CN111454165A - 用于递送核酸的新型脂质和脂质纳米颗粒制剂 - Google Patents
用于递送核酸的新型脂质和脂质纳米颗粒制剂 Download PDFInfo
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- CN111454165A CN111454165A CN202010373083.4A CN202010373083A CN111454165A CN 111454165 A CN111454165 A CN 111454165A CN 202010373083 A CN202010373083 A CN 202010373083A CN 111454165 A CN111454165 A CN 111454165A
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Abstract
Description
本申请是2015年06月05日提交的发明名称为“用于递送核酸的新型脂质和脂质纳米颗粒制剂”的第201580045176.1号中国专利申请的分案申请。
背景
技术领域
本发明总体上涉及新型阳离子脂质,其可用于与其他脂质组分(例如中性脂质、胆甾醇和聚合物缀合的脂质)结合,以便形成具有寡核苷酸的脂质纳米颗粒,从而促进体外和体内的治疗性核酸(例如,寡核苷酸、信使RNA)的细胞内递送。
相关领域描述
关于递送核酸以便在生物系统中产生所需的应答存在着诸多挑战。基于核酸的治疗具有巨大潜力,但需要将核酸更有效地递送至细胞或生物体内的适当位点,以便实现这种潜力。治疗性核酸包括,例如,信使RNA(mRNA)、反义寡核苷酸、核酶、DNA酶、质粒、免疫刺激核酸、antagomir、antimir、模拟物(mimic)、supermir和适配子。一些核酸,如mRNA或质粒,可以用于影响特定细胞产物的表达,正如其对于治疗例如与蛋白质或酶的缺乏有关的疾病是有用的。可翻译的核苷酸递送的治疗性应用是极其广泛的,这是因为可以合成构建体以产生任何所选蛋白质序列(不论是否为该系统固有的)。所述核酸的表达产物可以增大蛋白质的存在水平,取代缺失的或非功能的蛋白质型,或在细胞或生物体内引入新的蛋白质以及相关功能。
一些核酸,如miRNA抑制剂,可以用于影响由miRNA调控的特定细胞产物的表达,正如其对于治疗例如与蛋白质或酶的缺乏有关的疾病是有用的。miRNA抑制的治疗性应用是极其广泛的,其原因是可以合成构建体以抑制一种或多种进而调控mRNA产物表达的miRNA。内源性miRNA的抑制可以增加其下游的靶内源性蛋白质表达,并且恢复细胞或生物体内的适当功能,以治疗与特定miRNA或miRNA组有关的疾病。
其他的核酸可以下调特定mRNA的细胞内水平,并且,结果是,通过诸如RNA干扰(RNAi)或反义RNA的互补结合的过程下调相应的蛋白质的合成。反义寡核苷酸和RNAi的治疗性应用也是极其广泛的,因为可以通过直接对应靶mRNA的任何核苷酸序列合成寡核苷酸构建体。靶标可以包括来自正常细胞的mRNA、与病症(例如癌症)有关的mRNA以及感染因子(例如病毒)的mRNA。迄今为止,反义寡核苷酸构建体已显示出在体外和体内模型中通过同源mRNA的降解来特异性地下调靶蛋白质的能力。另外,反义寡核苷酸构建体目前正在临床研究中被评估。
然而,在治疗过程下使用寡核苷酸目前面临着两个问题。第一,游离的RNA易于在血浆中核酸酶消化。第二,游离RNA进入存在相关翻译机制的细胞内隔室的能力受限。由阳离子脂质与其他脂质组分(如中性脂质、胆甾醇、PEG、PEG化的脂质和寡核苷酸)形成的脂质纳米颗粒已用于阻止RNA在血浆中的降解并促进寡核苷酸的细胞摄取。
仍然需要改进的用于递送寡核苷酸的阳离子脂质和脂质纳米颗粒。优选地,这些脂质纳米颗粒会提供优化的药物:脂质比,保护核酸不在血清中被降解和清除,其适于全身性递送,并且提供核酸的细胞内递送。另外,这些脂质-核酸颗粒应当是耐受良好的,并且提供足够的治疗指数,从而以不对患者产生不可接受的毒性和/或风险的核酸的有效剂量来对患者进行治疗。本发明提供这些优点和相关的优点。
概述
简言之,本发明提供了脂质化合物,包括其立体异构体、药物可接受的盐或互变异构体,其可以单独使用,或者结合其他脂质组分,如中性脂质、带电脂质、甾族化合物(包括例如,所有甾醇类)和/或他们的类似物和/或聚合物缀合的脂质,以便形成用于递送治疗剂的脂质纳米颗粒。在一些实例中,所述脂质纳米颗粒用于递送核酸,如反义RNA和/或信使RNA。还提供了这类脂质纳米颗粒用于治疗各种疾病或病况(如感染性实体和/或蛋白质缺乏引起的疾病或病况)的方法。
在一个实施方案中,提供了具有下式(I)的化合物:
或其药物可接受的盐、互变异构体或立体异构体,其中Rla、Rlb、R2a、R2b、R3a、R3b、R4a、R4b、R5、R6、R7、R8、R9、L1、L2、a、b、c、d和e如本文所定义。
还提供了包含前述式(I)的化合物中的一种或多种和治疗剂的药物组合物。在一些实施方案中,所述药物组合物还包含一种或多种选自中性脂质、带电脂质、甾族化合物和聚合物缀合的脂质的组分。这类组合物对于形成用于递送治疗剂的脂质纳米颗粒是有用的。
在其他实施方案中,本发明提供了对有此需要的患者施用治疗剂的方法,该方法包括制备包含式(I)的化合物的脂质纳米颗粒与治疗剂的组合物,和将该组合物递送至患者。
在更多的实施方案中,本发明涉及具有以下结构(II)的聚乙二醇化的脂质:
或其药物可接受的盐、互变异构体或立体异构体,其中R10、R11和z如本文所定义。
本发明的这些和其他方面经参考以下详细描述将会是显而易见的。
附图简述
在附图中,相同的参考编号表示类似的要素。图中要素的尺寸和相对位置不必按比例绘制,并且这些要素中的一些被任意地放大和放置以便改善图的易读性。并且,所绘制要素的特定形状并非旨在表达有关特定要素的实际形状的信息,并且仅选择以便易于图中的识别。
图1示出了鼠肝脏中荧光素酶表达的时间过程。
图2例示了MC3作为与所公开脂质相关的代表性实例的pKa的计算。
图3提供了对于不同脂质的比较性的荧光素酶活性数据。
图4为示出了包含两种不同的聚乙二醇化的脂质的组合物的比较性数据的柱状图。
发明详述
在以下描述中,阐述了某些具体的详细内容,以便提供对本发明各种实施方案的透彻理解。然而,本领域的技术人员将理解,本发明可以在没有这些详细内容的情况下实施。
本发明部分基于新型阳离子(氨基)脂质的发现,该新型阳离子(氨基)脂质当在用于将活性剂或治疗剂(例如核酸)体内递送至哺乳动物细胞中的脂质纳米颗粒中使用时提供优点。特别地,本发明的实施方案提供了包含一种或多种本文描述的新型阳离子脂质的核酸-脂质纳米颗粒组合物,其提供增强的核酸活性和增强的组合物体内耐受性,使得相比先前描述的核酸-脂质纳米颗粒组合物在治疗指数上的显著提高。
在特定的实施方案中,本发明提供了新型阳离子脂质,其能够形成改善的用于体外和体内递送mRNA和/或其他寡核苷酸的组合物。在一些实施方案中,这些改善的脂质纳米颗粒组合物对于由mRNA编码的蛋白质的表达是有用的。在其他实施方案中,这些改善的脂质纳米颗粒组合物通过递送靶向一种特定miRNA或miRNA组(其调控一种靶mRNA或多种mRNA)的miRNA抑制剂从而对于上调内源性蛋白质表达是有用的。在其他实施方案中,这些改善的脂质纳米颗粒组合物对于下调(例如,沉默)靶基因的蛋白质水平和/或mRNA水平是有用的。在一些其他实施方案中,所述脂质纳米颗粒对用于转基因表达的mRNA和质粒的递送也是有用的。在其他实施方案中,所述脂质纳米颗粒组合物对于引发由蛋白质表达产生的药理学作用是有用的,所述药理学作用例如,通过递送适合的红细胞生成素mRNA产生增加的红细胞,或者通过递送用于编码适合抗体的mRNA来防止感染。
本发明的脂质纳米颗粒和组合物可以用于各种目的,包括在体外和体内将封装的或缔合的(例如,复合的)诸如核酸的治疗剂递送至细胞。因此,本发明的实施方案提供通过使有此需要的对象接触封装适合的治疗剂或与适合的治疗剂缔合的脂质纳米颗粒,来治疗或预防所述对象的疾病和病症的方法,其中所述脂质纳米颗粒包含一种或多种本文描述的新型阳离子脂质。
如本文所描述的,本发明的脂质纳米颗粒的实施方案对于核酸的递送是尤其有用的,所述核酸包括,例如,mRNA、反义寡核苷酸、质粒DNA、微小RNA(miRNA)、miRNA抑制剂(antagomir/antimir)、信使-RNA-干扰互补RNA(micRNA)、DNA、多价RNA、dicer底物RNA、互补DNA(cDNA)等。因此,本发明的脂质纳米颗粒和组合物可以用于通过使细胞接触包含一种或多种本文描述的新型阳离子脂质的脂质纳米颗粒,来在体外或体内引发所需蛋白质的表达,其中所述脂质纳米颗粒封装或缔合表达产生所需蛋白质的核酸(例如,编码所需蛋白质的信使RNA或质粒)。可选地,本发明的脂质纳米颗粒和组合物可以用于通过使细胞接触包含一种或多种本文描述的新型阳离子脂质的脂质纳米颗粒,来在体外或体内减少靶基因和靶蛋白质的表达,其中所述脂质纳米颗粒封装或缔合减少靶基因表达的核酸(例如,反义寡核苷酸或小干扰RNA(siRNA))。本发明的脂质纳米颗粒和组合物也可以用于单独或结合地共递送不同的核酸(例如mRNA和质粒DNA),例如可以适用于提供需要不同核酸(例如编码适合的基因修饰酶的mRNA和并入宿主基因组的DNA片段)共同定位的作用。
用于本发明的核酸可以根据任何可用的技术来制备。对于mRNA,主要的制备方法为,但不限于酶促合成(也称为体外转录),该方法目前代表着产生长序列特异的mRNA的最有效的方法。体外转录描述了由工程化的DNA模板进行RNA分子的模板导向合成的方法,该工程化的DNA模板包含上游噬菌体启动子序列(例如,包括但不限于来自T7、T3和SP6大肠杆菌噬菌体),其与下游编码相关的基因的序列连接。可以由本领域熟知的很多来源和适当的技术来制备模板DNA用于体外转录,所述来源和适当的技术包括,但不限于质粒DNA和聚合酶链反应扩增(参见Linpinsel,J.L和Conn,G.L.,General protocols for preparationof plasmid DNA template,以及Bowman,J.C.,Azizi,B.,Lenz,T.K.,Ray,P.和Williams,L.D.,RNA in vitro transcription and RNA purification by denaturing PAGE inRecombinant and in vitro RNA syntheses Methods v.941Conn G.L.(编著),New York,N.Y.Humana Press,2012)。
使用线性化DNA模板,在存在相应的RNA聚合酶以及腺苷、鸟苷、尿苷和胞苷核糖核苷三磷酸(rNTP)时,在支持聚合酶活性同时使得到的mRNA转录物可能的降解最小化的条件下,在体外发生RNA的转录。可以使用各种可商购的试剂盒以及可商购的试剂来进行体外转录,所述试剂盒包括,但不限于RiboMax大规模RNA生产系统(Promega)、MegaScript转录试剂盒(Life Technologies),所述试剂包括RNA聚合酶和rNTP。mRNA体外转录的方法是本领域熟知的。(参见,例如Losick,R.,1972,In vitro transcription,Ann Rev Biochem v.41409-46;Kamakaka,R.T.和Kraus,W.L.2001.In Vitro Transcription.Current Protocolsin Cell Biology.2:11.6:11.6.1-11.6.17;Beckert,B.和Masquida,B.,(2010)Synthesisof RNA by In Vitro Transcription in RNA in Methods in Molecular Biology v.703(Neilson,H.编著),New York,N.Y.Humana Press,2010;Brunelle,J.L.和Green,R.,2013,Chapter Five-In vitro transcription from plasmid or PCR-amplified DNA,Methodsin Enzymology v.530,101-114;通过引用将以上全部并入本文)。
然后将所需的体外转录的mRNA从转录或相关反应的不希望的组分(包括未并入的rNTP、蛋白质酶、盐、短RNA寡核苷酸等)中纯化。分离mRNA转录物的技术是本领域熟知的。熟知的程序包括苯酚/氯仿萃取或在单价阳离子或氯化锂的存在下用醇(乙醇、异丙醇)沉淀。另外,可以使用的纯化程序的非限定性实例包括尺寸排阻色谱(Lukavsky,P.J.和Puglisi,J.D.,2004,Large-scale preparation and purification of polyacrylamide-free RNAoligonucleotides,RNA v.10,889-893)、硅基亲和色谱和聚丙烯酰胺凝胶电泳(Bowman,J.C.,Azizi,B.,Lenz,T.K.,Ray,P.和Williams,L.D.,RNA in vitro transcription andRNA purification by denaturing PAGE in Recombinant and in vitro RNA synthesesMethods v.941 Conn G.L.(编著),New York,N.Y.Humana Press,2012)。可以使用各种可商购的试剂盒来进行纯化,所述试剂盒包括,但不限于SV总分离系统(Promega)以及体外转录清洁和浓缩试剂盒(Norgen Biotek)。
此外,虽然逆转录可以产生大量的mRNA,但产物可以含有大量与不希望的聚合酶活性有关的异常RNA杂质,所述杂质可需要从全长的mRNA制备物中去除。这些包括由失败的转录起始导致的短RNA以及由RNA依赖的RNA聚合酶活性生成的双链RNA(dsRNA),来自RNA模板的RNA引发的转录和自补3’延长。已经证明这些具有dsRNA结构的污染物可以通过与真核细胞中的功能为识别特定核酸结构并引发强效免疫应答的各种先天免疫传感器相互作用来导致不希望的免疫刺激活性。这可以进而显著减少mRNA翻译,因为先天细胞免疫应答期间的蛋白质合成减少。因此,已研发并为本领域所知晓的用于去除这些dsRNA污染物的另外的技术包括但不限于可调比例的HPLC纯化(参见,例如Kariko,K.,Muramatsu,H.,Ludwig,J.和Weissman,D.,2011,Generating the optimal mRNA for therapy:HPLCpurification eliminates immune activation and improves translation ofnucleoside-modified,protein-encoding mRNA,Nucl Acid Res,v.39 el42;Weissman,D.,Pardi,N.,Muramatsu,H.和Kariko,K.,HPLC Purification of in vitro transcribedlong RNA in Synthetic Messenger RNA and Cell Metabolism Modulation in Methodsin Molecular Biology v.969(Rabinovich,P.H.编著),2013)。已报导经HPLC纯化的mRNA以高得多的水平翻译,特别是在原代细胞中和体内。
本领域中已描述了很多种用于改变体外转录的mRNA的特定性质,并且改善其效用的修饰。这些修饰包括,但不限于对mRNA的5’末端和3’末端的修饰。内源性真核mRNA通常含有在成熟(mature)分子的5’-端上的帽结构,其在介导mRNA帽结合蛋白质(CBP)的结合中发挥重要作用,其进而负责增强细胞中的mRNA稳定性和mRNA翻译效率。因此,用加帽的mRNA转录物实现蛋白质表达的最高水平。5’-帽含有5’-多数核苷酸与鸟嘌呤核苷酸之间的5’-5’-三磷酸连接。缀合的鸟嘌呤核苷酸在N7位置被甲基化。另外的修饰包括多数在2’-羟基上的最后的和倒数第二的5’-核苷酸的甲基化。
