WO2016188444A1 - 一种尿酸转运蛋白抑制剂的钠盐及其结晶形式 - Google Patents

一种尿酸转运蛋白抑制剂的钠盐及其结晶形式 Download PDF

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WO2016188444A1
WO2016188444A1 PCT/CN2016/083423 CN2016083423W WO2016188444A1 WO 2016188444 A1 WO2016188444 A1 WO 2016188444A1 CN 2016083423 W CN2016083423 W CN 2016083423W WO 2016188444 A1 WO2016188444 A1 WO 2016188444A1
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crystal
formula
thio
uric acid
bromoquinolin
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PCT/CN2016/083423
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English (en)
French (fr)
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武乖利
邱振均
苏云鹏
芦熙
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江苏恒瑞医药股份有限公司
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Priority to DK16799331.0T priority Critical patent/DK3305768T3/da
Priority to CA2984961A priority patent/CA2984961C/en
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 US15/574,328 priority patent/US10196361B2/en
Priority to LTEP16799331.0T priority patent/LT3305768T/lt
Priority to AU2016269359A priority patent/AU2016269359B2/en
Priority to MX2017014319A priority patent/MX2017014319A/es
Priority to JP2017555478A priority patent/JP6738350B2/ja
Priority to ES16799331T priority patent/ES2811325T3/es
Priority to SI201630871T priority patent/SI3305768T1/sl
Priority to RS20200924A priority patent/RS60749B1/sr
Priority to BR112017022505-0A priority patent/BR112017022505A2/zh
Priority to RU2017142996A priority patent/RU2719484C2/ru
Priority to PL16799331T priority patent/PL3305768T3/pl
Priority to EP16799331.0A priority patent/EP3305768B1/en
Priority to CN201680003846.8A priority patent/CN107001276B/zh
Priority to KR1020177035949A priority patent/KR20180006441A/ko
Publication of WO2016188444A1 publication Critical patent/WO2016188444A1/zh
Priority to US16/157,696 priority patent/US10358424B2/en
Priority to HRP20201178TT priority patent/HRP20201178T1/hr
Priority to CY20201100720T priority patent/CY1123262T1/el

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    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/36—Sulfur atoms
    • 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 sodium 1-((6-bromoquinolin-4-yl)thio)cyclobutylcarboxylate, its type I crystal, and its preparation and use.
  • the compound of formula (I) obtained by the process according to the invention can be used for the treatment of gout diseases.
  • hyperuricemia is an important biochemical basis of gout and is closely related to the production of gout. Hyperuricemia is closely related to the occurrence of hypertension, hyperlipidemia, atherosclerosis, obesity, and insulin resistance, and has become a serious metabolic disease that threatens human health.
  • Uric acid is the terminal product of human sputum metabolism. Due to the uric acid gene mutation in human evolution, this enzyme is deficient, and uric acid cannot be metabolized to soluble allantoin and excreted in vitro. Therefore, serum uric acid with hyperuricemia The concentration is too high. The onset of hyperuricemia is due to: (1) increased production of uric acid, which accounts for 15% to 20% of the incidence of gout.
  • Uric Acid Transporter 1 located in the epithelial cells of the proximal tubules of the kidney.
  • URAT1 is a complete membrane protein located in the kidney, belonging to the solute transporter 22 (SLC22) family, which performs urate-anion exchange and is responsible for regulating the level of urate in the blood. Therefore URAT1 inhibitors can pass This reabsorption is inhibited and uric acid excretion is promoted.
  • WO2014183555 discloses a compound having a higher inhibitory activity on the uric acid transport protein URAT1, which can effectively inhibit the reabsorption of uric acid, excrete uric acid in the body, and thereby continuously reduce blood uric acid content, thereby achieving the purpose of treating gout, including the following Compound,
  • the sodium salt of this compound (Formula I)
  • the solubility in water also increased from the previous almost insoluble to about 0.14 mg/mL.
  • the crystalline structure of the pharmaceutically active ingredient often affects the chemical stability of the drug. Differences in crystallization conditions and storage conditions may result in changes in the crystal structure of the compound, sometimes accompanied by the formation of other forms of crystal form.
  • amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, and poor fluidity. Therefore, it is necessary to improve the various aspects of the above products.
  • the object of the present invention is to provide a compound of the formula (I), namely sodium 1-((6-bromoquinolin-4-yl)thio)cyclobutylcarboxylate, which improves to some extent the disclosure disclosed in WO2014183555.
