CN103992269A - 一种辣椒素衍生物及其制备方法 - Google Patents

一种辣椒素衍生物及其制备方法 Download PDF

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CN103992269A
CN103992269A CN201410221592.XA CN201410221592A CN103992269A CN 103992269 A CN103992269 A CN 103992269A CN 201410221592 A CN201410221592 A CN 201410221592A CN 103992269 A CN103992269 A CN 103992269A
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capsaicin
nicotinoyl
capsaicine
synthetic
vanillyl pelargonic
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CN103992269B (zh
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张定林
杨莹
唐渊
侯华
季卫刚
赵华文
赵先英
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Third Military Medical University TMMU
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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
    • C07D213/79—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

Abstract

一种辣椒素衍生物及其制备方法。该辣椒素衍生物是烟酰基任酸香草酰胺。其制备方法主要通过烟酸与合成辣椒素在催化剂作用下对合成辣椒素的酚羟基进行酰化反应制得。本发明的辣椒素酸衍生物在抑制人结肠癌CW-2细胞增殖方面，其效果比合成辣椒素更明显、更好；本发明所制备的辣椒素衍生物刺激作用明显小于合成辣椒素，且制备方法简单可行。

Description

一种辣椒素衍生物及其制备方法
技术领域
本发明涉及辣椒素的衍生物及相应的制备方法。
背景技术
合成辣椒素（Nonivamide ）的化学名称为壬酸香草酰胺，是一种生物碱。它与天然辣椒素有相似的结构，合成辣椒素的结构式为：
。
由于合成辣椒素更具有与天然辣椒素十分相近的生物活性和作用，且可以大量获得，价格也相对便宜，所以，在工业和医药上人们就多用合成辣椒素来替代天然辣椒素来作为原料使用。医药方面，在治疗风湿性关节炎、骨关节炎，治疗跌打损伤、冻伤，治疗带状疱疹后神经疼、严重银屑病，以及用于镇痛、止痒、杀菌消炎等多种外用药物中，许多都含有合成辣椒素的成分。最新研究表明，合成辣椒素在抗肿瘤和降脂、减肥方面也有一定的治疗效果。但是，在抗肿瘤方面，例如抑制人结肠癌CW-2细胞增殖，其效果还不够理想；又由于合成辣椒素与辣椒素一样具有辛辣性，其刺激作用较大，这就限制了在抗肿瘤方面的进一步开发应用。
发明内容
本发明的第一目的是，提供一种抑制人结肠癌CW-2细胞增殖的效果较好、且能够进一步开发应用的辣椒素衍生物。
本发明的第二目的是，提供一种制备实现所述第一目的之辣椒素衍生物的制备方法。
实现所述第一发明目的之技术方案，是这样一种辣椒素衍生物，它结构中的母体为合成辣椒素，其改进之处是，在所述合成辣椒素的酚羟基上连有烟酰基，构成的辣椒素衍生物是烟酰基壬酸香草酰胺，其结构式为：
。
实现所述第二发明目的之技术方案，是这样一种辣椒素衍生物的制备方法，其特征是，该方法制备的是实现第一发明目的所述的辣椒素衍生物——烟酰基壬酸香草酰胺；其制备步骤如下：
（1）将烟酸用二氯甲烷溶解，之后再加入N,N-二异丙基碳二亚胺进行活化；
（2）在步骤（1）所得溶液中加入合成辣椒素和催化剂DMAP，在15～35℃条件下作酰化反应；反应完全后用水洗去催化剂DMAP，然后再进行分液操作；
其中，催化剂DMAP的用量以摩尔量计算，不大于合成辣椒素的摩尔量；
（3）将分液后所得有机相用足量的无水硫酸钠干燥，然后减压浓缩而得烟酰基壬酸香草酰胺粗品；
（4）将所述粗品用二氯甲烷溶解，然后再用300～400目硅胶过柱分离，得呈白色粉末状的烟酰基壬酸香草酰胺纯品；
其中，过柱分离烟酰基壬酸香草酰胺粗品时所用洗脱剂为二氯甲烷和甲醇的混合液，其体积比为，二氯甲烷∶甲醇＝9∶1。
