WO2024002127A1 - Anti-tumor paclitaxel compound - Google Patents

Anti-tumor paclitaxel compound Download PDF

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Publication number
WO2024002127A1
WO2024002127A1 PCT/CN2023/103044 CN2023103044W WO2024002127A1 WO 2024002127 A1 WO2024002127 A1 WO 2024002127A1 CN 2023103044 W CN2023103044 W CN 2023103044W WO 2024002127 A1 WO2024002127 A1 WO 2024002127A1
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crystal form
hydrate
crystal
docetaxel
acetyl
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PCT/CN2023/103044
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French (fr)
Chinese (zh)
Inventor
曲凡志
张晓君
白洁
刘芳茹
邵永
赵媛媛
陈东健
王雪菲
董玥
刘海瑞
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石药集团中奇制药技术（石家庄）有限公司
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Publication of WO2024002127A1 publication Critical patent/WO2024002127A1/en

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and specifically relates to a paclitaxel anti-tumor compound and its preparation method and use.
  • Docetaxel is semi-synthetically produced from the non-cytotoxic precursor 10-deacetylbaccatin III extracted from the needles of yew. It is a paclitaxel analogue that acts on cell microtubules and can promote tubulin. Polymerization, while inhibiting microtubule depolymerization, causing cells to stagnate in the G2/M phase, inhibiting mitosis, thereby killing tumor cells. It has stronger anti-tumor activity than paclitaxel.
  • the inventor of the present application conducted systematic research on 2'-acetyl docetaxel as a drug for the first time. After a lot of experiments and screening, we finally obtained an API product with stable quality, low hygroscopicity and suitable for making pharmaceuticals.
  • the invention provides a hydrate of 2'-acetyl docetaxel:
  • n is 0.5-3, preferably 1-2.
  • the hydrate is sesquihydrate.
  • the present invention provides a crystalline form A of 2'-acetyl docetaxel, which uses Cu-K ⁇ radiation and has X-ray powder diffraction expressed at 2 ⁇ angle at 6.0 ⁇ 0.2°, 9.8 ⁇ 0.2°, There are characteristic peaks at 10.4 ⁇ 0.2°, 13.6 ⁇ 0.2°, and 19.0 ⁇ 0.2°.
  • the crystal form A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is 6.0 ⁇ 0.2°, 9.8 ⁇ 0.2°, 10.4 ⁇ 0.2°, 13.6 ⁇ 0.2°, 15.2 ⁇ 0.2°, 16.2 There are characteristic peaks at ⁇ 0.2° and 19.0 ⁇ 0.2°.
  • the crystal form A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is 6.0 ⁇ 0.2°, 9.8 ⁇ 0.2°, 10.4 ⁇ 0.2°, 11.4 ⁇ 0.2°, 12.4 ⁇ 0.2°, There are characteristic peaks at 13.6 ⁇ 0.2°, 15.2 ⁇ 0.2°, 16.2 ⁇ 0.2°, and 19.0 ⁇ 0.2°.
  • the crystalline Form A has an X-ray powder diffraction pattern substantially as shown in Figure 3.
  • the differential scanning calorimetry curve of the crystal form A has an endothermic peak starting point at 169.0 ⁇ 5°C.
  • the crystal form A has a DSC spectrum basically as shown in Figure 4.
  • the crystal form A has a TGA spectrum substantially as shown in Figure 5.
  • the crystal form A of 2'-acetyl docetaxel is preferably a hydrate, more preferably a sesquihydrate.
  • the present invention also provides a crystalline form B of 2'-acetyl docetaxel, which uses Cu-K ⁇ radiation and has X-ray powder diffraction expressed at a 2 ⁇ angle of 5.9 ⁇ 0.2° and 10.0 ⁇ 0.2°. There are characteristic peaks at , 10.4 ⁇ 0.2°, 13.6 ⁇ 0.2°, and 18.9 ⁇ 0.2°.
  • the crystal form B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is 5.9 ⁇ 0.2°, 10.0 ⁇ 0.2°, 10.4 ⁇ 0.2°, 13.6 ⁇ 0.2°, 16.1 ⁇ 0.2°, 18.9 There are characteristic peaks at ⁇ 0.2° and 19.6 ⁇ 0.2°.
  • the crystalline Form B has an X-ray powder diffraction pattern substantially as shown in Figure 8.
  • the present invention also provides a pharmaceutical composition, which comprises the aforementioned crystal form or hydrate of 2'-acetyl docetaxel.
  • the pharmaceutical composition of the present invention contains the aforementioned crystal form or hydrate of 2'-acetyl docetaxel and pharmaceutically acceptable excipients.
  • the present invention also provides the use of the crystal form or hydrate of 2'-acetyl docetaxel in the preparation of drugs for treating tumor diseases.
  • the present invention provides crystalline forms or hydrates of 2'-acetyl docetaxel for use in the treatment of neoplastic diseases.
