WO2022237710A1 - Crystal form of compound for treating influenza, and application thereof - Google Patents

Crystal form of compound for treating influenza, and application thereof Download PDF

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Publication number
WO2022237710A1
WO2022237710A1 PCT/CN2022/091605 CN2022091605W WO2022237710A1 WO 2022237710 A1 WO2022237710 A1 WO 2022237710A1 CN 2022091605 W CN2022091605 W CN 2022091605W WO 2022237710 A1 WO2022237710 A1 WO 2022237710A1
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crystal form
compound
solvent
xrpd
xrpd characteristic
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PCT/CN2022/091605
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French (fr)
Chinese (zh)
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郝小林
杨金夫
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南京征祥医药有限公司
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Priority to CN202280006852.4A priority Critical patent/CN116829153A/en
Publication of WO2022237710A1 publication Critical patent/WO2022237710A1/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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the temperature is lowered to crystallize so as to obtain the crystalline form of Compound A.
  • the term "about” or “approximately” is 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01%.
  • X-ray powder diffraction assay method among the present invention is the assay method commonly used by those skilled in the art, for example as follows: utilize the PANalytical EMPYREAN that has been equipped with PIXceI 1D detector to carry out crystal form analysis to the solid gained in the experiment, instrument parameter is as follows: Scanning range: 3°(2 ⁇ ) to 40°(2 ⁇ ); step size: 0.013°(2 ⁇ ); light tube voltage and current are 45KV and 40mA respectively.
  • the crystalline form further has at least one characteristic XRPD peak selected from the group consisting of about 14.1, about 18.8, about 20.6, and about 21.6 in 2 ⁇ .
  • at least one characteristic XRPD peak selected from the group consisting of about 14.1, about 18.8, about 20.6, and about 21.6 in 2 ⁇ .
  • the crystalline form further has at least one XRPD characteristic peak selected from the group consisting of 2 ⁇ of 14.1 ⁇ 0.2, 18.8 ⁇ 0.2, 20.6 ⁇ 0.2 and 21.6 ⁇ 0.2.
  • at least one XRPD characteristic peak selected from the group consisting of 2 ⁇ of 14.1 ⁇ 0.2, 18.8 ⁇ 0.2, 20.6 ⁇ 0.2 and 21.6 ⁇ 0.2.
  • the crystal form further has at least one selected from the group consisting of 2 ⁇ of 9.7 ⁇ 0.2, 16.4 ⁇ 0.2, 19.1 ⁇ 0.2, 22.2 ⁇ 0.2, 23.7 ⁇ 0.2, 25.6 ⁇ 0.2, 28.0 ⁇ 0.2, 28.3 ⁇ 0.2 and XRPD characteristic peak of 31.3 ⁇ 0.2.
  • XRPD characteristic peak of 31.3 ⁇ 0.2.
  • Compound A is dissolved in a single solvent or a mixed solvent
  • kits for practicing the methods of the disclosure comprising one or more crystalline forms of the compounds described herein or a pharmaceutical composition comprising a crystalline form of the compounds described herein.
  • the kits may employ crystalline forms of the compounds disclosed herein. Kits may be used for any one or more of the uses described herein, and thus may contain instructions for the treatment of diseases described herein.
  • Example 1 The crystal form of compound A was prepared according to the following method. Firstly, the following compound A (that is, the compound C-1 mentioned in the WO2021007506A1 publication) was prepared by referring to the method described in the publication number WO2021007506A1.
  • the crystal form of the solid obtained in the experiment was analyzed by PANalytical EMPYREAN equipped with PIXceI 1D detector.
  • the instrument parameters are as follows: scanning range: 3°(2 ⁇ ) to 40°(2 ⁇ ); step size: 0.013°(2 ⁇ ); light tube voltage and current are 45KV and 40mA, respectively.
  • the single crystal sample belongs to the monoclinic crystal system, the space group P 1 21 1, and the molecular formula is C 27 H 23 F 2 N 3 O 7 Se .
  • Each asymmetric unit contains one compound A molecule, and each unit cell contains 2 molecules.
  • the molecular structure contains two chiral carbon atoms, respectively "S" (C7) and “R” (C15) configurations.
  • the single crystal structure is consistent with the molecular structure. Its single crystal structure parameters are shown in Table 2 below.
  • Rapid cooling Weigh about 50 mg of sample B and dissolve it in 0.4 mL of methanol, dissolve it at 50°C, filter the solution while it is hot, and store the filtrate directly in a refrigerator at 5°C for about 20 hours. XRPD test was carried out on the precipitated crystals.
  • Evaporation crystallization experiments were carried out using mixed solvents to find out whether other crystals could be obtained. For example, weigh about 20 mg of sample B into a sample bottle, add 0.1-1 mL of a selected solvent (mixed solvent), filter the solution, place the filtrate in a sample bottle, and dry at room temperature at different rates. Prepare slow evaporating samples by covering vials with Parafilm with small holes. The obtained solid was characterized by PLM or XRPD.
  • Example 3 evaluates the effect of different mechanical treatments on the crystal form.
  • the effect on the crystal form 1 was investigated by grinding experiment and pressure experiment respectively. As follows:
  • Sample B was subjected to 7-day closed solid stability and chemical stability experiments at 40°C/75%RH and 60°C, respectively, and analyzed by XRPD and HPLC.

Abstract

Relating to the field of biomedicine, and specifically relating to to the crystal form of a compound and an application thereof. The compound is the compound as shown in formula A, and the crystal form has an XRPD characteristic peak having 2θ as 10.7±0.2, 13.1±0.2, 15.6±0.2, 16.0±0.2, 17.5±0.2, 20.1±0.2, 21.9±0.2, 24.1±0.2, 26.5±0.2 and 29.7±0.2. The provided crystal form of the compound can be used to treat influenza.

Description

治疗流感化合物的晶型及应用Crystal form and application of compound for treating influenza 技术领域technical field
本发明涉及抗感染药物领域，具体涉及一种治疗流感化合物的晶型及应用。The invention relates to the field of anti-infective drugs, in particular to a crystal form and application of a compound for treating influenza.
背景技术Background technique
每年的秋季和冬季都会面临流感大爆发。流感通常会导致伴有持续3至7天的发烧的呼吸道疾病。尽管有流感疫苗可用，每年季节性流感流行可导致全球5％～10％的成人和20％～30％的儿童罹患流感，引起重症病例人数达300～500万，死亡人数高达29～65万，死亡率为4.0～8.8/100,000，造成巨大的人道灾难和经济负担(WHO:Global Influenza Strategy 2019-2030和Iuliano AD等人，Lancet.2018,391,1285-300)。Influenza outbreaks occur every autumn and winter. Influenza usually causes respiratory illness with fever lasting 3 to 7 days. Although influenza vaccines are available, seasonal influenza epidemics can cause 5% to 10% of adults and 20% to 30% of children to suffer from influenza each year, causing 3 to 5 million severe cases and 290,000 to 650,000 deaths. The mortality rate is 4.0-8.8/100,000, causing a huge humanitarian disaster and economic burden (WHO: Global Influenza Strategy 2019-2030 and Iuliano AD et al., Lancet. 2018, 391, 1285-300).
流感病毒属于正粘病毒科(Orthomyxoviridae)，其是含有单链负义RNA基因组的包膜病毒。在过去几十年里，通常两类疗法可用于治疗流感病毒：M2离子通道抑制剂和神经氨酸酶抑制剂。然而，流感病毒不仅表现出对M2离子通道抑制剂的广泛抗药性，而且陆续产生对神经氨酸酶抑制剂的抗病毒抗药性。Influenza viruses belong to the Orthomyxoviridae family, which are enveloped viruses containing a single-stranded negative-sense RNA genome. In the past few decades, two classes of therapies have generally been used to treat influenza viruses: M2 ion channel inhibitors and neuraminidase inhibitors. However, influenza viruses not only show widespread drug resistance to M2 ion channel inhibitors, but also successively develop antiviral drug resistance to neuraminidase inhibitors.
Cap(帽)依赖性核酸内切酶抑制剂通过控制流感病毒复制的关键环节，抑制病毒从宿主细胞中获得宿主mRNA 5’端的Cap结构，从而抑制流感病毒自身mRNA的转录，达到治疗流感的效果。而且由于宿主细胞内不存在有类似机制的蛋白酶，Cap依赖性核酸内切酶抑制剂不会对宿主细胞产生影响。2018年，首个帽依赖性内切核酸酶(CEN)抑制剂巴洛沙韦酯(baloxavir marboxil)(商品名：Xofluza))在美国和日本批准用于治疗A型和B型流感。前药巴洛沙韦酯通过水解转化为其活性成分巴洛沙韦。巴洛沙韦抑制流感病毒聚合酶酸性(PA)蛋白质内切核酸酶，使病毒RNA的合成得以抑制，从而可以有效抑制流感病毒复制。然而，巴洛沙韦酯和其活性组分巴洛沙韦的口服利用度都很低。Cap (cap) dependent endonuclease inhibitor controls the key link of influenza virus replication, inhibits the virus from obtaining the Cap structure at the 5' end of the host mRNA from the host cell, thereby inhibiting the transcription of the influenza virus's own mRNA and achieving the effect of treating influenza . And since there is no protease with a similar mechanism in the host cell, the Cap-dependent endonuclease inhibitor will not affect the host cell. In 2018, the first cap-dependent endonuclease (CEN) inhibitor, baloxavir marboxil (trade name: Xofluza), was approved in the United States and Japan for the treatment of influenza A and B. The prodrug baloxavir dipivoxil is converted to its active ingredient baloxavir by hydrolysis. Baloxavir inhibits influenza virus polymerase acid (PA) protein endonuclease, inhibits the synthesis of viral RNA, and thus can effectively inhibit the replication of influenza virus. However, both baloxavir dipivoxil and its active component, baloxavir, have low oral availability.
公开号为WO2021/007506A1的专利申请中提供了一种Cap依赖性核酸内切酶抑制剂，能够用来治疗流感病毒，显示出优异的生物活性及药代动力学性质包括良好的口服生物利用度，且不受进食的影响。然而还需要进一步改进，以获得稳定且适合生产的治疗药物。The patent application with publication number WO2021/007506A1 provides a Cap-dependent endonuclease inhibitor, which can be used to treat influenza virus, showing excellent biological activity and pharmacokinetic properties including good oral bioavailability , and is not affected by eating. However, further improvements are needed to obtain stable and manufacturable therapeutics.
发明内容Contents of the invention
本发明旨在至少在一定程度上解决上述技术问题之一。本发明提供了一种治疗流感的 化合物的晶型及应用。所提供的化合物晶型更加稳定，吸湿性低，而且更适合GMP放大生产。本发明所提供的化合物的晶型可以作为流感病毒内切核酸酶抑制剂，抑制流感病毒的复制。该化合物的晶型尤其可以用于治疗或者预防人的流感病毒感染。The present invention aims to solve one of the above-mentioned technical problems at least to a certain extent. The invention provides a crystal form and application of a compound for treating influenza. The provided compound crystal form is more stable, has low hygroscopicity, and is more suitable for GMP scale-up production. The crystal form of the compound provided by the invention can be used as an influenza virus endonuclease inhibitor to inhibit the replication of influenza virus. The crystalline form of the compound is especially useful for treating or preventing human influenza virus infection.
本发明的第一方面提供了一种化合物的晶型，所述化合物为式A化合物，The first aspect of the present invention provides a crystal form of a compound, the compound is a compound of formula A,
Figure PCTCN2022091605-appb-000001
Figure PCTCN2022091605-appb-000001
所述晶型具有至少两个选自2θ为10.7±0.2、13.1±0.2、15.6±0.2，16.0±0.2、17.5±0.2、20.1±0.2、21.9±0.2、24.1±0.2、26.5±0.2和29.7±0.2的XRPD特征峰。The crystal form has at least two 2θ selected from 10.7±0.2, 13.1±0.2, 15.6±0.2, 16.0±0.2, 17.5±0.2, 20.1±0.2, 21.9±0.2, 24.1±0.2, 26.5±0.2 and 29.7±0.2 XRPD characteristic peak of 0.2.