  • the properties required of the compound as a pharmaceutically active ingredient are particularly important.
  • the compound of the formula (I) can be obtained by reacting 1-((6-bromoquinolin-4-yl)thio)cyclobutylcarboxylic acid with sodium hydroxide.
  • the DSC spectrum of the type I crystal in the present application shows that within 300 ° C, no absorption, indicating that its melting point is greater than 300 ° C, the X-ray powder diffraction pattern is shown in Figure 1, using Cu-Ka radiation, at 2 ⁇ angle and crystal
  • the X-ray powder diffraction pattern represented by the interplanar spacing (d value) is 9.08 (9.73), 11.73 (7.54), 12.19 (7.26), 15.59 (5.68), 16.28 (5.44), 17.73 (5.00), 18.16 (4.88).
  • the invention also provides a process for the preparation of Form I crystals of a compound of formula (I). Specifically, the following steps are included:
  • the solvent is selected from a mixed solvent of any one of an alcohol having a carbon atom of 3 or less and a ketone and water; more preferably water/isopropanol, water/acetone, acetone/water/acetone , acetone / water / isopropanol.
  • a preferred mixed solvent is a mixed solvent of acetone/water/acetone, and the ratio is not particularly limited. In a preferred embodiment of the present invention, the volume ratio of the three is 1:1:5.
  • the mixed solvent is acetone/water/acetone, it means that the sodium 1-((6-bromoquinolin-4-yl)thio)cyclobutylcarboxylate is firstly dissolved in a mixed solvent of acetone/water, and then the portion is added. Acetone crystallization. Acetone/water/isopropyl alcohol also refers to similar meanings.
  • the method of recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method.
  • the compound of the formula (I) can be slowly dissolved by heating and dissolving in an organic solvent, and after stirring, the desired crystal can be obtained by filtration and drying.
  • the crystals to be filtered are usually subjected to vacuum drying under reduced pressure at a temperature of about 30 to 100 ° C, preferably 40 to 60 ° C, to obtain an effect of removing the recrystallization solvent.
  • the obtained crystal was subjected to a crystal form study by differential scanning calorimetry (DSC) and X-ray diffraction pattern measurement, and the solvent residue of the obtained crystal was examined.
  • DSC differential scanning calorimetry
  • the crystal of the compound of the formula (I) prepared according to the method of the present invention does not contain or contains only a low content of residual solvent, and meets the limit requirement of the residual solvent of the pharmaceutical product according to the National Pharmacopoeia, and thus the crystal of the present invention can be preferably used as a medicine.
  • the active ingredient is used.
  • the type I crystal of the compound of the formula (I) prepared by the invention has good stability under the conditions of illumination, high temperature and high humidity, and the crystal form stability is good under the conditions of grinding, pressure and heat, and can satisfy
  • the medicinal requirements for the production of transport and storage, the production process is stable and repeatable and controllable, and can be adapted to industrial production.
  • Figure 2 is a DSC chart of Form I crystal of the compound of formula (I).
  • the crystals are about 9.08 (9.73), 11.73 (7.54), 12.19 (7.26), 15.59 (5.68), 16.28 (5.44), 17.73 (5.00), 18.16 (4.88), 18.80 (4.72), 19.48 (4.55), 20.80. (4.27), there are characteristic peaks near 23.16 (3.84), 27.54 (3.24) and 30.37 (2.94).
  • the DSC spectrum is shown in Fig. 2. Within 300 ° C, no absorption, indicating that its melting point is greater than 300 ° C, this crystal form is defined as the I crystal form.
  • Example 1 The samples of the type I crystal obtained in Example 1 were separately placed in an open position, and the stability of the sample under conditions of light (4,500 Lux), high temperature (40 ° C, 60 ° C), and high humidity (RH 75%, RH 90%) was examined.
  • the sampling time was 5 days and 10 days, and the purity of HPLC was shown in Table 1.
  • the stability investigation results show that the type I crystalline sample has good stability under light, high temperature and high humidity conditions under open conditions.
  • the rat pharmacokinetic test of the compound of Example 1 of the present invention using SD rats as test animals, using LC/MS/MS method to determine the plasma in rats at different times after intragastric administration and intravenous administration of the compound of Example 1.
  • the drug concentration, the pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
  • the pharmacokinetic parameters of the compound of the present invention are shown in Table 3.
