WO2023045360A1 - 大环类化合物的晶型及其制备方法和应用 - Google Patents

大环类化合物的晶型及其制备方法和应用 Download PDF

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WO2023045360A1
WO2023045360A1 PCT/CN2022/093322 CN2022093322W WO2023045360A1 WO 2023045360 A1 WO2023045360 A1 WO 2023045360A1 CN 2022093322 W CN2022093322 W CN 2022093322W WO 2023045360 A1 WO2023045360 A1 WO 2023045360A1
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crystal form
macrocyclic compound
solvent
filter residue
preparation
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郭睿智
王健松
罗志波
黄海文
秦飞
王玮
叶海鸿
钱日彬
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成都先导药物开发股份有限公司
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Priority to AU2022350240A priority patent/AU2022350240A1/en
Priority to CA3232913A priority patent/CA3232913A1/en
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Definitions

  • the invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to crystal forms of macrocyclic compounds and their preparation methods and applications.
  • Tropomyosin-related kinase (Trk kinase for short) is a kind of nerve growth factor receptor, and its family consists of highly homologous TrkA, TrkB and TrkC, encoded by NTRK1, NTRK2 and NTRK3 genes, respectively.
  • Trk protein is a high-affinity receptor for nerve growth factor. Trk proteins are expressed in neuronal tissues during organogenesis, and they play key roles in central and peripheral nervous system development. When chromosomal mutations lead to NTRK gene fusion, resulting in high expression of chimeric Trk protein, resulting in dysregulation of Trk kinase downstream signaling pathway, overactivation of this pathway can lead to cancer.
  • NTRK gene fusions occur in a variety of solid tumors in adults and children, including breast, colorectal, non-small cell lung cancer, and various sarcomas.
  • NTRK fusion genes include Trk kinase inhibitory activity, and most of them inhibit the catalytic activity of the kinase by competing with ATP for the binding site.
  • the prior art discloses a macrocyclic kinase inhibitor, this type of compound exhibits good Trk inhibitory activity and selectivity, and exhibits good tumor growth inhibitory effect in vivo.
  • the present invention aims to solve at least one of the technical problems in the above-mentioned prior art. For this reason, the present invention proposes a crystal form of a macrocyclic compound, which has good physical and chemical stability, has no hygroscopicity, and can exhibit good pharmacokinetic properties.
  • the first aspect of the present invention provides a crystal form of a macrocyclic compound.
  • the crystal form of a macrocyclic compound is (6R,16R)-9-fluoro-16-methyl-13-oxa-2,17,21,25-tetraazapenta Cyclo[16.6.2.0 2 , 6 .0 7 , 12 .0 22 , 26 ]hexacane-1(25),7,9,11,18(26),19,21,23-octane-19 - Nitrile
  • the X-ray diffraction pattern of the crystal form has 2 ⁇ values of 9.49 ⁇ 0.2, 10.60 ⁇ 0.2, 11.54 ⁇ 0.2, 14.10 ⁇ 0.2, 17.09 ⁇ 0.2, 19.15 ⁇ 0.2, 20.30 ⁇ 0.2, 22.85 ⁇ 0.2, 23.89 ⁇ 0.2 There are characteristic peaks at 0.2 and 27.74 ⁇ 0.2.
  • the X-ray diffraction pattern of the crystal form also has characteristic peaks at 2 ⁇ values of 18.75 ⁇ 0.2, 21.29 ⁇ 0.2, 24.25 ⁇ 0.2, 24.99 ⁇ 0.2, 28.74 ⁇ 0.2 and 31.35 ⁇ 0.2.
  • the X-ray diffraction pattern of the crystal form also has 2 ⁇ values of 5.69 ⁇ 0.2, 16.11 ⁇ 0.2, 25.62 ⁇ 0.2, 26.34 ⁇ 0.2, 27.26 ⁇ 0.2, 29.91 ⁇ 0.2, 32.19 ⁇ 0.2, 33.86 ⁇ 0.2, Features at 34.70 ⁇ 0.2, 35.59 ⁇ 0.2, 36.95 ⁇ 0.2, 37.40 ⁇ 0.2, 39.19 ⁇ 0.2, 40.33 ⁇ 0.2, 41.16 ⁇ 0.2, 42.56 ⁇ 0.2, 43.11 ⁇ 0.2, 45.30 ⁇ 0.2, 46.35 ⁇ 0.2 and 49.80 ⁇ 0.2 peak.
  • the differential scanning calorimetry of the crystal form has an endothermic peak at 233 ⁇ 5°C; further preferably, the differential scanning calorimetry of the crystal form has an endothermic peak at 233 ⁇ 3°C .
