WO2019141241A1 - 一种吲哚衍生物的晶型及其制备方法和用途 - Google Patents

一种吲哚衍生物的晶型及其制备方法和用途 Download PDF

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WO2019141241A1
WO2019141241A1 PCT/CN2019/072357 CN2019072357W WO2019141241A1 WO 2019141241 A1 WO2019141241 A1 WO 2019141241A1 CN 2019072357 W CN2019072357 W CN 2019072357W WO 2019141241 A1 WO2019141241 A1 WO 2019141241A1
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compound
benefit
crystalline
crth2
mediated disease
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PCT/CN2019/072357
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English (en)
French (fr)
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姚元山
陈斌
高峰
陈远
徐然
杨成帅
张生
黎健
陈曙辉
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正大天晴药业集团股份有限公司
南京明德新药研发股份有限公司
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Application filed by 正大天晴药业集团股份有限公司, 南京明德新药研发股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CA3088917A priority Critical patent/CA3088917A1/en
Priority to AU2019209725A priority patent/AU2019209725B2/en
Priority to EP19741497.2A priority patent/EP3741754A4/en
Priority to KR1020207023814A priority patent/KR20200111733A/ko
Priority to JP2020539286A priority patent/JP7296970B2/ja
Priority to US16/963,052 priority patent/US11034681B2/en
Priority to CN201980007825.7A priority patent/CN111542519B/zh
Publication of WO2019141241A1 publication Critical patent/WO2019141241A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

Definitions

  • the present application relates to a crystalline form of an anthracene derivative and a process for the preparation thereof, and to the use of the crystalline form for the preparation of a medicament for the treatment of a condition associated with the CRTH2 receptor.
  • CRTH2 (DP2 or GPR44) is a G protein-coupled receptor that, when combined with prostaglandin (PGD2), is involved in the activation and chemotaxis of Th2 lymphocytes, eosinophils, and basophils, inhibiting Th2 Apoptosis of lymphocytes stimulates the production of IL4, IL5 and IL13.
  • PGD2 prostaglandin
  • Ramatroban is an antagonist of the TP (thromboxane-type prostanoid receptor) receptor, which has strong blood vessel, bronchial smooth muscle contraction and platelet activation.
  • Rematriptan is a weaker CRTH2 receptor antagonist. Rema Quban has approved the treatment of allergic rhinitis in Japan.
  • WO2005044260 reports compound OC459
  • WO2005123731 reports compound QAW-039.
  • the application provides Form A of Compound 1, the X-ray powder diffraction pattern having diffraction peaks at the following 2 theta angles: 12.78 ⁇ 0.2 °, 15.43 ⁇ 0.2 °, 21.25 ⁇ 0.2 °,
  • the present application provides a process for the preparation of Form A of Compound 1, which comprises adding Compound 1 to an alcohol solvent, recrystallizing or beating.
  • the present application provides a crystalline composition wherein Form A of Compound 1 comprises more than 50% by weight of the crystalline composition, preferably more than 80%, more preferably more than 90%, most preferably It is more than 95%.
  • the application provides a pharmaceutical composition comprising a therapeutically effective amount of Form A of Compound 1, or a crystalline composition as described above.
  • the present application provides the use of Form A of Compound 1 or the above crystalline composition or the above pharmaceutical composition for the preparation of a medicament for the treatment of a CRTH2-mediated disease.
  • the application provides a method of treating a CRTH2 receptor mediated disease comprising administering to a mammal in need thereof, preferably a human, a therapeutically effective amount of Form A of Compound 1 or a crystalline composition as described above or a medicament as described above combination.
  • the application provides Form A of Compound 1 or a crystalline composition as described above or a pharmaceutical composition as described above for use in the treatment of a CRTH2 receptor mediated disease.
  • the application provides Form A of Compound 1, the X-ray powder diffraction pattern having diffraction peaks at the following 2 theta angles: 12.78 ⁇ 0.2 °, 15.43 ⁇ 0.2 °, 21.25 ⁇ 0.2 °,
  • the X-ray powder diffraction pattern of Form A of Compound 1 above has diffraction peaks at the following 2 theta angles: 7.12 ⁇ 0.2 °, 12.25 ⁇ 0.2 °, 12.78 ⁇ 0.2 °, 15.43 ⁇ 0.2 °, 18.76 ⁇ 0.2 °, 20.02 ⁇ 0.2 °, 20.77 ⁇ 0.2 °, 21.25 ⁇ 0.2 °.
