CN104710353A - 吡啶生物碱衍生物 - Google Patents

吡啶生物碱衍生物 Download PDF

Info

Publication number
CN104710353A
CN104710353A CN201310684185.8A CN201310684185A CN104710353A CN 104710353 A CN104710353 A CN 104710353A CN 201310684185 A CN201310684185 A CN 201310684185A CN 104710353 A CN104710353 A CN 104710353A
Authority
CN
China
Prior art keywords
compound
pharmaceutically acceptable
alkaloid derivative
acid
formula iii
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201310684185.8A
Other languages
English (en)
Inventor
不公告发明人
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Yizhi Pharmaceutical Technology Co Ltd
Original Assignee
Shanghai Yizhi Pharmaceutical Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Yizhi Pharmaceutical Technology Co Ltd filed Critical Shanghai Yizhi Pharmaceutical Technology Co Ltd
Priority to CN201310684185.8A priority Critical patent/CN104710353A/zh
Publication of CN104710353A publication Critical patent/CN104710353A/zh
Pending legal-status Critical Current

Links

Classifications

    • 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
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • 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
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及的吡啶衍生物马来酸盐或其药物学上可接受的溶剂化物及其在制备治疗代谢综合症的药物中的应用。

Description

吡啶生物碱衍生物
发明领域
本发明涉及药物化学领域，具体而言，本发明涉及吡啶生物碱衍生物有机酸盐及其制药应用。
背景技术
就目前而言，治疗代谢综合症的药物虽然已有很多种，但已有的这些药物易引起多而重的不良反应，已有的药物的治疗效果仍不够理想。中国发明专利申请公布号为CN102746220 A的专利文献中描述了一些具有治疗代谢综合症的活性化合物。
发明内容
本发明公开了某些新的化合物，这些化合物的制备方法，含有这些化合物的药物组合物以及这些化合物和组合物的制药应用。
这些化合物显示了良好的水溶性稳定性与固体形式稳定性。这些化合物的某些化合物显示特好的稳定性。这些化合物与相应的游离碱相比较其在水中具有很高的溶解性。
这些化合物与相应的游离碱相比较因两者之间的协同增效而惊奇地显示其治疗代谢综合症的活性更高。
这些化合物惊人与显著的稳定性、水溶性、治疗代谢综合症的活性为有效制剂与大量使用提供了优势。
因此，本发明提供了一种式（Ⅲ）化合物：
｛（Ⅰ）H｝+Ⅱˉ;
其中Ⅰ的化学结构如下：
其中Ⅱ的化学结构如下：
和/或药物上可接受的溶剂化物，其中：
Ⅱˉ表示抗衡离子。
适宜的抗衡离子Ⅱˉ包括由药物上可接受的有机酸提供的离子。
优选的药物可接受的有机酸包括胆酸、鹅去氧胆酸、熊去氧胆酸、去氧胆酸、酒石酸、马来酸、富马酸，特别是马来酸。
优选的抗衡离子是马来酸根离子。
式（Ⅲ）化合物是盐。
适宜的药物上可接受的溶剂化物是水合物。
此外，本发明还提供了式（Ⅲ）和/或药物上可接受的溶剂化物的制备方法。此方法包括将式（Ⅰ）化合物:
(Ⅰ)
与上述定义的抗衡离子Ⅱˉ源反应，此后如果有需要，再制备其药物上可接受的溶剂化物。
适宜的抗衡离子Ⅱˉ源是药物上可接受的有机酸。
优选的药物可接受的有机酸包括胆酸、鹅去氧胆酸、熊去氧胆酸、去氧胆酸、酒石酸、马来酸、富马酸，特别是马来酸。
优选的抗衡离子源是马来酸。
式（Ⅰ）化合物与抗衡离子Ⅱˉ源之间的反应通常是在常规成盐条件下进行，例如，在溶剂中，通常为C1---C4链烷醇溶剂如乙醇，在可提供生成所需适宜速率的任意温度下，通常在升高的温度例如溶剂回流的温度下，较适宜地是以约等的摩尔量但优选用略过量的抗衡离子Ⅱˉ源的情况下将式（Ⅰ）化合物与抗衡离子Ⅱˉ源混合然后结晶出所需产物（Ⅲ）。
式（Ⅲ）化合物的药物上可接受的溶剂化物可用常规的化学方法来制备。
式（Ⅰ）化合物可根据中国发明专利申请公布号为CN 102746220A的专利文献中描述的方法来制备。
适宜的抗衡离子源是公知的经商业途径可易获得，例如马来酸，或者可根据已知的方法制备所需的抗衡离子源。
本发明化合物的稳定性可用常规定量分析方法测定；例如固体化合物的稳定性可用加速的稳定性试验来测定，例如差示扫描量热法（DSC），热解重量分析法（TGA）与在升温中的等温线试验。此试验包括常温贮藏试验。（其中在公知期间内在温度和湿度控制条件下贮藏试验化合物）。试验化合物的定量分析是在贮藏期之前、贮藏期中或贮藏期之后。相对于适宜的参考标准测定试验化合物的稳定性。
如上所述，本发明的化合物与相应的游离碱相比较其在水中具有显著高的溶解性。这样测定本发明化合物在水溶液中的稳定性的常规方法包括在已知的温度条件和已知的期间内测定由试验化合物的水溶液中沉淀出母体游离碱的程度，我们发现式（Ⅲ）化合物显示出良好的水溶液稳定性。特别是其中Ⅱˉ表示的马来酸根的式(Ⅲ)化合物在水溶液中特别稳定。更惊奇的是其中Ⅱˉ表示的马来酸根的式(Ⅲ)化合物在水溶液中异常的稳定。
所述试验化合物定量分析试验可以常规方法，通常用色谱法，例如高压液相色谱法进行。
如上所述，本发明的化合物具有实用的治疗活性。
因此，本发明提供了用作治疗活性物质的式(Ⅲ)化合物和/或药物上可接受的溶剂化物。
这样，本发明提供了用作治疗代谢综合症的式(Ⅲ)化合物和/或药物上可接受的溶剂化物。
式(Ⅲ)化合物和/或药物上可接受的溶剂化物可以其自身的形式施用，优选的是也可以含有药物上可接受的载体的药物组合物的形式施用。
因此，本发明还提供了一种含有式(Ⅲ)化合物和/或药物上可接受的溶剂化物和药物上可接受的载体的药物组合物。
此处所用术语“药物上可接受的”包括对人和兽医两者使用的化合物、组合物和组分，例如，术语“药物上可接受的盐”包括兽医上可接受的盐。
适宜的药物组合物是单位剂型的组合物，例如口服液、片剂、胶囊剂、注射液、喷雾剂。
最适宜的药物组合物是口服液、喷雾剂。
根据常规的药物上的惯例，载体可包括稀释剂、填充剂、崩解剂、润湿剂、润滑剂、着色剂、调味剂或其它常规添加剂。
最适宜的组合物是配置成单位剂型。
通常，活性成分可以上述药物组合物形式施用。
本发明还提供了一种含有式(Ⅲ)化合物和/或药物上可接受的溶剂化物在生产治疗代谢综合症的药物上的应用。
下面给出本发明的实施例用于进一步说明和更详细地描述本发明。
实施例1
吡啶生物碱衍生物马来酸盐
将化合物吡啶生物碱衍生物0.36克（1mmol）和马来酸0.12克(1mmol)溶于沸腾的乙醇10毫升中。此热溶液经硅藻土过滤，然后在温和搅拌下缓慢冷却，在0—5℃的温度环境中静置数小时，析出吡啶生物碱衍生物马来酸盐晶体，滤出吡啶生物碱衍生物马来酸盐晶体，以冷乙醇洗涤并在50℃真空条件下干燥，得0.49克产物。
实施例2
吡啶生物碱衍生物马来酸盐
将化合物吡啶生物碱衍生物马来酸盐0.36克和马来酸0.12克在回流的乙醇10毫升中搅拌至固体全部溶解。加活性炭，将此热溶液经硅藻土过滤，搅拌中降温至室温。在0—5℃的温度环境中静置数小时，析出吡啶生物碱衍生物马来酸盐晶体，滤出吡啶生物碱衍生物马来酸盐晶体，以冷乙醇洗涤并在50℃真空条件下干燥，得0.47克产物。
本发明可用其他的不违背本发明的精神或主要特征的具体形式来概述。因此，无论从哪一点来看，本发明的上述实施方案都只能认为是对本发明的说明而不能限制本发明。

