CN116574100A - 一种吡啶并嘧啶酮类化合物的柠檬酸一盐的新晶型及其制备方法与应用 - Google Patents
一种吡啶并嘧啶酮类化合物的柠檬酸一盐的新晶型及其制备方法与应用 Download PDFInfo
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- CN116574100A CN116574100A CN202310450862.3A CN202310450862A CN116574100A CN 116574100 A CN116574100 A CN 116574100A CN 202310450862 A CN202310450862 A CN 202310450862A CN 116574100 A CN116574100 A CN 116574100A
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- XWGMFWLOQBZWMF-VOTSOKGWSA-N 6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-[1-[(E)-4-(dimethylamino)but-2-enoyl]piperidin-4-yl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one Chemical compound ClC1=C(C(=C(C=C1OC)OC)Cl)C1=CC2=C(N=C(N=C2)NC)N(C1=O)C1CCN(CC1)C(\C=C\CN(C)C)=O XWGMFWLOQBZWMF-VOTSOKGWSA-N 0.000 claims description 16
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/265—Citric acid
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明属于药物化学领域,公开了一种吡啶并嘧啶酮类化合物的柠檬酸一盐的新晶型及其制备方法与应用。本发明所述化合物的柠檬酸一盐晶型Form A使用Cu‑Kα辐射,以2θ角度表示的X‑射线粉末衍射图谱在以下位置具有特征峰:4.1±0.2°、12.8±0.2°、15.7±0.2°、17.2±0.2°、18.9±0.2°、20.7±0.2°。本发明所述晶型Form A为稳定的无水晶型,在37℃水中24h溶解度为6.36mg/mL,与游离态相比有显著提升,化学稳定性良好,无引湿性。本发明所述晶型Form A制备方法操作简单,适合于工业化生产。
Description
技术领域
本发明属于药物化学领域,具体涉及一种吡啶并嘧啶酮类化合物的柠檬酸一盐的新晶型及其制备方法与应用。
背景技术
近年研究发现,成纤维细胞生长因子受体(FGFR)家族调节着胚胎发育、细胞增殖、分化、迁移、凋亡、血管生成和代谢等许多关键的生物学过程,FGFR家族的异常激活与癌细胞的存活和迁移、肿瘤血管生成和不良预后,因此有必要开发用于治疗FGFR依赖性癌症的FGFR家族的有效选择性抑制剂。中国专利CN1110809576A公开了一类化合物成纤维细胞生长因子受体激酶抑制剂及其在治疗高增殖疾病中的用途。该类化合物不仅在体外作为FGFR激酶的抑制剂表现出比以前已知的化合物更高的效力,而且还发现它们是FGFR-3以及FGFR-1和FGFR-2的不可逆抑制剂,可作为多种高增殖性疾病(尤其是癌症)的治疗剂。其中包括一种吡啶并嘧啶酮类化合物,即(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮,结构式为
到目前为止,国内外尚无文献报道过上述化合物的盐的晶型以及其制备方法和用途。
晶型是影响药物质量、疗效和制剂加工性能的重要因素之一。多晶型现象,是指同一化合物,通过控制其不同的生成条件,可形成两种或两种以上的分子空间排列方式,从而产生不同的固体结晶的现象。同一化合物的不同晶型,其化学组成相同,但微观晶体结构不同,因而导致它们在外观形态、理化性质和生物活性上存在差异。这些特性直接影响药物的制剂加工性能,并且会影响药物的稳定性、溶解度和生物利用度,进而影响到药物的质量、安全性、有效性及其应用。因此,研究并制备单一、纯净的(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮的晶型化合物具有重要的意义。
发明内容
有鉴于此,本发明的目的是提供一种能够适合工业化生产、化学稳定性良好、无引湿性的(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮的柠檬酸一盐晶型。
(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮的柠檬酸一盐,其结构式如下:
申请人以该化合物的柠檬酸一盐为起始,设置了不同条件下的多晶型筛选试验。根据所得固体的XRPD结果,共发现12种多晶型,分别为Form A、Form B/B1、Form C、Form D、Form E、Form F、Form G、FormH、Form I、Form J和Form K。经研究发现,Form A和Form D为柠檬酸一盐的稳定晶型。对优势盐型柠檬酸一盐的Form A和Form D进行混悬竞争实验,结果显示柠檬酸一盐Form A为室温和50℃下热力学更稳定的无水晶型。
