WO2016169422A1 - 一种周期素依赖性蛋白激酶抑制剂的结晶形式及其制备方法 - Google Patents

一种周期素依赖性蛋白激酶抑制剂的结晶形式及其制备方法 Download PDF

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WO2016169422A1
WO2016169422A1 PCT/CN2016/079055 CN2016079055W WO2016169422A1 WO 2016169422 A1 WO2016169422 A1 WO 2016169422A1 CN 2016079055 W CN2016079055 W CN 2016079055W WO 2016169422 A1 WO2016169422 A1 WO 2016169422A1
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crystal
water
compound
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PCT/CN2016/079055
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武乖利
高晓晖
张全良
卢韵
吴玉霞
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江苏恒瑞医药股份有限公司
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • the present invention relates to 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d] Pyrimidine-7(8H)-one and its Form II.
  • the compounds of formula (I) obtained by the process according to the invention are useful in the treatment of breast cancer.
  • Breast cancer is one of the most common malignant tumors in women. It has a high incidence and is invasive, but the progress of the disease is slow.
  • the China Population Association released the "China Breast Diseases Investigation Report” in Beijing on February 1, 2010. The report shows that The mortality rate of breast cancer in urban areas in China has increased by 38.91%.
  • Breast cancer has become the most threatening disease for women.
  • At least 156 kinds of breast cancer drugs are currently under research and market, 68% of which are targeted therapeutic drugs.
  • Tumors were found to be abnormally associated with the cell cycle. Mutations in mitotic signaling proteins and defects in anti-mitotic signaling proteins in tumor cells lead to proliferation disorders. At the same time, most tumors have genomic instability (GIN) and genomic instability (CIN). These three basic cell cycle defects are caused directly or indirectly by the loss of control of CDKs. Cyclin Dependent Kinase (CDK) inhibitors are increasingly becoming a hot target.
  • CDK Cyclin Dependent Kinase
  • the second-generation drugs of greatest concern include the CDK4&6 inhibitor PD-0332991 jointly developed by Pfizer and Onyx. It inhibits the phosphorylation of Rb by inhibiting the activity of CDK4&6, making E2F- The Rb complex is retained in the cytosol, blocking the initiation of the cell cycle.
  • Clinical trial results (NCT00721409) showed that progression-free survival (PFS) was 7.5 months in patients treated with letrozole monotherapy, whereas no progress was observed in patients treated with letrozole and PD-0332991. The survival period was extended to 26.1 months. This remarkable advantage has received wide attention. In early 2013, after reviewing the interim results of this drug, the FDA thought it might be a breakthrough anticancer drug.
  • WO2014183520 discloses a CDK4&6 inhibitor similar in structure to PD-0332991, which has significant inhibitory activity and high selectivity for CDK4&6, including the following compounds:
  • WO 2014183520 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 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d A new crystalline form of pyrimidine-7(8H)-one (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 II crystal.
  • the DSC pattern of the type II crystal in the present application shows a melting endothermic peak near 294.42 ° C, and the X-ray powder diffraction pattern is shown in Fig.
  • the invention also provides the preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridine [2,3 -d]
  • the acid is a mineral acid, preferably hydrochloric acid;
  • the base is an inorganic base, preferably sodium hydroxide or potassium hydroxide.
  • the solvent described in step 1) is methanol, ethanol, isopropanol, acetone, acetonitrile or methanol/water, ethanol/water, acetone/water, acetonitrile/water, isopropanol/water; Ethanol.
  • the method of recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method.
  • the compound represented by the starting material (I) can be slowly cooled and crystallized by heating in an organic solvent, and after completion of crystallization, it can be dried by filtration to obtain a desired crystal.
  • 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 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 compound of the formula II type represented by 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 II 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.
  • Figure 1 is an X-ray powder diffraction pattern of the compound II type crystal represented by the formula (I).
  • Figure 2 is a DSC chart of the compound type II crystal of the formula (I).
  • the crystals are at about 5.84 (15.12), 6.16 (14.35), 10.75 (8.22), 12.56 (7.04), 12.96 (6.82), 16.25 (5.45), 17.24 (5.14), 18.97 (4.67), 20.22 (4.39), 21.74. (4.08), 22.99 (3.87), and 25.85 (3.44) have characteristic peaks.
  • the DSC spectrum is shown in Figure 2. There is a sharp melting endotherm peak of 294.42 ° C. This crystal form is defined as Form II.
  • Example 1 The sample of the type II crystal product obtained in Example 1 was separately placed in an open position, and the stability of the sample under illumination (4500 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.

