WO2019091400A1 - 吡啶并嘧啶类化合物的盐型和晶型及其制备方法 - Google Patents

吡啶并嘧啶类化合物的盐型和晶型及其制备方法 Download PDF

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WO2019091400A1
WO2019091400A1 PCT/CN2018/114354 CN2018114354W WO2019091400A1 WO 2019091400 A1 WO2019091400 A1 WO 2019091400A1 CN 2018114354 W CN2018114354 W CN 2018114354W WO 2019091400 A1 WO2019091400 A1 WO 2019091400A1
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compound
crystal form
formula
ray powder
diffraction pattern
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PCT/CN2018/114354
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French (fr)
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沈竞康
孟韬
于霆
马兰萍
王昕�
陈驎
张永良
唐伟
杨文谦
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中国科学院上海药物研究所
山东罗欣药业集团股份有限公司
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Priority to CN201880061016.XA priority Critical patent/CN111148747B/zh
Publication of WO2019091400A1 publication Critical patent/WO2019091400A1/zh

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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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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  • the present invention relates to a salt form and a crystal form of a pyridopyrimidine compound and a preparation method thereof, and specifically discloses a free base, a sulfate salt, a crystal form thereof and a preparation method thereof, and a salt form and a crystal of the compound of the formula (I).
  • PI3K-Akt-mTOR signaling pathway plays a key role in tumor cell growth, proliferation, invasion and metastasis. Blocking the intracellular PI3K-Akt-mTOR signaling pathway can inhibit tumor cell proliferation and even promote tumor cell death. Die.
  • PI3K-Akt-mTOR signaling pathway multiple key nodal proteins in the PI3K-Akt-mTOR signaling pathway are over-activated by mutation or amplification of the coding gene, such as mutation and amplification of upstream receptor-type tyrosine kinase, encoding p110 ⁇ -catalyzed
  • the subunit's PIK3CA gene is mutated and amplified in a variety of tumors, with over-activation of Akt and PDK1 and a general loss of the negative regulatory factor PTEN.
  • the mammalian target of rapamycin is one of the important substrates for Akt and belongs to a non-canonical serine/threonine protein kinase of the phosphatidylinositol-3-kinase-associated kinase (PIKK) family.
  • the mTOR signaling pathway is a key pathway regulating cell growth and proliferation, which integrates signals from nutrient molecules, energy states, and growth factors to regulate a large number of life processes. Abnormal activation of mTOR signaling pathway is a commonality of various tumorigenesis and development, and thus has become a hot spot for the development of anti-tumor inhibitors.
  • mTOR has at least two functional complexes, mTORC1 and mTORC2, which mediate both associated and independent biosignal functions.
  • Clinically used rapamycins (including rapamycin and its analogs) exert partial inhibition by allosteric binding to the FKBP12-rapamycin binding domain (FRB) near the catalytic site of mTORC1 The role of mTOR protein. These compounds do not directly inhibit mTORC2, nor do they completely block all signals mediated by mTORC1.
  • FRB FKBP12-rapamycin binding domain
  • rapamycin has shown some clinical efficacy in some tumors, the mode of action of these drugs does not fully exploit the potential of mTOR to target anti-tumor drugs.
  • mTORC2-mediated perphosphate (activation) of AKT is critical for tumor maintenance and growth, but mTORC2 is not inhibited by rapamycins.
  • ATP competitive and specific mTOR small molecule inhibitors have made it possible to treat a variety of cancers.
  • Some recently reported ATP competitive inhibitors have shown stronger inhibition against tumor cell growth and survival, protein synthesis, bioenergy metabolism, and the like, compared to rapamycin analogs.
  • these drugs have strong monotherapy antitumor activity against MDA361 breast cancer, U87MG glioma, A549 and H1975 lung cancer, A498 and 786-O kidney cancer.
  • the inventors of the present invention have determined that the mTOR inhibitor is an ATP competitive inhibitor, and thus its mechanism of action is a non-rapamycin-like compound.
  • the inventors of the present invention obtained a novel class of pyridopyrimidine or pyrimidopyrimidine compounds by rational design and comprehensive consideration of factors such as water solubility and metabolic stability of the compounds. Such compounds show good mTOR inhibitory activity at both enzyme and cell levels. After further optimization and screening, it is expected to be developed into a simple and more active anti-tumor drug.
