CN104072410A - 烟酰胺类衍生物的甲磺酸盐d晶型及其制备方法和应用 - Google Patents

烟酰胺类衍生物的甲磺酸盐d晶型及其制备方法和应用 Download PDF

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CN104072410A
CN104072410A CN201410322719.7A CN201410322719A CN104072410A CN 104072410 A CN104072410 A CN 104072410A CN 201410322719 A CN201410322719 A CN 201410322719A CN 104072410 A CN104072410 A CN 104072410A
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mesylate
nicotinamide derivative
crystal formation
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nicotinamide
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CN104072410B (zh
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于迎渌
陈金瑶
弋东旭
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SHANGHAI XUANCHUANG BIOLOGICAL SCIENCE & TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3

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  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种烟酰胺类衍生物的甲磺酸盐D晶型及其制备方法和应用，其中烟酰胺类衍生物的甲磺酸盐D晶型的XRPD图谱在2θ＝6.16、10.441、12.241、12.774、13.342、14.498、15.7、16.66、18.441、19.463、20.179、20.559、21.198、22.219、23、23.558、24.419、25.4、25.858、27.219、27.738、28.354、29.161、31.58处具有衍射峰，其中2θ值的误差范围为0.2。本发明提供的烟酰胺类衍生物的甲磺酸盐D晶型具有良好的光照稳定性，该晶型的研制为烟酰胺类衍生物的甲磺酸盐固体药物疗效的进一步研究具有重要的意义。