本发明采用国际上公认的X-射线粉末衍射法(XRPD)来研究和表征该化合物的柠檬酸一盐晶型Form A,其X-射线粉末衍射图如图1所示,以2θ角度表示,其X-射线粉末衍射图谱在以下位置具有特征峰:4.1±0.2°、12.8±0.2°、15.7±0.2°、17.2±0.2°、18.9±0.2°、20.7±0.2°。
进一步的,该化合物的柠檬酸一盐晶型Form A,以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰4.1±0.2°、9.8±0.2°、12.8±0.2°、13.7±0.2°、15.0±0.2°、15.7±0.2°、16.4±0.2°、17.2±0.2°、18.9±0.2°、19.9±0.2°、20.7±0.2°、21.3±0.2°。
进一步的,该化合物的柠檬酸一盐晶型Form A,以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰:4.1±0.2°、8.4±0.2°、9.8±0.2°、11.9±0.2°、12.8±0.2°、13.7±0.2°、15.0±0.2°、15.7±0.2°、16.4±0.2°、16.7±0.2°、17.2±0.2°、18.4±0.2°、18.9±0.2°、19.9±0.2°、20.7±0.2°、21.3±0.2°、21.9±0.2°、22.1±0.2°、22.6±0.2°、24.1±0.2°。
本发明还对上述化合物的柠檬酸一盐晶型Form A进行热重分析(TGA)和差示扫描量热(DSC)检测。TGA图谱如图2所示,显示样品在120℃之前有约1.1%的失重;DSC图谱如图3所示,显示样品的熔点约为178℃。上述化合物的柠檬酸一盐晶型Form A为无水物。
本发明还提供了制备所述的化合物(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮的柠檬酸一盐晶型Form A的方法,将上述化合物的柠檬酸一盐真空干燥结晶。
在一些实施方案中,所述真空干燥的温度为20~50℃,时间为2~24小时。在一些实施例中,所述真空干燥的温度为室温,时间为2小时。在一些实施例中,所述真空干燥的温度为室温,时间为16小时。在一些实施例中,所述真空干燥的温度为50℃,时间为2小时。在一些实施例中,所述真空干燥的温度为室温,时间为24小时。
其中,所述化合物的柠檬酸一盐的制备方法包括以下步骤:
(a)所述化合物加入柠檬酸和溶剂进行混合,形成混悬液;
(b)室温悬浮搅拌析出固体;
(c)分离得到所述化合物的柠檬酸一盐;
所述化合物为(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮。
在一些实施方案中,步骤(a)所述溶剂选自乙腈、异丙醇、丙酮、二氯甲烷和四氢呋喃中的至少一种。
在一些实施方案中,步骤(b)所述悬浮搅拌时间为10-72小时。在一些实施例中,步骤(b)所述悬浮搅拌时间为15小时。在一些实施例中,步骤(b)所述悬浮搅拌时间为72小时。
在一些实施方案中,步骤(c)所述分离为真空抽滤或离心分离。
本发明还提供了所述化合物的柠檬酸一盐晶型Form A在制备治疗与抑制成纤维细胞生长因子受体激酶相关的高增殖疾病的药物中的应用。
其中,所述高增殖疾病为肺癌、乳腺癌、卵巢癌、子宫内膜癌、尿路上皮癌、膀胱癌、胃癌、头颈部癌症、前列腺癌、多发性骨髓瘤、白血病、脑癌、眼癌、肝癌和皮肤癌中的一种或多种。
本发明还提供了一种治疗与抑制成纤维细胞生长因子受体激酶相关的高增殖疾病的药物组合物,由所述化合物的柠檬酸一盐晶型Form A和常规的药用辅料组合制成。
按照常规的制剂工艺,本发明所述化合物的柠檬酸一盐晶型Form A与至少一种常规的药用辅料混合,制备成任何一种适用于临床应用的口服制剂或注射制剂,如片剂、胶囊剂、丸剂、散剂、膏剂、分散剂、颗粒剂、注射剂、冻干粉针剂等。所述药用辅料包括柠檬酸钠、磷酸钙、填充剂、粘合剂、保湿剂、崩解剂、阻滞剂、吸收促进剂、湿润剂、吸收剂或润滑剂及它们的混合物。其中,填充剂如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;粘合剂如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯酮、蔗糖和阿拉伯胶;保湿剂如甘油;崩解剂如琼脂、碳酸钙、土豆淀粉或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠,低取代羟丙基纤维素;阻滞剂溶液如石蜡;吸收促进剂如季胺类化合物;湿润剂如十六醇和单硬脂酸甘油酯;吸收剂如白陶土和皂土;润滑剂如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂硫酸钠。
由上述技术方案可知,本发明提供了化合物的柠檬酸一盐晶型Form A及其制备方法与应用。本发明所述晶型Form A为稳定的无水晶型,在37℃水中24h溶解度为6.36mg/mL,与游离态相比有显著提升,化学稳定性良好,无引湿性。本发明所述晶型Form A制备方法操作简单,适合于工业化生产。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例中所需要使用的附图作简单地介绍。
