WO2017041622A1 - 一种雄性激素受体抑制剂的结晶形式及其制备方法 - Google Patents

一种雄性激素受体抑制剂的结晶形式及其制备方法 Download PDF

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WO2017041622A1
WO2017041622A1 PCT/CN2016/096381 CN2016096381W WO2017041622A1 WO 2017041622 A1 WO2017041622 A1 WO 2017041622A1 CN 2016096381 W CN2016096381 W CN 2016096381W WO 2017041622 A1 WO2017041622 A1 WO 2017041622A1
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crystal
compound
formula
ethyl acetate
solvent
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PCT/CN2016/096381
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English (en)
French (fr)
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武乖利
郭昌山
钟良
卢韵
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江苏恒瑞医药股份有限公司
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Priority to SI201630801T priority Critical patent/SI3348546T1/sl
Priority to BR112018003258-1A priority patent/BR112018003258A2/zh
Priority to EP16843560.0A priority patent/EP3348546B1/en
Priority to AU2016318700A priority patent/AU2016318700B2/en
Priority to DK16843560.0T priority patent/DK3348546T3/da
Priority to US15/757,652 priority patent/US10150739B2/en
Priority to PL16843560T priority patent/PL3348546T3/pl
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 CN201680003850.4A priority patent/CN107001284B/zh
Priority to RU2018109121A priority patent/RU2018109121A/ru
Priority to MX2018002759A priority patent/MX2018002759A/es
Priority to LTEP16843560.0T priority patent/LT3348546T/lt
Priority to JP2018508712A priority patent/JP6843116B2/ja
Priority to CA2996674A priority patent/CA2996674A1/en
Priority to ES16843560T priority patent/ES2794568T3/es
Priority to RS20200617A priority patent/RS60448B1/sr
Priority to KR1020187009184A priority patent/KR20180048939A/ko
Publication of WO2017041622A1 publication Critical patent/WO2017041622A1/zh
Priority to HRP20200852TT priority patent/HRP20200852T1/hr
Priority to CY20201100522T priority patent/CY1123027T1/el

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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 (S)-4-(3-(4-(2,3-dihydroxypropoxy)phenyl)-4,4-dimethyl-5-carbonyl-2-thioimidazoline-1 Form I crystal of 2-yl)-2-(trifluoromethyl)benzonitrile and a process for the preparation thereof.
  • Prostate cancer is a malignant tumor that occurs in male prostate tissue and is the result of abnormal disordered growth of prostate acinar cells.
  • the differentiation and growth of normal prostate epithelial cells and the development of prostate cancer depend on androgen.
  • Male hormones are mainly synthesized in the testis, accounting for about 80-90%.
  • the synthetic androgen enters the cell and binds to the Androgen receptor (AR), causing heat shock protein (HSP) to dissociate from the AR and allow AR to enter the nucleus, activating multiple downstream genes, including prostate specific antigen (PSA).
  • AR Androgen receptor
  • HSP heat shock protein
  • PSA prostate specific antigen
  • Early prostate cancer is sensitive to androgen, and orchiectomy (castration) can significantly inhibit the development of prostate cancer. However, castration surgery has a certain timeliness.
  • the first generation drugs for the purpose of inhibiting AR activity are bicalutamide or Casodec and Flutamide.
  • the second generation of AR antagonist drugs for AlPC treatment are MDV3100 and ARN-509.
  • MDV3100 is the world's first second-generation non-steroidal AR antagonist drug, which was approved by the US FDA at the end of August 2012.
  • MDV-3100 has an affinity for AR that is 5-8 times higher than that of bicalutamide, and can inhibit the growth of AlPC mouse and human tumors by inhibiting AR activity, and does not have the effect of promoting tumor cell growth.
  • WO2014036897A1 discloses a new class of AR antagonists, including compounds of formula (I), which have slightly better in vitro activity than MDV-3100, further improved hERG inhibition rate (IC50: 24.83 uM), and five major subclasses of CYP450.
  • the inhibitory half-life of the model was greater than 50uM.
  • the in vivo exposure of the rats in the same solvent was equivalent to MDV-3100, and the in vivo exposure of the dog was more than six times that of MDV-3100.
  • the compound of formula (I) has only one chiral center, and the chiral raw material is simple and easy to obtain, and the synthesis difficulty is greatly reduced.
