WO2022016836A1 - K-5a2化合物的晶型及其制备方法和应用 - Google Patents

K-5a2化合物的晶型及其制备方法和应用 Download PDF

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WO2022016836A1
WO2022016836A1 PCT/CN2021/072450 CN2021072450W WO2022016836A1 WO 2022016836 A1 WO2022016836 A1 WO 2022016836A1 CN 2021072450 W CN2021072450 W CN 2021072450W WO 2022016836 A1 WO2022016836 A1 WO 2022016836A1
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crystal form
compound
preparation
stirring
purified water
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刘新泳
郑家晴
张涛
孔令金
杨学谦
刘印
翟民
王孟
郑亮
张铮
林蒙
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SHANDONG QIDU PHARMACEUTICAL CO Ltd
Shandong University
Shandong Qidu Pharmaceutical Co Ltd
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Shandong University
Shandong Qidu Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the invention relates to the field of chemical medicine, in particular to a crystal form of a K-5a2 compound and a preparation method and application thereof.
  • AIDS Abundred Immune Deficiency Syndrome, HIV
  • AIDS Human Immunodeficiency Virus Type 1
  • HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors
  • NNRTIs are an important part of HAART therapy. These drugs have the advantages of high efficiency, low toxicity and strong specificity. However, the defects of easy drug resistance lead to the rapid loss of these drugs. Therefore, the development of novel, high-efficiency, low-toxicity, and broad-spectrum anti-drug resistance NNRTIs is one of the hotspots in current anti-HIV drug research.
  • Diarylpyrimidine is a typical class of HIV-1 NNRTIs, which have strong anti-HIV activity and also have a good inhibitory effect on drug-resistant mutant strains.
  • Etravirine and Rilpivirine are already on the market, and Dapivirine (TMC120) is also in the process of clinical research.
  • TMC120 Dapivirine
  • these compounds have poor water solubility and low oral bioavailability. Therefore, further modification of such chemical structures is of great significance for the discovery of new anti-HIV drugs with broad-spectrum, high efficiency, good bioavailability and independent intellectual property rights. .
  • K-5a2 belongs to the non-nucleoside reverse transcriptase inhibitor candidates for the treatment of AIDS.
  • K-5a2 is a thieno[3,2-d]pyrimidine derivative.
  • the activity of compound K-5a2 is particularly outstanding. Its EC50 value against HIV-1 wild strain is 1.4 nM, which is 177 times that of the first-generation drug nevirapine and 2.8 times that of the latest generation drug etravirine.
  • Compound K-5a2 also showed extremely high safety, and its selectivity index for HIV-1 wild strain was as high as 15910, which was much higher than that of the marketed drugs.
  • the structure of K-5a2 is shown in formula (I):
  • Crystal form is an important factor affecting the quality of a drug. Different crystal forms of the same drug may have great differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, etc. Therefore, in order to obtain an effective crystal form, a comprehensive investigation of the crystallization behavior of K-5a2 is required to obtain a crystal form that meets the production requirements.
  • the purpose of the present invention is to provide a crystal form of the K-5a2 compound, the crystal form has good stability and is conducive to the storage of the bulk drug and the development of preparations; the crystal form with good stability can effectively avoid The phenomenon of inversion during formulation development and the effect of bioavailability due to crystal form transformation.
  • the present invention also provides a preparation method and application thereof, with simple process and low cost.
  • the crystalline form of the K-5a2 compound of the present invention has an X-ray powder diffraction pattern at 2 ⁇ values of 4.3° ⁇ 0.2°, 11.2° ⁇ 0.2°, 11.6° ⁇ 0.2°, 14.8° ⁇ 0.2°, 15.0° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.2° ⁇ 0.2°, 19.0° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.6° ⁇ 0.2°, 21.8° ⁇ 0.2°, 23.0° ⁇ 0.2°, 23.4° ⁇ 0.2° , 25.5° ⁇ 0.2° have characteristic peaks.
  • the crystal form has exothermic heat at 237°C ⁇ 1°C and 324°C ⁇ 1°C, and significant weight loss at 315°C ⁇ 1°C.
  • the preparation method of the crystal form of the K-5a2 compound of the present invention comprises the following steps:
  • the amount of the dimethyl sulfoxide used is 10 times the volume to weight ratio of the crude K-5a2 compound.
  • the volume-to-weight ratio is volume:weight, L/kg.
  • the volume ratio of the dimethyl sulfoxide: purified water is 1:1-3.
  • the heating and stirring for dissolving is as follows: heating to 50-60° C. for stirring and dissolving.
  • the crystal form of the present invention is used for preparing non-nucleoside reverse transcriptase inhibitors.
  • the crystal form of the present invention has good stability, which is beneficial to the storage of the raw drug and the development of the preparation.
