CN105503905A - Triazolo pyrazine derivative B crystal form and preparation method thereof - Google Patents

Triazolo pyrazine derivative B crystal form and preparation method thereof Download PDF

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CN105503905A
CN105503905A CN 201510906046 CN201510906046A CN105503905A CN 105503905 A CN105503905 A CN 105503905A CN 201510906046 CN201510906046 CN 201510906046 CN 201510906046 A CN201510906046 A CN 201510906046A CN 105503905 A CN105503905 A CN 105503905A
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derivative
form
setback
polymorph
derivatives
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CN105503905B (en )
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任国宾
弋东旭
陈金姚
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上海宣创生物科技有限公司
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D519/00Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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Abstract

The invention provides a triazolo pyrazine derivative B crystal form as shown in formula (I), and the formula (I) is described in the specification. The x-ray powder diffraction (XRPD) spectrum has diffraction peaks when 2 theta is equal to 5.52, 7.954, 9.42, 10.821, 14.3, 16.18, 18.661, 19.459, 21.56, 23.461, 24.46, 26.238, 30.12, 32.521 and 32.96, wherein the error range of the 2 theta value is +/-0.2. The triazolo pyrazine derivative B crystal form has good high-humidity stability and stable solubility, can be applied to the medicines used for inhibiting c-Met activity and the medicines for treating or preventing cancers inhibiting c-Met sensitivity, and has better bioavailability; furthermore, the qualitative and quantitative information provided by the triazolo pyrazine derivative B crystal form has important significance in further studying the treatment effect of the solid medicines.

Description

一种三唑并吡嗪衍生物B晶型及其制备方法 One triazole and pyrazine derivatives and preparation method polymorph B

技术领域 FIELD

[00011本发明涉及一种作为c-Met抑制剂的三唑并吡嗪衍生物的多晶型,具体地,涉及一种三唑并吡嗪衍生物B晶型及其制备方法。 [00011 The invention relates to polymorphs, and specifically, to a triazolopyrazine derivatives polymorph B and a process for preparing a triazole c-Met inhibitor and a pyrazine derivative.

背景技术 Background technique

[0002] c-Met蛋白(也称为肝细胞生长因子(HGF)受体)是具有络氨酸激酶活性的跨膜190kDa异源二聚体,其由c-Met癌基因编码。 [0002] c-Met protein (also referred to as hepatocyte growth factor (HGF) receptor) is a transmembrane tyrosine kinase activity of the heterodimer 190kDa, which is encoded by the c-Met oncogene. 已有研究显示,HGF/c-Met信号通路具有多种细胞响应活性,包括促细胞有丝分裂、增殖、成形、血管生成等。 It has been shown, HGF / c-Met signaling pathway in response to a variety of cellular activities, including promoting mitosis, proliferation, shape, angiogenesis. 因此,HGF/c-Met信号通路的抑制具有显著的治疗癌症的潜力。 Thus, HGF inhibition / c-Met signaling pathway has significant potential for the treatment of cancer.

[0003] 本发明提供了一种三唑并吡嗪衍生物,化学名为(S)-1-(l_(咪唑[l,2_a]吡嗪-6-基)乙烷基)-6-α_甲基-1H-吡唑-4-基)-1Η-[1,2,3]三唑[4,5-b]吡嗪,如式(I)所示, [0003] The present invention provides a triazolopyrazine derivatives, the chemical name (S) -1- (l_ (imidazo [l, 2_a] pyrazin-6-yl) ethane-yl) -6-α _ -1H- pyrazol-4-yl-methyl) -1Η- [1,2,3] triazolo [4,5-b] pyrazine, of formula (I), the