  • the second aspect of the present invention provides a method for preparing the crystal form of the above-mentioned macrocyclic compound.
  • the preparation method of the crystal form of the above-mentioned macrocyclic compound is selected from one of the following three methods:
  • the macrocyclic compound is (6R,16R)-9-fluoro-16-methyl-13-oxa-2,17,21,25-tetraazapenta Cyclo[16.6.2.0 2 , 6 .0 7 , 12 .0 22 , 26 ]hexacane-1(25),7,9,11,18(26),19,21,23-octane-19 - Nitrile, the crystal form of the macrocyclic compound is not particularly limited, and other crystal forms or amorphous forms may be used.
  • the heating temperature is 40-100°C; more preferably, in mode (2), the heating temperature is 50-80°C.
  • the solvent described in modes (1)-(3) and the antisolvent described in mode (3) are selected from C 2 -C 7 hydrocarbons, C 2 -C 7 alcohols, C 2 -C 7 One or more of ketones, C 2 -C 7 nitriles, C 2 -C 7 ethers, C 2 -C 7 esters or water.
  • the C 2 -C 7 hydrocarbons include dichloromethane, n-heptane or toluene.
  • the C 2 -C 7 alcohols include methanol, ethanol, trifluoroethanol, n-propanol or isopropanol.
  • the C 2 -C 7 ketones include acetone or butanone.
  • the C 2 -C 7 nitrile substance comprises acetonitrile.
  • the C 2 -C 7 ethers include isopropyl ether, methyl tert-butyl ether, tetrahydrofuran or 1,4-dioxane.
  • the C 2 -C 7 esters include ethyl acetate or isopropyl acetate.
  • the solvent is at least one selected from methanol, ethanol, acetone, dichloromethane, tetrahydrofuran or water.
  • the anti-solvent is at least one selected from isopropyl ether, n-heptane or water.
  • the third aspect of the present invention provides the application of the crystal form of the above-mentioned macrocyclic compound.
  • the Trk kinase-related disease includes one of pain, malignant tumor, inflammatory disease or neurodegenerative disease.
  • the pain includes chronic pain and acute pain, including but not limited to bone pain, visceral pain, inflammatory pain, migraine, chronic low back pain, bladder pain caused by cancer, surgery, fracture, tumor metastasis, etc. syndrome and neuropathic pain.
  • said malignancy refers to any of a variety of diseases characterized by uncontrolled abnormal proliferation of cells, the ability of affected cells to spread to other parts of the body locally or through the bloodstream and lymphatic system (i.e. transfer) and any of a number of characteristic structural and/or molecular features.
  • the malignancy includes sarcoma, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer, fibrosarcoma, squamous cell carcinoma, melanoma or ovarian cancer.
  • the inflammatory disease includes various conditions characterized by histopathological inflammation.
  • Such inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, Airway inflammation or interstitial cystitis caused by house dust mites.
  • neuroretirement diseases include multiple sclerosis, Parkinson's disease and Alzheimer's disease.
  • the crystal form of the macrocyclic compound provided by the present invention has no hygroscopicity, and high temperature, high humidity or light conditions have little influence on its purity, and the crystal form has good chemical stability; the crystal form has a temperature of 40°C ⁇ 2°C , placed under accelerated conditions of 75% ⁇ 5% relative humidity for 6 months, the crystal form remains consistent and has good physical stability; in addition, the crystal form has good pharmacokinetic properties.
  • Fig. 1 is the PXRD spectrogram of the crystal form prepared in Example 1 of the present invention.
  • Fig. 2 is the DSC spectrogram of the crystal form prepared in Example 1 of the present invention.
  • Fig. 3 is the TGA spectrogram of the crystal form prepared in Example 1 of the present invention.
  • Fig. 4 is the amorphous PXRD spectrogram prepared by comparative example 1 of the present invention.
  • Fig. 5 is the DVS isothermal adsorption and desorption of the crystal form prepared in Example 1 of the present invention
  • Fig. 6 is the isothermal adsorption and desorption of the amorphous DVS prepared in Comparative Example 1 of the present invention.
  • the raw materials and reagents used in the following examples or comparative examples can be obtained from conventional commercial channels, or can be obtained by existing known methods, unless otherwise specified.
  • the main test instruments used in the following examples or comparative examples are shown in Table 1.
  • a method for preparing a crystal form of a macrocyclic compound comprising the following steps:
  • the obtained crystalline powder was subjected to X-ray powder diffraction, differential scanning calorimetry and thermogravimetric analysis. After the crystalline samples were characterized, they were named crystal forms. Its PXRD spectrogram (X-ray powder diffraction spectrogram) is shown in Fig. 1, and Fig.
