CN113061134A - 附子中海替生型c20二萜生物碱的制备及其用途 - Google Patents
附子中海替生型c20二萜生物碱的制备及其用途 Download PDFInfo
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Abstract
本发明属医药技术领域,公开了新的C20二萜生物碱类化合物在安全剂量下可剂量依赖性发挥的镇痛作用活性。动物实验结果证明:化合物1‑2具有明显的镇痛作用,有望成为与疼痛相关的疾病的治疗药物。
Description
技术领域
本发明涉及从中药附子中提取分离纯化得到新的C20二萜生物碱类化合物,及其衍生物和药用盐类在制备预防和治疗急性炎症、急性或慢性疼痛等疾病中的应用。属医药技术领域。
背景技术
附子为毛茛科乌头属植物乌头Aconitum carmichaeliiDebx.侧根的加工品,6 月下旬至8月上旬采挖,除去母根、须根及泥沙,得到习称的“泥附子”,再经不同方法炮制后得到常用和习称规格的“盐附子”、“黑顺片”和“白附片”等药用品[1]。附子具有回阳救逆,补火助阳,散寒止痛之功效,中医用于亡阳虚脱,肢冷脉微,心阳不足,胸痹心痛,虚寒吐泻,脘腹冷痛,肾阳虚衰,阳痿宫冷,阴寒水肿,阳虚外感,寒湿痹痛等症候治疗。同时,附子属有毒“下品”中药。由于附子明确的临床疗效和毒性,长期以来,一直是学者们重点研究的对象之一。
关于附子化学成分及其药理活性的研究发现其中的化学成分与同属其他植物相似,主要是结构复杂而独特的二萜生物碱类,并且发现二萜生物碱类在抗炎,镇痛,抗心律失常等方面作用显著[1-3]。因此,二萜生物碱类被认为是附子的主要有效成分[4-7]。具体包括乌头烷型C19二萜生物碱、海替生烷型C20二萜生物碱、阿替辛烷型C20二萜生物碱、异喹啉类生物碱、尿嘧啶以及神经酰胺类化合物。另外,还报道有黄酮类和甾体三糖苷类化合物[8-38]。其中,去甲乌药碱,又名附子一号,作为附子中发现的强心活性成分用于临床。同时,一类具有新颖骨架结构的含磺酸基的C20二萜生物碱在镇痛活性方面表现明显[39,40]。
附子具有回阳救逆的功效,是中医常用药物,但毒性极强,误食或用药不慎可致中毒,《神农本草经》载其辛温有毒,明朝李时珍著《本草纲目》也将其列为毒草类,并有“乌附毒药,非危病不用”的记载。附子的毒性成分是脂溶性乌头类生物碱,主要成分是乌头碱和N-甲基取代的同系物中乌头碱,这些生物碱具有剧毒 (毒性大小中乌头碱>乌头碱>3-乙酰乌头碱)[41],其主要毒性作用是抑制呼吸及引起心律失常,对心脏的毒性作用是通过兴奋中枢和对心脏的直接作用引起的,进一步的实验结果指出,乌头碱对心脏的直接毒性作用是使心肌细胞Na+通道开放,加速Na+的内流,促使细胞膜去极化,从而引起心律失常[42-50]。
附子中分离鉴定化学成分药理活性的研究主要包括:(1)镇痛镇静作用:早期研究发现附子经炮制后可以减少腹腔注射酒石酸锑钾或乙酸引起的扭体反应次数,延长小鼠对热痛反应的潜伏期[11-22]。进一步研究表明,附子通过k-阿片受体介导,对神经病理性疼痛大鼠产生镇痛作用,其有效成分为乌头碱,对脊髓系节后纤维神经节以及神经节所含有的肽类递质有减少作用,推测可能为P物质减少,使传导痛感的神经末梢物质减少,故疼痛减轻。醋酸扭体和甩尾实验中, mesaconitine都具有很强的镇痛活性,综合文献中对mesaconitin的镇痛机制研究可得出结论,mesaconitin通过激活下行抑制剂α2-肾上腺素和5-羟色胺能神经元来抑制痛觉传输。(2)抗炎作用:研究发现附子具有抑制二甲苯所致小鼠耳廓肿胀和角叉菜胶所致大鼠足趾肿胀和抑制肉芽肿形成及佐剂性关节炎的作用,经配伍以后的复方芍甘附子汤、芍甘附子汤和甘草附子汤等也表现出明显的治疗关节炎的作用,方剂去除附子后抗炎作用不再明显[20]。(3)强心作用:许多学者用不同的制剂在不同的动物模型上均证明附子具有肯定的强心作用,尤其在心功能不全实验动物上表现出的作用更为显著。附子的强心成分早期研究认为是乌头碱等成分的分解产物及其非生物碱成分的综合作用,但乌头碱在不引起心律失常的剂量下证明无明显的增强心肌收缩力的作用。其他化合物则有降压和抑制心肌收缩力作用。