本发明的第二方面提供了一种化合物的晶型，所述晶型为单斜晶体，所述化合物为式A所示化合物，The second aspect of the present invention provides a crystal form of a compound, the crystal form is a monoclinic crystal, and the compound is a compound represented by formula A,
Figure PCTCN2022091605-appb-000002
Figure PCTCN2022091605-appb-000002
所述晶型具有如下晶胞参数：The crystal form has the following unit cell parameters:
a为约7.1埃、b为约20.0埃、c为约9.4埃、α为约90.0°、β为约108.8°、γ为约90.0°。a is about 7.1 angstroms, b is about 20.0 angstroms, c is about 9.4 angstroms, α is about 90.0°, β is about 108.8°, and γ is about 90.0°.
本发明的第三方面提供了一种药物组合物，所述药物组合物包括上述晶型，以及药学上可接受的载体。The third aspect of the present invention provides a pharmaceutical composition, which comprises the above crystal form and a pharmaceutically acceptable carrier.
本发明的第四方面提供了一种在体外抑制流感病毒活性的方法，包括：在体外，将细胞和有效量的上述晶型或者药物组合物接触。The fourth aspect of the present invention provides a method for inhibiting the activity of influenza virus in vitro, comprising: contacting cells with an effective amount of the above-mentioned crystal form or pharmaceutical composition in vitro.
本发明的第五方面提供了一种预防或治疗流感的方法，包括向有需要的受试者给予有 效量的上述晶型或者上述药物组合物。The fifth aspect of the present invention provides a method for preventing or treating influenza, comprising administering an effective amount of the above-mentioned crystal form or the above-mentioned pharmaceutical composition to a subject in need.
本发明还提供了一种上述晶型的制备方法，在一些实施方案中，所提供的化合物A的晶型可以通过下述方法制备获得：The present invention also provides a method for preparing the above crystal form. In some embodiments, the provided crystal form of Compound A can be prepared by the following method:
将化合物A溶于单一溶剂或混合溶剂；Compound A is dissolved in a single solvent or a mixed solvent;
蒸发结晶以便去除所述化合物A的溶液中的溶剂，获得所述化合物A的晶型。Crystallization is evaporated to remove the solvent in the solution of Compound A to obtain the crystalline form of Compound A.
在一些实施方案中，所提供的化合物A的晶型可以通过下述方法制备获得：In some embodiments, the provided crystalline form of Compound A can be prepared by the following methods:
将化合物A溶于单一溶剂或混合溶剂；Compound A is dissolved in a single solvent or a mixed solvent;
蒸馏浓缩掉所述化合物A的溶液中的部分溶剂，以便获得化合物A的浓缩溶液；Part of the solvent in the solution of compound A is concentrated by distillation, so as to obtain a concentrated solution of compound A;
降温结晶以便获得所述化合物A的晶型。The temperature is lowered to crystallize so as to obtain the crystalline form of Compound A.
在至少具体一些实施方式中，所述单一溶剂为有机溶剂，所述混合溶剂为有机溶剂和水的混合液。所提到的有机溶剂包括但不限于乙腈、丙酮、异丙醇、正庚烷、甲基叔丁基醚、乙酸异丙酯、乙醇、甲苯、甲醇、乙酸乙酯等。In at least some specific embodiments, the single solvent is an organic solvent, and the mixed solvent is a mixed solution of an organic solvent and water. Organic solvents mentioned include, but are not limited to, acetonitrile, acetone, isopropanol, n-heptane, methyl tert-butyl ether, isopropyl acetate, ethanol, toluene, methanol, ethyl acetate, and the like.
在一些优选实施例中，通过重结晶的方法，以易溶溶剂丙酮为重结晶溶剂，在回流条件下，对化合物A粗品进行溶解，然后浓缩丙酮，加入不良溶剂甲基叔丁基醚(MTBE)析晶，结果发现可以显著提高化合物A的晶型的纯度，显著降低溶剂残留。In some preferred embodiments, by the method of recrystallization, the easily soluble solvent acetone is used as the recrystallization solvent, under reflux conditions, the crude product of compound A is dissolved, then the acetone is concentrated, and the poor solvent methyl tert-butyl ether (MTBE ) crystallization, it was found that the purity of the crystal form of compound A can be significantly improved, and the solvent residue can be significantly reduced.
在一些优选实施例中，将化合物A的粗品利用丙酮回流溶清，将丙酮溶剂浓缩到原来体积的0.2～0.3倍量，降温到10到30摄氏度，然后滴加原丙酮溶剂体积0.4～0.6倍量的甲基叔丁基醚，继续结晶，过滤得到晶型产物。In some preferred embodiments, the crude product of Compound A is dissolved by reflux with acetone, the acetone solvent is concentrated to 0.2 to 0.3 times the original volume, the temperature is lowered to 10 to 30 degrees Celsius, and then 0.4 to 0.6 times the volume of the original acetone solvent is added dropwise. A certain amount of methyl tert-butyl ether continued to crystallize and was filtered to obtain the crystalline product.
在一个最优实施例中，将化合物A的粗品，利用丙酮(7V)回流溶清，浓缩到体积约为1.5V，降温到20摄氏度，然后滴加3V甲基叔丁基醚继续结晶，过滤得到晶型产物；其中“V”代表溶剂和化合物A的体积质量比，单位为mL/g。In an optimal embodiment, the crude product of Compound A is refluxed with acetone (7V) to dissolve, concentrated to a volume of about 1.5V, cooled to 20 degrees Celsius, then added dropwise with 3V methyl tert-butyl ether to continue crystallization, filtered A crystalline product was obtained; wherein "V" represents the volume-to-mass ratio of the solvent to compound A, and the unit is mL/g.
附图说明Description of drawings
图1是根据本发明的实施例1提供的化合物A的晶型1的XRPD图谱结果。Fig. 1 is the XRPD spectrum result of the crystal form 1 of compound A provided according to Example 1 of the present invention.
图2是根据本发明的实施例1提供的化合物A的晶型1的DSC和TGA图谱结果。Fig. 2 is the DSC and TGA spectrum results of the crystal form 1 of Compound A provided in Example 1 of the present invention.
图3是根据本发明的实施例1提供的样品B(即，化合物A的晶型1)在不同条件下放置后的XRPD图谱结果。Fig. 3 is the XRPD pattern results of sample B (ie, the crystal form 1 of compound A) provided according to Example 1 of the present invention after being placed under different conditions.
图4是根据本发明的实施例5提供的不同处理组雪貂体重变化结果图。Fig. 4 is a graph showing the results of body weight changes of ferrets in different treatment groups according to Example 5 of the present invention.
图5是根据本发明的实施例5提供的不同处理组雪貂临床症状评分结果图。Fig. 5 is a graph showing the score results of clinical symptoms of ferrets in different treatment groups according to Example 5 of the present invention.
图6是根据本发明的实施例5提供的不同处理组甲型流感病毒滴度的测定结果图。Fig. 6 is a graph showing the determination results of influenza A virus titers in different treatment groups according to Example 5 of the present invention.
具体实施方式Detailed ways
下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。同时，对于文中出现的一些术语进行解释和说明，这些解释和说明仅用于方便本领域技术人员理解，不应看作是对本发明保护范围的限制。The embodiments described below by referring to the figures are exemplary and are intended to explain the present invention and should not be construed as limiting the present invention. At the same time, some terms appearing in the text are explained and illustrated, and these explanations and illustrations are only used to facilitate the understanding of those skilled in the art, and should not be regarded as limiting the protection scope of the present invention.
本文中对于化合物的晶型的描述，除非另有说明，否则说明书和权利要求中的数值均为近似值。考虑到仪器校准、仪器误差等因素，不同测定的数值可能会稍微变化，只要本领域技术人员能够判断为同一个化合物晶型即可。本文中，术语“约”或者“大约”意指为本领域技术人员所承认的可与所提供的化合物的晶型的参数相近，能够确认为同一晶型即可。在一些实施方案中，术语“约”或者“大约”为所列举的值或者所列举的数值范围的5％、4％、3％、2％、1％、0.9％、0.8％、0.7％、0.6％、0.5％、0.4％、0.3％、0.2％、0.1％、0.09％、0.08％、0.07％、0.06％、0.05％、0.04％、0.03％、0.02％或者0.01％。For the description of the crystal form of the compound herein, unless otherwise stated, the numerical values in the specification and claims are all approximate values. Taking into account factors such as instrument calibration and instrument error, the numerical values of different determinations may vary slightly, as long as those skilled in the art can judge that the crystal form of the compound is the same. Herein, the term "about" or "approximately" means that the parameter recognized by those skilled in the art may be similar to the crystal form of the provided compound, as long as it can be confirmed as the same crystal form. In some embodiments, the term "about" or "approximately" is 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01%.
本发明中X射线粉末衍射测定方法为本领域技术人员常用的测定方法，举例如下：利用配备了PIXceI 1D检测器的PANalytical EMPYREAN对实验中所得的固体进行了晶型分析，仪器参数如下所示：扫描范围：3°(2θ)to 40°(2θ)；步长：0.013°(2θ)；光管电压和电流分别为45KV和40mA。 X-ray powder diffraction assay method among the present invention is the assay method commonly used by those skilled in the art, for example as follows: utilize the PANalytical EMPYREAN that has been equipped with PIXceI 1D detector to carry out crystal form analysis to the solid gained in the experiment, instrument parameter is as follows: Scanning range: 3°(2θ) to 40°(2θ); step size: 0.013°(2θ); light tube voltage and current are 45KV and 40mA respectively.
化合物的晶型Crystal form of compound
本发明提供了一种化合物的晶型，所述化合物为式A所示化合物，The present invention provides a crystal form of a compound, the compound is a compound represented by formula A,
Figure PCTCN2022091605-appb-000003
Figure PCTCN2022091605-appb-000003
所述晶型具有至少一个选自2θ为约10.7、约13.1、约15.6、约16.0、约17.5、约20.1、约21.9、约24.1、约26.5和约29.7的XRPD特征峰。The crystalline form has at least one XRPD characteristic peak selected from the group consisting of about 10.7, about 13.1, about 15.6, about 16.0, about 17.5, about 20.1, about 21.9, about 24.1, about 26.5, and about 29.7 in 2Θ.
X射线粉末衍射(XPRD)是确定药物结晶度的方法，其通过X射线照射样品，照射到晶体上的X射线被晶格面反射并且相互干涉，表现出不同的规律。不同晶体的衍射线强度和分布都有着其特殊的规定，也可以确定晶型的变化、结晶度等信息。X-ray powder diffraction (XPRD) is a method to determine the crystallinity of drugs. It irradiates the sample with X-rays, and the X-rays irradiated on the crystal are reflected by the lattice planes and interfere with each other, showing different laws. The intensity and distribution of diffraction lines of different crystals have their own special regulations, and information such as changes in crystal forms and crystallinity can also be determined.
本发明所提供的化合物的晶型具有可区分的X射线粉末衍射曲线。例如可以通过衍射 峰特征来区分是否为式A所示化合物的晶型。所述晶型具有至少一个选自2θ为约10.7、约13.1、约15.6、约16.0、约17.5、约20.1、约21.9、约24.1、约26.5和约29.7的XRPD特征峰。优选具有至少两个、至少三个、至少四个、至少五个、至少六个、至少七个、至少八个、或者至少九个选自2θ为约10.7、约13.1、约15.6、约16.0、约17.5、约20.1、约21.9、约24.1、约26.5和约29.7的XRPD特征峰。在一些实施方案中，所述晶型具有2θ为约10.7、约13.1、约15.6、约16.0、约17.5、约20.1、约21.9、约24.1、约26.5和约29.7的XRPD特征峰。The crystal forms of the compounds provided by the present invention have distinguishable X-ray powder diffraction curves. For example, whether it is the crystal form of the compound shown in Formula A can be distinguished by the characteristics of the diffraction peaks. The crystalline form has at least one XRPD characteristic peak selected from the group consisting of about 10.7, about 13.1, about 15.6, about 16.0, about 17.5, about 20.1, about 21.9, about 24.1, about 26.5, and about 29.7 in 2Θ. Preferably having at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine selected from the group consisting of about 10.7, about 13.1, about 15.6, about 16.0, XRPD characteristic peaks at about 17.5, about 20.1, about 21.9, about 24.1, about 26.5, and about 29.7. In some embodiments, the crystalline form has an XRPD characteristic peak of about 10.7, about 13.1, about 15.6, about 16.0, about 17.5, about 20.1, about 21.9, about 24.1, about 26.5, and about 29.7 2Θ.
