CN110372688A - 8-二卤亚甲基二氢小檗碱型化合物及其抗感染抗炎用途 - Google Patents
8-二卤亚甲基二氢小檗碱型化合物及其抗感染抗炎用途 Download PDFInfo
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- CN110372688A CN110372688A CN201910282854.6A CN201910282854A CN110372688A CN 110372688 A CN110372688 A CN 110372688A CN 201910282854 A CN201910282854 A CN 201910282854A CN 110372688 A CN110372688 A CN 110372688A
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- salt
- methylene
- dihydroberberine
- dihalo
- acid
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Abstract
本发明公开了8‑二卤亚甲基二氢小檗碱型化合物及其抗感染抗炎用途，具体涉及如通式I所示的8‑二卤亚甲基二氢小檗碱型化合物及其生理上可接受的盐、其合成方法及其在制备预防、缓解和/或治疗微生物感染和炎症产品中的应用。所述的8‑二卤亚甲基二氢小檗碱型化合物与小檗碱型生物碱季铵盐底物比较，对革兰氏阳性菌和真菌显示出显著被提高的抗菌活性；对巴豆油致小鼠耳部急性肿胀模型动物显示出显著的抗炎活性；本发明化合物的药理作用强度明显高于对照药，并同时具有无毒性或低毒性的优点，能用于制备预防、缓解和/或治疗微生物感染和炎症的产品。
Description
技术领域
本发明涉及以多种天然存在的小檗碱季铵盐类化合物为底物，经衍生化反应获得的一类8-二卤亚甲基二氢小檗碱类衍生物或其生理上可接受的盐、其制备方法和在制备抗微生物感染和抗炎产品中的应用。属医药技术领域。
背景技术
抗微生物(或称为抗菌)感染药物是临床上使用的第一大类药物。当前临床上常用的抗菌药有很多，包括β-内酰胺类、氨基糖苷类、大环内酯类、喹诺酮类和四环素类等。但由于众所周知的抗菌药的过渡使用，使得细菌耐药性逐年增加，产生诸如耐甲氧西林金黄色葡萄球菌(MRSA)、耐青霉素的肺炎链球菌(PRSP)、耐万古霉素肠球菌(VRE)和多耐性结核杆菌等类型耐药菌。耐药菌的出现，致使一些抗菌药疗效降低，甚至无效；此外，近些年来又先后发现30余种新病原体，过去已经得到有效控制的一些传染性疾病如结核病等出现了再流行的趋势。这些都给人们的健康带来了威胁。因此，一方面要避免滥用抗菌药，减少耐药菌的产生，另一方面需要加快新型抗菌药物的研究与开发，寻找更高效、副作用更小的抗菌药物。
炎症是具有血管系统的活体组织对各种损伤因子刺激所产生的防御反应，可发生于肌体的任何部位和组织，是肌体清除刺激因素、对局部组织损伤进行修复的过程。炎症作为一种独特的肌体防御反应，其参与了多种疾病的发生和发展过程，主要包括组织损伤后释放活性介质的急性阶段、免疫系统被激活的免疫阶段、释放大量细胞因子的慢性炎症阶段3个阶段。在临床上，炎症典型的症状为病灶部位的红、肿、热、痛。由于炎症的发病特点，在临床药物使用中，抗炎药物是仅次于抗感染药物的第二大类药物。尽管临床上用于治疗炎症的药物已经很多，但是，一些令人头疼的问题仍然存在，包括已有的药物多为针对单靶点的药物，均有诸多不良反应，如非甾体类抗炎药对胃肠道的刺激和肾脏损害、选择性环氧和酶抑制剂增加了患者心血管疾病的风险、糖皮质激素类药可能诱发或加重感染等[刘莹，等.特产研究，2017，(1)：69]。因此，继续开展抗炎药物的研究与开发仍然具有必要性和迫切性。
天然存在的小檗碱型生物碱主要属于1-苄基四氢异喹啉类化合物(或简单分类为苄基异喹啉类化合物)，常见的有小檗碱季铵盐、巴马汀季铵盐、黄连碱季铵盐、表小檗碱季铵盐、药根碱季铵盐、异黄连碱季铵盐，等，或它们的四氢型还原产物。这些小檗碱型生物碱广泛存在于多种天然植物中，如毛茛科(Ranunculaceae)植物、芸香科(Rutaceae)植物、小檗科(Berberidaceae)植物、罂粟科(Papaveraceae)植物、防己科(Menispermaceae)植物、鼠李科(Rhamnaceae)植物，等。各种小檗碱型生物碱具有多方面的药理作用，例如，黄连碱季铵盐具有抑制A型单胺氧化酶活性、选择性抑制血管平滑肌细胞增殖活性、抑制破骨细胞分化和功能活性、双重抑制血管平滑肌细胞增殖活性、选择性调节血管平滑肌细胞中的多药耐药蛋白活性、抗真菌活性、心肌保护活性、胃黏膜保护活性等[张志辉，等.中国中药杂志，2013，38(17)：2750]；小檗碱季铵盐具有抗病原微生物、抗炎、抗肿瘤、心脏保护、降血糖、调节脂质代谢以及免疫抑制活性等[邢宇，等.中国药理学与毒理学杂志，2017,31(6)：491]；巴马汀季铵盐具有抗菌活性等[李志成，等.广东化工，2015,42(8)：7]。