  • the present invention provides methods of treating a neoplastic disease comprising administering a therapeutically effective amount of a crystalline form or hydrate of 2'-acetyl docetaxel.
  • the compounds disclosed herein and their crystalline forms may be administered in admixture with pharmaceutically acceptable excipients well known in the art. Specifically, as a drug for systemic administration, it may be formulated in a dosage form suitable for oral or parenteral administration.
  • crystalline forms of 2'-acetyl docetaxel can be co-administered with other therapeutic agents. Therefore, another aspect of the present invention provides a combination pharmaceutical composition for treating tumor diseases, which includes a therapeutically effective amount of a crystalline form of 2'-acetyl docetaxel and one or more other therapeutic agents.
  • the crystal form of 2'-acetyl docetaxel can be combined with other treatment methods, including but not limited to radiotherapy.
  • the present invention provides hydrates and crystal forms of 2'-acetyl docetaxel.
  • the inventor unexpectedly discovered that the hydrate or preferred crystal form A of 2'-acetyl docetaxel has excellent properties, such as stable physical and chemical stability, extremely low hygroscopicity, excellent mechanical stability, etc. . In particular, it is superior to other crystalline forms or amorphous forms in terms of hygroscopicity and stability, and has better pharmaceutical properties and clinical application value.
  • Figure 1 shows the XRPD spectrum of the amorphous form of 2'-acetyl docetaxel.
  • Figure 2 is a DVS diagram of the amorphous form of 2'-acetyl docetaxel.
  • Figure 3 is the XRPD spectrum of 2'-acetyl docetaxel crystal form A.
  • Figure 4 is the DSC spectrum of 2'-acetyl docetaxel crystal form A.
  • Figure 5 is the TGA spectrum of 2'-acetyl docetaxel crystal form A.
  • Figure 6 is a schematic diagram of the asymmetric unit of the single crystal structure of 2'-acetyl docetaxel form A.
  • Figure 7 is an XRPD overlay of the single crystal structure XRPD and the compound starting material crystal form A.
  • Figure 8 is the XRPD spectrum of 2'-acetyl docetaxel crystal form B.
  • Figure 9 is the DVS diagram of Form A.
  • Figure 10 shows the XRPD patterns of Form A before and after DVS testing.
  • Figure 11 shows the XRPD images of Form A before and after tableting and manual grinding.
  • DSC and TGA testing project instrument name and model TA Discovery 5500 TGA thermogravimetric analyzer and TA Discovery 2500 DSC differential scanning calorimeter.
  • the measurement parameters are as follows:
  • XRPD testing project instrument name and model PANalytical X'Pert3 and Empyrean X-ray powder diffraction analyzer.
  • the test parameters are as follows:
  • Dynamic moisture adsorption (DVS) curves were collected on the DVS Intrinsic of SMS (Surface Measurement Systems). Relative humidity at 25°C was corrected using the deliquescent points of LiCl, Mg( NO3 ) 2 and KCl. The test parameters are as follows:
  • FIG. 1 shows the obtained 2'-acetyl docetaxel.
  • Figure 2 shows the DVS diagram of this amorphous form.
  • the amorphous sample increased moisture by 4.0% to 4.6% under the conditions of 25°C/80%RH, indicating that it has hygroscopicity;
  • the XRPD results after the DVS test showed that a weak diffraction peak (similar to Crystalline form A is more consistent), indicating that there is a tendency to transform from amorphous to crystalline form A.
  • the XRPD detection results of the crystal form A are shown in Figure 3.
  • the diffraction peak data of XRPD are listed in Table 1. Its DSC, TGA The detection results are shown in Figures 4 and 5.
  • the DSC results of this crystal form show that there is an endothermic peak at 169.0°C (starting temperature).
  • Table 1 XRPD diffraction peak data of Form A
  • FIG. 6 is a schematic diagram of the asymmetric unit of the single crystal structure of Form A.
  • the asymmetric unit of the crystal structure contains one molecule and a total of about 1.5 crystal water molecules, which indicates that the single crystal is a hydrate crystal form.
  • Figure 7 shows the XRPD overlay of the calculated XRPD of the single crystal structure and the crystal form A of the starting material of the compound, and they are consistent.
  • the crystal form A obtained in Example 2 was heated to 150°C under the protection of N2 to obtain the crystal form B.
  • the XRPD detection results of the crystal form B are shown in Figure 8. Maintain N2 protection and cool to 30°C, crystal form B remains unchanged; crystal form B is exposed to room temperature humidity ( ⁇ 20% RH), and it is found that it immediately transforms back to crystal form A after testing.
  • the obtained crystal form B absorbs water and transforms back to crystal form A under humid conditions in the room, and cannot exist stably.
  • the hygroscopicity of Form A was evaluated by the dynamic moisture adsorption test (DVS) between 0% RH and 95% RH at 25°C.
  • the DVS results and the XRPD comparison results of the samples after testing are shown in Figures 9 and 10.