在一些实施方案中，所述晶型具有至少一个选自2θ为10.7±0.2、13.1±0.2、15.6±0.2、16.0±0.2、17.5±0.2、20.1±0.2、21.9±0.2、24.1±0.2、26.5±0.2和29.7±0.2的XRPD特征峰。优选具有至少两个、至少三个、至少四个、至少五个、至少六个、至少七个、至少八个、或者至少九个选自2θ为10.7±0.2、13.1±0.2、15.6±0.2、16.0±0.2、17.5±0.2、20.1±0.2、21.9±0.2、24.1±0.2、26.5±0.2和29.7±0.2的XRPD特征峰。In some embodiments, the crystal form has at least one selected from the group consisting of 2θ of 10.7±0.2, 13.1±0.2, 15.6±0.2, 16.0±0.2, 17.5±0.2, 20.1±0.2, 21.9±0.2, 24.1±0.2, 26.5 XRPD characteristic peaks of ±0.2 and 29.7±0.2. Preferably there are at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine selected from the group consisting of 2θ of 10.7±0.2, 13.1±0.2, 15.6±0.2, XRPD characteristic peaks of 16.0±0.2, 17.5±0.2, 20.1±0.2, 21.9±0.2, 24.1±0.2, 26.5±0.2 and 29.7±0.2.
在一些实施方案中，所述晶型具有2θ为10.7±0.2、13.1±0.2、15.6±0.2、16.0±0.2、17.5±0.2、20.1±0.2、21.9±0.2、24.1±0.2、26.5±0.2和29.7±0.2的XRPD特征峰。In some embodiments, the crystalline form has a 2θ of 10.7±0.2, 13.1±0.2, 15.6±0.2, 16.0±0.2, 17.5±0.2, 20.1±0.2, 21.9±0.2, 24.1±0.2, 26.5±0.2, and 29.7 XRPD characteristic peaks of ±0.2.
在一些实施方案中，所述晶型具有至少一个选自2θ为10.7±0.1、13.1±0.1、15.6±0.1、16.0±0.1、17.5±0.1、20.1±0.1、21.9±0.1、24.1±0.1、26.5±0.1和29.7±0.1的XRPD特征峰。优选具有至少两个、至少三个、至少四个、至少五个、至少六个、至少七个、至少八个、或者至少九个选自2θ为10.7±0.1、13.1±0.1、15.6±0.1、16.0±0.1、17.5±0.1、20.1±0.1、21.9±0.1、24.1±0.1、26.5±0.1和29.7±0.1的XRPD特征峰。In some embodiments, the crystal form has at least one selected from the group consisting of 2θ of 10.7±0.1, 13.1±0.1, 15.6±0.1, 16.0±0.1, 17.5±0.1, 20.1±0.1, 21.9±0.1, 24.1±0.1, 26.5 XRPD characteristic peaks of ±0.1 and 29.7±0.1. Preferably there are at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine selected from 2θ of 10.7±0.1, 13.1±0.1, 15.6±0.1, XRPD characteristic peaks of 16.0±0.1, 17.5±0.1, 20.1±0.1, 21.9±0.1, 24.1±0.1, 26.5±0.1 and 29.7±0.1.
在一些实施方案中，所述晶型具有2θ为10.7±0.1、13.1±0.1、15.6±0.1，16.0±0.1、17.5±0.1、20.1±0.1、21.9±0.1、24.1±0.1、26.5±0.1和29.7±0.1的XRPD特征峰。In some embodiments, the crystalline form has a 2θ of 10.7±0.1, 13.1±0.1, 15.6±0.1, 16.0±0.1, 17.5±0.1, 20.1±0.1, 21.9±0.1, 24.1±0.1, 26.5±0.1, and 29.7 XRPD characteristic peaks of ±0.1.
在一些实施方案中，所述晶型进一步具有至少一个选自2θ为约14.1、约18.8、约20.6和约21.6的XRPD特征峰。例如，具有一个、两个、三个或者四个选自2θ为约14.1、约18.8、约20.6和约21.6的XRPD特征峰。In some embodiments, the crystalline form further has at least one characteristic XRPD peak selected from the group consisting of about 14.1, about 18.8, about 20.6, and about 21.6 in 2Θ. For example, having one, two, three or four XRPD characteristic peaks selected from the group consisting of about 14.1, about 18.8, about 20.6, and about 21.6 in 2Θ.
在一些实施方案中，所述晶型进一步具有至少一个选自2θ为14.1±0.2，18.8±0.2、20.6±0.2和21.6±0.2的XRPD特征峰。例如，具有一个、两个、三个或者四个选自2θ为14.1±0.2，18.8±0.2、20.6±0.2和21.6±0.2的XRPD特征峰。In some embodiments, the crystalline form further has at least one XRPD characteristic peak selected from the group consisting of 2θ of 14.1±0.2, 18.8±0.2, 20.6±0.2 and 21.6±0.2. For example, having one, two, three or four XRPD characteristic peaks selected from 2Θ of 14.1±0.2, 18.8±0.2, 20.6±0.2 and 21.6±0.2.
在一些实施方案中，所述晶型进一步具有至少一个选自2θ为14.1±0.1，18.8±0.1、20.6±0.1和21.6±0.1的XRPD特征峰。例如，具有一个、两个、三个或者四个选自2θ为14.1±0.1，18.8±0.1、20.6±0.1和21.6±0.1的XRPD特征峰。In some embodiments, the crystalline form further has at least one XRPD characteristic peak selected from the group consisting of 2θ of 14.1±0.1, 18.8±0.1, 20.6±0.1 and 21.6±0.1. For example, having one, two, three or four XRPD characteristic peaks selected from 2Θ of 14.1±0.1, 18.8±0.1, 20.6±0.1 and 21.6±0.1.
在一些实施方案中，所述晶型进一步具有至少一个选自2θ为约9.7、约16.4、约19.1、 约22.2、约23.7、约25.6、约28.0、约28.3和约31.3的XRPD特征峰。例如，具有一个、两个、三个、四个、五个、六个、七个、八个或者九个选自2θ为约9.7、约16.4、约19.1、约22.2、约23.7、约25.6、约28.0、约28.3和约31.3的XRPD特征峰。In some embodiments, the crystalline form further has at least one XRPD characteristic peak selected from the group consisting of about 9.7, about 16.4, about 19.1, about 22.2, about 23.7, about 25.6, about 28.0, about 28.3, and about 31.3 in 2Θ. For example, having one, two, three, four, five, six, seven, eight or nine selected from the group consisting of about 9.7, about 16.4, about 19.1, about 22.2, about 23.7, about 25.6, Characteristic XRPD peaks at about 28.0, about 28.3 and about 31.3.
在一些实施方案中，所述晶型进一步具有至少一个选自2θ为9.7±0.2、16.4±0.2、19.1±0.2、22.2±0.2、23.7±0.2、25.6±0.2、28.0±0.2、28.3±0.2和31.3±0.2的XRPD特征峰。例如，具有一个、两个、三个、四个、五个、六个、七个、八个或者九个选自2θ为9.7±0.2、16.4±0.2、19.1±0.2、22.2±0.2、23.7±0.2、25.6±0.2、28.0±0.2、28.3±0.2和31.3±0.2的XRPD特征峰。In some embodiments, the crystal form further has at least one selected from the group consisting of 2θ of 9.7±0.2, 16.4±0.2, 19.1±0.2, 22.2±0.2, 23.7±0.2, 25.6±0.2, 28.0±0.2, 28.3±0.2 and XRPD characteristic peak of 31.3 ± 0.2. For example, having one, two, three, four, five, six, seven, eight or nine selected from 2θ of 9.7±0.2, 16.4±0.2, 19.1±0.2, 22.2±0.2, 23.7±0.2 XRPD characteristic peaks at 0.2, 25.6±0.2, 28.0±0.2, 28.3±0.2 and 31.3±0.2.
在一些实施方案中，所述晶型进一步具有至少一个选自2θ为9.7±0.1、16.4±0.1、19.1±0.1、22.2±0.1、23.7±0.1、25.6±0.1、28.0±0.1、28.3±0.1和31.3±0.1的XRPD特征峰。例如，具有一个、两个、三个、四个、五个、六个、七个、八个或者九个选自2θ为9.7±0.1、16.4±0.1、19.1±0.1、22.2±0.1、23.7±0.1、25.6±0.1、28.0±0.1、28.3±0.1和31.3±0.1的XRPD特征峰。In some embodiments, the crystal form further has at least one selected from the group consisting of 2θ of 9.7±0.1, 16.4±0.1, 19.1±0.1, 22.2±0.1, 23.7±0.1, 25.6±0.1, 28.0±0.1, 28.3±0.1 and XRPD characteristic peak of 31.3 ± 0.1. For example, having one, two, three, four, five, six, seven, eight or nine selected from 2θ of 9.7±0.1, 16.4±0.1, 19.1±0.1, 22.2±0.1, 23.7±0.1 XRPD characteristic peaks at 0.1, 25.6±0.1, 28.0±0.1, 28.3±0.1 and 31.3±0.1.
在一些实施方案中，所述晶型具有基本上如图1所示的X射线粉末衍射图案。In some embodiments, the crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
在一些实施方案中，所述晶型在221～224摄氏度具有熔融峰。In some embodiments, the crystalline form has a melting peak at 221-224 degrees Celsius.
在一些实施方案中，所述晶型具有基本上如图2所示的DSC和TGA图谱。In some embodiments, the crystalline form has a DSC and TGA profile substantially as shown in FIG. 2 .
本发明还提供了一种化合物的晶型，所述晶型为单斜晶体，所述化合物为式A所示化合物，The present invention also provides a crystal form of a compound, the crystal form is a monoclinic crystal, and the compound is a compound shown in formula A,
Figure PCTCN2022091605-appb-000004
Figure PCTCN2022091605-appb-000004
所述晶型具有如下晶胞参数：The crystal form has the following unit cell parameters:
a为约7.1埃、b为约20.0埃、c为约9.4埃、α为约90.0°、β为约108.8°、γ为约90.0°。a is about 7.1 angstroms, b is about 20.0 angstroms, c is about 9.4 angstroms, α is about 90.0°, β is about 108.8°, and γ is about 90.0°.
在具体的测定中，所述晶型具有如下晶胞参数：a为7.1465埃、b为19.9876埃、c＝9.4303埃、α为90.0°、β为108.762°、γ为90.0°。In a specific measurement, the crystal form has the following unit cell parameters: a is 7.1465 angstroms, b is 19.9876 angstroms, c=9.4303 angstroms, α is 90.0°, β is 108.762°, and γ is 90.0°.
所提供的化合物A呈现出基本上纯的结晶形式。所提到的基本上纯的结晶形式是指所 形成的结晶含有不超过10％的杂质，例如小于9％、小于8％、小于7％、小于6％、小于5％、小于4％、小于3％、小于2％、小于1％、小于0.5％、小于0.2％、小于0.1％的杂质。制备获得化合物的晶型可以通过本领域常用方法获得基本上纯的化合物的晶型。在一些实施方案中，提供了基本上纯的化合物A的晶型，纯度水平为97.0％，97.5％，98.0％，98.5％，98.6％，98.7％，98.8％，98.9％，99.0％，99.1％，99.2％，99.3％，99.4％，99.5％，99.6％，99.7％，或更高。Compound A is provided in a substantially pure crystalline form. Reference to substantially pure crystalline form means that the formed crystals contain no more than 10% impurities, for example less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, less than 0.1% impurities. Preparation of the crystal form of the compound The substantially pure crystal form of the compound can be obtained by common methods in the art. In some embodiments, a substantially pure crystalline form of Compound A is provided at a purity level of 97.0%, 97.5%, 98.0%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99.0%, 99.1% , 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, or higher.
