CN115160281A - 一种异香豆素类衍生物衍生物及其在抗疟药物中的应用 - Google Patents
一种异香豆素类衍生物衍生物及其在抗疟药物中的应用 Download PDFInfo
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- CN115160281A CN115160281A CN202110363055.9A CN202110363055A CN115160281A CN 115160281 A CN115160281 A CN 115160281A CN 202110363055 A CN202110363055 A CN 202110363055A CN 115160281 A CN115160281 A CN 115160281A
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- Prior art keywords
- compound
- organic solvent
- pharmaceutically acceptable
- compounds
- isocoumarin
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Abstract
涉及一种异香豆素类衍生物及其在药物中的应用,具体涉及本发明化合物、其互变异构体、立体异构体、外消旋体、对映异构体的非等量混合物、几何异构体、溶剂化物、药学上可接受的盐或前药,以及包含该化合物的药物组合物的制备及其作为抗疟药物的用途。本发明提供的异香豆素类衍生物具有被开发为新型作用于疟原虫多靶点的抗疟药物的潜力。
Description
技术领域
本发明涉及一种新型的作用于疟原虫多靶点的抗疟异香豆素类衍生物制备方法及其应用,并具体涉及异香豆素类衍生物及其药物组合物作为药物,尤其是作为新作用机制抗疟药物的用途。
背景技术
疟疾(malaria)是由疟原虫引起,经雌性按蚊叮咬而感染人类的虫媒传染病。引发人类疾病的疟原虫主要有恶性疟原虫、间日疟原虫、卵形疟原虫和三日疟原虫,其中恶性疟原虫(Plasmodium falciparum)易引发脑型疟,导致患者出现高热、剧烈头痛甚至昏迷等症状,是最致命的疟疾感染源。据WHO最新数据显示,在2018年,有2.28亿疟疾病例发生,40.5万人死于该病,主要为5岁以下儿童,涉及近百个国家和地区。抗疟主要依赖于传统药物,包括喹啉类、青蒿素类、嘧啶类和抗菌素。目前疟原虫对所有单一抗疟药物都产生了耐药性,基于青蒿素类的联合疗法(ACT)被用于疟疾的一线治疗。然而恶性疟原虫基因序列的突变(如Pfkelch13、Pfcrt及Pfmdr1基因突变等)和患者的长期不规范用药,ACT的耐药发生率也不断增加,特别是在东南亚地区。针对血红素激活的青蒿素类药物多靶点作用机制还尚不明确;恶性疟原虫复杂的生命周期致使有效且持久的疟疾疫苗开发也困难重重。为了预防抗药性恶性疟的流行,在有限的可供选择药物情况下,寻找新型作用于恶性疟原虫新作用机制的抗疟药物迫在眉睫。 (World Health Organization. Malaria Threats Map:visualizing biological challenges to malaria control and elimination, 2020.https://www.who.int/malaria/maps/threats-about/en/. World HealthOrganization. World malaria report 2019. Haldar K., Bhattacharjee S.,Safeukui I. Drug resistance in Plasmodium. Nat. Rev. Microbiol., 2018, 16,156–170. Beeson J. G., Kurtovic L., Dobaño C., et al. Challenges andstrategies for developing efficacious and long-lasting malaria vaccines. Sci.Transl. Med., 2019, 11, 1458–1474.)
文献Hoepfner D. et al. Selective and specific inhibition of thePlasmodium falciparum lysyl-tRNA synthetase by the fungal secondarymetabolite cladosporin. Cell. Host. Microbe., 11, 654–663 (2012). Das P. etal. Specific stereoisomeric conformations determine the drug potency ofcladosporin scaffold against malarial parasite. J. Med. Chem., 61, 5664–5678(2018).公开了如下所示化合物具有抗疟活性,其作用机制是通过直接靶向恶性疟原虫赖氨酰-tRNA合成酶的ATP结合位点发挥抗疟活性。