多个单独帽结构可以用于生成体外转录的合成的mRNA的5’-帽。合成的mRNA的5’-加帽可以用化学帽类似物与转录同时进行(即在体外转录过程中加帽)。例如,防逆转帽类似物(ARCA)帽含有5’-5’-三磷酸鸟嘌呤-鸟嘌呤连接,其中一个鸟嘌呤含有N7甲基以及3’-O-甲基。然而,多达20%的转录物在该共转录过程中保持未加帽,并且合成的帽类似物与真实细胞mRNA的5’-帽结构不相同,有可能降低可译性和细胞稳定性。或者,合成的mRNA分子也可以在转录后酶促地加帽。这可以生成更真实的5’-帽结构,其在结构上或功能上更接近地模拟内源性5’-帽,该内源性5’-帽具有增强的帽结合蛋白质的结合、增长的半衰期、降低的对5’内切酶的敏感性和/或减少的5’脱帽。已研发且本领域所熟知很多合成的5’-帽类似物以增强mRNA稳定性和可译性(参见,例如Grudzien-Nogalska,E.,Kowalska,J.,Su,W.,Kuhn,A.N.,Slepenkov,S.V.,Darynkiewicz,E.,Sahin,U.,Jemielity,J.和Rhoads,R.E.,Synthetic mRNAs with superior translation and stability properties inSynthetic Messenger RNA and Cell Metabolism Modulation in Methods inMolecular Biology v.969(Rabinovich,P.H.Ed),2013)。
在3’-末端,腺嘌呤核苷酸的长链(poly-A尾)通常在RNA加工期间加至mRNA分子。转录后,转录物的3’端立即断裂从而形成游离3’羟基,向该3’羟基,poly-A聚合酶在被称为聚腺苷酸化的过程中将腺嘌呤核苷酸链加至RNA。poly-A尾已广泛地表现出增强翻译效率和mRNA的稳定性(参见Bernstein,P.和Ross,J.,1989,Poly(A),poly(A)binding proteinand the regulation of mRNA stability,Trends Bio Sci v.14 373-377;Guhaniyogi,J.和Brewer,G.,2001,Regulation of mRNA stability in mammalian cells,Gene,v.265,11-23;Dreyfus,M.和Regnier,P.,2002,The poly(A)tail of mRNAs:Bodyguard ineukaryotes,scavenger in bacteria,Cell,v.lll,611-613)。
可以使用各种方法来实现体外转录的mRNA的Poly(A)加尾,所述方法包括,但不限于,将poly(T)片段克隆至DNA模板中,或者通过使用Poly(A)聚合酶在转录后添加。第一种情况允许体外转录具有限定长度(取决于poly(T)片段的尺寸)的poly(A)尾的mRNA,但需要对模板的另外操作。后一种情况涉及使用催化腺嘌呤残基在RNA的3’末端并入的poly(A)聚合酶,将poly(A)尾酶促添加至体外转录的mRNA,不需要对DNA模板的另外操作,但得到具有不同长度poly(A)尾的mRNA。可以使用各种可商购的试剂盒以及可商购的试剂、各种ARCA帽、Poly(A)聚合酶等来进行5’-加帽和3’-poly(A)加尾,所述试剂盒包括,但不限于Poly(A)聚合酶加尾试剂盒(EpiCenter)、mMESSAGE mMACHINE T7 Ultra试剂盒和Poly(A)加尾试剂盒(Life Technologies)。
除5’帽和3’聚腺苷酸化以外,也报导了对体外转录物的其他修饰以提供与翻译效率和稳定性有关的益处。本领域熟知,病原DNA和RNA可以通过各种真核细胞内的传感器识别,并引发强效先天免疫应答。已表现出,辨别致病DNA和RNA与自身DNA和RNA的能力至少部分基于结构修饰和核苷修饰,因为多数来自天然来源的核酸含有修饰的核苷。相反,体外合成的RNA缺少这些修饰,因此导致其为免疫刺激的,进而可以抑制上文概述的有效mRNA翻译。将修饰的核苷引入体外转录的mRNA可以用于阻止RNA传感器的识别和激活,由此缓和这种不希望的免疫刺激活性,并且增强翻译能力(translational capacity)(参见,例如Kariko,K.和Weissman,D.2007,Naturally occurring nucleoside modificationssuppress the immunostimulatory activity of RNA:implication for therapeuticRNA development,Curr Opin Drug Discov Devel,v.10 523-532;Pardi,N.,Muramatsu,H.,Weissman,D.,Kariko,K.,In vitro transcription of long RNA containingmodified nucleosides in Synthetic Messenger RNA and Cell MetabolismModulation,发表于Methods in Molecular Biology v.969(Rabinovich,P.H.编著),2013);Kariko,K.,Muramatsu,H.,Welsh,F.A.,Ludwig,J.,Kato,H.,Akira,S.,Weissman,D.,2008,Incorporation of Pseudouridine Into mRNA Yields SuperiorNonimmunogenic Vector With Increased Translational Capacity and BiologicalStability,Mol Ther v.16,1833-1840)。用于合成修饰的RNA的修饰的核苷和核苷酸可以使用本领域已知的一般方法和程序来制备、监控和使用。可使用很多种核苷修饰,其可以单独或结合其他修饰的核苷以一定程度并入体外转录的mRNA(参见,例如US2012/0251618)。已报导核苷修饰的mRNA的体外合成减小了激活免疫传感器的能力,伴随着增强了翻译能力。
可修饰以在可译性和稳定性方面提供益处的mRNA的其他组分包括5’和3’非翻译区(UTR)。针对两者的或单独的UTR优化(有利的5’和3’UTR可以得自细胞或病毒RNA)已显示出增强了体外转录的mRNA的mRNA稳定性和翻译效率(参见,例如Pardi,N.,Muramatsu,H.,Weissman,D.,Kariko,K.,In vitro transcription of long RNA containing modifiednucleosides in Synthetic Messenger RNA and Cell Metabolism Modulation inMethods in Molecular Biology v.969(Rabinovich,P.H.编著),2013)。
除mRNA以外,其他核酸净荷(payload)可以用于本发明。对于寡核苷酸,制备方法包括但不限于化学合成和较长前体的酶促、化学裂解、上文描述的体外转录等。合成DNA和RNA核苷酸的方法被广泛使用,并且为本领域所熟知(参见,例如,Gait,M.J.(编著)Oligonucleotide synthesis:a practical approach,Oxford[Oxfordshire],Washington,D.C.:IRL Press,1984;以及Herdewijn,P.(编著)Oligonucleotidesynthesis:methods and applications,Methods in Molecular Biology,v.288(Clifton,N.J.)Totowa,N.J.:Humana Press,2005;两者均通过引用并入本文)。
对于质粒DNA,用于本发明的制备通常使用但不限于,在含有相关的质粒的细菌的液体培养基中体外扩张和分离质粒DNA。相关的编码对特定抗生素(青霉素、卡那霉素等)的抗性的质粒内基因的存在允许那些含有相关质粒的细菌在含抗生素的培养基中选择性地生长。分离质粒DNA的方法被广泛使用,并且为本领域所熟知(参见,例如Heilig,J.,Elbing,K.L.和Brent,R(2001)Large-Scale Preparation of Plasmid DNA.CurrentProtocols in Molecular Biology.41:II:1.7:1.7.1-1.7.16;Rozkov,A.,Larsson,B.,S.,R.和Schmidt,S.R.(2008),Large-scale production ofendotoxin-free plasmids for transient expression in mammalian cellculture.Biotechnol.Bioeng.,99:557-566;以及US6197553B1)。可以使用各种可商购的试剂盒以及可商购的试剂来进行质粒分离,所述试剂盒包括,但不限于Plasmid Plus(Qiagen)、GenJET plasmid MaxiPrep(Thermo)和Pure Yield MaxiPrep(Promega)试剂盒。
本发明的阳离子脂质、脂质纳米颗粒和包含脂质纳米颗粒的组合物、以及它们递送诸如核酸的活性剂和治疗剂以调控基因和蛋白质表达的用途,以上的各种示例性实施方案在下文进一步详细地描述。
如本文所使用的,除非另外指明,以下术语具有它们被赋予的含义。
除非上下文另外需要,在本说明书和权利要求书中,词语“包含(comprise)”及其变形,如“包括”和“含有”,以开放且包括的含义解释,即,为“包括,但不限于”。
在本说明书中,提及“一个实施方案”或“实施方案”意指结合所述实施方案描述的特定特征、结构或特性包括在至少一个本发明的实施方案中。因此,在本说明中各处出现短语“在一个实施方案中”或“在实施方案中”不一定是全部指同一个实施方案。此外,所述特定特征、结构或特性可以以任何适合的方式与一个或多个实施方案结合。
除非另外定义,本文使用的所有技术和科技术语具有与本发明所属领域技术人员通常理解相同的含义。如本说明书和权利要求书所使用的,除非上下文另外明确指定,单数形式“一个”、“一种”和“所述”包括复数引用。
短语“引发所需蛋白质的表达”指核酸增加所需蛋白质表达的能力。为检验蛋白质表达的程度,使测试样品(例如,表达所需蛋白质的培养基中的细胞样品)或测试哺乳动物(例如,诸如人的哺乳动物或者诸如啮齿动物(例如,小鼠)或非人灵长类动物(例如,猴)模型的动物模型)接触核酸(例如,结合本发明脂质的核酸)。将测试样品或测试动物中的所需蛋白质的表达与未接触或未施用核酸的对照样品(例如,表达所需蛋白质的培养基中的细胞样品)或对照哺乳动物(例如,诸如人的哺乳动物或者诸如啮齿动物(例如,小鼠)或非人灵长类动物(例如,猴)模型的动物模型)中的所需蛋白质的表达相比较。当在对照样品或对照哺乳动物中存在所需蛋白质时,对照样品或对照哺乳动物中所需蛋白质的表达可以指定为1.0的值。在特定的实施方案中,当测试样品或测试哺乳动物中的所需蛋白质表达与对照样品或对照哺乳动物中的所需蛋白质表达水平的比例大于1时,例如,约1.1、1.5、2.0、5.0或10.0时,实现了引发所需蛋白质的表达。当对照样品或对照哺乳动物中不存在所需蛋白质时,当在测试样品或测试哺乳动物中检测到任何可测水平的所需蛋白质时,实现了引发所需蛋白质的表达。本领域的普通技术人员将理解,确定样品中蛋白质表达水平的适合的测定例如,斑点印迹、northern印迹、原位杂交、ELISA、免疫沉淀、酶作用和表型测定,或者基于在适当条件下可以产生荧光或发光的报告蛋白的测定。
短语“抑制靶基因的表达”指核酸沉默、减少或抑制靶基因表达的能力。为检验基因沉默的程度,使测试样品(例如,表达靶基因的培养基中的细胞样品)或测试哺乳动物(例如,诸如人的哺乳动物或者诸如啮齿动物(例如,小鼠)或非人灵长类动物(例如,猴)模型的动物模型)接触沉默、减少或抑制靶基因表达的核酸。将测试样品或测试动物中的靶基因的表达与未接触或未施用核酸的对照样品(例如,表达靶基因的培养基中的细胞样品)或对照哺乳动物(例如,诸如人的哺乳动物或者诸如啮齿动物(例如,小鼠)或非人灵长类动物(例如,猴)模型的动物模型)中的靶基因的表达相比较。对照样品或对照哺乳动物中的靶基因的表达可以指定为100%的值。在特定的实施方案中,当测试样品或测试哺乳动物中的靶基因表达水平相对于对照样品或对照哺乳动物中的靶基因表达水平为约95%、90%、85%、80%、75%、70%、65%、60%、55%、50%、45%、40%、35%、30%、25%、20%、15%、10%、5%或0%时,实现了沉默、抑制或减少靶基因的表达。换言之,相对于未接触或未施用核酸的对照样品或对照哺乳动物中的靶基因表达水平,在测试样品或测试哺乳动物中,所述核酸能够沉默、减少或抑制靶基因表达的至少约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或100%。确定靶基因表达水平的适合的测定包括,但不限于,使用本领域技术人员已知的技术进行的蛋白质或mRNA水平的检验,所述技术例如,本领域技术人员已知的斑点印迹、northern印迹、原位杂交、ELISA、免疫沉淀、酶作用以及表型测定。
活性剂或治疗剂(例如治疗性核酸)的“有效量”或“治疗有效量”是足以产生所需效果的量,所述所需效果例如,相比不存在核酸时检测的靶序列的正常表达水平,对靶序列表达的增加或抑制。当检测到任何可测水平的在不存在核酸时不存在的表达产物时,实现了靶序列表达的增加。在与核酸接触前,表达产物以一定水平存在的情况下,当使用诸如mRNA的核酸得到的值的提高倍数相对于对照为约1.05、1.1、1.2、1.3、1.4、1.5、1.75、2、2.5、3、4、5、6、7、8、9、10、15、20、25、30、40、50、75、100、250、500、750、1000、5000、10000或更大时,实现了表达增加。当使用诸如反义寡核苷酸的核酸得到的值相对于对照为约95%、90%、85%、80%、75%、70%、65%、60%、55%、50%、45%、40%、35%、30%、25%、20%、15%、10%、5%或0%时,实现了靶基因或靶序列表达的抑制。测量靶基因或靶序列表达的适合的测定包括,例如,使用本领域技术人员已知的技术进行的蛋白质或RNA水平的检验,所述技术例如本领域技术人员已知的斑点印迹、northern印迹、原位杂交、ELISA、免疫沉淀、酶作用、适合的报告蛋白的荧光或发光以及表型测定。
如本文所使用的,术语“核酸”指含有至少两个单链或双链形式的脱氧核糖核苷酸或核糖核苷酸的聚合物,并且包括DNA、RNA及其杂合体。DNA可以是以下形式:反义分子、质粒DNA、cDNA、PCR产物或载体。RNA可以是以下形式:小发夹RNA(shRNA)、信使RNA(mRNA)、反义RNA、miRNA、micRNA、多价RNA、dicer底物RNA或病毒RNA(vRNA),及其组合。核酸包括含有已知核苷酸类似物或修饰的骨架残基或连接的核酸,所述核苷酸类似物或修饰的骨架残基或连接是合成的、天然存在的和非天然存在的,并且具有与参考核酸(reference nucleicacid)类似的结合性质。这类类似物的实例包括,但不限于,硫代磷酸酯、氨基磷酸酯、甲基磷酸酯、手性-甲基磷酸酯、2’-O-甲基核糖核苷酸以及肽-核酸(PNA)。除非特别限定,该术语涵盖包含已知的具有与参考核酸类似的结合性质的天然核苷酸的类似物的核酸。除非另外表明,特定核酸序列也隐含地涵盖其保守修饰的变体(例如,简并密码子取代)、等位基因、直系同源物、单核苷酸多态性、和互补序列以及明确表明的序列。特别地,可以通过生成一个或多个所选(或全部)密码子的三位被混合碱基和/或脱氧肌苷残基取代的序列来实现简并密码子取代(Batzer等人,Nucleic Acid Res.,19:5081(1991);Ohtsuka等人,J.Biol.Chem.,260:2605-2608(1985);Rossolini等人,Mol.Cell.Probes,8:91-98(1994))。“核苷酸”含有糖(脱氧核糖(DNA)或核糖(RNA))、碱基和磷酸基团。核苷酸通过磷酸基团连接在一起。“碱基”包括嘌呤和嘧啶,其进一步包括天然化合物腺嘌呤、胸腺嘧啶、鸟嘌呤、胞嘧啶、尿嘧啶、肌苷和天然类似物,以及嘌呤和嘧啶的合成衍生物,其包括但不限于,配置新反应基团的修饰,所述新反应基团例如,但不限于,胺、醇、硫醇、羧化物和烃基卤化物。
术语“基因”指包含产生多肽或前体多肽所必须的部分长度或全长的编码序列的核酸(例如,DNA或RNA)序列。
如本文所使用的,“基因产物”指诸如RNA转录物或多肽的基因产物。
术语“脂质”指一组有机化合物,其包括但不限于脂肪酸的酯,并且特征通常为在水中具有差的溶解性,但在很多种有机溶剂中可溶。它们通常分为至少三类:(1)“简单脂质”,其包括脂肪和油以及蜡;(2)“化合物脂质”,其包括磷脂和糖脂;以及(3)“衍生脂质”,例如甾族化合物。
“甾族化合物”为包含以下碳骨架的化合物:
甾族化合物的非限定性实例包括胆甾醇等。