在一些实施方案中，所提供的化合物A的晶型可以通过下述方法制备获得：In some embodiments, the provided crystalline form of Compound A can be prepared by the following methods:
将化合物A溶于单一溶剂或混合溶剂；Compound A is dissolved in a single solvent or a mixed solvent;
蒸发结晶以便去除所述化合物A的溶液中的溶剂，获得所述化合物A的晶型。Crystallization is evaporated to remove the solvent in the solution of Compound A to obtain the crystalline form of Compound A.
在一些实施方案中，所提供的化合物A的晶型可以通过下述方法制备获得：In some embodiments, the provided crystalline form of Compound A can be prepared by the following methods:
将化合物A溶于单一溶剂或混合溶剂；Compound A is dissolved in a single solvent or a mixed solvent;
蒸馏浓缩掉所述化合物A的溶液中的部分溶剂，以便获得化合物A的浓缩溶液；Part of the solvent in the solution of compound A is concentrated by distillation, so as to obtain a concentrated solution of compound A;
降温结晶以便获得所述化合物A的晶型。The temperature is lowered to crystallize so as to obtain the crystalline form of Compound A.
在至少具体一些实施方式中，所述单一溶剂为有机溶剂，所述混合溶剂为有机溶剂和水的混合液。所提到的有机溶剂包括但不限于乙腈、丙酮、异丙醇、正庚烷、甲基叔丁基醚、乙酸异丙酯、乙醇、甲苯、甲醇、乙酸乙酯等。In at least some specific embodiments, the single solvent is an organic solvent, and the mixed solvent is a mixed solution of an organic solvent and water. Organic solvents mentioned include, but are not limited to, acetonitrile, acetone, isopropanol, n-heptane, methyl tert-butyl ether, isopropyl acetate, ethanol, toluene, methanol, ethyl acetate, and the like.
药物组合物pharmaceutical composition
本发明还提供了一种药物组合物，所述药物组合物包括上述任一项所述的晶型，以及药学上可接受的载体。The present invention also provides a pharmaceutical composition, which comprises any one of the crystal forms described above, and a pharmaceutically acceptable carrier.
药学上可接受的载体指除了活性成分以外对于受试者无毒的成分，这些药学上可接受的载体可以是本领域常用的载体。药学上可接受的载体可以根据功能包括缓冲剂、赋形剂、稳定剂或者防腐剂等。例如，可以是作为粘合剂、崩解剂、润滑剂、悬浮剂等的本领域常用辅料。A pharmaceutically acceptable carrier refers to an ingredient other than an active ingredient that is non-toxic to a subject, and these pharmaceutically acceptable carriers may be carriers commonly used in the art. Pharmaceutically acceptable carriers may include buffers, excipients, stabilizers or preservatives, etc. according to their functions. For example, it can be adjuvants commonly used in the art as binders, disintegrants, lubricants, suspending agents and the like.
治疗方法及用途Treatment and Use
本发明还提供了上述晶型或者上述药物组合物在制备预防或者治疗流感的药物中的用途。The present invention also provides the use of the above-mentioned crystal form or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing or treating influenza.
本发明还提供了一种预防或者治疗流感的方法，包括向有需要的受试者给予有效量的上述晶型或者上述药物组合物。The present invention also provides a method for preventing or treating influenza, comprising administering an effective amount of the above crystal form or the above pharmaceutical composition to a subject in need.
本发明还提供了一种预防或者治疗感染A型、B型或者C型流感病毒的受试者的方法， 包括向有需要的受试者给予有效量的上述晶型或者上述药物组合物。The present invention also provides a method for preventing or treating a subject infected with type A, B or C influenza virus, comprising administering an effective amount of the above crystal form or the above pharmaceutical composition to the subject in need.
本发明还提供了上述晶型或者上述药组合物，其用于预防或治疗流感，特别是A型流感病毒、B型流感病毒或C型流感病毒。The present invention also provides the above-mentioned crystal form or the above-mentioned pharmaceutical composition, which is used for preventing or treating influenza, especially type A influenza virus, type B influenza virus or type C influenza virus.
本文所公开的化合物的晶型展现出抑制或预防流感病毒复制的能力和药物性质，如通过下面的测试数据所示，可以被指示用于抑制流感病毒(特别是A型流感病毒、B型流感病毒或C型流感病毒)复制。因此，本发明的化合物可用于治疗由流感病毒引起的感染(特别是A型流感、B型流感或C型流感)，尤其在具有或处于感染流感病毒感染风险的人受试者中。作为又一方面，本发明提供如本文所述的化合物的晶型作为治疗剂的用途。所述化合物晶型适用于治疗具有或处于特别高的流感病毒感染(尤其A型流感、B型流感或C型流感)风险的受试者。The crystalline forms of the compounds disclosed herein exhibit the ability and pharmaceutical properties of inhibiting or preventing influenza virus replication, as shown by the following test data, can be indicated for inhibiting influenza virus (especially type A influenza virus, type B influenza virus or influenza C virus) replication. Accordingly, the compounds of the invention are useful in the treatment of infections caused by influenza viruses (particularly influenza A, B or C), especially in human subjects having or at risk of contracting an influenza virus infection. As a further aspect, the present invention provides the use of a crystalline form of a compound as described herein as a therapeutic agent. The crystalline forms of the compounds are suitable for use in the treatment of subjects having or being at particularly high risk of influenza virus infection, especially influenza A, B or C.
本文中所提到的“有效量”或者“有效剂量”是足以实现有益或所需结果的量。对于预防性用途而言，有益或所需结果包括诸如以下的结果：消除或降低疾病风险、减轻其严重程度或延迟其发作，所述疾病包括疾病的生物化学、组织学和/或行为症状、其在疾病发展期间呈现的并发症和中间病理学表型。对于治疗性用途而言，有益或所需结果包括改善、缓和、减轻、延迟或降低一种或多种疾病产生的症状、提高那些罹患疾病者的生活品质、降低治疗疾病所需其他药剂的剂量、诸如经由靶向增强另一药剂的效果、延迟疾病进展和/或延长存活。在一些实施方案中，有效量是足以延迟发展的量。在一些实施方案中，有效量是足以预防或延迟复发的量。有效剂量可以一次或多次给药来施用。出于本公开的目的，化合物晶型或含有该晶型的药物组合物的有效剂量是足以直接或间接地实现预防性或治疗性目的的量。应理解的是，化合物晶型或含有该晶型的药物组合物的有效剂量可以单独地或可与另一药物、化合物或药物组合物结合达成。因此，“有效剂量”可理解为在施用一种或多种治疗剂的背景下进行，并且如果结合一种或多种其他治疗剂可达成或达成合意的结果，则可认为单一剂是以有效量给予。An "effective amount" or "effective dose" as referred to herein is an amount sufficient to achieve a beneficial or desired result. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of disease, including biochemical, histological, and/or behavioral symptoms of disease, Its complications and intermediate pathological phenotypes presented during disease development. For therapeutic use, beneficial or desired results include amelioration, alleviation, alleviation, delay or reduction of symptoms produced by one or more diseases, improving the quality of life of those suffering from the diseases, reducing the dose of other agents needed to treat the diseases , such as via targeting to enhance the effect of another agent, delay disease progression and/or prolong survival. In some embodiments, an effective amount is an amount sufficient to delay development. In some embodiments, an effective amount is an amount sufficient to prevent or delay relapse. An effective dose can be administered in one or more doses. For the purposes of this disclosure, an effective dosage of a crystalline form of a compound or a pharmaceutical composition containing the crystalline form is an amount sufficient to achieve, directly or indirectly, a prophylactic or therapeutic purpose. It is understood that an effective dosage of a crystalline form of a compound or a pharmaceutical composition containing the crystalline form may be achieved alone or in combination with another drug, compound or pharmaceutical composition. Thus, an "effective dose" can be understood in the context of the administration of one or more therapeutic agents, and a single agent can be considered to be effective if the desired result is achieved or achieved in combination with one or more other therapeutic agents. amount to give.
本文中，术语“受试者”是哺乳动物，包括人。受试者包括但不限于人、牛、马、猫、狗、啮齿动物或灵长类动物。在一些实施方案中，受试者是人。Herein, the term "subject" is a mammal, including a human. Subjects include, but are not limited to, humans, cows, horses, cats, dogs, rodents or primates. In some embodiments, the subject is a human.
制品和试剂盒Products and Kits
本公开还提供在合适包装中包含本文所述的化合物的晶型、药物组合物和单位剂量的制品。在某些实施方案中，所述制品用于本文所述的任何方法中。合适包装为本领域中已知的，且包括例如小瓶、器皿、安瓿、瓶、广口瓶、柔性包装等。制品可进一步经灭菌和/或密封。The present disclosure also provides articles of manufacture comprising, in suitable packaging, the crystalline forms of the compounds described herein, pharmaceutical compositions and unit dosages. In certain embodiments, the article of manufacture is used in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampoules, bottles, jars, flexible packaging, and the like. The articles can be further sterilized and/or sealed.
本公开还提供用于实施本公开的方法的试剂盒，其包含一种或多种本文所述的化合物的晶型或包含本文所述的化合物的晶型的药物组合物。所述试剂盒可采用本文所公开的化合物的晶型。试剂盒可用于本文所述的任何一种或多种用途，因此试剂盒中可含有关于本文所述疾病的治疗的说明。The disclosure also provides kits for practicing the methods of the disclosure comprising one or more crystalline forms of the compounds described herein or a pharmaceutical composition comprising a crystalline form of the compounds described herein. The kits may employ crystalline forms of the compounds disclosed herein. Kits may be used for any one or more of the uses described herein, and thus may contain instructions for the treatment of diseases described herein.
试剂盒通常包含有合适的包装。试剂盒可包含一个或多个包含本文所述的化合物的晶型的容器。如果存在超过一种组分时，不同的组分可包装在单独的容器中，或者一些组分可组合在一个容器中。Kits usually contain suitable packaging. A kit may comprise one or more containers comprising a crystalline form of a compound described herein. If more than one component is present, the different components may be packaged in separate containers, or some components may be combined in one container.
试剂盒可为单位剂型、散装包装或亚单位剂量。例如，可提供试剂盒，其含有足够剂量的如本文所公开的化合物的晶型和/或可用于本文所详述的疾病的第二药学活性化合物。试剂盒还可包括多个单位剂量的化合物和使用说明，且以足以在药房中储存和使用的量包装。Kits may be in unit dosage form, bulk packs or subunit dosages. For example, kits may be provided containing sufficient doses of a crystalline form of a compound as disclosed herein and/or a second pharmaceutically active compound useful for a disease as detailed herein. The kit can also include multiple unit doses of the compound and instructions for use, and be packaged in quantities sufficient for storage and use in a pharmacy.
试剂盒还可以根据需要包括一组与本发明方法的一种或多种组分的使用相关的说明，通常为书面说明，也可以为电子存储媒体，例如磁碟或者光碟。试剂盒中所包括的说明通常包括关于组分和其对个体的施用的信息。The kit can also include a set of instructions related to the use of one or more components of the method of the present invention, usually written instructions, or electronic storage media, such as magnetic disks or optical disks. Instructions included in the kit typically include information regarding the components and their administration to an individual.
本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。Those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be considered as limiting the scope of the present invention. If no specific technique or condition is indicated in the examples, it shall be carried out according to the technique or condition described in the literature in this field or according to the product specification. The reagents or instruments used were not indicated by the manufacturer, and they were all commercially available conventional products.
本发明的化合物的合成可以参考本领域已知的方法进行。作为原料化合物，可以利用商购化合物、说明书中描述的化合物、说明书中引用的参考文献中描述的化合物和其他已知化合物。The synthesis of the compound of the present invention can be carried out with reference to methods known in the art. As the starting compound, commercially available compounds, compounds described in the specification, compounds described in references cited in the specification, and other known compounds can be utilized.