文献Fredenhagen, A., et al. Cladosporin Derivatives Obtained byBiotransformation Provide Guidance for the Focused Derivatization of thisAntimalarial Lead Compound. Chembiochem, 20(5), 650-654 (2019).公开了如下所示化合物具有抗疟活性,其作用机制是通过直接靶向恶性疟原虫赖氨酰-tRNA合成酶的ATP结合位点发挥抗疟活性。
文献 Rusch, M., et al. "Design and Synthesis of Metabolically StabletRNA Synthetase Inhibitors Derived from Cladosporin." Chembiochem, 20(5):644-649 (2019). 公开了如下所示化合物具有抗疟活性,其作用机制是通过直接靶向恶性疟原虫赖氨酰-tRNA合成酶的ATP结合位点发挥抗疟活性。
文献Sappapan R. et al. 11-Hydroxymonocerin from the plant endophyticfungus Exserohilum rostratum. J. Nat. Prod., 71: 1657–1659 (2008) .公开了如下所示化合物具有抗疟活性。
文献El Aouad, N., et al. Lasionectrin, a naphthopyrone from aLasionectria sp. J. Nat. Prod. 75, 1228‒1230 (2012).公开了如下所示化合物具有抗疟活性。
文献Xu L., He Z., Xue J., et al. β-Resorcylic acid lactones from aPaecilomyces fungus. J. Nat. Prod., 2010, 73: 885–889.公开了如下所示化合物具有抗疟活性。
文献Chinworrungsee, M., et al. Antimalarial halorosellinic acid fromthe marine fungus Halorosellinia oceanica. Bioorg. Med. Chem. Lett. 11(15):1965-1969 (2001). 公开了如下所示化合物具有抗疟活性,同时该化合物亦具有较强的毒性。
本发明主要涉及异香豆素类衍生物在制备抗疟方面的应用。已公开的化合物虽与本发明化合物结构相似,但是在结构上是有一定区别的。本发明的异香豆素类化合物仅仅微小的取代基改变和手性构型差异,会导致化合物的活性和毒性产生难以想象的变化。此外,本发明的异香豆素类化合物不仅具有强的抗疟活性,还具有非常高的安全系数,在抗疟作用机制方面与相关文献报道的化合物不同,本发明的化合物可抑制恶性疟原虫疟色素聚合、降低其线粒体膜电位,并抑制恶性疟原虫DNA解旋酶,可开发为新型针对多靶点的抗疟药物。
发明内容
本发明的目的在于提供一种来源于海洋真菌的异香豆素类衍生物的制备方法与作为抗疟方面的应用,它能满足现有技术的上述需求。菌种保藏信息:保藏单位名称:中国微生物菌种保藏管理委员会普通微生物中心;保藏单位地址:北京市朝阳区北辰西路 1 号院 3 号 中国科学院微生物研究所;保藏编号:CGMCC No. 21932;分类命名:Exserohilumsp.。
本发明提供一种异香豆素类衍生物1‒15, 其互变异构体、立体异构体、外消旋体、对映异构体的非等量混合物、几何异构体、溶剂化物、药学上可接受的盐或其盐的溶剂化物, 或前药,其特征在于化合物具有如下结构:
本发明包含所述的异香豆素类衍生物的制备方法, 其特征在于对真菌Exserohilum sp.中克级次级代谢产物monocerin经一步或多步地半合成制备反应,反应后得到本发明所述结构的异香豆素类化合物,涉及到的半合成反应包括酰化、甲基化、卤代、去甲基化和丙酮叉反应。
本发明包含所述的异香豆素类衍生物的半合成制备方法, 其特征在于,
酰化反应: 在氮气或氩气保护下发生酰化或者选择性酰化反应; 酰化反应条件为本领域常规条件: 有机溶剂中, 在碱和酰化试剂作用下反应, 其中酰化试剂选自酰卤和酸酐, 其中卤素选自氯, 溴, 碘; 碱选自碱金属碳酸盐 (包括碳酸钾、碳酸钠、碳酸铯), 碱金属醇化物 (包括甲醇钠, 乙醇钠, 叔丁醇钾), 三乙胺, 吡啶, 醋酸钠, 喹啉,咪唑, 二甲基苯胺, DMAP, 2,6-二甲基吡啶; 上述有机溶剂选自二氯甲烷, 乙腈, 苯,甲苯, 四氢呋喃, 乙醚, DMF, 二氧六环,在温度20-90°C下反应;
卤代反应条件: 在有机溶剂中, 低温下与卤化磷或卤化亚砜反应, 上述有机溶剂选自二氯甲烷, 乙腈, 苯, 甲苯, 四氢呋喃, 乙醚, DMF, 二氧六环;