  • the compound of formula (I) has no AR agonistic activity at 3uM and 10uM, and the ratio of drug concentration to plasma concentration in mouse brain tissue is much lower than that of MDV-3100 compound, and the possibility of epileptic side effects is smaller, so (I) Compounds have broad clinical prospects.
  • WO 2014036897 A1 does not delve into the crystalline form of the compound. It is well known to those skilled in the art that the crystalline structure of the pharmaceutically active ingredient often affects the chemical stability of the drug, and the crystallization conditions and storage conditions may cause changes in the crystal structure of the compound, sometimes accompanied by other Form of crystal form. In general, 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 properties of the above compounds, and we need to further study to find new crystal forms with higher crystal purity and good chemical stability.
  • the present invention provides (S)-4-(3-(4-(2,3-dihydroxypropyloxy)phenyl)-4,4-dimethyl-5-carbonyl-2-thioimidazoline- A new crystalline form of 1-yl)-2-(trifluoromethyl)benzonitrile (as shown in formula (I)).
  • a series of crystalline products obtained by the compound of the formula (I) under different crystallization conditions the obtained crystalline product was subjected to X-ray diffraction and DSC detection, and it was found that the compound of the formula (I) can be obtained under the conventional crystallization conditions.
  • a crystal form with good stability we call it type I crystal.
  • the DSC pattern of the type I crystal in the present application shows a melting endothermic peak near 157 ° C, and the X-ray powder diffraction pattern is shown in Fig.
  • the invention also provides the preparation of (S)-4-(3-(4-(2,3-dihydroxypropyloxy)phenyl)-4,4-dimethyl-5-carbonyl-2-thioimidazole
  • a compound of the formula (I) of any crystal form or amorphous form to an appropriate amount of an organic solvent, heating and dissolving, and cooling and crystallization, the solvent being selected from the group consisting of esters, ketones, nitriles, and ethers.
  • the solvent is selected from the group consisting of esters, ketones, nitriles, and ethers.
  • the solvent described in the step 1) is a single solvent such as ethyl acetate, acetone, isopropyl acetate, tetrahydrofuran or acetonitrile, and acetone/isopropyl ether, ethyl acetate/n-hexane, ethyl acetate/ Isopropyl ether, ethyl acetate/methyl tert-butyl ether; preferably ethyl acetate/isopropyl ether, the ratio of the two is not particularly limited, preferably from 1:10 to 10:1, in one embodiment of the present invention, the volume The ratio is 1:1.
  • 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 heated and dissolved in an organic solvent, and then slowly cooled and crystallized. After the crystallization is completed, it can be dried by filtration to obtain a desired crystal.
  • the crystals to be filtered are usually vacuum-dried under reduced pressure at a temperature of about 30 to 100 ° C, preferably 40 to 60 ° C, to remove the recrystallization solvent. Effect.
  • the crystal form of the obtained compound of the formula (I) was examined by differential scanning calorimetry (DSC) and X-ray diffraction pattern measurement, and the solvent residue of the obtained crystal was examined.
  • the type I 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 requirements of the national pharmacopoeia for the residual solvent of the pharmaceutical product, so that the crystal of the present invention can be compared It is used as a pharmaceutical active ingredient.
  • the type I crystal of the compound of the formula (I) prepared by the present 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. It can meet the medicinal requirements of production, transportation and storage.
  • the production process is stable and repeatable and controllable, and can be adapted to industrial production.
  • Another aspect of the invention provides a pharmaceutical composition comprising a crystalline form I of the compound of formula (I), the pharmaceutical composition comprising a crystalline form of the compound of formula (I) and a pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to the use of Form I crystal of the compound of the formula (I) of the present invention or the pharmaceutical composition of the present invention for the preparation of a medicament for treating an androgen receptor-related disease; the disease is preferably prostate cancer .
  • Figure 1 is an X-ray powder diffraction pattern of the compound I form crystal of the formula (I).
  • Figure 2 is a DSC chart of the Form I crystal of the compound of formula (I).
  • Figure 3 is an X-ray powder diffraction pattern of the compound II type crystal represented by the formula (I).
  • Figure 4 is a DSC chart of the compound type II crystal of the formula (I).
  • Figure 5 is an X-ray powder diffraction pattern of the compound type III crystal of the formula (I).