Figure CN105503905AD00031

[0005 ]该化合物是一种c -Me t活性的抑制剂,可以用于治疗或预防对抑制c -Me t敏感的癌症。 [0005] This compound is an inhibitor of the activity c -Me t, may be used for treatment or prevention of inhibition of c -Me t sensitive cancers. 在中国发明专利CN 102906092A(W02011/079804)中,公开了三唑并吡嗪衍生物的合成方法和用途。 In the Chinese patent CN 102906092A (W02011 / 079804), discloses the synthesis and use triazolopyrazine derivatives. 重复上述专利的制备方法,得到化合物粉末,经检测为无定形态。 Prepared by repeating the above patent, the compound powder obtained by detecting an amorphous state. 如本领域技术人员所知,无定形虽然在大多数场合都比晶型有更高的溶解度和溶出速率,但是其不稳定,吸湿性强,容易转为稳定的晶型。 As those skilled in the art, although amorphous higher solubility and dissolution rate than polymorph in most cases, but it is unstable, hygroscopic, readily converted to stable crystalline form. 因此,无定形存在加工稳定性和贮存稳定性差的问题, 并且在生产过程中,无定形粒子的松密度较小、表面自由能高,在生产过程中也容易造成凝聚、流动性差、弹性变形强等一系列制剂问题,严重影响无定形三唑并吡嗪衍生物的药物临床使用价值。 Thus, without the presence of processing stability and poor storage stability shaped, and in the production process, the smaller the bulk density of the particles of amorphous, high surface free energy, in the production process are likely to cause aggregation, poor mobility, the elastic-deformation and a series of preparations, which seriously affect the clinical value of amorphous Drug triazolopyrazine derivatives.

[0006] 众所周知,同一种药物,晶型不同,其生物利用度也可能会存在差别,另外其稳定性、流动性、可压缩性也可能会不同,这些理化性质对药物的应用产生一定的影响,从而影响药物的疗效。 [0006] is well known, the same drug, a different crystal form, the bioavailability may also exist differences, while its stability, flowability, compressibility may be different, the physicochemical properties of some impact medicament , thus affecting the efficacy of the drug. 因此,需要具有优越的生理化学特性的三唑并吡嗪衍生物的晶型,其可有利地在药物加工和药物组合物中使用。 Therefore, having superior physiochemical properties of polymorphs triazolopyrazine derivatives which can be used advantageously in pharmaceutical processing and pharmaceutical compositions. 本发明研制的三唑并吡嗪衍生物的新晶型未见报道。 The present inventors have developed new triazolopyrazine derivatives have not been reported polymorphs.

发明内容 SUMMARY

[0007] 本发明所要解决的问题是现有三唑并吡嗪衍生物的不稳定性、溶解度低和容易转为其他晶型等不利于药物加工和在药物组合物中使用的问题,本发明的三唑并吡嗪衍生物的新晶型,为固体药物的疗效研究提供更多的定性定量信息的问题。 [0007] The present invention is to solve the problem is the instability of prior triazolopyrazine derivatives, low solubility and readily converted to other crystal forms and pharmaceutical processing is not conducive to the problem used in the pharmaceutical compositions of the present invention triazolopyrazine derivatives new crystalline form, to provide qualitative and quantitative information is more problematic for the study of efficacy of solid drug.

[0008] 为了解决上述技术问题,本发明提供了一种三唑并吡嗪衍生物的新的晶型(以下称"三唑并吡嗪衍生物B晶型"),如式(I)所示。 [0008] To solve the above problems, the present invention provides a pyrazine derivative triazolo new crystalline form (hereinafter "triazolopyrazine derivatives Form B"), the formula (I), shows.

Figure CN105503905AD00041

[0010]其父1^〇图谱在20 = 5.52、7.954、9.42、1〇.821、14.3、16.18、18.661、19.459、 21.56、23.461、24.46、26.238、30.12、32.521、32.96处有衍射峰,其中29值误差范围为± 0·2〇 [0010] 1 ^ billion parent peaks at 20 = 5.52,7.954,9.42,1〇.821,14.3,16.18,18.661,19.459, diffraction peaks at 21.56,23.461,24.46,26.238,30.12,32.521,32.96, wherein 29 error range is ± 0 · 2〇

[0011]根据本发明的三挫并吡嗪衍生物Β晶型,具有与说明书附图图1基本上相同的XRH) 图谱。 [0011] The three-setback pyrazine derivatives of the present invention and Form Β, the accompanying drawings FIG pattern having substantially the same XRH 1).

[0012] 本发明还提供了制备三唑并吡嗪衍生物B晶型的方法,包括以下步骤:在三唑并吡嗪衍生物中以1:150~1: 250g/mL的比例加入有机溶剂,在室温下悬浮,蒸干溶剂得到固体, 然后真空干燥从而得到类白色粉末的三唑并吡嗪衍生物B晶型。 [0012] The present invention also provides methods of making pyrazine derivatives triazolo Form B, comprising the steps of: triazolopyrazine derivatives to 1: 150 to 1: 250g / mL of the organic solvent is added , was suspended at room temperature, the solvent was evaporated to give a solid, and then dried in vacuo to give a white powder and triazoles pyrazine derivative B polymorph.