从实现第一发明目的之方案中可以看出，本发明的辣椒素衍生物——烟酰基壬酸香草酰胺，是将合成辣椒素作为母体，并在其酚羟基上连了烟酰基的。验证表明，本发明的烟酰基壬酸香草酰胺在抑制人结肠癌CW-2细胞增殖方面的效果，明显优于合成辣椒素。由于本发明的辣椒素衍生物实际是对合成辣椒素的分子结构进行了改进，主要是对合成辣椒素的酚羟基进行了修饰，这与修饰水杨酸十分类似，水杨酸的酚羟基被乙酰化，制备成了乙酰水杨酸后，就成为刺激作用明显降低的药物——阿司匹林了。因此，其辛辣性和刺激作用就必然有所降低，自然也就适合于在抗肿瘤方面的进一步开发应用了。
从实现第二发明目的之方案中可以看出，本发明的制备方法也十分简单，也即能够用较低制备成本来得到有较好药用效果的烟酰基壬酸香草酰胺。因此，从成本方面讲，也非常有利于进一步开发应用。
下面结合具体实施方式对本发明作进一步的说明。
具体实施方式
一、一种辣椒素衍生物，它结构中的母体为合成辣椒素，本发明中，在所述合成辣椒素的酚羟基上连有烟酰基，构成的辣椒素衍生物是烟酰基壬酸香草酰胺，其结构式为：
。
二、一种辣椒素衍生物的制备方法，该方法制备的是本具体实施方式之一所述的辣椒素衍生物——烟酰基壬酸香草酰胺；其制备步骤如下：
（1）将烟酸用二氯甲烷（CH2Cl2）溶解，之后再加入N,N-二异丙基碳二亚胺（DIC）进行活化（显然，二氯甲烷的用量应当以能够将烟酸完全溶解为度，N,N-二异丙基碳二亚胺的用量应当以能够将溶解后的烟酸全部活化为准——本领域的技术人员清楚，要想真正确保能够全部活化，DIC通常需适度过量，例如过量5～10％）；
（2）在步骤（1）所得溶液中加入合成辣椒素和催化剂DMAP（4-二甲氨基吡啶），在15～35℃条件下作酰化反应（即实现将烟酰基连接在合成辣椒素的酚羟基上的反应。酰化反应时间通常为12～24小时；温度高，反应时间短，反之则反应时间长）；反应完全后用水洗去催化剂DMAP，然后再进行分液操作（本领域的技术人员清楚，活化剂DIC和催化剂DMAP一样，在水中也有较好的溶解度，因此水洗出除催化剂DMAP的同时，过量部分的活化剂DIC会一并被水洗掉）；
其中，催化剂DMAP的用量以摩尔量计算，不大于合成辣椒素的摩尔量（显然，在保证反应能完全进行的前提下，DMAP的用量可适量少些，以降低成本和减少杂质含量；同样显然的是，烟酸和合成辣椒素的配比，应当以反应完成后几乎没有剩余的烟酸或合成辣椒素为准）；
（3）将分液后所得有机相用足量的无水硫酸钠（元明粉，Na2SO4）干燥，然后减压浓缩而得烟酰基壬酸香草酰胺粗品（显然，无水硫酸钠的实际用量，以能够确保所述“干燥”会比较好而快地进行为度）；
（4）将所述粗品用二氯甲烷溶解，然后再用300～400目硅胶过柱分离，得呈白色粉末状的烟酰基壬酸香草酰胺纯品；
其中，过柱分离烟酰基壬酸香草酰胺粗品时所用洗脱剂为二氯甲烷和甲醇的混合液，其体积比为，二氯甲烷∶甲醇＝9∶1。
为本领域技术人员能够更加清楚地理解本发明，将步骤（1）、（2）合起来完成的酰化反应的反应式披露如下。
上式中，为烟酸的结构式。
本发明在实验室采用了核磁共振仪和红外光谱仪对所制得的辣椒素衍生物进行了结果确认。烟酰基壬酸香草酰胺的1HNMR和IR如下：
1HNMR: 9.20(1H), 8.87(1H), 8.42(1H), 8.07(1H), 7.05(1H), 6.86(1H), 6.54(1H), 4.27(2H), 3.72(3H)
IR: v/cm-1: 2926, 2857, 2115, 1731, 1643, 1603, 1559, 1281, 1125, 1029。
从上述1HNMR和IR中分析可以得出，该化合物的结构确为本发明的目标化合物结构。
然后，采用MTT［3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐，商品名：噻唑蓝］染色法，针对人结肠癌CW-2细胞增殖的抑制结果，用合成辣椒素和本发明的辣椒素衍生物（烟酰基壬酸香草酰胺）进行了对比验证。验证结果见下表的：
  抑制率（25umol/L） 抑制率（50umol/L）
合成辣椒素 10％ 42％
烟酰基壬酸香草酰胺 16％ 67％
从验证表中的抑制率可以看出，本发明的辣椒素衍生物在抑制人体结肠癌CW-2细胞增殖方面，几种浓度的效果均优于合成辣椒素。由于合成辣椒素和烟酰基壬酸香草酰胺在正常使用情况下，是无毒副作用的，所以，可用少量（自然是等量）合成辣椒素和烟酰基壬酸香草酰胺，通过试验者的感觉来比较其辛辣性和刺激作用。当发明人用鼻子嗅时，嗅到合成辣椒素就马上打喷嚏，而在同样距离去嗅烟酰基壬酸香草酰胺时，鼻子基本无异样感觉；用同样的量放在手背上时，用合成辣椒素就有明显的灼烧感，用烟酰基壬酸香草酰胺就基本没有灼烧感。由此可以证明，本发明的辣椒素衍生物——烟酰基壬酸香草酰胺的辛辣性和刺激作用明显低于合成辣椒素，所以具有进一步开发成为抗肿瘤，至少是抑制人结肠癌CW-2细胞增殖的药物原料之一。