  • the diffraction peak in the X-ray powder diffraction pattern of Form A of Compound 1 above has the following characteristics:
  • the X-ray powder diffraction (XRPD) pattern of Form A of Compound 1 above is substantially as shown in FIG.
  • the X-ray powder diffraction of the present application uses Cu-K ⁇ radiation.
  • the differential scanning calorimetry (DSC) curve for Form A of Compound 1 above has an onset of endothermic peak at 278.41 °C ⁇ 5 °C.
  • the DSC pattern of Form A of Compound 1 above is substantially as shown in Figure 2.
  • thermogravimetric analysis (TGA) pattern of Form A of Compound 1 above is substantially as shown in FIG.
  • the present application also provides a process for the preparation of Form A of Compound 1 above, which comprises adding Compound 1 to an alcohol solvent, recrystallizing or beating.
  • the above alcohol solvent is selected from one or more of the group consisting of methanol, ethanol, and isopropyl alcohol.
  • the above alcohol solvent is selected from the group consisting of ethanol.
  • the method of preparing Form A of Compound 1 above further comprises filtering and/or drying.
  • the method for preparing Form A of Compound 1 above has a beating temperature of 70-90 °C. In some embodiments of the present application, the pulping temperature of the method for preparing Form A of Compound 1 above is 80 °C.
  • the present application provides a crystalline composition wherein Form A of Compound 1 comprises more than 50% by weight of the crystalline composition, preferably more than 80%, more preferably more than 90%, most preferably It is more than 95%.
  • the present application also provides a pharmaceutical composition comprising the crystalline form A of Compound 1 above or the above crystalline composition.
  • the pharmaceutical compositions of the present application further comprise a pharmaceutically acceptable excipient.
  • the present application also provides the use of Form A of Compound 1 above or the above crystalline composition or the above pharmaceutical composition for the preparation of a medicament for the treatment of a CRTH2-mediated disease.
  • the invention provides a method of treating a CRTH2 receptor mediated disease comprising administering to a mammal in need of such treatment a therapeutically effective amount of Form A of Compound 1 or a crystalline composition as described above or a pharmaceutical composition as described above.
  • the mammal is a human.
  • the application provides Form A of Compound 1 or a crystalline composition as described above or a pharmaceutical composition as described above for use in the treatment of a CRTH2 receptor mediated disease.
  • the CRTH2 receptor mediated disease is asthma (can complement other disease types).
  • the crystal form A of the present compound has good stability and is easy to form a drug; its inhibitory effect on the CRTH2 receptor is obvious, and the mouse induced by ovalbumin (OVA) and aluminum hydroxide (Al(OH) 3 ) is chronic / In the acute asthma model, Compound A crystal form A significantly reduced the number of eosinophils.
  • pharmaceutically acceptable is in the sense of those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • auxiliary generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, any adjuvants, excipients, glidants, sweeteners, diluents, preservatives, dyes approved by the National Drug Administration for human or domestic use. Colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents and/or emulsifiers.
  • treating means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, including:
  • terapéuticaally effective amount refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect.
  • the determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • the diffraction spectrum obtained from the crystalline compound is often characteristic for a specific crystal form, wherein the relative intensity of the band (especially at a low angle) may be due to crystallization conditions.
  • the dominant orientation effect due to the difference in particle size and other measurement conditions varies. Therefore, the relative intensities of the diffraction peaks are not characteristic for the crystal form to be targeted.
  • the position of the peak can be shifted due to changes in temperature during sample analysis, sample movement, or calibration of the instrument, etc., and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2°. Therefore, this error should be taken into account when determining each crystal structure.
  • the peak positions of the XRD spectrum have similarities as a whole, and the relative intensity error may be large.
  • the DSC measures the transition temperature when the crystal absorbs or releases heat due to a change in crystal structure or crystal melting.
  • the thermal transition temperature and melting point error are typically within about 5 ° C in a continuous analysis.
  • a compound has a given DSC peak or melting point, this is Refers to the DSC peak or melting point ⁇ 5 ° C.
  • DSC provides an auxiliary method for identifying different crystal forms. Different crystal morphology can be identified based on their different transition temperature characteristics.
  • intermediate compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the present application.
  • DMF stands for N,N-dimethylformamide
  • MsOH stands for methanesulfonic acid
  • EtOH stands for ethanol
  • NaOH sodium hydroxide
  • the XRPD parameters are as follows:
  • DSC Differential Scanning Calorimeter
  • Test method A sample (0.5 to 1 mg) was placed in a DSC aluminum pan for testing, and the sample was heated from room temperature to 300 ° C at a heating rate of 10 ° C/min under a condition of 50 mL/min N 2 .
