WO2019149090A1 - 一种尿酸转运体1抑制剂的晶体及其制备方法和用途 - Google Patents

一种尿酸转运体1抑制剂的晶体及其制备方法和用途 Download PDF

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WO2019149090A1
WO2019149090A1 PCT/CN2019/072314 CN2019072314W WO2019149090A1 WO 2019149090 A1 WO2019149090 A1 WO 2019149090A1 CN 2019072314 W CN2019072314 W CN 2019072314W WO 2019149090 A1 WO2019149090 A1 WO 2019149090A1
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compound
preparation
crystal
hexane
pharmaceutical composition
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PCT/CN2019/072314
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French (fr)
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赵桂龙
刘长鹰
陈会慧
李玉荃
张海枝
刘旭圆
刘钰强
谢亚非
吴景卫
刘巍
徐为人
汤立达
邹美香
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天津药物研究院有限公司
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Priority to EP19748187.2A priority Critical patent/EP3747871A4/en
Priority to US16/966,271 priority patent/US11149013B2/en
Publication of WO2019149090A1 publication Critical patent/WO2019149090A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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

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  • the present invention relates to a crystal of a uric acid transporter 1 (URAT1) inhibitor which can be used for the treatment of gout and hyperuricemia, a process for the preparation of the crystal, and a pharmaceutical composition and use containing the same.
  • URAT1 uric acid transporter 1
  • the present inventors disclose in WO2016173503 the following compounds as inhibitors of uric acid transporter 1 (URAT1): 2-((5-bromo-4-((4-bromonaphthalen-1-yl)methyl)-4H-1, 2,4-Triazol-3-yl)thio)acetic acid.
  • URAT1 uric acid transporter 1
  • this compound is simply referred to as TY706 in the present application, and its structural formula is as shown in Formula I.
  • the compound can be used to prepare a medicament for treating gout and hyperuricemia.
  • the present inventors disclosed a preparation method of the compound TY706 in CN201610506171.0.
  • the inventors have found that when the compound TY706 is isolated from the solution by evaporation of the solvent at the later stage of the final preparation step, its physical form and appearance fluctuate between batches, making it difficult to maintain a constant appearance state. It is not suitable for direct use as a raw material medicine; at the same time, the purity of the solid obtained directly by evaporation of the solvent fluctuates greatly, which brings certain difficulties to the preparation of high-purity raw material medicine.
  • an object of the present invention is to provide a crystal of the compound TY706 which has the characteristics of stable appearance, high purity, stable storage, and the like, and can be stably supplied as a drug substance.
  • the crystal of the present invention may be simply referred to as Form A of Compound TY706 in the present invention.
  • the crystal form A of the compound TY706 of the present invention has the following characteristics: its X-ray powder diffraction (PXRD, Powder X-ray Diffraction) spectrum expressed by 2 ⁇ angle using Cu-K ⁇ radiation is 18.432 ⁇ 1, 19.846 ⁇ 1 There are diffraction peaks at 20.207 ⁇ 1, 20.327 ⁇ 1, 22.341 ⁇ 1, 22.735 ⁇ 1, 25.654 ⁇ 1, 26.119 ⁇ 1, 26.617 ⁇ 1 and 33.159 ⁇ 1.
  • the crystalline form A of the compound TY706 of the present invention has the following characteristics: its X-ray powder diffraction spectrum expressed by 2 ⁇ angle using Cu-K ⁇ radiation is 18.432 ⁇ 1, 19.846 ⁇ 1, 20.207 ⁇ 1, 20.327 ⁇ 1, 22.341 ⁇ 1, 22.735 ⁇ 1, 24.276 ⁇ 1, 24.417 ⁇ 1, 25.654 ⁇ 1, 26.119 ⁇ 1, 26.617 ⁇ 1, 26.819 ⁇ 1, 27.427 ⁇ 1, 29.185 ⁇ 1, 30.223 ⁇ 1 and 33.159 ⁇ 1 There is a diffraction peak at the place.
  • the crystalline form A of the compound TY706 of the present invention has the following characteristics: its X-ray powder diffraction spectrum expressed by 2 ⁇ angle using Cu-K ⁇ radiation is 6.547 ⁇ 1, 11.369 ⁇ 1, 12.158 ⁇ 1. 13.168 ⁇ 1, 14.124 ⁇ 1, 15.379 ⁇ 1, 15.868 ⁇ 1, 16.402 ⁇ 1, 16.925 ⁇ 1, 17.112 ⁇ 1, 17.707 ⁇ 1, 18.432 ⁇ 1, 18.918 ⁇ 1, 19.846 ⁇ 1, 20.207 ⁇ 1, 20.327 ⁇ 1, 21.88 ⁇ 1, 22.341 ⁇ 1, 22.735 ⁇ 1, 23.886 ⁇ 1, 24.276 ⁇ 1, 24.417 ⁇ 1, 24.994 ⁇ 1, 25.654 ⁇ 1, 26.119 ⁇ 1, 26.617 ⁇ 1, 26.819 ⁇ 1, 27.427 ⁇ 1, 27.692 ⁇ 1, 28.589 ⁇ 1, 28.982 ⁇ 1, 29.185 ⁇ 1, 29.640 ⁇ 1, 30.223 ⁇ 1, 33.159 ⁇ 1 have diffraction peaks.