去甲基化反应: 在有机溶剂中, 在氮气或氩气保护下选用BBr3进行反应, 上述有机溶剂选自二氯甲烷,三氯甲烷, 苯, 甲苯, 四氢呋喃, 乙醚, DMF, 二氧六环,在温度0-30°C下反应;
丙酮叉反应: 在有机溶剂中, 在氮气或氩气保护下与2, 2-二甲氧基丙烷进行反应, 上述有机溶剂选自丙酮, 二氯甲烷, 甲苯, 四氢呋喃, 乙醚, DMF, 二氧六环,在温度20-90°C下反应。
本发明包含本发明化合物及其药学上可接受的盐的应用, 用于生产医药产品治疗患者由疟原虫等引起的疾病, 包括那些本发明所描述的疾病, 本发明包含药物组合物,该药物组合物包括本发明所述化合物与至少一种药学上可接受的载体, 赋形剂, 稀释剂,辅剂, 媒介物的结合所需的有效治疗量。
另一方面, 本发明涉及一种使用本发明化合物或其药物组合物在阻止或治疗动物或人体由疟原虫等引起的各种疾病的方法用途, 该用途包含使用本发明的化合物或其药物组合物的药学上可接受的有效治疗量对人体或动物进行给药。
本发明所述的由间日疟原虫(Plasmodium vivax)、三日疟原虫(Plasmodium malariae)、恶性疟原虫(Plasmodium falciparum)和卵形疟原虫(Plasmodium ovale)引起的疾病, 包括疟疾等。
本发明同样包含治疗或减轻患者由疟原虫等引起的疾病, 或对此病症敏感的方法, 该方法包含使用本发明所述化合物的治疗有效量对患者进行治疗。
前面所述内容只概述了本发明的某些方面, 但并不限于这些方面。这些方面及其他的方面的内容将在下面作更加具体完整的描述。
定义和一般术语
本发明将会把确定的具体化的内容所对应的文献详细列出, 实施例都伴随有结构式和化学式的解释说明。本发明有预期地涵盖所有的选择余地、变体和同等物, 这些可能像权利要求所定义的那样包含在现有发明领域。所属领域的技术人员将识别许多类似或等同于在此所描述的方法和物质, 这些可以应用于本发明的实践中去。本发明绝非限于方法和物质的描述。有很多文献和相似的物质与本发明申请相区别或抵触, 其中包括但绝不限于术语的定义, 术语的用法, 描述的技术, 或像本发明申请所控制的范围。
本发明将应用以下定义除非其他方面表明。根据本发明的目的, 化学元素根据元素周期表, CAS版本和化学药品手册, 75, thEd, 1994来定义。另外, 有机化学一般原理见“Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito:1999, and “March's Advanced Organic Chemistry,” by Michael B. Smith and JerryMarch, John. Wiley&Sons, New York: 2007, 因此所有的内容都融合了参考文献。
除非其他方面表明, 本发明所描述的结构式包括所有的同分异构形式(如对映异构, 非对映异构, 和几何异构(或构象异构)):例如含有不对称中心的R、S构型, 双键的(Z)、(E)异构体, 和(Z)、(E)的构象异构体。因此, 本发明的化合物的单个立体化学异构体或其对映异构体, 非对映异构体, 或几何异构体(或构象异构体)的混合物都属于本发明的范围。
本发明所使用的术语“前药”, 代表一个化合物在体内转化为本发明所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯, 在现有的发明中酯可以作为前体药物的有苯酯类,脂肪族(C1-C24)酯类, 酰氧基甲基酯类, 碳酸酯, 氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基, 即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯, 如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献:T. Higuchi and V.Stella, Pro-drugsas NovelDelivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche,ed., Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design andClinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J. Hecker et al, Prodrugs of Phosphates and Phosphonates, J. Med. Chem.,2008, 51, 2328-2345.