目前，小檗碱型生物碱季铵盐类型的化合物或其还原产物中已有一些化合物作为上市药品在临床上应用于治疗相关疾病，例如氯化小檗碱季铵盐(也称为盐酸小檗碱)作为抗菌药物收载于中国药典；以小檗碱季铵盐、巴马汀季铵盐、黄连碱季铵盐、表小檗碱季铵盐和药根碱季铵盐为主要成分的黄连素在临床上用于治疗肠道细菌感染引起的泻痢；左旋四氢巴马汀作为镇痛药收载于中国药典，等。但小檗碱型生物碱季铵盐普遍存在着溶解度差、生物利用度低、药理作用不显著等缺陷；即，基于化学结构及已经明确的相关理化性质考虑，小檗碱型生物碱季铵盐普遍存在在纯水和常见的亲脂性有机溶剂中溶解性均非常差的问题，因此，导致了生物利用度低和一些药理作用不强等对成药性不利的结果。当然，溶解性能差的性质也可以被某些特殊的医疗需求加以利用，例如，上述的小檗碱型生物碱季铵盐在临床上治疗肠道致病微生物感染疾病方面的应用，正是利用了这种溶解性较差的特点，可以达到不经吸收而直接作用于肠道病灶部位的用药优点。但，毋庸置疑，多数情况下溶解性提高对于提高药物对生物体的药理作用强度是有显著作用的。基于此，科研人员通过化学方法对此类生物碱进行结构修饰与改造，通过改变化学结构达到提高成药性的努力从未停止。根据各种小檗碱型生物碱季铵盐在除肠道感染外的其他方面的药理作用，为了得到具有较好成药性的各种活性小檗碱型生物碱衍生物，采用衍生化反应改善相应底物的溶解性是药物化学研究中优先需要考虑的问题。因此，多年来，科研人员一直在以改善成药性为目的通过化学方法对此类生物碱进行结构修饰与改造。在已公开的研究资料中，13位取代小檗碱型生物碱季铵盐和9位修饰的小檗碱型生物碱季铵盐的抗菌活性与底物相比显示出一定程度的提高；而将底物还原成四氢小檗碱型化合物则导致抗菌活性的下降。由此得出结论，季铵结构、空间效应和取代基的亲脂性的提高有助于提高底物的抗菌活性。目前发表的小檗碱型生物碱类抗菌活性化合物主要是这些具有季铵结构的结构改造产品；对C-2和C-3位取代基团的考察表明，将C-2和C-3位的甲氧基替换成亚甲二氧基，有助于抗菌活性的提高。尽管四氢小檗碱型化合物的N-甲基型季铵盐结构与叔胺结构相比有提高其抗菌活性的作用，但是，这种作用相对较弱。并且所研究的目标化合物对金黄色葡萄球菌Staphylococcusaureus(革兰氏阳性菌)的抗菌活性较强，而对于大肠杆菌Escherichia coli(革兰氏阴性菌)和白色念珠菌Candida albicans(真菌)的抗菌作用较弱(Iwasa K,et al.Eur J MedChem,1996,31:469；Iwasa K,et al.Planta Med,1997,63:196；Iwasa K,et al.PlantaMed,1998,64:748)。
此外，小檗碱型生物碱的抗炎作用也越来越受到人们的关注。研究表明，小檗碱季铵盐具有抗炎作用，能抑制急慢性炎症。小檗碱季铵盐能抑制二甲苯引起的小鼠耳廓肿胀、对角叉菜胶引起的大鼠足趾肿胀和慢性棉球肉芽肿也有明显的抑制作用[叶宝娜，等.中国兽医杂志，2008，44(3)：85]；能显著降低炎性组织中前列腺素PEG2的含量[李宇馨，等.使用药物与临床，2013,16(1)：43]。以考察抗菌活性及其构效关系为目的的对小檗碱型生物碱的结构修饰主要集中在对季铵盐结构抗菌活性的研究，通过将小檗碱季铵盐和巴马汀季铵盐的C-9位甲氧基替换为其他体积较大的取代基而提高了一定的抗菌活性(Yasukawa K,etal.Chem Pharm Bull,1991,39(6):1462；Huang MY,et al.MedChemComm,2016,7,658)
已经公开的资料表明，各种母体上无取代的二氢小檗碱型结构的衍生物和8位丙酮基取代的二氢小檗碱型结构衍生物具有明确而显著的抗溃疡性结肠炎活性，但存在化学结构不稳定的性质，在多种溶剂中极易发生结构变化，从而影响药理作用。而为了改善二氢小檗碱型结构衍生物的化学稳定性设计并合成的8-亚氨基-二氢小檗碱型结构衍生物母体结构却没有抗溃疡性结肠炎的活性，只有N-二氢黄连碱-8亚基芳胺衍生物和N-二氢黄连碱-8亚基脂肪酰胺衍生物具有一定的抗溃疡性结肠炎活性(Xie M,et al.J Nat Prod,2016,79:775)。为了改善二氢型小檗碱型结构的稳定性，我们以多种天然存在的小檗碱季铵盐类化合物为底物，合成了另一类8-二卤亚甲基二氢小檗碱型结构衍生物。合成步骤包括：(1)在碱性条件下获得的反应物种三卤甲基负离子作为亲核试剂对底物的亲核加成获得了已知结构的8-三卤甲基二氢小檗碱类化合物；(2)8-三卤甲基二氢小檗碱类化合物在碱性条件下经消除反应获得了8-二卤亚甲基二氢小檗碱型结构衍生物。在对这些化合物进行广泛的药理活性筛选的过程中，尽管没有获得显著的抗溃疡性结肠炎活性，但发现了这些非季铵结构的8-二卤亚甲基二氢小檗碱型结构衍生物具有显著的抗真菌活性，同时也具有很好的抗革兰氏阳性菌的活性；抗真菌活性明显强于抗革兰氏阳性菌活性。在采用巴豆油致小鼠耳部急性肿胀模型进行的抗炎活性动物实验中，发现了本发明化合物具有显著的抗炎活性。这是一个特别的发现，与已经公开的具有一定的抗炎活性的小檗碱季铵盐型的结构明显不同。在采用体外培养正常细胞系293T细胞对本发明化合物进行的毒性(细胞存活率)检测试验中，本发明化合物对正常细胞生长的抑制率分别是-5.82％、0.71％、-4.18％和-4.12％，表明属低毒性或无毒性的特异性抗菌抗炎化合物。尽管在抗炎实验中本发明化合物的用药剂量100mg/Kg大于阳性对照药吲哚美辛的5mg/Kg，但是，鉴于本发明化合物是低毒性的生物活性化合物的突出特征，因此，全面地从药物的特异性、有效性和安全性方面考虑(药物研究不能仅考虑药理作用强度，药物的安全性同等重要)，本发明化合物给药剂量大，抗炎作用比阳性对照药强，实验动物又能够耐受高剂量的本发明化合物反而正说明了本发明化合物比阳性对照药在制备预防、缓解和/或治疗炎症的药物、护肤品、化妆品和保健品产品中更具有应用价值。