  • the abscissa in Figure 2 is Temperature (Temperature), and the ordinate is Heat Flow (Heat Flow).
  • Figure 2 shows that the sample has an endothermic peak at 233°C.
  • TGA spectrogram thermogravimetric analysis spectrogram
  • abscissa is temperature (Temperature) in Fig. 3
  • ordinate is weight (Weight)
  • Fig. 3 shows that sample has about 0.3% slow weight loss before 150 °C, is Anhydrous, the decomposition temperature is about 295°C.
  • a method for preparing a crystal form of a macrocyclic compound comprising the following steps:
  • a method for preparing a crystal form of a macrocyclic compound comprising the following steps:
  • a method for preparing a crystal form of a macrocyclic compound comprising the following steps:
  • a preparation method of an amorphous macrocyclic compound comprising the following steps:
  • the obtained crystalline powder was subjected to X-ray powder diffraction, differential scanning calorimetry and thermogravimetric analysis.
  • the sample is characterized by X-ray powder diffraction, and is determined to be amorphous, and the PXRD spectrum (X-ray powder diffraction spectrum) is shown in Fig. 4, and the abscissa in Fig. 4 is 2 ⁇ (Two-theta), and the ordinate is intensity (Intensity) .
  • the hygroscopicity evaluation is carried out on the crystal form and amorphous form of the macrocyclic compounds provided by the present invention.
  • the hygroscopicity data is detected by a dynamic moisture adsorption instrument.
  • the description of hygroscopicity characteristics and the definition of hygroscopicity weight gain refer to the four general rules of "Chinese Pharmacopoeia" 2020 edition 9103, as shown in Table 2.
  • Hygroscopic Characteristic Description Humidity gain deliquescence Absorb enough water to form a liquid Very hygroscopic Not less than 15% Hygroscopic Less than 15% but not less than 2% slightly hygroscopic Less than 2% but not less than 0.2% Little or no hygroscopicity less than 0.2%
  • FIG. 5 The isothermal adsorption and detachment of the crystal form prepared in Example 1 are shown in Fig. 5, the abscissa in Fig. 5 is relative humidity (Relative Humidity), and the ordinate is weight percentage (Weight/%), and the two curves in Fig. 5 represent respectively Adsorption and desorption curves, due to possible hysteresis during desorption, the two curves do not overlap.
  • Figure 5 shows that when the relative humidity (RH) of the sample is between 0% and 80%, as the humidity increases, the weight change is about 0.1%, indicating that the sample is not hygroscopic and has no hygroscopicity.
  • RH relative humidity
  • FIG. 6 The isothermal adsorption of the amorphous macrocyclic compound prepared in Comparative Example 1, the drawing is shown in Fig. 6, the abscissa in Fig. 6 is relative humidity (Relative Humidity), and the ordinate is weight percent (Weight/%), in Fig. 6
  • the two curves represent the adsorption and desorption curves respectively. Because there may be hysteresis during desorption, the two curves do not overlap.
  • Figure 6 shows that the sample is between 0% and 80% relative humidity. As the humidity increases, the weight increases It is about 21.6%, indicating that the sample is extremely hygroscopic and extremely hygroscopic.
  • the experimental results show that, in terms of hygroscopicity, the crystalline form shows better properties than the amorphous form.
  • the stability of the influencing factors of the crystalline form and amorphous form of the macrocyclic compounds provided by the present invention was inspected, and the inspection conditions were referred to the fourth general rule 9103 of the 2020 edition of the Chinese Pharmacopoeia.
  • the inspection content is as follows: the crystal form of the macrocyclic compound prepared in the embodiment and the amorphous macrocyclic compound prepared in Comparative Example 1 were placed in the open, and investigated at high temperature (60°C ⁇ 2°C) and high humidity (90% ⁇ 2°C).
  • the investigation period is 30 days
  • the sampling time points are 5 days, 10 days and 30 days
  • the purity of the samples at the corresponding time points is determined by the high-efficiency Liquid chromatography detection, calculated by area normalization method, the results are shown in Table 3.
  • the accelerated stability inspection is carried out on the crystal form of the macrocyclic compound provided by the present invention, and the stability of the crystal form is investigated.
  • the inspection conditions refer to the "Chinese Pharmacopoeia” 2020 edition four general rules 9103.
  • the inspection content is as follows: place the crystal sample in a sealed place, and investigate the stability of the crystal form at a temperature of 40°C ⁇ 2°C and a relative humidity of 75% ⁇ 5%.