  • the invention provides a crystalline form I of a compound of formula (I) having an X-ray powder diffraction pattern (preferably measured using Cu-k ⁇ ) having characteristic diffraction at the following 2 theta angle Peaks: 7.600 ⁇ 0.2 °, 9.374 ⁇ 0.2 °, 13.838 ⁇ 0.2 °, 14.179 ⁇ 0.2 °, 15.218 ⁇ 0.2 °, 17.659 ⁇ 0.2 °, 21.018 ⁇ 0.2 °, 21.700 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I (preferably, measured using Cu-k ⁇ ) is in nine or more, ten or more, eleven or more, twelve One or more, or thirteen or more, from the 2 ⁇ angle selected from the group consisting of characteristic diffraction peaks: 7.600 ⁇ 0.2°, 9.374 ⁇ 0.2°, 13.838 ⁇ 0.2°, 14.179 ⁇ 0.2°, 15.218 ⁇ 0.2 °, 17.162 ⁇ 0.2 °, 17.659 ⁇ 0.2 °, 18.663 ⁇ 0.2 °, 19.521 ⁇ 0.2 °, 20.160 ⁇ 0.2 °, 21.018 ⁇ 0.2 °, 21.700 ⁇ 0.2 °, 22.939 ⁇ 0.2 °, 23.478 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I (preferably, measured using Cu-k[alpha]) is shown in FIG.
  • the X-ray powder diffraction pattern analysis data for Form I (preferably, measured using Cu-k ⁇ ) is as shown in Table 1.
  • the differential scanning calorimetry curve for Form I has an endothermic peak at 238.1 ⁇ 3 °C.
  • thermogravimetric analysis curve for Form I loses about 0.224% at 150 ⁇ 3 °C.
  • thermogravimetric analysis curve for Form I is shown in FIG.
  • the present invention also provides a method for preparing Form I, comprising:
  • the invention provides a sulphate of a compound of formula (I).
  • the present invention provides a crystalline form II of a sulfate of a compound of formula (I) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angle: 6.889 ⁇ 0.2°, 8.523 ⁇ 0.2 °, 17.306 ⁇ 0.2 °, 18.668 ⁇ 0.2 °, 20.443 ⁇ 0.2 °, 21.196 ⁇ 0.2 °, 23.684 ⁇ 0.2 °.
  • Form II is in eight or more, nine or more, ten or more, eleven or more, twelve or more, or ten Three or more characteristic diffraction peaks at a 2 ⁇ angle selected from the group consisting of 6.889 ⁇ 0.2°, 8.523 ⁇ 0.2°, 9.295 ⁇ 0.2°, 12.554 ⁇ 0.2°, 12.886 ⁇ 0.2°, 13.797 ⁇ 0.2°, 15.758 ⁇ 0.2°, 16.634 ⁇ 0.2°, 17.306 ⁇ 0.2°, 18.668 ⁇ 0.2°, 20.443 ⁇ 0.2°, 21.196 ⁇ 0.2°, 23.186 ⁇ 0.2°, 23.684 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form II is as shown in FIG.
  • the X-ray powder diffraction pattern analysis data for Form II is as shown in Table 2.
  • the differential scanning calorimetry curve of Form II has an endothermic peak at 318.6 ⁇ 3 °C.
  • the differential scanning calorimetry curve for Form II is as shown in FIG.
  • thermogravimetric analysis curve for Form II has a weight loss of about 0.447% at 150 ⁇ 3 °C.
  • thermogravimetric analysis curve for Form II is shown in FIG.
  • the present invention also provides a method for preparing Form II, comprising:
  • the invention provides the use of any of the above-described salt forms and crystal forms for the manufacture of a medicament for the treatment of a disease or condition caused by a dysfunction of the PI3K-Akt-mTOR signaling pathway.
  • Figure 1 shows an X-ray powder diffraction pattern of Form I.
  • Figure 2 shows the differential scanning calorimetry curve for Form I.
  • Figure 3 shows the thermogravimetric analysis curve for Form I.
  • Figure 4 shows an X-ray powder diffraction pattern of Form II.
  • Figure 5 shows the differential scanning calorimetry curve for Form II.
  • Figure 6 shows the thermogravimetric analysis curve of Form II.
  • Figure 7 shows the results of dynamic vapor sorption analysis of Form I, in which the solid line of the diamond is the adsorption curve and the solid line of the square represents the desorption curve.