Abstract

提供一种周期素依赖性蛋白激酶（CDK4&6）抑制剂的结晶形式及其制备方法。具体地，提供6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮(式(I)化合物)的II型结晶及其制备方法，所述结晶具有如图1所示的X-射线粉末衍射图谱，其具备良好的化学稳定性和晶型稳定性，并且使用低毒、低残留的结晶溶剂，可更好地用于临床治疗。

Description

一种周期素依赖性蛋白激酶抑制剂的结晶形式及其制备方法 技术领域
本发明涉及6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮及其II晶型。根据本发明的方法制备获得的式(I)化合物可用于乳腺癌的治疗。
背景技术
乳腺癌是女性最常见的恶性肿瘤之一，具有发病率高，颇具侵袭性，但病程进展缓慢，中国人口协会2010年2月1日在北京发布了《中国乳腺疾病调查报告》，报告显示，我国城市地区乳腺癌的死亡率增长了38.91％，乳腺癌已经成为对妇女健康威胁最大的疾病，目前在研和上市的乳腺癌药物至少有156种，其中68％为靶向治疗药物，大量研究发现肿瘤与细胞周期反常相关，肿瘤细胞中有丝***信号蛋白的大量突变和抗有丝***信号蛋白缺陷导致增殖紊乱；同时大部分肿瘤都存在基因组不稳定性(GIN)和染色体组不稳定性(CIN)，这三种基本的细胞周期缺陷都直接或间接由CDKs的失控引起。周期素依赖性蛋白激酶(CDK，Cyclin Dependent Kinase)抑制剂日益成为热门靶标。
目前开发的一代二代CDK抑制剂很多，最受关注的二代药物包括Pfizer公司和Onyx公司共同开发的CDK4&6抑制剂PD-0332991，其通过抑制CDK4&6的活性，抑制Rb的磷酸化，使E2F-Rb复合物留滞在胞浆中，阻断细胞周期的启动。临床试验结果(NCT00721409)显示，来曲唑单药治疗的患者的无进展存活期(Progression-free survival,PFS)为7.5月，而来曲唑和PD-0332991药物联用治疗的患者其无进展存活期则延长至26.1月，这一显著优势获得了广泛关注，2013年初FDA在审核了这种药物的中期结果后认为这可能是一种突破性的抗癌药物。
WO2014183520公开了与PD-0332991结构相似的CDK4&6抑制剂，具有显著的CDK4&6的抑制活性和高度选择性，其中包括如下化合物：
Figure PCTCN2016079055-appb-000001
但WO2014183520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6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮(如式(I)所示)的新的结晶形式。
Figure PCTCN2016079055-appb-000002
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II型结晶。本申请中的II型结晶的DSC图谱显示在294.42℃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5.84(15.12)，6.16(14.35)，10.75(8.22)，12.56(7.04)，12.96(6.82)，16.25(5.45)，17.24(5.14)，18.97(4.67)，20.22(4.39)，21.74(4.08)，22.99(3.87)，和25.85(3.44)有特征峰。
本发明还提供了制备6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮的II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溶剂中，加入酸，溶清后加入碱，析晶，所述溶剂选自碳原子数小于等于3的醇类、酮类、腈类的任意一种或它们与水的混合溶剂；
2)过滤结晶并洗涤，干燥。
在优选的实施方案中所述酸为无机酸，优选为盐酸；所述碱为无机碱，优选为氢氧化钠或氢氧化钾。
在优选的实施方案中步骤1)中所述的溶剂为甲醇、乙醇、异丙醇、丙酮、乙腈或甲醇/水、乙醇/水、丙酮/水、乙腈/水、异丙醇/水；优选乙醇。
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II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II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)所示化合物II型结晶的X-射线粉末衍射图谱。
图2式(I)所示化合物II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：40-350℃
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，2.24mmol)式(I)所示化合物(按WO2014183520提供的方法制备)加入到250ml锥形瓶中，加入40ml乙醇，室温下搅拌，然后滴入稀盐酸(219mg，6.01mmol)(溶于4ml水)，加热至60℃，溶清，滴入氢氧化钠溶液(576mg，14.40mmol)(溶于40ml水)中，降温至室温搅拌过夜。干燥得固体0.88g，收率为88.0％。该结晶样品的X-射线衍射谱图见图1。该结晶在约5.84(15.12)，6.16(14.35)，10.75(8.22)，12.56(7.04)，12.96(6.82)，16.25(5.45)，17.24(5.14)，18.97(4.67)，20.22(4.39)，21.74(4.08)，22.99(3.87)，和25.85(3.44)有特征峰。DSC谱图见图2，有尖锐熔融吸热峰294.42℃，将此晶型定义为II晶型。
实施例2
取(1.0g，2.24mmol)式(I)所示化合物(按实施例1制备)加入到250ml锥形瓶中，加入40ml甲醇，室温下搅拌，然后滴入稀盐酸(219mg，6.01mmol)(溶于4ml水)，加热至60℃，溶清，滴入氢氧 化钠溶液(576g，14.40mmol)(溶于40ml水)中，降温至室温搅拌过夜。干燥得固体0.86g，收率为86.0％。其X-衍射和DSC图谱经研究比对，确定产物为II晶型。
实施例3
取(1.0g，2.24mmol)式(I)所示化合物(按实施例1制备)加入到250ml锥形瓶中，加入40ml异丙醇，室温下搅拌，然后滴入稀盐酸(219mg，6.01mmol)(溶于4ml水)，加热至60℃，溶清，滴入氢氧化钠溶液(576mg，14.40mmol)(溶于40ml水)中，降温至室温搅拌过夜。干燥得固体0.90g，收率为90.0％。其X-衍射和DSC图谱经研究比对，确定产物为II晶型。
实施例4
取(1.0g，2.24mmol)式(I)所示化合物(按实施例1制备)加入到250ml锥形瓶中，加入40ml丙酮，室温下搅拌，然后滴入稀盐酸(219mg，6.01mmol)(溶于4ml水)，加热至60℃，溶清，滴入氢氧化钠溶液(576mg，14.40mmol)(溶于40ml水)中，降温至室温搅拌过夜。干燥得固体0.86g，收率为86.0％。其X-衍射和DSC图谱经研究比对，确定产物为II晶型。
实施例5
取(1.0g，2.24mmol)式(I)所示化合物(按实施例1制备)加入到250ml锥形瓶中，加入40ml乙腈，室温下搅拌，然后滴入稀盐酸(219mg，6.01mmol)(溶于4ml水)，加热至60℃，溶清，滴入氢氧化钠溶液(576mg，14.40mmol)(溶于40ml水)中，降温至室温搅拌过夜。干燥得固体0.60g，收率为60.0％。其X-衍射和DSC图谱经研究比对，确定产物为II晶型。
实施例6
取(1.0g，2.24mmol)式(I)所示化合物(按实施例1制备)加入到250ml锥形瓶中，加入40ml四氢呋喃，室温下搅拌，然后滴入稀盐酸(219mg，6.01mmol)(溶于4ml水)，加热至60℃，溶清，滴入氢氧化钠溶液(576mg，14.40mmol)(溶于40ml水)中，降温至室温搅拌过夜。干燥得固体0.76g，收率为76.0％。其X-衍射和DSC图谱经研究比对，确定产物为II晶型。
实施例7
将实施例1所得的II型结晶产物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II晶型样品的稳定性比较
Figure PCTCN2016079055-appb-000003
稳定性考察结果表明式(I)所示化合物II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8
将按实施例1方法制得的式(I)所示化合物II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II晶型特殊稳定性研究
Figure PCTCN2016079055-appb-000004