  • Figure 6 is a DSC chart of the compound type III crystal of the formula (I).
  • the crystal is about 8.89 (9.94), 9.97 (8.87), 11.22 (7.88), 14.28 (6.20), 15.17 (5.83), 15.51 (5.71), 16.77 ( 5.28), 19.91 (4.46), 21.13 (4.20), 22.48 (3.95), 24.06 (3.70), 26.37 (3.38) have characteristic peaks; the DSC spectrum is shown in Figure 2, with a sharp melting endothermic peak of 157 ° C, The crystal form is defined as the I crystal form.
  • the reaction mixture was concentrated under reduced pressure to remove acetic acid, and then 100 mL of water and 100 mL of ethyl acetate were added, and the mixture was partitioned.
  • the organic phase was washed with saturated sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel chromatography to afford crystals of Compound I (1.1 g, 55.0%).
  • the X-ray diffraction and DSC spectra of the crystalline sample were compared by study and confirmed to be not the I crystalline form, which is defined herein as the III crystalline form.
  • Example 1 The type I crystal samples obtained in Example 1 were separately placed in an open position, and the stability of the sample under illumination (4,500 Lux), heating (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 crystal of the compound type I represented by the formula (I) obtained by the method of Example 1 was subjected to grinding, heating and tableting. The results of the study showed that the crystal form was stable. For detailed experimental data, see Table 2 below.
  • the crystalline product of the compound I of the formula (I) obtained by the method of Example 1 was opened and spread evenly Place and examine the stability of the sample for long-term retention at room temperature (25 ° C, RH 60%). See Table 3 below for detailed experimental data.
  • the product was placed at 25 ° C, RH60% for a long time, and was sampled and measured regularly. The results showed that the crystal form of the sample was stable, the purity did not change significantly, and the crystal form was stable, indicating that the product was stable under the conditions for 36 months.

Abstract

提供了一种雄性激素受体抑制剂的结晶形式及其制备方法。具体地，提供了(S)-4-(3-(4-(2，3-二羟基丙氧基)苯基)-4，4-二甲基-5-羰基-2-硫代咪唑啉-1-基)-2-(三氟甲基)苯甲腈（式（I）化合物）的I型结晶及其制备方法，所述方法包括：1）将任意晶型或无定型的式（I）所示化合物加入适量的有机溶剂中，加热溶清后冷却析晶，所述有机溶剂选自碳原子数小于等于5的酯类、酮类、腈类、醚类的任意一种或它们的混合溶剂；2）过滤结晶并洗涤，干燥。所得式（I）化合物的I型结晶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

一种雄性激素受体抑制剂的结晶形式及其制备方法 技术领域