  • the reagents and methods employed in the examples of the present invention are conventional reagents and conventional methods in the art. It should be clear to those skilled in the art that, hereinafter, unless otherwise specified, the temperature is expressed in degrees Celsius (° C.), the operating temperature is performed in a room temperature environment, and the room temperature is referred to as 10° C. to 30° C., preferably 20° C. to 25° C.; The allowable error of the melting point is ⁇ 1%; the yield is a mass percentage.
  • the XRPD data of each crystal form was determined by the XRD-6000 instrument of Shimadzu by Macro XRPD, and the diffraction parameters were as follows:
  • DSC Differential scanning calorimeter
  • the DSC data for each crystal form was determined by PerkinElmer's Diamond-type differential scanning calorimeter.
  • the thermal analysis parameters are as follows:
  • the TGA data for each crystal form was determined by PerkinElmer's Pyris 1 instrument.
  • the thermal analysis parameters are as follows:
  • the advantages of the crystal form of the invention include high solubility, high stability, low hygroscopicity/hygroscopicity, etc., and have good application prospects.
  • the intermediate (1) (195 g) was dissolved in toluene (1 L), DMF-DMA (195 ml) was added, and the solution was heated to reflux. Reaction for 6 hours. After the reaction was completed, the solvent was evaporated to dryness crystals. 400 ml of methyl tert-butyl ether was added, filtered, and dried under reduced pressure to give 191 g (yield (2)). The yield was 75%.
  • 6-Aminouracil (109 g) was dissolved in 2.5 L of acetic acid, and the intermediate (2) (167 g) was added portionwise to the system and stirred and heated to 100 °C. Reaction for 12 hours. The reaction was checked to completion, and the mixed solvent was removed under reduced pressure. The pH was adjusted to 7 with a 2N aqueous potassium hydroxide solution and filtered. The solid was stirred in 400 ml of a saturated aqueous solution of citric acid (1.5 L) for 1 hour, filtered, and the filter cake was washed with water to neutral to afford 204 g of yellow powder (the intermediate (3)). Yield: 95.8%.
  • the intermediate (3) (200 g) was dissolved in 3 L of phosphorus oxychloride, and the mixture was heated to reflux at 120 ° C for 18 hours. After the completion of the reaction, the solvent was evaporated to dryness, ethyl acetate (2L) was added and the mixture was filtered and filtered, and the solvent was evaporated to dryness to give a solid (202%). Yield: 90.9%.
  • the intermediate (5) (50 g) was dissolved in 1.5 L of DMF, and DIEA (31.5 g) and 3-S-methylmorpholine (18.5 g) were sequentially added, and the mixture was heated at 140 ° C to reflux for 24 hours. Cool to room temperature. The solvent was concentrated under reduced pressure. EtOAc was evaporated, evaporated, evaporated. The crude product was taken up in 300 ml of ethyl acetate and filtered, filtered, and dried under reduced Yield: 70.7%.
  • the intermediate (6) (40 g) was dissolved in a 30% methylamine solution (1100 ml), and the mixture was heated at 40-45 ° C for 22 hours. After the reaction was completed, the solvent was evaporated, evaporated, evaporated, evaporated, Concentrate under reduced pressure. The solid was slurried with 400 mL of ethyl acetate and filtered and dried. 36 g of the compound of the formula (I) are obtained.
  • FaSSIF Simulated Small Intestinal Fluid under Fasted state
  • the solubility of Form I is pH-dependent, the solubility under acidic conditions is better, the solubility in 0.1N HCL is more than 3mg/ml, the solubility under alkaline conditions is decreased, and the solubility is reduced to 0.01mg under pH6.8. /ml.
  • Form II can significantly increase solubility, especially in water and alkaline solutions.
  • the solubility of Form II in water can be greater than 3 mg/ml.
  • the DVS data for Form I was determined by SMS's DVS intrinsic instrument.
  • the test parameters are as follows:
  • the form I has a small hygroscopicity, and when the relative humidity is 95%, the moisture absorption gain is less than 0.25%.