Claims (2)

1.一种辣椒素衍生物，它结构中的母体为合成辣椒素，其特征在于，在所述合成辣椒素的酚羟基上连有烟酰基，构成的辣椒素衍生物是烟酰基壬酸香草酰胺，其结构式为：
。
2.一种辣椒素衍生物的制备方法，其特征在于，该方法制备的是权利要求1所述的辣椒素衍生物——烟酰基壬酸香草酰胺；其制备步骤如下：
（1）将烟酸用二氯甲烷溶解，之后再加入N,N-二异丙基碳二亚胺进行活化；
（2）在步骤（1）所得溶液中加入合成辣椒素和催化剂DMAP，在15～35℃条件下作酰化反应；反应完全后用水洗去催化剂DMAP，然后再进行分液操作；
其中，催化剂DMAP的用量以摩尔量计算，不大于合成辣椒素的摩尔量；
（3）将分液后所得有机相用足量的无水硫酸钠干燥，然后减压浓缩而得烟酰基壬酸香草酰胺粗品；
（4）将所述粗品用二氯甲烷溶解，然后再用300～400目硅胶过柱分离，得呈白色粉末状的烟酰基壬酸香草酰胺纯品；
其中，过柱分离烟酰基壬酸香草酰胺粗品时所用洗脱剂为二氯甲烷和甲醇的混合液，其体积比为，二氯甲烷∶甲醇＝9∶1。
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CN108069898A (zh) * 2016-11-16 2018-05-25 南华大学 含烟酸辣椒碱酯衍生物、制备方法及其用途
CN114524747A (zh) * 2022-04-22 2022-05-24 中国中医科学院中药研究所 一种辣椒素衍生物及其制备方法与应用

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CN101774938A (zh) * 2010-01-20 2010-07-14 中国药科大学 一类辣椒碱衍生物、其制备方法及其医疗用途

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WO2009021058A2 (en) * 2007-08-06 2009-02-12 Trinity Labortories, Inc. Pharmaceutical compositions for treating chronic pain and pain associated with neuropathy
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108069898A (zh) * 2016-11-16 2018-05-25 南华大学 含烟酸辣椒碱酯衍生物、制备方法及其用途
CN108069898B (zh) * 2016-11-16 2021-11-23 南华大学 含烟酸辣椒碱酯衍生物、制备方法及其用途
CN114524747A (zh) * 2022-04-22 2022-05-24 中国中医科学院中药研究所 一种辣椒素衍生物及其制备方法与应用
CN114524747B (zh) * 2022-04-22 2022-07-15 中国中医科学院中药研究所 一种辣椒素衍生物及其制备方法与应用

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