[0013] 在一些实施例中,所述有机溶剂为一种以上脂肪烃类和一种以上卤化烃类溶剂以任意比例的混合溶剂。 [0013] In some embodiments, the organic solvent is one or more aliphatic hydrocarbons and one or more halogenated hydrocarbon solvent is a mixed solvent in any proportion.

[0014] 在一些优选的实施例中,所述脂肪烃类有机溶剂为环己烷;所述烃类有机溶剂为二氯甲烷。 [0014] In some preferred embodiments, the organic solvent is aliphatic hydrocarbon is cyclohexane; the hydrocarbon organic solvent is methylene chloride. 并且环己烷和二氯甲烷的混合比例为1:4或4:1。 And the mixing ratio of cyclohexane and dichloromethane is 1: 4 or 4: 1.

[0015] 在上述步骤中,三唑并吡嗪衍生物与溶剂的比例优选为1:200g/mL。 [0015] In the above steps, triazolopyrazine derivatives and the solvent ratio is preferably 1: 200g / mL.

[0016] 本领域普通技术人员可以根据其知识和经验,对本发明方法所用试剂的用量进行调整,包括按比例放大或缩小原料用量和调整溶剂用量,这些调整的方案也包含在本发明的方法中。 [0016] Those of ordinary skill in the art can be based on their knowledge and experience, the amount of the process of the invention the reagent is adjusted, including by scaling up or down feed amount and to adjust the amount of solvent, of these adjustments and is included in the process of the present invention .

[0017]具有本发明的三唑并吡嗪衍生物B晶型的化合物是用于抑制c-Met活性的抑制剂, 可以用于治疗或预防对抑制c-Met敏感的癌症。 Triazolopyrazine derivatives of compounds having B-type crystal of the present invention [0017] is used to inhibit the activity of c-Met inhibitors useful in the treatment or prevention of inhibition of c-Met sensitive cancers.

[0018] 因此,本发明提供了三唑并吡嗪衍生物B晶型在制备用于抑制C-Met活性的药物中的用途;以及在制备用于治疗或预防对抑制c-Met敏感的癌症的药物中的用途。 [0018] Accordingly, the present invention provides a pharmaceutical triazolopyrazine derivatives in crystal form B for the preparation of C-Met inhibition in the activity; and for the treatment or prevention of inhibition of c-Met-sensitive cancer use of a medicament.

[0019] 本发明还提供了药物组合物,其包含根据本发明的三唑并吡嗪衍生物B晶型以及一种或多种药学上可接受的载体、赋形剂或稀释剂。 [0019] The present invention also provides a pharmaceutical composition comprising the triazole derivative of the present invention and pyrazine Form B and one or more pharmaceutically acceptable carrier, excipient or diluent.

[0020] 在本发明的一些实施例中,上述药物组合物进一步包含另外的治疗剂,所述的治疗剂选自化疗或抗增殖剂、抗炎剂、免疫调节或免疫抑制剂、神经营养因子、抗肿瘤药剂或抗癌药剂等。 [0020] In some embodiments of the present invention, the above pharmaceutical composition further comprising additional therapeutic agent, the therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an antiinflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor , antineoplastic or anti-cancer agents and the like.

[0021] 根据本发明的三唑并吡嗪衍生物B晶型,具有优秀的高湿度稳定性,也具有稳定的溶解度,有利于药物加工和在药物组合物中使用,可以在抑制c-Met活性及治疗或预防对抑制c-Met敏感的癌症的药物中应用,并且具有较好的生物利用度,同时提供的定性定量信息,对进一步研究此类固体药物的疗效具有重要的意义。 [0021] According to the present invention, triazole and B polymorph pyrazine derivatives, has excellent stability and high humidity, has stable solubility, facilitate processing and use of the drug in the pharmaceutical composition may be in inhibiting c-Met activity and therapeutic or prophylactic agent for inhibition of c-Met cancer sensitive applications, and has good bioavailability, while providing a qualitative and quantitative information, is significant for further study of such solid pharmaceutical efficacy.