对于附子中强心成分和强心机制,许多学者也做了比较深入的研究,发现从附子中分离得到的尿嘧啶、附子苷、去甲乌药碱、撑棍碱、去甲猪毛菜碱、mesaconine、 hypaconine和beiwutinine等成分均表现出了明显的强心作用,其中mesaconine对大鼠心肌缺血再灌注损伤有保护作用,包括改善性肌力作用和左室舒张功能,但对心率几乎没有影响[18,21,51-54]。(4)抗心律失常作用:研究证明附子提取物及其化学成分,包括次乌头碱、Mesaconitine和去甲猪毛菜碱等,对动物缺氧和急性心肌缺血损伤的范围和程度有明显的缩小和减轻作用,能提高小鼠的缺氧耐受力,对大鼠心肌缺血和心律失常有显著的对抗作用。实验证明附子中引起心律失常的物质是乌头碱,但同时也证明,附子中同时存在抗乌头碱的物质。附子水溶部分均能特异性预防和治疗乌头碱诱导的心律失常,在200-400mg/kg范围内作用强度随剂量增加而加强[55,56]。(5)其他:大量研究还发现,附子的提取物以及化学成分具有抗癌、抗衰老、抗肿瘤和增强免疫等作用[57-67]。
抗炎镇痛药物在临床上的使用非常广泛,无论是处方药物,还是非处方药物,都具有非常大的使用量。目前,临床上应用范围最广的抗炎镇痛药物为传统的非甾体类药物,代表性药物主要为阿司匹林、对乙酰氨基酚和布洛芬。然而,传统的非甾体类抗炎镇痛药物治疗过程中通过抑制环氧合酶Ⅱ作用的发挥,进而抑制炎症性前列腺素合成来实现抗炎和镇痛。但在药物作用发挥过程中,环氧合酶Ⅰ也会受到抑制,从而导致生理性前列腺素的合成大量减少,导致患者出现胃肠道副反应,比如胃肠粘膜糜烂、溃疡等,严重时,患者会出现凝血功能障碍、肾脏毒性等症状。此外,血液系统症状、心血管系统症状等也为抗炎镇痛药物服用过程中经常发生的不良反应,严重影响患者用药的安全性病极大限制了传统抗炎镇痛药物的临床应用范围。因此,急需研制出副作用小、临床应用范围广的新型抗炎镇痛药物。
从天然产物中寻找抗炎镇痛活性成分逐渐成为近年来的研究热点。研究发现,皂苷、多糖、生物碱、黄酮、香豆素等天然产物均具有一定的抗炎镇痛作用,其效果主要表现为可以显著抑制化学及物理刺激引起的炎性肿胀或肉芽肿,并可降低致炎后腹腔毛细血管的通透性,抑制炎症因子及其基因的表达等;天然产物的镇痛作用,通常可表现为能延长多种致痛因素如热痛、压痛以及化学刺激的痛阈值等。本申请中的化合物即为从传统中药附子中分离获取得到的具有镇痛作用的天然产物。
参考文献:
[1]国家药典委员会.中华人民共和国药典2010年版一部[M].北京:中国医药科技出版社,2010:177.
[2]Wang,F.P.;Liang,X.T.InTheAlkaloids:Chemistry and Biology;CordellG.A.Ed.;Elsevier Science:New York,2002,59,pp 1–280.
[3]Wang,F.P.;Chen,Q.H.,et al.InTheAlkaloids:Chemistry and Biology;Cordell G.A.Ed.; Elsevier Science:New York,2009;67,pp 1–78.
[4]Wang,F.P.;Chen,Q.H.InTheAlkaloids:Chemistry and Biology;CordellG.A.Ed.;Elsevier Science:New York,2010;Vol.69,pp 1–577.
[5]Ameri,A.Prog Neurobiol,1998,56,211–235.
[6]Kitagawa,I.;Chen Z.L.;Yoshihara,M.;Yoshikawa,M.YakugakuZasshi1984,104,848–57.
[7]Konno C.;Shirasaka M.;Hikino,H.J.Nat.Prod.1982,45,128–133.
[8]王洁之;韩公羽.药学学报1985,20,71–73.
[9]韩公羽;梁华清.天然产物研究与开发1997,9,30–34.
[10]Kitagawa I.;Chen Z.L.;Yoshihara,M.;Kobayashi,K.;Yoshikawa,M.;Ono,N.; Yoshimura,Y.J.Yakugaku Zasshi1984,104,858–866.
[11]陈嬿;朱元龙;朱任宏.药学学报1965,12,435–439.
[12]Hikino H.;Kuroiwa Y.;Konno,C.J.Nat.Prod.1983,46,178–182.