  • the experimental results show that the compound of the present invention has good absorption and obvious Oral absorption effect. Based on the average value of AUC0-t, the absolute bioavailability of the rats after a single intragastric administration of 3 mg/kg of the compound was 74.1%.
  • Canine pharmacokinetic test of the compound of Example 1 of the present invention The Beagle dog was used as the test animal, and the concentration of the drug in the plasma at different times after the administration of the compound of Example 1 by intragastric administration and intravenous injection was determined by LC/MS/MS method.
  • the pharmacokinetic behavior of the compounds of the invention in dogs was investigated and their pharmacokinetic characteristics were evaluated.
  • the pharmacokinetic parameters of the compound of the present invention are shown in Table 4. The results of the study indicate that the compound of the present invention has good absorption of the drug and has an obvious oral absorption effect. Based on the AUC 0-t average, the absolute bioavailability of the dog after a single gavage of 3 mg/kg of the compound was 59.5%.

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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

本发明涉及一种尿酸转运蛋白抑制剂的钠盐及其结晶形式。具体而言，本发明涉及一种尿酸转运蛋白(URAT1)抑制剂的钠盐、其I型结晶及制备方法。本发明涉及1-((6-溴喹啉-4-基)硫基)环丁基甲酸钠(式(I)化合物)、其I型结晶及其制备方法。本发明所得到式(I)化合物的I型结晶具备良好的晶型稳定性和化学稳定性，并且所用结晶溶剂低毒低残留，可更好地用于临床治疗。

Description

一种尿酸转运蛋白抑制剂的钠盐及其结晶形式 技术领域
本发明涉及1-((6-溴喹啉-4-基)硫基)环丁基甲酸钠、其I型结晶及其制备方法和用途。根据本发明的方法制备获得的式(I)化合物可用于痛风疾病的治疗。
背景技术
近年来，随着经济生活水平的改善，痛风的患病率逐年上升，发病年龄呈现低龄化趋势。好发于男性、绝经期女性，40-50岁为发病高峰。其临床表现是高尿酸血症、痛风性急性关节炎反复发作、痛风石沉积、特征性慢性关节炎和关节畸形，常累及肾引起慢性间质性肾炎和肾尿酸结石等。痛风发病的先决条件是高尿酸血症，即37℃时，血清尿酸的饱和浓度约为420umol/L(70mg/L)，高于此值即为高尿酸血症。然而高尿酸血症者仅一部分发展为临床痛风，其转变机制未明，只有高尿酸血症患者出现尿酸盐结晶沉积、关节炎和(或)肾病、肾结石等时，才能称之为痛风。因此，高尿酸血症是痛风的重要生化基础标志与痛风的产生密切相关。高尿酸血症与高血压、高脂血症、动脉粥样硬化、肥胖、胰岛素抵抗的发生密切相关，已成为威胁人类健康的严重代谢性疾病。