Description

烟酰胺类衍生物的甲磺酸盐D晶型及其制备方法和应用
技术领域
本发明涉及分子靶向抗肿瘤药物，具体涉及烟酰胺类衍生物的甲磺酸盐D晶型及其制备方法和应用。
背景技术
烟酰胺类衍生物(aptinib)，分子式C25H27N5O4S，化学名称为N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺，是一种分子靶向抗肿瘤药物，是一种典型的小分子血管内皮生长因子酪氨酸激酶抑制剂，可用于治疗晚期非小细胞肺癌、胃癌、肝癌以及乳腺癌等。中国发明专利CN101676267公开了上述烟酰胺类衍生物的甲磺酸盐制备方法及应用。
众所周知，同一药物的不同晶型，其稳定性以及生物利用度等方面可能会存在明显差异，从而影响药物的疗效。因此，研发烟酰胺类衍生物的新晶型，对固体药物晶型研究提供更多的定性定量信息具有非常重要的意义。
发明内容
本发明所要解决的问题是如何研发烟酰胺类衍生物的新晶型，为固体药物的疗效研究提供更多的定性定量信息的问题。
为了解决上述技术问题，本发明所采用的技术方案是提供一种烟酰胺类衍生物的甲磺酸盐D晶型，其XRPD图谱在2θ＝6.16、10.441、12.241、12.774、13.342、14.498、15.7、16.66、18.441、19.463、20.179、20.559、21.198、22.219、23、23.558、24.419、25.4、25.858、27.219、27.738、28.354、29.161、31.58处具有衍射峰，其中2θ值的误差范围为0.2。
在上述烟酰胺类衍生物的甲磺酸盐D晶型中，其XRPD图谱如附图1所示。
在上述烟酰胺类衍生物的甲磺酸盐D晶型中，含水量为2.5～4.5％。
本发明还提供了一种制备上述烟酰胺类衍生物的甲磺酸盐D晶型的方法，包括以下步骤：将500mg烟酰胺类衍生物的甲磺酸盐投入到100ml的纯净水中，室温下摇床震荡48小时，然后过滤、真空干燥，所得白色粉末即为烟酰胺类衍生物的甲磺酸盐D晶型。
本发明还提供了上述烟酰胺类衍生物的甲磺酸盐D晶型在治疗晚期非小细胞肺癌、胃癌、肝癌或乳腺癌的药物中的应用。
本发明提供的烟酰胺类衍生物的甲磺酸盐D晶型具有良好的光照稳定性，可应用于治疗晚期非小细胞肺癌、胃癌、肝癌以及乳腺癌的药物中，该晶型的研制为烟酰胺类衍生物的甲磺酸盐固体药物晶型研究提供了更多的定性定量信息。
附图说明
图1为本发明提供的烟酰胺类衍生物的甲磺酸盐D晶型的XRPD图谱；
图2为本发明提供的烟酰胺类衍生物的甲磺酸盐D晶型高温稳定性测试的XRPD图谱；
图3为本发明提供的烟酰胺类衍生物的甲磺酸盐D晶型高湿稳定性测试的XRPD图谱；
图4为本发明提供的烟酰胺类衍生物的甲磺酸盐D晶型光照稳定性测试的XRPD图谱。
具体实施方式
下面结合说明书附图对本发明做出详细的说明。
本发明提供的烟酰胺类衍生物的甲磺酸盐D晶型，其XRPD(X射线粉末衍射)图谱如附图1所示，具体表征如下：
2-Theta(2θ) d I％
6.16 14.3357 14.1
10.441 8.466 9.3
12.241 7.2245 52.3
12.774 6.924 2.4
13.342 6.6306 5.3
14.498 6.1045 6
15.7 5.6398 23
16.66 5.317 4.8
18.441 4.8073 100
19.463 4.557 3.7
20.179 4.3969 19.4
20.559 4.3164 20.4
21.198 4.1877 9.2
22.219 3.9976 7.2
23 3.8636 7.7
23.558 3.7734 4.8
24.419 3.6423 6.8
25.4 3.5037 12.1
25.858 3.4427 6.8
27.219 3.2736 6.4
27.738 3.2135 6.9
28.354 3.145 4.1
29.161 3.0598 14.5
31.58 2.8308 4.7
d是晶体晶格中相邻两个晶面的面间距，以埃为单位，I％是强度。
由图1可知，本发明提供的烟酰胺类衍生物的甲磺酸盐D晶型的XRPD图谱在2θ＝6.16、10.441、12.241、12.774、13.342、14.498、15.7、16.66、18.441、19.463、20.179、20.559、21.198、22.219、23、23.558、24.419、25.4、25.858、27.219、27.738、28.354、29.161、31.58处具有衍射峰，其中2θ值的误差范围为0.2。
本发明提供的上述烟酰胺类衍生物的甲磺酸盐D晶型的制备方法如下：
实施例1。
将500mg烟酰胺类衍生物的甲磺酸盐投入到100ml的纯净水中，室温下摇床震荡48小时，然后过滤、真空干燥，所得白色粉末即为烟酰胺类衍生物的甲磺酸盐D晶型。
本发明提供的烟酰胺类衍生物的甲磺酸盐D晶型，采用自动水分仪检测，其含水量为2.5～4.5％。
本发明提供的烟酰胺类衍生物的甲磺酸盐D晶型具有较好的光照稳定性，但在高湿和高温环境下稳定性一般，具体实验结果如下：
(1)高温稳定性考察。
将烟酰胺类衍生物的甲磺酸盐D晶型样品置于60℃的密闭烘箱内，5天后取出进行XRPD测试，其XRPD图谱如图2所示，通过图1与图2的比较结果表明，烟酰胺类衍生物的甲磺酸盐D晶型在此温度稳定性一般。
(2)高湿稳定性。
将烟酰胺类衍生物的甲磺酸盐D晶型样品置于92.5％湿度条件下的密闭容器中，5天后取出进行XRPD测试，其XRPD图谱如图3所示，通过图1与图3的比较结果表明，烟酰胺类衍生物的甲磺酸盐D晶型在此高湿环境下稳定性一般。
(3)光照稳定性。
将烟酰胺类衍生物的甲磺酸盐D晶型样品置于透明的密闭容器中，并处于4500lux光照强度下，5天后取出进行XRPD测试，其XRPD图谱如图4所示，通过图1与图4的比较结果表明，烟酰胺类衍生物的甲磺酸盐D晶型具有良好的光照稳定性。
本发明提供的烟酰胺类衍生物的甲磺酸盐D晶型可以应用于治疗晚期非小细胞肺癌、胃癌、肝癌或乳腺癌的药物，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。
本发明不局限于上述最佳实施方式，任何人应该得知在本发明的启示下作出的结构变化，凡是与本发明具有相同或相近的技术方案，均落入本发明的保护范围之内。