  • the crystal form with good stability can effectively avoid the phenomenon of crystal transformation in the process of formulation development and the influence of bioavailability caused by crystal form transformation.
  • the preparation method of the crystal form of the present invention is easy to operate, suitable for industrial production, all materials are conventional materials, the price is low, and the cost is easy to control, which lays a foundation for the future listing of the drug.
  • Fig. 1 is the XRPD pattern of the K-5a2 compound crystal form of Example 1;
  • Fig. 2 is the TG-DSC chart of the K-5a2 compound crystal form of Example 1;
  • FIG. 3 is the XRPD pattern of the K-5a2 compound crystal form of Example 2.
  • the raw materials used in the examples are all commercially available raw materials.
  • TG-DSC Thermogravimetric Analysis - Differential Scanning Calorimetry.
  • the X-ray powder diffractograms described were collected on a Bruker D8 FOCUS X-ray powder diffractometer.
  • thermogravimetric analysis-differential scanning calorimetry (TG-DSC) graphs were collected on NETZSCH STA 449.
  • the XRPD pattern of the K-5a2 compound crystal form obtained in Example 1 is shown in FIG. 1 .
  • the X-ray powder diffraction data are shown in Table 1.
  • the TG-DSC chart of the K-5a2 compound crystal form obtained in Example 1 is shown in FIG. 2 .
  • Example 2 The crystal form obtained in Example 1 was placed in a high temperature and high humidity environment, and the stability in 10 days, 20 days and 30 days was investigated. The results are shown in Table 2.
  • the XRPD pattern of the K-5a2 compound crystal form obtained in Example 2 is shown in FIG. 2 .
  • the X-ray powder diffraction data are shown in Table 3.
  • the X-ray powder diffraction data of the crystal form obtained in Example 3 has no obvious difference with the data in Table 1 and Table 3, and the powder diffraction pattern has no obvious difference with FIG. 1 .
  • the crystal form prepared by the present invention has good stability, which is beneficial to the storage of the raw drug and the development of the preparation.