“阳离子脂质”指能够带正电的脂质。示例性的阳离子脂质包括一种或多种带有正电荷的胺基团。优选的阳离子脂质是可电离的,以便它们可以根据pH值以带正电的形式或中性形式存在。阳离子脂质的电离影响脂质纳米颗粒在不同pH条件下的表面电荷。这种电荷状态可以影响血浆蛋白质吸收、血液清除和组织分布(Semple,S.C.等人,Adv.DrugDeliv Rev 32:3-17(1998))以及形成核内体溶解(endosomolytic)非双层结构的能力(Hafez,I.M.等人,Gene Ther 8:1188-1196(2001)),对于核酸的细胞内递送是至关重要的。
术语“脂质纳米颗粒”指在纳米量级上具有至少一个维度(例如,1nm至1,000nm),包含一种或多种式(I)的化合物或其他特定阳离子脂质的颗粒。在一些实施方案中,脂质纳米颗粒包含在可用于将诸如核酸(例如,mRNA)的活性剂或治疗剂递送至相关的靶位点(例如,细胞、组织、器官、肿瘤等)的制剂中。在一些实施方案中,本发明的脂质纳米颗粒包含核酸。这类脂质纳米颗粒通常包含式(I)的化合物以及一种或多种选自中性脂质、带电脂质、甾族化合物和聚合物缀合的脂质的赋形剂。在一些实施方案中,诸如核酸的活性剂或治疗剂可以封装于脂质纳米颗粒的脂质部分中,或者封装于由脂质纳米颗粒的一些或全部脂质部分包裹的水性空间中,从而保护保护其不被酶促降解,或者不受到由宿主生物体或细胞的机制引发的其他的不希望的作用,例如不良的免疫应答。
在各种实施方案中,脂质纳米颗粒具有以下的平均直径:约30nm至约150nm、约40nm至约150nm、约50nm至约150nm、约60nm至约130nm、约70nm至约110nm、约70nm至约100nm、约80nm至约100nm、约90nm至约100nm、约70至约90nm、约80nm至约90nm、约70nm至约80nm、或者约30nm、35nm、40nm、45nm、50nm、55nm、60nm、65nm、70nm、75nm、80nm、85nm、90nm、95nm、100nm、105nm、110nm、115nm、120nm、125nm、130nm、135nm、140nm、145nm或150nm,并且是基本无毒的。在某些实施方案中,核酸当存在于脂质纳米颗粒时,其在水溶液中抵抗被核酸酶降解。在例如,美国专利公开第2004/0142025、2007/0042031号和PCT公开第WO 2013/016058和WO 2013/086373号中公开了包含核酸的脂质纳米颗粒及其制备方法,其全部公开内容为了所有目的通过引用整体并入本文。
如本文所使用的,“封装的脂质”指提供完全封装、部分封装、或其两种封装的诸如核酸(例如,mRNA)的活性剂或治疗剂的脂质纳米颗粒。在一个实施方案中,核酸(例如,mRNA)完全封装于脂质纳米颗粒中。
术语“聚合物缀合的脂质”指包含脂质部分和聚合物部分的分子。聚合物缀合的脂质的实例为聚乙二醇化的脂质。术语“聚乙二醇化的脂质”指包含脂质部分和聚乙二醇部分的分子。聚乙二醇化的脂质是本领域已知的,并且包括l-(单甲氧基-聚乙二醇)-2,3-二肉豆蔻酰甘油(PEG-DMG)等。
术语“中性脂质”指在所选pH值下以不带电形式或中性两性离子形式存在的多种脂质物质中的任一种。在生理pH下,这类脂质包括但不限于,磷脂酰胆碱,如l,2-二硬脂酰基-sn-甘油基-3-磷酸胆碱(DSPC)、l,2-二棕榈酰基-sn-甘油基-3-磷酸胆碱(DPPC)、l,2-二肉豆蔻酰基-sn-甘油基-3-磷酸胆碱(DMPC)、1-棕榈酰基-2-油酰基-sn-甘油基-3-磷酸胆碱(POPC)、1,2-二油酰基-sn-甘油基-3-磷酸胆碱(DOPC);磷脂酰乙醇胺,如l,2-二油酰基-sn-甘油基-3-磷酸乙醇胺(DOPE)、鞘磷脂(SM)、神经酰胺;甾族化合物,如甾醇类及其衍生物。中性脂质可以是合成的或天然衍生的。
术语“带电的脂质”指不受有用的生理范围内的pH值(例如pH~3至pH~9)约束,以带正电或带负电的形式存在的多种脂质物质中的任一种。带电的脂质可以是合成的或天然衍生的。带电的脂质的实例包括磷脂酰丝氨酸、磷脂酸、磷脂酰甘油、磷脂酰肌醇、甾醇半琥珀酸酯、二烃基三甲基铵丙烷(例如DOTAP、DOTMA)、二烃基二甲基氨基丙烷、乙基磷酸胆碱、二甲基氨基乙烷氨基甲酰基甾醇(例如DC-Choi)。
如本文所使用的,术语“水溶液”指包含水的组合物。
就核酸-脂质纳米颗粒而言,“血清稳定的”意指核苷酸在暴露于血清后或在暴露于会显著降解游离DNA或RNA的核酸酶测定后,不会显著降解。适合的测定包括,例如,标准的血清测定、DNA酶测定或RNA酶测定。
如本文所使用的,“全身性递送”指可以导致活性剂在生物体内广泛暴露的治疗性产物的递送。一些施用技术可以导致某些试剂的全身性递送,但不会全身性递送其他试剂。全身性递送意味着有用量的,优选治疗量的试剂暴露于身体的多数部位。脂质纳米颗粒的全身性递送可以通过本领域已知的任何方式进行,包括,例如,静脉内、动脉内、皮下和腹膜内递送。在一些实施方案中,脂质纳米颗粒的全身性递送通过静脉内递送。
如本文所使用的,“局部递送”指将活性剂直接递送至生物体内的靶位点。例如,可以通过在诸如肿瘤的疾病位点,诸如炎症位点的其他靶位点,或诸如肝、心、胰腺、肾等靶器官中直接注射来局部递送试剂。局部递送也可以包括局部应用或局部注射技术,例如肌内、皮下或皮内注射。局部递送不妨碍全身性的药理学作用。
“烃基”指仅由碳原子和氢原子组成的直链或支链的烃链自由基,其为饱和的或不饱和的(即,含有一个或多个双键和/或三键),含有1至24个碳原子(C1-C24烃基)、1至12个碳原子(C1-C12烃基)、1至8个碳原子(C1-C8烃基)或1至6个碳原子(C1-C6烃基),并且其与分子的剩余部分通过单键连接,例如,甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基、1,1-二甲基乙基(叔丁基)、3-甲基己基、2-甲基己基、乙烯基、丙-1-烯基、丁-1-烯基、戊-1-烯基、戊-1,4-二烯基、乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。除非在本说明书中另外明确示出,烃基是任选取代的。
“环烃基”或“碳环”指仅有碳原子和氢原子组成的稳定的非芳香单环或多环烃自由基,其可以包括稠合或桥接的环系统,含有3至15个碳原子,优选含有3至10个碳原子,并且其为饱和的或不饱和的,并且通过单键与分子的剩余部分连接。单环自由基包括,例如,环丙基、环丁基、环戊基、环己基、环庚基和环辛基。多环自由基包括,例如,金刚烷基、降冰片基、十氢化萘基、7,7-二甲基-双环[2.2.1]庚基等。除非在本说明书中另外明确示出,环烃基是任选取代的。
“杂环基”或“杂环”指2至12个碳原子和1至6个选自氮、氧和硫的杂原子组成的稳定的3元至18元非芳香环自由基。除非在本说明书中另外明确示出,杂环基自由基可以是单环、双环、三环或四环的环系统,这些环系统可以包括稠合或桥接的环系统;并且所述杂环基自由基中的氮、碳或硫原子可以任选地被氧化;所述氮原子可以任选地季铵化;并且所述杂环基自由基可以是部分或完全饱和的。这类杂环基自由基的实例包括,但不限于,二氧戊环基、噻吩基[1,3]二噻烷基、十氢异喹啉基、咪唑啉基、咪唑烷基、异噻唑烷基、异噁唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、噁唑烷基、哌啶基、哌嗪基、4-哌啶酮基、吡咯烷基、吡唑烷基、奎宁环基、噻唑烷基、四氢呋喃基、三噻烷基、四氢吡喃基、硫代吗啉基(thiomorpholinyl)、硫吗啉基(thiamorpholinyl)、1-氧代-硫代吗啉基和1,1-二氧代-硫代吗啉基。除非在本说明书中另外明确示出,杂环基可以任选地取代。
本文使用的术语“取代的”意指任何上述基团(例如,烃基、环烃基或杂环基)其中至少一个氢原子被与非氢原子连接的键取代,该非氢原子例如,但不限于:诸如F、Cl、Br和I的卤素原子;氧代基团(=O);羟基(-OH);烃氧基(-ORa,其中Ra为C1-C12烃基或环烃基);羧基(-OC(=O)Ra或-C(=O)ORa,其中Ra为H、C1-C12烃基或环烃基);胺基团(-NRaRb,其中Ra和Rb各自独立地为H、C1-C12烃基或环烃基);C1-C12烃基;和环烃基。在一些实施方案中,所述取代基为C1-C12烃基。在其他实施方案中,所述取代基为环烃基。在其他实施方案中,所述取代基为卤代基团,例如氟代。在其他实施方案中,所述取代基为氧代基团。在其他实施方案中,所述取代基为羟基。在其他实施方案中,所述取代基为烃氧基。在其他实施方案中,所述取代基为羧基。在其他实施方案中,所述取代基为胺基团。
“任选的”或“任选地”(例如,任选取代的)意味着其后描述的情况事件可发生也可不发生,并且该描述包括所述事件或情况发生的实例以及所述事件或情况不发生的实例。例如,“任选取代的烃基”意味着所述烃基自由基可以被取代也可以不被取代,并且该描述包括取代的烃基自由基和不含取代的烃基自由基。
“前药”意在表明在生理条件下或通过溶剂解可以转化为本发明的生物活性化合物的化合物。因此,术语“前药”指药物可接受的本发明化合物的代谢前体。前药在对有此需要的对象施用时可以是惰性的,但在体内转化为本发明的活性化合物。前药通常在体内快速转化得到本发明的母体化合物,例如,通过在血液中水解。所述前药化合物通常提供在哺乳动物生物体内的溶解性、组织相容性或延迟释放的优点(参见,Bundgard,H.,Design ofProdrugs(1985),7-9,21-24页(Elsevier,阿姆斯特丹))。在Higuchi,T.等人,A.C.S.Symposium Series,第14卷,以及Bioreversible Carriers in Drug Design,编著Edward B.Roche,American Pharmaceutical Association和Pergamon Press,1987中提供了对前药的讨论。
术语“前药”还意在包括任何共价键合的载体,当这类前药对哺乳动物对象施用时,所述载体在体内释放本发明的活性化合物。本发明化合物的前药可以通过修饰本发明化合物中存在的官能团来制备,通过这种方式,所述修饰通过常规操作或在体内裂解成为本发明的母体化合物。前药包括以下本发明化合物:其中羟基、氨基或巯基与任何基团键合,当本发明化合物的前药对哺乳动物对象施用时,裂解分别形成游离羟基、游离氨基或游离巯基。前药的实例包括,但不限于,本发明化合物中胺官能团的醇或酰胺衍生物的乙酸酯、甲酸酯和苯甲酸酯衍生物等。
本文公开的本发明还意在涵盖所有通过将一个或多个原子取代成为具有不同原子量或质量数的原子而被同位素标记的式(I)或式(II)化合物的药物可接受的化合物。可并入所公开化合物的同位素的实例包括氢、碳、氮、氧、磷、氟、氯和碘的同位素,分别例如2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、36Cl、123I和125I。这些放射性标记的化合物可以有用于:通过表征,例如,作用的位点或方式,或与药理学重要的作用位点的结合亲和力来帮助确定或测量化合物的效果。某些同位素标记的结构(I)或(II)的化合物,例如,那些并入放射性同位素的结构(I)或(II)的化合物,在药物和/或底物组织分布研究中是有用的。放射性同位素氚(即,3H)和碳-14(即,14C),由于它们易于并入并且有现有的检测手段,对于这一目的是特别有用的。
用诸如氘(即,2H)的更重的同位素取代,可以提供归因于更强的代谢稳定性的某些治疗优点,例如,增长的体内半衰期或减少的剂量需要量,并且因此在一些情况下可以是优选的。
用正电子发射同位素(例如11C、18F、15O和13N)取代,在用于检验底物受体占有率的正电子发射断层扫描(PET)研究中可以是有用的。通常可以通过本领域技术人员已知的常规技术,或者通过与下文阐述的制备和实施例中所描述类似的方法,使用适当的同位素标记的试剂代替先前使用的未标记的试剂来制备同位素标记的结构(I)或(II)的化合物。
本文公开的本发明还意在涵盖所公开化合物的体内代谢产物。这类产物可以得自,例如,所施用化合物的,主要由于酶促过程的氧化、还原、水解、酰胺化、酯化等。因此,本发明包括由以下方法所产生的化合物:将本发明的化合物对哺乳动物施用足以产生其代谢产物的时间。这类产物通常通过以下方式来确认:将放射性标记的本发明化合物以可测剂量对诸如大鼠、小鼠、豚鼠、猴的动物施用,或者对人施用,持续足够的时间以允许代谢发生,并将其转化产物从尿、血液或其他生物样品分离。
“稳定的化合物”和“稳定的结构”意在表明足够稳定以便在从反应混合物分离至有用纯度以及在配制成为有效治疗剂的过程中得以保留的化合物。
“哺乳动物”包括人;还包括家养动物,例如实验动物和家庭宠物(例如,猫、狗、猪、牛、绵羊、山羊、马、兔);以及非家养动物,例如野生动物等。
“药物可接受的载体、稀释剂或赋形剂”包括但不限于:经美国食品药品管理局批准,用于人或家养动物可接受的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染色/着色剂、增味剂、表面活性剂、润湿剂、分散剂、悬浮剂、稳定剂、等渗剂、溶剂或乳化剂。
“药物可接受的盐”包括酸加成盐和碱加成盐。
“药物可接受的酸加成盐”指保留游离碱的生物效果和性质,不是生物上或其他方面不良的,并且与以下无机酸和有机酸形成的那些盐,所述无机酸例如,但不限于盐酸、氢溴酸、硫酸、硝酸、磷酸等,而所述有机酸例如,但不限于乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基乙磺酸、甲酸、富马酸、半乳糖二酸、龙胆酸、葡庚糖酸、葡糖酸、葡糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、乙醇酸、马尿酸、异丁酸、乳酸、乳糖酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、粘酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、琥珀酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、十一碳烯酸等。
“药物可接受的碱加成盐”指保留游离酸的非生物上或其他方面不良的生物效果和性质的那些盐。这些盐通过无机碱或有机碱与游离酸的加成来制备。来源于无机碱的盐包括,但不限于,钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐和镁盐。来源于有机碱的盐包括,但不限于,下列伯胺、仲胺和叔胺,取代的胺(包括天然存在的取代的胺)、环状胺和碱性离子交换树脂的盐:例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、丹醇、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己基胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明(hydrabamine)、胆碱、甜菜碱、苯乙苄胺(benethamine)、苄星青霉素(benzathine)、乙二胺、葡糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。特别优选的有机碱为异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱和咖啡因。
结晶通常产生本发明化合物的溶剂化物。如本文所使用的,术语“溶剂化物”指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集物。所述溶剂可以是水,在这种情况下所述溶剂化物可以是水合物。或者,所述溶剂可以是有机溶剂。因此,本发明的化合物可以以水合物存在,包括一水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等,以及以相应的溶剂化形式存在。本发明的化合物可以是真正的溶剂化物,而在其他情况下,本发明的化合物可以仅保留偶生的(adventitious)水,或者是水加上偶生溶剂的混合物。
“药物组合物”指本发明化合物与本领域通常公认用于向哺乳动物(例如,人)递送生物活性化合物的介质的制剂。因此这类介质包括所有药物可接受的载体、稀释剂或赋形剂。
“有效量”或“治疗有效量”指当对哺乳动物(优选为人)施用时,足以产生对哺乳动物(优选为人)的治疗的本发明化合物的量。构成“治疗有效量”的本发明脂质纳米颗粒的量将取决于化合物、病况及其严重性、施用方式以及待治疗哺乳动物的年龄,但可以由本领域的普通技术人员依据其自身的知识和本公开内容来常规确定。
本文使用的“治疗(Treating)”或“治疗(treatment)”涵盖针对患有相关的疾病或病况的哺乳动物(优选为人)的所述相关的疾病或病况的治疗,并且包括:
(i)预防疾病或病况在哺乳动物中出现,尤其是,当这些哺乳动物倾向患有所述病况,但尚未被诊断为患有所述病况时;
(ii)抑制所述疾病或病况,即,控制其发展;
(iii)减轻所述疾病或病况,即,使所述疾病或病况消退;或者
(iv)减轻由所述疾病或病况导致的症状,即,在不解决根本疾病或病况的情况下减轻疼痛。如本文所使用的,术语“疾病”和“病况”可以交换使用,或者可以是不同的,因为特定的疾病或病况可能没有已知的病原体(因此尚未找出病因),因此尚未被认为是疾病,而仅作为不希望的病况或综合征,其中临床医生已经在一定程度上鉴定了特定组的症状。
本发明的化合物或其药物可接受的盐可以含有一个或多个不对称中心,并且可以由此产生对映异构体、非对映异构体和其他立体异构形式,对于氨基酸,其可以根据绝对立体化学定义为(R)-或(S)-,或者定义为(D)-或(L)-。本发明意在包括所有这些可能的异构体,以及其外消旋形式和光学纯的形式。光学活性的(+)和(-)、(R)-和(S)-、或(D)-和(L)-异构体可以使用手性合成子或手性试剂来制备,或者使用常规技术,例如色谱法和分级结晶来拆分。用于制备/分离单一对映异构体的常规技术包括由适合的光学纯前体手性合成,或者使用,例如,手性高压液相层析法(HPLC)的外消旋体(或盐或衍生物的外消旋体)的拆分。当本文描述的化合物含有烯族双键或其他几何不对称中心时,除非另外指定,意指该化合物包括E型和Z型几何异构体。同样地,也意在包括所有的互变异构形式。
“立体异构体”指由相同的键连接的相同原子组成,但具有不同三维结构的化合物,其不可互变。本发明涵盖各种立体异构体及其混合物,并且包括“对映异构体”,所述对映异构体指分子互为不可重叠的(nonsuperimposeable)镜像的两个立体异构体。
“互变异构体”指质子从分子的一个原子转移至同一分子的另一个原子。本发明包括任何所述化合物的互变异构体。
化合物
一方面,本发明提供新型脂质化合物,其能够与其他脂质组分(例如中性脂质、带电脂质、甾族化合物和/或聚合物缀合的脂质)结合形成具有寡核苷酸的脂质纳米颗粒。不希望受理论束缚,认为这些脂质纳米颗粒保护寡核苷酸不在血清中降解,并且在体外和体内提供对细胞的寡核苷酸有效递送。
在一个实施方案中,脂质化合物具有式(I)的结构:
或其药物可接受的盐、互变异构体、前药或立体异构体,其中:
L1和L2各自独立地为–O(C=O)-、-(C=O)O-或碳-碳双键;
R1a和R1b在每次出现时独立地(a)为H或C1-C12烃基,或(b)R1a为H或C1-C12烃基,并且R1b连同其连接的碳原子与相邻的R1b连同其连接的碳原子一起以形成碳-碳双键;
R2a和R2b在每次出现时独立地(a)为H或C1-C12烃基,或(b)R2a为H或C1-C12烃基,并且R2b连同其连接的碳原子结合相邻的R2b及其连接的碳原子,以形成碳-碳双键;
R3a和R3b在每次出现时独立地为(a)H或C1-C12烃基,或(b)R3a为H或C1-C12烃基,并且R3b连同其连接的碳原子结合相邻的R3b及其连接的碳原子,以形成碳-碳双键;
R4a和R4b在每次出现时独立地(a)为H或C1-C12烃基,或(b)R4a为H或C1-C12烃基,并且R4b连同其连接的碳原子结合相邻的R4b及其连接的碳原子,以形成碳-碳双键;
R5和R6各自独立地为甲基或环烃基;
R7在每次出现时独立地为H或C1-C12烃基;
R8和R9各自独立地为未取代的C1-C12烃基;或者R8和R9,连同其连接的氮原子,一起形成包含一个氮原子的5元、6元或7元杂环;
a和d各自独立地为0至24的整数;
b和c各自独立地为1至24的整数;并且
e为1或2。
在某些式(I)化合物的实施方案中,R1a、R2a、R3a或R4a中的至少一个为C1-C12烃基,或者L1或L2中的至少一个为–O(C=O)-或–(C=O)O-。在其他实施方案中,R1a和R1b当a为6时不为异丙基,或当a为8时不为正丁基。
在其他实施方案中,R1a、R2a、R3a或R4a中的至少一个为C1-C12烃基,或者L1或L2中的至少一个为–O(C=O)-或–(C=O)O-;并且
R1a和R1b当a为6时不为异丙基,或当a为8时不为正丁基。
在式I的化合物中,L1或L2中的任一个可以为-O(C=O)-或碳-碳双键。L1和L2可以各自为-O(C=O)-,或者可以各自为碳-碳双键。
在一些实施方案中,L1或L2之一为-O(C=O)-。在其他实施方案中,L1和L2均为-O(C=O)-。
在一些实施方案中,L1或L2之一为-(C=O)O-。在其他实施方案中,L1和L2均为-(C=O)O-。
在一些实施方案中,L1或L2之一为碳-碳双键。在其他实施方案中,L1和L2均为碳-碳双键。
在其他实施方案中,L1或L2之一为-O(C=O)-,并且L1或L2中的另一个为-(C=O)O-。在更多的实施方案中,L1或L2之一为-O(C=O)-,并且L1或L2中的另一个为碳-碳双键。在更多的实施方案中,L1或L2之一为-(C=O)O-,并且L1或L2中的另一个为碳-碳双键。
应理解“碳-碳”双键指以下结构之一:
其中Ra和Rb在每次出现时独立地为H或取代基。例如,在一些实施方案中,Ra和Rb在每次出现时独立地为H、C1-C12烃基或环烃基,例如H或C1-C12烃基。
在其他实施方案中,脂质化合物具有以下结构(Ia):
在其他实施方案中,脂质化合物具有以下结构(Ib):
在其他实施方案中,脂质化合物具有以下结构(Ic):
在某些前述实施方案中,a、b、c和d各自独立地为2至12的整数或4至12的整数。在其他实施方案中,a、b、c和d各自独立地为8至12的整数或5至9的整数。在某一些实施方案中,a为0。在一些实施方案中,a为1。在其他实施方案中,a为2。在更多的实施方案中,a为3。在其他实施方案中,a为4。在一些实施方案中,a为5。在其他实施方案中,a为6。在更多的实施方案中,a为7。在其他实施方案中,a为8。在一些实施方案中,a为9。在其他实施方案中,a为10。在更多的实施方案中,a为11。在其他实施方案中,a为12。在一些实施方案中,a为13。在其他实施方案中,a为14。在更多的实施方案中,a为15。在其他实施方案中,a为16。
在一些实施方案中,b为1。在其他实施方案中,b为2。在更多的实施方案中,b为3。在其他实施方案中,b为4。在一些实施方案中,b为5。在其他实施方案中,b为6。在更多的实施方案中,b为7。在其他实施方案中,b为8。在一些实施方案中,b为9。在其他实施方案中,b为10。在更多的实施方案中,b为11。在其他实施方案中,b为12。在一些实施方案中,b为13。在其他实施方案中,b为14。在更多的实施方案中,b为15。在其他实施方案中,b为16。
在一些实施方案中,c为1。在其他实施方案中,c为2。在更多的实施方案中,c为3。在其他实施方案中,c为4。在一些实施方案中,c为5。在其他实施方案中,c为6。在更多的实施方案中,c为7。在其他实施方案中,c为8。在一些实施方案中,c为9。在其他实施方案中,c为10。在更多的实施方案中,c为11。在其他实施方案中,c为12。在一些实施方案中,c为13。在其他实施方案中,c为14。在更多的实施方案中,c为15。在其他实施方案中,c为16。
在某一些实施方案中,d为0。在一些实施方案中,d为1。在其他实施方案中,d为2。在更多的实施方案中,d为3。在其他实施方案中,d为4。在一些实施方案中,d为5。在其他实施方案中,d为6。在更多的实施方案中,d为7。在其他实施方案中,d为8。在一些实施方案中,d为9。在其他实施方案中,d为10。在更多的实施方案中,d为11。在其他实施方案中,d为12。在一些实施方案中,d为13。在其他实施方案中,d为14。在更多的实施方案中,d为15。在其他实施方案中,d为16。
在一些其他不同实施方案中,a和d相同。在一些其他实施方案中,b和c相同。在一些其他特定实施方案中,a和d相同,并且b和c相同。
a和b的总和以及c和d的总和是可变因素,以获得具有所需性质的脂质。在一个实施方案中,选择a和b使得它们的总和为14至24的整数。在其他实施方案中,选择c和d使得它们的总数为14至24的整数。在其他实施方案中,a和b的总数与c和d的总数相同。例如,在一些实施方案中,a和b的总数与c和d的总数是相同的,其可为从14至24的整数。在更多的实施方案中,选择a、b、c和d使得a和b的总数以及c和d的总数为12或更大。
在一些实施方案中,e为1。在其他实施方案中,e为2。
R1a、R2a、R3a和R4a处的取代基未做特别限定。在某些实施方案中,R1a、R2a、R3a和R4a在每次出现时为H。在某些其他实施方案中,R1a、R2a、R3a和R4a中的至少一个为C1-C12烃基。在某些其他实施方案中,R1a、R2a、R3a和R4a中的至少一个为C1-C8烃基。在某些其他实施方案中,R1a、R2a、R3a和R4a中的至少一个为C1-C6烃基。在一些前述实施方案中,所述C1-C8烃基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正己基或正辛基。
在某些前述实施方案中,R1a、R1b、R4a和R4b在每次出现时为C1-C12烃基。
在其他前述实施方案中,R1b、R2b、R3b和R4b中的至少一个为H,或者R1b、R2b、R3b和R4b在每次出现时为H。
在某些前述实施方案中,R1b连同其连接的碳原子结合相邻的R1b及其连接的碳原子,以形成碳-碳双键。在其他前述实施方案中,R4b连同其连接的碳原子结合相邻的R4b及其连接的碳原子,以形成碳-碳双键。
在前述实施方案中,R5和R6处的取代基未做特别限定。在某些实施方案中,R5或R6之一或两者为甲基。在某些其他实施方案中,R5或R6之一或两者为环烃基,例如环己基。在这些实施方案中,所述环烃基可以是取代的或未取代的。在某些其他实施方案中,所述环烃基被C1-C12烃基(例如叔丁基)取代。
在前述实施方案中,R7处的取代基未做特别限定。在某些实施方案中,至少一个R7为H。在一些其他实施方案中,R7在每次出现时为H。在某些其他实施方案中,R7为C1-C12烃基。
在某些其他的前述实施方案中,R8或R9之一为甲基。在其他实施方案中,R8和R9均为甲基。
在一些不同的实施方案中,R8和R9,连同其连接的氮原子,形成5元、6元或7元杂环。在一些前述实施方案中,R8和R9,连同其连接的氮原子,形成5元杂环,例如吡咯烷基环。
在各种不同的实施方案中,所述化合物具有以下表1中所示的结构之一。
表1
代表性化合物
应理解,如上文所述的式(I)化合物的任何实施方案,以及如上文所述的化合物式(I)中的任何特定取代基和/或变量,可以独立地与式(I)化合物的其他实施方案和/或取代基和/或变量结合,以形成上文未明确阐述的本发明的实施方案。另外,在对于特定实施方案和/或权利要求中的任何特定R基团、L基团或变量a-e列举出取代基和/或变量的情况下,应理解,各个单独的取代基和/或变量可以从所述特定实施方案和/或权利要求中删除,并且剩余的取代基和/或变量的列举将会被认为在本发明的范围内。
应理解,在本说明书中,所述式的取代基和/或变量的组合仅在这些贡献得到稳定化合物时才是允许的。
在各种实施方案中,应理解,以下化合物不包括在本发明的范围内:
其中各个Rc和Rd为H,或者Rc和Rd结合形成氧代,并且x和y各自独立地为0至6的整数。
在各种实施方案中还提供了聚乙二醇化的脂质。例如在一个实施方案中,所述聚乙二醇化的脂质具有以下结构(II):
或其药物可接受的盐、互变异构体或立体异构体,其中:
R10和R11各自独立地为含有10至30个碳原子的直链或支链、饱和或不饱和的烃基链,其中所述烃基链任选地被一个或多个酯键中断;并且
z具有30至60的平均值。
在前述一些聚乙二醇化的脂质(II)的实施方案中,当z为42时R10和R11不均为正十八烷基。在一些实施方案中,R10和R11各自独立地为含有10至18个碳原子的直链或支链、饱和或不饱和的烃基链。在一些实施方案中,R10和R11各自独立地为含有12至16个碳原子的直链或支链、饱和或不饱和的烃基链。在一些实施方案中,R10和R11各自独立地为含有12个碳原子的直链或支链、饱和或不饱和的烃基链。在一些实施方案中,R10和R11各自独立地为含有14个碳原子的直链或支链、饱和或不饱和的烃基链。在其他实施方案中,R10和R11各自独立地为含有16个碳原子的直链或支链、饱和或不饱和的烃基链。在更多的实施方案中,R10和R11各自独立地为含有18个碳原子的直链或支链、饱和或不饱和的烃基链。在其他实施方案中,R10为含有12个碳原子的直链或支链、饱和或不饱和的烃基链,并且R11为含有14个碳原子的直链或支链、饱和或不饱和的烃基链。
在各种实施方案中,z所选的范围使得(II)的PEG部分具有约400至约6000g/mol的平均分子量。在一些实施方案中,平均值z为约45。
在其他实施方案中,聚乙二醇化的脂质具有以下结构之一:
其中n的范围使得所述聚乙二醇化的脂质的平均分子量为约2500g/mol。
还提供了包含(II)和阳离子脂质的组合物。所述阳离子脂质可以选自任何阳离子脂质。在各种实施方案中,所述阳离子脂质为具有上述结构(I)的化合物,包括任何表1中的子结构和特定化合物。
在一些实施方案中,提供了包含式(I)化合物中的任一个或多个的组合物。例如,在一些实施方案中,所述组合物包含任何式(I)化合物和治疗剂以及一种或多种选自中性脂质、甾族化合物和聚乙二醇化的脂质的赋形剂。其他药物可接受的赋形剂和/或载体也包括在组合物的各种实施方案内。
在某些实施方案中,治疗剂包含核酸,例如反义寡核苷酸或信使RNA。在一些实施方案中,中性脂质选自DSPC、DPPC、DMPC、DOPC、POPC、DOPE和SM。在各种实施方案中,化合物与中性脂质的摩尔比为约2:1至约8:1。
在各种实施方案中,组合物还包含甾族化合物或甾族化合物类似物。在某些实施方案中,所述甾族化合物或甾族化合物类似物为胆甾醇。在一些这样的实施方案中,化合物与胆甾醇的摩尔比为约2:1至1:1。
在各种实施方案中,组合物包含聚乙二醇化的脂质。例如,一些实施方案包括PEG-DMG。在各种实施方案中,化合物与聚乙二醇化的脂质的摩尔比为约100:1至约25:1。
在一些实施方案中,组合物包含具有以下结构(II)的聚乙二醇化的脂质:
或其药物可接受的盐、互变异构体或立体异构体,其中:
R10和R11各自独立地为含有10至30个碳原子的直链或支链、饱和或不饱和的烃基链,其中所述烃基链任选地被一个或多个酯键中断;并且
z具有30至60的平均值。
在一些实施方案中,R10和R11各自独立地为含有12至16个碳原子的直链的、饱和的烃基链。在其他实施方案中,平均值z为约45。
在一些前述组合物的实施方案中,治疗剂包含核酸。例如,在一些实施方案中,所述核酸选自反义、质粒DNA和信使RNA。
出于施用目的,本发明的化合物(通常是脂质纳米颗粒与治疗剂结合的形式)可以以粗化学品施用,或者可以配制为药物组合物。本发明的药物组合物包含式(I)的化合物和一种或多种药物可接受的载体、稀释剂或赋形剂。式(I)的化合物以有效形成脂质纳米颗粒并递送治疗剂以便,例如,治疗相关的特定疾病或病况的量存在于组合物中。本领域技术人员可以容易地确定适当的浓度和剂量。
本发明组合物的施用可以通过任何用于类似效用的试剂的可接受施用方式来进行。本发明的药物组合物可以配制成固体、半固体、液体或气体形式的制剂,例如片剂、胶囊、粉末、颗粒、软膏、溶液、悬浮液、栓剂、注射剂、吸入剂、胶、微球和气溶胶。施用这类药物组合物的典型途径包括,但不限于,口服、局部、经皮、吸入、胃肠外、舌下、口含、直肠、阴道和鼻内途径。本文使用的术语胃肠外包括皮下注射,静脉内、肌内、皮内、胸骨内注射或输注技术。配制本发明的药物组合物以便允许经过对患者施用该组合物后其中含有的活性成分是生物可利用的。待向对象或患者施用的组合物是一个或多个剂量单位的形式,其中,例如,片剂可以是单剂量单位,而本发明气溶胶形式的化合物的容器可以具有多个剂量单位。制备这些剂型的现行的方法是已知的,或者对于本领域的技术人员是显而易见的;例如,参见Remington:The Science and Practice of Pharmacy,第20版(Philadelphia Collegeof Pharmacy and Science,2000)。在任何情况下,待施用的组合物将会含有治疗有效量的本发明化合物或其药物可接受的盐,以便根据本发明的教导治疗相关的疾病或病况。
本发明的药物组合物可以是固体或液体的形式。一方面,载体是微粒,使得组合物是,例如,片剂或粉末形式。载体可以是液体,此时组合物是,例如,口服糖浆、可注射液体或气溶胶,所述气溶胶适用于,例如,吸入施用。
当用于口服施用时,药物组合物优选为固体或液体形式,其中本文认为是固体或液体的形式包括半固体、半液体、悬浮液和胶形式。