尿酸是人类嘌呤代谢的终末产物，由于人类进化中的尿酸酶基因突变而导致此酶缺乏，不能将尿酸代谢为可溶性的尿囊素(allantoin)而排出体外，因此高尿酸血症的血清尿酸浓度过高。高尿酸血症的发病时由于：(1)尿酸的生成增多，其导致痛风发病所占的比例为15％～20％。过量摄入高嘌呤饮食，或者包括体内氨基酸、核苷酸合成尿酸增多和核酸分解代谢产生了过多的尿酸；(2)尿酸的排泄减少和重吸收增多是高尿酸血症和痛风发病的主要机制，约占80％～85％。尿酸约95％的重吸收是由位于肾近端小管中上皮细胞的尿酸转运蛋白1(Uric Acid Transporter 1，URAT1)来完成的。URAT1是一个位于肾脏的完整的膜蛋白，属于溶质运载蛋白22(SLC22)家族，执行尿酸盐—阴离子交换，负责调节血液中尿酸盐的水平。因此URAT1抑制剂能通过 抑制这种重吸收，促进尿酸的排泄。
我国医药市场上的抗痛风药品种很少，市场没有新的更好的抗痛风药物开发出来。依然以别嘌呤醇和苯溴马隆为主。2009年FDA批准的非布索坦属于黄嘌呤氧化酶XO抑制剂，通过减少尿酸的生成来治疗痛风。Ardea Biosciences公司开发的RDEA-594(Lesinurad)，它是通过抑制URAT1(Uric Acid Transporter 1)尿酸转运蛋白来促进尿酸排泄，进而达到降低血清尿酸浓度的目的。疗效不受肾功能和别嘌呤醇剂量影响。在临床计量范围内并不会影响OAT1/OAT3(Organic Anion Transporter 1/3)的转运作用，并且比其它的排尿酸剂对靶点专一性更高、与其他药物相互作用更少。
Figure PCTCN2016083423-appb-000001
但是，RDEA-594是在研究治疗HIV感染药物临床试验中被发现的，其对尿酸转运蛋白URAT1的活性并不高，IC50大约是7uM。而且在临床使用中剂量较高。因此针对靶点尿酸转运蛋白URAT1还有很大的探索空间。
WO2014183555公开了一类对尿酸转运蛋白URAT1的抑制活性更高的化合物，可高效抑制尿酸的重吸收，排出体内的尿酸，进而持久降低血尿酸含量，达到治疗痛风的目的，其中包括如下所示的化合物，
Figure PCTCN2016083423-appb-000002
为了进一步改善其在水中的溶解度，我们开发了该化合物的钠盐(式I)，水中的溶解度也从之前的几乎不溶增大至约0.14mg/mL。另一方面药用的活性成分的晶型结构往往影响到该药物的化学稳定性， 结晶条件及储存条件的不同有可能导致化合物的晶型结构的变化，有时还会伴随着产生其他形态的晶型。一般来说，无定型的药物产品没有规则的晶型结构，往往具有其它缺陷，比如产物稳定性较差，析晶较细，过滤较难，易结块，流动性差等。因此，改善上述产物的各方面性质是很有必要的，在发现其新的开发形式的基础上，我们还需要深入研究找到晶型纯度较高并且具备良好化学稳定的新晶型。
发明内容
本发明的目的是提供如式(I)所示的化合物，即1-((6-溴喹啉-4-基)硫基)环丁基甲酸钠，其在一定程度上改善了WO2014183555中公开的化合物在作为药用活性成分时所需要的性质。
Figure PCTCN2016083423-appb-000003
式(I)所示化合物可由1-((6-溴喹啉-4-基)硫基)环丁基甲酸和氢氧化钠反应得到。
我们考察了式(I)化合物在不同结晶条件下得到的一系列结晶产物，对所得结晶产物进行了X-衍射及DSC检测，发现在某些特定的结晶条件下，可以得到一种稳定性良好的晶型，我们称其为I型结晶。本申请中的I型结晶的DSC图谱显示，在300℃以内，无吸收，表明其熔点大于300℃，X-射线粉末衍射图谱如图1所示，使用Cu-Ka辐射，以2θ角度和晶面间距(d值)表示的X-射线粉末衍射图谱，其中在9.08(9.73)，11.73(7.54)，12.19(7.26)，15.59(5.68)，16.28(5.44)，17.73(5.00)，18.16(4.88)，18.80(4.72)，19.48(4.55)，20.80(4.27)，23.16(3.84)，27.54(3.24)和30.37(2.94)附近有特征峰。
本发明还提供了式(I)化合物的I型结晶的制备方法。具体的，包括以下步骤：
(1)将任意晶型或无定型的1-((6-溴喹啉-4-基)硫基)环丁基甲酸钠固体加热溶解于适量的溶剂中，冷却析晶；
(2)过滤、洗涤、干燥。
步骤(1)中，所述溶剂选自碳原子小于等于3的醇类、酮类的任意一种与水的混合溶剂；更优选为水/异丙醇、水/丙酮、丙酮/水/丙酮、丙酮/水/异丙醇。
在本发明的一个实施方案中，优选的混合溶剂为丙酮/水/丙酮的混合溶剂，比例没有特别限制，在本发明优选的实施方案中，三者体积比为1:1:5。其中当混合溶剂为丙酮/水/丙酮时，意指先使用丙酮/水的混合溶剂将1-((6-溴喹啉-4-基)硫基)环丁基甲酸钠溶清后，再加入部分丙酮析晶。丙酮/水/异丙醇也指代相似的含义。