  • TGA Thermal Gravimetric Analyzer
  • Test method A sample (2 to 5 mg) was placed in a TGA platinum pot for testing, and the sample was heated from room temperature to 300 ° C at a heating rate of 10 ° C/min under a condition of 25 mL/min N 2 .
  • Figure 1 is an XRPD spectrum of Form A of Compound 1;
  • Figure 2 is a DSC spectrum of Form A of Compound 1;
  • Figure 3 is a TGA spectrum of Form A of Compound 1.
  • Trifluoroacetic acid (5.14 g, 45.05 mmol) and three were added sequentially to a solution of compound 1f (3.70 g, 15.02 mmol) and compound 1 g (2.24 g, 15.02 mmol) in 50 mL of 1,2-dichloroethane under a nitrogen atmosphere.
  • Ethyl silane (8.73 g, 75.08 mmol).
  • the resulting mixture was stirred at 60 ° C for 2 hours.
  • 90 mL of a saturated aqueous sodium hydrogencarbonate solution and dichloromethane (30 mL x 3) were added to the mixture.
  • the organic phase was dried with anhydrous sodium
  • Compound 1 (100.0 g) was beaten with ethanol (400 mL) at 80 ° C for 48 hours. After cooling to room temperature and suction filtration, a white solid was obtained, and dried under vacuum at 45 ° C for 24 hours to obtain the crystal form A of Compound 1.
  • the XRPD spectrum of the A crystal form of the obtained Compound 1 is shown in Fig. 1; the DSC spectrum of the A crystal form of the obtained Compound 1 is shown in Fig. 2; the TGA spectrum of the A crystal form of the obtained Compound 1 is shown in Fig. 3. .
  • CHO-K1CRTH2 ⁇ -arrestin cells (DiscoverX, Cat. No. 93-0291C2) were grown under standard conditions and seeded at 5,000 cells/well in a white walled 384-well plate with 20 ⁇ l of Cell Plating Reagent 1 per well. Cells were incubated overnight at 37 ° C / 5% CO 2 before testing.
  • the test compounds were serially diluted in DMSO with a dilution factor of 3 to give 8 concentrations of test compounds in serial dilutions. Shortly before the test, the previously serially diluted test compound was further diluted with test buffer to a concentration of 5 times the test concentration.
  • Plasma pharmacokinetic experiments were performed using 12 female C57BL/6 mice, randomly divided into two groups of 6 animals each. The first group of animals was given an intravenous drug test dose of 1 mg/kg, and the second group was given a drug test dose of 5 mg/kg.
  • Formulation solvent contains HPbCD and cosolvent
  • the formulation, the obtained intravenous or intragastric preparations are clear solutions.
  • blood was collected using the saphenous vein at 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration, and each sample was 3 samples. Plasma samples collected by intragastric administration were stored frozen at -80 ° C and thawed prior to LC-MS/MS sample analysis.
  • the thawed plasma samples were subjected to protein precipitation by adding acetonitrile containing an internal standard in a certain ratio, and centrifuged to obtain a supernatant for LC-MS/MS injection.
  • the analytical instrument used API4000 or 5500, and the column was ACQUITY UPLC BEH C18 (2.1 ⁇ 50 mm, 1.7 ⁇ m), and the ionization of the test compound was performed using an ESI positive or negative ion source.
  • Each analysis batch contains 8 concentrations of the standard, the ratio of the peak area to the internal standard (IS) peak area of the test compound is Y, and the concentration of the test compound in the plasma sample is X, and is 1/ x 2 is a linear regression of the weighting coefficients, and a regression equation for determining the response and concentration is obtained.
  • Each analysis batch also contains the corresponding quality control samples. Use Phoenix 6.3 Perform data processing and obtain the corresponding PK parameters. The test results are shown in Table 3.