作为用于口服施用的固体组合物,药物组合物可以配制成粉末、颗粒、压缩的片剂、丸剂、胶囊、咀嚼胶、水等形式。这类固体组合物通常将含有一种或多种惰性稀释剂或可食用载体。另外,可以存在以下的一种或多种:结合剂,例如羧甲基纤维素、乙基纤维素、微晶纤维素、黄蓍胶或明胶;赋形剂,例如淀粉、乳糖或糊精;崩解剂,例如海藻酸、海藻酸钠、Primogel、玉米淀粉等;润滑剂,例如硬脂酸镁或Sterotex;助流剂,例如胶体二氧化硅;甜味剂,例如蔗糖或糖精;调味剂,例如薄荷、水杨酸甲酯或橙味调味剂;以及着色剂。
当药物组合物是胶囊(例如,明胶胶囊)形式时,其可以含有上述类型材料之外的液体载体,例如聚乙二醇或油。
药物组合物可以是液体的形式,例如,酏剂、糖浆、溶液、乳液或悬浮液。作为两种实例,液体可以用于口服施用或用于注射递送。当用于口服施用时,优选的组合物含有,除本化合物之外的,甜味剂、防腐剂、染色/着色剂和增味剂中的一种或多种。在通过注射施用的组合物中,可以包括表面活性剂、防腐剂、润湿剂、分散剂、悬浮剂、缓冲剂、稳定剂和等渗剂中的一种或多种。
本发明的液体药物组合物,不论其为溶液、悬浮液还是其他类似的形式,可以包括以下佐剂中的一种或多种:无菌稀释剂,例如注射用的水、盐水溶液、优选生理盐水、林格氏溶液、等渗氯化钠;不挥发性油类,例如可用作溶剂或悬浮介质的合成的单甘酯或双甘酯,聚乙二醇、甘油、丙二醇或其他溶剂;抗菌剂,例如苄醇或尼泊金甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;螯合剂,例如乙二胺四乙酸;缓冲剂,例如乙酸盐、柠檬酸盐或磷酸盐;以及用于调节张力的制剂,例如氯化钠或葡萄糖;用作冷冻保护剂的试剂,例如蔗糖或海藻糖。胃肠外制剂可以封装在玻璃或塑料制作的安瓿、一次性注射器或多剂量瓶中。生理盐水是优选的佐剂。可注射的药物组合物优选为无菌的。
用于胃肠外施用或口服施用的本发明的液体药物组合物应含有可获得适合剂量的本发明化合物的量。
本发明的药物组合物可以用于局部施用,在这种情况下,载体可以适当地包含溶液基质、乳液基质、软膏基质或凝胶基质。例如,所述基质可以包含以下的一种或多种:矿脂、羊毛脂、聚乙二醇、蜂蜡、矿物油、诸如水和醇的稀释剂、以及乳化剂和稳定剂。增稠剂可以存在于用于局部施用的药物组合物中。如果用于经皮施用,组合物可以包括经皮贴片或离子电渗装置。
本发明的药物组合物可以用于直肠施用,例如,为栓剂的形式,其在直肠中溶解并释放药物。用于直肠施用的组合物可以含有油脂性基质作为适合的无刺激性赋形剂。这类基质包括但不限于羊毛脂、可可脂和聚乙二醇。
本发明的药物组合物可以包括修饰固体或液体剂量单位的物理形式的各种材料。例如,组合物可以包括形成活性成分周围的包衣壳的材料。形成包衣壳的材料通常是惰性的,并且可以选自,例如,糖、虫胶、和其他肠溶包衣试剂。或者,活性成分可以封装在明胶胶囊中。
固体或液体形式的本发明药物组合物可以包括与本发明化合物结合并由此有助于所述化合物递送的试剂。可以以这种能力作用的适合的试剂包括单克隆或多克隆抗体或蛋白质。
本发明的药物组合物可以由可作为气溶胶施用的剂量单位组成。术语气溶胶用于表示从胶体性质的系统到由加压包装组成的系统的各种系统。可以通过液化气和压缩气来递送,或者通过分散活性成分的适合的泵系统来递送。本发明化合物的气溶胶可以以单相、双相系统或三相系统来递送,以便递送活性成分。气溶胶的递送包括必要的容器、活化器、阀、子容器等,其在一起可以形成试剂盒。本领域的技术人员在进行常规实验的情况下可以确定优选的气溶胶。
本发明的药物组合物可以通过制药领域熟知的方法来制备。例如,用于通过注射施用的药物组合物可以通过将本发明的脂质纳米颗粒与无菌、蒸馏的水或其他载体结合以便形成溶液来制备。可以加入表面活性剂以促进形成均匀的溶液或悬浮液。表面活性剂是与本发明化合物非共价地相互作用以便促进所述化合物在水性递送系统中溶解或均匀悬浮的化合物。
本发明的组合物或其药物可接受的盐以治疗有效量施用,所述量将会根据多种因素变化,包括使用的具体治疗剂的活性;治疗剂的代谢稳定性和作用时长;患者的年龄、体重、一般健康状况、性别和饮食;施用的方式和时间;排泄速率;药物组合;具体病症或病况的严重性;以及经受治疗的对象。
本发明的组合物也可以在施用一种或多种其他治疗剂的同时、之前或之后施用。这类组合治疗包括施用本发明组合物和一种或多种另外的活性剂的单一药物剂量制剂,以及施用本发明组合物和各个在其自身单独药物剂量制剂中的活性剂。例如,本发明组合物和其他活性剂可以以单一口服剂量组合物(例如片剂或胶囊)一起向患者施用,或者各个试剂以不同的口服剂量制剂施用。当使用不同的剂量制剂时,本发明化合物和一种或多种另外的活性剂可以在基本同一时间(即,同时)施用,或者在相互交错的时间(即,依序)施用;应理解组合治疗包括所有的这些给药方案。
上述化合物和组合物的制备方法在下文描述,和/或在本领域已知。
本领域的技术人员将会认识到,在本文描述的方法中,中间化合物的官能团可能需要通过适合的保护基保护。这类官能团包括羟基、氨基、巯基和羧酸。用于羟基的适合的保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如,叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。用于氨基、脒基和胍基的适合的保护基包括叔丁氧基羰基、苄氧基羰基等。用于巯基的适合的保护基包括-C(O)-R”(其中R”为烃基、芳基或芳烃基)、对甲氧基苄基、三苯甲基等。用于羧酸的适合的保护基包括烃基、芳基或芳烃基酯。保护基可以根据标准技术添加或去除,所述标准技术是本领域技术人员已知的和本文中描述的。在Green,T.W.和P.G.M.Wutz,Protective Groups in OrganicSynthesis(1999),第3版,Wiley中详细描述了保护基团的使用。正如本领域技术人员会认识到的,保护基也可以是聚合物树脂,例如Wang树脂、Rink树脂或2-氯三苯甲基-氯树脂。
本领域技术人员还将认识到,虽然本发明化合物的这类经保护的衍生物可以不由此具有药理活性,但其可以对哺乳动物施用并且之后在体内代谢形成药理活性的本发明化合物。这类衍生物因此可以被描述为“前药”。所有本发明化合物的前药包括在本发明的范围内。
此外,所有以游离碱或游离酸形式存在的本发明化合物可以根据本领域技术人员已知的方法用适当的无机或有机的碱或酸处理来转化为其药物可接受的盐。本发明化合物的盐可以通过标准技术转化为其游离碱或酸形式。
以下反应方案说明了制备本发明化合物,即,式(I)的化合物的方法:
其中R1a、R1b、R2a、R2b、R3a、R3b、R4a、R4b、R5、R6、R7、R8、R9、a、b、c、d和e如本文所定义。应理解,本领域技术人员能够通过类似的方法或者通过结合本领域技术人员已知的其他方法来制备这些化合物。还应理解,本领域技术人员能够以下文描述的类似的方式,通过使用适当的起始组分并按照需要修改合成的参数,来制备下文未明确说明的式(I)的其他化合物。通常,起始组分可以得自诸如Sigma Aldrich、Lancaster Synthesis,Inc.、Maybridge、Matrix Scientific、TCI和Fluorochem USA等来源,或者根据本领域技术人员已知的资源(参见,例如,Advanced Organic Chemistry:Reactions,Mechanisms,and Structure,第5版(Wiley,2000年12月)),或者如本发明描述来制备。
一般反应方案1
结构(I)的化合物(例如,化合物A-5)的实施方案可以根据一般反应方案1(“方法A”)制备,其中R为饱和或不饱和的C1-C24烃基,或者为饱和或不饱和的环烃基,m为0或1并且n为1至24的整数。参考一般反应方案1,结构A-1的化合物可以从商业来源购得,或者根据本领域普通技术人员熟悉的方法制备。用DCC处理A-1、A-2和DMAP的混合物以得到溴化物A-3。在足以在任何必要的后处理和/或纯化步骤后产生A-5的温度和时间下,将溴化物A-3、碱(例如,N,N-二异丙基乙胺)和N,N-二甲基二胺A-4的混合物加热。
一般反应方案2
结构(I)的化合物(例如,化合物B-5)的实施方案可以根据一般反应方案2(“方法B”)制备,其中R为饱和或不饱和的C1-C24烃基,或者为饱和或不饱和的环烃基,m为0或1并且n为1至24的整数。如一般反应方案2所示,结构B-1的化合物可以从商业来源购得,或者根据本领域普通技术人员熟悉的方法制备。用酰氯B-2(1当量)和碱(例如,三乙胺)处理B-1(1当量)的溶液。用氧化剂(例如,氯铬酸吡啶鎓盐)处理粗产物,并且回收中间产物B-3。然后用还原剂(例如,三乙酰氧基硼氢化钠)处理粗制B-3、酸(例如,乙酸)和N,N-二甲基氨基胺B-4的溶液,以便在任何必要的后处理和/或纯化后获得B-5。
应注意,虽然起始材料A-1和B-1在上文描述为仅包含饱和的亚甲基碳,但包含碳-碳双键的起始材料也可以用于制备包含碳-碳双键的化合物。
一般反应方案3
结构(I)的化合物(例如,化合物C-7或C9)的实施方案可以根据一般反应方案3(“方法C”)制备,其中R为饱和或不饱和的C1-C24烃基,或者为饱和或不饱和的环烃基,m为0或1并且n为1至24的整数。参考一般反应方案3,结构C-1的化合物可以从商业来源购得,或者根据本领域普通技术人员熟悉的方法制备。
提供了以下实施例,其目的在于说明而并非限定。
实施例1
化合物1的合成
根据如下的方法B制备化合物1:
用2-乙基己酰氯(10g)处理辛-1,8-二醇(9.8g)在二氯甲烷(100mL)和四氢呋喃(60mL)中的溶液。缓慢加入三乙胺(15mL),并且将溶液搅拌三天。将反应混合物过滤,并且用卤水(2x)洗涤滤液。有机部分经无水硫酸镁干燥,过滤并去除溶剂。使用二氯甲烷将粗产物过滤通过硅胶(20g),得到15.8g粗产物。将得到的油状物溶解于二氯甲烷(100mL),并用氯铬酸吡啶鎓盐(13g)处理两小时。加入乙醚(400mL)并将上层清液通过硅胶床过滤。从滤液去除溶剂,并使用乙酸乙酯/己烷(0-6%)梯度使得到的油状物通过硅胶(77g)柱。回收8-O-(2’-乙基己酰氧基)辛醛(6.7g),为油状物。
将8-O-(2’-乙基己酰氧基)辛醛(6.7g)、乙酸(25滴)和2-N,N-二甲基氨基乙胺(0.54g)在二氯甲烷(40mL)中的溶液用三乙酰氧基硼氢化钠(1.5g)处理过夜。该溶液用碳酸氢钠水溶液洗涤,然后用卤水洗涤。有机相经无水硫酸镁干燥,过滤并去除溶剂。使用甲醇/二氯甲烷(0-10%)梯度使残余物通过硅胶(75g)柱,然后通过第二根柱(20g),以得到化合物1(1g),为无色油状物。
实施例2
化合物2的合成
根据如下的方法A制备化合物2:
在氩气气氛下,向装有溶于二氯甲烷(20mL)的叶绿醇(593mg,2mmol)、6-溴己酸(780mg,4mmol)和4-(二甲基氨基)吡啶(60mg)的圆底烧瓶加入二环己基碳二亚胺(908mg,4.4mmol)。通过过滤将沉淀抛弃。浓缩滤液,并且得到的残余物通过在用含乙酸乙酯的己烷的梯度混合物(0%至3%)洗脱的硅胶上进行柱层析来纯化。这得到(E)-3,7,11,15-四甲基十六碳-2-烯基6-溴己酸酯的无色油状物(0.79g1.67mmol,83%)。
将(E)-3,7,11,15-四甲基十六碳-2-烯基6-溴己酸酯(0.42g,0.887mmol)、N,N-二异丙基乙胺(1.5mol当量,1.33mmol,MW 129.25,171mg)和N,N-二甲基乙二胺(39mg,0.44mmol)在DMF(4mL)中的溶液在77℃下加热18h。然后将反应混合物冷却,并用己烷(3x20mL)萃取。合并己烷萃取物,经硫酸钠干燥,过滤并浓缩。其与第2次反应合并(总计约0.7g)。粗产物通过在用含甲醇的DCM的梯度混合物(0%至5%)洗脱的硅胶进行柱层析来纯化多次。这得到所需产物的淡黄色油状物(39mg)。1HNMR(400MHz,CDCl3)δ:5.33(m,2H),4.59(m,4H),2.85-2.25(m,18H)。
实施例3
化合物3的合成
通过与化合物2类似的方式,从溴乙酸起始,而不是从6-溴己酸起始,来制备化合物3,得到22mg浓稠无色油状物,0.029mmol,6%。1HNMR(400MHz,CDCl3)δ:5.32(m,2H),4.62(m,4H),3.62(s,2H),3.60(s,2H),3.28-2.33(m,10H),2.09-2.00(m,4H),1.76(s,3H),1.70(s,3H),1.60-1.47(m,6H),1.47-0.97(32H),0.89-0.84(m,24H)。
实施例4
化合物4的合成
根据如下的方法B来制备化合物4:
用2-乙基己酸(7.2g)、DCC(10.5g)、DMAP(3.5g)和三乙胺(10mL)处理十二烷-1,12-二醇(10g)在二氯甲烷(100mL)和四氢呋喃(50mL)中的溶液。将该溶液搅拌四天。将反应混合物过滤,并且用稀盐酸洗涤滤液。有机部分经无水硫酸镁干燥,过滤并去除溶剂。将残余物溶解于二氯甲烷(50mL),使其静置过夜,并过滤。去除溶剂以得到12.1g粗产物。
将粗产物溶解于二氯甲烷(100mL),并用氯铬酸吡啶鎓盐(8g)处理过夜。加入乙醚(400mL),并将上层清液通过硅胶床过滤。从滤液去除溶剂,并使用乙酸乙酯/己烷(0-6%)梯度使得到的油状物通过硅胶(75g)柱。回收粗制12-O-(2’-乙基己酰氧基)十二醛(3.5g),为油状物。
将粗产物(3.5g)、乙酸(60滴)和2-N,N-二甲基氨基乙胺(0.30g)在二氯甲烷(20mL)中的溶液用三乙酰氧基硼氢化钠(0.86g)处理过夜。该溶液用碳酸氢钠水溶液洗涤,然后用卤水洗涤。有机相经无水硫酸镁干燥,过滤并去除溶剂。使用甲醇/二氯甲烷(0-8%)梯度使残余物通过硅胶(20g)柱,然后通过第二根柱(20g),以得到所需产物(0.6g),为无色油状物。
实施例5
化合物5的合成
根据如下方法B制备化合物5:
用2-己基癸酰氯(10g)和三乙胺(10mL)处理己-1,6-二醇(10g)在二氯甲烷(40mL)和四氢呋喃(20mL)中的溶液。将溶液搅拌一小时并去除溶剂。将反应混合物悬浮于己烷中,过滤并用水洗涤滤液。去除溶剂,并使用己烷和之后的二氯甲烷作为洗脱液使残余物通过硅胶(50g)柱,得到6-(2’-己基癸酰氧基)己-1-醇,为油状物(7.4g)。
将纯化的产物(7.4g)溶解于二氯甲烷(50mL),并用氯铬酸吡啶鎓盐(5.2g)处理两小时。加入乙醚(200mL),并将上层清液通过硅胶床过滤。从滤液去除溶剂,并使用乙酸乙酯/己烷(0-5%)梯度使得到的油状物通过硅胶(50g)柱。回收6-(2’-己基癸酰氧基)十二醛(5.4g),为油状物。
将产物(4.9g)、乙酸(0.33g)和2-N,N-二甲基氨基乙胺(0.40g)在二氯甲烷(20mL)中的溶液用三乙酰氧基硼氢化钠(2.1g)处理两小时。用氢氧化钠水溶液洗涤该溶液。有机相经无水硫酸镁干燥,过滤并去除溶剂。使用甲醇/二氯甲烷(0-8%)梯度使残余物通过硅胶(50g)柱,以得到所需产物(1.4g),为无色油状物。
实施例6
化合物6的合成
根据如下方法B制备化合物6:
用2-己基癸酸(10.0g)、DCC(8.7g)和DMAP(5.7g)处理壬-1,9-二醇(12.6g)的二氯甲烷(80mL)溶液。将溶液搅拌两小时。将反应混合物过滤并去除溶剂。将残余物溶解于加热的己烷(250mL),并允许结晶。将溶液过滤,并去除溶剂。将残余物溶解于二氯甲烷,并用稀盐酸洗涤。有机部分经无水硫酸镁干燥,过滤并去除溶剂。使用0-12%乙酸乙酯/己烷作为洗脱液,使残余物通过硅胶柱(75g),得到9-(2’-己基癸酰氧基)壬-1-醇(9.5g),为油状物。
将产物溶解于二氯甲烷(60mL),并用氯铬酸吡啶鎓盐(6.4g)处理两小时。加入乙醚(200mL),并将上层清液通过硅胶床过滤。从滤液去除溶剂,并使用乙酸乙酯/己烷(0-12%)梯度使得到的油状物通过硅胶(75g)柱,得到9-(2’-乙基己酰氧基)壬醛(6.1g),为油状物。
将粗产物(6.1g)、乙酸(0.34g)和2-N,N-二甲基氨基乙胺(0.46g)在二氯甲烷(20mL)中的溶液用三乙酰氧基硼氢化钠(2.9g)处理两小时。该溶液用二氯甲烷稀释,用氢氧化钠水溶液洗涤,然后用水洗涤。有机相经无水硫酸镁干燥,过滤并去除溶剂。使用甲醇/二氯甲烷(0-8%)梯度使残余物通过硅胶(75g)柱,然后使用二氯甲烷/乙酸/甲醇梯度通过第二根柱(20g)。将纯化的流份溶解于二氯甲烷,用稀氢氧化钠水溶液洗涤,经无水硫酸镁干燥,过滤并去除溶剂,以得到所需产物(1.6g),为无色油状物。
实施例7
化合物7的合成
根据方法A,由3,5,5-三甲基己基10-溴癸酸酯和N,N-二甲基乙烷-1,2-二胺制备化合物7,得到144mg淡黄色油状物(0.21mmol,11%)。1HNMR(400MHz,CDCl3)δ:4.09(似三重峰,6.6Hz,4H),2.58-2.51(m,2H),2.44-2.34(m,6H),2.29(似三重峰,7.5Hz,4H),2.25(s,6H),1.67-1.57(m,8H),1.52-1.39(m,6H),1.36-1.21(m,24H),0.95(d,6.6Hz,6H),0.90(s,18H)。