Claims (2)

1.吡啶衍生物（Ⅰ）马来酸（Ⅱ）盐（Ⅲ）;
2.权利要求1的化合物在制备治疗代谢综合症的药物中的应用。
CN201310684185.8A 2013-12-13 2013-12-13 吡啶生物碱衍生物 Pending CN104710353A (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310684185.8A CN104710353A (zh) 2013-12-13 2013-12-13 吡啶生物碱衍生物

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201310684185.8A CN104710353A (zh) 2013-12-13 2013-12-13 吡啶生物碱衍生物

Publications (1)

Publication Number Publication Date
CN104710353A true CN104710353A (zh) 2015-06-17

Family

ID=53410143

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310684185.8A Pending CN104710353A (zh) 2013-12-13 2013-12-13 吡啶生物碱衍生物

Country Status (1)

Country Link
CN (1) CN104710353A (zh)

Similar Documents

Publication Publication Date Title
CN104710422A (zh) 金雀花碱衍生物
CN103833757A (zh) 甲氧基铁屎米酮衍生物的盐
CN103626773A (zh) 鸭嘴花碱衍生物的盐
CN104710353A (zh) 吡啶生物碱衍生物
CN103772475A (zh) 锥丝亚胺衍生物的盐
CN103833758A (zh) 羟基铁屎米酮衍生物的盐
CN104693212A (zh) 氧化石蒜碱衍生物
CN104710362A (zh) 异紫堇二酮衍生物
CN103121993A (zh) 2,6-二氯-3-氟苯基衍生物的盐
CN104693202A (zh) N-氧化槐定碱衍生物
CN103833747A (zh) 黄连碱衍生物的盐
CN104710416A (zh) 延胡素乙素衍生物
CN104710418A (zh) 马齿苋酰胺e的衍生物
CN104710370A (zh) 吡嗪酮衍生物
CN104693197A (zh) 樟柳碱衍生物
CN104693118A (zh) N-脱乙基查斯蔓宁的衍生物
CN104447552A (zh) 紫堇定碱衍生物的药物用途
CN104693117A (zh) 查斯蔓宁的衍生物
CN104387381A (zh) 羟基菲并喹喏里西定衍生物的药物用途
CN104693116A (zh) N-脱乙基-二乙酰查斯蔓宁衍生物
CN103772470A (zh) 锥丝明衍生物的盐
CN103772474A (zh) 锥丝碱衍生物的盐
CN103121965A (zh) 吲哚酮衍生物的盐
CN103508952A (zh) 降荷叶碱衍生物的盐
CN103508953A (zh) 荷叶碱衍生物的盐

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20150617

WD01 Invention patent application deemed withdrawn after publication