CN116063300A - 一种含氮化合物的盐酸盐 - Google Patents

一种含氮化合物的盐酸盐 Download PDF

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CN116063300A
CN116063300A CN202111291373.5A CN202111291373A CN116063300A CN 116063300 A CN116063300 A CN 116063300A CN 202111291373 A CN202111291373 A CN 202111291373A CN 116063300 A CN116063300 A CN 116063300A
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hydrochloride
nitrogen
containing compound
hydrochloride salt
sample
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吴冬冬
胡永韩
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Suzhou Sinoway Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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Abstract

本发明公开了一种如式I所示的含氮化合物的盐酸盐。

Description

一种含氮化合物的盐酸盐
技术领域
本发明涉及一种含氮化合物的盐酸盐。
背景技术
CN107056755B公开了化合物
Figure BDA0003333435470000011
并表明其对AB型斑马鱼体轴发育、AB型斑马鱼剪尾再生和Wnt信号通路具有抑制活性，能够治疗癌症。
发明内容
本发明所要解决的技术问题是对如式I所示的含氮化合物游离碱进行盐型筛选，以推进该药物的后续IND开发。
本发明提供了一种如式I所示的含氮化合物的盐酸盐。
Figure BDA0003333435470000012
该盐酸盐性状较好，且DSC显示单一的熔融峰。根据小试所得盐型的表征结果，盐酸盐可以顺利放大制备。溶解度结果显示，盐酸盐在0.1NHCl，SGF中有较好的溶解度。在水中，成盐后，溶解度有所提升，在其它介质中,盐酸盐溶解度较小。通过一周的稳定性数据来看盐酸盐均在1周内稳定。通过两周的稳定性数据来看，盐酸盐两周内稳定。
甲醇中制备的盐酸盐TGA显示从RT到120℃的失重较小(1.51％)，DSC显示为单一的熔点峰(205.9～212.2～216.4℃)。说明从甲醇制备的盐酸盐为无水物。从丙酮中制备盐酸盐的DSC图谱上显示两个吸热峰，结合TGA结果，第一个吸热峰为脱溶剂峰。说明从丙酮中制备的盐酸盐为溶剂化物。
具体实施方式
本发明实施例中所使用的检测仪器如下所述：
X-射线粉末衍射(XRPD)
设备为Shimadzu XRD-6000，光管的最小操作电压与电流分别为40kV和30mA，射线源为Cu～Kα靶
Figure BDA0003333435470000021
样品扫描范围的2-Theta值从5度到50度。扫描速度为5deg/min。
热重分析与差示热量扫描(TGA和DSC)
热重分析仪：称取大约5mg样品于坩埚中，氮气保护，从30度升温至400度，升温速率为20℃/min。扫描时，用一条空白TGA背景曲线对结果进行校正。
差示热量扫描仪：称取大约1～5mg粉末样品放置在一个封闭的铝坩埚中，坩埚盖上扎一针孔。氮气保护，从30度升温到300度进行差示热量扫描，升温速率为20℃/min。
动态水分吸附
动态水分吸附实验由吸附和解吸附两步组成。通常认为在一个设定的相对湿度下，随时间增加，样品重量不发生改变即为实验终点，也就是当dm/dt≦0.01％时，便认为样品在该相对湿度下对水分的吸附或解吸附已达到平衡。
样品室温保持25度。相对湿度从0％升到95％，再降到0％，每步变化5％RH。
偏振光显微观察
在载玻片中央滴一滴硅油，并加入少量的样品并使其分散均匀。然后，盖上盖玻片。通过偏振光观察样品是否具有明显的双折射。
初步溶解度测试
为了选择合适的方法进行盐型筛选，对该化合物进行了大致溶剂度测试。测试方法：称取约5mg化合物，逐步加入适当体积溶剂，记录所用溶剂的总体积，溶解度很差的溶剂的所加总量不超过5ml。
实施例1在甲醇体系中制备盐酸盐：
称取大约100mg的式I化合物至每个小瓶中，加入10ml甲醇，并在室温下搅拌得均匀的混悬液(10mg/ml)。然后将盐酸按摩尔比1:1.05(碱:酸)缓慢滴加到混悬液中，记录加入酸后的反应现象。所有样品均在室温下磁力搅拌过夜。
搅拌过夜后，如果小瓶中的样品为混悬液，且固体量较多，则采用离心法收集固体；如果小瓶中的样品为澄清溶液或者固体量较少，则采用氮气吹扫的方式浓缩溶剂、或者冷却结晶的方式富集固体。对所收集固体在40℃条件下减压真空干燥4小时，并对干燥后的固体进行X-射线粉末衍射检测。
如果干燥后固体其XRPD图与空白对照组、起始游离碱的XRPD图不一致，则将这些干燥后的固体进行进一步表征，包括TGA、DSC、DVS、1H-NMR等。
实施例2在乙醇体系中制备盐酸盐：
由于在甲醇中制备盐酸盐收率较低(约60％)，因此尝试在乙醇中制备盐酸盐，同时考察加入不同比例的盐酸，来考察成盐摩尔比。
称取50mg式I化合物原料药于4ml的小瓶中，加入2ml的乙醇，适当超声，使样品形成均匀的混悬液，加入磁力搅拌子进行搅拌，同时按照游离碱:盐酸的摩尔比1:1,1:2,1:3分别加入2mol/L的盐酸乙醇溶液，边加边搅拌，按上述方法制备空白。所有样品均在室温条件下搅拌过夜。然后采用离心法分离并收集湿的固体。将所收集的固体减压真空干燥2h，然后测定其XRPD。
实施例3在丙酮体系中制备盐酸盐
称取大约100mg的式I化合物至每个小瓶中，加入5ml丙酮，并在室温下搅拌得均匀的混悬液(20mg/ml)。然后将盐酸、富马酸、马来酸、琥珀酸、柠檬酸、甲磺酸、苯磺酸、硫酸按摩尔比1:1.05(碱:酸)缓慢滴加到混悬液中。所有样品均在室温下磁力搅拌过夜。
搅拌过夜后，如果小瓶中的样品为混悬液，且固体量较多，则采用离心法收集固体；如果小瓶中的样品为澄清溶液或者固体量较少，则采用氮气吹扫的方式浓缩溶剂、或者冷却结晶的方式富集固体。对所收集固体在40℃条件下减压真空干燥8小时，并对干燥后的固体进行X-射线粉末衍射检测。
如果干燥后固体其XRPD图与空白对照组、起始游离碱的XRPD图不一致，则将这些干燥后的固体进行进一步表征，包括TGA、DSC、DVS、1H-NMR等。

Claims (4)

1.一种如式I所示的含氮化合物的盐酸盐，
Figure FDA0003333435460000011
2.一种药物组合物，其包含如权利要求1所示的盐酸盐和药用辅料。
3.一种如权利要求1或2所述的如式I所示的含氮化合物的盐酸盐在制备Wnt信号通路抑制剂中的应用。
4.一种如权利要求3所述的应用，该应用为用于治疗与异常的Wnt信号活性相关的细胞增殖性疾病或消化系统疾病的药物；或者，所述的药物为用于治疗肿瘤的药物。
CN202111291373.5A 2021-11-02 2021-11-02 一种含氮化合物的盐酸盐 Pending CN116063300A (zh)

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