除非其他方面表明, 本发明的化合物的所有互变异构形式都包含在本发明的范围之内。另外, 除非其他方面表明, 本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定, 其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化, 还原, 水解, 酰氨化, 脱酰氨作用, 酯化, 脱脂作用, 酶裂解等等方法得到。相应地, 本发明包括化合物的代谢产物, 包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明的化合物可以包含不对称中心或手性中心, 因此存在不同的立体异构体。本发明的化合物所有的立体异构形式, 包括但绝不限于, 非对映体, 对映异构体, 阻转异构体, 和它们的混合物, 如外消旋混合物, 组成了本发明的一部分。很多有机化合物都以光学活性形式存在, 即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时,前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀D、L或(+)、(-)用来命名化合物平面偏振光旋转的符号, (-)或L是指化合物是左旋的, 前缀(+)或D是指化合物是右旋的。这些立体异构体的化学结构是相同的, 但是它们的立体结构不一样。特定的立体异构体可以是对映体, 异构体的混合物通常称为对映异构体混合物。50: 50的对映体混合物被称为外消旋混合物或外消旋体, 这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物, 缺乏光学活性。
术语“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低能垒互相转化。例如质子互变异构体(即质子移变的互变异构体)包括通过质子迁移的互变, 如酮式-烯醇式和亚胺-烯胺的同分异构化作用。原子价(化合价)互变异构体包括重组成键电子的互变。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的, 如文献:S. M. Berge et al., describepharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences,66: 1-19, 1977.所记载的。药学上可接受的无毒的酸形成的盐包括, 但并不限于, 与氨基基团反应形成的无机酸盐有盐酸盐, 氢溴酸盐, 磷酸盐, 硫酸盐, 高氯酸盐, 和有机酸盐, 如乙酸盐, 草酸盐, 马来酸盐, 酒石酸盐, 柠檬酸盐, 琥珀酸盐, 丙二酸盐, 或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括: 己二酸盐, 藻酸盐, 抗坏血酸盐, 天冬氨酸盐, 苯磺酸盐, 苯甲酸盐, 重硫酸盐,硼酸盐, 丁酸盐, 樟脑酸盐, 樟脑磺酸盐, 环戊基丙酸盐, 二葡萄糖酸盐, 十二烷基硫酸盐, 乙磺酸盐, 甲酸盐, 反丁烯二酸盐, 葡庚糖酸盐, 甘油磷酸盐, 葡萄糖酸盐, 半硫酸盐, 庚酸盐, 己酸盐, 氢碘酸盐, 2-羟基-乙磺酸盐, 乳糖醛酸盐, 乳酸盐, 月桂酸盐, 月桂基硫酸盐, 苹果酸盐, 丙二酸盐, 甲磺酸盐, 2-萘磺酸盐, 烟酸盐, 硝酸盐,油酸盐, 棕榈酸盐, 扑酸盐, 果胶酸盐, 过硫酸盐, 3-苯基丙酸盐, 苦味酸盐, 特戊酸盐, 丙酸盐, 硬脂酸盐, 硫氰酸盐, 对甲苯磺酸盐, 十一酸盐, 戊酸盐, 等等。通过适当的碱得到的盐包括碱金属, 碱土金属, 铵和N+ (C1-C4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠, 锂, 钾, 钙, 镁, 等等。药学上可接受的盐进一步包括适当的、无毒的铵, 季铵盐和抗平衡离子形成的胺阳离子, 如卤化物, 氢氧化物, 羧化物, 硫酸化物, 磷酸化物, 硝酸化物, C1-C8磺酸化物和芳香磺酸化物。
本发明所述的的部分化合物的盐可以如下所示的具体化合物的盐来说明, 但并不限定本发明。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括, 但并不限于, 水, 异丙醇, 乙醇, 甲醇, 二甲亚砜, 乙酸乙酯, 乙酸, 氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
本发明的部分化合物的溶剂化物或其盐的溶剂化物可以用如下列出的具体化合物的盐来说明,但不限定于本发明:
本发明的化合物的盐还包括用于制备或纯化本发明所示化合物的中间体或本发明所示化合物分离的对映异构体的盐, 但不一定是药学上可接受的盐。
如果本发明的化合物是碱性的, 则想得到的盐可以通过文献上提供的任何合适的方法制备得到, 例如, 使用无机酸, 如盐酸, 氢溴酸, 硫酸, 硝酸和磷酸等等。或者使用有机酸, 如乙酸, 马来酸, 琥珀酸, 扁桃酸, 富马酸, 丙二酸, 丙酮酸, 草酸, 羟乙酸和水杨酸; 吡喃糖酸, 如葡萄糖醛酸和半乳糖醛酸; α-羟酸, 如柠檬酸和酒石酸; 氨基酸, 如天门冬氨酸和谷氨酸; 芳香族酸, 如苯甲酸和肉桂酸; 磺酸, 如对甲苯磺酸,乙磺酸, 等等。
如果本发明的化合物是酸性的, 则想得到的盐可以通过合适的方法制备得到,如, 使用无机碱或有机碱, 如氨(伯氨, 仲氨, 叔氨), 碱金属氢氧化物或碱土金属氢氧化物, 等等。合适的盐包括但并不限于, 从氨基酸得到的有机盐, 如甘氨酸和精氨酸,氨, 如伯氨、仲氨和叔氨, 和环状氨, 如哌啶, 吗啉和哌嗪等, 和从钠, 钙, 钾, 镁,锰, 铁, 铜, 锌, 铝和锂得到无机盐。