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Abstract

一种吲哚衍生物（化合物1）的晶型及其药物组合物和制备方法被公开，所述晶型用于制备治疗与CRTH2受体相关病症的药物。

Description

一种吲哚衍生物的晶型及其制备方法和用途
相关申请的交叉引用
本申请要求于2018年01月19日向中国国家知识产权局提交的第201810052775.1号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本申请涉及一种吲哚衍生物的晶型及其制备方法，还涉及所述晶型在制备用于治疗与CRTH2受体相关的病症的药物中的应用。
背景技术
CRTH2(DP2或GPR44)是G蛋白偶联受体，和前列腺素(Prostaglandin)(PGD2)结合后会参与Th2淋巴细胞、嗜酸性粒细胞和嗜碱性粒细胞的活化和趋化作用，抑制Th2淋巴细胞的凋亡，刺激产生IL4、IL5和IL13。这些白细胞介素参与重要的生物反应，包括嗜酸性粒细胞的募集和存活，粘液分泌、气道高反应性和免疫球蛋白E(IgE)的产生。
雷马曲班(Ramatroban)是TP(thromboxane-type prostanoid receptor)受体的拮抗剂，具有极强的血管、支气管平滑肌收缩作用和血小板活化作用。雷马曲班是较弱的CRTH2受体拮抗剂。雷马曲班已在日本批准治疗过敏性鼻炎。
WO2005044260报道了化合物OC459，WO2005123731报道了化合物QAW-039。
Figure PCTCN2019072357-appb-000001
发明概述
一方面，本申请提供了化合物1的A晶型，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：12.78±0.2°、15.43±0.2°、21.25±0.2°，
Figure PCTCN2019072357-appb-000002
另一方面，本申请提供了化合物1的A晶型的制备方法，包括将化合物1加入到醇类溶剂中，经重结晶或打浆制得。
另一方面，本申请提供了结晶组合物，其中化合物1的A晶型占所述结晶组合物重量的50％以上，较好的是80％以上，更好的是90％以上，最好的是95％以上。
又一方面，本申请提供了药物组合物，其包含治疗有效量的化合物1的A晶型或者上述结晶组合物。
再一方面，本申请提供了化合物1的A晶型或上述结晶组合物或上述药物组合物在制备用于治疗CRTH2介导的疾病的药物中的应用。
另一方面，本申请提供了治疗CRTH2受体介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人，给予治疗有效量的化合物1的A晶型或上述结晶组合物或上述药物组合物。
另一方面，本申请提供了用于治疗CRTH2受体介导的疾病的化合物1的A晶型或上述结晶组合物或上述药物组合物。
发明详述
一方面，本申请提供了化合物1的A晶型，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：12.78±0.2°、15.43±0.2°、21.25±0.2°，
Figure PCTCN2019072357-appb-000003
本申请的一些实施方案中，上述化合物1的A晶型的X射线粉末衍射图谱在下列2θ角处具有衍射峰：7.12±0.2°、12.25±0.2°、12.78±0.2°、15.43±0.2°、18.76±0.2°、20.02±0.2°、20.77±0.2°、21.25±0.2°。
本申请的一些实施方案中，上述化合物1的A晶型的X射线粉末衍射图谱中的衍射峰具有如下特征：
编号 2θ角(°) 相对高度(％) 编号 2θ角(°) 相对高度(％)
1 7.12 19 20 24.58 21
2 12.25 18 21 24.93 9
3 12.78 44 22 25.37 7
4 14.05 6 23 25.60 25
5 15.43 59 24 26.10 17
6 16.22 12 25 26.75 11
7 17.34 7 26 27.24 5
8 17.84 15 27 27.99 12
9 18.76 31 28 28.46 6
10 19.65 10 29 28.84 13
11 20.02 52 30 29.19 5
12 20.30 8 31 31.07 21
13 20.77 57 32 31.44 6
14 21.25 100 33 32.00 6
15 21.91 6 34 32.69 9
16 22.15 16 35 34.07 8
17 22.68 17 36 34.25 8
18 23.28 7 37 35.57 9
19 24.14 8 38 36.12 5
本申请的一些实施方案中，上述化合物1的A晶型的X射线粉末衍射(XRPD)图谱基本如图1所示。
本申请的X射线粉末衍射使用Cu-Kα辐射。本申请的一些实施方案中，上述化合物1的A晶型的差示扫描量热(DSC)曲线在278.41℃±5℃处具有吸热峰的起始点。
本申请的一些实施方案中，上述化合物1的A晶型的DSC图谱基本如图2所示。