合成实施例Synthetic example
实施例中所用到的试剂例如溶剂可自商业来源获得。在Varian III plus 300MHz上记录 1H NMR谱且将TMS用作内标。将有效峰以如下顺序列表：多重性(s，单峰；d，双峰；t，三重峰；q，四重峰；m，多重峰；br s，宽单峰)、以赫兹(Hz)计的偶合常数和质子数。质谱结果以质荷比报告，之后以括号中各离子的相对丰度报告。在Agilent LC/MSD 1200系列的四极质谱仪(管柱：Welchrom XB-C18(50×4.6mm,5μm)；T＝30℃；流速＝1.5ml/分钟；检测波长：214nm)上进行电喷雾电离(ESI)质谱分析。 Reagents such as solvents used in the examples are available from commercial sources. 1 H NMR spectra were recorded on a Varian III plus 300 MHz and TMS was used as internal standard. List valid peaks in the following order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet), in hertz (Hz) Calculated coupling constant and proton number. Mass spectral results are reported as mass-to-charge ratios, followed by the relative abundance of each ion in parentheses. Perform electrospray on Agilent LC/MSD 1200 series quadrupole mass spectrometer (column: Welchrom XB-C18 (50×4.6mm, 5μm); T=30°C; flow rate=1.5ml/min; detection wavelength: 214nm) Ionization (ESI) mass spectrometry.
术语“溶剂”是指在所描述的反应条件下，表现为惰性的溶剂，即不参与反应过程的溶剂。下述实施例中涉及到的溶剂包括例如乙腈、丙酮、异丙醇、正庚烷、甲基叔丁基醚、乙 酸异丙酯、乙醇、甲苯、甲醇、乙酸乙酯、水、二氯甲烷、二甲基亚砜、丁酮、四氢呋喃等。除非说明相反的情形，否则用于本发明反应中的溶剂为惰性有机溶剂。The term "solvent" refers to a solvent that behaves inertly under the described reaction conditions, ie, does not take part in the reaction process. Solvents involved in the following examples include, for example, acetonitrile, acetone, isopropanol, n-heptane, methyl tert-butyl ether, isopropyl acetate, ethanol, toluene, methanol, ethyl acetate, water, dichloromethane , dimethyl sulfoxide, butanone, tetrahydrofuran, etc. Unless stated to the contrary, the solvents used in the reactions of the present invention are inert organic solvents.
在研究过程中，对于化合物A及其原药的盐及其所形成的晶型进行了研究，发现所形成的盐不稳定，对于进一步改善和提高化合物A的稳定性以及放大生产等本身没有帮助。在研究过程中创造性发现可通过制备化合物A晶型，获得稳定性高、吸湿性极低的晶型产品，适合放大生产。During the research process, the salt of compound A and its original drug and its formed crystal form were studied, and it was found that the formed salt was unstable, which did not help to further improve and enhance the stability of compound A and scale up production. . During the research process, it was creatively discovered that the crystal form product with high stability and extremely low hygroscopicity can be obtained by preparing the crystal form of compound A, which is suitable for scale-up production.
实施例1Example 1
实施例1根据下述方法制备化合物A的晶型。首先参考公开号为WO2021007506A1中记载的方法制备获得下述化合物A(即WO2021007506A1公开文本中提到的化合物C-1)。Example 1 The crystal form of compound A was prepared according to the following method. Firstly, the following compound A (that is, the compound C-1 mentioned in the WO2021007506A1 publication) was prepared by referring to the method described in the publication number WO2021007506A1.
Figure PCTCN2022091605-appb-000005
Figure PCTCN2022091605-appb-000005
通过制备型HPLC(Pre-HPLC)对于含有产物的乙腈/水溶液进行纯化，然后通过旋蒸的方式除去溶液中的乙腈，获得结晶的产物，过滤获得相应的结晶，即获得样品B。The acetonitrile/water solution containing the product was purified by preparative HPLC (Pre-HPLC), and then the acetonitrile in the solution was removed by rotary evaporation to obtain a crystallized product, and the corresponding crystal was obtained by filtration, that is, sample B was obtained.
对上述制备的样品B进行XRPD、DSC、TGA表征。The sample B prepared above was characterized by XRPD, DSC and TGA.
其中X射线粉末衍射测定方法如下：Wherein the X-ray powder diffraction determination method is as follows:
利用配备了PIXceI 1D检测器的PANalytical EMPYREAN对实验中所得的固体进行了晶型分析。仪器参数如下所示：扫描范围：3°(2θ)to 40°(2θ)；步长：0.013°(2θ)；光管电压和电流分别为45KV和40mA。 The crystal form of the solid obtained in the experiment was analyzed by PANalytical EMPYREAN equipped with PIXceI 1D detector. The instrument parameters are as follows: scanning range: 3°(2θ) to 40°(2θ); step size: 0.013°(2θ); light tube voltage and current are 45KV and 40mA, respectively.
结果表明，所制备得到的样品B为晶型1，其XRPD图谱基本上如图1所示。XRPD结果如下表1所示：The results show that the prepared sample B is crystal form 1, and its XRPD pattern is basically shown in FIG. 1 . The XRPD results are shown in Table 1 below:
表1 XRPD表征结果Table 1 XRPD characterization results
2θ值2θ value 强度(％)strength(%) 2θ值2θ value 强度(％)strength(%)
8.698.69 100100 22.1722.17 7.67.6
9.749.74 6.56.5 22.8422.84 1.11.1
10.6810.68 25.625.6 23.7523.75 7.37.3
12.9112.91 6.66.6 24.1224.12 20.820.8
13.1013.10 14.714.7 25.0425.04 3.13.1
13.6313.63 0.90.9 25.6125.61 6.46.4
14.1114.11 10.210.2 25.8725.87 11
15.6115.61 14.914.9 26.4626.46 40.540.5
16.0416.04 18.118.1 26.9826.98 1.81.8
16.3816.38 5.95.9 27.3727.37 0.90.9
17.5217.52 35.835.8 27.5427.54 1.11.1
18.4718.47 3.13.1 28.0428.04 44
18.8318.83 9.79.7 28.2828.28 4.44.4
19.1519.15 77 28.5928.59 1.81.8
19.6319.63 3.73.7 29.3129.31 1.51.5
20.1220.12 41.441.4 29.6829.68 19.719.7
20.6220.62 9.49.4 30.0430.04 1.91.9
21.5521.55 9.79.7 31.2831.28 4.74.7
21.8621.86 16.216.2 -- --
差示扫描量热分析(DSC)是用于热分析的主要测量方法之一，可以用于测量作为原子/分子聚集体的物质的热特性。通过DSC测量物质随温度或者时间的热容变化，并且将获得的数据对温度或时间绘图，可以获得差示扫描量热曲线。基于该曲线，可以获得物质的起始浓度、吸热最大值和熔融峰等。其分析方法如下：Differential Scanning Calorimetry (DSC) is one of the main measurement methods used in thermal analysis and can be used to measure the thermal properties of substances as aggregates of atoms/molecules. The differential scanning calorimetry curve can be obtained by measuring the heat capacity change of a substance with temperature or time by DSC, and plotting the obtained data against temperature or time. Based on this curve, the initial concentration, endothermic maximum, and melting peak of the substance, etc. can be obtained. Its analysis method is as follows:
利用Discovery DSC 250(TA Instruments,US)对样品进行了热分析。称取样品置于DSC样品盘中并扎孔。将样品在25℃平衡后以10℃/min的速率加热至最后的温度。The samples were thermally analyzed using a Discovery DSC 250 (TA Instruments, US). The sample was weighed and placed in the DSC sample pan and punched. The sample was equilibrated at 25°C and heated to the final temperature at a rate of 10°C/min.
热重分析(TGA)方法如下：The thermogravimetric analysis (TGA) method is as follows:
利用TGA 55(TA Instruments,US)对样品进行热重分析。将样品置于已去皮的开口铝制样品盘重，样品质量在TGA加热炉内自动称量后，将样品以10℃/min的速率加热到最后的温度。Utilize TGA 55 (TA Instruments, US) to carry out thermogravimetric analysis to the sample. The sample was placed on a peeled open aluminum sample pan, and after the sample was automatically weighed in the TGA heating furnace, the sample was heated to the final temperature at a rate of 10°C/min.
实验结果表明，样品B在约225摄氏度有一个吸热峰，为晶型熔融吸热导致，熔点约为221摄氏度；TGA结果显示样品在熔融前有轻微失重(约1.8％)，如图2所示。The experimental results show that sample B has an endothermic peak at about 225 degrees Celsius, which is caused by the endothermic melting of the crystal form, and the melting point is about 221 degrees Celsius; TGA results show that the sample has a slight weight loss (about 1.8%) before melting, as shown in Figure 2 Show.
另外，实施例1通过缓慢冷却结晶的方法制备获得化合物A的单晶。将约50mg实施例1制备的化合物A样品在加热条件下溶解在0.5mL甲醇中。过滤溶液，将滤液放置室温过夜。在甲醇中冷却结晶得到了棒状结晶。In addition, in Example 1, a single crystal of Compound A was prepared by slow cooling and crystallization. About 50 mg of the compound A sample prepared in Example 1 was dissolved in 0.5 mL of methanol under heating. The solution was filtered and the filtrate was left at room temperature overnight. Cooling and crystallization in methanol gave rod-like crystals.
通过带有Ga Ka射线
Figure PCTCN2022091605-appb-000006
的Bruker D8X-射线衍射仪在169.99K下收集化合物A的单晶X-射线衍射数据。利用Olex2，用SHELXT结构解析程序采用内禀相位法对结构进行解析，并用SHELXL优化包利用最小二乘法进行优化。 by Ga Ka rays
Figure PCTCN2022091605-appb-000006
The single crystal X-ray diffraction data of Compound A were collected by a Bruker D8 X-ray diffractometer at 169.99K. Using Olex2, the SHELXT structure analysis program was used to analyze the structure using the intrinsic phase method, and the SHELXL optimization package was used to optimize the structure using the least square method.
该单晶样品属于单斜晶系，P 1 21 1空间群，分子式为C 27H 23F 2N 3O 7S e。每个不对称单元包含一个化合物A分子，每个晶胞包含2个分子。分子结构中包含两个手性碳原子，分别为“S”(C7)和“R”(C15)构型。单晶结构与分子结构一致。其单晶结构参数如下表2所示。 The single crystal sample belongs to the monoclinic crystal system, the space group P 1 21 1, and the molecular formula is C 27 H 23 F 2 N 3 O 7 Se . Each asymmetric unit contains one compound A molecule, and each unit cell contains 2 molecules. The molecular structure contains two chiral carbon atoms, respectively "S" (C7) and "R" (C15) configurations. The single crystal structure is consistent with the molecular structure. Its single crystal structure parameters are shown in Table 2 below.
表2 单晶结构参数Table 2 Single crystal structure parameters
Figure PCTCN2022091605-appb-000007
Figure PCTCN2022091605-appb-000007
通过单晶用Mercury拟合的XRPD与上述实验测得的XRPD进行比较，发现二者高度匹配。The XRPD fitted by Mercury through the single crystal is compared with the XRPD measured by the above experiment, and it is found that the two are highly matched.
实施例2Example 2
实施例2利用实施例1所获得的晶型1作为起始原料，探究了通过不同的实验手段对于晶型1的影响，如下所示：Example 2 Using the crystal form 1 obtained in Example 1 as the starting material, the influence of different experimental methods on the crystal form 1 was explored, as follows:
1、悬浮搅拌1. Suspension stirring
将起始原料置于单一溶剂(异丙醇、正庚烷、水、甲基叔丁基醚、乙酸异丙酯、乙醇、甲苯、甲醇或乙酸乙酯)中配成悬浮液，在室温或高温条件下(50℃)悬浮搅拌3天，过 滤所得固体进行XRPD表征，通过比较晶型1以及晶型1作为起始原料进行悬浮搅拌后的XPRD结果，表明在所有溶剂中均得到了稳定存在的晶型1，且结晶度好。具体结果如表3和表4所示。Put the starting material into a single solvent (isopropanol, n-heptane, water, methyl tert-butyl ether, isopropyl acetate, ethanol, toluene, methanol or ethyl acetate) to form a suspension, at room temperature or Suspended and stirred under high temperature conditions (50°C) for 3 days, filtered the obtained solid for XRPD characterization, and compared the XPRD results of crystal form 1 and crystal form 1 after suspension and stirring as the starting material, indicating that it was stable in all solvents. Crystal form 1 with good crystallinity. The specific results are shown in Table 3 and Table 4.
