制成药学上可接受的任一剂型。例如，本发明的式(I)所示的化合物的III晶型或药物制剂可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
此外，本发明所述药物组合物还可以以任何合适的给药方式，例如口服、肠胃外、直肠、经肺或局部给药等方式施用于需要这种治疗的患者或受试者。当用于口服给药时，所述药物组合物可制成口服制剂，例如口服固体制剂， 如片剂、胶囊剂、丸剂、颗粒剂等；或，口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。当制成口服制剂时，所述药物制剂还可包含适宜的填充剂、粘合剂、崩解剂、润滑剂等。当用于肠胃外给药时，所述药物制剂可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。当制成注射剂时，所述药物组合物可采用现有制药领域中的常规方法来进行生产。当配制注射剂时，所述药物制剂中可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。当用于直肠给药时，所述药物制剂可制成栓剂等。用于经肺给药时，所述药物制剂可制成吸入剂或喷雾剂等。在某些优选的实施方案中，本发明的式(I)所示的化合物的III晶型以治疗和/或预防有效量存在于药物组合物或药物中。在某些优选的实施方案中，本发明式(I)所示的化合物的III晶型以单位剂量的形式存在于药物组合物或药物中。
本发明式(I)化合物、其III晶型可用于制备治疗与肾外髓质分泌钾通道(ROMK)抑制剂有关疾病或病症的药物中的用途。因此，本申请还涉及，本发明式(I)化合物的III晶型用于制备药物的用途，所述药物用于治疗与肾外髓质分泌钾通道(ROMK)抑制剂有关的疾病的药物中的用途。此外，本申请还涉及，一种抑制与肾外髓质分泌钾通道(ROMK)抑制剂有关的疾病的方法，其包括给有此需要的受试者施用治疗和/或预防有效量的本发明式(I)化合物的III晶型，或者本发明的药物组合物。
在某些优选的实施方案中，所述疾病为与肾外髓质分泌钾通道(ROMK)抑制剂有关的疾病，选自高血压或心力衰竭。
发明的有益效果
与现有技术相比，本发明的技术方案具有以下优点：
经研究表明，本发明制备的式(I)所示化合物的III晶型溶解性良好、纯度较高，在高温、高湿、光照的条件下晶型经XRPD检测均未发生改变、晶型稳定性良好；本发明技术方案得到的式(I)所示化合物的III晶型能够满足生产运输储存的药用要求，生产工艺稳定、可重复可控，能够适应于工 业化生产。
附图说明
图1为式(I)所示化合物III晶型的XRPD图谱。
图2为式(I)所示化合物III晶型的DSC图谱。
图3为式(I)所示化合物I晶型的XRPD图谱。
图4为式(I)所示化合物II晶型的XRPD图谱。
具体实施方式
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。
实验所用的测试仪器
1、DSC谱
仪器型号：MettlerToledo DSC 1 Staree System
吹扫气：氮气
升温速率：10.0℃/min
温度范围：40-350℃
2、X-射线衍射谱
仪器型号：Bruker D8 Focus X-射线粉末衍射仪
射线：单色Cu-Kα射线(λ＝1.5406)
扫描方式：θ/2θ，扫描范围：2-40°
电压：40KV，电流：40mA
式(II)所示化合物(游离态)参照专利申请WO2016091042A1(公开日2016.06.16)中的方法制备。
对比例1、晶型I的制备
取(0.4g，2.66mmol)L-酒石酸加入到50ml反应瓶中，加入30ml甲醇，加热至70℃溶解，加入(1.0g，2.22mmol)(R)-5-氰基-N-(1-(2-羟基-2-(4-甲基-1-羰基-1,3-二氢异苯并呋喃-5-基)乙基)哌啶-4-基)-4-甲氧基吡啶甲酰胺(专利申请WO2016091042A1(公开日2016.06.16)中的方法制备)，70℃下反应24h，降至室温抽滤干燥得固体1.22g，产率91.7％。其X-射线粉末衍射谱图见图3，该晶型定义为I晶型。
对比例2、晶型II的制备