根据另一方面, 本发明的药物组合物的特点包括本发明所示化合物, 或实施例所示的化合物, 和药学上可接受的载体, 辅剂, 或赋形剂。本发明的组合物中化合物的量能有效地可探测地治疗或减轻患者由疟原虫等引起的疾病。
本发明的化合物存在自由形态, 或合适的、作为药学上可接受的衍生物。根据本发明, 药学上可接受的衍生物包括但并不限于, 药学上可接受的前药, 盐, 酯, 酯类的盐, 或能直接或间接地根据患者的需要给药的其他任何加合物或衍生物, 本发明其他方面所描述的化合物, 其代谢产物或他的残留物。
像本发明所描述的, 本发明药学上可接受的组合物进一步包含药学上可接受的载体, 辅剂, 或赋形剂, 这些像本发明所应用的, 包括任何溶剂, 稀释剂, 或其他液体赋形剂, 分散剂或悬浮剂, 表面活性剂, 等渗剂, 增稠剂, 乳化剂, 防腐剂, 固体粘合剂或润滑剂等等, 适合于特有的目标剂型。如以下文献所描述的:In Remington: TheScience and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy,Lippincott Williams Wilkins, Phil adelphia, and Encyclopedia ofPharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999,Marcel Dekker, New York, 综合此处文献的内容, 表明不同的载体可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的载体媒介与本发明的化合物不相容的范围, 例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用, 它们的用途也是本发明所考虑的范围。
可作为药学上可接受载体的物质包括但并不限于, 离子交换剂, 铝, 硬脂酸铝,卵磷脂, 血清蛋白, 如人血清蛋白, 缓冲物质如磷酸盐, 甘氨酸, 山梨酸, 山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物, 水, 盐或电解质, 如硫酸鱼精蛋白, 磷酸氢二钠,磷酸氢钾, 氯化钠, 锌盐, 胶体硅, 三硅酸镁, 聚乙烯吡咯烷酮, 聚丙烯酸脂, 蜡, 聚乙烯-聚氧丙烯-阻断聚合体, 羊毛脂, 糖, 如乳糖, 葡萄糖和蔗糖; 淀粉如玉米淀粉和土豆淀粉; 纤维素和它的衍生物如羧甲基纤维素钠, 乙基纤维素和乙酸纤维素; 树胶粉;麦芽; 明胶; 滑石粉; 辅料如可可豆脂和栓剂蜡状物; 油如花生油, 棉子油, 红花油,麻油, 橄榄油, 玉米油和豆油; 二醇类化合物, 如丙二醇和聚乙二醇; 酯类如乙基油酸酯和乙基月桂酸酯; 琼脂; 缓冲剂如氢氧化镁和氢氧化铝; 海藻酸; 无热原的水; 等渗盐; 林格(氏)溶液; 乙醇, 磷酸缓冲溶液, 和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁, 着色剂, 释放剂, 包衣衣料, 甜味剂, 调味剂和香料, 防腐剂和抗氧化剂。
本发明的药物组合物可以是口服给药, 注射给药, 喷雾吸入法, 局部给药, 经直肠给药, 经鼻给药, 含服给药, 阴道给药或通过植入性药盒给药。可以是胶囊, 片剂,丸剂, 粉剂、粒剂和水制悬浮液或溶液。口服给药可以用如下形式:片剂、丸剂、胶囊、可分散的粉末、颗粒或悬浮液、糖浆、和酏剂, 或以外用方式给药:软膏剂、凝胶、含药胶布等,或者以无菌可注射溶液或悬浮液形式进行非肠胃给药。本发明化合物也可肠胃外或腹腔内给药。也可在适当混合有表面活性剂(如羟丙基纤维素、聚乙烯吡咯烷酮)的水中制备这些活性化合物(作为游离碱或药学上可接受的盐)的溶液或悬浮液。还可在甘油、液体、聚乙二醇及其在油中的混合物中制备分散液。在常规储存和使用条件下, 这些制剂中含有防腐剂以防止微生物生长。
适于注射的药物形式包括:无菌水溶液或分散液和无菌粉(用于临时制备无菌注射溶液或分散液)。在所有情况下, 这些形式必须是无菌的且必须是流体以易于注射器排出流体。在制造和储存条件下必须是稳定的, 且必须能防止微生物(如细菌和真菌)的污染影响。载体可以是溶剂或分散介质, 其中含有如水、醇(如甘油、丙二醇和液态聚乙二醇)、它们的适当混合物和植物油。
化合物可以以局部方式施用, 而不以系统方式施用。例如通常以稀释制剂或持续释放制剂的形式将化合物直接注射至器官内。此外, 含有本发明化合物的药物组合物可以在靶向药物传递系统中使用, 例如在用器官特异性抗体包衣的脂质体中递送。所述脂质体将靶向所述器官并被该器官选择性摄取。此外, 含有本发明化合物的组合物可以以快速释放制剂、延时释放制剂或即时释放制剂的形式提供。
对于吸入施用, 本发明的化合物可以是气溶胶、气雾剂或粉末形式。本发明化合物的药物组合物可以方便地以气溶胶喷雾剂形式递送, 所述气溶胶喷雾剂可以装在压力容器或雾化器中, 使用合适的抛射剂例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体。在压力气溶胶的情况下, 剂量单位可以通过阀门进行确定以递送计量量。例如, 以胶囊剂和药筒为例, 用于吸入器或吹药器的明胶可以制备为含有所述化合物与适当粉末基质例如乳糖或淀粉的粉末混合物。