Claims (7)

  1. 如式(I)所示化合物的II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5.84(15.12)，6.16(14.35)，10.75(8.22)，12.56(7.04)，12.96(6.82)，16.25(5.45)，17.24(5.14)，18.97(4.67)，20.22(4.39)，21.74(4.08)，22.99(3.87)，和25.85(3.44)有特征峰，
    Figure PCTCN2016079055-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II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溶剂中，加入酸，溶清后加入碱，析晶，所述溶剂选自碳原子数小于等于3的醇类、酮类、腈类的任意一种或它们与水的混合溶剂；
    2)过滤结晶并洗涤，干燥。
  3. 根据权利要求2所述的制备方法，其中所述酸为无机酸，优选为盐酸。
  4. 根据权利要求2所述的制备方法，其中所述碱为无机碱，优选为氢氧化钠或氢氧化钾。
  5. 根据权利要求2所述的方法，其特征在于步骤1)中所述的溶剂为甲醇、乙醇、异丙醇、丙酮、乙腈、四氢呋喃；或甲醇/水、乙醇/水、丙酮/水、乙腈/水、异丙醇/水、四氢呋喃/水；优选乙醇。
  6. 一种药物组合物，其含有权利要求1所述的如式(I)所示化合 物的II型结晶以及药学上可接受的载体。
  7. 根据权利要求1所述的如式(I)所示化合物的II型结晶或权利要求6所述的药物组合物在制备治疗与周期素依赖性蛋白激酶(CDK4&6)有关的疾病的药物中的用途；所述疾病优选乳腺癌。
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