发明内容
本发明所要解决的技术问题是借助化学合成方法提供一类8-二卤亚甲基二氢小檗碱型结构衍生物或其生理上可接受的盐及其制备方法，并提供以本发明化合物为生物活性化合物的产品组合物和其在制备抗微生物感染和抗炎产品中的用途。本发明以多种小檗碱型季铵盐类生物碱为原料，这些原料包括氯化小檗碱季铵盐、氯化黄连碱季铵盐、氯化巴马汀季铵盐和氯化异黄连碱季铵盐，等，合成具有结构新颖性的8-二卤亚甲基二氢小檗碱型结构衍生物；采用药理学方法对本发明化合物进行药理活性筛选，结果表明，本发明化合物具有显著的抗微生物感染和抗炎活性。在获得低毒性甚至无毒性的本发明化合物的情况下，本发明还显著地改善了二氢型小檗碱型结构衍生物的稳定性，在制备抗微生物感染和抗炎产品方面具有显著的应用价值。
为解决上述技术问题，本发明提供了如下技术方案：
本发明第一方面提供了如通式I所示的作为本发明化合物的具有低毒性和亲脂性特征的8-二卤亚甲基二氢小檗碱型结构衍生物或其生理上可接受的盐。
本发明第二方面提供了如通式I所示的作为本发明化合物的具有低毒性和亲脂性特征的8-二卤亚甲基二氢小檗碱型结构衍生物的制备方法。
本发明第三方面提供了通式I所示的作为本发明化合物的具有低毒性和亲脂性特征的8-二卤亚甲基二氢小檗碱型结构衍生物的产品组合物；所述的产品选自药品、护肤品、化妆品、保健品。
本发明第四方面提供了如通式I所示的作为本发明化合物的具有低毒性和亲脂性特征的8-二卤亚甲基二氢小檗碱型结构衍生物的预防、缓解和/或治疗微生物感染的用途。
本发明第五方面提供了通式I所示的作为本发明化合物的具有低毒性和亲脂性特征的8-二卤亚甲基二氢小檗碱型结构衍生物的预防、缓解和/或治疗炎症的用途。
本发明第一方面提供的通式I所示的作为本发明化合物的具有低毒性和亲脂性特征的8-二卤亚甲基二氢小檗碱型结构衍生物的化学结构式如下式I所示：
在通式I中，R2、R3各自独立地选自H、OH或烷氧基或R2与R3连接成为亚烃基二氧基；X1和X2各自独立地选自F、Cl、Br或I；R9、R10、R11各自独立地选自H、OH或烷氧基或者R9与R10连接成为亚烃基二氧基而R11选自H或者R9选自H而R10与R11连接成为亚烃基二氧基；所述的烷氧基选自C1-4烷氧基，并优选自甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基；所述的亚烃基二氧基选自亚甲二氧基、亚乙二氧基、亚丙二氧基、亚丁二氧基，并优选自亚甲二氧基。
此外，所述的生理上可接受的盐选自无机酸盐或有机酸盐；所述的无机酸盐选自氢卤酸盐、硫酸氢盐、碳酸氢盐、磷酸二氢盐、次卤酸盐、亚卤酸盐、卤酸盐、高卤酸盐、硫酸盐、碳酸盐、磷酸氢盐；所述的有机酸盐选自甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、对羟基苯甲酸盐、水杨酸盐、原儿茶酸盐、阿魏酸盐、异阿魏酸盐、尿黑酸盐、桂皮酸盐、对羟基桂皮酸盐、咖啡酸盐、苯乙酸盐、莨菪酸盐、没食子酸盐、藜芦酸盐、胡椒酸盐、3,4,5-三甲氧基苯甲酸盐、苔藓酸盐、莽草酸盐、(S)-乳酸盐、(R)-乳酸盐、(±)-乳酸盐、呋喃甲酸盐、(2R,3R)-(+)-酒石酸氢盐、(2S,3S)-(-)-酒石酸氢盐、(±)-酒石酸氢盐、柠檬酸(枸橼酸)二氢盐、羟基柠檬酸(枸橼酸)二氢盐、马来酸氢盐、富马酸氢盐、L-苹果酸氢盐、D-苹果酸氢盐、(dl)-苹果酸氢盐、草酸氢盐、胡萝卜酸氢盐、戊二酸氢盐、己二酸氢盐、庚二酸氢盐、辛二酸氢盐、壬二酸氢盐、葵二酸氢盐、苯磺酸盐、葡萄糖酸盐、抗坏血酸盐、(2R,3R)-(+)-酒石酸盐、(2S,3S)-(-)-酒石酸盐、(±)-酒石酸盐、柠檬酸(枸橼酸)氢盐、羟基柠檬酸(枸橼酸)氢盐、马来酸盐、富马酸盐、L-苹果酸盐、D-苹果酸盐、(dl)-苹果酸盐、草酸盐、胡萝卜酸盐、戊二酸盐、己二酸盐、庚二酸盐、辛二酸盐、壬二酸盐、葵二酸盐。
本发明最优选的化合物选自如下化合物群组：
本发明第二方面提供了本发明化合物的制备方法：
所述的本发明具有低毒性和亲脂性特征的8-二卤亚甲基二氢小檗碱型结构衍生物可通过如下合成路线通式合成(路线1；具体合成条件见实验例)：
路线1.本发明化合物的合成通式
合成步骤：(1)在碱性条件下获得的反应物种三卤甲基负离子作为亲核试剂对底物的亲核加成获得了8-三卤甲基二氢小檗碱类化合物；(2)8-三卤甲基二氢小檗碱类化合物在碱性条件下经消除反应获得了8-二卤亚甲基二氢小檗碱型结构衍生物。
本发明第三方面还涉及以本发明第一方面所述具有低毒性和亲脂性特征的8-二卤亚甲基二氢小檗碱型结构衍生物及其生理上可接受的盐作为活性成份的药物组合物、护肤品组合物、化妆品组合物、保健品组合物。该药物组合物、护肤品组合物、化妆品组合物、保健品组合物可根据各领域公知的方法制备。可通过将本发明化合物与一种或多种药学、护肤品、化妆品、保健品领域上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物、护肤品组合物、化妆品组合物、保健品组合物中的含量通常为0.1-99.9％(W/W)。