[13]Pelletier S.W.;Mody N V.;Varughese,K.I.Heterocycles1982,18,47–49.
[14]陈泗英;刘玉青;王济承.云南植物研究1982,4,73–75.
[15]Wang X.K.;Zhao T.F.;Lai,S.Chin.Chem.Lett.1994,5,671–672.
[16]王宪楷;赵同芳;赖盛.中国药学杂志1996,31,74–77.
[17]唐庆旭.黑龙江医药2005,18,344–345.
[18]Iwasa J.,Naruto S.Yakugaku Zasshi1966,86,585–590.
[19]Kitagawa,I.;YoshikawaM.;Chen Z.L.;Kobayashi,K.Chem.Pharm.Bull.1982,30, 758–761.
[20]王宪楷,赵赖.华西医科大学学报1996,30,716–718.
[21]Zhang D.H.,Li H.Y.,et al.中草药1982,13,481–484.
[22]Hang G.Y.,CaiP.;Wang,J.Z.;Snyder,J.K.J.Nat.Prod.1988,51,364–366.
[23]熊江;古昆;谭宁化.天然产物研究与开发2008,20,440–443,465.
[24]Shim S.H.;Kim J.S.;Kang,S.S.Chem.Pharm.Bull.2003,51,999–1002.
[25]张卫东;韩梁.药学学报1992,27,670–673.
[26]Shim S.H.;Lee,S.Y.;Kim,J.S.;Son,K.H.;Kang,S.S.Arch.Pharm.Res.2005,28, 1239–1243.
[27]Taki,M.;Niitu,K.;Yuji,O.;Masamichi,N.;Mikio,F.;Masaki,A.;Minoru,A.Planta Med.2003,69,800–803.
[28]陈洪超;王宪楷;赵同芳;廖循.天然产物研究与开发2003,15,324–325,340.
[29]洪波;司云珊;赵宏峰.吉林农业大学学报,2004,26,57–58,65.
[30]Liu X.-X.;Jian X.-X.;Cai,X.F.;Chao,R.-B.;Chen,Q.-H.;Chen,D.-L.;Wang,X.-L.;Wang, F.-P.Chem.Pharm.Bull.2012,60,144–149.
[31]陈海生;韩公羽;刘明珠;梁华清.第二军医大学学报,1992,13,167–168.
[32]Kosuge T.;Yokota M.Chem.Pharm.Bull.1976,24,176–178.
[33]横田正实;倪边.中药通报1984,9,23.
[34]陈迪华;梁晓天.药学学报1982,17,792–794.
[35]Konno C.;Shirasaka,M.;Attia,M.A.;El–Duweini,A.K.;Ghazal,A.M.Planta Med.1979, 35,150–155.
[36]Jiang,B.;Lin,S.;Zhu,C.;Wang,S.;Wang,Y.;Chen,M.;Zhang,J.;Hu,J.;Chen,N.;Yang, Y.;Shi,J.J.Nat.Prod.2012,75,1145-59,1878,and 2008.
[37]Jiang,Z.-B.;Jiang,B.-Y.;Zhu,C.-G.;Guo,Q.-L.;Peng,Y.;Wang,X.-L.;Lin,S.;Shi,J.-G. J.Asian Nat.Prod.Res.2014,16,891–900.
[38].Jiang,Z.-B.;Meng,X.-H.;Jiang,B.-Y.;Zhu,C.-G.;Guo,Q.-L.;Wang,S.-J.;Lin,S.;Shi, J.-G.Chin.Chem.Lett.2015,26,653–656.
[39].Guo,Q.-L.;Xia,H.;Shi G.-N.;Zhang T.-T.;Shi,J.-G.Org.Lett.2018,20,816-819.
[40].Wu,Y.-Z;Shao,S.;Guo,Q.-L.;Xu,C.-B.;Xia,H.;Zhang T.-T.;Shi,J.-G.Org.Lett. 2019,10.1021/acs.orglett.9b02479.
[41].Meng,X.-H.;Jiang,Z.-B.;Zhu,C.-G.;Guo,Q.-L.;Xu,C.-B.;Shi, J.-G.Chin.Chem.Lett.2016,27,993–1003.
[42].Meng,X.-H.;Jiang,Z.-B.;Guo,Q.-L.;Shi,J.-G.Chin.Chem.Lett.2017,28,588–592.
[43].Meng,X.-H.;Guo,Q.-L.;Zhu,C.-G.;Shi,J.-G.Chin.Chem.Lett.2017,28,1705–1710.
[44].Schmidt H.,Schmitt,O.Pflugers Arch.1974,349,133–148.
[45].Catterall W.A.Annu.Rev.Pharmacol.Toxicol1980,20,15–43.
[46].Catterall W.A.Trends Pharmacol.Sci.1987,8,57–65.
[47].Catterall W.A.1988,242,50–61.