Claims (5)

1.烟酰胺类衍生物的甲磺酸盐D晶型，其特征在于，其XRPD图谱在2θ＝6.16、10.441、12.241、12.774、13.342、14.498、15.7、16.66、18.441、19.463、20.179、20.559、21.198、22.219、23、23.558、24.419、25.4、25.858、27.219、27.738、28.354、29.161、31.58处具有衍射峰，其中2θ值的误差范围为0.2。
2.如权利要求1所述的烟酰胺类衍生物的甲磺酸盐D晶型，其特征在于，其XRPD图谱如附图1所示。
3.如权利要求1或2所述的烟酰胺类衍生物的甲磺酸盐D晶型，其特征在于，含水量为2.5～4.5％。
4.制备如权利要求3所述的烟酰胺类衍生物的甲磺酸盐D晶型的方法，其特征在于，包括以下步骤：将500mg烟酰胺类衍生物的甲磺酸盐投入到100ml的纯净水中，室温下摇床震荡48小时，然后过滤、真空干燥，所得白色粉末即为烟酰胺类衍生物的甲磺酸盐D晶型。
5.如权利要求书3所述烟酰胺类衍生物的甲磺酸盐D晶型在治疗晚期非小细胞肺癌、胃癌、肝癌或乳腺癌的药物中的应用。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105801476A (zh) * 2016-04-13 2016-07-27 上海宣创生物科技有限公司 阿帕替尼甲磺酸盐ii晶型及其制备方法和应用
WO2020051173A1 (en) 2018-09-05 2020-03-12 Assia Chemical Industries Ltd New crystalline polymorphs of rivoceranib and rivoceranib mesylate

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1502608A (zh) * 2002-11-27 2004-06-09 南京凯衡科贸有限公司 具有抑制血管生成活性的六员氨基酰胺类衍生物
CN101676267A (zh) * 2008-09-16 2010-03-24 江苏恒瑞医药股份有限公司 N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺的盐
CN102579454A (zh) * 2009-10-28 2012-07-18 江苏恒瑞医药股份有限公司 治疗肿瘤疾病的药物组合物
EP2626066A1 (en) * 2012-02-10 2013-08-14 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Combination therapy comprising selective VEGFR-2 inhibitors and MEK inhibitors
WO2013180949A1 (en) * 2012-05-27 2013-12-05 Ning Xi Substituted quinoline compounds and methods of use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1502608A (zh) * 2002-11-27 2004-06-09 南京凯衡科贸有限公司 具有抑制血管生成活性的六员氨基酰胺类衍生物
CN101676267A (zh) * 2008-09-16 2010-03-24 江苏恒瑞医药股份有限公司 N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺的盐
CN102579454A (zh) * 2009-10-28 2012-07-18 江苏恒瑞医药股份有限公司 治疗肿瘤疾病的药物组合物
EP2626066A1 (en) * 2012-02-10 2013-08-14 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Combination therapy comprising selective VEGFR-2 inhibitors and MEK inhibitors
WO2013180949A1 (en) * 2012-05-27 2013-12-05 Ning Xi Substituted quinoline compounds and methods of use

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105801476A (zh) * 2016-04-13 2016-07-27 上海宣创生物科技有限公司 阿帕替尼甲磺酸盐ii晶型及其制备方法和应用
WO2020051173A1 (en) 2018-09-05 2020-03-12 Assia Chemical Industries Ltd New crystalline polymorphs of rivoceranib and rivoceranib mesylate
US11434202B2 (en) 2018-09-05 2022-09-06 Assia Chemical Industries Ltd. Crystalline polymorphs of Rivoceranib and Rivoceranib mesylate
US12043597B2 (en) 2018-09-05 2024-07-23 Assia Chemical Industries Ltd. Crystalline polymorphs of Rivoceranib and Rivoceranib mesylate

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