  • the crystalline form A of the compound TY706 of the present invention is characterized in that its X-ray powder diffraction spectrum expressed by 2 ⁇ angle using Cu-K ⁇ radiation is as shown in FIG.
  • the A crystal form of the compound TY706 of the present invention has a d-pitch as shown in Table 1 using an X-ray powder diffraction spectrum expressed by a 2 ⁇ angle using Cu-K ⁇ radiation.
  • the differential scanning calorimetry (DSC) curve of Form A of Compound TY706 of the present invention has an endothermic peak at 189.30 °C.
  • the preparation method of the crystal form A of the compound TY706 of the present invention may include the following steps: mixing the compound TY706 with a single solvent or a mixed solvent, heating and refluxing for 1-3 hours, then cooling to room temperature, collecting the crystal by suction filtration, and drying after obtaining .
  • the single solvent may be selected from a C 1 -C 4 lower alcohol (such as methanol or ethanol), a C 3 -C 6 lower ketone (such as acetone or methyl ethyl ketone), a C 1 - C 3 lower acid (such as acetic acid).
  • a C 1 -C 4 lower alcohol such as methanol or ethanol
  • a C 3 -C 6 lower ketone such as acetone or methyl ethyl ketone
  • a C 1 - C 3 lower acid such as acetic acid
  • tetrahydrofuran 1,4-dioxane
  • a lower ester consisting of a C 1 -C 4 lower acid and a C 1 -C 4 lower alcohol
  • the mixed solvent may be a mixture of two or more of the above single solvents, for example, a mixture of ethyl acetate and n-hexane in a volume ratio of 1:1, a mixture of acetone and n-hexane in a volume ratio of 1:1. Or a mixture of tetrahydrofuran and n-hexane in a volume ratio of 1:1.
  • the physical form and appearance of the sample isolated from the solution of the compound TY 706 by evaporation of the solvent fluctuate between batches, and it is difficult to maintain a constant appearance state, and the range of variation is large, and it is not suitable for use as a drug substance directly;
  • the crystal form A of TY706 has the characteristics of stable appearance, high purity, stable storage, and the like, and can be stably supplied to prepare a drug substance, and thus has industrial applicability.
  • the crystal form A of the compound TY706 of the present invention is stable in the continuous scale of preparation of 10 batches or more in the range of 1 g-500 g of synthetic scale, and the appearance is white crystalline solid, after powder X-ray diffraction (PXRD) And differential scanning calorimetry (DSC) to determine that each batch is Form A. HPLC analysis of each batch showed that the purity of Form A was significantly higher than that used to prepare Form A. In the two-week impact factor test, Form A has certain stability to light, heat and humidity.
  • the invention also provides a pharmaceutical composition comprising Form A of Compound TY706 and optionally a pharmaceutically acceptable adjuvant.
  • Form A of Compound TY706 of the present invention may be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical composition.
  • the pharmaceutical composition may be in the form of a solid oral preparation, a liquid oral preparation or an injection.
  • the solid oral preparation may be a dispersible tablet, an enteric coated tablet, a chewable tablet, an orally disintegrating tablet, a capsule or a granule; the liquid oral preparation is an oral solution; the injection may be a water jet needle, a lyophilized powder for injection , large infusion or small infusion.
  • the pharmaceutical composition of the present invention may comprise one or more selected from the group consisting of fillers, binders, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, coating materials or shaping agents.
  • a pharmaceutically acceptable excipient for the agent may comprise one or more selected from the group consisting of fillers, binders, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, coating materials or shaping agents.
  • the filler is selected from one or more of the group consisting of lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate or microcrystalline cellulose.
  • the binder is selected from the group consisting of sucrose, starch, povidone, sodium carboxymethylcellulose, hypromellose, hydroxypropylcellulose, methylcellulose, polyethylene glycol, medicinal ethanol or water.
  • the disintegrant is selected from the group consisting of starch, crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose or an effervescent disintegrant One or more.
  • the crystal form A of the compound TY706 of the present invention has an inhibitory action on human uric acid transporter 1 (URAT1), and can be used as an active ingredient for the preparation of a therapeutic drug such as gout and hyperuricemia.
  • URAT1 human uric acid transporter 1
  • the activity of Form A of TY706 of the present invention was verified by an in vitro inhibition model of humanized URAT1.
  • the present invention provides the use of a pharmaceutical composition of Form A of Compound TY706, or Form A comprising Compound TY706, for the manufacture of a medicament for the treatment of gout and/or hyperuricemia.
  • Form A of the compound TY706 of the present invention is effective over a relatively wide dosage range.
  • a daily dose of about 1 mg to 500 mg per person can be divided into one or several administrations.
  • the dose of Form A which is actually administered with the compound TY706 of the present invention can be determined by a doctor according to the relevant circumstances. These conditions include: the subject's physical condition, route of administration, age, weight, individual response to the drug, severity of symptoms, and the like.
  • PXRD powder X-ray powder diffraction
  • Figure 2 shows X-ray powder diffraction data for Form A of Compound TY706 of the present invention.
  • Figure 3 shows a differential scanning calorimetry (DSC) curve for Form A of Compound TY706 of the present invention.
