CN115073376B - 附子中的c20二萜生物碱、其制备及其用途 - Google Patents
附子中的c20二萜生物碱、其制备及其用途 Download PDFInfo
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- CN115073376B CN115073376B CN202110275762.2A CN202110275762A CN115073376B CN 115073376 B CN115073376 B CN 115073376B CN 202110275762 A CN202110275762 A CN 202110275762A CN 115073376 B CN115073376 B CN 115073376B
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- diterpenoid
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Abstract
本发明属医药技术领域,公开了附子中的C20二萜生物碱、其制备及其用途。具体公开了如通式(I)所示的一类C20二萜生物碱类化合物,其药物组合物和应用。本发明的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:化合物具有一定的镇痛作用,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,以及在制备预防和治疗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
附子是中医应用最广泛、历史最悠久的药物之一,被誉为“回阳救逆第一要药”。主产于四川、陕西、云南等地,为毛茛科乌头属植物乌头(Aconitum carmichaelii Debx.)的侧根及其加工品[1,2]。一般于6月下旬至7月上旬采挖,除去母根、须根及泥沙的药材称“泥附子”[2],后根据炮制方法的不同,生产出不同的饮片,分别称为生附子、盐附子、黑附子(黑顺片)、白附片、淡附片等[3,4]。目前,市场流通的饮片主要来源于四川江油道地产区[5]。
附子始载于《神农本草经》,被列为有毒下品中药,具有回阳救逆、补火助阳、散寒止痛之功效,常用于治疗亡阳虚脱、肢冷脉微、虚寒吐泻久痢、寒湿痹痛等病症[1,2,6]。在《伤寒论》和《金匮要略》中记载37个方剂中使用附子,如四逆汤等[7]。现代研究表明,附子提取物及一些成分具有抗炎镇痛、强心、抗心律失常、扩张血管、心肌保护和抗肿瘤等活性,中医临床主要用于心血管疾病、炎症和癌症等治疗[8–10]。除明确的临床疗效外,附子具有极强的心脏和神经毒性,误食或用药不慎可至中毒[11]。鉴于其疗效佳和毒性强的特点,长久以来一直是中药相关研究的热点之一。
附子的化学成分研究始于20世纪60年代。目前为止,从附子中已分离鉴定了200余个化合物,主要为二萜生物碱类[9,10]。其中C19-二萜生物碱占据了近一半的数量,其次为C20-二萜生物碱。此外,还有黄酮类、木质素类、异喹啉类生物碱、神经酰胺类、脂肪酸类等[12–22]。尽管附子传统以水煎煮使用,然而以往关于附子化学成分的研究,以有机溶剂(甲醇或乙醇)提取为主,并且在提取分离过程中多数情况使用碱化(Na2CO3或NH4OH)和酸化(HCl或H2SO3)处理[12–41];尤其是已有大量研究结果显示,煎煮过程可使毒性较大的双酯型二萜生物碱降解为毒性较小或无毒性的单酯型或醇胺型二萜生物碱,同时有可能产生药效物质,从而起到减毒增效的作用[8,11]。针对临床实际使用、更具药用价值的附子水煎剂化学成分的研究很少。本项目组围绕附子水提取物化学成分,开展了十余年的系统研究,取得了一系列研究进展[42-51]。
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。
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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C20二萜类生物碱及其衍生物,属于本项目组发现的新化合物;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C20二萜类生物碱及其衍生物、其制备方法和应用。
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)所示的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:
其中,R选自H、CH3、CH2CH3、CH2CH2CH3、CH3CHCH3、CH2CH2CH2CH3、CH2CH(CH3)2、C(CH3)3。
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)。其中C1-4-2用Dowex 50W*8离子交换树脂分离,依次用去离子水和2%的二乙胺水溶液洗脱,得到C1-4-2-1-C1-4-2-5。其中C1-4-2-5用Sephadex LH-20(甲醇)分离,得到洗脱部分C1-4-2-5-1-C1-4-2-5-3,C1-4-2-5-3再用反相C18 flash CH3OHin H2O(0%-100%,v/v)得到C1-4-2-5-3-1-C1-4-2-5-3-6,组分C1-4-2-5-3-1再用正相硅胶flash(二氯甲烷:甲醇体系)分离得到C1-4-2-5-3-1-1-C1-4-2-5-3-1-16.C1-4-2-5-3-1-15用高效液相色谱纯化得到化合物(I)。
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)所示的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)所示的C20二萜类生物碱在制备用于预防或治疗疼痛疾病的药物中应用。所述的疼痛包括躯体性疼痛、内脏性疼痛、神经性疼痛或癌性疼痛等。
本发明技术方案的第四方面是还提供了如通式(I)所示的C20二萜类生物碱在制备预防或治疗急性或慢性疼痛等疾病的应用。所述的疼痛选自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)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)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)在整体动物水平很好的具有镇痛作用。化合物(I)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。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在整体动物水平具有一定的镇痛作用,且具有剂量依赖性。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的分离流程图
图2、化合物1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)。
其中C1-4-2(25g)用Dowex 50W*8离子交换树脂分离,依次用去离子水和2%的二乙胺水溶液洗脱,得到五个洗脱组份(C1-4-2-1-C1-4-2-5)。其中C1-4-2-5(1.8g)用Sephadex LH-20(甲醇)分离,得到洗脱部分C1-4-2-5-1-C1-4-2-5-3,C1-4-2-5-3(977mg)再用反相C18 flash CH3OH in H2O(0%-100%,v/v)得到C1-4-2-5-3-1-C1-4-2-5-3-6,组分C1-4-2-5-3-1(371mg)再用正相硅胶flash(二氯甲烷:甲醇体系)分离得到C1-4-2-5-3-1-1-C1-4-2-5-3-1-16.C1-4-2-5-3-1-15(12mg)用高效液相色谱纯化(ADME色谱柱,10%甲醇水溶液,含0.1%TFA,流速2.0mL/min)得到化合物1,(1.3mg,保留时间:39.7分钟)。
化合物1:白色无定形粉末;[α]20D+13.5(c 1.33,H2O);UV(H2O)λmax(logε)218(3.27),196(3.54)nm;CD(H2O):Δε250nm-0.35,Δε208nm+2.58;IRνmax 3356,2943,2888,1679,1430,1355,1204,1136,1064,956,840,802,732,617,520cm-1;(+)-HR-ESI-MS:m/z392.2424[M+H]+(calcd for C22H34NO5,392.2432).
实验例1、镇痛作用、化合物1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,阳性药为3-乙酰乌头碱。
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(3-乙酰乌头碱,1.0mg/kg);化合物1高剂量组(3.0mg/kg)、化合物1中剂量组(1.0mg/kg)、化合物1低剂量组(0.3mg/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58.22%、43.78%、31.78%,具有明显的剂量依赖作用。说明化合物1具有一定的镇痛作用,且具有剂量依赖性。具体结果见表1和图2。
表1.化合物1的镇痛作用
注:扭体次数用Mean±SEM表示,与模型组比较,*p<0.05,**p<0.01,***p<0.001.
Claims (7)
1.如下所示的化合物1及其药学上可接受的盐:
2.根据权利要求1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化合物1与有机酸或无机酸所成的盐。
3.一种药物组合物,其特征在于,所述的药物组合物包括权利要求1和2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。
4.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或权利要求3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。
5.根据权利要求4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。
6.根据权利要求4的应用,其特征在于,所述疼痛选自急性疼痛或慢性疼痛。
7.根据权利要求4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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