附图说明 BRIEF DESCRIPTION

[0022]图1为本发明提供的三唑并吡嗪衍生物B晶型的XRPD图谱。 [0022] FIG triazol-1 of the present invention is to provide a pyrazine derivative XRPD pattern of Form B.

[0023]图2为本发明提供的三唑并吡嗪衍生物B晶型五天高温稳定性XRH)图谱。 [0023] FIG triazol-2 of the present invention is to provide a pyrazine derivative B polymorph high temperature stability XRH five days) spectrum.

[0024]图3为本发明提供的三唑并吡嗪衍生物B晶型五天高湿稳定性XRH)图谱。 [0024] FIG triazol-3 of the present invention is to provide a pyrazine derivative B polymorph humidity stability XRH five days) spectrum.

[0025]图4为本发明提供的三唑并吡嗪衍生物B晶型五天光照稳定性XRH)图谱。 [0025] FIG triazol-4 of the present invention is to provide a pyrazine derivative B polymorph light stability XRH five days) spectrum.

[0026]图5为本发明提供的三唑并吡嗪衍生物B晶型十天高温稳定性XRH)图谱。 [0026] FIG triazol-5 of the present invention is to provide a pyrazine derivative B polymorph high temperature stability XRH ten days) spectrum.

[0027]图6为本发明提供的三唑并吡嗪衍生物B晶型十天高湿稳定性XRH)图谱。 [0027] FIG. 6 of the present invention is to provide triazole derivative B polymorph pyrazine-humidity stability XRH ten days) spectrum.

[0028]图7为本发明提供的三唑并吡嗪衍生物B晶型十天光照稳定性XRH)图谱。 [0028] FIG. 7 of the present invention is to provide triazole pyrazine derivatives polymorph B light stability XRH ten days) spectrum.

[0029]图8为现有的三唑并吡嗪衍生物无定形的XRH)图谱。 [0029] FIG. 8 is a conventional triazolopyrazine derivatives amorphous XRH) map.

[0030]图9为本发明提供的三唑并吡嗪衍生物B晶型和无定形的溶解度曲线。 [0030] FIG. 9 of the present invention is to provide triazole pyrazine derivatives and amorphous Form B solubility profiles.

[0031]图10为现有的三唑并吡嗪衍生物无定形的五天高温稳定性XRH)图谱。 [0031] FIG. 10 is a conventional triazolopyrazine derivatives amorphous high-temperature stability XRH five days) spectrum.

[0032]图11为现有的三唑并吡嗪衍生物无定形的五天光照稳定性XRH)图谱。 [0032] FIG. 11 is a conventional triazolopyrazine derivatives amorphous light stability XRH five days) spectrum.

具体实施方式 Detailed ways

[0033]从下文的详细描述中,本发明的上述方面和本发明的其他方面将是明显的。 [0033] From the following detailed description, the above aspects and other aspects of the present invention will be apparent.

[0034]实施例1至2三唑并吡嗪衍生物B晶型的制备 And Preparation [0034] Example 1-2 triazole pyrazine derivative of Form B

[0035] 称取500mg三唑并吡嗪衍生物原料于容器中,分别加入100mL表1中的混合溶剂(分析纯),35°C悬浮24小时,蒸干溶剂得到固体,真空干燥后得类白色粉末。 [0035] triazolo weighed 500mg pyrazine derivative starting material in the container were the mixed solvent in Table 1 was added 100mL (analytical grade), 35 ° C suspension of 24 hours, the solvent was evaporated to give a solid, and dried in vacuo to give the class White powder. 称量计算其收率。 Calculated yield was weighed. [0036]表1三唑并吡嗪衍生物B晶型的制备 Table 1 Preparation triazolopyrazine derivatives of polymorph B [0036]

Figure CN105503905AD00051

[0038] 实施例3.通过XRH)图来表征三唑并吡嗪衍生物B晶型 [0038] Example 3. By XRH) FIG characterized triazolopyrazine derivatives polymorph B

[0039] X射线粉末衍射(XRPD)图谱的测量,使用Rigaku UltimalV型号组合式多功能X射线衍射仪进行,具体采集信息如下:Cu阳极(40kV,40mA),扫描速度20°/分钟、扫描范围(2Θ 范围)5~45°、扫描步长0.02、狭缝宽度0.01。 [0039] X-ray powder diffraction (XRPD) pattern measured using a Rigaku UltimalV modular multi-functional type X-ray diffractometer, the following specific information collection: Cu anode (40kV, 40mA), the scanning speed of 20 ° / min, scanning range (2 [Theta range) 5 ~ 45 °, scan step size 0.02, 0.01 slit width. 采用载玻片直接在测试板压制对样品进行处理。 Using the press plate slides directly in the test sample is processed. 其后的XRPD图谱均采用类似的测量方法。 Subsequent XRPD patterns were measured using a similar method.