  • the differential scanning calorimetry (DSC) conditions for the determination of the compound TY706 crystal form A used in the present invention are: 8.8900 mg of the crystalline form A of the compound TY706, the heating rate is 10 ° C / min, and the scanning temperature range is 30.0-220.0 ° C,
  • the instrument used was a Mettler Toledo DSC822e type TG/DSC analyzer.
  • PXRD powder X-ray diffraction
  • Mobile phase A B 0 25 75 30 40 60 45 50 50 60 70 30 70 70 30 71 25 75 75 25 75
  • the compound TY706 of the present invention can be produced by the following steps:
  • TY706 can be prepared according to the preparation method disclosed in CN201610506171.0, and the specific operation is as follows.
  • reaction mixture was cooled to room temperature, poured into ice water (3 L), extracted with dichloromethane (500 mL ⁇ 3), and the combined phases were combined with 5% aqueous Na 2 CO 3 (500 mL ⁇ 5), 10% Na 2 S 2
  • the aqueous solution of O 3 (500 mL) and 5% brine (500 mL) were washed and dried over anhydrous Na 2 SO 4 .
  • the dried organic phase was evaporated to dryness on a rotary evaporator and the residue obtained was purified by column chromatography to afford product 2. Colorless oil, 39.80 g, yield 90%.
  • reaction mixture was evaporated to dryness on a rotary evaporator, the residue obtained is the crude compound 5 in DMF (80mL) was dissolved, was added a solid K 2 CO 3 (3.46g, 25mol ) and water (10mL) was prepared. The reaction mixture was stirred at 50 ° C until the reaction was complete (usually 5 hours).
  • reaction mixture was poured into ice water (400 mL), stirred, and extracted with CH 2 Cl 2 (100mL ⁇ 5 ).
  • the combined organic phases were washed with 5% brine (200mL) washed, dried over anhydrous Na 2 SO 4.
  • the dried organic phase was evaporated to dryness elution elution elution elution Melting point 112.5-114 ° C.
  • the combined organic phases were washed with 5% brine (200mL) washed, dried over anhydrous Na 2 SO 4.
  • the dried organic phase was evaporated to dryness elution elution elution elution Melting point 169.5-171.5 ° C.
  • the active ingredient, pregelatinized starch and microcrystalline cellulose are sieved, thoroughly mixed, added to polyvinylpyrrolidone solution, mixed, softened, sieved, wet granules, dried at 50-60 ° C, and carboxymethyl starch
  • the sodium salt, magnesium stearate and talc are previously sieved and then added to the above granules for tableting.
  • the IC 50 value of the crystal form A of TY706 of the present invention for inhibition of URAT1 was measured by the following method.
  • the expression cells (HEK293) and mock cells stably expressing the URAT1 gene were inoculated into a lysine-coated 24-well culture plate at a cell seeding density of 1 ⁇ 10 5 cells/well at 37 ° C, 5%. The cells were cultured for 2 days in an incubator of CO 2 and saturated humidity.
  • the culture medium in the culture plate was removed, the cultured cells were washed twice with DPBS, and incubated in 37° CD PBS buffer for 10 min, then 500 ⁇ L of radiolabeled probe substrate ([8- 14 C] uric acid) and one A series concentration of the test compound (0.001-10 ⁇ M) or a blank solution was substituted for DPBS, the concentration of [8- 14 C] uric acid was 30 ⁇ M, and the radiation intensity per well was 0.867 ⁇ Ci. After 2 min, the reaction was stopped with ice bath DPBS buffer and washed 3 times.
  • Inhibition rate (control-test compound) / (control-mock) ⁇ 100%
  • control no radioactivity corresponding to the pores of the compound to be tested
  • Test compound radiation intensity corresponding to the pore of the test compound
  • Example 21 Purity test of TY702 crystal form A sample
  • Example 1 the TY706 Form A sample of the present invention had an HPLC purity of 99.76% and contained 4 impurities; and the TY706 raw material used to prepare the Form A had an HPLC purity of 99.31% and contained 11 impurities. It can be seen that the purity of crystal form A is obviously improved, and it is suitable for the production of raw materials for TY706.
  • Example 22 Influencing factors test of TY702 crystal form A sample
  • the crystal form A sample of TY706 prepared in Example 1 and the raw material for preparing crystal form A were simultaneously subjected to influencing factor tests, respectively, in light (5000 Lx ⁇ hr, weighing bottle opening), high heat (60 ° C, weighing bottle). Placed under high humidity (92.5% RH, weighing bottle opening) for 14 days, compared with day 0, appearance, number of impurities and total amount of impurities (measured by HPLC). The results are shown in Table 5-7. .