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Abstract

提供一种吡啶并嘧啶类化合物的盐型和晶型及其制备方法，具体公开了式（Ⅰ）的化合物的游离碱、硫酸盐、其晶型及其制备方法，还包括这些盐型和晶型在制备用于治疗由PI3K-Akt-mTOR信号通路功能失调而导致的疾病或病症的药物中的应用。

Description

吡啶并嘧啶类化合物的盐型和晶型及其制备方法 技术领域
本发明涉及吡啶并嘧啶类化合物的盐型和晶型及其制备方法，具体公开了式(I)的化合物的游离碱、硫酸盐、其晶型及其制备方法，还包括这些盐型和晶型在制备用于治疗由PI3K-Akt-mTOR信号通路功能失调而导致的疾病或病症的药物中的应用。
背景技术
近年来的研究发现，PI3K-Akt-mTOR信号通路在肿瘤细胞生长、增殖、侵袭和转移中起关键作用，阻断细胞内的PI3K-Akt-mTOR信号通路能够抑制肿瘤细胞增殖甚至促进肿瘤细胞凋亡。在多种人类肿瘤中，PI3K-Akt-mTOR信号通路中多个关键节点蛋白因编码基因存在突变或扩增而过度激活，如上游受体型酪氨酸激酶的突变和扩增，编码p110α催化亚基的PIK3CA基因在多种肿瘤中存在突变和扩增，Akt和PDK1的过度活化以及负调控因子PTEN普遍缺失。
哺乳动物雷帕霉素靶蛋白(mTOR)是Akt重要的底物之一，属于磷脂酰肌醇-3-激酶相关激酶(PIKK)家族的一个非经典丝氨酸/苏氨酸蛋白激酶。mTOR信号通路是调控细胞生长与增殖的一个关键通路，该通路将从营养分子、能量状态以及生长因子传来的信号整合在一起，能够调控大量生命过程。mTOR信号通路的异常激活是多种肿瘤发生和发展的共性，因而已成为抗肿瘤抑制剂研发的热点。
然而，研究发现mTOR至少存在两种功能性复合物，mTORC1和mTORC2，它们介导既关联又独立的生物信号功能。临床上使用的雷帕霉素类药物(包括雷帕霉素及其类似物)通过变构结合到mTORC1催化位点附近的FKBP12蛋白结合位点(FKBP12-rapamycin binding domain,FRB)，发挥部分抑制mTOR蛋白的作用。这些化合物不能直接抑制mTORC2，也不能完全阻滞mTORC1介导的所有信号。尽管雷帕霉素类药物已在某些瘤谱中显示出一定的临床疗效，但这类药物的作用方式并不能完全发挥mTOR靶向抗肿瘤药物的潜力。特别是，在一些主要的实体瘤中，mTORC2介导的AKT的过磷酸(活化)对于肿瘤的维持和生长至关重要，但mTORC2不能被雷帕霉素类药物抑制。
开发ATP竞争性及特异性mTOR小分子抑制剂为多种癌症治疗提供了可能。与雷帕霉素类似物相比，近期报道的一些ATP竞争性抑制剂对肿瘤细胞生长和存活、蛋白质合成、生物能量代谢等已经显示出更强的抑制作用。在动物实验中，该类药物对MDA361乳腺癌、U87MG胶质瘤、A549和H1975肺癌、A498和786-O肾癌有很强的单药抗肿瘤活性。
综上所述，鉴于多种瘤谱中都涉及到mTOR信号通路，开发更有效的mTOR抑制剂为新型广谱抗肿瘤药物提供了新的思路和策略。目前已有数个mTOR抑制剂进入临床研究阶段，这预示ATP竞争性mTOR抑制剂有可能成为新一代的抗肿瘤药物进入临床使用。
本发明的发明人己确定mTOR抑制剂是ATP竞争性抑制剂，因而其作用机制是非雷帕霉素样的化合物。另外，本发明的发明人在原有已报道的化合物的基础上，通过合理设计，综合考虑化合物的水溶性、代谢稳定性等因素，得到了一类新型吡啶并嘧啶或嘧啶并嘧啶类化合物。该类化合物在酶、细胞水平上均能显示较好的mTOR抑制活性。经过进一步的优化和筛选后，有望研发成为制备简便、活性更高的抗肿瘤药物。
发明内容
在本发明的第一方面中，本发明提供了一种式(I)的化合物的晶型I，其X射线粉末衍射图谱(优选地，使用Cu-kα测量)在以下2θ角处具有特征衍射峰：7.600±0.2°，9.374±0.2°，13.838±0.2°，14.179±0.2°，15.218±0.2°，17.659±0.2°，21.018±0.2°，21.700±0.2°。
Figure PCTCN2018114354-appb-000001