[48].Ritchie J.M.Annu Rev.Neurosci.1979,2,341–62.
[49].王思芦.动物医学进展2013,34,106–110.
[50].郎茜;叶婧.健康之路2015,14,23.
[51].Catterall W.A.J.Biol.Chem.1977,252,8669–8676.
[52].徐红萌,姜慧卿.中华麻醉学杂志2005,25,381–384.
[53].Hikino H.,Murayama M.Br.J.Pharmacol.1985,85,575–580.
[54].Oyama,T.;Isono,T.;Suzuki,Y.;Hayakawa,Y.Am.J.Chin.Med.1994,22,175–182.
[55].Murayama M.;Ito T.;Konno,C.;Hikino,H.Eur.J.Pharmacol.1984,101,29–36.
[56].陈长勋;金若敏.中国中医药科技.1996,3,12–14.
[57]李立纪;张风雷;吴荣祖;刘培儒;林青.中药药理与临床2005,21,31–33.
[58].饶曼人.药学学报1966,13,195–203.
[59].张梅;张艺;陈海红;孟宪丽;赵剑;凌辉伦.时珍国医国药2000,11,193–194.
[60].王培德;马学民;张慧灵;杨玉梅;杨煜荣;王洪诚;劳爱娜.中国药理学通报1997, 13,73–75.
[61].韩旭.河北:河北医科大学,2011.
[62].陈蕊;林大勇;付勇强.中华中医药学刊2008,26,1081–1083.
[63].杨景锋;赵天才.陕西中医学院学报2004,27,65–67.
[64].辜学敏;陆彦;苏小茹.中国民族民间医药2008,17,19–20,32.
[65].杨洁红;张宇燕;万海同.中草药2010,3,439–444.
[66].Hikino H.;Takata H.;Mitsuo,F.;Chohachi,K.;Kazuo,H.Eur.J.Pharmacol.1982,82, 65–71.
[67].杨煜荣;耿慕筠;张福全.药学学报1966,13,573–576.
尽管文献报道从附子中得到了如上所述多种多样的化学成分以及附子提取物和部分附子中化学成分的药理活性,但是到目前为止,本发明涉及的新的含磺酸基的海替生型C20二萜类生物碱及其衍生物,不但尚无人从附子中得到,也无人通过分离纯化从其他动植物及微生物中分离得到或通过化学合成及生物合成等方法制备得到;更无人报道这些化合物或其衍生物具有镇痛的功能。
发明内容
本发明要解决的技术问题是,提供一类新的具有镇痛作用的药物。
为解决本发明的技术问题,本发明提供如下技术方案:
本发明技术方案的第一方面是提供了一种如通式(I)和(Ⅱ)所示的新型C20二萜类生物碱及其衍生物。
具体而言,提供了如通式(I)所示的化合物及其药学上可接受的盐:
R1与C-2、R2与C-11或R3与C-13的连接方式可以各自独立的选自单键或双键;
当R1与C-2、R2与C-11或R3与C-13的连接方式为单键时,则R1、R2或R3各自独立的选自H、OH、OCH3、OCH2CH3;
当R1与C-2、R2与C-11或R3与C-13的连接方式为双键时,则R1、R2或R3为O;
C-12与C-16的连接方式为未连接或单键;
a)当C-12与C-16未连接时;C-15与C-16的连接方式可以为单键或双键;
当C-15与C-16的连接方式为单键时,则R4与C-16连接方式可为单键,且 R4选自H、OH、OCH3、OCH2CH3,或R4与C-16连接方式为双键,且R4为O;
当C-15与C-16的连接方式为双键,则R4与C-16连接方式为单键,且R4可选自H、OH、OCH3、OCH2CH3;
b)当C-12与C-16连接形成单键时;C-15与C-16的连接方式可以为单键或双键;
当C-15与C-16的连接方式为单键时,则R4与C-16连接方式为单键,且R4可选自H、OH、OCH3、OCH2CH3;
当C-15与C-16的连接方式为双键时,则无R4取代基存在。
提供了如通式(II)所示的化合物及其药学上可接受的盐:
R5可选自H、CH3、CH2CH3、CH2CH3OH;
R1与C-2、R2与C-11或R3与C-13的连接方式可以各自独立的选自单键或双键;
当R1与C-2、R2与C-11或R3与C-13的连接方式为单键时,则R1、R2或R3各自独立的选自H、OH、OCH3、OCH2CH3;
当R1与C-2、R2与C-11或R3与C-13的连接方式为双键时,则R1、R2或R3为O;
C-12与C-16的连接方式为未连接或单键;
a)当C-12与C-16未连接时;C-15与C-16的连接方式可以为单键或双键;
当C-15与C-16的连接方式为单键时,则R4与C-16连接方式可为单键,且 R4选自H、OH、OCH3、OCH2CH3,或R4与C-16连接方式为双键,且R4为O;
当C-15与C-16的连接方式为双键,则R4与C-16连接方式为单键,且R4可选自H、OH、OCH3、OCH2CH3;
b)当C-12与C-16连接形成单键时;C-15与C-16的连接方式可以为单键或双键;