[0040] 测定根据实施例1所述方法制备的三唑并吡嗪衍生物B晶型的XRP D图谱,在2 Θ = 5·52、7·954、9·42、10·821、14·3、16·18、18·661、19·459、21·56、23·461、24·46、26·238、 3〇.12、32.521、32.96处有衍射峰,如图1所示。 [0040] Determination triazole prepared according to the method described in Example 1 and XRP D pattern B polymorph of pyrazine derivative, at 2 Θ = 5 · 52,7 · 954,9 · 42,10 · 821,14 · · · 3,16 18,18 661,19 * 459,21 * 461,24 * 56,23 * 46,26 * 238, at 3〇.12,32.521,32.96 diffraction peaks, as shown in FIG. 其中20值误差范围为±〇.2。 Wherein the error range is ± 20 〇.2. 经检测,20值误差范围也可以为±0.15。 After testing, the error range may be 20 to ± 0.15. 根据实施例2所述方法制备的三唑并吡嗪衍生物Β晶型,其XRPD图谱与附图1所示图谱基本相同。 Triazole prepared according to the method of Example 2 and pyrazine derivatives Β polymorphs, its XRPD pattern map shown in FIG. 1 is substantially the same with the accompanying drawings.

[0041] 本领域技术人员应理解,这些衍射峰不代表三唑并吡嗪衍生物B晶型所显示衍射峰的详尽情况。 [0041] skilled in the art will appreciate that the diffraction peaks do not represent triazolopyrazine derivatives where B polymorph detailed diffraction peaks displayed. X-射线粉末衍射图的2Θ值是可以随着机器以及随着样品制备中的变化和批次间变化而轻微变化,所引用的值不视为绝对值。 2Θ values ​​of X- ray powder diffraction pattern as well as the machine is varied between sample preparation and batch changes slightly changes, the values ​​quoted are not considered as absolute values. 还应理解的是,峰的相对强度可能随取向效应而变,因此本发明所含的XRD迹线中所示的强度是示例性的,并不用于绝对比较。 It should also be understood that the relative intensities of peaks may vary with the orientation effects, the intensity of XRD traces shown in the present invention is contained in the exemplary, and are not used for absolute comparison.

[0042]实施例4.三唑并吡嗪衍生物B晶型的高温稳定性考察 [0042] Example 4. triazolo high temperature stability of Form B pyrazine derivatives embodiment

[0043]将三唑并吡嗪衍生物B晶型样品置于60°C烘箱内,5天和10天后将样品取出进行XRro测试(如图2和图5所示),以考察样品对温度的晶型稳定性。 [0043] The pyrazine derivatives and triazole Form B sample was placed in an oven at 60 ° C, 5 days and 10 days after the test sample was taken out XRro (FIG. 2 and FIG. 5), in order to investigate the temperature of the sample the polymorphic stability. 结果表明,高温条件下B晶型样品稳定性一般。 The results showed that, B polymorph sample stability at high temperatures in general.

[0044]实施例5.三唑并吡嗪衍生物B晶型的高湿稳定性考察 [0044] Example 5. triazolo humidity stability of the crystalline form B pyrazine derivative

[0045] 将三唑并吡嗪衍生物B晶型样品置于92.5%湿度条件下,5天和10天后将样品取出进行XRro测试(如图3和图6所示),以考察样品对湿度的晶型稳定性。 [0045] The pyrazine derivatives and triazole Form B sample was placed under a humidity of 92.5%, 5 and 10 days the samples were taken out XRro tested (FIGS. 3 and 6), in order to examine the sample moisture the polymorphic stability. 结果表明,高湿条件下B晶型样品稳定。 The results show that under high-humidity conditions Form B sample stability.