在一个实施方式中，晶型I的X射线粉末衍射图谱(优选地，使用Cu-kα测量)在九个或更多个、十个或更多个、十一个或更多个、十二个或更多个，或十三个 或更多个选自下组的2θ角处具有特征衍射峰：7.600±0.2°，9.374±0.2°，13.838±0.2°，14.179±0.2°，15.218±0.2°，17.162±0.2°，17.659±0.2°，18.663±0.2°，19.521±0.2°，20.160±0.2°，21.018±0.2°，21.700±0.2°，22.939±0.2°，23.478±0.2°。
在另一个实施方式中，晶型I的X射线粉末衍射图谱(优选地，使用Cu-kα测量)如图1所示。
在另一个实施方式中，晶型I的X射线粉末衍射图谱解析数据(优选地，使用Cu-kα测量)如表1所示。
表1.晶型I的X射线粉末衍射图谱解析数据
Figure PCTCN2018114354-appb-000002
在另一个实施方式中，晶型I的差示扫描量热曲线在238.1±3℃处具有吸热峰。
在另一个实施方式中，晶型I的差示扫描量热曲线如图2所示。
在另一个实施方式中，晶型I的热重分析曲线在150±3℃处失重为约0.224％。
在另一个实施方式中，晶型I的热重分析曲线如图3所示。
在另一个实施方式中，本发明还提供了一种晶型I的制备方法，包括：
a)混合式(I)的化合物、异丙醇和乙酸乙酯，加热并搅拌；
b)将温度调整至0～10℃并搅拌，缓慢降温析晶；
c)过滤、洗涤、干燥。
在本发明的第二方面中，本发明提供了一种式(I)的化合物的硫酸盐。
在一个实施方式中，本发明提供了一种式(I)的化合物的硫酸盐的晶型II，其X射线粉末衍射图谱在以下2θ角处具有特征衍射峰：6.889±0.2°，8.523±0.2°，17.306±0.2°，18.668±0.2°，20.443±0.2°，21.196±0.2°，23.684±0.2°。
在另一个实施方式中，晶型II在八个或更多个、九个或更多个、十个或更多个、十一个或更多个、十二个或更多个，或十三个或更多个选自下组的2θ角处具有特征衍射峰：6.889±0.2°，8.523±0.2°，9.295±0.2°，12.554±0.2°，12.886±0.2°，13.797±0.2°，15.758±0.2°，16.634±0.2°，17.306±0.2°，18.668±0.2°，20.443±0.2°，21.196±0.2°，23.186±0.2°，23.684±0.2°。
在另一个实施方式中，晶型II的X射线粉末衍射图谱如图4所示。
在另一个实施方式中，晶型II的X射线粉末衍射图谱解析数据如表2所示。
表2.晶型II的X射线粉末衍射图谱解析数据
Figure PCTCN2018114354-appb-000003
Figure PCTCN2018114354-appb-000004
在另一个实施方式中，晶型II的差示扫描量热曲线在318.6±3℃处具有吸热 峰。
在另一个实施方式中，晶型II的差示扫描量热曲线如图5所示。
在另一个实施方式中，晶型II的热重分析曲线在150±3℃处失重为约0.447％。
在另一个实施方式中，晶型II的热重分析曲线如图6所示。
在另一个实施方式中，本发明还提供了一种晶型II的制备方法，包括：
a)混合式(I)的化合物和甲醇，加热并搅拌；
b)边搅拌边加入硫酸溶液，并在加热条件下搅拌；
c)将溶液吹干后加入乙腈，并在加热条件下搅拌；
d)过滤、干燥。
在本发明的第三方面中，本发明提供了上述任意一种盐型和晶型在制备用于治疗由PI3K-Akt-mTOR信号通路功能失调而导致的疾病或病症的药物中的应用。
附图说明
图1显示晶型I的X射线粉末衍射图谱。
图2显示晶型I的差示扫描量热曲线。
图3显示晶型I的热重分析曲线。
图4显示晶型II的X射线粉末衍射图谱。
图5显示晶型II的差示扫描量热曲线。
图6显示晶型II的热重分析曲线。
图7显示晶型I的动态蒸汽吸附分析结果，其中菱形实线为吸附曲线，方形实线表示解吸附曲线。
具体实施方式
下面结合附图和实施例对本发明进行进一步的说明。但应理解，这些实施例仅仅是用于更详细具体地说明本发明，而不应理解为用于以任何形式限定本发明。