当C-15与C-16的连接方式为单键时,则R4与C-16连接方式为单键,且R4可选自H、OH、OCH3、OCH2CH3;
当C-15与C-16的连接方式为双键时,则无R4取代基存在。
本发明进一步优选的化合物选自如下群组:
本发明技术方案的第二方面是提供了第一方面所述化合物的制备方法。
干燥附子,粉碎后用蒸馏水在35~50℃下提取2~4次,每次4~8小时,提取液合并,减压回收溶剂得到浸膏,用大孔树脂柱色谱分离,依次用水:乙醇1:0~0:1 梯度洗脱,TLC或HPLC监测,每个流分均洗脱至样品无明显被洗脱下来,减压回收溶剂得到相应的洗脱部分,其中50%乙醇部分用MCI树脂分离,依次用水:乙醇1:0~0:1梯度洗脱,TLC或HPLC监测合并相同组分。其中,水洗脱部位用 C-18反相硅胶柱色谱分离,依次用水:甲醇1:0~0:1梯度洗脱,TLC或HPLC监测合并相同组分,得到相应洗脱部分(C1-1-C1-12)。C1-4经Sephadex LH-20凝胶柱色谱,纯净水为流动相分离,TLC或HPLC监测合并相同组分,得到洗脱部分(C1-4-1-C1-4-4)。亚组分C1-4-3再经C-18反相硅胶柱色谱分离,10%~15%甲醇水依次洗脱,TLC或HPLC监测合并相同组分得到C1-4-3-1-C1-4-3-10,其中 C1-4-3-8用C-18反相硅胶柱色谱分离,5%~10%甲醇水作为流动相,TLC或HPLC 监测合并相同组分得到C1-4-3-8-1-C1-4-3-8-7。C1-4-3-8-6用HW-40F凝胶树脂柱色谱,5%~10%甲醇水洗脱,TLC或HPLC监测合并相同组分,得到组分 C1-4-3-8-6-1-C1-4-3-8-21。其中C1-4-3-8-7通过HW-40F凝胶树脂柱色谱,甲醇:二氯甲烷1:1作为流动相分离并结合反相HPLC制备,即可获得化合物(I)和 (Ⅱ)。
本发明技术方案的第三方面是提供了一种药物组合物,其中包括作为有效成分的如通式(I)和(Ⅱ)所示的新型C20二萜类生物碱,和制药领域中常用的载体。
通常本发明药物组合物含有0.1-95%重量的本发明化合物。
本发明化合物的药物组合物可根据本领域公知的方法制备。用于此目的时,如果需要,可将本发明的化合物与一种或多种固体或液体药物赋形剂和/或辅剂结合,制成可作为人药或兽药使用的适当的施用形式或剂量形式。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等,优选口服。
本发明化合物或含有它的药物组合物的给药途径可为注射给药。注射包括静脉注射、肌肉注射、皮下注射和皮内注射等。
给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
本发明提取物或化合物可以制成普通制剂、也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将单位给药剂型制成片剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等;湿润剂与粘合剂,如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等;崩解剂,例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等;崩解抑制剂,例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等;吸收促进剂,例如季铵盐、十二烷基硫酸钠等;润滑剂,例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
例如为了将给药单元制成丸剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等;粘合剂,如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等;崩解剂,如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
例如为了将给药单元制成胶囊,将有效成分本发明提取物或化合物与上述的各种载体混合,并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分本发明化合物制成微囊剂,混悬于水性介质中形成混悬剂,亦可装入硬胶囊中或制成注射剂应用。