[0046] 实施例6三唑并吡嗪衍生物B晶型的光照稳定性考察 Pyrazine derivative and light stability of crystalline form B [0046] Example 6 triazole

[0047] 将三唑并吡嗪衍生物B晶型样品置于45001UX光照强度下,5天和10天后将样品取出进行XRPD测试(如图4和图7所示),以考察样品对光照的晶型稳定性。 [0047] The pyrazine derivatives and triazole Form B sample was placed under a light intensity 45001UX, 5 and 10 days the samples were removed for XRPD testing (FIG. 4 and FIG. 7), in order to examine a sample of illumination polymorphic stability. 结果表明,光照条件下B晶型样品稳定性一般。 The results showed that, B polymorph sample stability in general lighting conditions.

[0048]比较例1三唑并吡嗪衍生物的无定形的制备 Preparation of Amorphous [0048] Comparative Example 1 triazolopyrazine derivatives

[0049]根据中国发明专利CN 102906092A中公开的合成方法,合成了本发明的三唑并吡嗪衍生物及其手性异构体的混合物,然后通过手性HPLC分离该混合物,制得本发明的三唑并吡嗪衍生物。 [0049] The synthetic method of Chinese Patent CN 102906092A invention disclosed in the present invention were synthesized and triazole pyrazine derivatives and mixtures of enantiomers, and the mixture was then separated by chiral HPLC, the present invention was prepared the pyrazine derivatives and triazole. 在得到含有三唑并吡嗪衍生物的有机溶液后,将有机层经无水MgS〇4干燥并真空蒸发。 After obtaining triazolopyrazine derivatives containing organic solution, the organic layer was dried over anhydrous MgS〇4 and evaporated in vacuo. 通过快速色谱或者制备HPLC纯化后获得最终化合物。 After purification by preparative HPLC or by flash chromatography to obtain the final compound.

[0050] 如图8所示,经XRro测定,所得的最终产物为无定形样品。 [0050] As shown in FIG 8, the XRro measurement, the final product was obtained as an amorphous sample.

[0051 ]实施例7三唑并吡嗪衍生物B晶型和无定形的溶解度比较 [0051] Example 7 triazolopyrazine derivatives and amorphous Form B Solubility Comparison

[0052]在20mL样品瓶中分别加入过量B晶型和无定形粉末,加入适量的水,室温下震荡12 小时,采用紫外分光光度计分别在30分钟、1小时、2小时、3小时、5小时和12小时取样检测溶解度。 [0052] Form B were added and excess amorphous powder in 20mL vial, adding an appropriate amount of water, shaking at room temperature for 12 hours, respectively, using an ultraviolet spectrophotometer at 30 minutes, 1 hour, 2 hours, 3 hours, 5 and 12 hours sample testing solubility. 溶解度曲线如图9所示。 Solubility curve shown in Fig.

[0053]如溶解度曲线所示,无定形初始溶解度在1小时时达到峰值,但是随后下降,在3小时附近达到与B晶型药物相近的溶解度。 [0053] As shown in the solubility curve, the initial solubility of amorphous peaked at 1 hour, but then decreases and in the vicinity of three hours to achieve similar drugs Form B solubility. 3小时之后,B晶型的溶解度超过无定形。 After 3 hours, B polymorph solubility than amorphous. 尽管无定形药物初始溶解曲线优于B晶型药物,但是其具体溶解度不能稳定在较高水平,而是随着已经溶解的药物浓度而变化。 Although the initial amorphous drug dissolution profile than polymorph B drug solubility but not particularly stable at a high level, but with the dissolved drug concentration changes. 这在给药固态药物到患者时会带来难以预测的溶出情况。 This will bring the administration of solid pharmaceutical dissolution cases are difficult to predict when the patient. 如果以最终溶解度为依据规定给药量,则其初始溶解会造成局部药物浓度过高,产生严重的副作用;如果以初始溶解度为依据规定给药量,则最终药物浓度可能不足,影响药效。 If the final solubility under the provisions of dose, its initial dissolution will result in too high local drug concentration, have serious side effects; if prescribed initial dose based on solubility, the final concentration of the drug may not be enough to affect efficacy. 此外,无定形药物在药物剂型中也可能发生晶型转变,进一步影响其溶出行为。 In addition, amorphous drug may be the phase transformation occurs in the pharmaceutical dosage form, which further affect the dissolution behavior. 因此,采用稳定的B 晶型加工为药物剂型,能够确保稳定的药效,获得更好的治疗效果。 Therefore, the stable polymorph B processed into pharmaceutical dosage form, to ensure a stable efficacy, better therapeutic effect.