本发明化合物或含有它们的药物组合物、护肤品组合物、化妆品组合物、保健品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、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠、涂布于皮肤病灶部位，等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括O/W型、W/O型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、乳膏型、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也可制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛使用相关领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；润湿剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、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。
为了将给药单元制成胶囊剂，可以将有效成分(本发明化合物)与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分(本发明化合物)先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量药学领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调节剂可以是磷酸盐、醋酸盐、盐酸盐、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂、化妆品、护肤品、保健品中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药、护肤、化妆和保健目的，增强治疗效果，本发明的药物或药物组合物、护肤品组合物、化妆品组合物、保健品组合物可用任何公知的给药方法和应用方式给药和使用。
本发明化合物药物组合物、护肤品组合物、化妆品组合物和保健品组合物的给药(应用)或用药(使用)剂量依照所要预防或治疗微生物感染和炎症的性质和严重程度，患者或动物的个体情况，给药(应用)途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-300mg/Kg体重，优选为0.1-100mg/Kg体重，更优选为1-60mg/Kg体重，最优选为2-30mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验和治疗的进展以及包括运用其它治疗(应用)手段的给药(使用)方案。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
本发明第四方面提供了如通式I所示的具有低毒性和亲脂性特征的8-二卤亚甲基二氢小檗碱型结构衍生物及其生理上可接受的盐在制备预防、缓解和/或治疗微生物感染产品方面的用途；尤其是在预防、缓解和/或治疗革兰氏阳性菌和真菌感染中的应用；其中，所述的产品包括药物或护肤品或化妆品或保健品。
本发明第五方面提供了如通式I所示的具有低毒性和亲脂性特征的8-二卤亚甲基二氢小檗碱型结构衍生物及其生理上可接受的盐在制备预防、缓解和/或治疗炎症产品方面的用途。其中，所述的产品包括药品或护肤品或化妆品或保健品。
有益技术效果
通过对理化指标和生物学指标进行考察和评价，结果表明，本发明化合物具有显著的药用有效性和安全性；因此在护肤品、化妆品和保健品领域的应用前景也非常显著。
本发明化合物具有显著的抗微生物活性。与对应的小檗碱型生物碱季铵盐底物对比，本发明化合物的抗金黄色葡萄球菌和白色念珠菌的抗菌活性显著更强。在平行实验中，作为小檗碱型生物碱季铵盐底物的黄连碱盐酸盐、小檗碱盐酸盐和巴马汀盐酸盐对金黄色葡萄球菌Staphylococcus aureus和白色念珠菌Candida albicans的最低抑菌浓度(MIC)分别是>250μg/mL、125μg/mL、250μg/mL和250μg/mL、250μg/mL、>250μg/mL；本发明化合物8-二氯亚甲基二氢黄连碱(1)、8-二氯亚甲基二氢小檗碱(3)和8-二氯亚甲基二氢巴马汀(4)对金黄色葡萄球菌的MIC均是15.6μg/mL；本发明化合物8-二氯亚甲基二氢黄连碱(1)、8-二氯亚甲基二氢异黄连碱(2)、8-二氯亚甲基二氢小檗碱(3)和8-二氯亚甲基二氢巴马汀(4)对白色念珠菌的MIC分别是0.78μg/mL、1.95μg/mL、3.9μg/mL和15.6μg/mL。化合物1表现出最强的抗微生物感染活性，对白色念珠菌的MIC是黄连碱盐酸盐抗菌效力的320倍。尽管本发明化合物抗金黄色葡萄球菌的作用强度以MIC评价不及阳性对照药物左氧氟沙星(Levofloxacin)，但是，鉴于本发明化合物是低毒性的生物活性化合物，因此，甚至比左氧氟沙星有更广阔的应用前景；并且本发明化合物抗白色念珠菌的药理作用强度以MIC评价显著高于阳性对照药物左氧氟沙星(左氧氟沙星的MIC>250μg/mL)。