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)化合物在有机溶剂加热溶解后慢慢冷却搅拌析晶，结晶完成后，经过滤干燥，即可得到所需要的结晶。需特别说明的是，所滤取的结晶体通常在减压下，在30～100℃左右，优选40～60℃的加热条件下进行真空干燥，就能达到去除重结晶溶剂的效果。
通过差示扫描热分析(DSC)、X-衍射图谱测定，对得到的结晶体进行了晶型研究，同时对所得结晶的溶剂残留进行了检测。
按照本发明的方法制备的式(I)化合物结晶不含有或仅含有较低含量的残留溶剂，符合国家药典规定的有关医药产品残留溶剂的限量要求，因而本发明的结晶可以较好地作为医药活性成分使用。
经研究表明，本发明制备的式(I)化合物的I型结晶在光照、高温、高湿的条件下稳定性良好，且在研磨、压力和受热等条件下，晶型稳定性良好，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式(I)化合物的I型结晶的X-射线粉末衍射图谱。
图2式(I)化合物的I型结晶的DSC谱图。
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：Mettler Toledo DSC 1Staree System
吹扫气：氮气
升温速率：10.0℃/min
温度范围：40-300℃
2、X-射线衍射谱
仪器型号：Bruker D8Focus 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
实施例1
25℃下，将(1.0g，2.96mmol)1-((6-溴喹啉-4-基)硫基)环丁基甲酸(按WO 2014/183555公开方法制备)加入50mL三口反应瓶中，加入4.0g无水乙醇。搅拌下滴加(118mg，2.96mmol)氢氧化钠的水(0.5ml)溶液，搅拌反应。过滤，滤饼用无水乙醇洗涤，后40℃真空干燥，得到白色至淡黄色粉末850mg，收率为84.0％。该结晶样品的X-射线衍射谱图见图1。该结晶在约9.08(9.73)，11.73(7.54)，12.19(7.26)，15.59(5.68)，16.28(5.44)，17.73(5.00)，18.16(4.88)，18.80(4.72)，19.48(4.55)，20.80(4.27)，23.16(3.84)，27.54(3.24)和30.37(2.94)附近有特征峰。DSC谱图见图2，在300℃以内，无吸收，表明其熔点大于300℃，将此晶型定义为I晶型。
实施例2
取(1.0g，2.78mmol)式(I)化合物(按实施例1制备)于250ml单口瓶中，加入30ml水，加热回流溶清，然后减压浓缩至约3ml，缓慢加入150ml异丙醇，搅拌析晶，次日，抽滤，干燥得白色固体689mg，收率为68.9％。该结晶样品的X-射线衍射图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例3
取(1.0g，2.78mmol)式(I)化合物(按实施例1制备)于150ml单口瓶中，加入30ml水，加热回流溶清，然后减压浓缩至干，直接加入30ml异丙醇，搅拌转晶，次日，抽滤，干燥得白色固体812mg，收率为81.2％。该结晶样品的X-射线衍射图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例4
取(1.0g，2.78mmol)式(I)化合物(按实施例1制备)于150ml单口瓶中，加入30ml水，加热回流溶清，然后减压浓缩至约3ml，缓慢加入30ml丙酮，搅拌析晶，次日，抽滤，干燥得白色固体918mg，收率为91.8％。该结晶样品的X-射线衍射图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例5
取(1.0g，2.78mmol)式(I)化合物(按实施例1制备)于150ml单口瓶中，加入丙酮/水(v/v＝1:1)24ml，加热回流溶清，后缓慢加入60ml丙酮，继续回流10min，停止加热，搅拌析晶，次日，抽滤，干燥得白色固体688mg，收率为68.8％。该结晶样品的X-射线衍射图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例6
取(1.0g，2.78mmol)式(I)化合物(按实施例1制备)于150ml单口瓶中，加入丙酮/水(v/v＝1:1)24ml，加热回流溶清，后缓慢加入60ml异丙醇，继续回流10min，停止加热，搅拌析晶，次日，抽滤，干燥得白色固体752mg，收率为75.2％。该结晶样品的X-射线衍射图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例7