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Abstract

本发明提供了一种尿酸转运体1抑制剂的晶体及其制备方法和用途。该晶体具有外观状态稳定，能进一步提高该化合物的纯度、保存稳定性等特点，适合作为原料药。

Description

一种尿酸转运体1抑制剂的晶体及其制备方法和用途 技术领域
本发明涉及可以一种用于痛风和高尿酸血症治疗的尿酸转运体1(URAT1)抑制剂的晶体，还涉及该晶体的制备方法以及含有这种晶体的药物组合物和用途。
背景技术
本发明人在WO2016173503中公开了下列化合物作为尿酸转运体1(URAT1)抑制剂：2-((5-溴-4-((4-溴萘-1-基)甲基)-4H-1,2,4-三唑-3-基)硫)乙酸。为了方便，在本申请中将该化合物简称为TY706，其结构式如式I所示。该化合物可以用于制备治疗痛风和高尿酸血症的药物。本发明人在CN201610506171.0中公开了化合物TY706的一种制备方法。
Figure PCTCN2019072314-appb-000001
在进一步的研究中，本发明人发现，化合物TY706在最后一步制备步骤的后期从溶液中通过蒸干溶剂分离得到时，其物理形态和外观在批次之间波动不定，难以保持恒定的外观状态，不适合直接作为原料药使用；同时，通过蒸干溶剂直接得到的固体纯度波动较大，给制备高纯度的原料药带来了一定的困难。
发明内容
为此，本发明的目的是提供一种化合物TY706的晶体，其具有外观状态稳定、纯度高、保存稳定等特点，可以稳定地供给以作为原料药。本发明所述的晶体在本发明中可简称为化合物TY706的A晶型。
Figure PCTCN2019072314-appb-000002
本发明所述的化合物TY706的A晶型具有以下特征：其使用Cu-Kα辐射的以2θ角度表示的X-射线粉末衍射(PXRD，Powder X-ray Diffraction)光谱在18.432±1、19.846±1、20.207±1、20.327±1、22.341±1、22.735±1、25.654±1、26.119±1、26.617±1和33.159±1处具有衍射峰。
优选地，本发明所述的化合物TY706的A晶型具有以下特征：其使用Cu-Kα辐射的以2θ角度表示的X-射线粉末衍射光谱在18.432±1、19.846±1、20.207±1、20.327±1、22.341±1、22.735±1、24.276±1、24.417±1、25.654±1、26.119±1、26.617±1、26.819±1、27.427±1、29.185±1、30.223±1和33.159±1处具有衍射峰。
更优选地，本发明所述的化合物TY706的A晶型具有以下特征：其使用Cu-Kα辐射的以2θ角度表示的X-射线粉末衍射光谱在6.547±1、11.369±1、12.158±1、13.168±1、14.124±1、15.379±1、15.868±1、16.402±1、16.925±1、17.112±1、17.707±1、18.432±1、18.918±1、19.846±1、20.207±1、20.327±1、21.88±1、22.341±1、22.735±1、23.886±1、24.276±1、24.417±1、24.994±1、25.654±1、26.119±1、26.617±1、26.819±1、27.427±1、27.692±1、28.589±1、28.982±1、29.185±1、29.640±1、30.223±1、33.159±1处具有衍射峰。
最优选地，本发明所述的化合物TY706的A晶型具有以下特征：其使用Cu-Kα辐射的以2θ角度表示的X-射线粉末衍射光谱如图1所示。
具体地，本发明所述的化合物TY706的A晶型使用Cu-Kα辐射的以2θ角度表示的X-射线粉末衍射光谱具有如表1所示的d间距
Figure PCTCN2019072314-appb-000003
表1本发明所述的化合物TY706的晶型A的粉末X-射线衍射特征峰d间距
Figure PCTCN2019072314-appb-000004
本发明所述的化合物TY706的A晶型的差示扫描量热分析(DSC,differential scanning calorimetry)曲线在189.30℃处具有一吸热峰。
本发明所述化合物TY706的晶型A的制备方法可以包括以下步骤：将化合物TY706与单一溶剂或者混合溶剂混合，加热回流1-3小时，然后降温至室温，抽滤收集晶体，干燥后即得。
所述单一溶剂可以选自C 1-C 4的低级醇(如甲醇或乙醇)，C 3-C 6的低级酮(如丙酮或丁酮)，C 1-C 3的低级酸(如乙酸)，四氢呋喃，1,4-二氧六环，由C 1-C 4的低级酸和C 1-C 4的低级醇组成的低级酯(如乙酸乙酯、乙酸甲酯、乙酸丁酯、甲酸乙酯、甲酸丁酯或丁酸乙酯)，乙醚，甲基叔丁基醚，二异丙基醚，C 5-C 8的直链或支链烷烃(如正己烷)，或C 5-C 8的环烷烃。
所述混合溶剂可以为由上述单一溶剂中的两种或者两种以上组成的混合物，例如体积比1:1的乙酸乙酯和正己烷的混合物，体积比1:1的丙酮和正己烷的混合物或体积比1:1的四氢呋喃与正己烷的混合物。
化合物TY706通过蒸干溶剂从溶液中分离得到的样品的物理形态和外观在批次之间波动不定，难以保持恒定的外观状态，变化范围较大，不适合直接作为原料药使用；而本发明公开的TY706的晶型A具有外观状态稳定、纯度高、保存稳定等特点，可以稳定地供给制备原料药，因此具有工业实用性。