在通过建模并采用巴豆油致小鼠耳部急性肿胀模型进行的抗炎活性动物实验中，以治疗后化合物对实验动物病灶部位肿胀程度的抑制率为考察指标进行疗效评价{抑制率(％)＝[(模型组肿胀度-给药组肿胀度)/模型组肿胀度]×100(％)}，结果表明本发明化合物具有显著的抗炎活性。在100mg/Kg的给药剂量下，本发明化合物2的抗炎的作用强度明显高于阳性对照吲哚美辛的治疗效果；在实验结束观察疗效中发现，本发明化合物8-二氯亚甲基二氢异黄连碱(2)的炎性肿胀程度抑制率在给药剂量为100mg/Kg时达到40.07％#(#p<0.05，与模型组相比)；与阳性对照药的肿胀程度抑制率26.01％#(#p<0.05，与模型组相比)相比，疗效显著提高。尽管实验中本发明化合物的用药剂量大于阳性对照药吲哚美辛的5mg/Kg，但是，同样鉴于本发明化合物是低毒性的生物活性化合物的突出特征，因此，全面地从药物的有效性和安全性方面考虑(药物研究不能仅考虑药理作用强度，药物的安全性同等重要)，本发明化合物给药剂量大，抗炎作用比阳性对照药强，实验动物又能够耐受高剂量的本发明化合物反而正说明了本发明化合物比阳性对照药在制备预防、缓解和/或治疗炎症的药物、护肤品、化妆品和保健品产品中更具有应用价值。
除了本发明药理活性显著提高的突出特征以外，根据对药理作用特异性的研究，本发明化合物的另一个突出特点是其同时具有无毒性或低毒性的优点。在采用体外培养正常293T细胞对化合物1、2、3和4进行的毒性(细胞存活率)检测试验中，化合物1、2、3和4对正常细胞生长的抑制率分别是-5.82％、0.71％、-4.18％和-4.12％，因此，属于低毒性或无毒性的特异性抗微生物感染和抗炎化合物。
具体实施方式
本发明的具体实施方式不以任意方式限制本发明。
本发明活性化合物的制备工艺及结构鉴定数据，其中化合物编号与本发明内容中的具体化合物编号相对应。
实验例(1)化合物1的制备工艺及结构鉴定数据
将黄连碱盐酸盐(2.0g，5.62mmol)溶解于反应瓶中200mL氯仿-甲醇(3:1)混合溶剂中，加入浓氨水24ml，于室温下搅拌反应24h，然后分出氯仿层，并用水洗涤氯仿层2次，用无水MgSO4干燥后过滤；将滤液蒸干，所得残余粗品经硅胶柱色谱纯化，用二氯甲烷洗脱，浓缩洗脱物得8-三氯甲基二氢黄连碱淡黄色固体617mg，收率25.0％。1H NMR(500MHz,CDCl3)δ:2.63–2.78(m,1H,NCH2CH 2),3.35(m,1H,NCH2CH 2),3.71(m,1H,NCH 2CH2),3.78-3.90(m,1H,NCH 2CH2),5.42(s,1H,CH-CCl3),5.91(br,1H,OCH2O),5.95(br,2H,OCH2O),6.02(br,2H,OCH2O,C＝CH),6.61(s,1H,ArH),6.67(d,J＝8.0Hz,1H,ArH),6.86(d,J＝8.0Hz,1H,ArH),7.16(s,1H,ArH)。称取8-三氯甲基二氢黄连碱(585mg，1.33mmol)并溶解于反应瓶中10mlt-BuOH与10ml DMSO的混合溶剂中，加入t-BuOK(761mg，6.65mmol)，在磁力搅拌器上通过油浴升温至80℃，在搅拌下反应1.5h，反应过程经TLC检测至反应完毕，将反应液减压浓缩除去大部分溶剂，加入冰水至沉淀完全；将溶液减压抽滤，得滤饼；用水洗涤滤饼至中性，将滤饼晾干，用乙酸乙酯重结晶，得8-二氯亚甲基二氢黄连碱黄色固体115mg，收率21.4％。1HNMR(500MHz,DMSO-d6)δ:3.01(br,2H,NCH2CH 2),3.60(br,2H,NCH 2CH2),6.03(s,2H,OCH2O),6.07(s,2H,OCH2O),6.66(s,1H,ArCH＝C),6.77(d,J＝8.0Hz,1H,ArH),6.82(s,1H,ArH),7.00(d,J＝8.0Hz,1H,ArH),7.43(s,1H,ArH)；13C NMR(100MHz,DMSO-d6)δ:29.1,47.1,98.9,100.7,101.1,103.5,105.8,108.38,108.44,109.6,116.1,122.6,128.4,129.7,134.8,137.1,141.3,145.8,146.4,147.3；ESI-MS(m/z):402.0[M+H]+。
实验例(2)化合物2的制备工艺及结构鉴定数据