  • the inspection period is 6 months, and the sampling time points are January, February In January, March and June, the crystal forms of samples at corresponding time points were detected by X-ray powder diffractometer, and the results are shown in Table 4.

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Abstract

本发明属于药物合成技术领域，公开了大环类化合物的晶型及其制备方法和应用。该大环类化合物为(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.02,6.07,12.022,26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈，该晶型的X射线衍射图在2θ值为9.49±0.2、10.60±0.2、11.54±0.2、14.10±0.2、17.09±0.2、19.15±0.2、20.30±0.2、22.85±0.2、23.89±0.2和27.74±0.2处具有特征峰。该晶型无引湿性，具有良好稳定性和药代动力学性质。

Description

大环类化合物的晶型及其制备方法和应用 技术领域
本发明属于药物合成技术领域，具体涉及大环类化合物的晶型及其制备方法和应用。
背景技术
原肌球蛋白相关激酶(简称Trk激酶)是一类神经生长因子受体，其家族由高度同源性的TrkA、TrkB以及TrkC组成，分别由NTRK1、NTRK2和NTRK3基因编码。正常生理条件下，Trk蛋白是神经生长因子的高亲和力受体。在器官形成过程中，Trk蛋白在神经元组织中表达，它们在中枢和外周神经系统发育中起关键作用。当染色体变异发生NTRK基因融合，导致嵌合型Trk蛋白的高表达，致使Trk激酶下游信号通路调控失常，该通路的过度激活可导致癌症产生。
NTRK基因融合出现在多种成人和儿童实体瘤之中，包括乳腺癌、结直肠癌、非小细胞肺癌，以及各种肉瘤。目前靶向NTRK融合基因的临床在研新药有多种，它们都具有Trk激酶抑制活性，大多通过与ATP竞争结合位点实现抑制激酶催化活性。现有技术公开了一种大环类激酶抑制剂，该类化合物显示良好的Trk抑制活性和选择性，并且展示出良好的体内肿瘤生长抑制作用。经研究发现，其中的大环类化合物(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.02,6.07,12.022,26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈具有较佳的效果，大环类化合物的结构如下图所示。
Figure PCTCN2022093322-appb-000001
现有技术虽然公开了大环类化合物的一般制备方法，但没有提供化合物的结晶形式以及结晶形式相应的制备方法。
众所周知，药物分子通常具有多种排列方式，不同的排列方式构成了不同的晶型，即药物的多晶型现象，其一般表现为药物原料在固体状态下的存在形式。一种药物可以有多种晶 型，同一种药物的不同晶型，除了稳定性有差异以外，其在体内的溶解和吸收也可能有所不同，从而影响临床疗效和安全性。而目前并没有对大环类化合物(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.0 2, 6.0 7, 12.0 22, 26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈相关晶型的研究，无定型的化合物其引湿性、稳定性差，制备的药物不能发挥良好的作用。
因此，亟需提供一种大环类化合物的晶型，具有良好的物理、化学稳定性，且无引湿性，能够表现出良好的药代动力学性质。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此，本发明提出大环类化合物的晶型，具有良好的物理、化学稳定性，且无引湿性，能够表现出良好的药代动力学性质。
本发明第一方面提供了大环类化合物的晶型。
具体的，大环类化合物的晶型，所述大环类化合物为(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.0 2, 6.0 7, 12.0 22, 26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈，所述晶型的X射线衍射图在2θ值为9.49±0.2、10.60±0.2、11.54±0.2、14.10±0.2、17.09±0.2、19.15±0.2、20.30±0.2、22.85±0.2、23.89±0.2和27.74±0.2处具有特征峰。