取(1.0g，2.22mmol)(R)-5-氰基-N-(1-(2-羟基-2-(4-甲基-1-羰基-1,3-二氢异苯并呋喃-5-基)乙基)哌啶-4-基)-4-甲氧基吡啶甲酰胺(专利申请WO2016091042A1(公开日2016.06.16)中的方法制备)、(0.4g，2.66mmol)L-酒石酸加入到50ml反应瓶中，加入30ml异丙醇/四氢呋喃/水(V:V:V＝20:10:1)，加热至70℃反应24h，降至室温抽滤干燥得固体1.15g，产率86.5％。其X-射线粉末衍射谱图见图4，该晶型定义为II晶型。
实施例1、晶型III的制备
取(0.4g，2.66mmol)L-酒石酸加入到反应瓶中，加入25mL乙醇，加热至70℃，溶解，加入(1.0g，2.22mmol)(R)-5-氰基-N-(1-(2-羟基-2-(4-甲基-1-羰基-1,3-二氢异苯并呋喃-5-基)乙基)哌啶-4-基)-4-甲氧基吡啶甲酰胺(专利申请WO2016091042A1(公开日2016.06.16)中的方法制备)，70℃下反应24h，降至室温抽滤干燥得固体1.23g，产率为92.3％。该结晶样品的X-射线粉末衍射谱图(XRPD图谱)见图1、DSC谱图见图2，在227.60℃有尖锐熔融吸热峰，将此晶型定义为III晶型，其2θ特征峰位置如下表所示：
表1、III晶型特征峰
Figure PCTCN2018119310-appb-000005
Figure PCTCN2018119310-appb-000006
Figure PCTCN2018119310-appb-000007
实施例2、晶型III的制备
取(1.0g，2.22mmol)(R)-5-氰基-N-(1-(2-羟基-2-(4-甲基-1-羰基-1,3-二氢异苯并呋喃-5-基)乙基)哌啶-4-基)-4-甲氧基吡啶甲酰胺(专利申请WO2016091042A1(公开日2016.06.16)中的方法制备)加入到反应瓶A中，加入10mL二甲基亚砜，加热至70℃溶解，取(0.4g，2.66mmol)L-酒石酸加入到反应瓶B中，加入20mL无水乙醇，加热至70℃溶解，将反应瓶B中的溶清液加入到反应瓶A中，70℃反应4h，降至室温，搅拌过夜。抽滤、干燥得固体1.13g，产率为85.0％。其X-射线粉末衍射谱图和DSC图谱经研究比对，确定产物为III晶型。
实施例3、晶型III的制备
取(1.0g，2.22mmol)(R)-5-氰基-N-(1-(2-羟基-2-(4-甲基-1-羰基-1,3-二氢异苯并呋喃-5-基)乙基)哌啶-4-基)-4-甲氧基吡啶甲酰胺(专利申请WO2016091042A1(公开日2016.06.16)中的方法制备)加入到反应瓶A中，加入10mL N,N-二甲基甲酰胺，加热至70℃热溶解，取(0.4g，2.66mmol)L-酒石酸加入到反应瓶B中，加入20mL无水乙醇，加热至70乙溶解，将反应瓶B中的溶清液加入到反应瓶A中，70℃反应4h，降至室温，搅拌过夜。抽滤、干燥得固体1.10g，产率为82.7％。其X-射线粉末衍射谱图和DSC图谱经研究比对，确定产物为III晶型。
实施例4、晶型III的制备
取(1.0g，2.22mmol)(R)-5-氰基-N-(1-(2-羟基-2-(4-甲基-1-羰基-1,3-二氢异苯并呋喃-5-基)乙基)哌啶-4-基)-4-甲氧基吡啶甲酰胺(专利申请WO2016091042A1(公开日2016.06.16)中的方法制备)加入到反应瓶A中，加入10mL N,N-二甲基乙酰胺，加热至70℃热溶解，取(0.4g，2.66mmol)L-酒石酸加入到反应瓶B中，加入20mL无水乙醇，加热至70℃溶解，将反应瓶B中的溶清液加入到反应瓶A中，70℃反应4h，降至室温，搅拌过夜。抽滤、干燥得固体1.12g，产率为84.2％。其X-射线粉末衍射谱图和DSC图谱经研究比对，确定产物为III晶型。
实施例5、晶型III的制备
取(1.0g，1.67mmol)式(I)所示化合物(按实施例1制备)加入到反应瓶中，加入6mL N,N-二甲基甲酰胺，70℃搅拌溶解，然后加入12mL预热的无水乙醇，70℃反应4h，降至室温，搅拌过夜。抽滤、干燥得固体816mg，产率为81.6％。其X-射线粉末衍射谱图和DSC图谱经研究比对，确定产物为III晶型。
实施例6、晶型III的制备
取(1.0g，1.67mmol)式(I)所示化合物(按实施例1制备)加入到反应瓶中，加入6mL N,N-二甲基乙酰胺，70℃搅拌溶解，然后加入12mL预热的无水乙醇，70℃反应4h，降至室温，搅拌过夜。抽滤、干燥得固体828mg，产率为82.8％。其X-射线粉末衍射谱图和DSC图谱经研究比对，确定产物为III晶型。
实施例7、晶型III的制备