  • the evaluation results show that the hygroscopic weight gain of crystalline form A is 1.8% under the conditions of 25°C/80%RH, indicating that it is only slightly hygroscopic, which is significantly lower than the hygroscopicity of the amorphous form measured under the same conditions in Example 1 ( 4.0% ⁇ 4.6%).
  • no obvious plateau of changes in water absorption was observed during the adsorption and desorption processes.
  • the XRPD results showed that the crystal form of Form A did not change before and after the DVS test.
  • crystal form A was tableted (350MPa pressure) and manually ground. The samples after tableting and manual grinding were subjected to XRPD testing. The results are shown in Figure 11. After tableting under a pressure of 350MPa and after manual grinding for 3 minutes, the crystalline form A did not undergo crystalline transformation.

Abstract

Provided is an anti-tumor paclitaxel compound. Specifically, provided are a hydrate and a crystal form of 2'-acetyl docetaxel. The hydrate or the preferred crystal form A of 2'-acetyl docetaxel is superior to other crystal forms or amorphous forms in terms of solid stability, hygroscopicity, and mechanical stability, and has better druggability and clinical application values.

Description

紫杉醇类抗肿瘤化合物Paclitaxel antitumor compounds 技术领域Technical field
本发明属于药物化学技术领域，具体涉及到一种紫杉醇类抗肿瘤化合物及其制备方法和用途。The invention belongs to the technical field of medicinal chemistry, and specifically relates to a paclitaxel anti-tumor compound and its preparation method and use.
背景技术Background technique
多西他赛是由红豆杉的针叶中提取的非细胞毒性前体10-去乙酰浆果赤霉素III半合成生产所得，是紫杉醇类似物，其作用于细胞微管，可促进微管蛋白聚合，同时抑制微管解聚，使细胞停滞于G2/M期，抑制有丝分裂，从而杀死肿瘤细胞，其较紫杉醇有更强的抗肿瘤活性。2'-乙酰基多西他赛(CAS：151509-27-2)，作为多西他赛的合成中间体或合成副产物，最早公开在期刊文献中(Tetrahedron(1993),49(30),6533-44，作者Dubois,Joelle等)，其结构如下所示。
Docetaxel is semi-synthetically produced from the non-cytotoxic precursor 10-deacetylbaccatin III extracted from the needles of yew. It is a paclitaxel analogue that acts on cell microtubules and can promote tubulin. Polymerization, while inhibiting microtubule depolymerization, causing cells to stagnate in the G2/M phase, inhibiting mitosis, thereby killing tumor cells. It has stronger anti-tumor activity than paclitaxel. 2'-Acetyl docetaxel (CAS: 151509-27-2), as a synthetic intermediate or synthetic by-product of docetaxel, was first published in journal literature (Tetrahedron (1993), 49(30), 6533-44, author Dubois, Joelle, etc.), its structure is as follows.
发明内容Contents of the invention
本申请发明人首次对2'-乙酰基多西他赛作为药物进行了系统研究。经过大量的实验和筛选，终于获得一种质量稳定、吸湿性低、适于成药的原料药产品。The inventor of the present application conducted systematic research on 2'-acetyl docetaxel as a drug for the first time. After a lot of experiments and screening, we finally obtained an API product with stable quality, low hygroscopicity and suitable for making pharmaceuticals.
因此，一方面，本发明提供一种2'-乙酰基多西他赛的水合物：
Therefore, in one aspect, the invention provides a hydrate of 2'-acetyl docetaxel:
其中，n为0.5～3，优选为1～2。Among them, n is 0.5-3, preferably 1-2.
优选地，所述水合物为倍半水合物。Preferably, the hydrate is sesquihydrate.
另一方面，本发明提供一种2'-乙酰基多西他赛的晶型A，其使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射在6.0±0.2°、9.8±0.2°、10.4±0.2°、13.6±0.2°、19.0±0.2°处具有特征峰。On the other hand, the present invention provides a crystalline form A of 2'-acetyl docetaxel, which uses Cu-Kα radiation and has X-ray powder diffraction expressed at 2θ angle at 6.0±0.2°, 9.8±0.2°, There are characteristic peaks at 10.4±0.2°, 13.6±0.2°, and 19.0±0.2°.
优选地，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射在6.0±0.2°、9.8±0.2°、10.4±0.2°、13.6±0.2°、15.2±0.2°、16.2±0.2°、19.0±0.2°处具有特征峰。Preferably, the crystal form A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angle is 6.0±0.2°, 9.8±0.2°, 10.4±0.2°, 13.6±0.2°, 15.2±0.2°, 16.2 There are characteristic peaks at ±0.2° and 19.0±0.2°.
还优选地，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射在6.0±0.2°、9.8±0.2°、10.4±0.2°、11.4±0.2°、12.4±0.2°、13.6±0.2°、15.2±0.2°、16.2±0.2°、19.0±0.2°处具有特征峰。It is also preferred that the crystal form A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angle is 6.0±0.2°, 9.8±0.2°, 10.4±0.2°, 11.4±0.2°, 12.4±0.2°, There are characteristic peaks at 13.6±0.2°, 15.2±0.2°, 16.2±0.2°, and 19.0±0.2°.