本发明实施例中所使用的试剂和采用的方法均是本领域的常规试剂和常规方法。本领域技术人员应当清楚，在下文中，如未特别说明，温度以摄氏度(℃)表示，操作温度在室温环境下进行，所示室温是指10℃～30℃，优选20℃～25℃； 所述熔点的可允许误差在±1％；所述的收率为质量百分比。
实验方法
1.X射线粉末衍射(X-ray powder diffraction,XRPD)
各晶型的XRPD数据由岛津公司(Shimadzu)的XRD-6000仪器通过Macro XRPD测定，衍射参数如下：
X射线：Cu,kα,
Figure PCTCN2018114354-appb-000005
1.54056
X射线光管设定：40kV,30mA
发散狭缝：自动
单色器：无
扫描模式：连续
扫描范围(°2Theta)：5°-50°
扫描速度(°/分钟)：5
2.差示扫描量热分析(Differential scanning calorimeter,DSC)
各晶型的DSC数据由珀金埃尔默公司(PerkinElmer)的Diamond型差示扫描量热仪测定，热分析参数如下：
温度范围(℃)：30-300
扫描速率(℃/分钟)：20
保护气体：氮气
3.热重分析(Thermogravimetric analysis,TGA)
各晶型的TGA数据由珀金埃尔默公司的Pyris 1仪器测定，热分析参数如下：
温度范围(℃)：30-350℃
扫描速率(℃/分钟)：20
保护气体：氮气
技术效果
本发明的晶型的优势包括溶解度高、稳定性高、吸湿性/引湿性低等，具有良好的应用前景。
实施例
以下实施例仅用于说明本发明的具体实施方式，而非任何对本发明的限制。
实施例1.式(I)的化合物的制备
将3-乙酰基苯甲酸(200g)溶于2L甲醇(或乙醇、丙醇)，室温缓慢加入128ml浓硫酸。将混合物升温回流，反应过夜。检测反应完全后，减压浓缩除去甲醇。将剩余油状物溶于2L乙酸乙酯，分别用1L水洗1次、1L饱和碳酸氢钠洗涤2次、0.5L饱和盐水洗涤1次。将有机相用无水硫酸钠干燥后，将乙酸乙酯减压浓缩除去，得到红色油状物，冷却至室温析出黄色固体(中间体(1))189g。收率87％。
将中间体(1)(195g)溶于甲苯(1L)中，加入DMF-DMA(195ml)，将溶液加热回流。反应6小时。检测反应完全后减压浓缩除去溶剂得到棕色油状物。加入400ml甲基叔丁基醚，过滤，减压干燥得到191g黄色固体(中间体(2))。收率75％。
将6-氨基尿嘧啶(109g)溶解在2.5L乙酸中，将中间体(2)(167g)分批加入体系中，搅拌加热至100℃。反应12小时。检测反应完全，减压除去混合溶剂。用2N氢氧化钾水溶液调节pH＝7，过滤。将固体在400ml饱和柠檬酸水溶液(1.5L)中搅拌1小时，过滤，滤饼用水洗至中性，得到204g黄色粉末(中间体(3))。收率：95.8％。
将中间体(3)(200g)溶于3L三氯氧磷，升温至120℃回流18小时。检测反应完全后蒸干溶剂，加入乙酸乙酯(2L)打浆，抽滤，减压除去残留溶剂，得到202g絮状固体(中间体(4))。收率：90.9％。
将中间体(4)(100g)溶于四氢呋喃(4L)，加入桥环吗啉盐酸盐(53.7g)，和DIEA(152ml)，室温搅拌3小时。待检测反应完全，蒸干反应液，得到红色固体，加入乙酸乙酯(2L)打浆，抽滤，用减压除去残留溶剂得到113g微红色固体(中间体(5))。收率：91.5％。
将中间体(5)(50g)溶于1.5L DMF，依次加入DIEA(31.5g)和3-S-甲基吗啉(18.5g)，加热140℃至回流24小时。冷却至室温。减压浓缩除去溶剂，加入3L 乙酸乙酯溶解，用2000ml水洗2次，1000ml饱和盐水洗1次，使用无水硫酸钠干燥，减压浓缩得到黄色固体粗产品。将粗产品加入300ml乙酸乙酯打浆，抽滤，减压干燥得到41g中间体(6)。收率：70.7％。
将中间体(6)(40g)溶于30％甲胺醇溶液(1100ml)，升温40-45℃反应22小时。检测反应完全后减压浓缩除去溶剂，将剩余物加入2L二氯甲烷，用500ml水洗3次，500ml饱和盐水洗1次，有机层用无水硫酸钠干燥。减压浓缩。将固体用400ml乙酸乙酯打浆，过滤干燥。得到式(I)的化合物36g。
实施例2.晶型I的制备