取(1.0g，1.67mmol)式(I)所示化合物(按实施例1制备)加入到反应瓶中，加入5mL二甲基亚砜，70℃搅拌溶解，然后加入10mL预热的甲醇，70℃反应4h，降至室温，搅拌过夜。抽滤、干燥得固体794mg，产率为79.4％。其X-射线粉末衍射谱图和DSC图谱经研究比对，确定产物为III晶型。
实施例8、晶型III的制备
取(1.0g，1.67mmol)式(I)所示化合物(按实施例1制备)加入到反应瓶中，加入5mL二甲基亚砜，70℃搅拌溶解，然后加入10mL预热的无水乙醇，70℃反应4h，降至室温，搅拌过夜。抽滤、干燥得固体864mg，产率为86.4％。其X-射线粉末衍射谱图和DSC图谱经研究比对，确定产物为III晶型。
实施例9、晶型III的制备
取(1.0g，1.67mmol)式(I)所示化合物(按实施例1制备)加入到反应瓶中，加入5mL二甲基亚砜，70℃搅拌溶解，然后加入10mL预热的异丙醇，70℃反应4h，降至室温，搅拌过夜。抽滤、干燥得固体906mg，产率为90.6％。其X-射线粉末衍射谱图和DSC图谱经研究比对，确定产物为III晶型。
实施例10、晶型III的制备
取(1.0g，1.67mmol)式(I)所示化合物(按实施例1制备)加入到反应瓶中，加入5mL二甲基亚砜，70℃搅拌溶解，然后加入10mL预热的正丁醇，70℃反应4h，降至室温，搅拌过夜。抽滤、干燥得固体896mg，产率为89.6％。其X-射线粉末衍射谱图和DSC图谱经研究比对，确定产物为III晶型。
实施例11、晶型稳定性考察
将实施例1所得的式(I)所示化合物的III晶型及对比例1、对比例2所得的I晶型、II晶型样品分别敞口平摊放置，考察在光照(4500Lux)、加热(40℃，60℃)、高湿(75％RH、90％RH)条件下样品的稳定性。考察取样时间为5天和10天，HPLC检测纯度。
实验结果：
表2、式(I)所示化合物I、II、III晶型样品的稳定性比较
Figure PCTCN2018119310-appb-000008
Figure PCTCN2018119310-appb-000009
实验结论：
稳定性考察结果表明式(I)所示化合物I、II、III晶型样品分别在敞口的条件下放置，光照、高湿、高温条件下，III晶型的HPLC纯度均高于I晶型、II晶型，说明本发明的III晶型的稳定性优于I晶型、II晶型。
实施例13、晶型的特殊稳定性考察
将实施例1所得的III晶型进行研磨、加热及压片处理，考察样品稳定性。
实验结果：
表3、式(I)所示化合物III晶型特殊稳定性研究
Figure PCTCN2018119310-appb-000010
实验结论：
由表3数据表明式(I)所示化合物的III晶型在研磨、高温加热、压片处理条件下，晶型均未发生转变，说明本发明的III晶型的稳定性较高。
实施例14、本发明III晶型的引湿性研究
采用TAQ5000VSA，在25℃，湿度从10-90％，步进为10％，判断标准为10000min之内质量变化小于0.01％，循环两圈。
实验结果
表4、本发明III晶型引湿性考察结果
Figure PCTCN2018119310-appb-000011
实验结论：
由表4可知，本发明式(I)化合物的III晶型样品在25℃的条件下，在10.0％RH-80.0％RH之间随着湿度的增加吸水量也在增加，重量变化为0.9332％，小于15％但不小于2％，该样品略有引湿性；0％-85％的湿度变化过程中，该样品的解吸附过程与吸附过程基本重合。
实施例15、本发明晶型III、游离态在大鼠体内药代动力学实验
以SD大鼠为受试动物，应用LC/MS/MS法测定了SD大鼠灌胃给予式(I)所示化合物的III晶型、游离态后不同时刻血浆中的药物浓度，研究本发明式(I)所示化合物的III晶型、游离态在SD大鼠体内的药代动力学行为，评价其药动学特征。
供试品：式(I)所示化合物的III晶型(其制备方法见实施例1)、游离态(其制备方法可参照专利申请WO2016091042A1中的方法制备)。
试验动物：健康SD大鼠8只，雌雄各半，分成2组，购自西普尔-必凯实验动物有限公司提供，动物生产许可证号SCXK(沪)2008-0016。
药物配制：0.5％CMC-Na，超声制成均匀混悬液，配制浓度为0.5mg/mL，用于口服给药。
给药：健康SD大鼠8只，雌雄各半，禁食一夜后灌胃给药，给药体积10mL/kg。
方法：