例如,将本发明提取物或化合物制成注射用制剂,如溶液剂、混悬剂溶液剂、乳剂、冻干粉针剂,这种制剂可以是含水或非水的,可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外,为了制备等渗注射液,可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油,此外,还可以添加常规的助溶剂、缓冲剂、pH调节剂等。这些辅料是本领域常用的。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物、药物组合物的给药剂量取决于许多因素,例如所要预防或治疗疾病的性质和严重程度,患者或动物的性别、年龄、体重、性格及个体反应,给药途径、给药次数、治疗目的,因此本发明的治疗剂量可以有大范围的变化。一般来讲,本发明中药学成分的使用剂量是本领域技术人员公知的。可以根据本发明化合物组合物中最后的制剂中所含有的实际药物数量,加以适当的调整,以达到其治疗有效量的要求,完成本发明的预防或治疗目的。本发明化合物的每天的合适剂量范围本发明的提取物或化合物的用量为0.001-150mg/kg体重,优选为 0.01-100mg/kg体重,更优选为0.01-60mg/kg体重,最优选为0.1-10mg/kg体重。上述剂量可以单一剂量形式或分成几个,例如二、三或四个剂量形式给药这受限于给药医生的临床经验以及包括运用其它治疗手段的给药方案。
每一种治疗所需总剂量可分成多次或按一次剂量给药。本发明的化合物、组合物可单独服用,或与其他治疗药物或对症药物合并使用并调整剂量。
本发明技术方案的第四方面是提供了如通式(I)和(Ⅱ)所示的新型C20二萜类生物碱在制备用于躯体性疼痛、内脏性疼痛、神经性疼痛或癌性疼痛等疾病的药物中应用。
本发明还涉及附子提取物在制备预防或治疗急性或慢性疼痛等疾病的应用。所述的各种疼痛包括与中枢神经系统或外周神经系统有关的疼痛、各种急性或慢性疼痛、伤害感受性疼痛、躯体性疼痛、内脏性疼痛、神经性疼痛或癌性疼痛。
发明人发现本发明的化合物(I)和(Ⅱ)及药学上可接受的盐具一定的镇痛作用。因此,本发明的化合物(I)和(Ⅱ)及药学上可接受的盐另一方面涉及治疗、改善与镇痛相关的疾病的方法。所述方法包括对需要治疗的患者给予治疗有效量的式I或药学上可接受的盐的化合物或其药物组合物。
本发明显示化合物(I)和(Ⅱ)在整体动物水平很好的具有镇痛作用。化合物(I)和(Ⅱ)或药学上可接受的盐未见公开报道。
有益技术效果
本发明的发明人在对传统中药附子的活性成分研究过程中,通过活性跟踪的方法从附子中分离得到了新的C20二萜类生物碱1、2和3。通过醋酸扭体实验,对该类化合物进行了活性评价,结果显示化合物1、2在整体动物水平具有一定的镇痛作用,且具有剂量依赖性;化合物3具有一定的镇痛作用。属于镇痛药物研发过程中具有价值的新的先导化合物。
附图说明
图1、化合物1-3的分离流程图
图2、化合物1镇痛作用
图3、化合物2镇痛作用
图4、化合物3镇痛作用
具体实施方式
下面的实验实施例可进一步说明本发明,但不以任何方式限制本发明。
实施例1、化合物1、2和3为从附子中提取分离纯化的新的C20二萜类生物碱,其分离纯化过程如下:
干燥附子50Kg,粉碎后用水在40℃下提取3次,每次6小时,提取液合并,减压回收溶剂至120L,用大孔树脂(HPD-110,19kg)柱色谱(20×200cm)分离,依次用水(50L)、30%乙醇(120L)、50%乙醇(120L)、和95%乙醇(100L) 洗脱,减压回收溶剂得到相应的洗脱部分(A-D),其中C部分用MCI树脂(CHP 20P) 分离,依次用水(10L)、30%乙醇(30L)、50%乙醇(20L)和95%乙醇(10L) 洗脱得到相应洗脱部分(C1-C4)。水洗脱部位(C1,750g)用C-18反向硅胶(Ultrapure Silica Dels)分离,依次用0-50%甲醇水(80L)溶液,100%甲醇醇溶液(10L) 洗脱,得到相应洗脱部分(C1-1-C1-12)。C1-4(75g)经Sephadex LH-20(H2O)分离,得到洗脱部分(C1-4-1-C1-4-4)。亚组分C1-4-3(26g)再经C-18反向硅胶 (Ultrapure SilicaDels)分离(10%-15%甲醇水)得到C1-4-3-1-C1-4-3-10,其中 C1-4-3-8(20g)用C-18反向硅胶(Ultrapure Silica Dels)分离(6%甲醇水),得到 C1-4-3-8-1-C1-4-3-8-7。C1-4-3-8-6(12g)用HW-40F凝胶柱色谱,CH3OH-H2O(6%) 定度洗脱,得到组分C1-4-3-8-6-1-C1-4-3-8-21。其中C1-4-3-8-7(2g)通过HW-40F 凝胶柱色谱(甲醇:二氯甲烷=1:1)分离得到C1-4-3-8-7-1-C1-4-3-8-7-8。其中 C1-4-3-8-7-4(320mg)经反相HPLC制备(ADME色谱柱,12%乙腈-水,含0.3%TFA,流速2.0mL/min)得到化合物1(4.4mg,tR=12.5min)和化合物3(1.1mg,tR=24 min)。C1-4-3-8-7-5(900mg)经反相HPLC制备(ADME色谱柱,33%甲醇-水,含0.2%TFA,流速2.0mL/min)得到化合物2(4.2mg,tR=7min)。