本申请的一些实施方案中，上述化合物1的A晶型的热重分析(TGA)图谱基本如图3所示。
另一方面，本申请还提供了上述化合物1的A晶型的制备方法，包括将化合物1加入到醇类溶剂中，经重结晶或打浆制得。
本申请的一些实施方案中，上述醇类溶剂选自甲醇、乙醇和异丙醇中的一种或多种。
本申请的一些实施方案中，上述醇类溶剂选自乙醇。
本申请的一些实施方案中，上述化合物1的A晶型的制备方法还包括过滤和/或干燥。
本申请的一些实施方案中，上述化合物1的A晶型制备方法的打浆温度为70-90℃。本申请的一些实施方案中，上述化合物1的A晶型制备方法的打浆温度为80℃。
另一方面，本申请提供了结晶组合物，其中化合物1的A晶型占所述结晶组合物重量的50％以上，较好的是80％以上，更好的是90％以上，最好的是95％以上。
另一方面，本申请还提供了药物组合物，其包含上述化合物1的A晶型或上述结晶组合物。在一些实施方案中，本申请的药物组合物还包含药学上可接受的辅料。
另一方面，本申请还提供了上述化合物1的A晶型或上述结晶组合物或上述药物组合物在制备用于治疗CRTH2介导的疾病的药物中的应用。
另一方面，本申请提供了治疗CRTH2受体介导的疾病的方法，包括对需要该治疗的哺乳动物给予治疗有效量的化合物1的A晶型或上述结晶组合物或上述药物组合物。优选地，哺乳动物为人。
另一方面，本申请提供了用于治疗CRTH2受体介导的疾病的化合物1的A晶型或上述结晶组合物或上述药物组合物。
本申请的一些实施方案中，上述CRTH2受体介导的疾病为哮喘(可补充其它疾病类型)。本申请化合物1的A晶型稳定性好，易于成药；其对CRTH2受体的抑制作用明显，并通过卵清蛋白(OVA)和氢氧化铝(Al(OH) 3)诱导的小鼠慢性/急性哮喘模型中，化合物1的A晶型能显著降低嗜酸性细胞数。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“辅料”通常是指配制有效的药物组合物所需要的载体、稀释剂和/或介质。
“药物可接受的载体”包括但不限于任何被国家药品管理机构批准为可接受用于人或家畜的佐剂、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增味剂、表面活性剂、润湿剂、分散剂、悬浮剂、稳定剂、等张剂、溶剂和/或乳化剂。
术语“治疗”是指将本申请所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，包括：
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；
(ii)抑制疾病或疾病状态，即遏制其发展；
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
针对药物或药理学活性剂而言，术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
需要说明的是，在X-射线衍射光谱中，由结晶化合物得到的衍射谱图对于特定的晶型往往是特征性的，其中谱带(尤其是在低角度)的相对强度可能会因为结晶条件、粒径和其它测定条件的差异而产生的优势取向效果而变化。因此，衍射峰的相对强度对所针对的晶型并非是特征性的，判断是否与已知的晶型相同时，更应该注意的是峰的相对位置而不是它们的相对强度。此外，对任何给定的晶型而言，峰的位置可能存在轻微误差，这在晶体学领域中也是公知的。例如，由于分析样品时温度的变化、样品移动、或仪器的标定等，峰的位置可以移动，2θ值的测定误差有时约为±0.2°。因此，在确定每种晶型结构时，应该将此误差考虑在内。在XRD图谱中通常用2θ角或晶面距d表示峰位置，两者之间具有简单的换算关系：d＝λ/2sinθ，其中d代表晶面距，λ代表入射X射线的波长，θ为衍射角。对于同种化合物的同种晶型，其XRD谱的峰位置在整体上具有相似性，相对强度误差可能较大。还应指出的是，在混合物的鉴定中，由于含量下降等因素会造成部分衍射线的缺失，此时，无需依赖高纯试样中观察到的全部谱带，甚至一条谱带也可能对给定的晶体是特征性的。
需要说明的是，DSC测定当晶体由于其晶体结构发生变化或晶体熔融而吸收或释放热时的转变温度。对于同种化合物的同种晶型，在连续的分析中，热转变温度和熔点误差典型的在约5℃之内，当我们说一个化合物具有某一给定的DSC峰或熔点时，这是指该DSC峰或熔点±5℃。DSC提供了一种辨别不同晶型的辅助方法。不同的晶体形态可根据其不同的转变温度特征而加以识别。
本申请的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下 面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请所使用的所有溶剂是市售的，无需进一步纯化即可使用。
本申请采用下述缩略词：DMF代表N,N-二甲基甲酰胺；MsOH代表甲磺酸；EtOH代表乙醇；NaOH代表氢氧化钠。
市售化合物采用供应商目录名称。
本申请粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法
XRPD参数如下：
光管：Cu,kα,