优选的，所述晶型的X射线衍射图还在2θ值为18.75±0.2、21.29±0.2、24.25±0.2、24.99±0.2、28.74±0.2和31.35±0.2处具有特征峰。
进一步优选的，所述晶型的X射线衍射图还在2θ值为5.69±0.2、16.11±0.2、25.62±0.2、26.34±0.2、27.26±0.2、29.91±0.2、32.19±0.2、33.86±0.2、34.70±0.2、35.59±0.2、36.95±0.2、37.40±0.2、39.19±0.2、40.33±0.2、41.16±0.2、42.56±0.2、43.11±0.2、45.30±0.2、46.35±0.2和49.80±0.2处具有特征峰。
优选的，所述晶型的差示扫描量热图在233±5℃处有吸热峰；进一步优选的，所述晶型的差示扫描量热图在233±3℃处有吸热峰。
本发明第二方面提供了上述大环类化合物的晶型的制备方法。
具体的，上述大环类化合物的晶型的制备方法，选自以下三种方式之一：
(1)向所述大环类化合物中加入溶剂至过饱和状态，然后搅拌，析晶，再经过滤得滤渣，将所述滤渣干燥即制得晶型；
或，
(2)将所述大环类化合物加热溶解于溶剂中，然后冷却析晶，再经过滤得滤渣，将所述滤渣干燥即制得晶型；
或，
(3)将所述大环类化合物溶解于溶剂中，然后加入抗溶剂，析晶，再经过滤得滤渣，将所述滤渣干燥即制得晶型。
在方式(1)-(3)中，所述大环类化合物为(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.0 2, 6.0 7, 12.0 22, 26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈，所述大环类化合物的晶型没有特别限定，可以使用其他结晶形式或无定型。
优选的，在方式(2)中，所述加热的温度为40-100℃；进一步优选的，在方式(2)中，所述加热的温度为50-80℃。
优选的，方式(1)-(3)中所述溶剂和方式(3)中所述抗溶剂选自C 2-C 7烃类物质、C 2-C 7醇类物质、C 2-C 7酮类物质、C 2-C 7腈类物质、C 2-C 7醚类物质、C 2-C 7酯类物质或水中的一种或几种。
优选的，所述C 2-C 7烃类物质包含二氯甲烷、正庚烷或甲苯。
优选的，所述C 2-C 7醇类物质包含甲醇、乙醇、三氟乙醇、正丙醇或异丙醇。
优选的，所述C 2-C 7酮类物质包含丙酮或丁酮。
优选的，所述C 2-C 7腈类物质包含乙腈。
优选的，所述C 2-C 7醚类物质包含异丙醚、甲基叔丁基醚、四氢呋喃或1,4-二氧六环。
优选的，所述C 2-C 7酯类物质包含乙酸乙酯或乙酸异丙酯。
优选的，所述溶剂选自甲醇、乙醇、丙酮、二氯甲烷、四氢呋喃或水中的至少一种。
优选的，所述抗溶剂选自异丙醚、正庚烷或水中的至少一种。
本发明第三方面提供了上述大环类化合物的晶型的应用。
具体的，上述大环类化合物的晶型在制备Trk激酶相关疾病的药物中的应用。
优选的，所述Trk激酶相关疾病包括疼痛、恶性肿瘤、炎性疾病或神经退行性疾病中的一种。
优选的，所述疼痛包括慢性疼痛和急性疼痛，包括但不限于由癌症、外科手术、骨折、 肿瘤转移等引起的骨痛、内脏痛、炎性痛、偏头痛、慢性腰背痛、膀胱疼痛综合征和神经性疼痛。
优选的，所述恶性肿瘤是指以不受控制的细胞异常增殖为特征的多种疾病中的任何一种，受影响的细胞在局部或通过血流和淋巴系统扩散到其他部位的能力的身体(即转移)以及许多特征结构和/或分子特征中的任何一个。所述恶性肿瘤包括肉瘤、乳腺癌、肺癌、脑癌、骨癌、肝癌、肾癌、结肠癌、纤维肉瘤、鳞状细胞癌、黑素瘤或卵巢癌。
优选的，所述炎性疾病包括以组织病理性炎症为特征的多种病症。所述炎性疾病包括寻常性痤疮、哮喘、腹腔疾病、慢性前列腺炎、肾小球性肾炎、炎症性肠病、盆腔炎、再灌注损伤、类风湿性关节炎、结节病、血管炎、房尘螨引起的气道炎症或间质性膀胱炎。炎性疾病与自身免疫性疾病之间存在显著重叠。
优选的，神经退休性疾病包括多发性硬化症、帕金森氏症和阿尔茨海默症。
相对于现有技术，本发明的有益效果如下：
本发明提供的大环类化合物的晶型无引湿性，且高温、高湿或光照条件对其纯度的影响小，该晶型具有良好的化学稳定性；该晶型在温度40℃±2℃，相对湿度75％±5％的加速条件下放置6个月，其晶型仍然保持一致，具有良好的物理稳定性；此外，该晶型具有良好的药代动力学性质。
附图说明
图1为本发明实施例1制备的晶型的PXRD谱图；
图2为本发明实施例1制备的晶型的DSC谱图；
图3为本发明实施例1制备的晶型的TGA谱图；
图4为本发明对比例1制备的无定型的PXRD谱图；
图5为本发明实施例1制备的晶型的DVS等温吸附、脱附图；
图6为本发明对比例1制备的无定型的DVS等温吸附、脱附图。
具体实施方式
为了让本领域技术人员更加清楚明白本发明所述技术方案，现列举以下实施例进行说明。需要指出的是，以下实施例对本发明要求的保护范围不构成限制作用。
以下实施例或对比例中所用的原料、试剂如无特殊说明，均可从常规商业途径得到，或 者可以通过现有已知方法得到。以下实施例或对比例中所用的主要测试仪器如表1所示。
表1
仪器名称 仪器型号