化合物1:白色无定形粉末;[α]20 D 270.7(c 0.44,H2O);UV(H2O)λmax(log ε)203.2(3.94),289.0(2.80)nm;CD(H2O)λmax(Δε)201.0(+1.50),297.0 (+1.47)nm;IRνmax3340,2959,2924,1715,1416,1220,1149,1023,787, 663,594,551,517cm-1;(+)-HRESIMS m/z426.1581[M+H]+(calcd.for C20H28NO7S, 426.1581);(-)-HRESIMS m/z 424.1438[M-H]-(calcd.for C20H26NO7S,424.1436)。
化合物2:无色方晶(H2O),m.p.m 300℃;[α]20 D 71.9(c 0.70,H2O);UV (H2O)λmax(logε)200.3(3.85)nm;CD(H2O)λmax(Δε)207.0(+5.77)nm; IRνmax3492,3371,2959,2916,2584,2503,1662,1224,1174,1035,956, 766,662,631,572,633cm-1;(+)-HRESIMS m/z410.1627[M+H]+(calcd.for C20H28NO6S, 410.1632);(-)-HRESIMS m/z 408.1479[M-H]-(calcd.for C20H26NO6S,408.1486)。
化合物3:白色无定形粉末;[α]20 D 20.0(c 0.11,H2O);UV(H2O)λmax(log ε)204.4(3.35),274.4(2.61)nm;CD(H2O)λmax(Δε)200.5(+0.20),253.0 (-0.07),294.0(+0.16)nm;IRνmax3314,2975,1718,1644,1414,1221,1034, 986,870,836,807,787,682,624,584,537cm-1;1H NMR(D2O,600MHz) 数据见Table 1;(+)-HRESIMS m/z 444.1680[M+H]+(calcd.for C20H30NO8S,444.1687);(-) -HRESIMS m/z 442.1533[M-H]-(calcd.forC20H28NO8S,442.1541)。
实验例1、镇痛作用、化合物1-3对醋酸致小鼠疼痛的影响
醋酸扭体实验是通过醋酸刺激引起小鼠腹膜炎症而产生疼痛,是外周镇痛的经典模型,常作为评价和筛选镇痛药的方法之一。将一定容积和浓度的醋酸注入小鼠腹腔内,刺激脏层和壁层腹膜,引起深部较大面积、较长时间的炎性疼痛,致使小鼠出现腹部内凹、躯干与后肢伸张、臀部高起等行为反应,称为扭体反应。该反应在注射后15min内出现频率高,故以注射后15min内发生的扭体次数或发生反应的鼠数为疼痛定量指标。[魏伟,吴希美,李元建.药理实验方法学.人民卫生出版社.第4版.p770.]
试验动物:健康成年雌性ICR小鼠,清洁级,体重18-22g。实验动物饲养于12h-12h昼夜交替的独立环境中,室温维持在24±2℃,自由饮水和摄食,在适应环境1周后进行实验。对动物的所有处理均遵循国际疼痛研究协会伦理委员会的要求。
受试化合物:受试物为化合物1-3,阳性药为吗啡
方法:将ICR雌性小鼠分为5组,每组10只,分别为模型对照组(生理盐水)、阳性对照组(吗啡,0.3mg/kg);化合物1高剂量组(1.0mg/kg)、化合物1中剂量组(0.3mg/kg)、化合物1低剂量组(0.1mg/kg)。除模型组外,其余生理盐水蒸馏水。各组均于给药后30分钟腹腔注射化学刺激物醋酸溶液1%(0.1ml/10g),记录注射醋酸后15min内小鼠扭体数,按下式计算药物对扭体反应的抑制率,评判药物镇痛效果:
抑制率%=[(阴性对照组扭体均数-实验组扭体均数)/(阴性对照组扭体均数)]×100%。
实验结果:与模型组组比较,化合物1高、中、低剂量组的扭体次数均线数少于模型组,镇痛抑制率分别为95.89%、70.39%、39.38%,具有明显的剂量依赖作用;化合物2高、中、低剂量组的扭体次数均线数少于模型组,镇痛抑制率分别为 71.92%、61.98%、44.18%;具有明显的剂量依赖作用。阳性药物的镇痛效果也非常明显,镇痛抑制率达66.82%。说明化合物1和2具有明显的镇痛作用,且具有剂量依赖性。具体结果见表1和图2-4。
表1.化合物1-3的镇痛作用
注:扭体次数用Mean±SEM表示,与模型组比较,**p<0.01,***p<0.001。
Claims (9)
1.一种如式(I)所示的化合物及其药学上可接受的盐:
R1与C-2、R2与C-11或R3与C-13的连接方式可以各自独立的选自单键或双键;
当R1与C-2、R2与C-11或R3与C-13的连接方式为单键时,则R1、R2或R3各自独立的选自H、OH、OCH3、OCH2CH3;
当R1与C-2、R2与C-11或R3与C-13的连接方式为双键时,则R1、R2或R3为O;
C-12与C-16的连接方式为未连接或单键;
a)当C-12与C-16未连接时;C-15与C-16的连接方式可以为单键或双键;
当C-15与C-16的连接方式为单键时,则R4与C-16连接方式可为单键,且R4选自H、OH、OCH3、OCH2CH3,或R4与C-16连接方式为双键,且R4为O;