Figure PCTCN2019072357-appb-000004
光管电压：40kV，光管电流：40mA
发散狭缝：0.60mm
探测器狭缝：10.50mm
防散射狭缝：7.10mm
扫描范围：5-40deg
步径：0.02deg
步长：0.12秒
样品盘转速：15rpm
本申请差热分析(Differential Scanning Calorimeter,DSC)方法
测试方法：取样品(0.5～1mg)置于DSC铝锅内进行测试，在50mL/min N 2条件下，以10℃/min的升温速率，加热样品从室温到300℃。
本申请热重分析(Thermal Gravimetric Analyzer,TGA)方法
测试方法：取样品(2～5mg)置于TGA铂金锅内进行测试，在25mL/min N 2条件下，以10℃/min的升温速率，加热样品从室温到300℃。
附图说明
图1为化合物1的A晶型的XRPD谱图；
图2为化合物1的A晶型的DSC谱图；
图3为化合物1的A晶型的TGA谱图。
发明详述
为了更好地理解本申请的内容，下面结合具体实施例来做进一步的说明，但具体的实施 方式并不是对本申请的内容所做的限制。
实施例1
Figure PCTCN2019072357-appb-000005
第一步
将化合物1a(10.0g,41.13mmol)溶于甲醇(60mL)中，然后加入N,N-二甲基甲酰胺(20mL)，三乙胺(20mL)和[1,1-双(二苯基膦基)二茂铁]二氯化钯(3.01g,4.11mmol)。反应液在80℃和一氧化碳气氛(50psi)下搅拌10小时后，反应液过滤，减压浓缩后用100mL乙酸乙酯和50mL水稀释，用乙酸乙酯(60mL×2)萃取。有机相合并后用饱和食盐水(60mL×3)洗涤，无水硫酸钠干燥，减压浓缩干后，经硅胶柱层析(石油醚/乙酸乙酯＝100-0％)纯化得到化合物1b(7.80g)。 1H NMR(400MHz,CDCl 3)δ8.75(s,1H),8.03-8.00(dd,J＝6.0Hz,J＝8.0Hz,1H),7.37-7.35(d,J＝8.0Hz,1H),3.93(s,3H),3.32-3.28(m,2H),3.04-3.00(m,2H).
第二步
将化合物1b(7.00g，31.49mmol)分批地缓慢加入到双(2-甲氧基乙基)氨基的三氟化硫溶液(35mL)中。所得反应液在90℃下搅拌4小时。反应完毕，将反应液冷却至室温，加入二氯甲烷(40mL)稀释反应液，在0℃条件下，将反应液缓慢加入至饱和碳酸氢钠水溶液(100mL)中淬灭。用二氯甲烷(50mL×2)萃取，合并有机相，饱和食盐水洗涤(100mL×1)，无水硫酸 钠干燥，过滤，减压浓缩，剩余物用硅胶柱色谱法分离纯化(石油醚/乙酸乙酯＝100-0％)，得到化合物1c(5.80g)。 1H NMR(400MHz,CDCl 3)δ8.38(s,1H),7.94-7.91(m,1H),7.25-7.23(m,1H),3.93(s,3H),3.22-3.19(m,2H),2.65-2.54(m,2H).
第三步
将化合物1c(5.56g,22.93mmol)溶于二氯甲烷(60mL)中，在0℃下加入间氯过氧苯甲酸(9.31g,45.85mmol,85％)。所得反应液在25℃下搅拌3小时。反应完毕后，将反应液过滤，滤液加入饱和硫代硫酸钠溶液(20mL)淬灭，有机相再用饱和碳酸氢钠水溶液(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，剩余物用硅胶柱色谱法分离纯化(石油醚/乙酸乙酯＝100-0％)，得到化合物1d(4.40g)。 1H NMR(400MHz,CDCl 3)δ8.47(s,1H),8.36-8.34(m,1H),8.05-8.03(m,1H),4.00(s,3H),3.65-3.62(m,2H),3.12-3.06(m,2H).
第四步
在0℃下，向化合物1d(4.4g，15.93mmol)的50mL四氢呋喃溶液中缓慢滴加二异丁基氢化铝(1M，23.89mL)。反应液在此温度下反应2小时。用50mL饱和酒石酸钾钠水溶液淬灭反应，用乙酸乙酯(20mL×2)萃取。合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，得到粗品化合物1e(4.10g)。 1H NMR(400MHz,CDCl 3)δ:7.95-7.93(m,1H),7.82-7.82(m,1H),7.72-7.70(m,1H),4.85(s,2H),3.61-3.58(m,2H),3.10-3.03(m,2H).
第五步
将化合物1e(4.10g,16.52mmol)溶于二氯甲烷(40mL)中，加入活性二氧化锰(10.05g,115.61mmol)，反应液在室温下搅拌2小时后过滤，滤液直接浓缩，剩余物用硅胶柱色谱法分离纯化(石油醚/乙酸乙酯＝100-0％)，得到化合物1f(3.70g)。
1H NMR(400MHz,CDCl 3)δ10.14(s,1H),8.31(s,1H),8.23-8.21(m,1H),8.15-8.13(m,1H),3.68-3.64(m,2H),3.12-3.06(m,2H).