图1为所述化合物的柠檬酸一盐晶型Form A的X-射线粉末衍射图;
图2为所述化合物的柠檬酸一盐晶型Form A的热重分析图;
图3为所述化合物的柠檬酸一盐晶型Form A的差示扫描量热图;
图4为稳定性样品放置前后的X-射线粉末衍射图;
图5为所述化合物的柠檬酸一盐晶型Form A的DVS图;
图6为所述化合物的柠檬酸一盐晶型Form A的DVS测试前后的X-射线粉末衍射图。
具体实施方式
本发明提供了化合物(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮的柠檬酸一盐晶型Form A及其制备方法与应用,本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。
本发明采用的试材皆为普通市售品,皆可于市场购得。
下面结合实施例,进一步阐述本发明。其中,X-射线粉末衍射(XRPD)所使用的仪器为Bruker D8Advance,采用铜靶波长为的Kαradiation,在40kV和40mA的操作条件下、θ-2θ测角仪、镍片过滤,SSD160-2探测器。仪器在使用前用仪器自带的标准品(刚玉)校准。样品在室温条件下测试,把需要检测的样品放在无反射板上。详细检测条件如下,角度范围:3~40°2θ,步长:0.02°2θ,速度:0.2秒/步。
热重分析(TGA)数据采自于梅特勒-托利多TGA2,仪器控制软件是STAResoftware,分析软件是STARe software。通常取1~10mg的样品放置于氧化铝坩埚内,采用分段高分辨检测的方式,以10k/min的升温速度在50mL/min干燥氮气的保护下将样品从30℃升至350℃。
差热分析(DSC)数据采自于梅特勒-托利多DSC3,仪器控制软件是STAResoftware,分析软件是STARe software。通常取0.5-5mg的样品放置于铝坩埚(加盖打孔)内,以10k/min的升温速度在50mL/min干燥氮气的保护下将样品从30℃升至300℃。
实施例一、
称取5000.73mg游离态样品((E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮)和2172.27mg柠檬酸加入到50mL单口瓶中,加入20mL乙腈室温超声溶解。加入搅拌子,将单口瓶放于室温条件下搅拌3天,将悬浊液真空抽滤取得白色固体。取固体放入室温真空烘箱中干燥24小时,得到化合物(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮的柠檬酸一盐晶型Form A。
对所得化合物的柠檬酸一盐晶型Form A进行X-射线粉末衍射热重分析(TGA)和差示扫描量热(DSC)检测,结果见图1-3。
如图1所示,所述化合物的柠檬酸一盐晶型Form A,以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰:4.1±0.2°、8.4±0.2°、9.8±0.2°、11.9±0.2°、12.8±0.2°、13.7±0.2°、15.0±0.2°、15.7±0.2°、16.4±0.2°、16.7±0.2°、17.2±0.2°、18.4±0.2°、18.9±0.2°、19.9±0.2°、20.7±0.2°、21.3±0.2°、21.9±0.2°、22.1±0.2°、22.6±0.2°、24.1±0.2°。
如图2所示,TGA图谱显示所述化合物的柠檬酸一盐晶型Form A在120℃之前有约1.1%的失重。
如图3所示,DSC图谱显示所述化合物的柠檬酸一盐晶型Form A的熔点约为178℃。
实施例二、
称取约200mg游离态样品((E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮)于20mL玻璃小瓶中,加入86.91mg柠檬酸,加入8mL乙腈,超声促溶,形成混悬液;加入搅拌子,在磁力搅拌器上进行室温悬浮搅拌;室温下搅拌约3天后,真空抽滤分离所得固体,室温真空干燥2小时得到化合物的柠檬酸一盐晶型Form A。X-射线粉末衍射、热重分析和差热分析与实施例一结果一致。
实施例三、
称取约20mg游离态样品((E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮)于3mL玻璃小瓶中,加入8mg柠檬酸,加入0.5mL异丙醇,超声促溶,形成混悬液;加入搅拌子,在磁力搅拌器上进行室温悬浮搅拌;室温下搅拌约3天后,对混悬液进行离心,分离所得固体,室温真空干燥16小时得到化合物的柠檬酸一盐晶型Form A。X-射线粉末衍射、热重分析和差热分析与实施例一结果一致。
实施例四、
称取5000.73mg游离态样品((E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮)和2172.27mg柠檬酸加入到50mL单口瓶中,加入20mL乙腈室温超声溶解。加入搅拌子,将单口瓶放于室温条件下搅拌3天,将悬浊液真空抽滤取得白色固体。取固体放入50℃真空烘箱中干燥2小时,得到化合物的柠檬酸一盐晶型Form A。
实施例五、化合物的柠檬酸一盐晶型Form A晶型评估
对制得的化合物的柠檬酸一盐晶型Form A进行晶型评估,评估内容包括水中平衡溶解度、固态理化稳定性和引湿性。
1、水中平衡溶解度