实施例8
化合物8的合成
通过方法A制备化合物8,产率15%。1HNMR(400MHz,CDCl3)δ:5.11-5.04(m,2H),2.60-2.54(m,2H),2.47-2.36(m,6H),2.27(似三重峰,7.4Hz,4H),2.25(s,6H),1.66-1.40(m,16H),1.34-1.23(m,24H),0.91(d,6.5Hz,24H)。
实施例9
化合物9的合成
根据如下方法B制备化合物9:
用香茅酰氯(10.1g,由香茅酸和草酰氯制备)和三乙胺(10mL)处理壬-1,9-二醇(10.0g)的二氯甲烷(100mL)溶液,并搅拌三天。反应混合物用二氯甲烷稀释,并用稀盐酸洗涤。有机部分经无水硫酸镁干燥,过滤并去除溶剂。将残余物溶于己烷,过滤并去除溶剂。使用己烷和之后的二氯甲烷作为洗脱液,使残余物通过一系列的硅胶柱(60-70g),得到9-(香茅酰氧基)壬-1-醇(7.6g),为油状物。
将产物溶解于二氯甲烷(50mL),并用氯铬酸吡啶鎓盐(6.4g)处理90分钟。加入乙醚(200mL),并将上层清液通过硅胶床过滤。将残余物溶解于己烷,并使用己烷作为洗脱液使其通过硅胶(20g)柱,得到9-(香茅酰氧基)壬醛(5g),为油状物。
将粗产物(5g)、乙酸(0.33g)和2-N,N-二甲基氨基乙胺(0.48g)在二氯甲烷(40mL)中的溶液用三乙酰氧基硼氢化钠(1.2g)处理过夜。该溶液用二氯甲烷稀释,并用氢氧化钠水溶液洗涤。有机相经无水硫酸镁干燥,过滤并去除溶剂。使用0-12%甲醇/二氯甲烷梯度使残余物通过硅胶(50g)柱,然后使用相同的梯度使其通过第二根硅胶柱(20g),以得到所需产物(0.6g),为无色油状物。
实施例10
化合物10的合成
根据方法A制备化合物10,以得到147mg无色油状物,0.23mmol,17%。1HNMR(400MHz,CDCl3)δ:4.11(t,6.9Hz,4H),2.56-2.52(m,2H),2.44-2.35(m,6H),2.29(似三重峰,7.5Hz,4H),2.24(s,6H),1.75-1.66(m,8H),1.66-1.57(m,4H),1.52(类四重峰,6.9Hz,4H),1.46-1.38(m,4H),1.38-1.13(m,30H),0.98-0.87(m,4H)。
实施例11
化合物11的合成
根据方法A制备化合物11,以得到154mg淡黄色油状物(0.22mmol,14%)。1HNMR(400MHz,CDCl3)δ:4.88(五重峰,6.2Hz,2H),3.20-2.40(m,8H),2.39(s,6H),2.29(t,7.5Hz,4H),1.67-1.56(m,4H),1.56-1.48(m,8H),1.38-1.21(m,44H),0.92-0.86(m,12H)。
实施例12
化合物12的合成
根据方法A制备化合物12,以得到169mg淡黄色油状物(0.26mmol,17%)。1HNMR(400MHz,CDCl3)δ:4.03-3.95(ABX样式,4H),2.54(m,2H),2.44-2.35(m,6H),2.30(似三重峰,7.5Hz,4H),2.25(s,6H),1.66-1.54(m,6H),1.47-1.23(m,40H),0.92-0.88(m,12H)。
实施例13
化合物13的合成
根据方法A制备化合物13,以得到152mg白色糊状物,0.23mmol,16%。1HNMR(400MHz,CDCl3)δ:4.03(t,6.7Hz,4H),3.10-2.41(非常宽的峰,8H),2.34(s,6H),2.30(t,7.5Hz,4H),1.66-1.46(m,12H),1.39-1.21(m,40H),0.89(似三重峰,6.9Hz,6H)。
实施例14
化合物14的合成
根据方法A制备化合物14,以得到111mg无色油状物,0.16mmol,11%。1HNMR(400MHz,CDCl3)δ:5.09(m,2H),4.16-4.05(m,4H),3.10-2.40(非常宽的峰,8H),2.31(s,6H),2.29(t,7.5Hz,4H),2.06-1.89(m,4H),1.69(d,0.8Hz,6H),1.61(s,6H),1.73-1.13(m,50H),0.92(d,6.6Hz,6H)。
实施例15
化合物15的合成
根据方法A制备化合物15,以得到116mg白色糊状物,0.16mmol,10%。1HNMR(400MHz,CDCl3)δ:4.06(t,6.7Hz,4H),2.62-2.51(宽峰,2H),2.48-2.33(br.,6H),2.29(t,7.5Hz,4H),2.25(s,6H),1.69(五重峰,7.0Hz,8H),1.48-1.38(br.,4H),1.38-1.21(m,52H),0.89(似三重峰,6.8Hz,6H)。
实施例16
化合物16的合成
根据方法A制备化合物16,以得到118mg无色油状物,0.17mmol,12%。1HNMR(400MHz,CDCl3)δ:4.06(t,6.8Hz,4H),2.57-2.52(m,2H),2.44-2.34(m,6H),2.29(t,7.6Hz,4H),2.25(s,6H),1.62(似五重峰,7.0Hz,8H),1.47-1.39(m,4H),1.37-1.22(m,44H),0.89(似三重峰,6.8Hz,6H)。
实施例17
化合物17的合成
根据方法A制备化合物17,以得到145mg淡黄色油状物,0.21mmol,13%。1HNMR(400MHz,CDCl3)δ:5.01(m,0.27H来自顺式异构体),4.63(tt,11.2Hz,4.5Hz,1.73H来自反式异构体),2.61-2.24(18H),2.01(m,4H),1.81(m,4H),1.61(似五重峰,7.2Hz,4H),1.44(m,4H),1.36-1.21(24H),1.11(m,4H),1.01(m,2H),0.87(s,2.7H来自顺式异构体),0.86(s,15.3H来自反式异构体)。
实施例18
化合物18的合成
根据方法A制备化合物18,以得到111mg无色油状物,0.17mmol,14%。1HNMR(400MHz,CDCl3)δ:4.88(五重峰,6.2Hz,2H),2.61-2.51(br.,2H),2.48-2.34(br,6H),2.29(t,7.6Hz,4H),2.25(s,6H),1.62(似五重峰,7.3Hz,4H),1.55-1.48(m,8H),1.47-1.39(m,4H),1.37-1.21(m,32H),0.91-0.86(m,12H)。
实施例19
化合物19的合成
根据方法A制备化合物19,以得到76mg无色油状物,0.11mmol,6%。1HNMR(400MHz,CDCl3)δ:5.77(似双三重峰,14.4Hz,6.6Hz,2H),5.55(似dtt峰,14.4Hz,6.5Hz,1.4Hz,2H),4.51(dd,6.6Hz,0.6Hz,4H),2.61-2.50(br.,2H),2.50-2.34(br.6H),2.30(t,7.5Hz,4H),2.25(s,6H),2.04(q,7.1Hz,4H),1.62(五重峰,7.3Hz,4H),1.48-1.21(40H),0.88(似三重峰,6.8Hz,6H)。
实施例20
化合物20的合成
根据一般程序A制备化合物20,以得到157mg无色油状物,0.22mmol,14%。1HNMR(400MHz,CDCl3)δ:3.97(d,5.8Hz,4H),2.57-2.51(m,2H),2.44-2.33(m,6H),2.30(t,7.5Hz,4H),2.24(s,6H),1.63(似五重峰,7.3Hz,6H),1.43(似五重峰,7.3Hz,4H),1.36-1.21(44H),0.93-0.86(m,12H)。
实施例21
化合物21的合成
根据一般程序A制备化合物21,以得到164mg无色油状物,0.21mmol,14%。1HNMR(400MHz,CDCl3)δ:3.97(d,5.8Hz,4H),2.57-2.51(m,2H),2.44-2.34(m,6H),2.30(t,7.5Hz,4H),2.24(s,6H),1.62(似五重峰,7.3Hz,6H),1.43(似五重峰,7.3Hz,4H),1.36-1.21(52H),0.93-0.86(m,12H)。
实施例22
化合物22的合成
根据如下方法A制备化合物22:
步骤1.
向6-溴己酸(20mmol,3.901g)、2-己基-1-癸醇(1.8当量,36mmol,8.72g)和4-二甲基氨基吡啶(DMAP 0.5当量,10mmol,1.22g)在DCM(80mL)中的溶液加入DCC(1.1当量,22mmol,4.54g)。将得到的混合物在室温下搅拌16h。通过过滤将沉淀抛弃。浓缩滤液。残余物通过在用含乙酸乙酯的己烷(0%至2%)的梯度混合物洗脱的硅胶上进行柱层析来纯化。这得到了所需产物,为无色油状物(7.88g,18.8mmol,94%)。
步骤2.
将来自步骤1的溴化物(1.34当量,7.88g,18.8mmol)、N,N-二异丙基乙胺(1.96当量,27.48mmol,4.78mL)和N,N-二甲基乙二胺(1当量,14.02mmol,1.236g,1.531mL)在乙腈(70mL)中的混合物,在装配有冷凝器的250mL烧瓶中于79℃(油浴)下加热16h。将反应混合物冷却至室温并浓缩。将残余物溶于乙酸乙酯和己烷(1:9)和水的混合物中。将各相分离,用水(100mL)和卤水洗涤。经硫酸钠干燥并浓缩(8.7g油状物)。粗产物(8.7g油状物)通过在硅胶(0%至3%MeOH于氯仿中)上进行柱层析来纯化。合并含有期望产物的流份,并浓缩。将残余物溶解于1mL己烷中,并通过硅胶层(3-4mm,用8mL己烷洗涤)过滤。用Ar流将滤液吹干,并在真空中充分地干燥过夜(1.30g,mmol,%,无色油状物,所需产物)。1HNMR(400MHz,CDCl3)δ:3.96(d,5.8Hz,4H),2.55-2.50(m,2H),2.43-2.39(m,4H),3.37-3.32(m,2H),2.30(t,7.5Hz,4H),2.23(s,6H),1.63(似五重峰,7.6Hz,6H),1.48-1.40(m,4H),1.34-1.20(52H),0.88(似三重峰,6.8Hz,12H)。
实施例23
化合物23的合成
根据一般程序A制备化合物23,以得到200mg无色油状物,0.24mmol,16%。1HNMR(400MHz,CDCl3)δ:3.97(d,5.8Hz,4H),2.57-2.51(m,2H),2.44-2.34(m,6H),2.30(t,7.5Hz,4H),2.24(s,6H),1.67-1.58(m,6H),1.43(似五重峰,7.3Hz,4H),1.36-1.21(60H),0.89(似三重峰,6.8Hz,12H)。
实施例24
化合物24的合成
根据一般程序A制备化合物24,以得到138mg无色油状物,0.18mmol,12%。1HNMR(400MHz,CDCl3)δ:4.90(类六重峰,6.3Hz,2H),2.63-2.33(br.8H),2.27(t,7.5Hz,4H),2.26(s,6H),1.66-1.57(m,4H),1.51-1.39(m,6H),1.35-1.21(54H),1.20(d,6.2Hz,6H),0.89(似三重峰,6.8Hz,6H)。
实施例25
化合物25的合成
根据一般程序A制备化合物25,以得到214mg无色油状物,0.24mmol,17%。1HNMR(400MHz,CDCl3)δ:3.97(d,5.8Hz,4H),2.58-2.52(m,2H),2.45-2.35(m,6H),2.30(t,7.5Hz,4H),2.25(s,6H),1.62(似五重峰,7.0Hz,6H),1.43(似五重峰,7.0Hz,4H),1.36-1.21(68H),0.89(似三重峰,6.7Hz,12H)。
实施例26
化合物26的合成
根据一般程序A制备化合物26,以得到170mg无色油状物,0.21mmol,13%。1HNMR(400MHz,CDCl3)δ:5.42-5.29(m,8H),4.05(t,6.8Hz,4H),2.77(t,6.5Hz,4H),2.55-2.50(m,2H),2.43-2.39(m,4H),2.37-2.32(m,2H),2.29(t,7.6Hz,4H),2.23(s,6H),2.05(q,6.8Hz,8H),1.63(似五重峰,7.5Hz,8H),1.48-1.40(m,4H),1.39-1.23(36H),0.90(似三重峰,6.8Hz,6H)。
实施例27
化合物27的合成
根据一般程序A制备化合物27,以得到255mg无色油状物,0.29mmol,18%。1HNMR(400MHz,CDCl3)δ:3.96(d,5.8Hz,4H),2.55-2.50(m,2H),2.43-2.39(m,4H),3.37-3.32(m,2H),2.30(t,7.5Hz,4H),2.23(s,6H),1.63(似五重峰,7.6Hz,6H),1.48-1.40(m,4H),1.34-1.20(68H),0.88(似三重峰,6.8Hz,12H)。
实施例28
化合物28的合成
根据一般程序A制备化合物28,以得到248mg无色油状物,0.27mmol,19%。1HNMR(400MHz,CDCl3)δ:3.97(d,5.8Hz,4H),2.57-2.52(m,2H),2.44-2.34(m,6H),2.30(t,7.5Hz,4H),2.24(s,6H),1.67-1.58(m,6H),1.43(似五重峰,7.3Hz,4H),1.36-1.21(76H),0.89(似三重峰,6.8Hz,12H)。
实施例29
化合物29的合成
根据一般程序A制备化合物29,以得到181mg无色油状物,0.23mmol,17%。1HNMR(400MHz,CDCl3)δ:4.87(五重峰,6.3Hz,4H),2.56-2.51(m,2H),2.43-2.34(m,6H),2.27(t,7.5Hz,4H),2.24(s,6H),1.61(似五重峰,7.3Hz,4H),1.55-1.46(m,8H),1.46-1.37(m,4H),1.36-1.08(52H),0.88(似三重峰,6.8Hz,12H)。
实施例30
化合物30的合成
根据一般程序A制备化合物30,以得到88mg无色油状物,0.11mmol,3%。1HNMR(400MHz,CDCl3)δ:3.97(d,5.5Hz,4H),2.58-2.51(m,2H),2.49-2.44(m,4H),2.38-2.30(m,6H),2.24(s,6H),1.75(似五重峰,7.3Hz,4H),1.66-1.54(m,2H),1.35-1.06(64H),0.89(似三重峰,6.4Hz,12H)。
实施例31
化合物31的合成
根据一般程序C制备化合物31,以得到275mg淡黄色油状物,0.30mmol,三步的总产率35%。1HNMR(400MHz,CDCl3)δ:3.97(d,5.8Hz,4H),2.63-2.47(m,8H),2.45-2.41(m,4H),2.31(t,7.5Hz,4H),1.82-1.74(m,4H),1.64(似五重峰,7.6Hz,6H),1.46(似五重峰,7.6Hz,4H),1.36-1.18(68H),0.89(似三重峰,6.8Hz,12H)。
实施例32
化合物32的合成
根据如下方法C制备化合物32:
步骤1.
在Ar下向2-氨基乙醇(116mg,1.9mmol,115uL,MW 61.08,d1.012)在15ml无水THF中的溶液加入,2-己基癸基6-溴己酸酯(1.9当量,1.52g,3.62mmol)、碳酸钾(1.9当量,3.62mmol,500mg)、碳酸铯(0.3当量,0.57mmol,186mg,)和碘化钠(10mg),并加热至回流持续6天。在减压下蒸发溶剂,并将残余物溶于己烷,并用水和卤水洗涤。分离有机层,经无水硫酸钠干燥,过滤并在减压下蒸发以获得无色油状物。粗产物通过在硅胶(230-400目硅胶,含MeOH的氯仿,0%至4%)上进行快速柱层析来纯化,以得到936mg无色油状物(1.27mmol,70%)。
步骤2.
在Ar气氛下,向磁力搅拌且冰浴冷却的936mg(1.27mmol)步骤1的产物在2mLCHC13中的溶液中,逐滴加入在15mL氯仿中的亚硫酰氯(2.9当量,3.70mmol,440mg,270uL)。SOCl2加入完成后,将冰浴移除,并且将反应混合物在Ar气氛下于室温下搅拌16h。在减压下去除CHC13和SOCl2,得到浓稠黄色油状物。
步骤3.