将异黄连碱盐酸盐(1.0g，2.81mmol)溶于反应瓶中80ml氯仿中，冰欲下加入NaH(450mg,18.75mmol)，缓慢升温至室温并搅拌反应24h后减压浓缩反应液至得到残余物；在残余物中先加入乙酸乙酯，再加入适量纯净水，用乙酸乙酯萃取3次，合并乙酸乙酯萃取液，用无水MgSO4干燥，过滤，将滤液蒸干，所得粗品经硅胶柱色谱纯化，用石油醚/乙酸乙酯(3/1，v/v)洗脱，洗脱部分经浓缩得8-三氯甲基二氢异黄连碱黄色固体995mg，收率80.7％。1HNMR(500MHz,CDCl3)δ:2.68(d,J＝15.5Hz,1H,NCH2CH 2),3.35-3.40(m,1H,NCH2CH 2),3.70(t,J＝8.5Hz,1H,NCH 2CH2),3.75(m,1H,NCH 2CH2),5.09(s,1H,CH-CCl3),5.93(br s,2H,OCH2O),5.94(br s,2H,OCH2O),6.03(s,1H,PhCH＝C),6.59(s,1H,ArH),6.63(s,1H,ArH),6.89(s,1H,ArH),7.15(s,1H,ArH)。将8-三氯甲基二氢异黄连碱(267mg，0.61mmol)置于反应瓶中，加入27ml四氢呋喃，在氩气保护下缓慢加入t-BuOK(346mg,3.05mmol)，反应混合液经加热回流反应1h，并经TLC监测反应至完全后，冷却至室温；将反应液减压浓缩除去大部分溶剂，并加入10ml水稀释沉淀后抽滤，得滤饼；将滤饼用水洗涤至中性，晾干后即得8-二氯亚甲基-二氢异黄连碱黄色固体190mg，收率77.6％。1H NMR(400MHz,CDCl3)δ:3.03(t,J＝5.6Hz,2H,NCH2CH 2),3.69(t,J＝5.6Hz,2H,NCH 2CH2),5.96(br s,2H,OCH2O),5.97(br s,2H,OCH2O),6.26(s,1H,ArCH＝C),6.62(s,1H,ArH),6.65(s,1H,ArH),7.17(s,1H,ArH),7.44(s,1H,ArH)；13C NMR(125MHz,CDCl3)δ:29.9,48.8,99.4,101.1×2,103.4,103.6,104.6,106.5,108.3,116.8,123.5,128.7,130.4,138.3,138.4,145.1,146.8,147.8,148.0；ESI-MS(m/z):402.0[M+H]+。
实验例(3)化合物3的制备工艺及结构鉴定数据
将小檗碱盐酸盐(2.0g，5.38mmol)在反应瓶中溶解于60ml氯仿中，加入浓氨水24ml，在室温下搅拌反应24h，然后分出氯仿层，用水洗涤氯仿溶液2次，用无水MgSO4干燥氯仿溶液后过滤，将滤液蒸干，得残余物；此残余物经硅胶柱色谱分离纯化，用二氯甲烷洗脱，将洗脱液蒸干，得8-三氯甲基二氢小檗碱淡黄色固体1.775g，收率78.9％。1H NMR(500MHz,CDCl3)δ:2.73(d,J＝15.5Hz,1H,NCH2CH 2),3.33(m,1H,NCH2CH 2),3.71(m,1H,NCH 2CH2),3.87(ov,4H,ArOCH3,NCH 2CH2),3.94(s,3H,ArOCH3),5.65(s,1H,CH-CCl3),5.94(s,2H,OCH2O),6.08(br s,1H,C＝CHAr),6.61(s,1H,ArH),6.87(d,J＝7.0Hz,1H,ArH),6.97(d,J＝7.0Hz,1H,ArH),7.17(s,1H,ArH)。称取8-三氯甲基二氢小檗碱(814mg，1.79mmol)并溶解于反应瓶中15ml t-BuOH与15ml DMSO的混合溶剂中；在加入t-BuOK(1.025g，8.95mmol)后升温至80℃并在搅拌下反应1.5h；反应过程经TLC检测至反应完毕后将反应液减压浓缩除去大部分溶剂，并在向残余物中加入冰水混悬后减压抽滤；将所得滤饼用水洗涤至中性，晾干，用乙酸乙酯重结晶，得8-二氯亚甲基二氢小檗碱淡黄色固体218mg，收率29.1％。1H NMR(500MHz,DMSO-d6)δ:2.76(br,1H,NCH2CH 2),3.31(br,1H,NCH2CH 2),3.46(br,1H,NCH 2CH2),3.73(ov,4H,ArOCH3,NCH 2CH2),3.80(s,3H,ArOCH3,),6.03(s,2H,OCH2O),6.56(s,1H,ArCH＝C),6.82(s,1H,ArH),6.92(d,J＝8.5Hz,1H,ArH),7.10(d,J＝8.5Hz,1H,ArH),7.43(s,1H,ArH)；13C NMR(125MHz,DMSO-d6)δ:29.0,46.5,56.2,60.8,97.7,101.0,103.6,108.4,110.4,114.6,114.8,117.6,122.6,128.3,129.5,135.9,137.1,144.3,146.4,147.3,150.0；ESI-MS(m/z):418.1[M+H]+。
实验例(4)化合物4的制备工艺及结构鉴定数据
称取巴马汀盐酸盐(5.0g，12.9mmol)并溶解于反应瓶中200ml氯仿中，进一步加入浓氨水30ml；在室温下搅拌反应24h后分出氯仿层，用水洗涤氯仿溶液2次，用无水MgSO4干燥，过滤；将滤液蒸干后的粗品经硅胶柱色谱纯化，用二氯甲烷洗脱，将洗脱液蒸干得8-三氯甲基二氢巴马汀淡黄色固体4.545g，收率74.9％。1H NMR(500MHz,CDCl3)δ:2.76(d,J＝15.5Hz,1H,NCH2CH 2),3.42(m,1H,NCH2CH 2),3.77(m,1H,NCH 2CH2),3.88(br ov,4H,NCH 2CH2,ArOCH3),3.90(s,3H,ArOCH3),3.948(s,3H,ArOCH3),3.953(s,3H,ArOCH3),5.66(s,1H,CH-CCl3),6.12(s,1H,C＝CH),6.65(s,1H,ArH),6.92(d,J＝8.5Hz,1H,ArH),6.99(d,J＝8.5Hz,1H,ArH),7.22(s,1H,ArH)。