对实施例一制得的FormA晶型样品测试24h水中平衡溶解度。试验中,取约20m g固体与1毫升水在3mL玻璃小瓶中混合,加入搅拌子,再将玻璃小瓶固定在磁力搅拌器上,并将磁力搅拌器放置于37℃恒温箱中开启搅拌。24小时后,分离滤液测试HPLC浓度。结果如表1所示,Form A晶型在水中24h的平衡溶解度为6.36mg/mL,相对于疏水的游离碱(化合物(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮)有显著提升。
表1水中平衡溶解度结果
固体形态 | 37℃水中平衡溶解度(mg/mL) |
Form A | 6.36 |
游离碱 | 0 |
2、胃模拟液中平衡溶解度
对实施例一制得的FormA晶型样品测试24h胃模拟液中平衡溶解度。试验中,取约20mg固体与1毫升水在3m L,玻璃小瓶中混合,加入搅拌子,再将玻璃小瓶固定在磁力搅拌器上,并将磁力搅拌器放置于37℃恒温箱中开启搅拌。24小时后,分离滤液测试HPLC浓度。结果如表2所示,Form A晶型在胃模拟液中24h的平衡溶解度为1.30mg/ml。
表2胃模拟液中平衡溶解度数据
固体形态 | 37℃水中平衡溶解度(mg/mL) |
Form A | 1.30 |
3、一周稳定性
对实施例一制得的FormA晶型样品分别在25℃/60%RH(长期)和40℃/75%RH(加速)条件下放置一周后,测试HPLC纯度及晶型变化。结果如表3所示。
表3一周稳定性评估结果
Form A晶型在两种测试条件下放置一周后,HPLC纯度无明显下降,化学稳定性良好,样品未观察到晶型变化,晶型稳定性较好。稳定性样品放置前后的XRPD如图4所示。
4、引湿性评估
评估25℃下实施例一制得的FormA晶型样品随湿度变化的稳定性风险,对Form A进行了DVS测试,收集测试后的固体样品进行XRPD测试。结果见表4,在90%RH条件下,FormA晶型吸水最大约0.047%,样品无引湿性,晶型亦未发生变化。DVS及XRPD测试结果如图5和图6所示。
表4引湿性评估结果
固体形态 | DVS最高增重(%) | 测试前后晶型是否变化 | 引湿性 |
Form A | 0.04657 | 否 | 无引湿性 |
以上所述,仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应以权利要求的保护范围为准。
Claims (10)
1.(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮的柠檬酸一盐晶型Form A,其特征在于,使用Cu-Kα辐射,晶型A以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰:4.1±0.2°、12.8±0.2°、15.7±0.2°、17.2±0.2°、18.9±0.2°、20.7±0.2°。
2.制备权利要求1所述的(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮的柠檬酸一盐晶型Form A的方法,其特征在于,将(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮的柠檬酸一盐真空干燥结晶。
3.根据权利要求2所述的方法,其特征在于,所述真空干燥的温度为20~50℃,时间为2~24小时。
4.根据权利要求2或3所述的方法,其特征在于,(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮的柠檬酸一盐的制备方法包括以下步骤:
(a)(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮加入柠檬酸和溶剂进行混合,形成混悬液;
(b)室温悬浮搅拌析出固体;
(c)分离得到(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮的柠檬酸一盐。
5.根据权利要求4所述的方法,其特征在于,步骤(a)所述溶剂选自乙腈、异丙醇、丙酮、二氯甲烷和四氢呋喃中的至少一种。
6.根据权利要求4所述的方法,其特征在于,步骤(b)所述悬浮搅拌时间为10~72小时。
7.根据权利要求4所述的方法,其特征在于,步骤(c)所述分离为真空抽滤或离心分离。
8.权利要求1所述(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮的柠檬酸一盐晶型Form A在制备治疗与抑制成纤维细胞生长因子受体激酶相关的高增殖疾病的药物中的应用。
9.根据权利要求8所述应用,其特征在于,所述高增殖疾病为肺癌、乳腺癌、卵巢癌、子宫内膜癌、尿路上皮癌、膀胱癌、胃癌、头颈部癌症、前列腺癌、多发性骨髓瘤、白血病、脑癌、眼癌、肝癌和皮肤癌中的一种或多种。
10.一种治疗与抑制成纤维细胞生长因子受体激酶相关的高增殖疾病的药物组合物,其特征在于,由权利要求1所述(E)-6-(2,6-二氯-3,5-二甲氧基苯基)-8-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-4-基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮的柠檬酸一盐晶型Form A和常规的药用辅料组合制成。
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