第六步
在氮气氛下，向化合物1f(3.70g，15.02mmol)和化合物1g(2.24g，15.02mmol)的50mL1,2-二氯乙烷溶液中依次加入三氟乙酸(5.14g，45.05mmol)和三乙基硅烷(8.73g，75.08mmol)。所得混合液在60℃下搅拌2小时。反应结束后，向反应液中加入90mL饱和碳酸氢钠水溶液，二氯甲烷(30mL x 3)萃取。有机相经无水硫酸钠干燥，过滤，减压浓缩得到粗品1h(5.9g)。
第七步
氮气保护下，将化合物1h(5.70g,15.02mmol)溶于N,N-二甲基甲酰胺(80mL)中，加入碳酸铯(9.79g,30.05mmol)，边搅拌边慢慢滴加溴乙酸甲酯(2.76g,18.03mmol)。反应液 在25℃下搅拌2小时后倒入水(60mL)中，用乙酸乙酯(50mL×2)萃取。无水硫酸钠干燥，过滤，减压浓缩，粗产品经色谱硅胶柱(石油醚/乙酸乙酯＝100-0％)纯化得到化合物1i(5.1g)。
第八步
将化合物1i(5.20g，11.52mmol)溶于四氢呋喃(80mL)和水(20mL)的混合溶剂中。然后在氮气氛下加入一水合氢氧化锂(1.93g，46.07mmol)。反应液升温至50℃反应1小时。反应结束后，减压蒸馏除去大部分四氢呋喃，加水50mL。用1mol/L的稀盐酸调节pH＝4，用乙酸乙酯(100mL x 3)萃取。有机相经无水硫酸钠干燥，过滤，滤液减压浓缩将所得产品分散于20mL乙醇中，加热至80℃并持续搅拌30分钟，然后冷却至室温，过滤。所得粗品经制备HPLC分离纯化得到化合物1(2.75g)。 1H NMR(400MHz,DMSO-d6)δ13.02(s,1H),7.84-7.82(m,1H),7.71-7.70(m,1H),7.64-7.61(m,1H),7.38-7.37(m,1H),7.22-7.19(m,1H),6.90-6.86(m,1H),4.98(s,2H),4.20(s,2H),3.81-3.78(m,2H),3.02-2.94(m,2H),2.32(s,3H).MS-ESI计算值[M+H] +438，实测值438。
实施例2：A晶型的制备
化合物1(100.0g)经乙醇(400mL)在80℃打浆48小时。冷却至室温，抽滤，得白色固体，45℃真空干燥24小时得化合物1的A晶型。
所得化合物1的A晶型的XRPD谱图如图1所示；所得化合物1的A晶型的DSC谱图如图2所示；所得化合物1的A晶型的TGA谱图如图3所示。
实验例1
将
Figure PCTCN2019072357-appb-000006
的CHO-K1CRTH2β-arrestin细胞(DiscoverX，目录号93-0291C2)在标准条件下生长，并在白壁的384微孔板以5000个细胞/孔接种，每孔用20微升的Cell Plating Reagent 1。测试前细胞在37℃/5％CO 2下孵育过夜。将测试化合物在DMSO中以3倍的稀释系数进行一系列稀释，得到连续稀释的8个浓度的测试化合物。测试前不久，对前述连续稀释的测试化合物再用测试缓冲液进一步稀释成测试浓度的5倍。将5微升进一步稀释后的测试化合物加入到细胞中并在37℃下孵育30分钟。溶媒浓度为1％。再将5微升的6X EC 80激动剂(PGD2)的缓冲液加入到细胞中并在37℃下孵育90分钟。通过一次性添加15微升(50％v/v)PathHunter检测混合液试剂和随后进行的一小时孵育来生成测定信号。通过PerkinElmer Envision TM仪器的化学发光信号来阅读微孔板。测试化合物的生物活性是通过CBIS数据分析套件(ChemInnovation，CA)分析的，以IC 50值显示。实验结果如表2中所示。
表2
化合物 IC 50
化合物1 ＜0.1μM
结论：化合物1对CRTH2受体有强的拮抗作用。
实验例2
血浆药代动力学实验使用12只雌性C57BL/6小鼠，随机分为两组，每组6只动物。第一组动物给予静脉注射被测药物1mg/kg，第二组给予灌胃被测药物5mg/kg。制剂溶媒使用含有HPbCD以及助溶剂
Figure PCTCN2019072357-appb-000007