表3 室温单一悬浮搅拌结果Table 3 Stirring results of single suspension at room temperature
编号Numbering 溶剂solvent XRPD结果XRPD results 评价Evaluation
S1 S1 异丙醇Isopropanol 晶型1Form 1 结晶度好Good crystallinity
S2S2 正庚烷n-heptane 晶型1Form 1 结晶度好Good crystallinity
S3 S3 水water 晶型1Form 1 结晶度好Good crystallinity
S4S4 甲基叔丁基醚methyl tert-butyl ether 晶型1Form 1 结晶度好Good crystallinity
S5S5 乙酸异丙酯 Isopropyl acetate 晶型1Form 1 结晶度好Good crystallinity
S6 S6 乙醇ethanol 晶型1Form 1 结晶度好Good crystallinity
S7 S7 甲苯Toluene 晶型1Form 1 结晶度好Good crystallinity
S8 S8 甲醇Methanol 晶型1Form 1 结晶度好Good crystallinity
S9S9 乙酸乙酯 ethyl acetate 晶型1Form 1 结晶度好Good crystallinity
表4 高温单一悬浮搅拌结果Table 4 High temperature single suspension stirring results
编号Numbering 溶剂solvent XRPD结果XRPD results 评价Evaluation
S10 S10 异丙醇Isopropanol 晶型1Form 1 结晶度好Good crystallinity
S11S11 正庚烷n-heptane 晶型1Form 1 结晶度好Good crystallinity
S12 S12 水water 晶型1Form 1 结晶度好Good crystallinity
S13S13 甲基叔丁基醚methyl tert-butyl ether 晶型1Form 1 结晶度好Good crystallinity
S14S14 乙酸异丙酯 Isopropyl acetate 晶型1Form 1 结晶度好Good crystallinity
S15 S15 乙醇ethanol 晶型1Form 1 结晶度好Good crystallinity
S16 S16 甲苯toluene 晶型1Form 1 结晶度好Good crystallinity
S17 S17 甲醇Methanol 晶型1Form 1 结晶度好Good crystallinity
S18S18 乙酸乙酯 ethyl acetate 晶型1Form 1 结晶度好Good crystallinity
以上结果表明，所制备获得的晶型1不易受溶剂的影响，稳定性好，结晶度好。The above results show that the prepared crystal form 1 is not easily affected by the solvent, has good stability and good crystallinity.
2、反溶剂沉淀2. Anti-solvent precipitation
取一定量的起始原料溶解于0.1-1.2mL良溶剂中，滤后清液加入到不良溶剂中进行沉淀实验。例如以二氯甲烷、乙腈、二甲基亚砜、丁酮、丙酮、四氢呋喃作良溶剂，异丙醇、正庚烷、水等作反溶剂的体系中进行了反溶剂沉淀，均得到了晶型1。对过滤得到的固体进行表征，结果如表5。Take a certain amount of starting material and dissolve it in 0.1-1.2mL of good solvent, and add the clear liquid after filtration into the poor solvent for precipitation experiment. For example, anti-solvent precipitation was carried out in a system in which dichloromethane, acetonitrile, dimethyl sulfoxide, butanone, acetone, and tetrahydrofuran were used as good solvents, and isopropanol, n-heptane, water, etc. were used as anti-solvents, and crystals were obtained. Type 1. The solid obtained by filtration was characterized, and the results are shown in Table 5.
表5 反溶剂沉淀结果Table 5 Anti-solvent precipitation results
Figure PCTCN2022091605-appb-000008
Figure PCTCN2022091605-appb-000008
3、冷却结晶3. Cooling and crystallization
快速冷却：称取约50mg的样品B溶解到0.4mL甲醇中，在50℃条件下溶解，趁热过滤该溶液，将滤液直接放置到5℃的冰箱中保存约20h。对析出的晶体进行XRPD测试。Rapid cooling: Weigh about 50 mg of sample B and dissolve it in 0.4 mL of methanol, dissolve it at 50°C, filter the solution while it is hot, and store the filtrate directly in a refrigerator at 5°C for about 20 hours. XRPD test was carried out on the precipitated crystals.
慢速冷却：称取约50mg的样品B溶解到0.4mL甲醇中，在50℃条件下溶解，趁热过滤该溶液，将滤液放置在室温中缓慢降温约20h。对析出的晶体进行XRPD测试。Slow cooling: Weigh about 50 mg of sample B and dissolve it in 0.4 mL of methanol, dissolve it at 50°C, filter the solution while it is hot, and place the filtrate at room temperature to cool down slowly for about 20 hours. XRPD test was carried out on the precipitated crystals.
实验结果表明，采用两种速度进行冷却结晶，均获得了晶型1。The experimental results show that crystal form 1 was obtained by cooling and crystallizing at two speeds.
4、蒸发结晶4. Evaporation crystallization
采用混合溶剂进行蒸发结晶实验，寻找是否能得到其他的晶体。例如，称取约20mg的样品B置于样品瓶中，加入0.1-1mL的选定溶剂(混合溶剂)，过滤该溶液，将滤液放置于样品瓶中，采取不同的速率在室温中干燥。利用在样品瓶上覆盖带有小孔的封口膜的方式制备慢速挥发样品。所得到的固体采用PLM或者XRPD表征。Evaporation crystallization experiments were carried out using mixed solvents to find out whether other crystals could be obtained. For example, weigh about 20 mg of sample B into a sample bottle, add 0.1-1 mL of a selected solvent (mixed solvent), filter the solution, place the filtrate in a sample bottle, and dry at room temperature at different rates. Prepare slow evaporating samples by covering vials with Parafilm with small holes. The obtained solid was characterized by PLM or XRPD.
结果表明，在混合溶剂蒸发结晶实验中，混合体系如二氯甲烷/丁酮和二氯甲烷/丙酮二元溶剂体系中仍能获得结晶度较好的晶型1，在一些二元溶剂体系如乙腈/丁酮、丁酮/四氢呋喃中获得的固体为无定形样品。实验并未发现有新的晶型。The results show that in mixed solvent evaporation crystallization experiments, mixed systems such as dichloromethane/butanone and dichloromethane/acetone binary solvent systems can still obtain crystal form 1 with better crystallinity, and in some binary solvent systems such as The solids obtained in acetonitrile/butanone, butanone/tetrahydrofuran were amorphous samples. No new crystal form was found in the experiment.
实施例3Example 3
实施例3评价了不同机械处理对于晶型的影响。实验分别采用研磨实验和加压实验考察了对于晶型1的影响。如下所示：Example 3 evaluates the effect of different mechanical treatments on the crystal form. In the experiment, the effect on the crystal form 1 was investigated by grinding experiment and pressure experiment respectively. As follows:
1、研磨实验1. Grinding experiment
将适量的样品B置于研钵中，室温下研磨2-5分钟，在两分钟和五分钟的时候收集固体进行XRPD检测。实验结果表明，研磨后晶型不变。An appropriate amount of sample B was placed in a mortar and ground for 2-5 minutes at room temperature, and the solids were collected at two and five minutes for XRPD detection. Experimental results show that the crystal form remains unchanged after grinding.
2、加压实验2. Pressurization experiment
将适量的起始原料置于40Mpa压力下，加压约1分钟，收集固体进行XRPD检测。实验结果表明加压后晶型不变，均为晶型1。Put an appropriate amount of starting material under a pressure of 40Mpa, pressurize for about 1 minute, and collect the solid for XRPD detection. The experimental results show that the crystal form remains unchanged after pressurization, all of which are crystal form 1.
3、固态稳定性实验3. Solid state stability test
对样品B分别进行了40℃/75％RH和60℃闭口的7天固体稳定性和化学稳定性实验，并用XRPD和HPLC手段进行分析。Sample B was subjected to 7-day closed solid stability and chemical stability experiments at 40°C/75%RH and 60°C, respectively, and analyzed by XRPD and HPLC.
高效液相色谱分析(HPLC)用到的测定仪器为Agilent HPLC 1260系列仪器。HPLC测量方法如表6所示。The measuring instruments used in high performance liquid chromatography (HPLC) are Agilent HPLC 1260 series instruments. The HPLC measurement method is shown in Table 6.
表6 HPLC测量方法参数Table 6 HPLC measurement method parameters
Figure PCTCN2022091605-appb-000009
Figure PCTCN2022091605-appb-000009
XRPD结果显示晶型1在40℃/75％RH和60℃闭口条件下放置7天晶型不变(如图3所示)。HPLC结果表明晶型1在40℃/75％RH条件下放置7天化学纯度不会下降，稳定性良好。在60℃闭口条件下放置7天，其化学纯度仅下降0.14％，结果如表7。The XRPD results showed that the crystal form of Form 1 remained unchanged after 7 days under the conditions of 40°C/75%RH and 60°C with closed doors (as shown in Figure 3). The results of HPLC showed that the chemical purity of the crystal form 1 would not decrease when placed under the condition of 40°C/75%RH for 7 days, and the stability was good. The chemical purity was only decreased by 0.14% when placed under closed conditions at 60°C for 7 days. The results are shown in Table 7.
表7 晶型1的稳定性样品的HPLC结果The HPLC result of the stability sample of table 7 crystal form 1
条件condition XRPDXRPD HPLC检测纯度HPLC detection of purity
0day 0day 晶型1Form 1 100％100%
40℃/75％一周40℃/75% for one week 晶型1Form 1 100％100%
60℃/闭口一周60°C/closed mouth for one week 晶型1Form 1 99.86％99.86%
实施例4Example 4
首先，制备了样品C，其制备方法如下：First, Sample C was prepared as follows:
获得化合物A的粗品产物，利用丙酮(7V)回流溶清，蒸馏结晶，浓缩到体积约为1.5V，降温到20摄氏度，然后滴加3V甲基叔丁基醚继续结晶，过滤得到产物，命名为样品C。所制备得到的样品C为晶型1。Obtain the crude product of compound A, use acetone (7V) to reflux to dissolve, distill and crystallize, concentrate to a volume of about 1.5V, cool down to 20 degrees Celsius, then add 3V methyl tert-butyl ether dropwise to continue crystallization, filter to obtain the product, named For sample C. The prepared sample C is crystal form 1.
通过动态水蒸气吸附测定样品C在25℃/80％RH条件下的吸湿增重情况，检测结果表明：样品C在25℃/80％RH条件下吸湿增重仅为0.03％，几乎无引湿性。The moisture absorption weight gain of sample C under the condition of 25°C/80%RH was measured by dynamic water vapor adsorption, and the test results showed that the moisture absorption weight gain of sample C was only 0.03% under the condition of 25°C/80%RH, almost no hygroscopicity .
另外，在研究过程中发现：化合物A的晶型1在放大生产过程中更能表现出稳定性，也更适合生产放大。例如，通过重结晶的方法，以易溶溶剂丙酮为重结晶溶剂，在55℃下，对粗品进行溶解，然后浓缩丙酮，加入不良溶剂甲基叔丁基醚(MTBE)析晶，结果发现可以显著提高含有化合物A晶型1的产物的纯度，显著降低溶剂残留。In addition, during the research process, it was found that the crystal form 1 of compound A is more stable during the scale-up production process, and is more suitable for production scale-up. For example, by the method of recrystallization, the easily soluble solvent acetone is used as the recrystallization solvent, at 55 ° C, the crude product is dissolved, then the acetone is concentrated, and the poor solvent methyl tert-butyl ether (MTBE) is added for crystallization, and it is found that The purity of the product containing compound A crystal form 1 is significantly improved, and the residual solvent is significantly reduced.