本发明所述的化合物TY706的晶型A在1g-500g的合成规模范围内，保持连续制备10个批次以上都是稳定的，外观均为白色结晶性固体，经过 粉末X-射线衍射(PXRD)和差示扫描量热分析(DSC)确定每批均是晶型A。各批次经过HPLC分析表明，A晶型纯度显著高于用于制备晶型A所用的原料。在为期两周的影响因素试验中，晶型A对光、热、湿具有一定的稳定性。
本发明还提供了一种药物组合物，其包含化合物TY706的晶型A以及任选的药学上可接受的辅料。本发明所述的化合物TY706的晶型A可以与一种或多种药学上可接受的载体、赋形剂或稀释剂共同制成药物组合物。该药物组合物可以为固体口服制剂、液体口服制剂或注射剂等剂型。所述固体口服制剂可以为分散片、肠溶片、咀嚼片、口崩片、胶囊或颗粒剂；所述液体口服制剂为口服溶液；所述注射剂可以为射用水针、注射用冻干粉针、大输液或小输液等。
本发明的药物组合物可以包括一种或多种选自填充剂、粘合剂、崩解剂、润滑剂、助流剂、泡腾剂、矫味剂、防腐剂、包衣材料或赋形剂的药学上可接受辅料。
具体地，所述填充剂选自乳糖、蔗糖、糊精、淀粉、预胶化淀粉、甘露醇、山梨醇、磷酸氢钙、硫酸钙、碳酸钙或微晶纤维素中的一种或多种；所述粘合剂选自蔗糖、淀粉、聚维酮、羧甲基纤维素钠、羟丙甲纤维素、羟丙纤维素、甲基纤维素、聚乙二醇、药用乙醇或水中的一种或多种；所述崩解剂选自淀粉、交联聚维酮、交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲纤维素钠或泡腾崩解剂中的一种或多种。
本发明所述的化合物TY706的晶型A具有人尿酸转运体1(URAT1)的抑制作用，可作为有效成分用于制备痛风和高尿酸血症等的治疗药物。本发明所述的TY706的晶型A的活性是通过体外对人源化URAT1的抑制模型验证的。由此，本发明提供了化合物TY706的晶型A、或包含化合物TY706的晶型A的药物组合物在制备治疗痛风和/或高尿酸血症的药物中的应用。
本发明所述的化合物TY706的晶型A在相当宽的剂量范围内是有效的。例如每天服用的剂量约在1mg-500mg/人范围内，可分为一次或数次给药。实际服用本发明所述的化合物TY706的晶型A的剂量可由医生根据有关的情况来决定。这些情况包括：被治疗者的身体状态、给药途径、年龄、体重、对药物的个体反应，症状的严重程度等。
附图的简要说明
图1为本发明的化合物TY706的晶型A的粉末X-射线粉末衍射(PXRD)图谱。
图2显示本发明的化合物TY706的晶型A的X-射线粉末衍射数据。
图3显示本发明的化合物TY706的晶型A的差示扫描量热分析(DSC)曲线。
实施发明的最佳方式
下面结合实施例对本发明作进一步的说明。需要说明的是，下述实施例仅是用于说明，而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
本发明所用的测定化合物TY706晶型A的差示扫描量热分析(DSC)条件为：化合物TY706的晶型A样品8.8900mg，升温速率10℃/min，扫描温度范围为30.0-220.0℃，参比物Al 2O 3，所用仪器为Mettler Toledo DSC822e型TG/DSC分析仪。
本发明所用的测定化合物TY706晶型A的粉末X-射线衍射(PXRD)分析数据在日本理学SmartLab 3KW型粉末衍射仪上测试，产生X-射线的管压为40KV，管流为40mA，靶为Cu-Kα，2θ＝3.0000-40.0000°，扫描速度：10.4018°/min。
本发明所述的测定化合物TY706晶型A及其原料的HPLC条件为：色谱柱：C 18，5μ，Φ4.6×150mm，Waters Atlantis T3；流动相A：乙腈-甲醇＝9：1，流动相B：10mM磷酸氢二铵(磷酸调pH至4.30±0.03)，采用梯度洗脱(表2)；检测波长：225nm；柱温：35℃；流速：1.0mL/min；样品浓度：0.3mg/mL；进样体积：15μL；溶解溶剂：磷酸盐缓冲液(pH7.8-8.0；取磷酸氢二钾5.59g与磷酸二氢钾0.41g，加水使溶解成1000mL即得)。
表2 TY706HPLC测试的梯度洗脱
流动相 A B
0 25 75
30 40 60
45 50 50
60 70 30
70 70 30
71 25 75
75 25 75
实施例1：TY706的晶型A的制备
(1)本发明的化合物TY706可以通过下列步骤制备：
TY706可以按照CN201610506171.0中公开的制备方法制备，具体操作如下。
Figure PCTCN2019072314-appb-000005
步骤1：化合物2的合成
向一只1L的干燥圆底烧瓶中加入化合物1(1-甲基萘,28.44g,200mmol)、NBS(42.72g,240mmol)和MeCN(700mL)，所得混合物在30℃-40℃下搅拌12小时。
反应混合物冷却到室温，倾倒到冰水(3L)中，二氯甲烷(500mL×3)萃取，合并萃取相，依次用5％Na 2CO 3水溶液(500mL×5)、10％Na 2S 2O 3水溶液(500mL)和5％食盐水(500mL)洗涤，无水Na 2SO 4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物2。无色油状物，39.80g，收率90％。