的配方，获得的静脉或者灌胃制剂均为澄清溶液。静脉组以及灌胃组动物均于给药后0.0833、0.25、0.5、1、2、4、8以及24小时，使用隐静脉进行采血，每个时间点为3个样品。灌胃给药收集的血浆样品冻存于-80℃，并在LC-MS/MS样品分析前进行解冻。解冻后的血浆样品，按照一定的比例加入含有内标的乙腈进行蛋白沉淀，并离心后取得上清液进行LC-MS/MS进样。分析仪器使用API4000或者5500，色谱柱为ACQUITY UPLC BEH C18(2.1×50mm,1.7μm)，采用ESI正或者负离子源进行检测化合物的离子化。每个分析批中，含有8个浓度的标样，以被测化合物的峰面积对内标(IS)峰面积之比为Y，被测化合物在血浆样品中的浓度为X，并以1/x 2为加权系数进行线性回归，求得测定响应与浓度的回归方程。每个分析批中，亦含有相应的质控样品。使用Phoenix 6.3
Figure PCTCN2019072357-appb-000008
进行数据处理，并获得相应的PK参数。试验结果如表3所示。
表3
Figure PCTCN2019072357-appb-000009
结论：化合物1的A晶型在小鼠中有很好的药代动力学性质。
实验例3
按照中国药典2015年版四部9001《原料药物与制剂稳定性试验指导原则》对化合物1的A晶型进行稳定性影响因素试验。
称取化合物1的A晶型15mg，置于玻璃样品瓶的底部，摊成薄薄一层。高温及高湿条件下放置的样品用铝箔纸封瓶口，并在铝箔纸上扎些小孔，保证样品能与环境空气充分接触； 强光照条件下放置的样品用螺纹瓶盖密封。试验结果见下表4-6所示：
表4化合物1的A晶型的固体稳定性试验结果
Figure PCTCN2019072357-appb-000010
表5
Figure PCTCN2019072357-appb-000011
表6
Figure PCTCN2019072357-appb-000012

Claims (14)

  1. 化合物1的A晶型，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：12.78±0.2°、15.43±0.2°、21.25±0.2°，
    Figure PCTCN2019072357-appb-100001
  2. 权利要求1所述化合物1的A晶型，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：7.12±0.2°、12.25±0.2°、12.78±0.2°、15.43±0.2°、18.76±0.2°、20.02±0.2°、20.77±0.2°、21.25±0.2°。
  3. 权利要求2所述化合物1的A晶型，其X射线粉末衍射图谱基本如图1所示。
  4. 权利要求1-3中任一项所述化合物1的A晶型，其差示扫描量热曲线在278.41℃±5℃处具有吸热峰的起始点。
  5. 权利要求4所述化合物1的A晶型，其差示扫描量热图谱基本如图2所示。
  6. 权利要求1-5中任一项所述化合物1的A晶型，其热重分析图谱基本如图3所示。
  7. 权利要求1-6中任一项所述化合物1的A晶型的制备方法，包括将化合物1加入到醇类溶剂中，通过重结晶或打浆制得。
  8. 权利要求7所述的制备方法，其中，所述醇类溶剂选自甲醇、乙醇和异丙醇中的一种或多种。
  9. 权利要求8所述的制备方法，其中，所述醇类溶剂为乙醇。
  10. 结晶组合物，其中权利要求1-6中任一项所述的化合物1的A晶型占所述结晶组合物重量的50％以上，较好的是80％以上，更好的是90％以上，最好的是95％以上。
  11. 药物组合物，其包含权利要求1-6中任一项所述的化合物1的A晶型或权利要求10所述的结晶组合物。
  12. 权利要求1-6中任一项所述的化合物1的A晶型或权利要求10所述的结晶组合物或权利要求11所述的药物组合物在制备用于治疗CRTH2介导的疾病的药物中的应用；优选地，所述治疗CRTH2介导的疾病为哮喘。
  13. 治疗CRTH2受体介导的疾病的方法，包括对需要该治疗的哺乳动物给予治疗有效量的权利要求1-6中任一项所述的化合物1的A晶型或权利要求10所述的结晶组合物或权利要求11所述的药物组合物；优选地，所述治疗CRTH2介导的疾病为哮喘。
  14. 用于治疗CRTH2受体介导的疾病的权利要求1-6中任一项所述的化合物1的A晶型或权利要求10所述的结晶组合物或权利要求11所述的药物组合物；优选地，所述治疗CRTH2介导的疾病为哮喘。
PCT/CN2019/072357 2018-01-19 2019-01-18 一种吲哚衍生物的晶型及其制备方法和用途 WO2019141241A1 (zh)

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