本发明涉及(S)-4-(3-(4-(2，3-二羟基丙氧基)苯基)-4，4-二甲基-5-羰基-2-硫代咪唑啉-1-基)-2-(三氟甲基)苯甲腈的I型结晶及其制备方法。
背景技术
前列腺癌(prostate cancer，PCa)是发生于男性前列腺组织中的恶性肿瘤，是前列腺腺泡细胞异常无序生长的结果。正常前列腺上皮细胞的分化与生长以及前列腺癌的发展依赖于雄性激素，雄性激素主要在睾丸中被合成，大约占80～90％。合成的雄性激素进入细胞后结合雄性激素受体(Androgen receptor，AR)，引起热休克蛋白(HSP)从AR上解离并使AR进入细胞核，激活多个下游基因，包括前列腺特异抗原(PSA)。早期的前列腺癌对雄性激素敏感，施行睾丸切除术(去势)能够明显抑制前列腺癌的发展。但是去势手术具有一定的时效性，许多患者经过去势后一段时间经历了从雄性激素依赖性到雄性激素非依赖性的转变，对于抗雄性激素治疗不再有效，发展为雄激素非依赖性前列腺癌(androgen independent prostate cancer，AIPC)，而AlPC的发生仍与PCa细胞内AR信号通路的活化有重要关系。
以抑制AR活性为目的的第一代药物有比卡鲁胺(Bicalutamide或Casodex)和氟他胺(Flutamide)。针对AlPC治疗的第二代AR拮抗剂药物有MDV3100和ARN-509。MDV3100是世界上首个第二代非固醇类AR拮抗剂药物，已于2012年8月底被美国FDA批准上市。MDV-3100对AR的亲和力比比卡鲁胺高5～8倍，能够通过抑制AR活性从而抑制AlPC小鼠和人肿瘤的生长，并且不具有促进肿瘤细胞生长的作用。
Figure PCTCN2016096381-appb-000001
WO2014036897A1公开了一类新的AR拮抗剂，其中包括式(I)所示化合物，该化合物体外活性略优于MDV-3100，hERG抑制率进一步改善(IC50：24.83uM)，对CYP450五个主要亚型的抑制半衰期均大于50uM，同剂量，同溶媒下大鼠药代体内暴露量与MDV-3100相当，犬药代体内暴露量达MDV-3100的六倍以上。式(I)化合物仅有一个手性中心，其手性原料简单易得，合成难度大大降低。另外，式(I)化合物在3uM和10uM均没有AR激动活性，且在小鼠脑组织中药物浓度与血药浓度比值远低于MDV-3100化合物，出现癫痫副作用的可能性更小，因此式(I)化合物具有广阔的临床前景。
Figure PCTCN2016096381-appb-000002
但WO2014036897A1未深入研究该化合物的结晶形式。本领域技术人员公知，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，改善上述化合物的各方面性质是很有必要的，我们需要深入研究找到晶型纯度较高并且具备良好化学稳定性的新晶型。
发明内容
本发明提供了(S)-4-(3-(4-(2，3-二羟基丙氧基)苯基)-4，4-二甲基-5-羰基-2-硫代咪唑啉-1-基)-2-(三氟甲基)苯甲腈(如式(I)所示)的新晶型。
Figure PCTCN2016096381-appb-000003
式(I)所示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，发现式(I)所示化合物在常规的结晶条件下，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157℃附近有熔融吸热峰，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8.89(9.94)，9.97(8.87)，11.22(7.88)，14.28(6.20)，15.17(5.83)，15.51(5.71)，16.77(5.28)，19.91(4.46)，21.13(4.20)，22.48(3.95)，24.06(3.70)，26.37(3.38)有特征峰。
本发明还提供了制备(S)-4-(3-(4-(2,3-二羟基丙氧基)苯基)-4，4-二甲基-5-羰基-2-硫代咪唑啉-1-基)-2-(三氟甲基)苯甲腈的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式(I)所示化合物加入适量的有机溶剂中，加热溶清后冷却析晶，所述溶剂选自酯类、酮类、腈类、醚类的任意一种或它们的混合溶剂；优选所述溶剂的碳原子数小于等于5。
2)过滤结晶并洗涤，干燥。
在优选的实施方案中步骤1)中所述的溶剂为乙酸乙酯、丙酮、醋酸异丙酯、四氢呋喃、乙腈等单一溶剂以及丙酮/异丙醚、乙酸乙酯/正己烷、乙酸乙酯/异丙醚、乙酸乙酯/甲基叔丁基醚；优选乙酸乙酯/异丙醚，两者的比例没有特别限制，优选1：10至10：1，在本发明的一个实施例中体积比为1:1。
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加热溶解后慢慢冷却析晶，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，对得到的式(I)所示化合物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)所示化合物I型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)所示化合物的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。
本发明另一方面提供了含有式(I)所示化合物I型结晶的药物组合物，该药用组合物包含式(I)所示化合物结晶和药学上可接受的载体。