进一步优选地，所述晶型A具有基本上如图3所示的X射线粉末衍射谱图。Further preferably, the crystalline Form A has an X-ray powder diffraction pattern substantially as shown in Figure 3.
本发明的一些方案中，所述晶型A，其差示扫描量热曲线在169.0±5℃有一个吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve of the crystal form A has an endothermic peak starting point at 169.0±5°C.
本发明的一些方案中，所述晶型A具有基本如图4所示的DSC谱图。In some aspects of the present invention, the crystal form A has a DSC spectrum basically as shown in Figure 4.
本发明的一些方案中，所述晶型A具有基本如图5所示的TGA谱图。In some aspects of the present invention, the crystal form A has a TGA spectrum substantially as shown in Figure 5.
根据本发明，2'-乙酰基多西他赛的晶型A优选为水合物，更优选为倍半水合物。According to the present invention, the crystal form A of 2'-acetyl docetaxel is preferably a hydrate, more preferably a sesquihydrate.
另一方面，本发明还提供一种2'-乙酰基多西他赛的晶型B，其使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射在5.9±0.2°、10.0±0.2°、10.4±0.2°、13.6±0.2°、18.9±0.2°处具有特征峰。On the other hand, the present invention also provides a crystalline form B of 2'-acetyl docetaxel, which uses Cu-Kα radiation and has X-ray powder diffraction expressed at a 2θ angle of 5.9±0.2° and 10.0±0.2°. There are characteristic peaks at , 10.4±0.2°, 13.6±0.2°, and 18.9±0.2°.
优选地，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射在5.9±0.2°、10.0±0.2°、10.4±0.2°、13.6±0.2°、16.1±0.2°、18.9±0.2°、19.6±0.2°处具有特征峰。Preferably, the crystal form B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angle is 5.9±0.2°, 10.0±0.2°, 10.4±0.2°, 13.6±0.2°, 16.1±0.2°, 18.9 There are characteristic peaks at ±0.2° and 19.6±0.2°.
进一步优选地，所述晶型B具有基本上如图8所示的X射线粉末衍射谱图。Further preferably, the crystalline Form B has an X-ray powder diffraction pattern substantially as shown in Figure 8.
又一方面，本发明还提供一种药物组合物，所述组合物包含前述2'-乙酰基多西他赛的晶型或水合物。In another aspect, the present invention also provides a pharmaceutical composition, which comprises the aforementioned crystal form or hydrate of 2'-acetyl docetaxel.
优选地，本发明所述的药物组合物包含前述2'-乙酰基多西他赛的晶型或水合物和药学上可接受的辅料。Preferably, the pharmaceutical composition of the present invention contains the aforementioned crystal form or hydrate of 2'-acetyl docetaxel and pharmaceutically acceptable excipients.
又一方面，本发明还提供2'-乙酰基多西他赛的晶型或水合物在制备治疗肿瘤疾病的药物中的用途。在其它实施方式中，本发明提供了在治疗肿瘤疾病中应用的2'-乙酰基多西他赛的晶型或水合物。在其它实施方式中，本发明提供了治疗肿瘤疾病的方法，所述方法包括施用治疗有效量的2'-乙酰基多西他赛的晶型或水合物。 In another aspect, the present invention also provides the use of the crystal form or hydrate of 2'-acetyl docetaxel in the preparation of drugs for treating tumor diseases. In other embodiments, the present invention provides crystalline forms or hydrates of 2'-acetyl docetaxel for use in the treatment of neoplastic diseases. In other embodiments, the present invention provides methods of treating a neoplastic disease comprising administering a therapeutically effective amount of a crystalline form or hydrate of 2'-acetyl docetaxel.
本领域技术人员容易理解，本文公开的化合物及其晶型的施用可以与本领域熟知的药学上可接受的赋形剂混合。具体而言，作为全身施用的药物，其可以配制成适合口腔或肠胃外给药剂型。Those skilled in the art will readily appreciate that the compounds disclosed herein and their crystalline forms may be administered in admixture with pharmaceutically acceptable excipients well known in the art. Specifically, as a drug for systemic administration, it may be formulated in a dosage form suitable for oral or parenteral administration.
为了治疗肿瘤疾病，2'-乙酰基多西他赛的晶型可以与其它治疗剂共同给药。因此，本发明的另一方面提供一种用于治疗肿瘤疾病的联用药物组合物，其包括治疗有效量的2'-乙酰基多西他赛的晶型和一种或多种其它治疗剂。为了治疗肿瘤疾病，2'-乙酰基多西他赛的晶型可以联合其它治疗手段共同进行治疗，所述其它治疗手段包括但不限于放射性治疗。For the treatment of neoplastic diseases, crystalline forms of 2'-acetyl docetaxel can be co-administered with other therapeutic agents. Therefore, another aspect of the present invention provides a combination pharmaceutical composition for treating tumor diseases, which includes a therapeutically effective amount of a crystalline form of 2'-acetyl docetaxel and one or more other therapeutic agents. . In order to treat tumor diseases, the crystal form of 2'-acetyl docetaxel can be combined with other treatment methods, including but not limited to radiotherapy.