称取8-三氯甲基二氢巴马汀(1.0g，2.12mmol)溶解于反应瓶中20ml t-BuOH与20ml DMSO的混合溶剂中；在加入t-BuOK(1.21g，10.6mmol)后升温至80℃并在搅拌下反应1.5h，反应过程经TLC检测至反应完毕，将反应液减压浓缩除去大部分溶剂；在向残余物中加入冰水后，用二氯甲烷萃取3次；合并二氯甲烷萃取液，无水MgSO4干燥，过滤，将滤液蒸干，残余物用乙酸乙酯重结晶，得8-二氯亚甲基二氢巴马汀黄色晶体426mg，收率46.2％。1H NMR(500MHz,DMSO-d6)δ:2.78(br,1H,NCH2CH 2),3.31(br,1H,NCH2CH 2),3.49(br,1H,NCH 2CH2),3.73(br ov,4H,NCH 2CH2,ArOCH3),3.78(s,3H,ArOCH3),3.80(s,3H,ArOCH3),3.82(s,3H,ArOCH3),6.61(s,1H,ArCH＝C),6.82(s,1H,ArH),6.95(d,J＝8.0Hz,1H,ArH),7.11(d,J＝8.0Hz,1H,ArH),7.34(s,1H,ArH)；13C NMR(100MHz,DMSO-d6)δ:28.5,46.6,55.4,55.7,56.2,60.8,97.2,107.1,110.4,111.6,114.7,114.8,117.5,121.1,126.7,129.6,136.0,137.2,144.3,147.5,149.1,149.8；ESI-MS(m/z): 434.1[M+H]+。
药理实验
实验例1：本发明化合物的抗微生物活性评价
1、材料与方法
(1)菌株：金黄色葡萄球菌Staphylococcus aureus、大肠杆菌Escherichia coli、白色念珠菌Candida albicans MCC(F)98001。
(2)实验方法：通过采用二倍微量肉汤稀释法测定最低抑菌浓度(MIC)对本发明化合物的抗菌活性进行评价。将本发明化合物与对照品(小檗碱型生物碱季铵盐底物和左氧氟沙星)用DMSO配成20000μg/mL的储备液待用。将金黄色葡萄球菌和大肠杆菌用MHB(Mueller-Hinton Broth)培养基稀释，白色念珠菌用沙氏培养基稀释，均配成106CFU(colony forming unit)浓度作为菌悬液备用。MIC的测定步骤如下。首先，向无菌的96孔板每行的第1个孔中转移MHB培养基(金黄色葡萄球菌和大肠杆菌)或沙氏培养基(白色念珠菌)180μL，第2-11孔均转移100μL，第12孔中转移200μL作为阴性空白对照孔。取20μL样品储备液加入到第1孔中，混合均匀后吸取100μL加入到第2孔中，同前述，将第二孔混合均匀；然后从第2孔中吸取100μL加入到第3孔中，同前述操作。如此连续操作至第10孔，最后从第10孔中吸取100μL溶液，弃去。向上述第1-11孔中分别加入100μL菌悬液，混合均匀。每个样品设置3个平行组。将上述96孔板置于培养箱中培养24h，其中测定金黄色葡萄球菌与大肠杆菌的MIC温度设置为37℃，测定白色念珠菌的MIC温度设置为25℃。肉眼观察并记录每个待测样品与对照品的MIC值。
2、实验结果
见表一。
表一：本发明化合物抗微生物实验的最低MIC值测定结果
备注：“-”表示没有进行测定；“*”表示将待测化合物储备液浓度降为2000μg/mL以进一步测定MIC值时，检测结果为0.78μg/mL。
实验例2：本发明化合物在巴豆油致小鼠耳部急性肿胀模型中的抗炎药效学评价
1、材料和方法
(1)动物：Balb/c小鼠，雄性(20-22g)；每组8只。
(2)分组：本实验分为模型组、阳性药吲哚美辛(Sigma公司)组、本发明化合物2给药组。
(3)给药剂量及次数:阳性药5mg/kg；本发明各化合物100mg/kg。每天1次，给药3天。
(4)实验方法：模型组小鼠以0.9％生理盐水灌胃(给药体积：10ml/kg)，阳性药组以0.9％生理盐水为溶剂按5mg/kg的剂量配制并灌胃给药(给药体积：10ml/kg)，本发明各化合物给药组小鼠以0.9％生理盐水为溶剂按100mg/kg的剂量配制并灌胃给药(给药体积：10ml/kg)。末次给药后，全体小鼠于右耳两面涂抹巴豆油丙酮液20μL造模致炎，左耳不涂为正常对照耳。造模4h后处死小鼠，沿耳廓基线剪下双耳，用打孔器在同一部位取下耳片，称重，以右耳片重量与左耳片重量差值表示炎性肿胀程度，并将各给药组和阳性药组的耳肿胀程度值与模型组数据比较计算药物对耳肿胀程度的抑制率(％)。
抑制率(％)＝[(模型组肿胀度-给药组肿胀度)/模型组肿胀度]×100(％)
(5)统计分析：实验结果以“均值±标准差(mean±sd)”表示。两两组间统计学差异采用t检验方法计算分析。#，表示p<0.05(与模型组相比)。
2、实验结果
见表二。
表二：本发明化合物2在巴豆油致小鼠耳部急性肿胀模型中的肿胀抑制实验结果
注：#p<0.05，与模型组相比。
3、结果分析
(1)与模型组相比，阳性药吲哚美辛具有较强的抑制耳肿胀作用(#p<0.05)，提示实验体系合理、准确、可靠。