健康SD大鼠8只，雌雄各半，禁食过夜后灌胃给药，于给药前及给药后0.5，1，2，4，6，8，12，24h经颈静脉穿刺采血0.1mL，肝素钠抗凝，3500rpm离心10min分离血浆，于-20℃保存。用LC/MS/MS法测定化合物灌胃给药后SD大鼠血浆中的待测化合物含量。
实验结果
表5、SD大鼠药代评价结果(po:5.0mg/kg)
Figure PCTCN2018119310-appb-000012
其中，T 1/2为半衰期；AUC last为药时曲线下面积0→t；Cl/F为清除率；Vz/F为表观分布容积。
实验结论：
由表5的实验结果可知，与游离态比较，本发明式(I)所示化合物的III晶型的半衰期比游离态更长，清除率更低、暴露量更高，说明本发明式(I)所示化合物的III晶型的药代动力学性质良好。

Claims (8)

  1. 一种式(I)所示化合物的III晶型，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在3.88、7.54、14.76、18.64和22.21处有特征峰，
    Figure PCTCN2018119310-appb-100001
  2. 如权利要求1所述的III晶型，其特征在于，所述III晶型在3.88、7.54、11.22、14.76、17.29、18.64、20.28、22.21、23.79、25.34和27.09处有特征峰。
  3. 如权利要求1所述的III晶型，其特征在于，所述III晶型在3.88、7.54、11.22、11.61、12.26、12.73、13.35、13.64、14.76、15.98、16.47、17.07、17.29、18.64、20.28、20.62、22.21、23.16、23.79、24.14、24.85、25.34、26.08、26.85、27.09、28.77、29.74、32.22、33.66、34.50、35.60、37.42和39.27处有特征峰。
  4. 如权利要求1-3任一项所述的III晶型，其特征在于所述2θ角度的误差范围为±0.2。
  5. 一种制备如权利要求1-4中任一项所述III晶型的方法，其特征在于，所述方法选自：
    方法(1)将式(I)所示化合物的游离态与L-酒石酸在一种溶剂或混合溶剂中反应，搅拌，析晶，过滤，干燥后即得目标III晶型；所述溶剂选自亚砜类溶剂、酰胺类溶剂或醇类溶剂，所述混合溶剂选自亚砜类溶剂与醇类溶剂的混合溶剂或酰胺类溶剂与醇类溶剂的混合溶剂；所述亚砜类溶剂优选二甲基亚砜，所述酰胺类溶剂优选N,N-二甲基甲酰胺或N,N-二甲基乙酰胺，所 述醇类溶剂优选甲醇、乙醇、正丙醇、异丙醇或正丁醇；
    方法(2)将式(I)所示化合物溶解于一种溶剂或混合溶剂中，析晶，过滤，干燥后即得目标III晶型；所述析晶的方法选自室温析晶、冷却析晶、挥发溶剂析晶或加入晶种诱导析晶，所述冷却析晶的温度选自-10℃～25℃，优选室温析晶；所述溶剂选自亚砜类溶剂、酰胺类溶剂或醇类溶剂，所述混合溶剂选自亚砜类溶剂与醇类溶剂的混合溶剂或酰胺类溶剂与醇类溶剂的混合溶剂；所述亚砜类溶剂优选二甲基亚砜，所述酰胺类溶剂优选N,N-二甲基甲酰胺或N,N-二甲基乙酰胺，所述醇类溶剂优选甲醇、乙醇、正丙醇、异丙醇或正丁醇，所述混合溶剂更优选二甲基亚砜/甲醇、二甲基亚砜/乙醇、二甲基亚砜/正丙醇、二甲基亚砜/异丙醇、二甲基亚砜/正丁醇、N,N-二甲基甲酰胺/乙醇或N,N-二甲基乙酰胺/乙醇。
  6. 一种药物组合物，其包含权利要求1-4中任一项所述的III晶型与药学上可接受的载体、稀释剂或赋形剂。
  7. 一种制备药物组合物的方法，其特征在于，所述方法包括由权利要求1-4中任一项所述的III晶型与药学上可接受的载体、稀释剂或赋形剂混合的步骤。
  8. 一种如权利要求1-4任一项所述的III晶型、或如权利要求6所述的药物组合物在制备治疗和/或预防与肾外髓质分泌钾通道(ROMK)抑制剂有关的疾病或病症的药物中的用途，所述疾病或病症优选高血压或心力衰竭。
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EP3722293A4 (en) 2021-06-02
EP3722293A1 (en) 2020-10-14
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MX2020005930A (es) 2020-08-24
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