将式(I)的化合物10g(21.07mmol)和异丙醇(7.8g,10mL,0.78X,1V)加入到500ml三口瓶中，加乙酸乙酯(90g,100mL,9.0X,10V)，然后升温至70～80℃，在70～80℃温度下搅拌1-2小时，调整温度至0～10℃，在0～10℃温度下搅拌2-3小时，缓慢降温析晶。过滤并用乙酸乙酯(9g,10mL,0.9X,1V)洗涤滤饼，将滤饼置于50～55℃温度下干燥10-15小时，得到9.2g淡黄色固体状的晶型I。
实施例3.晶型II的制备
称取约200mg式(I)的化合物于玻璃瓶中，加入甲醇2ml并加热至50～60℃，搅拌约10分钟，样品为澄清溶液。边搅拌边逐滴加入0.25mol/L H 2SO 4溶液3ml(摩尔比为1:1.8)于50～60℃下搅拌1小时，为澄清溶液。该溶液室温下用氮气吹干后加入2ml乙腈于50～60℃下搅拌2小时。混悬液过滤，固形物于40～50℃烘干过夜，得到晶型II。
实施例4.溶解度实验
为考察不同盐型和晶型在不同pH缓冲液，模拟人工胃液、肠液下的溶解度。精密称取约3mg固体于液相进样瓶中并加入不同溶剂1ml，超声10分钟。使其分散均匀后于200rpm，25℃下振摇20小时，取出，在15000rpm下离心15分钟，吸取上清液并使用相应溶剂按一定倍数稀释后使用HPLC测定浓度，并测定pH值。HPLC条件如表3所示。溶解度测定结果如表4所示。
表3.HPLC条件
Figure PCTCN2018114354-appb-000006
表4.溶解度实验结果
Figure PCTCN2018114354-appb-000007
缩写：
SGF：人工胃液(Simulated Gastric Fluid)
FaSSIF：禁食态人工肠液(Simulated Small Intestinal Fluid under Fasted state)
FeSSIF：饱食态人工肠液(Simulated Small Intestinal Fluid under Fed state)
由溶解度实验结果可知，晶型I的溶解度呈pH依赖性，酸性条件下溶解度较好，0.1N HCL中溶解度大于3mg/ml，碱性条件下溶解度下降，pH6.8条件下溶解度下降至0.01mg/ml。晶型II能显著提高溶解度，特别是提高在水和碱性溶液中 的溶解度。晶型II在水中的溶解度可大于3mg/ml。
实施例5.溶液稳定性实验
在溶解度实验的基础上配制0.1N HCL、0.05M醋酸盐缓冲液pH4.5、0.05M磷酸盐缓冲液pH6.8和水的样品溶液，浓度在100-500μg/ml范围内。样品溶液置于40℃下于0小时和24小时取样检测有关物质。实验结果如表5所示，表明各晶型在上述条件下稳定性较好。
表5.溶液稳定性实验结果
Figure PCTCN2018114354-appb-000008
实施例6.晶型I的动态蒸汽吸附分析(DVS)
晶型I的DVS数据由SMS公司的DVS intrinsic仪器测定，试验参数如下：
温度(℃)：25
起始湿度(％RH)：0
终点湿度(％RH)：95
湿度梯度(％RH)：5
循环次数：1
根据图7所示，晶型I的吸湿性小，相对湿度为95％时吸湿增重小于0.25％。
实施例7.晶型II的引湿性分析
按中国药典2010版二部附录XIX J药物引湿性试验指导原则进行试验。分别 取三批晶型II样品适量，平铺于试验前一天已放于25±1℃恒温干燥器(下部放置饱和氯化铵溶液，相对湿度80％)饱和的称量瓶中，厚度约为1mm，精密称重。将称量瓶敞口置于上述恒温恒湿干燥器中，放置24小时后，精密称重。结果见表6，表明本品没有引湿性(中国药典2010版附录XIX J药物引湿性试验指导原则：引湿增重小于0.2％表示无或几乎无引湿性)。
表6.晶型II的引湿性结果
Figure PCTCN2018114354-appb-000009
应理解，以上实施例只用于对本发明进行进一步说明，而非对本发明保护范围的限制，本领域的技术人员根据本发明的上述内容做出的一些非本质的改进和调整均属于本发明的保护范围。

Claims (10)

  1. 式(I)的化合物的晶型I，其X射线粉末衍射图谱在以下2θ角处具有特征衍射峰：7.600±0.2°，9.374±0.2°，13.838±0.2°，14.179±0.2°，15.218±0.2°，17.659±0.2°，21.018±0.2°，21.700±0.2°。