有益效果beneficial effects
本发明提供了2'-乙酰基多西他赛的水合物和晶型。发明人意外地发现，所述2'-乙酰基多西他赛的水合物或优选晶型A具有优良性质，如稳定的物理化学稳定性、极低的引湿性、优异的机械力稳定性等。尤其是其在引湿性和稳定性方面优于其它晶型形态或无定型态，具有更好的成药性及临床应用价值。The present invention provides hydrates and crystal forms of 2'-acetyl docetaxel. The inventor unexpectedly discovered that the hydrate or preferred crystal form A of 2'-acetyl docetaxel has excellent properties, such as stable physical and chemical stability, extremely low hygroscopicity, excellent mechanical stability, etc. . In particular, it is superior to other crystalline forms or amorphous forms in terms of hygroscopicity and stability, and has better pharmaceutical properties and clinical application value.
附图说明Description of drawings
图1为2'-乙酰基多西他赛无定型形式的XRPD谱图。Figure 1 shows the XRPD spectrum of the amorphous form of 2'-acetyl docetaxel.
图2为2'-乙酰基多西他赛无定形形式的DVS图。Figure 2 is a DVS diagram of the amorphous form of 2'-acetyl docetaxel.
图3为2'-乙酰基多西他赛晶型A的XRPD谱图。Figure 3 is the XRPD spectrum of 2'-acetyl docetaxel crystal form A.
图4为2'-乙酰基多西他赛晶型A的DSC谱图。Figure 4 is the DSC spectrum of 2'-acetyl docetaxel crystal form A.
图5为2'-乙酰基多西他赛晶型A的TGA谱图。Figure 5 is the TGA spectrum of 2'-acetyl docetaxel crystal form A.
图6为2'-乙酰基多西他赛晶型A单晶结构的不对称单元示意图。Figure 6 is a schematic diagram of the asymmetric unit of the single crystal structure of 2'-acetyl docetaxel form A.
图7为单晶结构XRPD与化合物起始物料晶型A的XRPD叠图。Figure 7 is an XRPD overlay of the single crystal structure XRPD and the compound starting material crystal form A.
图8为2'-乙酰基多西他赛晶型B的XRPD谱图。Figure 8 is the XRPD spectrum of 2'-acetyl docetaxel crystal form B.
图9为晶型A的DVS图。Figure 9 is the DVS diagram of Form A.
图10为晶型A在DVS测试前后的XRPD图。Figure 10 shows the XRPD patterns of Form A before and after DVS testing.
图11为晶型A在压片及手动研磨前后的XRPD图。Figure 11 shows the XRPD images of Form A before and after tableting and manual grinding.
具体实施方式Detailed ways
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。 The technical solution of the present invention will be further described in detail below with reference to specific embodiments. The following examples are only illustrative and explain the present invention and should not be construed as limiting the scope of the present invention. All technologies implemented based on the above contents of the present invention are covered by the scope of protection intended by the present invention.
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.
DSC、TGA检测项目仪器名称及型号：TA Discovery 5500 TGA热重分析仪和TA Discovery 2500 DSC差示扫描量热仪。测定参数如下：
DSC and TGA testing project instrument name and model: TA Discovery 5500 TGA thermogravimetric analyzer and TA Discovery 2500 DSC differential scanning calorimeter. The measurement parameters are as follows:
XRPD检测项目仪器名称及型号：帕纳科X’Pert3和Empyrean X射线粉末衍射分析仪。测试参数如下：
XRPD testing project instrument name and model: PANalytical X'Pert3 and Empyrean X-ray powder diffraction analyzer. The test parameters are as follows:
动态水分吸附(DVS)曲线在SMS(Surface Measurement Systems)的DVS Intrinsic上采集。在25℃时的相对湿度用LiCl、Mg(NO3)2和KCl的潮解点校正。测试参数如下：
Dynamic moisture adsorption (DVS) curves were collected on the DVS Intrinsic of SMS (Surface Measurement Systems). Relative humidity at 25°C was corrected using the deliquescent points of LiCl, Mg( NO3 ) 2 and KCl. The test parameters are as follows:
单晶衍射项目仪器名称及型号：Bruker D8 VENTURE型单晶衍射仪，测试条件如下：
Single crystal diffraction project instrument name and model: Bruker D8 VENTURE single crystal diffractometer. The test conditions are as follows:
实施例1.2'-乙酰基多西他赛的制备Example 1. Preparation of 2'-acetyl docetaxel
根据现有技术专利CN102050804A中实施例1中步骤1-3的方法得到2'-乙酰基多西他赛。2'-acetyl docetaxel was obtained according to the method of steps 1-3 in Example 1 of the prior art patent CN102050804A.