本发明另一方面涉及本发明的式(I)所示化合物的I型结晶或本发明的药物组合物在制备治疗与雄性激素受体有关的疾病的药物中的用途；所述疾病优选前列腺癌。
附图说明
图1式(I)所示化合物I型结晶的X-射线粉末衍射图谱。
图2式(I)所示化合物I型结晶的DSC图谱。
图3式(I)所示化合物II型结晶的X-射线粉末衍射图谱。
图4式(I)所示化合物II型结晶的DSC图谱。
图5式(I)所示化合物III型结晶的X-射线粉末衍射图谱。
图6式(I)所示化合物III型结晶的DSC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 1Staree System
吹扫气：氮气
升温速率：10.0℃/min
温度范围：40～250℃
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
取(1.0g，2.09mmol)式(I)所示化合物(按WO2014036897A1提供的方法制备)25ml单口瓶中，加入4.0ml乙酸乙酯，加热回流溶清，继续回流10min，冷却，搅拌析晶，抽滤，干燥得固体560mg，收率为56.0％。该结晶样品的X-射线衍射谱图见图1，该结晶在约8.89(9.94)，9.97(8.87)，11.22(7.88)，14.28(6.20)，15.17(5.83)，15.51(5.71)，16.77(5.28)，19.91(4.46)，21.13(4.20)，22.48(3.95)，24.06(3.70)，26.37(3.38)处有特征峰；DSC谱图见图2，有尖锐熔融吸热峰157℃，将此晶型定义为I晶型。
实施例2
取(1.0g，2.09mmol)式(I)所示化合物(按实施例1制备)于25ml单口瓶中，加入4.0ml丙酮，加热回流溶清，继续回流10min，冷却，搅拌析晶，抽滤，干燥得固体438mg，收率为43.8％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例3
取(1.0g，2.09mmol)式(I)所示化合物(按实施例1制备)于25ml单口瓶中，加入4.0ml乙酸乙酯，加热回流溶清，然后滴加4.0ml正己烷，继续回流10min，冷却，搅拌析晶，抽滤，干燥得固体711mg，收率为71.1％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例4
取(1.0g，2.09mmol)式(I)所示化合物(按实施例1制备)于 25ml单口瓶中，加入5.0ml乙酸乙酯，加热回流溶清，然后滴加5.0ml异丙醚，继续回流10min，冷却，搅拌析晶，抽滤，干燥得固体678mg，收率为67.8％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例5
取(1.0g，2.09mmol)式(I)所示化合物(按实施例1制备)于25ml单口瓶中，加入5.0ml乙酸乙酯，加热回流溶清，然后滴加5.0ml甲基叔丁基醚，继续回流10min，冷却，搅拌析晶，抽滤，干燥得固体682mg，收率为68.2％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例6
取(1.0g，2.09mmol)式(I)所示化合物(按实施例1制备)于25ml单口瓶中，加入6.0ml醋酸异丙酯，加热回流溶清，继续回流10min，冷却，搅拌析晶，抽滤，干燥得固体612mg，收率为61.2％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例7
取(1.0g，2.09mmol)式(I)所示化合物(按实施例1制备)于25ml单口瓶中，加入5.0ml丙酮，加热回流溶清，然后滴加5.0ml水，继续回流10min，冷却，搅拌析晶，抽滤，干燥得固体476mg，收率为47.6％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例8
取(1.0g，2.09mmol)式(I)所示化合物(按实施例1制备)于25ml单口瓶中，加入5.0ml丙酮，加热回流溶清，然后滴加5ml异丙醚，继续回流10min，冷却，搅拌析晶，抽滤，干燥得固体521mg，收率为52.1％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例9
取(1.0g，2.09mmol)式(I)所示化合物(按实施例1制备)于25ml单口瓶中，加入2.0ml四氢呋喃，加热回流溶清，继续回流10min，冷却，搅拌析晶，抽滤，干燥得固体327mg，收率为32.7％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例10
取(1.0g，2.09mmol)式(I)所示化合物(按实施例1制备)于 25ml单口瓶中，加入2.0ml乙腈，加热回流溶清，继续回流10min，冷却，搅拌析晶，抽滤，干燥得固体242mg，收率为24.2％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例11
重复WO2014036897A1实施例44的全部操作，将(R)-4-(3-(4-((2，2-二甲基-1，3-二氧戊环-4-基)甲氧基)苯基)-4，4-二甲基-5-酮-2-硫代咪唑啉-1-基)-2-(三氟甲基)苯腈(2.2g，4.20mmol)溶解于100mL乙酸中，加入50mL水，升温至70℃搅拌反应1小时，反应液减压浓缩除去乙酸，加入100mL水和100mL乙酸乙酯，静置分层，有机相用饱和碳酸氢钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶色谱法纯化，得到化合物I的结晶(1.1g，55.0％)。该结晶样品的经X-射线衍射和DSC谱图经研究比对，证实并非I晶型，此处将其定义为III晶型。