本发明化合物还可以制备为直肠组合物例如灌肠剂、直肠凝胶剂、直肠泡沫剂、直肠气溶胶、栓剂、凝胶栓剂(gel suppository)或保留灌肠剂(retention enema), 其中含有常规的栓剂基质例如可可脂或其他甘油酯以及合成聚合物例如聚乙烯吡咯烷酮、PEG等。在组合物的栓剂形式中, 低熔点蜡例如但不限于脂肪酸甘油酯任选与可可脂的混合物首先被熔化。
此外, 本发明化合物还可与抗疟药物联用。具体包括但不限于, 青蒿素类、喹啉类、乙胺嘧啶和阿托伐醌等。
可以根据常规方式用一种或多种生理学可接受的载体制备药物组合物, 其中包括可帮助将活性化合物加工为可药用制剂的赋形剂和辅剂。所选择的施用途径决定适当的剂型。任何熟知的技术、载体和赋形剂都可以根据现有技术中的理解适当的使用。含有本发明化合物的药物组合物可以根据常规方法制备, 例如通过常规的混合、溶解、制粒、制锭、研磨、乳化、包囊、包封或压制过程制备。
药物组合物将包含至少一种可药用载体、稀释剂或赋形剂和游离酸、游离碱或可药用盐形式的本发明的化合物作为活性成分。此外, 药物组合物还可包括其它医学或药学活性剂、载体、辅剂、例如防腐剂、稳定剂、湿润剂或乳化剂、溶解促进剂、调节渗透压的盐或缓冲剂。此外, 药物组合物还可含有其它有治疗价值的物质。
含有本文所述化合物的组合物的制备方法包括将化合物与一种或多种惰性的可药用赋形剂或载体一起制备为固体、半固体或液体形式。固体组合物包括但不限于散剂、片剂、可分散颗粒剂、胶囊剂、扁囊剂和栓剂。液体组合物包括其中溶解有化合物的溶液剂、含有化合物的乳剂、含有包含本文公开化合物的脂质体、胶团或纳米粒子的溶液剂。半固体组合物包括但不限于凝胶剂、混悬剂和乳膏剂。组合物可以是液体溶液剂或混悬剂形式、适合于在使用前溶解或悬浮在液体中的固体形式或乳剂形式。这些组合物还可以含有少量无毒的辅剂, 例如湿润剂或乳化剂、pH缓冲剂等。
本发明的化合物优选地按制剂配方制备成剂量单位型以减轻给药量和剂量的均匀性。术语“剂量单位型”在此处是指患者得到适当治疗所需药物的物理分散单位。然而,应了解本发明的化合物或组合物每日总的用法将通过主治医生根据可靠的医学范围判断来确定。具体的有效剂量水平对于任何一个特殊的患者或有机体将取决于许多因素包括被治疗的病症和病症的严重性, 具体化合物的活性, 所用的具体组合物, 患者的年龄、体重、健康状况、性别和饮食习惯, 给药时间, 给药途径和所用具体化合物的排泄速率, 治疗的持续时间, 药物应用于联合用药或与有特效的化合物联用, 以及其他一些药学领域公知的因素。
可以将本发明化合物通过附加适宜的官能团进行修饰以提高选择性生物特性。这样的修饰是本领域己知的并且包括向生物腔隙(例如血液、淋巴系统、中枢神经系统)渗透、提高口服有效性、提高溶解性以便可以通过注射给药、改变代谢和改变排泄的修饰。可以将本发明化合物通过附加适宜的官能团进行修饰以提高选择性生物特性。这样的修饰是本领域己知的并且包括向生物腔隙(例如血液、淋巴系统、中枢神经系统)渗透、提高口服有效性、提高溶解性以便可以通过注射给药、改变代谢和改变排泄的修饰。
一般的, 本发明的化合物可以通过本发明所描述的方法制备得到, 除非有进一步的说明, 下面的反应方案和实施例用将进一步举例说明本发明的内容。
所属领域的技术人员将认识到:本发明所描述的化学反应可以用来合适的制备本发明的其他化合物, 且用于制备本发明的化合物的其他方法都被认为是在本发明的范围之内。例如, 根据本发明那些非例证的化合物的合成可以成功的被所属领域的技术人员通过修饰方法完成, 如适当的保护干扰基团, 通过利用其它已知的试剂除了本发明所描述的, 或将反应条件做一些常规的修改。另外, 本发明所公开的反应或已知的反应条件也公认的适用于本发明其他化合物的制备。
本发明所用溶剂, 如无水四氢呋喃、二氧六环、甲苯、乙醚等是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯、石油醚、正己烷、N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经过无水硫酸钠事先干燥使用。甲醇、乙醇等质子性溶剂是经过多次减压蒸馏后再用无水硫酸钠干燥后使用。
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明), 反应瓶都塞上合适的橡皮筋, 底物通过注射器打入。玻璃器皿均是经过干燥的。
本发明化合物的制备方法,参考但不限于以下文献: Shao, C. L.; Wu, H. X.;Wang, C. Y., et al. Potent antifouling resorcylic acid lactones from thegorgonian-derived fungus Cochliobolus lunatus.J. Nat. Prod., 2011, 74, 629–633.