1H NMR(DMSO-d 6,400MHz),δ8.14-8.16(m,1H),8.07-8.09(m,1H),7.76(d,1H,J＝7.6Hz),7.66-7.70(m,2H),7.30(d,1H,J＝7.6Hz),2.63(s,3H)。
步骤2：化合物3的合成
室温下向一只干燥的1L的圆底烧瓶中加入正己烷(400mL)，搅拌下加入化合物2(35.37g,160mmol)、过氧化苯甲酰(BPO,0.775g,3.2mmol)和NBS(34.17g,192mmol)，搅拌升温至回流，直到TLC显示反应完成(反应开始后每8小时添加0.775g BPO一次；反应通常在36小时以内完成)。
反应结束后，将体系降至室温，搅拌2小时后抽滤，滤饼加入800mL水中室温搅拌1小时，抽滤，滤液弃去，滤饼再次加入800mL水中室温搅拌1小时，抽滤，滤液弃去。所得滤饼用800mL正己烷打浆搅拌2小时，抽滤，滤饼干燥即得化合物3纯品，白色固体，34.56g，收率72％。熔点104.0-105.5℃。
1H NMR(DMSO-d 6,400MHz),δ8.20-8.26(m,2H),7.86(d,1H,J＝8.0Hz),7.72-7.78(m,2H),7.62(d,1H,J＝7.6Hz),5.21(s,2H)。
步骤3：化合物4的合成
向一只干燥的1L的圆底烧瓶中加入化合物3(30.00g,100mmol)，以干燥的DMF(300mL)溶解，而后搅拌下升温至140℃，在1分钟内分三批加入KSCN(11.66g,120mmol)。加完后，反应混合物在140℃下继续搅拌1小时。
反应混合物冷却到室温后，倾倒入搅拌的冰水(2000mL)中，搅拌，以CH 2Cl 2(300mL×3)萃取。合并有机相，用5％食盐水(200mL×5)洗涤，无水Na 2SO 4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到化合物4，白色固体，25.59g，产率92％。熔点94.5-97.5℃。
1H NMR(DMSO-d 6,400MHz),δ8.21-8.24(m,1H),8.11-8.14(m,1H),7.92(d,1H,J＝7.6Hz),7.73-7.78(m,2H),7.52(d,1H,J＝8.0Hz),5.41(s,2H)。
步骤4：化合物5和化合物6的合成
上述粗品化合物4(6.95g,按25mmol计)以THF(100mL)溶解，室温下搅拌，加入甲酰肼(1.80g,30mmol)，然后继续搅拌过夜，此时TLC检测反应完成。
反应混合物在旋蒸仪上蒸干，得到的残余物即为化合物5的粗品，以DMF(80mL)溶解，加入由固体K 2CO 3(3.46g,25mol)和水(10mL)配制的溶液。反应混合物在50℃下搅拌，直到反应完成(通常5小时)。
反应混合物冷却到室温后，倾倒到冰水(400mL)中，搅拌，以盐酸调节pH＝5-6，用CH 2Cl 2(150mL×5)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na 2SO 4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物F，白色固体， 1H NMR显示其中含有约5％的脱溴副产物，将该产物F粗品使用乙酸乙酯结晶两次，可以得到纯品化合物6，6.96g,产率87％(化合物4→化合物6合并收率)。熔点243-244℃。
1H NMR(DMSO-d 6,400MHz),δ13.88(brs,1H),8.37(s,1H),8.22(d,2H,J＝7.6Hz),7.90(d,1H,J＝7.2Hz),7.72(m,2H),7.18(d,1H,J＝7.2Hz),5.61(s,2H)。
步骤5：化合物7的合成
化合物6(6.40g,20mmol)溶于DMF(100mL)中，室温下搅拌，加入固体K 2CO 3(8.29g,60mmol)和溴乙酸甲酯(3.67g,24mmol)。所得反应混合物在室温下继续搅拌，直到TLC检测发现反应完成(通常5小时以内)。
反应混合物倾倒到冰水(400mL)中，搅拌，用CH 2Cl 2(100mL×5)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na 2SO 4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到化合物7，白色固体，7.37g，产率94％。熔点112.5-114℃。
1H NMR(DMSO-d 6,400MHz),δ8.67(s,1H),8.22-8.25(m,1H),8.15-8.17(m,1H),7.88(d,1H,J＝7.6Hz),7.72-7.79(m,2H),6.92(d,1H,J＝7.6Hz),5.72(s,2H),4.07(s,2H),3.62(s,3H)。
步骤6：化合物8的合成
化合物7(3.92g,10mmol)溶于乙腈(50mL)中，室温下搅拌，加入NBS(2.14g,12mmol)，继续在室温下搅拌，直到TLC检测反应完成(通常12小时以内)。
反应混合物倾倒到冰水(200mL)中，搅拌，用CH 2Cl 2(100mL×3)萃取。合并有机相，依次用饱和Na 2CO 3溶液(100mL×3)和5％食盐水(200mL)洗涤，无水Na 2SO 4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物8，白色固体，熔点141-143℃，3.49g，产率74％。