当C-15与C-16的连接方式为双键,则R4与C-16连接方式为单键,且R4可选自H、OH、OCH3、OCH2CH3;
b)当C-12与C-16连接形成单键时;C-15与C-16的连接方式可以为单键或双键;
当C-15与C-16的连接方式为单键时,则R4与C-16连接方式为单键,且R4可选自H、OH、OCH3、OCH2CH3;
当C-15与C-16的连接方式为双键时,则无R4取代基存在。
2.如通式(Ⅱ)所示的化合物及其药学上可接受的盐:
R5可选自H、CH3、CH2CH3、CH2CH3OH;
R1与C-2、R2与C-11或R3与C-13的连接方式可以各自独立的选自单键或双键;
当R1与C-2、R2与C-11或R3与C-13的连接方式为单键时,则R1、R2或R3各自独立的选自H、OH、OCH3、OCH2CH3;
当R1与C-2、R2与C-11或R3与C-13的连接方式为双键时,则R1、R2或R3为O;
C-12与C-16的连接方式为未连接或单键;
a)当C-12与C-16未连接时;C-15与C-16的连接方式可以为单键或双键;
当C-15与C-16的连接方式为单键时,则R4与C-16连接方式可为单键,且R4选自H、OH、OCH3、OCH2CH3,或R4与C-16连接方式为双键,且R4为O;
当C-15与C-16的连接方式为双键,则R4与C-16连接方式为单键,且R4可选自H、OH、OCH3、OCH2CH3;
b)当C-12与C-16连接形成单键时;C-15与C-16的连接方式可以为单键或双键;
当C-15与C-16的连接方式为单键时,则R4与C-16连接方式为单键,且R4可选自H、OH、OCH3、OCH2CH3;
当C-15与C-16的连接方式为双键时,则无R4取代基存在。
3.根据权利要求1和2任一项所述的化合物及其药学上可接受的盐,其特征在于,所述药学上可接受的盐选自通式化合物(I)或(Ⅱ)与有机酸或无机酸所成的盐。
5.一种药物组合物,其特征在于,所述的药物组合物包括权利要求1-4任一项所述的化合物及其药学上可接受的盐以及药学上可接受的载体或赋形剂。
6.权利要求1-4任一项所述的化合物及其药学上可接受的盐或权利要求5所述的药物组合物在制备预防或治疗疼痛的药物中的应用。
7.根据权利要求6的应用,其特征在于,所述的疼痛与中枢神经系统或外周神经系统有关。
8.根据权利要求6中的应用,其特征在于,所述疼痛包括急性疼痛或慢性疼痛。
9.根据权利要求6中的应用,其特征在于,所述疼痛是躯体性疼痛、内脏性疼痛或神经性疼痛。
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CN109942491A (zh) * | 2017-12-20 | 2019-06-28 | 中国医学科学院药物研究所 | 附子中具有抗炎镇痛作用的c20二萜生物碱及其用途 |
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Publication number | Priority date | Publication date | Assignee | Title |
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Non-Patent Citations (8)
Title |
---|
"Hetisine型C_(20)二萜生物碱绣线菊碱Ⅳ和Ⅺ的全合成", 有机化学, no. 03 * |
QINGLAN GUO等: "Aconicarmisulfonine A, a Sulfonated C 20 -Diterpenoid Alkaloid from the Lateral Roots of Aconitum carmichaelii", ORG. LETT., vol. 20, pages 816 * |
YUZHUO WU等: "Aconicatisulfonines A and B, Analgesic Zwitterionic C 20 -Diterpenoid Alkaloids with a Rearranged Atisane Skeleton from Aconitum carmichaelii", ORG. LETT., vol. 21, pages 6850 * |
吴克红;唐力英;王祝举;徐义龙;周喜丹;: "附子的化学和生物活性研究进展", 中国实验方剂学杂志, no. 02 * |
唐梅;赵立春;徐敏;冷静;唐农;扈芷怡;张谦华;: "附子化学成分和药理作用研究进展", 广西植物, no. 12 * |
张思佳;刘敏卓;刘静涵;孔令义;: "附子的化学成分研究", 药学与临床研究, no. 03 * |
斯琴巴特尔;席琳图雅;青格勒;刘杰;琳娜;张志琴;: "附子生物碱类化学成分的研究进展", 世界最新医学信息文摘, no. 98 * |
蔡超群;杨春华;梁敬钰;刘静涵;: "乌头属二萜生物碱成分构效关系研究进展", 海峡药学, no. 03 * |
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