实施例12
取(1.0g，2.09mmol)式(I)所示化合物(按实施例1制备)于25ml单口瓶中，加入5.0ml甲醇，加热回流溶清，继续回流10min，冷却，搅拌析晶，抽滤，干燥得固体516mg，收率为51.6％。该结晶在约4.63(19.06)，7.37(11.99)，9.25(9.55)，10.91(8.11)，11.48(7.70)，12.40(7.13)，13.05(6.78)，13.73(6.45)，15.03(5.89)，16.04(5.52)，16.96(5.22)，17.87(4.96)，19.03(4.66)，19.45(4.56)，20.59(4.31)，21.87(4.06)，22.50(3.95)，23.11(3.85)，23.53(3.78)，23.96(3.71)，25.43(3.50)，27.00(3.30)，27.60(3.23)，29.77(3.00)处有特征峰。DSC谱图见图2，有尖锐熔融吸热峰119℃，将此晶型定义为II晶型。
实施例13
取(0.5g，1.04mmol)式(I)所示化合物(按实施例1制备)和(0.5g，1.04mmol)式(I)所示化合物(按实施例11制备)于25ml单口瓶中，加入4.0ml乙酸乙酯-异丙醚(v:v＝1:1)，室温打浆，抽滤，干燥得固体872mg，收率为87.2％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。可见，III晶型可以在室温条件下转变为I晶型，可以确认I晶型是更为稳定的晶型。
实施例14
取(0.5g，1.04mmol)式(I)所示化合物(按实施例1制备)和(0.5g， 1.04mmol)式(I)所示化合物(按实施例12制备)于25ml单口瓶中，加入4.0ml乙酸乙酯-异丙醚(v:v＝1:1)，室温打浆，抽滤，干燥得固体850mg，收率为85.0％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。可见，II晶型可以在室温条件下转变为I晶型，可以确认I晶型是更为稳定的晶型。
实施例15
将实施例1所得的I型结晶样品分别敞口平摊放置，考察在光照(4500Lux)，加热(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)所示化合物I晶型样品的稳定性比较
Figure PCTCN2016096381-appb-000004
稳定性考察结果表明式(I)所示化合物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16
将按实施例1方法制得的式(I)所示化合物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)所示化合物I晶型特殊稳定性研究
Figure PCTCN2016096381-appb-000005
实施例17
将按实施例1方法制得的式(I)所示化合物I型结晶产物敞口平摊 放置，考察样品在室温(25℃，RH60％)长期留样的稳定性，详细的实验数据参见下表3。
表3.式(I)所示化合物的I晶型样品室温留样条件下稳定性考察
Figure PCTCN2016096381-appb-000006
本品经25℃、RH60％条件长期放置，定期取样测定，结果表明样品晶型稳定，纯度未见明显变化，晶型稳定，表明本品在该条件下放置36个月是稳定的。

Claims (6)

  1. 如式(I)所示化合物的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8.89(9.94)，9.97(8.87)，11.22(7.88)，14.28(6.20)，15.17(5.83)，15.51(5.71)，16.77(5.28)，19.91(4.46)，21.13(4.20)，22.48(3.95)，24.06(3.70)，26.37(3.38)有特征峰
    Figure PCTCN2016096381-appb-100001
  2. 一种制备根据权利要求1所述的如式(I)所示化合物的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式(I)所示化合物加入适量的有机溶剂中，加热溶清后冷却析晶，所述有机溶剂选自碳原子数小于等于5的酯类、酮类、腈类、醚类的任意一种或它们的混合溶剂；
    2)过滤结晶并洗涤，干燥。
  3. 根据权利要求2所述的方法，其特征在于在步骤1)中所述的溶剂为乙酸乙酯、丙酮、醋酸异丙酯、四氢呋喃、乙腈等单一溶剂以及选自丙酮/异丙醚、乙酸乙酯/正己烷、乙酸乙酯/异丙醚、乙酸乙酯/甲基叔丁基醚的混合溶剂，优选乙酸乙酯/异丙醚。
  4. 根据权利要求3所述的方法，其中所述混合溶剂的体积比为1：10至10：1，优选1：1。
  5. 一种药物组合物，其含有根据权利要求1所述的如式(I)所示化合物的I型结晶以及药学上可接受的载体。
  6. 根据权利要求1所述的如式(I)所示化合物的I型结晶或根据权利要求4所述的药物组合物在制备治疗与雄性激素受体有关的疾病的药物中的用途；所述疾病优选前列腺癌。
PCT/CN2016/096381 2015-09-10 2016-08-23 一种雄性激素受体抑制剂的结晶形式及其制备方法 WO2017041622A1 (zh)

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