将步骤2的粗产物溶解于THF(20mL)。向该THF溶液中加入吡咯烷(1.6mL,1.36g,19mmol)。将密封的混合物在64℃下加热过夜。浓缩反应混合物(暗棕色油状物)。残余物通过在硅胶(含MeOH的氯仿,0%至4%)上进行快速干柱层析来纯化。这得到所需产物,为淡黄色油状物(419mg,0.53mmol,83%)。1HNMR(400MHz,CDCl3)δ:3.97(d,5.8Hz,4H),2.65-2.47(m,8H),2.45-2.41(m,4H),2.31(t,7.5Hz,4H),1.81-1.74(m,4H),1.64(似五重峰,7.6Hz,6H),1.46(似五重峰,7.6Hz,4H),1.36-1.21(52H),0.89(似三重峰,6.8Hz,12H)。
实施例33
化合物33的合成
根据一般程序C制备化合物33,以得到419mg淡黄色油状物,0.54mmol,三步的总产率60%。1HNMR(400MHz,CDCl3)δ:3.97(d,5.8Hz,4H),2.57-2.53(m,2H),2.46-2.40(m,8H),2.31(t,7.5Hz,4H),2.23(s,3H),1.64(似五重峰,7.6Hz,6H),1.46(似五重峰,7.6Hz,4H),1.36-1.20(52H),1.06(t,7.2Hz,3H),0.89(似三重峰,6.8Hz,12H)。
实施例34
化合物34的合成
根据如下方法B制备化合物34:
用2-乙基己酸(4.5g)、DCC(7.7g)和DMAP(4.2g)处理壬-1,9-二醇(10g)的二氯甲烷(250mL)溶液。将溶液搅拌三天。将反应混合物过滤,并向滤液中加入己烷(200mL)。将混合物搅拌,并使沉淀析出。倾倒出上层清液,并去除溶剂。将残余物悬浮于己烷(70mL)中,并沉淀。倾倒出上层清液,并去除溶剂。将残余物溶解于己烷,使其在室温下静置,然后过滤。去除溶剂,并使用0%–10%乙酸乙酯/己烷梯度以及之后的0%–8%甲醇/二氯甲烷梯度使残余物通过硅胶柱(50g),得到5.6g的9-(2’-乙基己酰氧基)壬-1-醇,为无色油状物。
将产物溶解于二氯甲烷(70mL),并用氯铬酸吡啶鎓盐(5g)处理两小时。加入乙醚(250mL),并将上层清液通过硅胶床过滤。从滤液去除溶剂,并将得到的油状物溶解于己烷。将悬浮液通过硅胶塞过滤,并去除溶剂,得到粗制的9-(2’-乙基己酰氧基)壬醛(3.4g),为油状物。
将粗产物(3.4g)、乙酸(0.52g)和2-N,N-二甲基氨基乙胺(0.33g)在二氯甲烷(50mL)中的溶液用三乙酰氧基硼氢化钠(1.86g)处理过夜。用氢氧化钠水溶液洗涤该溶液。有机相经无水硫酸镁干燥,过滤并去除溶剂。使用乙酸/甲醇/二氯甲烷(2-0%/0-12%/98-88%)梯度使残余物通过硅胶(50g)柱。纯化的流份用碳酸氢钠水溶液洗涤,经硫酸镁干燥,过滤并去除溶剂,得到化合物34,为油状物(0.86g)。
实施例35
化合物35的合成
根据如下方法B制备化合物35:
用香茅酸(7.5g)、DCC(10.0g)和DMAP(9.5g)处理十二烷-1,12-二醇(18.1g)的二氯甲烷(90mL)溶液。将该溶液搅拌过夜。过滤反应混合物,并用稀盐酸洗涤滤液。有机部分经无水硫酸镁干燥,过滤并去除溶剂以得到12.2g的粗制12-香茅酰氧基十二烷-1-醇。
将粗产物溶解于二氯甲烷(60mL),并用氯铬酸吡啶鎓盐(6.8g)处理三小时。加入乙醚(200mL),并将上层清液通过硅胶床过滤。从滤液去除溶剂,并使用乙酸乙酯/己烷(0-12%)梯度使得到的油状物通过硅胶(75g)柱。回收粗制的12-香茅酰氧基十二醛(6.2g),为油状物。
将粗产物(6.2g)、乙酸(0.44g)和2-N,N-二甲基氨基乙胺(0.50g)在二氯甲烷(40mL)中的溶液用三乙酰氧基硼氢化钠(2.9g)处理过夜。该溶液用碳酸氢钠水溶液洗涤,然后用卤水洗涤。有机相经无水硫酸镁干燥,过滤并去除溶剂。使用乙酸/甲醇/二氯甲烷(2-0%/0-12%/98-88%)梯度使残余物通过硅胶(75g)柱。纯化的流份用碳酸氢钠水溶液洗涤,经硫酸镁干燥,过滤并去除溶剂,得到化合物35(1.68g),为油状物。
实施例36
化合物36的合成
根据一般程序C制备化合物36,以得到108mg无色油状物(0.14mmol)。1HNMR(400MHz,CDCl3)δ:4.87(五重峰,6.3Hz,2H),2.56-2.51(m,2H),2.45-2.40(m,4H),2.38-2.33(m,2H),2.29(t,7.5Hz,4H),2.24(s,6H),1.64(似五重峰,7.7Hz,4H),1.55-1.41(m,12H),1.35-1.18(m,52H),0.89(似三重峰,6.8Hz,12H)。
实施例37
化合物37的合成
根据一般程序C制备化合物37,以得到330mg无色油状物(0.40mmol,三步的总产率80%)。1HNMR(400MHz,CDCl3)δ:4.87(五重峰,6.5Hz,2H),2.64-2.47(m,8H),2.45-2.40(m,4H),2.29(t,7.5Hz,4H),1.81-1.74(m,4H),1.64(似五重峰,7.6Hz,4H),1.55-1.41(m,12H),1.35-1.18(m,50H),0.89(似三重峰,6.8Hz,12H)。
实施例38
化合物38的合成
根据如下方法B制备化合物38:
用2-丁基辛酸(10g)、DCC(10.3g)和DMAP(6.7g)处理壬-1,9-二醇(16g)的二氯甲烷(100mL)溶液。将该溶液搅拌三天。将反应混合物过滤,并向滤液中加入己烷(250mL)。将混合物搅拌,并使沉淀析出。倾倒出上层清液,并去除溶剂。将残余物悬浮于己烷中,并沉淀。倾倒出上层清液,并去除溶剂(重复两次)。将残余物溶解于己烷,使其在室温下静置,然后过滤。去除溶剂,并使用二氯甲烷使残余物通过硅胶柱(18g),得到粗制9-(2’-丁基辛酰氧基)壬-1-醇(17.7g),为油状物。
将粗产物溶解于二氯甲烷(250mL),并用氯铬酸吡啶鎓盐(11.2g)处理过夜。加入乙醚(750mL),并将上层清液通过硅胶床过滤。从滤液去除溶剂,并将得到的油状物溶解于己烷(150mL)。将悬浮液通过硅胶塞过滤,并去除溶剂。使用0-6%乙酸乙酯/己烷梯度使粗产物通过硅胶(80g)柱,得到9-(2’-丁基辛酰氧基)壬醛(5.3g),为油状物。
将产物(5.3g)、乙酸(0.37g)和2-N,N-二甲基氨基乙胺(0.47g)在二氯甲烷(50mL)中的溶液用三乙酰氧基硼氢化钠(3.35g)处理过夜。用氢氧化钠水溶液洗涤该溶液。有机相经无水硫酸镁干燥,过滤并去除溶剂。使用乙酸/甲醇/二氯甲烷(2-0%/0-12%/98-88%)梯度使残余物通过硅胶(60g)柱。纯化的流份用碳酸氢钠水溶液洗涤,经硫酸镁干燥,过滤并去除溶剂,得到化合物38,为油状物(2.3g)。
实施例39
化合物39的合成
根据如下方法B制备化合物39:
用2-癸基十四烷酸(17.5g)、DCC(11.3g)和DMAP(6.8g)处理己-1,6-二醇(12g)的二氯甲烷(250mL)溶液。将该溶液搅拌过夜。将反应混合物过滤,并向滤液中加入己烷。将混合物搅拌,并使沉淀析出。倾倒出上层清液,并去除溶剂。使用己烷以及之后的0-1%甲醇/二氯甲烷使残余物通过硅胶柱(80g),得到粗制的6-(2’-癸基十四烷酰氧基)己-1-醇(5.8g),为油状物。
将粗产物溶解于二氯甲烷(70mL),并用氯铬酸吡啶鎓盐(2.9g)处理两小时。加入乙醚(250mL),并将上层清液通过硅胶床过滤。从滤液去除溶剂,并将得到的油状物溶解于己烷。将悬浮液通过硅胶塞过滤,并去除溶剂。使用0-5%乙酸乙酯/己烷梯度使粗产物通过硅胶(10g)柱,得到6-(2’-癸基十四烷酰氧基)己醛(3.2g),为油状物。
将产物(3.2g)、乙酸(0.28g)和2-N,N-二甲基氨基乙胺(0.15g)在二氯甲烷(20mL)中的溶液用三乙酰氧基硼氢化钠(0.98g)处理过夜。用氢氧化钠水溶液洗涤该溶液。有机相经无水硫酸镁干燥,过滤并去除溶剂。使用乙酸/甲醇/二氯甲烷(2-0%/0-12%/98-88%)梯度使残余物通过硅胶(50g)柱。纯化的流份用碳酸氢钠水溶液洗涤,经硫酸镁干燥,过滤并去除溶剂,得到化合物39,为油状物(1.2g)。
实施例40
化合物40的合成
根据如下方法B制备化合物40:
用2-辛基十二烷酸(10.0g)、DCC(8.3g)和DMAP(5.0g)处理壬-1,9-二醇(10.1g)的二氯甲烷(200mL)溶液。将该溶液搅拌过夜。将反应混合物过滤,并向滤液中加入己烷(200mL)。将混合物搅拌,并使沉淀析出。倾倒出上层清液,并去除溶剂。将该过程重复两次。使用己烷以及之后的4-10%甲醇/二氯甲烷使残余物通过硅胶柱(75g),得到粗制的9-(2’-辛基十二烷酰氧基)壬-1-醇(~11g),为油状物。
将粗产物溶解于二氯甲烷(70mL),并用氯铬酸吡啶鎓盐(8g)处理两小时。加入乙醚(400mL),并将上层清液通过硅胶床过滤。从滤液去除溶剂,并将得到的油状物溶解于己烷。将悬浮液通过硅胶塞过滤,并去除溶剂,得到粗制的9-(2’-辛基十二烷酰氧基)壬醛(8.4g),为油状物。
将产物(8.4g)、乙酸(0.84g)和2-N,N-二甲基氨基乙胺(0.55g)在二氯甲烷(60mL)中的溶液用三乙酰氧基硼氢化钠(2.9g)处理两小时。用氢氧化钠水溶液洗涤该溶液。有机相经无水硫酸镁干燥,过滤并去除溶剂。使用乙酸/甲醇/二氯甲烷(2-0%/0-12%/98-88%)梯度使残余物通过硅胶(75g)柱。纯化的流份用碳酸氢钠水溶液洗涤,经硫酸镁干燥,过滤并去除溶剂,得到化合物40,为油状物(3.2g)。
实施例41
化合物41的合成
根据如下方法B制备化合物41:
用2-癸基十四烷酸(8.4g)、DCC(8.6g)和DMAP(5.0g)处理壬-1,9-二醇(9.6g)的二氯甲烷(200mL)溶液。将该溶液搅拌过夜。将反应混合物过滤,并向滤液中加入己烷(200mL)。将混合物搅拌,并使沉淀析出。倾倒出上层清液,并去除溶剂。将该过程重复两次。使用己烷以及之后的4-10%甲醇/二氯甲烷使残余物通过硅胶柱(75g),得到粗制的9-(2’-癸基十四烷酰氧基)壬-1-醇(6.4g),为油状物。
将粗产物溶解于二氯甲烷(50mL),并用氯铬酸吡啶鎓盐(5.7g)处理两小时。加入乙醚(200mL),并将上层清液通过硅胶床过滤。从滤液去除溶剂,并将得到的油状物溶解于己烷。将悬浮液通过硅胶塞过滤,并去除溶剂,得到粗制的9-(2’-癸基十四烷酰氧基)壬醛(5g),为油状物。
将产物(5g)、乙酸(0.45g)和2-N,N-二甲基氨基乙胺(0.32g)在二氯甲烷(20mL)中的溶液用三乙酰氧基硼氢化钠(1.6g)处理两小时。用氢氧化钠水溶液洗涤该溶液。有机相经无水硫酸镁干燥,过滤并去除溶剂。使用乙酸/甲醇/二氯甲烷(2-0%/0-12%/98-88%)梯度使残余物通过硅胶(50g)柱。纯化的流份用碳酸氢钠水溶液洗涤,经硫酸镁干燥,过滤并去除溶剂,得到化合物41,为油状物(2.2g)。
实施例42
PEG脂质的合成
根据上述反应方案制备聚乙二醇化的脂质42-6(“PEG-DMA”),其中n接近于聚乙二醇化的脂质中乙烯氧化物重复单元的范围中心。
42-1和42-2的合成
在室温下向肉豆蔻酸(6g,26mmol)的甲苯(50mL)溶液加入草酰氯(39mmol,1.5当量,5g)。将得到的混合物在70℃下加热2h后,将混合物浓缩。将残余物溶于甲苯并再次浓缩。在10℃下,通过注射器将残余的油状物加入浓缩的氨溶液(20mL)。将反应混合物过滤,并用水洗涤。将白色固体在真空中干燥。获得所需产物,为白色固体(3.47g,15mmol,58.7%)。
42-3的合成
在室温下,经30min的时间,向20-2(3.47g,15mmol)在THF(70mL)中的悬浮液分批加入氢化铝锂(1.14g,30mmol)。然后将混合物缓慢加热至回流(65℃油浴)过夜。将混合物冷却至5℃,并加入硫酸钠9水合物。将混合物搅拌2h,通过硅藻土层过滤,用含15%MeOH的DCM(200mL)洗涤。将滤液和洗液合并,并浓缩。将残余的固体在真空中干燥。获得所需产物,为白色固体(2.86 13.4mmol,89.5%)。
42-4的合成
在室温下,向肉豆蔻酸(3.86g,16.9mmol)在苯(40mL)和DMF(1滴)中的溶液加入草酰氯(25.35mmol,1.5当量3.22g)。将混合物在室温下搅拌1.5h。在60℃下加热30min。将混合物浓缩。将残余物溶于甲苯,并再次浓缩。将残余的油状物(淡黄色)溶于20mL的苯,并在10℃下通过注射器将其加入20-3(2.86 13.4mmol)和三乙胺(3.53mL,1.5当量)在苯(40mL)中的溶液。加入后,将得到的混合物在室温下搅拌过夜。反应混合物用水稀释,并用20%H2SO4调节至pH 6-7。将混合物过滤并用水洗涤。获得灰白色固体。将粗产物从甲醇中重结晶。这得到所需产物,为淡白色固体(5.65g,13mmol,100%)。
42-5的合成
在室温下,经30min的时间,向20-4(5.65g,13mmol)在THF(60mL)中的悬浮液分批加入氢化铝锂(0.99g,26mmol)。然后将混合物缓慢加热至回流过夜。将混合物冷却至0℃,并加入硫酸钠九水合物。将混合物搅拌2h,然后通过硅藻土和硅胶的垫过滤,并首先用乙醚洗涤。滤液变为浑浊并形成沉淀,过滤得到白色固体。将固体从MeOH重结晶,并获得无色晶状固体(2.43g)。
然后用含5%MeOH的DCM(400mL),再用含有1%三乙胺的含10%MeOH的DCM(300mL)洗涤硅藻土和硅胶的垫。合并含有所需产物的流份,并浓缩。获得白色固体。将固体从MeOH重结晶,并获得无色晶状固体(0.79g)。将上述两份固体(2.43g和0.79g)合并,并在真空中干燥(3.20g,60%)。1HNMR(CDCl3于7.27ppm处)δ:2.58(似三重峰,7.2Hz,4H),1.52-1.44(m,4H),1.33-1.24(m,44H),0.89(似三重峰,6.6Hz,6H),2.1-1.3(非常宽的峰,1H)。
42-6的合成
向20-5(7mmol,2.87g)和三乙胺(30mmol,4.18mL)在DCM(100mL)中的溶液加入mPEG-NHS(得自NOF,5.0mmol,9.97g,PEG MW约2,000,n=约45)的DCM(120mL)溶液。24h后,用水(300mL)洗涤反应溶液。用DCM(100mLx2)将水相萃取两次。合并DCM萃取物,用卤水(100mL)洗涤。有机相经硫酸钠干燥,过滤,部分浓缩。将浓缩的溶液(约300mL)在约–15℃下冷却。过滤得到白色固体(1.030g,未反应的起始的胺)。向过滤物加入Et3N(1.6mmol,0.222mL,4当量)和乙酸酐(1.6mmol,164mg)。将混合物在室温下搅拌3h,然后浓缩至固体。残余的固体通过在硅胶(含0-8%甲醇的DCM)上进行柱层析来纯化。这得到所需产物,为白色固体(9.211g)。1HNMR(CDCl3于7.27ppm处)δ:4.19(s,2H),3.83-3.45(m,180-200H),3.38(s,3H),3.28(似三重峰,7.6Hz,2H,CH2N),3.18(似三重峰,7.8Hz,2H,CH2N),1.89(s,6.6H,水),1.58-1.48(m,4H),1.36-1.21(m,48-50H),0.88(似三重峰,6.6Hz,6H)。
实施例43
PEG脂质的合成
将棕榈酸(10g)在苯(50mL)中的悬浮液用草酰氯(5mL)处理三小时。去除溶剂,并将残余物溶解于二氯甲烷(40mL)。将该溶液缓慢加入搅拌中的浓缩的氨(100mL)。将得到的悬浮液过滤,并用水洗涤。将沉淀悬浮于甲醇中,升温至50℃以溶解固体,然后冷却至室温。将重结晶的粗产物过滤并干燥,得到十六烷酰基酰胺,为白色固体(8.7g)。
将粗产物悬浮于THF(50mL)中,并用氢化铝锂(1.1g,缓慢加入)处理。将反应混合物搅拌一小时。缓慢加入过量的甲醇,然后缓慢加入水(2mL)。加入二氯甲烷(200mL),并将混合物过滤。从滤液去除溶剂,得到粗制的十六烷基胺(7g)。
将如上制备的十六烷酰氯(10.5g)的二氯甲烷(40mL)溶液缓慢加入搅拌中的粗制十六烷基胺的二氯甲烷(40mL)溶液。加入三乙胺(15mL),并将溶液在室温下搅拌过夜。将溶液过滤,并将收集的沉淀(N-(十六烷酰基)十六烷基酰胺,约10.7g)在真空下干燥。
将粗产物悬浮于THF(60mL)中并用氢化铝锂(1.1g,缓慢加入)处理。将反应混合物在室温下搅拌过夜。缓慢加入过量的甲醇,然后缓慢加入水(3mL)。加入二氯甲烷(250mL),并将溶液过滤。去除溶剂,得到粗制的二(十六烷基)胺(7.6g),为白色粉末。