[0054]比较例2.三唑并吡嗪衍生物无定形的高温稳定性考察 [0054] Comparative Example 2. triazolopyrazine derivatives temperature stability of amorphous

[0055] 将三唑并吡嗪衍生物无定形样品置于60°C烘箱内,5天后将样品取出进行XRPD测试(如图10所示),以考察样品对温度的晶型稳定性。 [0055] The pyrazine derivatives and triazole amorphous sample placed in an oven at 60 ° C, 5 days after the test samples were removed for XRPD (FIG. 10), the temperature of the sample to examine the crystal form stability. 结果表明,高温条件下无定形样品不稳定。 The results showed that amorphous sample is unstable under high temperature conditions.

[0056] 而且,通过比较高温条件下5天后无定形的XRPD图谱和B晶型的XRPD图谱可以发现,三唑并吡嗪衍生物的无定形在高温下转化不同于本发明的三唑并吡嗪衍生物B晶型的其他晶型。 [0056] Furthermore, it was found that after 5 days and the amorphous XRPD pattern XRPD pattern of Form B at a relatively high temperature, amorphous triazolo pyrazine derivative at a high temperature conversion of the present invention is different from the triazole and pyrazole triazine derivatives other polymorph B crystalline form.

[0057]比较例3.三唑并吡嗪衍生物无定形的光照稳定性考察 [0057] Comparative Example 3. The pyrazine derivatives and triazole light stability of amorphous

[0058]将三唑并吡嗪衍生物无定形样品置于92.5%湿度条件下,5天后将样品取出进行XRro测试(如图11所示),以考察样品对光照的晶型稳定性。 [0058] The pyrazine derivatives of triazole and 92.5% amorphous sample was placed under conditions of humidity, the samples were taken out 5 days XRro tested (Figure 11), in order to examine a sample of polymorphic stability to light. 结果表明,光照条件下无定形样品不稳定。 The results showed that amorphous sample unstable lighting conditions.

[0059] 而且,通过比较高湿条件下5天后无定形的XRPD图谱和B晶型的XRPD图谱可以发现,三唑并吡嗪衍生物的无定形在高温下转化不同于本发明的三唑并吡嗪衍生物B晶型的其他晶型。 [0059] Furthermore, it was found that after 5 days and the amorphous XRPD pattern XRPD pattern of Form B under relatively high humidity conditions, the amorphous triazolo triazole pyrazine derivative of the present invention differs from the conversion at elevated temperature and pyrazine derivative Form B crystalline form of the other.

[0060] 综上所述,三唑并吡嗪衍生物B晶型在高湿度条件下能够保持稳定,优于无定形产物。 [0060] In summary, triazolopyrazine derivatives Form B under high humidity conditions can be maintained stable than the amorphous product. 如本领域技术人员已知的,不稳定的无定形会在一定条件下转变为其他晶型,因此稳定的晶型在药物制剂的生产过程中具有优势。 As known to those skilled in unstable amorphous under certain conditions will change for other polymorph, thus stabilizing the crystalline form has an advantage in the production process of pharmaceutical preparations. 由于三唑并吡嗪衍生物B晶型具有的稳定性,其在各种固态剂型的药物加工过程中能够保持稳定,能够确定最终获得的药物中的药物活性成分的晶型,能够确保已知的生物利用度,不会发生因为晶型转变而带来的药效差异。 Since triazolopyrazine derivatives having stable polymorph B, which remain stable in a variety of solid dosage forms of pharmaceutical processing process, capable of determining polymorph pharmaceutically active ingredient in the pharmaceutical finally obtained, can be secured known bioavailability, pharmacodynamic differences brought as crystal transition does not occur.

[0061] 本领域的技术人员应当明了,尽管为了举例说明的目的,本文描述了本发明的具体实施方式,但可以对其进行各种修改而不偏离本发明的精神和范围。 [0061] Those skilled in the art should be apparent, although for illustrative purposes, described herein specific embodiments of the present invention, but various modifications may be made thereto without departing from the spirit and scope of the invention. 因此,本发明的具体实施方式和实施例不应当视为限制本发明的范围。 Thus, embodiments of the present invention and the embodiments should not be construed as limiting the scope of the present invention. 本发明仅受所附权利要求的限制。 The present invention is limited only by the appended claims. 本申请中引用的所有文献均完整地并入本文作为参考。 All documents cited in this application are fully incorporated herein by reference.