  • the crystal form with good stability can effectively avoid the phenomenon of crystal transformation in the process of formulation development and the influence of bioavailability caused by crystal form transformation.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • AIDS & HIV (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及化学医药领域，特别是涉及一种K-5a2化合物的晶型及其制备方法和应用。所述晶型，其X射线粉末衍射图在2θ值为4.3°±0.2°、11.2°±0.2°、11.6°±0.2°、14.8°±0.2°、15.0°±0.2°、15.7°±0.2°、18.2°±0.2°、19.0°±0.2°、20.7°±0.2°、21.6°±0.2°、21.8°±0.2°、23.0°±0.2°、23.4°±0.2°、25.5°±0.2°处具有特征峰。本发明晶型稳定性好，有利于该原料药储存、制剂的开发，稳定性良好的晶型能够有效避免制剂开发过程中转晶现象以及因晶型转变造成生物利用度影响。

Description

K-5a2化合物的晶型及其制备方法和应用 技术领域
本发明涉及化学医药领域，特别是涉及一种K-5a2化合物的晶型及其制备方法和应用。
背景技术
艾滋病(Acquired Immune Deficiency Syndrome,AIDS)目前已经成为危害人类生命健康的重大传染性疾病，其主要病原体是人免疫缺陷病毒1型(Human Immunodeficiency Virus Type1，HIV-1)。尽管高效抗逆转录疗法(Highly Active Antiretroviral Therapy，HAART)的实施显著延长患者的生存时间，但是耐药问题和药物毒副作用以及长期服用药物的费用等问题，迫使研究者研发高效低毒的新型HIV抑制剂。HIV-1非核苷类逆转录酶抑制剂(NNRTIs)是HAART疗法的重要组成部分，该类药物具有高效低毒、特异性强的优点，然而易产生耐药性的缺陷使该类药物迅速丧失临床效价，因此，新型、高效、低毒、广谱抗耐药性的NNRTIs的研发是目前抗HIV药物研究的热点之一。
二芳基嘧啶(diarylpyrimidine,DAPY)类是一类典型的HIV-1NNRTIs，具有较强的抗HIV活性，对耐药突变毒株也有很好的抑制作用。该类药物中依曲韦林(Etravirine)和利匹韦林(Rilpivirine)已经上市，达匹韦林(Dapivirine,TMC120)也正处于临床研究过程中。但该类化合物水溶性较差，口服生物利用度较低，因此，将该类化学结构进行进一步修饰，对发现广谱高效、生物利用度好且具有自主知识产权的新型抗HIV药物具有重大意义。
K-5a2属于治疗艾滋病的非核苷类逆转录酶抑制剂候选物。K-5a2是一种噻吩并[3,2-d]嘧啶衍生物。化合物K-5a2的活性尤为突出，其对HIV-1野生株的EC50值为1.4nM，是第一代上市药物奈韦拉平的177倍，最新一代药物依曲韦林的2.8倍。化合物K-5a2亦表现出了极高的安全性，其对HIV-1野生株的选择性指数高达15910，远远高于上市药物。K-5a2结构如式(I)所示：
Figure PCTCN2021072450-appb-000001
晶型是影响药品质量的重要因素，同一药物的不同晶型在外观、流动性、溶解度、储存 稳定性等理化性质方面可能会存在极大差异，从而对药物的储存转移、应用、稳定性、生物利用度、疗效等产生影响；因此，为了得到有效的晶型，需要对K-5a2的结晶行为进行全面的考察，以得到满足生产要求的晶型。
发明内容
针对现有技术的不足，本发明的目的是提供一种K-5a2化合物的晶型，该晶型稳定性好，有利于该原料药储存、制剂的开发；稳定性良好的晶型能够有效避免制剂开发过程中转晶现象以及因晶型转变造成生物利用度影响。本发明还提供其制备方法和应用，工艺简单，成本低廉。
本发明所述的K-5a2化合物的晶型，其X射线粉末衍射图在2θ值为4.3°±0.2°、11.2°±0.2°、11.6°±0.2°、14.8°±0.2°、15.0°±0.2°、15.7°±0.2°、18.2°±0.2°、19.0°±0.2°、20.7°±0.2°、21.6°±0.2°、21.8°±0.2°、23.0°±0.2°、23.4°±0.2°、25.5°±0.2°处具有特征峰。
所述的晶型在237℃±1℃，324℃±1℃处有放热，在315℃±1℃失重明显。
本发明所述的K-5a2化合物的晶型的制备方法，包括如下步骤：
将K-5a2化合物粗品加入到二甲基亚砜中加热搅拌溶解后，将溶液加入到纯化水中；在20-50℃温度条件下搅拌析晶，离心所得固体经纯化水泡洗后，再次离心，收集固体并干燥后，得K-5a2化合物的晶型。
所述的二甲基亚砜的用量为K-5a2化合物粗品的体积重量比为10倍。体积重量比即体积：重量，L/kg。
所述的二甲基亚砜：纯化水的体积比为1：1-3。
所述的加热搅拌溶解为：加热至50-60℃搅拌溶解。
本发明所述的晶型用于制备非核苷类逆转录酶抑制剂。
与现有技术相比，本发明的有益效果如下：
1、本发明的晶型稳定性好，有利于该原料药储存、制剂的开发。稳定性良好的晶型能够有效避免制剂开发过程中转晶现象以及因晶型转变造成生物利用度影响。
2、本发明晶型的制备方法，易于操作，适合工业化生产，所有物料均为常规物料，价格低，易于成本控制，对未来该药物的上市奠定基础。
附图说明
图1为实施例1的K-5a2化合物晶型的XRPD图；
图2为实施例1的K-5a2化合物晶型的TG-DSC图；
图3为实施例2的K-5a2化合物晶型的XRPD图。
具体实施方式
下面结合实施例对本发明做进一步的说明，但并不用于限制本发明的保护范围。
实施例中所用原料均为市售原料。
本发明中，XRPD、DSC、TGA含义如下：
XRPD：X射线粉末衍射。
TG-DSC：热重分析-差示扫描量热分析。
TGA：热重分析。
所述的X射线粉末衍射图在Bruker D8 FOCUS X射线粉末衍射仪上采集。