本发明所选化学反应为本领域常规化学反应或组合,参考以上文献但又与文献涉及的方法和策略是完全不同的,制备了系列异香豆素新衍生物。
附图说明
图1体外β-hematin形成试验结果。
图2Exserohilide-1(1)、他莫西芬(Tamoxifen)和氯喹对DNA旋转酶活性的抑制结果。
图3评估Exserohilide-1(1)与羰基氰化氯苯腙CCCP对线粒体膜电位的影响。
实施例1
步骤1:化合物monocerin (30.0 mg, 0.10 mmol)溶解于15 mL的二氯甲烷溶液中,在N2作用下,向体系中缓慢滴加二氯甲烷稀释后的BBr3溶液 (24 μL BBr3溶解于2 mL的CH2Cl2),反应1.5 h后,加入20 mL的冰水终止反应,然后加入20 mL的二氯甲烷。有机相萃取浓缩得到反应物,经半制备HPLC获得产物Exserohilide-1(1) (5.5 mg)和中间体I (10.2mg)。
Exserohilide-1(1):[α]25 D +117.1 (c 0.1, MeOH); 1H NMR (500 MHz, CDCl3)δ 11.11 (1H, s), 6.49 (1H, s), 5.05 (1H, m), 4.13(1H, d, J = 2.9 Hz), 3.96(4H, overlapped), 3.90 (3H), 3.42 (3H), 1.86 (1H), 1.63 (2H, m), 1.38 (4H,overlapped), 0.91 (3H, t, J = 6.0 Hz); 13C NMR (125 MHz, CDCl3) δ167.9 (C),158.5 (C), 156.4 (C), 137.0 (C), 133.4 (C), 103.3 (CH), 102.3 (C), 78.9 (CH),76.9 (CH), 67.5 (CH), 60.9 (CH3), 57.1 (CH3), 56.4 (CH3), 40.3 (CH2), 39.6(CH2), 18.8 (CH2), 14.1 (CH3); HRESIMS m/z 339.1449 [M - H]- (calcd forC17H23O7, 339.1449).
实施例2
步骤1: Exserohilide-1(1)(5 mg)溶于丙酮中,加入足量干燥的K2CO3粉末,乙酸酐0.5 mL, 加热至40℃反应12 h,加入水终止反应,用乙酸乙酯萃取浓缩得到有机相,经硅胶柱层析(石油醚: 乙酸乙酯 = 3 : 1)得到化合物3(2.8 mg), ESI-MS: 383.2 [M+H]+。
实施例3
步骤1: 称取中间体I(10.0 mg)溶于丙酮中,加入微量的对甲苯磺酸,2, 2-二甲氧基丙烷5 mL, 室温反应1 h,减压浓缩得到反应产物10(10.7 mg,), ESI-MS: 353.1 [M+H]+。
实施例4
称取10.0 mg的化合物10置于圆底烧瓶内,加入25.0 mL干燥的二氯甲烷进行溶解,在0 ºC条件下,缓慢加入三溴化磷 (10.0 μL), 反应3 h后,加入10.0 mL的水溶液终止反应。然后用二氯甲烷萃取两次,有机相浓缩后经正相柱层析 (石油醚:乙酸乙酯 = 1: 1)获得化合物15 (2.5 mg),ESI-MS: 415.1 [M+H]+。
实施例5
抗疟活性测试方法:将恶性疟原虫株用改进的Trager和Jensen法[5]进行体外培养, 培养基由RPMI1640 (Sigma-Aldrich, USA)培养液添加10%灭活的O型人血清,25 mMNaHCO3,2 mM谷氨酸盐,以及25 mM HEPES组成。将密度为2%以下原虫,2%当地志愿者的O型血细胞, 于96孔培养板中在37 °C条件下含有5% CO2,5% O2以及90% N2的混合气体培养箱里培养48 h。取150 μL培养液到新的96孔板, 加入50 μL含有TE buffer,PicoGreen和用无DNA酶的双蒸水稀释的2% trition X-100的荧光混合物, 标记原虫DNA。将96孔板在暗处放置5-30 min, 测定在485/20 nm激发光与528/20 nm发射光下的RFU (相关荧光单位)。
将待测化合物样品溶于DMSO,配制成10 µg/mL,样本一式两份。选择DMSO终浓度为0.1%的RPMI1640为阴性对照, 氯喹为阳性对照。于96孔板加待测试样品进行无原虫培养,所获取的荧光信号减去待测样品和疟原虫共同培养所测定的荧光信号来评价对疟原虫的抑制率。抑制率低于75%被认为是无活性,如果化合物有活性,则将母液逐倍稀释以下浓度10,2,0.4,0.08和0.016 μg/mL来评价其IC50值。
活性测试数据
表中“++++”表示IC50在10-5000 nM之间,“+++”表示IC50在5000-10000 nM之间,“++”表示IC50在10000-100000 nM之间,“+”表示IC50在100000-1000000 nM之间。