1H-NMR 600MHz(CDCl3)：δ1.119(s，3H)，1.227(s，3H)，1.332(s，9H)，1.744(s，3H)，1.831-1.874(m，1H)，1.935(s，3H)，2.078(s，3H)，2.152-2.328(m，2H)，2.433(s，3H)，2.550-2.600(m，1H)，3.919-3.929(m，1H)，4.190-4.204(m，1H)，4.252-4.281(m，1H)，4.312-4.327(m，1H)，4.955-4.970(m，1H)，5.219(s，1H)，5.366(s，1H)，5.477-5.490(m，2H)，5.676-5.687(m，1H)，6.242(s，1H)，7.281-7.324(m，3H)，7.380-7.404(m，2H)，7.490-7.514(m，2H)，7.593-7.617(m，1H)，8.102-8.115(m，2H)；MS m/z 850.45([M+H]+)。 1 H-NMR 600MHz (CDCl 3 ): δ1.119 (s, 3H), 1.227 (s, 3H), 1.332 (s, 9H), 1.744 (s, 3H), 1.831-1.874 (m, 1H), 1.935 (s, 3H), 2.078 (s, 3H), 2.152-2.328 (m, 2H), 2.433 (s, 3H), 2.550-2.600 (m, 1H), 3.919-3.929 (m, 1H), 4.190-4.204 (m, 1H), 4.252-4.281 (m, 1H), 4.312-4.327 (m, 1H), 4.955-4.970 (m, 1H), 5.219 (s, 1H), 5.366 (s, 1H), 5.477-5.490 (m, 2H), 5.676-5.687 (m, 1H), 6.242 (s, 1H), 7.281-7.324 (m, 3H), 7.380-7.404 (m, 2H), 7.490-7.514 (m, 2H), 7.593 -7.617 (m, 1H), 8.102-8.115 (m, 2H); MS m/z 850.45 ([M+H]+).
获得的2'-乙酰基多西他赛经检测为无定型形式，XRPD检测结果如图1所示。图2显示了该无定形形式的DVS图。如图2所示，无定形样品在25℃/80％RH条件下吸湿增重4.0％～4.6％，表明其有引湿性；在DVS测试后的XRPD结果显示可观察到微弱的衍射峰(与晶型A较吻合)，表明无定形存在向晶型A转变的趋势。The obtained 2'-acetyl docetaxel was detected as an amorphous form, and the XRPD detection results are shown in Figure 1. Figure 2 shows the DVS diagram of this amorphous form. As shown in Figure 2, the amorphous sample increased moisture by 4.0% to 4.6% under the conditions of 25°C/80%RH, indicating that it has hygroscopicity; the XRPD results after the DVS test showed that a weak diffraction peak (similar to Crystalline form A is more consistent), indicating that there is a tendency to transform from amorphous to crystalline form A.
实施例2至5.2'-乙酰基多西他赛晶型A的制备Examples 2 to 5. Preparation of 2'-acetyl docetaxel crystal form A
称取约20mg每份的2'-乙酰基多西他赛于3mL小瓶中，加入1.0～2.0mL如下所示的溶剂，在50℃下搅拌过夜后过滤(孔径0.45μm的PTFE滤膜)取滤液，将所得滤液放置在生化培养箱中，以0.1℃/分钟的降温速度从50℃降温至5℃，缓慢降温后经XRPD、TGA和DSC检测得到一种晶型A。
Weigh approximately 20 mg of each portion of 2'-acetyl docetaxel into a 3 mL vial, add 1.0 to 2.0 mL of the solvent shown below, stir at 50°C overnight, and then filter (PTFE filter membrane with a pore size of 0.45 μm) to take the The filtrate was placed in a biochemical incubator and cooled from 50°C to 5°C at a cooling rate of 0.1°C/min. After slow cooling, a crystal form A was detected by XRPD, TGA and DSC.
所述晶型A的XRPD检测结果如图3所示，XRPD的衍射峰数据列于表1，其DSC、TGA 检测结果如图4、5所示。由该晶型的DSC结果所示，在169.0℃(起始温度)处有一个吸热峰。The XRPD detection results of the crystal form A are shown in Figure 3. The diffraction peak data of XRPD are listed in Table 1. Its DSC, TGA The detection results are shown in Figures 4 and 5. The DSC results of this crystal form show that there is an endothermic peak at 169.0°C (starting temperature).
表1：晶型A的XRPD衍射峰数据
Table 1: XRPD diffraction peak data of Form A
值得注意的是，当使用实施例2-5相同的方法，仅仅将溶剂换成甲基叔丁基醚或四氢呋喃/水(体积比1:1)，得到的却是2'-乙酰基多西他赛无定型形态。It is worth noting that when using the same method as Example 2-5, only changing the solvent to methyl tert-butyl ether or tetrahydrofuran/water (volume ratio 1:1), what is obtained is 2'-acetyl doxyl. His game has no definite form.