X-射线粉末衍射仪(PXRD) Bruker D8 Advance Diffractometer
差示扫描量热仪(DSC) TA Instruments Q200 DSC
热重分析仪(TGA) TA Instruments Q500 TGA
动态水分吸附仪(DVS) TA Instruments Q5000 TGA
高效液相色谱(HPLC) Agilent 1260 HPLC
实施例1
一种大环类化合物的晶型的制备方法，包括以下步骤：
将1mg按专利CN110386945A实施例1制备得到的大环类化合物(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.0 2, 6.0 7, 12.0 22, 26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈加入1.0mL甲醇中，室温(25±5℃)下搅拌溶清后，缓慢滴加0.8mL水，析出固体后，继续搅拌一段时间，过滤，将滤渣干燥，得结晶性粉末。
对得到的结晶性粉末进行X-射线粉末衍射、差热扫描量热分析以及热重分析。该结晶样品经表征后，命名为晶型。其PXRD谱图(X射线粉末衍射谱图)见图1，图1表明样品在2θ值为5.69、9.49、10.60、11.54、14.10、16.11、17.09、18.75、19.15、20.30、21.29、22.85、23.89、24.25、24.99、25.62、26.34、27.26、27.74、28.74、29.91、31.35、32.19、33.86、34.70、35.59、36.95、37.40、39.19、40.33、41.16、42.56、43.11、45.30、46.35和49.80处有特征峰，其中2θ角度的仪器测量误差值为±0.2。DSC谱图(差示扫描量热谱图)见图2，图2中横坐标为温度(Temperature)，纵坐标为热流量(Heat Flow)，图2显示样品在233℃处有吸热峰。TGA谱图(热重分析谱图)见图3，图3中横坐标为温度(Temperature)，纵坐标为重量(Weight)，图3显示样品在150℃前有约0.3％的缓慢失重，为无水物，分解温度约为295℃。
实施例2
一种大环类化合物的晶型的制备方法，包括以下步骤：
将15mg(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.0 2, 6.0 7, 12.0 22, 26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈加入0.4mL甲醇中，室温搅拌溶清后，将溶液缓慢加 入0.8mL水中，析出固体后，继续搅拌一段时间后，过滤，干燥，得浅黄色结晶性粉末。该结晶样品的PXRD谱图和DSC谱图经对比后，确定为与实施例1相同晶型。
实施例3
一种大环类化合物的晶型的制备方法，包括以下步骤：
将15mg(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.0 2, 6.0 7, 12.0 22, 26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈加入0.2mL二氯甲烷中，室温搅拌溶清后，缓慢滴加3.6mL正庚烷，析出固体后，继续搅拌一段时间后，过滤，干燥，得结晶性粉末。该结晶样品的PXRD谱图和DSC谱图经对比后，确定为与实施例1相同晶型。
实施例4
一种大环类化合物的晶型的制备方法，包括以下步骤：
将15mg(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.0 2, 6.0 7, 12.0 22, 26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈加入1.8mL甲醇和0.2mL水的混合溶剂中，加热至65℃，搅拌溶清后，缓慢冷却，在4℃下保温搅拌，析出固体后，过滤，干燥，得结晶性粉末。该结晶样品的PXRD谱图和DSC谱图经对比后，确定为与实施例1相同晶型。
对比例1
一种无定型的大环类化合物的制备方法，包括以下步骤：
将15mg按专利CN110386945A所公开的方法制备得到的化合物(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.0 2, 6.0 7, 12.0 22, 26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈加入0.4mL二甲基亚砜中，室温搅拌溶清后，缓慢滴加0.6mL水，析出固体后，继续搅拌一段时间后，过滤，干燥，得结晶性粉末。对得到的结晶性粉末进行X-射线粉末衍射、差热扫描量热分析以及热重分析。该样品经X-射线粉末衍射表征，确定为无定型，PXRD谱图(X射线粉末衍射谱图)见图4，图4中横坐标为2θ(Two-theta)，纵坐标为强度(Intensity)。
产品效果测试
(1)引湿性测试