1H NMR(DMSO-d 6,400MHz),δ8.21-8.26(m,2H),7.84(d,1H,J＝8.0Hz),7.76-7.82(m,2H),6.49(d,1H,J＝7.6Hz),5.74(s,2H),4.08(s,2H),3.61(s,3H)。
步骤7：TY706的合成
化合物8(3.30g,7mmol)加入甲醇(50mL)中，室温下搅拌，加入由LiOH·H 2O(0.84g,20mmol)和水(3mL)配成的溶液，而后室温下搅拌，直到TLC检测发现反应完成(通常2小时)。
反应混合物倾倒到冰水(200mL)中，搅拌，用盐酸调节pH＝2-3，用CH 2Cl 2(100mL×4)萃取。合并有机相，用5％食盐水(200mL)洗涤，无水Na 2SO 4干燥。干燥后的有机相在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到产物TY706，白色固体，2.82g，产率88％。熔点169.5-171.5℃。
1H NMR(DMSO-d 6,400MHz),δ12.97(brs,1H),8.22-8.26(m,2H),7.83(d,1H,J＝8.0Hz),7.76-7.81(m,2H),6.51(d,1H,J＝8.0Hz),5.73(s,2H),4.01(s,2H)。
(2)本发明所述化合物TY706的晶型A可以通过下列方法制备：
取20.00g化合物TY706置于500mL的圆底烧瓶中，加入丙酮200mL，搅拌回流3小时。而后在搅拌下自动降温至室温。抽滤收集固体，并在真空油泵上25℃下干燥12小时，得到本发明所述的化合物TY706的晶型A。19.00 g，回收率95％。经过粉末X-射线衍射(PXRD)和差示扫描量热分析(DSC)分析确定是晶型A。图1和图2分别为本发明所述化合物TY706的晶型A的X-射线粉末衍射(PXRD)分析图谱及数据。图3为本发明所述化合物TY706的晶型A的差示扫描量热分析(DSC)图谱。
实施例2-18：TY706晶型A的制备
根据实施例1中化合物TY706晶型A的制备方法，更换其他溶剂或者溶剂组合物，得到下列结果(表3)。
表3实施例2-18：更换不同溶剂制备化合物TY706晶型A的结果
Figure PCTCN2019072314-appb-000006
实施例19
Figure PCTCN2019072314-appb-000007
Figure PCTCN2019072314-appb-000008
将活性成分、预胶化淀粉和微晶纤维素过筛，充分混合，加入聚乙烯吡咯烷酮溶液，混合，制软材，过筛，制湿颗粒，于50-60℃干燥，将羧甲基淀粉钠盐，硬脂酸镁和滑石粉预先过筛，然后加入到上述的颗粒中压片。
实施例20
本发明所述的TY706的晶型A对URAT1抑制的IC 50值按照如下方法测定。
胰酶消化后，将稳定表达URAT1基因的表达细胞(HEK293)和mock细胞均接种于赖氨酸包被24孔培养盘，细胞接种密度为1×10 5个/孔，在37℃、5％CO 2、饱和湿度的培养箱内培养2天。移去培养板内培养液，将培养细胞用DPBS清洗两次，并在37℃DPBS缓冲液中温浴10min，然后以500μL含有放射性标记的探针底物([8- 14C]尿酸)和一系列浓度的待测化合物(0.001-10μM)或者空白溶液置换DPBS，[8- 14C]尿酸的浓度为30μM，每孔放射强度为0.867μCi。2min后，用冰浴DPBS缓冲液终止反应，并清洗3次，然后各孔添加500μL 0.1mol/L NaOH裂解细胞，提取裂解液于闪烁瓶中，添加3mL的闪烁液(Aquasol-2)，并用Tri-Carb 2910TR液闪仪(PerkinElmer,Waltham,USA)测定样品中的放射性强度。
使用上述测定的数据根据下列公式计算待测化合物对URAT1的抑制率：
抑制率＝(control-test compound)/(control-mock)×100％
其中：control＝无待测化合物的孔对应的放射性强度
test compound＝待测化合物的孔对应的放射性强度
mock＝未转染URAT1的空白细胞的孔对应的放射性强度
测定结果如表4所示。
表4 TY706和lesinurad体外抑制URAT1的实验结果
化合物 IC 50(hURAT1,μM)
TY706 0.081
lesinurad 7.18
上述IC 50的测定结果表明，化合物TY706的晶型A对人URAT1抑制作用很强，体外活性接近尿酸转运体1(URAT1)抑制剂lesinurad的两个数量级，可以用于制备痛风和高尿酸血症的治疗。
实施例21：TY702晶型A样品的纯度试验
在实施例1中，本发明所述TY706晶型A样品的HPLC纯度为99.76％，含有4个杂质；而用于制备该晶型A的TY706原料的HPLC纯度为99.31％，含有11个杂质。由此可见晶型A的纯度明显提高，适合用于TY706的原料药生产。
实施例22：TY702晶型A样品的影响因素试验
将实施例1中制得的TY706的晶型A样品与制备晶型A的原料同时进行影响因素试验，分别在光照(5000Lx·hr，称量瓶开口放置)、高热(60℃，称量瓶开口放置)和高湿(92.5％RH，称量瓶开口放置)的条件下放置14天，与第0天比较外观、杂质个数和杂质总量(以HPLC测定)，结果见表5-7。
表5 TY706晶型A对光稳定性的试验数据
Figure PCTCN2019072314-appb-000009
表6 TY706晶型A对高热稳定性的试验数据
Figure PCTCN2019072314-appb-000010