(2)与模型组相比，化合物2组显示出抗炎活性，作用强度高于阳性药；统计学上具有显著性差异，#p<0.05。
4、结论：在100mg/kg剂量灌胃给药的情况下，化合物2具有较强抗巴豆油致小鼠耳肿胀的活性。
实验例3：本发明化合物对体外培养正常细胞系293T细胞的毒性(细胞存活率)检测
(1)实验方法：将体外培养生长至90％汇合状态的293T正常细胞系细胞以0.1％胰酶/0.1％EDTA消化并接种于96孔细胞培养板，每孔细胞数为3×103。培养次日去除原培养基，每孔加入含1×10-5mol/L(即10μM)的本发明化合物工作液继续培养，空白对照孔内加入同等体积的完全细胞培养液。于293T细胞与本发明化合物共培养48h后通过CCK8法检测本发明化合物对293T细胞的细胞毒性(n＝6)。按下列公式计算本发明化合物对293T正常细胞系细胞的毒性作用，并以抑制率表示：
抑制率(％)＝[(对照孔吸光度-给药孔吸光度)/对照孔吸光度]×100(％)
(2)结果：在实验测定的时间范围内，1×10-5mol/L(即10μM)的本发明系列化合物对于293T正常细胞系细胞均无明显的细胞毒性，表现为其抑制率在-5.82％～0.71，统计学上检测无显著性差异。细胞生长抑制率见表三。
表三 本发明化合物对293T细胞的毒性检测结果(生长抑制率)
(3)结论：本发明系列化合物对正常细胞系293T细胞的生长无显著毒性，适于进行下游实验的筛选。
Claims (11)
1.通式I所示的8-二卤亚甲基二氢小檗碱型化合物及其生理上可接受的盐：
R2、R3各自独立地选自H、OH或C1-4烷氧基，或R2与R3连接成为亚烃基二氧基；
X1和X2各自独立地选自F、Cl、Br或I；
R9、R10、R11各自独立地选自H、OH或C1-4烷氧基，或者R9与R10连接成为亚烃基二氧基而R11选自H，或者R9选自H而R10与R11连接成为亚烃基二氧基。
2.根据权利要求1的8-二卤亚甲基二氢小檗碱型化合物及其生理上可接受的盐，其特征在于，所述的C1-4烷氧基选自甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基。
3.根据权利要求1的8-二卤亚甲基二氢小檗碱型化合物及其生理上可接受的盐，其特征在于，所述的亚烃基二氧基选自亚甲二氧基、亚乙二氧基、亚丙二氧基、亚丁二氧基。
4.根据权利要求1的8-二卤亚甲基二氢小檗碱型化合物及其生理上可接受的盐，其特征在于，所述的生理上可接受的盐选自无机酸盐或有机酸盐。
5.根据权利要求1的8-二卤亚甲基二氢小檗碱型化合物及其生理上可接受的盐，其特征在于，所述的无机酸盐选自氢卤酸盐、硫酸氢盐、碳酸氢盐、磷酸二氢盐、次卤酸盐、亚卤酸盐、卤酸盐、高卤酸盐、硫酸盐、碳酸盐、磷酸氢盐；所述的有机酸盐选自甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、对羟基苯甲酸盐、水杨酸盐、原儿茶酸盐、阿魏酸盐、异阿魏酸盐、尿黑酸盐、桂皮酸盐、对羟基桂皮酸盐、咖啡酸盐、苯乙酸盐、莨菪酸盐、没食子酸盐、藜芦酸盐、胡椒酸盐、3,4,5-三甲氧基苯甲酸盐、苔藓酸盐、莽草酸盐、(S)-乳酸盐、(R)-乳酸盐、(±)-乳酸盐、呋喃甲酸盐、(2R,3R)-(+)-酒石酸氢盐、(2S,3S)-(-)-酒石酸氢盐、(±)-酒石酸氢盐、柠檬酸(枸橼酸)二氢盐、羟基柠檬酸(枸橼酸)二氢盐、马来酸氢盐、富马酸氢盐、L-苹果酸氢盐、D-苹果酸氢盐、(dl)-苹果酸氢盐、草酸氢盐、胡萝卜酸氢盐、戊二酸氢盐、己二酸氢盐、庚二酸氢盐、辛二酸氢盐、壬二酸氢盐、葵二酸氢盐、苯磺酸盐、葡萄糖酸盐、抗坏血酸盐、(2R,3R)-(+)-酒石酸盐、(2S,3S)-(-)-酒石酸盐、(±)-酒石酸盐、柠檬酸(枸橼酸)氢盐、羟基柠檬酸(枸橼酸)氢盐、马来酸盐、富马酸盐、L-苹果酸盐、D-苹果酸盐、(dl)-苹果酸盐、草酸盐、胡萝卜酸盐、戊二酸盐、己二酸盐、庚二酸盐、辛二酸盐、壬二酸盐、葵二酸盐。
6.根据权利要求1的8-二卤亚甲基二氢小檗碱型化合物及其生理上可接受的盐，其特征在于，所述的8-二卤亚甲基二氢小檗碱型化合物选自如下化合物群组：
7.一种产品组合物，其特征在于，含有有效剂量的权利要求1-6任一项的8-二卤亚甲基二氢小檗碱型化合物及其生理上可接受的盐和药学上可接受的载体或赋形剂。
8.权利要求1-6任一项的8-二卤亚甲基二氢小檗碱型化合物及其生理上可接受的盐或权利要求7的产品组合物在制备预防、缓解和/或治疗微生物感染产品中的应用。
9.根据权利要求8的应用，其特征在于，所述的微生物包括革兰氏阳性菌和真菌。
10.权利要求1-6任一项的8-二卤亚甲基二氢小檗碱型化合物及其生理上可接受的盐或权利要求7的产品组合物在制备预防、缓解和/或治疗炎症产品中的应用。
11.根据权利要求7-10的应用，其特征在于，所述的产品选自药品、护肤品、化妆品、保健品。
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| CN115340538B (zh) * | 2021-05-13 | 2023-10-20 | 中国医学科学院药物研究所 | 8-苯亚胺基甲基小檗碱型衍生物及其制备药物的应用 |
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