Claims (10)

  1. 1. 一种式(I)的S挫并化嗦衍生物B晶型,其特征在于, A of formula (I) and the setback of the S derivative winded polymorph B, wherein,
    Figure CN105503905AC00021
    其XRPD 图谱在2 目=5.52、7.954、9.42、10.821、14.3、16.18、18.661、19.459、21.56、 23.461、24.46、26.238、30.12、32.521、32.96处有衍射峰,其中2 目值误差范围为±0.2。 In its XRPD pattern 2 = 5.52,7.954,9.42,10.821,14.3,16.18,18.661,19.459,21.56 mesh, the mesh 23.461,24.46,26.238,30.12,32.521,32.96 2 wherein the range of error ± 0.2 diffraction peaks, .
  2. 2. 如权利要求1所述的=挫并化嗦衍生物B晶型,其特征在于,其具有与说明书附图图1 基本上相同的XRTO图谱。 As claimed in claim 1 and setback = winded derivative of polymorph B, which is characterized in that it has a pattern substantially identical with the description, the drawings XRTO FIG.
  3. 3. 制备如权利要求1或2所述的=挫并化嗦衍生物B晶型的方法,其特征在于,包括W下步骤:在S挫并化嗦衍生物中W1:150~1:250g/mL的比例加入有机溶剂,在室溫下悬浮,蒸干溶剂得到固体,然后真空干燥从而得到类白色粉末的=挫并化嗦衍生物B晶型。 B = setback and derivatives crystalline form of winded, wherein W comprises at Step 3. Preparation as claimed in claim 1 or 2: and fell W1 of repetitious derivative in S: 150 ~ 1: 250g / mL in the ratio of organic solvent is added, the suspension, the solvent was evaporated to give a solid at room temperature and then dried in vacuo to give an off-white powder = setback of repetitious and derivative B polymorph.
  4. 4. 如权利要求3所述的方法,其特征在于,所述有机溶剂为一种W上脂肪控类和一种W 上面化控类溶剂W任意比例的混合溶剂。 4. The method according to claim 3, wherein said organic solvent is a mixed solvent in any ratio of fat-based control and one solvent control of the above W W W on one kind.
  5. 5. 如权利要求4所述的方法,其特征在于, 所述脂肪控类有机溶剂为环己烧; 所述控类有机溶剂为二氯甲烧;并且环己烧和二氯甲烧的混合比例为1:4或4:1。 And cyclohexyl burn and burn mixed methylene; 5. The method as claimed in claim 4, wherein said organic solvent is a fat-based control burn cyclohexyl; said control-based organic solvent is methylene burn ratio of 1: 4 or 4: 1.
  6. 6. 如权利要求1或2所述的S挫并化嗦衍生物B晶型在制备用于抑制C-Met的药物中的用途。 6. S setback claim 1 or claim 2 and Form B of repetitious derivative in the manufacture of C-Met for inhibiting medicament.
  7. 7. 如权利要求1或2所述的S挫并化嗦衍生物B晶型在制备用于治疗或预防对抑制C-Met敏感的癌症的药物中的用途。 7. S setback claim 1 or claim 2 and Form B of repetitious derivative in the manufacture of a medicament for the treatment or prevention of inhibition of C-Met-sensitive cancer.
  8. 8. 药物组合物,其包含如权利要求1或2所述的立挫并化嗦衍生物B晶型。 8. A pharmaceutical composition, comprising a stand or the frustration of claim 1 and Form B of repetitious derivatives.
  9. 9. 如权利要求8所述的药物组合物,其还包含一种或多种药学上可接受的载体、赋形剂或稀释剂。 9. A pharmaceutical composition according to claim 8, further comprising one or more pharmaceutically acceptable carrier, excipient or diluent.
  10. 10. 如权利要求8或9所述的药物组合物,其进一步包含另外的治疗剂,所述的治疗剂选自化疗或抗增殖剂、抗炎剂、免疫调节或免疫抑制剂、神经营养因子、抗肿瘤药剂或抗癌药剂。 10. The pharmaceutical composition of claim 8 or claim 9, further comprising an additional therapeutic agent, the therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an antiinflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor , antineoplastic or anti-cancer agents.
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