从上述实施例获得的晶型A培养得到的片状晶体样品中切割并挑选出衍射质量合适的一颗单晶，对其进行单晶X-射线衍射表征并解析其晶体结构。单晶X-射线衍射表征结果显示：该晶体属正交晶系，P212121空间群，其单胞参数为：{ α＝90°,β＝90°,γ＝90°,}。图6是晶型A单晶结构的不对称单元示意图，该晶体结构的不对称单元中包含有一个分子以及总数约为1.5个的结晶水分子，这表明该单晶为水合物晶型。图7为单晶结构计算XRPD与化合物起始物料晶型A的XRPD叠图，两者一致。Cut and select a single crystal with suitable diffraction quality from the flake crystal sample obtained by culturing the crystal form A obtained in the above example, perform single crystal X-ray diffraction characterization on it and analyze its crystal structure. The single crystal X-ray diffraction characterization results show that the crystal belongs to the orthorhombic crystal system, P2 1 2 1 2 1 space group, and its unit cell parameters are: { α＝90°, β＝90°, γ＝90°, }. Figure 6 is a schematic diagram of the asymmetric unit of the single crystal structure of Form A. The asymmetric unit of the crystal structure contains one molecule and a total of about 1.5 crystal water molecules, which indicates that the single crystal is a hydrate crystal form. Figure 7 shows the XRPD overlay of the calculated XRPD of the single crystal structure and the crystal form A of the starting material of the compound, and they are consistent.
实施例6.2'-乙酰基多西他赛晶型B的制备Example 6. Preparation of 2'-acetyl docetaxel crystal form B
将实施例2得到的晶型A在N2保护下加热至150℃，获得晶型B。所述晶型B的XRPD检测结果如图8所示。保持N2保护并降温至30℃，晶型B保持不变；将晶型B暴露于室温室湿(～20％RH)下，测试后发现其立刻即转变回晶型A。获得的晶型B在室湿条件下吸水转变回晶型A，不能稳定存在。The crystal form A obtained in Example 2 was heated to 150°C under the protection of N2 to obtain the crystal form B. The XRPD detection results of the crystal form B are shown in Figure 8. Maintain N2 protection and cool to 30°C, crystal form B remains unchanged; crystal form B is exposed to room temperature humidity (~20% RH), and it is found that it immediately transforms back to crystal form A after testing. The obtained crystal form B absorbs water and transforms back to crystal form A under humid conditions in the room, and cannot exist stably.
测试例1.固态稳定性 Test example 1. Solid state stability
称取适量晶型A样品，设置在60℃/闭口/1天、25℃/60％RH/敞口/1周和40℃/75％RH/敞口/1周条件下的稳定性实验。将不同条件下的固体样品，分别通过XRPD测试晶型评估物理稳定性，UPLC测试纯度评估化学稳定性。晶型A的物理稳定性评估结果汇总于表2中，化学稳定性评估结果汇总于表3中。固态稳定性结果表明，晶型A在评估条件下放置后均未发生晶型转变或UPLC纯度的明显降低，表明晶型A在评估条件下具有较好的物理和化学稳定性。Weigh an appropriate amount of Form A sample and set up stability experiments under the conditions of 60°C/closed/1 day, 25°C/60%RH/open/1 week, and 40°C/75%RH/open/1 week. The solid samples under different conditions were tested by XRPD to test the crystal form to evaluate the physical stability, and UPLC to test the purity to evaluate the chemical stability. The physical stability evaluation results of Form A are summarized in Table 2, and the chemical stability evaluation results are summarized in Table 3. The solid-state stability results show that Form A did not undergo crystalline transformation or significant decrease in UPLC purity after being placed under the evaluation conditions, indicating that Form A has good physical and chemical stability under the evaluation conditions.
表2晶型A的固态稳定性评估结果汇总
Table 2 Summary of solid-state stability evaluation results of Form A
表3晶型A固态稳定性评估的UPLC结果
Table 3 UPLC results for solid state stability evaluation of Form A
测试例2.引湿性Test example 2. Hygroscopicity
通过25℃下0％RH～95％RH之间的动态水分吸附试验(DVS)对晶型A的引湿性进行了评估。DVS结果及测试后样品的XRPD对比结果见图9和图10。评估结果表明：晶型A在25℃/80％RH条件下吸湿增重1.8％，表明其仅略有引湿性，明显低于实施例1中在同样条件下测定的无定型形式的吸湿性(4.0％～4.6％)。此外，在吸附及脱附过程中未观察到明显的吸水量变化的平台。XRPD结果显示晶型A在DVS测试前后晶型未发生转变。The hygroscopicity of Form A was evaluated by the dynamic moisture adsorption test (DVS) between 0% RH and 95% RH at 25°C. The DVS results and the XRPD comparison results of the samples after testing are shown in Figures 9 and 10. The evaluation results show that the hygroscopic weight gain of crystalline form A is 1.8% under the conditions of 25°C/80%RH, indicating that it is only slightly hygroscopic, which is significantly lower than the hygroscopicity of the amorphous form measured under the same conditions in Example 1 ( 4.0%～4.6%). In addition, no obvious plateau of changes in water absorption was observed during the adsorption and desorption processes. The XRPD results showed that the crystal form of Form A did not change before and after the DVS test.