    Figure PCTCN2018114354-appb-100001
  2. 根据权利要求1所述的晶型，其X射线粉末衍射图谱在九个或更多个、十个或更多个、十一个或更多个、十二个或更多个，或十三个或更多个选自下组的2θ角处具有特征衍射峰：7.600±0.2°，9.374±0.2°，13.838±0.2°，14.179±0.2°，15.218±0.2°，17.162±0.2°，17.659±0.2°，18.663±0.2°，19.521±0.2°，20.160±0.2°，21.018±0.2°，21.700±0.2°，22.939±0.2°，23.478±0.2°。
  3. 根据权利要求2所述的晶型，其X射线粉末衍射图谱如图1所示。
  4. 根据权利要求1所述的晶型，其差示扫描量热曲线在238.1±3℃处具有吸热峰，和/或其热重分析曲线在150±3℃处失重为约0.224％。
  5. 式(I)的化合物的硫酸盐的晶型II，其X射线粉末衍射图谱在以下2θ角处具有特征衍射峰：6.889±0.2°，8.523±0.2°，17.306±0.2°，18.668±0.2°，20.443±0.2°，21.196±0.2°，23.684±0.2°。
  6. 根据权利要求5所述的晶型，其X射线粉末衍射图谱在八个或更多个、九个或更多个、十个或更多个、十一个或更多个、十二个或更多个，或十三个或更多个选自下组的2θ角处具有特征衍射峰：6.889±0.2°，8.523±0.2°，9.295±0.2°，12.554±0.2°，12.886±0.2°，13.797±0.2°，15.758±0.2°，16.634±0.2°，17.306±0.2°，18.668±0.2°，20.443±0.2°，21.196±0.2°，23.186±0.2°，23.684±0.2°。
  7. 根据权利要求6所述的晶型，其X射线粉末衍射图谱如图4所示。
  8. 根据权利要求5所述的晶型，其差示扫描量热曲线在318.6±3℃处具有吸热峰， 和/或其热重分析曲线在150±3℃处失重为约0.447％。
  9. 一种式(I)的化合物的晶型的制备方法，包括
    a)混合式(I)的化合物、异丙醇和乙酸乙酯，加热并搅拌；
    b)将温度调整至0～10℃并搅拌，缓慢降温析晶；以及
    c)过滤、洗涤、干燥。
  10. 一种式(I)的化合物的盐的晶型的制备方法，包括：
    a)混合式(I)的化合物和甲醇，加热并搅拌；
    b)边搅拌边加入酸溶液，并在加热条件下搅拌；
    c)将溶液吹干后加入乙腈，并在加热条件下搅拌；以及
    d)过滤、干燥。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102887895A (zh) * 2011-07-22 2013-01-23 山东轩竹医药科技有限公司 吡啶并嘧啶类mTOR抑制剂
CN103588792A (zh) * 2013-03-04 2014-02-19 中国科学院上海药物研究所 吡啶并嘧啶或嘧啶并嘧啶类化合物、其制备方法、药物组合物及其用途
WO2016150396A1 (zh) * 2015-03-25 2016-09-29 中国科学院上海药物研究所 取代吡啶并嘧啶类化合物的合成工艺

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102887895A (zh) * 2011-07-22 2013-01-23 山东轩竹医药科技有限公司 吡啶并嘧啶类mTOR抑制剂
CN103588792A (zh) * 2013-03-04 2014-02-19 中国科学院上海药物研究所 吡啶并嘧啶或嘧啶并嘧啶类化合物、其制备方法、药物组合物及其用途
WO2016150396A1 (zh) * 2015-03-25 2016-09-29 中国科学院上海药物研究所 取代吡啶并嘧啶类化合物的合成工艺

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