表7 TY706晶型A对高湿稳定性的试验数据
Figure PCTCN2019072314-appb-000011
由以上数据可见，TY706晶型A对光、高热、高湿的稳定性均比制备TY706晶型A的原料要稳定，说明了TY706晶型A适合用于TY706的原料药生产。
尽管本发明已进行了一定程度的描述，明显地，在不脱离本发明的精神和范围的条件下，可进行各个条件的适当变化。可以理解，本发明不限于所述实施方案，而归于权利要求的范围，其包括所述每个因素的等同替换。

Claims (10)

  1. 一种式I所示的化合物的晶体，其特征在于：其使用Cu-Kα辐射的以2θ角度表示的粉末X-射线衍射光谱在18.432±1、19.846±1、20.207±1、20.327±1、22.341±1、22.735±1、25.654±1、26.119±1、26.617±1和33.159±1处具有衍射峰，
    Figure PCTCN2019072314-appb-100001
  2. 根据权利要求1所述的晶体，其特征在于：其使用Cu-Kα辐射的以2θ角度表示的X-射线粉末衍射光谱在18.432±1、19.846±1、20.207±1、20.327±1、22.341±1、22.735±1、24.276±1、24.417±1、25.654±1、26.119±1、26.617±1、26.819±1、27.427±1、29.185±1、30.223±1和33.159±1处具有衍射峰；
    优选地，其使用Cu-Kα辐射的以2θ角度表示的X-射线粉末衍射光谱在6.547±1、11.369±1、12.158±1、13.168±1、14.124±1、15.379±1、15.868±1、16.402±1、16.925±1、17.112±1、17.707±1、18.432±1、18.918±1、19.846±1、20.207±1、20.327±1、21.88±1、22.341±1、22.735±1、23.886±1、24.276±1、24.417±1、24.994±1、25.654±1、26.119±1、26.617±1、26.819±1、27.427±1、27.692±1、28.589±1、28.982±1、29.185±1、29.640±1、30.223±1、33.159±1处具有衍射峰。
    更优选地，其使用Cu-Kα辐射的以2θ角度表示的X-射线粉末衍射光谱如图1所示。
  3. 根据权利要求1或2所述的晶体，其特征在于，其差示扫描量热分析曲线在189.30℃处具有一吸热峰。
  4. 根据权利要求1至3中任一项所述的晶体的制备方法，其特征在于：将式I所示的化合物与单一溶剂或者混合溶剂混合，加热回流1-3小时，然后降温至室温，抽滤收集晶体，干燥后即得。
  5. 根据权利要求4所述的制备方法，其特征在于，所述单一溶剂选自C 1-C 4的低级醇，例如甲醇或乙醇；C 3-C 6的低级酮，例如丙酮或丁酮；C 1-C 3 的低级酸，例如乙酸；四氢呋喃；1,4-二氧六环；由C 1-C 4的低级酸和C 1-C 4的低级醇组成的低级酯，例如乙酸乙酯、乙酸甲酯、乙酸丁酯、甲酸乙酯、甲酸丁酯或丁酸乙酯；乙醚，甲基叔丁基醚，二异丙基醚；C 5-C 8的直链和支链烷烃，例如正己烷，或C 5-C 8的环烷烃；优选地，所述单一溶剂选自甲醇、乙醇、丙酮、丁酮、乙酸、四氢呋喃、1,4-二氧六环、乙酸甲酯、乙酸乙酯、乙酸丁酯、甲酸乙酯、甲酸丁酯、丁酸乙酯、二异丙基醚或正己烷；
    所述混合溶剂为由所述单一溶剂中的两种或者两种以上组成的混合物，例如体积比1:1的乙酸乙酯和正己烷的混合物，体积比1:1的丙酮和正己烷的混合物或体积比1:1的四氢呋喃与正己烷的混合物。
  6. 一种药物组合物，其特征在于：其包含根据权利要求1-3中的任一项所述的晶体，或根据权利要求4或5的制备方法制备的晶体，以及任选的药学上可接受的辅料。
  7. 根据权利要求6所述的药物组合物，其特征在于：其为固体口服制剂、液体口服制剂或注射剂；
    优选地，所述固体口服制剂为分散片、肠溶片、咀嚼片、口崩片、胶囊或颗粒剂；所述液体口服制剂为口服溶液；所述注射剂为注射用水针、注射用冻干粉针、大输液或小输液。
  8. 根据权利要求6或7所述的药物组合物，其特征在于：所述药学上可接受的辅料选自填充剂、粘合剂、崩解剂、润滑剂、助流剂、泡腾剂、矫味剂、防腐剂、包衣材料或赋形剂中的一种或多种；
    优选地，所述填充剂选自乳糖、蔗糖、糊精、淀粉、预胶化淀粉、甘露醇、山梨醇、磷酸氢钙、硫酸钙、碳酸钙或微晶纤维素中的一种或多种；所述粘合剂选自蔗糖、淀粉、聚维酮、羧甲基纤维素钠、羟丙甲纤维素、羟丙纤维素、甲基纤维素、聚乙二醇、药用乙醇或水中的一种或多种；所述崩解剂选自淀粉、交联聚维酮、交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲纤维素钠或泡腾崩解剂中的一种或多种。
  9. 根据权利要求1至3中任一项所述的晶体、根据权利要求4或5的制备方法制备的晶体、或根据权利要求6至8中任一项所述的药物组合物在制备治疗痛风的药物中的应用。
  10. 根据权利要求1至3中任一项所述的晶体、根据权利要求4或5的制备方法制备的晶体、或根据权利要求6至8中任一项所述的药物组合物在制备治疗高尿酸血症的药物中的应用。
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