实施例5Example 5
实施例5应用甲型流感病毒雪貂感染模型对实施例4中制备的样品C的体内抗病毒药效进行了评价。Example 5 The in vivo antiviral efficacy of the sample C prepared in Example 4 was evaluated using the influenza A virus ferret infection model.
实验选择雌性M.putorius雪貂(购自于无锡珊瑚礁生物科技有限公司)通过滴鼻方式感染甲型流感病毒(流感病毒A/PR/8/34，病毒株购于ATCC，货号:VR-1469)，感染量为每只动物5.4*10 6PFU(plaque forming unit,噬斑形成单位)，接种体积为0.2mL(0.1mL/每鼻孔)；然后进行灌胃给药，并在感染后第72小时收集实验雪貂的鼻腔灌洗液，检测其中的病毒滴度以评估样品对病毒复制的抑制作用。 In the experiment, female M.putorius ferrets (purchased from Wuxi Coral Reef Biotechnology Co., Ltd.) were infected with influenza A virus (influenza virus A/PR/8/34, purchased from ATCC, article number: VR-1469 ), the infection dose was 5.4*10 6 PFU (plaque forming unit, plaque forming unit) per animal, and the inoculation volume was 0.2 mL (0.1 mL/each nostril); The nasal lavage fluid of experimental ferrets was collected every hour, and the virus titer in it was detected to evaluate the inhibitory effect of the samples on virus replication.
实验动物分成4组。各处理组分别如下：Experimental animals were divided into 4 groups. The treatment groups are as follows:
样品C给药组：称取适量样品C，溶于5体积％DMSO+40体积％PEG400+55体积％DI水中，配制浓度分别为0.3mg/mL、2.0mg/mL。Sample C administration group: Weigh an appropriate amount of sample C and dissolve it in 5 vol% DMSO + 40 vol% PEG400 + 55 vol% DI water, and the prepared concentrations are 0.3 mg/mL and 2.0 mg/mL respectively.
阳性对照组：称取巴洛沙韦酯(货号：1627-125-22)粉末，溶于适量20体积％PEG400+20体积％(30％solutol HS 15水溶液)+60体积％普通生理盐水(0.9％)中，配制浓度为2.0mg/mL。Positive control group: Weigh baloxavir dipivoxil (article number: 1627-125-22) powder, dissolve in an appropriate amount of 20% by volume PEG400+20% by volume (30% solutol HS 15 aqueous solution)+60% by volume normal saline (0.9 %), the preparation concentration is 2.0mg/mL.
溶媒组：包括5体积％DMSO+40体积％PEG400+55体积％DI水。Vehicle group: including 5 vol% DMSO + 40 vol% PEG400 + 55 vol% DI water.
给药方式如下：Administration is as follows:
以5mL/kg的给药体积连续给药，第1-4组连续给药3天，首次给药时间为病毒接种前2小时。每天给药2次，间隔8/16小时，方式为灌胃。The administration volume of 5mL/kg was continuously administered for 3 days in groups 1-4, and the first administration time was 2 hours before virus inoculation. Administer twice a day with an interval of 8/16 hours by gavage.
(1)测定不同处理组雪貂的体重变化，结果如图4所示。以第0天体重为基准体重，计算雪貂每日体重变化百分比。误差线为标准误差，虚线为人道终点，任何雪貂体重下降低 于此标准(20％)将被执行安乐死。(1) Determination of body weight changes of ferrets in different treatment groups, the results are shown in Figure 4. Taking day 0 body weight as the baseline body weight, the percentage of daily body weight change of ferrets was calculated. Error bars are standard errors and dashed lines are humane endpoints below which any ferret that lost body weight (20%) will be euthanized.
(2)对于不同处理组雪貂的临床症状进行评分。评分标准如下：(2) Scoring the clinical symptoms of ferrets in different treatment groups. The scoring criteria are as follows:
活动量：活动量正常0分，活动量减少1分，不活跃，嗜睡2分；Activity level: 0 points for normal activity level, 1 point for decreased activity level, 2 points for inactivity and lethargy;
分泌物：无鼻分泌物0分，有鼻分泌物1分；Secretion: 0 points for no nasal secretions, 1 point for nasal secretions;
喷嚏：没有打喷嚏0分，打喷嚏1分。Sneezing: 0 points for no sneezing, 1 point for sneezing.
临床症状每日观察4次(9：00--21：00)，每4个小时观察一次，每次观察20分钟。The clinical symptoms were observed 4 times a day (9:00--21:00), once every 4 hours, and 20 minutes each time.
病毒接种后，各组雪貂的临床症状评分结果如图5所示。溶媒组雪貂受病毒感染影响，临床观察到嗜睡、鼻分泌物、喷嚏的次数明显增加。对照化合物巴洛沙韦组(10mg/kg)雪貂临床症状有所缓解，嗜睡、鼻分泌物、喷嚏症状的频次有所降低。而给药样品C，在设定剂量下(1.5mg/kg，10mg/kg)下，雪貂临床症状均优于溶媒组，嗜睡、鼻分泌物、喷嚏的症状得到显著改善，且随剂量增加，临床症状越轻微。After virus inoculation, the clinical symptom score results of the ferrets in each group are shown in Figure 5. The ferrets in the vehicle group were affected by the virus infection, and the frequency of lethargy, nasal secretions, and sneezing was significantly increased clinically. The clinical symptoms of ferrets in the control compound baloxavir group (10mg/kg) were relieved, and the frequency of lethargy, nasal secretions, and sneezing symptoms decreased. And administration sample C, under setting dosage (1.5mg/kg, 10mg/kg), ferret clinical symptom is all better than vehicle group, and lethargy, nasal discharge, the symptom of sneezing are significantly improved, and increases with dosage , the milder the clinical symptoms.
其中图5中，与溶媒组相比：*(第2组)，p<0.05；#(第3组)，p<0.05；^(第4组)，p<0.05,^^,p<0.01,^^^,p<0.001，Two Way ANOVA。Wherein in Fig. 5, compared with vehicle group: * (the 2nd group), p<0.05; # (the 3rd group), p<0.05; ^ (the 4th group), p<0.05, ^^, p<0.01 ,^^^, p<0.001, Two Way ANOVA.
(3)病毒接种后72小时收集鼻腔灌洗液样品，各组雪貂鼻腔灌洗液中甲型流感病毒的滴度总结于图6，采用空斑法测定，其中第一组为溶媒组，第二组为巴洛沙韦酯10mg/kg处理组，第三组为样品C 1.5mg/kg处理组，第四组为样品C 10mg/kg处理组，图6中LLOQ为定量下限。其中，溶媒组雪貂鼻腔灌洗液中的病毒滴度平均值为5.056Log 10(空斑数/mL鼻腔灌洗液，下同)，对照化合物巴洛沙韦酯(10mg/kg)组样品中的病毒滴度平均值为1.402Log 10；与溶媒组相比，差异均具有统计学意义(p<0.001)，显示了预期的抗病毒药效。(3) 72 hours after the virus inoculation, the nasal cavity lavage samples were collected. The titers of influenza A virus in the ferret nasal cavity lavages of each group were summarized in Fig. 6, and were measured by plaque method, wherein the first group was the vehicle group, The second group is the baloxavir dipivoxil 10mg/kg treatment group, the third group is the sample C 1.5mg/kg treatment group, the fourth group is the sample C 10mg/kg treatment group, and LLOQ is the lower limit of quantitation among Fig. 6 . Wherein, the virus titer mean value in vehicle group ferret nasal cavity lavage fluid is 5.056Log 10 (plaque number/mL nasal cavity lavage fluid, the same below), contrast compound baloxavir dipivoxil (10mg/kg) group sample The mean value of virus titers in the medium was 1.402Log 10; Compared with the vehicle group, the differences were statistically significant (p<0.001), showing expected antiviral efficacy.
而给药样品C(1.5mg/kg，10mg/kg)组：感染前2小时首次给药，在设定剂量(1.5mg/kg，10mg/kg)下雪貂鼻腔灌洗液中的病毒滴度分别为1.280Log 10和检测下限1.00Log 10。与溶媒组相比，病毒滴度平均值分别下降了3.776Log 10、4.056Log 10，所有差异均具有统计学意义(p<0.001)。与巴洛沙韦酯组相比，病毒滴度平均值分别下降了0.122Log 10、0.402Log10，所有差异均具有统计学意义(p<0.001)。And the administration sample C (1.5mg/kg, 10mg/kg) group: 2 hours before the first administration of infection, the virus drops in ferret nasal cavity lavage fluid under the set dose (1.5mg/kg, 10mg/kg) The degrees were 1.280 Log 10 and the lower limit of detection was 1.00 Log 10. Compared with the vehicle group, the average virus titers decreased by 3.776 Log 10 and 4.056 Log 10, respectively, and all the differences were statistically significant (p<0.001). Compared with the baloxavir dipivoxil group, the average virus titers decreased by 0.122 Log 10 and 0.402 Log 10 respectively, and all the differences were statistically significant (p<0.001).
其中图6中误差线显示标准误差。采用One Way ANOVA,Tukey’s多重比较(Tukey’s multiple comparisons test)进行统计学分析，与溶媒组相比：***,p<0.001。The error bars in Figure 6 show the standard error. One Way ANOVA, Tukey's multiple comparisons test was used for statistical analysis, compared with the vehicle group: ***, p<0.001.
上述结果表明，与对照组和10mg/kg巴洛沙韦组相比，1.5mg/kg和10mg/kg样品C组中，动物体重略微增加，显示样品C保护受感染动物体重下降，同时样品C可以改善动物临床症状并显著降低鼻腔灌洗液中的病毒载量，体现了极佳的体内抗病毒药效。The above results show that compared with the control group and 10mg/kg baloxavir group, in the 1.5mg/kg and 10mg/kg sample C groups, the animal body weight increased slightly, showing that sample C protected the infected animals from weight loss, while sample C It can improve the clinical symptoms of animals and significantly reduce the viral load in nasal lavage fluid, reflecting excellent antiviral efficacy in vivo.
需要说明的是，尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。It should be noted that although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limitations on the present invention. Variations, modifications, substitutions and variations are possible within the scope of the above-described embodiments.

Claims (16)

  1. 一种化合物的晶型，其特征在于，所述化合物为式A所示化合物，A crystal form of a compound, characterized in that the compound is a compound shown in formula A,
    Figure PCTCN2022091605-appb-100001
    Figure PCTCN2022091605-appb-100001
    所述晶型具有至少两个选自2θ为10.7±0.2、13.1±0.2、15.6±0.2、16.0±0.2、17.5±0.2、20.1±0.2、21.9±0.2、24.1±0.2、26.5±0.2和29.7±0.2的XRPD特征峰。The crystal form has at least two 2θ selected from 10.7±0.2, 13.1±0.2, 15.6±0.2, 16.0±0.2, 17.5±0.2, 20.1±0.2, 21.9±0.2, 24.1±0.2, 26.5±0.2 and 29.7±0.2 XRPD characteristic peak of 0.2.
  2. 根据权利要求1所述的晶型，其特征在于，所述晶型具有至少三个、至少四个、至少五个、至少六个、至少七个、至少八个或至少九个选自2θ为10.7±0.2、13.1±0.2、15.6±0.2、16.0±0.2、17.5±0.2、20.1±0.2、21.9±0.2、24.1±0.2、26.5±0.2和29.7±0.2的XRPD特征峰；The crystal form according to claim 1, characterized in that, the crystal form has at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine selected from 2θ being XRPD characteristic peaks of 10.7±0.2, 13.1±0.2, 15.6±0.2, 16.0±0.2, 17.5±0.2, 20.1±0.2, 21.9±0.2, 24.1±0.2, 26.5±0.2 and 29.7±0.2;
    优选地，所述晶型具有2θ为10.7±0.2、13.1±0.2、15.6±0.2、16.0±0.2、17.5±0.2、20.1±0.2、21.9±0.2、24.1±0.2、26.5±0.2和29.7±0.2的XRPD特征峰。Preferably, the crystal form has a 2θ of 10.7±0.2, 13.1±0.2, 15.6±0.2, 16.0±0.2, 17.5±0.2, 20.1±0.2, 21.9±0.2, 24.1±0.2, 26.5±0.2 and 29.7±0.2 XRPD characteristic peaks.