活性测试表明:本发明异香豆素类化合物抗疟活性强于阳性药或与阳性药相当,且化合物均无细胞毒性,安全系数高,显示出较好的应用前景。
实施例6
氯喹发挥抗疟作用主要是通过抑制疟原虫对血红蛋白的消化,作用于血红素的处置,减少了 疟原虫生存必需氨基酸的供应;也能抑制血红素聚合酶活性,使有毒的血红素转化为疟色素 受阻,从而减少对人体伤害。本发明使用体外β-hematin形成试验评估了Exserohilide-1 (1)通过这一途径发挥作用的可能性。实验方法参见文献Pandey,A.V.;Singh,N.;Tekwani, B.L.;Puri,S.K.;Chauhan,V.S.J.Pharm.Biomed.Anal.1999,20,203–207.如图1所示,使 用该化合物处理24小时(51.14%)后,合成的β-hematin的数量显著减少,与氯喹(68.2%)相 似,但略低(p≤0.01)。
DNA旋转酶(DNA gyrase)是ATP依赖酶家族的一员,称为II型拓扑异构酶。这些酶参与许多涉及DNA复制和基因表达的生物过程。顶质体是疟原虫生存所必须的一种细胞器,DNA旋转酶在该细胞器中发挥重要作用。如图2所示,Exserohilide-1(1)对DNA旋 转酶活性的抑制显著为48%,与已知的该酶抑制剂他莫西芬(Tamoxifen)在100μM时(51%) 的抑制水平相当,而氯喹(CQ,50μM)对该酶的抑制作用不太明显(p≤0.0001)。
为了评估Exserohilide-1(1)是否通过细胞凋亡活性来诱导抗增殖作用,本发明研究 了线粒体膜电位的改变。膜染料DiO6用于检测活细胞线粒体膜电位,发现1导致线粒体膜 电位中断,与对照组相比,荧光细胞的比例减少。这种减少在第一次将寄生虫暴露于化合物 3小时后更加明显,与阳性药羰基氰化氯苯腙CCCP相当,图3为分别在疟原虫裂殖期用10 μM化合物处理3小时和6小时后线粒体膜电位的变化(*p≤0.05;**p≤0.01.***p≤0.001)。
抗疟作用机制研究表明,异香豆素类衍生物Exserohilide-1(1)可抑制疟原虫疟色素聚合,降低其线粒体膜电位,同时通过抑制DNA旋转酶抑制DNA复制,与目前已产生耐药性的喹啉类药物如氯喹作用机制明显不同。
Claims (7)
2.权利要求1所述的异香豆素类衍生物的制备方法, 其特征在于对真菌Exserohilumsp.中的克级次级代谢产物monocerin经一步或多步地半合成制备反应,反应后得到权利要求1所述的异香豆素类化合物; 涉及到的半合成反应包括酰化、甲基化、卤代、去甲基化和丙酮叉反应。
3.权利要求2所述的异香豆素类衍生物的制备方法, 其特征在于,酰化反应: 在氮气或氩气保护下发生酰化或者选择性酰化反应; 酰化反应条件为本领域常规条件: 有机溶剂中, 在碱和酰化试剂作用下反应, 其中酰化试剂选自酰卤和酸酐, 其中卤素选自氯,溴, 碘; 碱选自碱金属碳酸盐 (包括碳酸钾、碳酸钠、碳酸铯), 碱金属醇化物 (包括甲醇钠, 乙醇钠, 叔丁醇钾), 三乙胺, 吡啶, 醋酸钠, 喹啉, 咪唑, 二甲基苯胺, DMAP, 2,6-二甲基吡啶; 上述有机溶剂选自二氯甲烷, 乙腈, 苯, 甲苯, 四氢呋喃, 乙醚, DMF,二氧六环,在温度20-90°C下反应;
卤代反应条件: 在有机溶剂中, 低温下与卤化磷或卤化亚砜反应, 上述有机溶剂选自二氯甲烷, 乙腈, 苯, 甲苯, 四氢呋喃, 乙醚, DMF, 二氧六环;
去甲基化反应: 在有机溶剂中, 在氮气或氩气保护下选用BBr3进行反应, 上述有机溶剂选自二氯甲烷,三氯甲烷, 苯, 甲苯, 四氢呋喃, 乙醚, DMF, 二氧六环,在温度0-30°C下反应;
丙酮叉反应: 在有机溶剂中, 在氮气或氩气保护下与2, 2-二甲氧基丙烷进行反应,上述有机溶剂选自丙酮, 二氯甲烷, 甲苯, 四氢呋喃, 乙醚, DMF, 二氧六环,在温度20-90°C下反应。
4.一种抗疟药物,其特征在于其含有权利要求1所述的异香豆素类衍生物或其药学上可接受的盐作为有效成分。
5.一种药物组合物,其包含根据权利要求1所述的一种化合物或几种化合物或其互变异构体、立体异构体、外消旋体、对映异构体的非等量混合物、几何异构体、溶剂化物、药学上可接受的盐或其盐的溶剂化物中的任意一种或几种作为有效成分; 该药物组合物还包含至少一种药学上可接受的载体、稀释剂或赋形剂。
6.权利要求5所述的药物组合物,其特征在于该药物组合物还包含至少一种其他抗疟药物,具体包括但不限于青蒿素、氯喹、奎宁、乙胺嘧啶;该药物组合物选自注射剂、口服制剂、冻干粉针剂、悬浮剂。
7.权利要求1所述的化合物或其互变异构体、其立体异构体、其外消旋体、其对映异构体的非等量混合物、其几何异构体、其溶剂化物、其药学上可接受的盐或其盐的溶剂化物在抗疟药物先导化合物中的应用。
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