对本发明提供的大环类化合物的晶型与无定型进行引湿性评价，引湿性数据利用动态水分吸附仪进行检测，引湿性特征描述与引湿性增重的界定参照《中国药典》2020年版四部通则9103，如表2所示。
表2
引湿性特征描述 引湿增重
潮解 吸收足量水分形成液体
极具引湿性 不小于15％
有引湿性 小于15％但不小于2％
略有引湿性 小于2％但不小于0.2％
无或几乎无引湿性 小于0.2％
实施例1制备的晶型的等温吸附、脱附图见图5，图5中横坐标为相对湿度(Relative Humidity)，纵坐标为重量百分数(Weight/％)，图5中两条曲线分别代表吸附与脱附曲线，由于脱附时可能存在滞后现象，导致两条曲线不重合。图5显示样品在相对湿度(RH)为0％-80％之间，随着湿度增加，重量变化约为0.1％，表明样品不吸湿，无引湿性。对比例1制备的无定型的大环类化合物的等温吸附、脱附图见图6，图6中横坐标为相对湿度(Relative Humidity)，纵坐标为重量百分数(Weight/％)，图6中两条曲线分别代表吸附与脱附曲线，由于脱附时可能存在滞后现象，导致两条曲线不重合，图6显示样品在相对湿度为0％-80％之间，随着湿度增加，重量增加约为21.6％，表明样品极易吸湿，极具引湿性。实验结果表明，在引湿性方面，该晶型比无定型显示出更优良的性质。
(2)影响因素稳定性测试
对本发明提供的大环类化合物的晶型与无定型进行影响因素稳定性考察，考察条件参照《中国药典》2020年版四部通则9103。考察内容如下：将实施例制备的大环类化合物的晶型和对比例1制备的无定型的大环类化合物敞口放置，考察在高温(60℃±2℃)、高湿(90％±5％RH、25℃±2℃)以及光照(4500±500Lx)条件下的稳定性，考察周期为30天，取样时间点为5天、10天和30天，对应时间点的样品纯度通过高效液相色谱检测，以面积归一化法计算，结果如表3所示。
表3
Figure PCTCN2022093322-appb-000002
Figure PCTCN2022093322-appb-000003
实验显示对比例1制备的无定型的大环类化合物在高温、高湿和光照条件下，考察周期内的纯度均有下降，尤其是在30天后，高温、光照使得化合物的纯度下降明显。而实施例1制备的晶型的杂质含量仅在光照条件下略微增长，其余条件下无显著变化。
(3)加速稳定性试验
对本发明提供的大环类化合物的晶型进行加速稳定性考察，考察晶型的稳定性。考察条件参照《中国药典》2020年版四部通则9103。考察内容如下：将晶型样品密封放置，考察在温度40℃±2℃，相对湿度75％±5％条件下的晶型稳定性，考察周期为6个月，取样时间点为1月、2月、3月和6月，对应时间点的样品晶型通过X-射线粉末衍射仪检测，结果如表4所示。
表4
Figure PCTCN2022093322-appb-000004
Figure PCTCN2022093322-appb-000005
实验显示本发明提供的大环类化合物的晶型样品在加速试验条件下，放置6个月化合物的晶型仍然保持一致，本发明提供的大环类化合物的晶型具有更良好的物理稳定性。
(4)药代动力学试验
取雄性比格犬，3只为一组，单次经口灌胃给予本发明提供的大环类化合物的晶型样品，剂量为8mg/kg，采样时间点为0.25、0.5、1.0、2.0、4.0、6.0、8.0和24小时。根据样品浓度建立合适范围的标准曲线，并测定血浆样品中供试样品的浓度，进行定量分析和计算药代动力学参数，结果如表5所示。表5中，C max为药物的达峰浓度，AUC 0-last是药时曲线下面积，T max为药物作用的达峰时间，T 1/2为药物的消除半衰期。
表5
Figure PCTCN2022093322-appb-000006
由表5可知，本发明提供的大环类化合物的晶型在比格犬体内吸收较快，血浆暴露量较大，表明其具有良好的药代动力学性质。

Claims (10)

  1. 一种大环类化合物的晶型，所述大环类化合物为(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.0 2, 6.0 7, 12.0 22, 26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈，其特征在于，所述晶型的X射线衍射图在2θ值为9.49±0.2、10.60±0.2、11.54±0.2、14.10±0.2、17.09±0.2、19.15±0.2、20.30±0.2、22.85±0.2、23.89±0.2和27.74±0.2处具有特征峰。
  2. 根据权利要求1所述的大环类化合物的晶型，其特征在于，所述晶型的X射线衍射图还在2θ值为18.75±0.2、21.29±0.2、24.25±0.2、24.99±0.2、28.74±0.2和31.35±0.2处具有特征峰。
  3. 根据权利要求1或2所述的晶型，其特征在于，所述晶型的X射线衍射图还在2θ值为5.69±0.2、16.11±0.2、25.62±0.2、26.34±0.2、27.26±0.2、29.91±0.2、32.19±0.2、33.86±0.2、34.70±0.2、35.59±0.2、36.95±0.2、37.40±0.2、39.19±0.2、40.33±0.2、41.16±0.2、42.56±0.2、43.11±0.2、45.30±0.2、46.35±0.2和49.80±0.2处具有特征峰。