  3. 根据权利要求1所述的晶型，其特征在于，所述晶型进一步具有至少一个选自2θ为14.1±0.2、18.8±0.2、20.6±0.2和21.6±0.2的XRPD特征峰；The crystal form according to claim 1, wherein the crystal form further has at least one XRPD characteristic peak selected from 2θ of 14.1±0.2, 18.8±0.2, 20.6±0.2 and 21.6±0.2;
    优选地，所述晶型进一步具有至少两个选自2θ为14.1±0.2、18.8±0.2、20.6±0.2和21.6±0.2的XRPD特征峰；Preferably, the crystal form further has at least two XRPD characteristic peaks selected from 2θ of 14.1±0.2, 18.8±0.2, 20.6±0.2 and 21.6±0.2;
    优选地，所述晶型进一步具有至少三个选自2θ为14.1±0.2、18.8±0.2、20.6±0.2和21.6±0.2的XRPD特征峰；Preferably, the crystal form further has at least three XRPD characteristic peaks selected from 2θ of 14.1±0.2, 18.8±0.2, 20.6±0.2 and 21.6±0.2;
    优选地，所述晶型进一步具有2θ为14.1±0.2、18.8±0.2、20.6±0.2和21.6±0.2的XRPD特征峰。Preferably, the crystal form further has XRPD characteristic peaks with 2θ of 14.1±0.2, 18.8±0.2, 20.6±0.2 and 21.6±0.2.
  4. 根据权利要求1所述的晶型，其特征在于，所述晶型进一步具有至少一个选自2θ为9.7±0.2、16.4±0.2、19.1±0.2、22.2±0.2、23.7±0.2、25.6±0.2、28.0±0.2、28.3±0.2和31.3±0.2的XRPD特征峰；The crystal form according to claim 1, wherein the crystal form further has at least one selected from the group consisting of 2θ of 9.7±0.2, 16.4±0.2, 19.1±0.2, 22.2±0.2, 23.7±0.2, 25.6±0.2, XRPD characteristic peaks of 28.0±0.2, 28.3±0.2 and 31.3±0.2;
    优选地，所述晶型进一步具有至少两个选自2θ为9.7±0.2、16.4±0.2、19.1±0.2、22.2±0.2、 23.7±0.2、25.6±0.2、28.0±0.2、28.3±0.2和31.3±0.2的XRPD特征峰；Preferably, the crystal form further has at least two 2θ selected from 9.7±0.2, 16.4±0.2, 19.1±0.2, 22.2±0.2, 23.7±0.2, 25.6±0.2, 28.0±0.2, 28.3±0.2 and 31.3±0.2 XRPD characteristic peak of 0.2;
    优选地，所述晶型进一步具有至少三个选自2θ为9.7±0.2、16.4±0.2、19.1±0.2、22.2±0.2、23.7±0.2、25.6±0.2、28.0±0.2、28.3±0.2和31.3±0.2的XRPD特征峰；Preferably, the crystal form further has at least three 2θ selected from 9.7±0.2, 16.4±0.2, 19.1±0.2, 22.2±0.2, 23.7±0.2, 25.6±0.2, 28.0±0.2, 28.3±0.2 and 31.3±0.2 XRPD characteristic peak of 0.2;
    优选地，所述晶型进一步具有至少四个选自2θ为9.7±0.2、16.4±0.2、19.1±0.2、22.2±0.2、23.7±0.2、25.6±0.2、28.0±0.2、28.3±0.2和31.3±0.2的XRPD特征峰；Preferably, the crystal form further has at least four 2θ selected from 9.7±0.2, 16.4±0.2, 19.1±0.2, 22.2±0.2, 23.7±0.2, 25.6±0.2, 28.0±0.2, 28.3±0.2 and 31.3±0.2 XRPD characteristic peak of 0.2;
    优选地，所述晶型进一步具有至少五个选自2θ为9.7±0.2、16.4±0.2、19.1±0.2、22.2±0.2、23.7±0.2、25.6±0.2、28.0±0.2、28.3±0.2和31.3±0.2的XRPD特征峰；Preferably, the crystal form further has at least five 2θ selected from 9.7±0.2, 16.4±0.2, 19.1±0.2, 22.2±0.2, 23.7±0.2, 25.6±0.2, 28.0±0.2, 28.3±0.2 and 31.3±0.2 XRPD characteristic peak of 0.2;
    优选地，所述晶型进一步具有至少六个选自2θ为9.7±0.2、16.4±0.2、19.1±0.2、22.2±0.2、23.7±0.2、25.6±0.2、28.0±0.2、28.3±0.2和31.3±0.2的XRPD特征峰；Preferably, the crystal form further has at least six 2θ selected from 9.7±0.2, 16.4±0.2, 19.1±0.2, 22.2±0.2, 23.7±0.2, 25.6±0.2, 28.0±0.2, 28.3±0.2 and 31.3±0.2 XRPD characteristic peak of 0.2;
    优选地，所述晶型进一步具有至少七个选自2θ为9.7±0.2、16.4±0.2、19.1±0.2、22.2±0.2、23.7±0.2、25.6±0.2、28.0±0.2、28.3±0.2和31.3±0.2的XRPD特征峰；Preferably, the crystal form further has at least seven 2θ selected from 9.7±0.2, 16.4±0.2, 19.1±0.2, 22.2±0.2, 23.7±0.2, 25.6±0.2, 28.0±0.2, 28.3±0.2 and 31.3±0.2 XRPD characteristic peak of 0.2;
    优选地，所述晶型进一步具有至少八个选自2θ为9.7±0.2、16.4±0.2、19.1±0.2、22.2±0.2、23.7±0.2、25.6±0.2、28.0±0.2、28.3±0.2和31.3±0.2的XRPD特征峰；Preferably, the crystal form further has at least eight 2θ selected from 9.7±0.2, 16.4±0.2, 19.1±0.2, 22.2±0.2, 23.7±0.2, 25.6±0.2, 28.0±0.2, 28.3±0.2 and 31.3±0.2 XRPD characteristic peak of 0.2;
    优选地，所述晶型进一步具有选自2θ为9.7±0.2、16.4±0.2、19.1±0.2、22.2±0.2、23.7±0.2、25.6±0.2、28.0±0.2、28.3±0.2和31.3±0.2的XRPD特征峰。Preferably, the crystalline form further has an XRPD selected from 2θ of 9.7±0.2, 16.4±0.2, 19.1±0.2, 22.2±0.2, 23.7±0.2, 25.6±0.2, 28.0±0.2, 28.3±0.2 and 31.3±0.2 Characteristic peaks.
  5. 根据权利要求1所述的晶型，其特征在于，所述晶型具有基本上如图1所示的X射线粉末衍射图案。The crystal form according to claim 1, wherein the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  6. 根据权利要求1所述的晶型，其特征在于，所述晶型在221～224摄氏度具有熔融峰。The crystal form according to claim 1, characterized in that the crystal form has a melting peak at 221-224 degrees Celsius.
  7. 根据权利要求1所述的晶型，其特征在于，所述晶型具有基本上如图2所示的DSC和TGA图谱结果。The crystal form according to claim 1, characterized in that the crystal form has the results of DSC and TGA spectra substantially as shown in FIG. 2 .
  8. 一种化合物的晶型，其特征在于，所述晶型为单斜晶体，所述化合物为式A所示化合物，A crystal form of a compound, characterized in that the crystal form is a monoclinic crystal, and the compound is a compound shown in Formula A,
    Figure PCTCN2022091605-appb-100002
    Figure PCTCN2022091605-appb-100002
    所述晶型具有如下晶胞参数：The crystal form has the following unit cell parameters:
    a为约7.1埃、b为约20.0埃、c为约9.4埃、α为约90.0°、β为约108.8°、γ为约90.0°。a is about 7.1 angstroms, b is about 20.0 angstroms, c is about 9.4 angstroms, α is about 90.0°, β is about 108.8°, and γ is about 90.0°.
  9. 一种权利要求1～8任一项所述晶型的制备方法，其特征在于，将化合物A溶于单一溶剂或混合溶剂，蒸馏浓缩掉所述化合物A的溶液中的部分溶剂，以便获得化合物A的浓缩溶液，降温结晶以便获得所述化合物A的晶型。A method for preparing the crystal form according to any one of claims 1 to 8, characterized in that compound A is dissolved in a single solvent or a mixed solvent, and part of the solvent in the solution of compound A is concentrated by distillation to obtain compound Concentrated solution of A, cooling crystallization in order to obtain the crystal form of compound A.
  10. 根据权利要求9所述的制备方法，其特征在于，所述单一溶剂为有机溶剂，所述混合溶剂为有机溶剂和水的混合液，其中有机溶剂选自乙腈、丙酮、异丙醇、正庚烷、甲基叔丁基醚、乙酸异丙酯、乙醇、甲苯、甲醇和乙酸乙酯。The preparation method according to claim 9, wherein the single solvent is an organic solvent, and the mixed solvent is a mixed solution of an organic solvent and water, wherein the organic solvent is selected from acetonitrile, acetone, isopropanol, n-heptyl alkanes, methyl tert-butyl ether, isopropyl acetate, ethanol, toluene, methanol and ethyl acetate.
  11. 根据权利要求9所述的制备方法，其特征在于，所述方法进一步包括，以易溶溶剂丙酮为重结晶溶剂，在回流条件下，对化合物A粗品进行溶解，然后浓缩丙酮，加入不良溶剂甲基叔丁基醚(MTBE)析晶。The preparation method according to claim 9, characterized in that, the method further comprises, using the easily soluble solvent acetone as the recrystallization solvent, under reflux conditions, dissolving the crude product of compound A, then concentrating the acetone, adding the poor solvent A Methyl tert-butyl ether (MTBE) crystallization.
  12. 根据权利要求9所述的制备方法，其特征在于，所述方法进一步包括，将化合物A的粗品利用丙酮回流溶清，将丙酮溶剂浓缩到原来体积的0.2～0.3倍量，降温到10到30摄氏度，然后滴加原丙酮溶剂体积0.4～0.6倍量的甲基叔丁基醚，继续结晶，过滤得到晶型产物。The preparation method according to claim 9, characterized in that, the method further comprises, using acetone to reflux the crude product of compound A to dissolve it, concentrating the acetone solvent to 0.2 to 0.3 times the original volume, cooling down to 10 to 30 Celsius, then dropwise add methyl tert-butyl ether in an amount 0.4 to 0.6 times the volume of the original acetone solvent, continue to crystallize, and filter to obtain a crystalline product.
  13. 一种药物组合物，其特征在于，所述药物组合物包括权利要求1～8中任一项所述的晶型，以及药学上可接受的载体。A pharmaceutical composition, characterized in that the pharmaceutical composition comprises the crystal form according to any one of claims 1-8, and a pharmaceutically acceptable carrier.
  14. 一种在体外抑制流感病毒活性的方法，其特征在于，包括：在体外，将细胞和有效 量的权利要求1～8中任一项所述的晶型或者权利要求13所述的药物组合物接触。A method for inhibiting the activity of influenza virus in vitro, characterized by comprising: in vitro, combining cells and an effective amount of the crystal form according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 13 touch.
  15. 一种预防或治疗流感的方法，其特征在于，包括向有需要的受试者给予有效量的权利要求1～8中任一项所述的晶型或者权利要求13所述的药物组合物。A method for preventing or treating influenza, characterized by comprising administering an effective amount of the crystal form of any one of claims 1 to 8 or the pharmaceutical composition of claim 13 to a subject in need.
  16. 权利要求1～8中任一项所述的晶型或者权利要求13所述的药物组合物在制备预防或治疗流感的药物中的用途。Use of the crystal form according to any one of claims 1-8 or the pharmaceutical composition according to claim 13 in the preparation of a medicament for preventing or treating influenza.
PCT/CN2022/091605 2021-05-10 2022-05-09 Crystal form of compound for treating influenza, and application thereof WO2022237710A1 (en)

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