所述的热重分析-差示扫描量热分析(TG-DSC)图在NETZSCH STA 449上采集。
实施例1
K-5a2化合物晶型的制备方法：
将1.00kg K-5a2固体粉末加入到20L的反应釜中，加入10L二甲基亚砜，加热到55℃，搅拌至目测全部溶解，过滤除掉不溶性杂质，然后缓慢将滤液加入到20L纯化水中，25℃搅拌1小时，离心所得固体用20L纯化水泡洗，泡洗完毕，再次离心，将离心所得固体鼓风干燥，得到类白色固体粉末0.92kg，产率92.0％，干燥后产品为所要晶型。
实施例1得到的K-5a2化合物晶型的XRPD图如附图1所示。X射线粉末衍射数据见表1。
实施例1得到的K-5a2化合物晶型的TG-DSC图如附图2所示。
表1 K-5a2晶型的X射线粉末衍射数据
2θ d间隔 相对强度％
4.34 20.38 34.74
11.23 7.88 59.14
11.61 7.62 90.35
11.79 7.50 58.64
14.80 5.98 32.76
15.01 5.90 22.50
15.66 5.66 36.72
18.17 4.88 16.22
18.97 4.66 29.84
19.87 4.47 100.00
20.39 4.36 16.97
20.70 4.29 16.24
21.62 4.11 33.28
21.84 4.07 45.92
23.01 3.87 32.48
23.39 3.80 22.81
25.54 3.49 17.15
稳定性试验：
将实施例1所得晶型放置高温高湿环境中，考察在10天、20天、30天的稳定性，结果见表2。
Figure PCTCN2021072450-appb-000002
实施例2
将1.0kg K-5a2固体粉末加入到20L的反应釜中，加入10L二甲基亚砜，加热到50℃，搅拌至目测全部溶解，过滤除掉不溶性杂质，然后缓慢将滤液加入到30L纯化水中，35℃搅拌1小时，离心所得固体用20L纯化水泡洗，泡洗完毕，再次离心，将离心所得固体鼓风干燥，得到类白色固体粉末0.91kg，产率91.0％，干燥后产品为所要晶型。
实施例2得到的K-5a2化合物晶型的XRPD图如附图2所示。X射线粉末衍射数据见表3。
表3 K-5a2晶型的X射线粉末衍射数据
2θ d间隔 相对强度％
4.35 20.33 37.05
11.20 7.90 57.02
11.62 7.61 78.47
11.79 7.50 76.72
14.80 5.98 39.99
14.98 5.92 24.42
15.72 5.64 48.13
18.19 4.88 20.69
18.95 4.68 44.10
19.88 4.46 100.00
20.71 4.29 17.03
21.62 4.11 38.91
21.85 4.07 52.88
22.98 3.87 32.09
23.31 3.82 22.50
25.57 3.48 21.07
实施例3
将1.0kg K-5a2固体粉末加入到20L的反应釜中，加入10L二甲基亚砜，加热到60℃，搅拌至目测全部溶解，过滤除掉不溶性杂质，然后缓慢将滤液加入到30L纯化水中，45℃搅拌1小时，离心所得固体用20L纯化水泡洗，泡洗完毕，再次离心，将离心所得固体鼓风干燥，得到类白色固体粉末0.91kg，产率91.0％，干燥后产品为所要晶型。
实施例3得到的晶型的X射线粉末衍射数据与表1、表3数据无明显差异，粉末衍射图谱与图1无明显差异。
由上述实施例中可以看出，本发明制备得到的晶型稳定性好，有利于该原料药储存、制剂的开发。稳定性良好的晶型能够有效避免制剂开发过程中转晶现象以及因晶型转变造成生物利用度影响。
当然，上述内容仅为本发明的较佳实施例，不能被认为用于限定对本发明的实施例范围。本发明也并不仅限于上述举例，本技术领域的普通技术人员在本发明的实质范围内所做出的均等变化与改进等，均应归属于本发明的专利涵盖范围内。本领域技术人员可在权利要求范围内对制备方法和使用仪器做出改进，这些改进也应视为本发明的保护范围。

Claims (7)

  1. 一种K-5a2化合物的晶型，其特征在于：其X射线粉末衍射图在2θ值为4.3°±0.2°、11.2°±0.2°、11.6°±0.2°、14.8°±0.2°、15.0°±0.2°、15.7°±0.2°、18.2°±0.2°、19.0°±0.2°、20.7°±0.2°、21.6°±0.2°、21.8°±0.2°、23.0°±0.2°、23.4°±0.2°、25.5°±0.2°处具有特征峰。
  2. 根据权利要求1所述的K-5a2化合物的晶型，其特征在于：所述的晶型在237℃±1℃，324℃±1℃处有放热，在315℃±1℃失重明显。
  3. 一种权利要求1或2所述的K-5a2化合物的晶型的制备方法，其特征在于：包括如下步骤：
    将K-5a2化合物粗品加入到二甲基亚砜中加热搅拌溶解后，将溶液加入到纯化水中；在20-50℃温度条件下搅拌析晶，离心所得固体经纯化水泡洗后，再次离心，收集固体并干燥后，得K-5a2化合物的晶型。
  4. 根据权利要求3所述的K-5a2化合物的晶型的制备方法，其特征在于：所述的二甲基亚砜的用量为K-5a2化合物粗品的体积重量比为10倍。
  5. 根据权利要求3所述的K-5a2化合物的晶型的制备方法，其特征在于：所述的二甲基亚砜：纯化水的体积比为1：1-3。
  6. 根据权利要求3所述的K-5a2化合物的晶型的制备方法，其特征在于：所述的加热搅拌溶解为：加热至50-60℃搅拌溶解。
  7. 一种权利要求1或2所述的K-5a2化合物的晶型的应用，其特征在于：所述的晶型用于制备非核苷类逆转录酶抑制剂。
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