  4. 根据权利要求1所述的大环类化合物的晶型，其特征在于，所述晶型的差示扫描量热图在233±5℃处有吸热峰。
  5. 权利要求1-4中任一项所述的大环类化合物的晶型的制备方法，其特征在于，选自以下三种方式之一：
    (1)向所述大环类化合物中加入溶剂至过饱和状态，然后搅拌，析晶，再经过滤得滤渣，将所述滤渣干燥即制得晶型；
    或，
    (2)将所述大环类化合物加热溶解于溶剂中，然后冷却析晶，再经过滤得滤渣，将所述滤渣干燥即制得晶型；
    或，
    (3)将所述大环类化合物溶解于溶剂中，然后加入抗溶剂，析晶，再经过滤得滤渣，将所述滤渣干燥即制得晶型。
  6. 根据权利要求5所述的制备方法，其特征在于，方式(1)-(3)中所述溶剂和方式(3)中所述抗溶剂选自C 2-C 7烃类物质、C 2-C 7醇类物质、C 2-C 7酮类物质、C 2-C 7腈类物质、C 2-C 7 醚类物质、C 2-C 7酯类物质或水中的一种或几种。
  7. 根据权利要求6所述的制备方法，其特征在于，所述C 2-C 7烃类物质包含二氯甲烷、正庚烷或甲苯；所述C 2-C 7醇类物质包含甲醇、乙醇、三氟乙醇、正丙醇或异丙醇；所述C 2-C 7酮类物质包含丙酮或丁酮；所述C 2-C 7腈类物质包含乙腈；所述C 2-C 7醚类物质包含异丙醚、甲基叔丁基醚、四氢呋喃或1,4-二氧六环；所述C 2-C 7酯类物质包含乙酸乙酯或乙酸异丙酯。
  8. 根据权利要求6所述的制备方法，其特征在于，所述溶剂选自甲醇、乙醇、丙酮、二氯甲烷、四氢呋喃或水中的至少一种；所述抗溶剂选自异丙醚、正庚烷或水中的至少一种。
  9. 权利要求1-4中任一项所述的大环类化合物的晶型在制备Trk激酶相关疾病的药物中的应用。
  10. 根据权利要求9所述的应用，其特征在于，所述Trk激酶相关疾病包括疼痛、恶性肿瘤、炎性疾病或神经退行性疾病中的一种。
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010085597A1 (en) * 2009-01-23 2010-07-29 Incyte Corporation Macrocyclic compounds and their use as kinase inhibitors
CN110386945A (zh) 2018-04-18 2019-10-29 成都先导药物开发股份有限公司 一种大环类激酶抑制剂
CN112174982A (zh) * 2020-09-10 2021-01-05 上海希迈医药科技有限公司 一种洛普替尼晶型及其制备方法
CN113121568A (zh) * 2019-12-31 2021-07-16 成都倍特药业股份有限公司 一种大环结构化合物的盐及其制备方法
CN113754657A (zh) * 2021-09-22 2021-12-07 广州白云山医药集团股份有限公司白云山制药总厂 大环类化合物的晶型及其制备方法和应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109956957B (zh) * 2017-12-22 2021-11-09 广州白云山医药集团股份有限公司白云山制药总厂 一种咪唑并[1,2-b]哒嗪大环类激酶抑制剂
CN113045587A (zh) * 2019-12-27 2021-06-29 成都倍特药业股份有限公司 一种大环结构化合物的晶型及其制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010085597A1 (en) * 2009-01-23 2010-07-29 Incyte Corporation Macrocyclic compounds and their use as kinase inhibitors
CN110386945A (zh) 2018-04-18 2019-10-29 成都先导药物开发股份有限公司 一种大环类激酶抑制剂
CN113121568A (zh) * 2019-12-31 2021-07-16 成都倍特药业股份有限公司 一种大环结构化合物的盐及其制备方法
CN112174982A (zh) * 2020-09-10 2021-01-05 上海希迈医药科技有限公司 一种洛普替尼晶型及其制备方法
CN113754657A (zh) * 2021-09-22 2021-12-07 广州白云山医药集团股份有限公司白云山制药总厂 大环类化合物的晶型及其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"China Pharmacopoeia", 2020, pages: 9103

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