测试例3.机械力稳定性Test example 3. Mechanical stability
为评估晶型A的机械力稳定性，对晶型A进行压片(350MPa压力)和手动研磨，对压片及手动研磨后的样品进行XRPD测试。结果如图11所示，在350MPa压强下压片后和手动研磨3分钟后，晶型A未发生晶型转变。 In order to evaluate the mechanical stability of crystal form A, crystal form A was tableted (350MPa pressure) and manually ground. The samples after tableting and manual grinding were subjected to XRPD testing. The results are shown in Figure 11. After tableting under a pressure of 350MPa and after manual grinding for 3 minutes, the crystalline form A did not undergo crystalline transformation.
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。 The embodiments of the present invention have been described above. However, the present invention is not limited to the above-described embodiment. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims (11)

  1. 一种2'-乙酰基多西他赛的水合物：
    A hydrate of 2'-acetyl docetaxel:
    其中，n为0.5～3，优选为1～2。Among them, n is 0.5-3, preferably 1-2.
  2. 根据权利要求1所述的2'-乙酰基多西他赛的水合物，其中，所述水合物为倍半水合物。The hydrate of 2'-acetyl docetaxel according to claim 1, wherein the hydrate is sesquihydrate.
  3. 一种2'-乙酰基多西他赛的晶型A，其中，使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射在6.0±0.2°、9.8±0.2°、10.4±0.2°、13.6±0.2°、19.0±0.2°处具有特征峰。A crystal form A of 2'-acetyl docetaxel, in which X-ray powder diffraction in 2θ angles using Cu-Kα radiation is at 6.0±0.2°, 9.8±0.2°, 10.4±0.2°, 13.6 There are characteristic peaks at ±0.2° and 19.0±0.2°.
  4. 根据权利要求3所述的晶型，其中，所述晶型使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射在6.0±0.2°、9.8±0.2°、10.4±0.2°、13.6±0.2°、15.2±0.2°、16.2±0.2°、19.0±0.2°处具有特征峰。The crystal form according to claim 3, wherein the crystal form uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angle is 6.0±0.2°, 9.8±0.2°, 10.4±0.2°, 13.6±0.2 There are characteristic peaks at 15.2±0.2°, 16.2±0.2°, and 19.0±0.2°.
  5. 根据权利要求3所述的晶型，其中，所述晶型使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射在6.0±0.2°、9.8±0.2°、10.4±0.2°、11.4±0.2°、12.4±0.2°、13.6±0.2°、15.2±0.2°、16.2±0.2°、19.0±0.2°处具有特征峰。The crystal form according to claim 3, wherein the crystal form uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angle is 6.0±0.2°, 9.8±0.2°, 10.4±0.2°, 11.4±0.2 There are characteristic peaks at 12.4±0.2°, 13.6±0.2°, 15.2±0.2°, 16.2±0.2°, and 19.0±0.2°.
  6. 根据权利要求3-5中任一项所述的晶型，其中，所述晶型具有基本上如图3所示的X射线粉末衍射谱图。The crystalline form according to any one of claims 3-5, wherein the crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure 3.
  7. 根据权利要求3-6中任一项所述的晶型，其中，所述晶型的差示扫描量热曲线在169.0±5℃有一个吸热峰的起始点。The crystal form according to any one of claims 3 to 6, wherein the differential scanning calorimetry curve of the crystal form has a starting point of an endothermic peak at 169.0±5°C.
  8. 根据权利要求3-7中任一项所述的晶型，其中，所述晶型具有基本如图4所示的DSC谱图。The crystalline form according to any one of claims 3-7, wherein the crystalline form has a DSC spectrum substantially as shown in Figure 4.
  9. 根据权利要求3-8中任一项所述的晶型，其中，所述晶型具有基本如图5所示的TGA谱图。The crystal form according to any one of claims 3-8, wherein the crystal form has a TGA spectrum substantially as shown in Figure 5.
  10. 根据权利要求3-9中任一项所述的晶型，其中，所述晶型为水合物，优选为倍半水合物。 The crystal form according to any one of claims 3 to 9, wherein the crystal form is a hydrate, preferably a sesquihydrate.
  11. 一种药物组合物，其包含权利要求1-2中任一项所述的水合物或权利要求3-10中任一项所述的晶型。 A pharmaceutical composition comprising the hydrate described in any one of claims 1-2 or the crystal form described in any one of claims 3-10.
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