取(1.0g，2.78mmol)式(I)化合物(按实施例1制备)于500ml单口瓶中，加入30ml水，加热回流溶清，缓慢加入300ml丙酮，搅拌析晶，次日，抽滤，干燥得白色固体728mg，收率为72.8％。该结晶样 品的X-射线衍射图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例8
将实施例1所得的I型结晶的样品分别敞口平摊放置，考察在光照(4500Lux)，高温(40℃，60℃)，高湿(RH75％，RH90％)条件下样品的稳定性。考察取样时间为5天和10天，HPLC检测纯度见表1。
表1、式(I)化合物I型结晶样品的稳定性
Figure PCTCN2016083423-appb-000004
稳定性考察结果表明，I型结晶样品在敞口放置的条件下，经光照、高温和高湿条件下的稳定性良好。
实施例9
将按实施例1方法制得式(I)化合物的I型结晶进行研磨、加热及压片处理，研究结果表明晶型稳定，详细的实验数据参见下表2。
表2.式(I)化合物I型结晶特殊稳定性研究
Figure PCTCN2016083423-appb-000005
实施例10
本发明实施例1化合物的大鼠药代动力学测试，以SD大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃和静脉注射给予实施例1化合物后不同时刻血浆中的药物浓度，研究本发明的化合物在大鼠体内的药代动力学行为，评价其药动学特征。本发明化合物的药代动力学参数见表3，实验结果表明：本发明化合物的药代吸收良好，具有明显 的口服吸收效果。以AUC0-t平均值计算，大鼠单次灌胃给予3mg/kg化合物后的绝对生物利用度为74.1％。
表3、化合物大鼠单次灌胃及静脉注射给药后的药动学参数(n＝6，雌雄各半)
Figure PCTCN2016083423-appb-000006
实施例11
本发明实施例1化合物的犬药代动力学测试以Beagle犬为受试动物，应用LC/MS/MS法测定了犬灌胃和静脉注射给予实施例1化合物后不同时刻血浆中的药物浓度，研究本发明的化合物在犬体内的药代动力学行为，评价其药动学特征。本发明化合物的药代动力学参数见表4，研究结果表明：本发明化合物的药代吸收良好，具有明显的口服吸收效果。以AUC0-t平均值计算，犬单次灌胃给予3mg/kg化合物后的绝对生物利用度为59.5％。
表4、化合物犬单次灌胃及静脉注射给药后的药动学参数(n＝6，雌雄各半)
Figure PCTCN2016083423-appb-000007

Claims (8)

  1. 式(I)所示1-((6-溴喹啉-4-基)硫基)环丁基甲酸钠，
    Figure PCTCN2016083423-appb-100001
  2. 根据权利要求1所述的式(I)所示1-((6-溴喹啉-4-基)硫基)环丁基甲酸钠的I型结晶，其特征在于使用Cu-Ka辐射，得到以2θ角度和晶面间距表示的X-射线粉末衍射图谱，所述结晶具有如图1所示的X-射线粉末衍射图谱，其中在约9.08(9.73)，11.73(7.54)，12.19(7.26)，15.59(5.68)，16.28(5.44)，17.73(5.00)，18.16(4.88)，18.80(4.72)，19.48(4.55)，20.80(4.27)，23.16(3.84)，27.54(3.24)和30.37(2.94)附近有特征峰。
  3. 一种制备根据权利要求1所述的式(I)所示1-((6-溴喹啉-4-基)硫基)环丁基甲酸钠的方法，包括将1-((6-溴喹啉-4-基)硫基)环丁基甲酸和氢氧化钠反应的步骤。
  4. 一种制备根据权利要求2所述的I型结晶的方法，所述方法包括下述步骤：
    1)将任意晶型或无定型的1-((6-溴喹啉-4-基)硫基)环丁基甲酸钠固体加热溶解于适量的溶剂中，冷却、析晶，所述溶剂选自碳原子小于等于3的醇类、酮类的任意一种与水的混合溶剂；
    2)过滤结晶并洗涤，干燥。
  5. 根据权利要求4所述的方法，其特征在于在步骤1)中所述的溶剂优选为水/异丙醇、水/丙酮、丙酮/水/丙酮、丙酮/水/异丙醇。
  6. 一种药物组合物，其含有根据权利要求1所述的式(I)所示 1-((6-溴喹啉-4-基)硫基)环丁基甲酸钠或权利要求2所述的I型结晶以及药学上可接受的载体。
  7. 根据权利要求1所述的式(I)所示1-((6-溴喹啉-4-基)硫基)环丁基甲酸钠、权利要求2所述的I型结晶或权利要求6所述的药物组合物在制备治疗与尿酸转运蛋白(URAT1)有关的疾病的药物中的用途。
  8. 根据权利要求7所述的用途，其中所述疾病为痛风。
PCT/CN2016/083423 2015-05-27 2016-05-26 一种尿酸转运蛋白抑制剂的钠盐及其结晶形式 WO2016188444A1 (zh)

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