将二(十六烷基)胺(3g)和单甲氧基-PEG-2000-乙酰基N-羟基琥珀酰亚胺酯(10g)在二氯甲烷(60mL)中的溶液用三乙胺(3mL)处理并搅拌过夜。加入乙酸酐(1mL),并将溶液搅拌30分钟。反应混合物用二氯甲烷稀释,并用卤水洗涤。有机部分经硫酸镁干燥,过滤并去除溶剂。使用0-8%甲醇/二氯甲烷梯度使残余物通过硅胶(75g)柱,以得到43-1,为白色粉末(5.2g)。
实施例44
PEG脂质的合成
将硬脂酸(6.5g)在苯(20mL)中的悬浮液用草酰氯(7mL)处理三天。去除溶剂,并将残余物溶解于苯(40mL)中。在搅拌下,缓慢加入浓缩的氨(50mL)。将得到的悬浮液过滤,并用水洗涤。将沉淀悬浮于甲醇中,并过滤。收集的沉淀用甲醇洗涤并干燥,得到十八烷酰基酰胺,为白色粉末(6.5g)。
将粗产物悬浮于THF(80mL)中,并用过量的氢化铝锂(1.6g,缓慢加入)处理。将反应混合物搅拌一小时。缓慢加入过量的甲醇,然后缓慢加入浓盐酸,直至沉淀溶解。反应混合物用水稀释,并使其重结晶。将溶液过滤,并将收集的沉淀干燥,得到粗制的十八烷基胺(5.9g)。
在搅拌下,用粗制的十八烷基胺处理如上制备的十八烷酰氯(8g)的二氯甲烷(40mL)溶液。加入三乙胺(15mL)和己烷(100mL),并将溶液在45℃下搅拌一小时。将溶液冷却,过滤,并用甲醇洗涤收集的沉淀。将沉淀从二氯甲烷重结晶,得到N-(十八烷酰基)十八烷基酰胺(6.8g),为白色粉末。
将产物悬浮于THF(150mL)中,并用氢化铝锂(1.5g,缓慢加入)处理。将反应混合物回流过夜。缓慢加入过量的甲醇,然后缓慢加入浓盐酸,直至沉淀溶解。溶液用水稀释,并使其结晶。将溶液过滤,并用水(4x)洗涤收集的沉淀。将沉淀在真空下干燥,得到二十八烷基胺(6.2g),为白色粉末。
将二十八烷基胺(4.5g)和单甲氧基-PEG-2000-乙酰基N-羟基琥珀酰亚胺酯(9g)在氯仿(90mL)中的溶液用三乙胺(40mL)处理并在50℃下搅拌30分钟。将溶液过滤。将乙酸酐(1mL)加入滤液,并将溶液搅拌15分钟。加入氨(150mL),然后加入卤水(150mL)。用二氯甲烷萃取反应混合物,并用稀盐酸洗涤有机相。有机部分经硫酸镁干燥,过滤并去除溶剂。使用0-8%甲醇/二氯甲烷梯度使残余物通过硅胶(75g)柱,以得到44-1,为白色粉末(7.4g)。
实施例45
PEG脂质的合成
将月桂酸(10g)在苯(20mL)中的悬浮液用草酰氯(10mL)处理一小时。去除溶剂,并将残余物溶解于二氯甲烷(50mL)。将该溶液缓慢加入搅拌中的浓缩的氨(150mL)。用二氯甲烷洗涤反应混合物。有机相经硫酸镁干燥,过滤并去除溶剂,得到粗制的十二烷酰基酰胺,为白色粉末(10g)。
将产物悬浮于THF(150mL)中,并用氢化铝锂(3g,缓慢加入)处理。将反应混合物搅拌一小时。缓慢加入过量的甲醇,然后缓慢加入氢氧化钠水溶液(5mL)。加入二氯甲烷(100mL),并将得到的悬浮液过滤。从滤液去除溶剂,并使用甲醇/二氯甲烷梯度使残余物通过硅胶(80g)柱,得到十二烷基胺(4.5g)。
将月桂酸(7.3g)、粗制的十四烷基胺(4.5g)和N-羟基琥珀酰亚胺(4.2g)在二氯甲烷(200mL)中的溶液用EDC(7.0g)处理,然后用三乙胺(15mL)处理,并将溶液在室温下搅拌过夜。将溶液过滤,得到粗制的N-十二烷酰基十二烷基酰胺(1g)粉末。从滤液去除溶剂,将残余物悬浮于甲醇并过滤,又得到2g粗制的N-十二烷酰基十二烷基酰胺。
将粗产物(3g)悬浮于THF(60mL)中,并用氢化铝锂(过量,缓慢加入)处理两小时。缓慢加入过量的甲醇,然后缓慢加入水(1mL)。加入二氯甲烷(100mL),并将悬浮液过滤。从滤液去除溶剂,并使用0-12%甲醇/二氯甲烷梯度使残余物通过硅胶柱(20g),得到N-十二烷酰基十二烷基胺(1.4g),为蜡状固体。
将N-十二烷基十二烷基胺(0.52g)和单甲氧基-PEG-2000-乙酰基N-羟基琥珀酰亚胺酯(1.5g)在二氯甲烷(10mL)中的溶液用三乙胺(0.2mL)处理并搅拌过夜。将溶剂去除,并使用0-6%甲醇/二氯甲烷梯度使产物通过硅胶柱(20g)。将乙酸酐(5滴)和三甲胺(10滴)加入回收产物的二氯甲烷溶液,并使其搅拌一小时。将溶剂去除,并使用0-4%甲醇/二氯甲烷梯度使残余物通过硅胶(20g)柱,以得到MePEGA-2000-DLA,为白色粉末(0.44g)。
实施例46
PEG脂质的合成
将肉豆蔻酸(30g)在苯(100mL)中的悬浮液用草酰氯(15mL)处理过夜。将溶剂去除,并将残余物溶解于二氯甲烷(100mL)。将溶液缓慢加入至搅拌中的浓缩的氨(70mL)。将得到悬浮液过滤,并用水洗涤。将沉淀干燥,得到粗制的十四烷酰基酰胺,为白色固体(27g)。
将产物悬浮于THF(200mL)中,并用氢化铝锂(4.5g,缓慢加入)处理。将反应混合物搅拌一小时。缓慢加入过量的甲醇,然后缓慢加入水(10mL)。加入二氯甲烷(250mL),并将得到的悬浮液过滤。从滤液去除溶剂,得到粗制的十四烷基胺(17.6g)。
将月桂酸(3.5g)、粗制的十四烷基胺(3g)和N-羟基琥珀酰亚胺(1.9g)在二氯甲烷(40mL)中的溶液用EDC(3.3g)处理,然后用三乙胺(4mL)处理,并将溶液在室温下搅拌三天。将溶液过滤,并将收集的沉淀干燥,得到粗制的N-月桂酰基十四烷基胺(2.6g)粉末。
将粗产物悬浮于THF(60mL)中,并用氢化铝锂(0.8g,缓慢加入)处理一小时。缓慢加入过量的甲醇,然后缓慢加入水(2mL)。加入二氯甲烷,并将悬浮液过滤。将溶剂去除,并将残余物溶解于热的甲醇(100mL)。将溶液冷却并过滤,以得到0.5g的N-十二烷基十四烷基胺。从滤液去除溶剂,并用20mL甲醇重复该过程,产生第二批N-十二烷基十四烷基胺(0.9g)。
将N-十二烷基十四烷基胺(0.5g)和单甲氧基-PEG-2000-乙酰基N-羟基琥珀酰亚胺酯(1.5g)在二氯甲烷(10mL)的溶液用三乙胺(0.2mL)处理并搅拌过夜。将溶剂去除,并使用0-6%甲醇/二氯甲烷梯度使产物通过硅胶柱(20g)。将乙酸酐(5滴)和三甲胺(10滴)加入回收产物的二氯甲烷溶液,并使其搅拌一小时。将溶剂去除,并使用0-4%甲醇/二氯甲烷梯度使残余物通过硅胶(20g)柱,以得到MePEGA-2000-LMA,为白色粉末(0.76g)。
实施例47
使用脂质纳米颗粒组合物的荧光素酶mRNA体内评估
将阳离子脂质(MC3)、DSPC、胆甾醇和PEG-脂质以50:10:38.5:1.5的摩尔比溶解于乙醇。以约10:1至30:1的总脂质与mRNA的重量比制备脂质纳米颗粒(LNP)。简略地,将mRNA在10至50mM柠檬酸盐缓冲液(pH 4)中稀释至0.2mg/mL。使用注射器泵,将脂质的乙醇溶液与mRNA水溶液以约1:5至1:3(体积/体积)的比例混合,总流速为15ml/min以上。然后去除乙醇,并通过透析用PBS替代外部的缓冲液。最后,将脂质纳米颗粒通过0.2μm孔无菌过滤器过滤。使用Nicomp 370亚微米粒度分选器(Santa Barbara,CA)通过准弹性光散射确定的脂质纳米颗粒的粒径为直径70-90nm。
根据实验动物管理委员会(ACC)和加拿大动物管理委员会(CCAC)制定的指南,在6-8周大的雌性C57BL/6小鼠(Charles River)中进行研究。通过尾静脉注射全身性施用不同剂量的mRNA-脂质纳米颗粒,并将动物在施用后的特定时间点(1、2、4、8和24hrs)执行安乐死。将肝和脾收集在经过预称重的管中,确定重量,立即在液氮中快速冷冻,并且在-80℃下储存,直至用于分析。
对于肝,切割约50mg以便在2mL FastPrep管(MP Biomedicals,Solon OH)中进行分析。向各个管中加入1/4”陶瓷球(MP Biomedicals),并且将与室温相匹配的500μL Glo溶胞缓冲液–GLB(Promega,Madison WI)加入肝组织。使用FastPrep24仪(MP Biomedicals)将肝组织在2x 6.0m/s下匀化15秒。将匀浆在室温下孵育5分钟,然后在GLB中进行1:4稀释,并使用SteadyGlo荧光素酶测定系统(Promega)进行评估。具体地,将50μL稀释的组织匀浆与50μL SteadyGlo底物反应,震摇10秒,然后孵育5分钟,然后使用CentroXS3 LB 960光度计(Berthold Technologies,Germany)定量。使用BCA蛋白质测定试剂盒(Pierce,RockfordIL)来确定测定的蛋白质的量。然后将相对荧光单位(RLU)以测定蛋白质的总ug数进行归一化。为了将RLU转化为ng荧光素酶,用QuantiLum重组荧光素酶(Promega)生成了标准曲线。基于图1中提供的数据,选择四小时时间点用于脂质制剂的功效评估(参见实施例48)。
得自Trilink Biotechnologies的FLuc mRNA(L-6107)将表达最初从萤火虫Photinus pyralis分离的荧光素酶蛋白。FLuc常用于哺乳动物细胞培养以测量基因表达和细胞活度。其在萤光素底物的存在下发射出生物光。这种加帽并且聚腺苷酸化的mRNA是被5-甲基胞苷和假尿苷完全取代的。
实施例48
使用体内荧光素酶mRNA表达的啮齿动物模型确定含有各种阳离子脂质的脂质纳米颗粒制剂的功效
预先用核酸检测了表2中示出的阳离子脂质。为了比较,这些脂质也用于使用串联(in line)混合方法配制含有FLuc mRNA(L-6107)的脂质纳米颗粒,所述串联混合方法如实施例47和PCT/US10/22614(由此通过引用整体并入本文)中所描述。使用以下摩尔比来配制脂质纳米颗粒:50%阳离子脂质/10%二硬脂酰磷脂酰胆碱(DSPC)/38.5%胆甾醇/1.5%PEG脂质(“PEG-DMG”,即,(1-(单甲氧基-聚乙二醇)-2,3-二肉豆蔻酰基甘油,具有2000的平均PEG分子量)。在如实施例47所述的尾静脉注射施用之后的4小时内,通过测量肝中的荧光素酶表达来确定相对活性。所述活性在0.3和1.0mg mRNA/kg的剂量比较,并且,以如实施例47所述的施用后4小时测量的ng荧光素酶/g肝来表达。
表2
与mRNA表现出活性的脂质
表3中示出的本发明的新型脂质使用以下摩尔比来配制:50%阳离子脂质/10%二硬脂酰磷脂酰胆碱(DSPC)/38.5%胆甾醇/1.5%PEG脂质(“PEG-DMA”化合物42-6)。在如实施例47所述的尾静脉注射施用之后的4小时内,通过测量肝中的荧光素酶表达来确定相对活性。所述活性在0.3和1.0mg mRNA/kg的剂量比较,并且,以如实施例47所述的施用后4小时测量的ng荧光素酶/g肝来表达。
表3
新型阳离子脂质
实施例49
所配制脂质pKA的确定
如本文其他部分所述,所配制阳离子脂质的pKa与LNP递送核酸的效果有关(参见Jayaraman等人,Angewandte Chemie,国际版(2012),51(34),8529-8533;Semple等人,Nature Biotechnology 28,172-176(2010))。优选的pKa范围是约5至约7。使用基于2-(对甲苯胺基)-6-萘磺酸(TNS)的荧光的测定来在脂质纳米颗粒测定各阳离子脂质的pKa。使用实施例47中描述的串联方法来制备以0.4mM总脂质浓度于PBS中的含有阳离子脂质/DSPC/胆甾醇/PEG-脂质(50/10/38.5/1.5mol%)的脂质纳米颗粒。TNS制成为蒸馏水中的100μM储备溶液。将囊泡稀释为于2mL缓冲溶液中的24μM脂质,所述缓冲溶液含有10mM HEPES、10mMMES、10mM乙酸铵、130mM NaCl,其中pH为2.5至11。加入等份的TNS溶液以得到1μM的最终浓度,然后在室温下于SLM Aminco Series 2发光分光光度计中使用321nm和445nm的激发和发射波长来测量涡流混合荧光强度。对荧光数据进行反曲最佳拟合分析,并且按照得到半最大荧光强度的pH测量pKa(参见图2)。
实施例50
氨基脂质的比较活性和烃链结构的影响
表5中示出的阳离子脂质使用以下摩尔比来配制:50%阳离子脂质/10%二硬脂酰磷脂酰胆碱(DSPC)/38.5%胆甾醇/1.5%PEG-脂质(42-6)。在如实施例48所述的尾静脉注射施用之后的4小时内,通过测量肝中的荧光素酶表达来确定相对活性。所述活性在0.1、0.3和1.0mg mRNA/kg的剂量比较,并且,以如实施例48所述的施用后4小时测量的ng荧光素酶/g肝来表达。在图3中绘制数据(从顶部至底部:菱形=化合物6;正方形=化合物5;三角形=MC3;以及圆形=化合物A)。化合物A、化合物5和化合物6具有共同的首基(headgroup)但具有不同的烃链结构。
表5
比较数据
实施例51
阳离子脂质的比较活性和首基链长度的影响
表6中示出的阳离子脂质使用以下摩尔比来配制:50%阳离子脂质/10%二硬脂酰磷脂酰胆碱(DSPC)/38.5%胆甾醇/1.5%PEG-脂质(42-6)。在如实施例48所述的尾静脉注射施用之后的4小时内,通过测量肝中的荧光素酶表达来确定相对活性。所述活性在0.1、0.3和1.0mg mRNA/kg的剂量比较,并且,以如实施例48所述的施用后4小时测量的ng荧光素酶/g肝来表达。化合A、B和C具有共同的烃链结构,但具有不同的首基链长度。化合物6与化合物A共享优选的首基,并且证明了将首基与烃链结构结合的出乎意料的优点。
表6
比较数据
实施例52
PEG-DMG和PEG-DMA脂质的比较活性
图4中示出了PEG-DMG和PEG-DMA脂质的比较活性。使用以下摩尔比配制LNP:50%MC3脂质/10%二硬脂酰磷脂酰胆碱(DSPC)/38.5%胆甾醇/1.5%PEG-脂质(PEG-DMG或PEG-DMA)。在如实施例48所述的尾静脉注射施用之后的4小时内,通过测量肝中的荧光素酶表达来确定相对活性。所述活性在0.1、0.3和1.0mg mRNA/kg的剂量比较,并且,以如实施例48所述的施用后4小时测量的ng荧光素酶/g肝来表达。
数据以柱状图形式在图4中呈现。
实施例53
使用红色荧光蛋白(称为樱桃红(CR))mRNA的LNP活性
如实施例47所述,使用化合物6配制具有mRNA的LNP,该mRNA为红色荧光蛋白(称为樱桃红(CR,例如TriLink Biotechnologies product L-6113))编码。如实施例47所述进行体内研究,并且处理肝组织切片并通过共焦荧光显微镜在施用后的4、6和24小时观察。表达水平在约6小时处达到最大值,并且保持到至少24小时。观察到的组织切片证明了在肝中的均匀表达。
实施例54
LNP将人FIX mRNA体内递送至肝细胞而引起小鼠血浆中的hFIX蛋白质的治疗水平
将表7中示出的具有阳离子脂质的LNP与编码人FIX(例如TriLinkBiotechnologies product L-6110)的mRNA进行配制,使用如实施例47所述的脂质摩尔比:50%脂质/10%二硬脂酰磷脂酰胆碱(DSPC)/38.5%胆甾醇/1.5%PEG-脂质。按照各个供应商的说明使用可商购的试剂盒(例如Abcam ab108831),通过ELISA分析血浆蛋白质。对于化合物5和化合物6的LNP,在表7中给出的测量的hFIX表达水平是临床相关的,并且以1mg/kg的剂量施用这些hFIX mRNA LNP会得到足以使患者从严重的疾病状态转为轻微的疾病状态的hFIX蛋白浓度。hFIX处于这些水平的时间是约15小时或更长。
表7
比较数据
示例性的实施方案包括以下:
实施方案1.具有式I结构的化合物:
或其药物可接受的盐、互变异构体、前药或立体异构体,其中:
L1和L2各自独立地为–O(C=O)-、-(C=O)O-或碳-碳双键;
R1a和R1b在每次出现时独立地(a)为H或C1-C12烃基,或(b)R1a为H或C1-C12烃基,并且R1b连同其连接的碳原子与相邻的R1b连同其连接的碳原子一起以形成碳-碳双键;
R2a和R2b在每次出现时独立地(a)为H或C1-C12烃基,或(b)R2a为H或C1-C12烃基,并且R2b连同其连接的碳原子结合相邻的R2b及其连接的碳原子,以形成碳-碳双键;
R3a和R3b在每次出现时独立地(a)为H或C1-C12烃基,或(b)R3a为H或C1-C12烃基,并且R3b连同其连接的碳原子结合相邻的R3b及其连接的碳原子,以形成碳-碳双键;
R4a和R4b在每次出现时独立地(a)为H或C1-C12烃基,或(b)R4a为H或C1-C12烃基,并且R4b连同其连接的碳原子结合相邻的R4b及其连接的碳原子,以形成碳-碳双键;
R5和R6各自独立地为甲基或环烃基;
R7在每次出现时独立地为H或C1-C12烃基;
R8和R9各自独立地为未取代的C1-C12烃基;或者R8和R9,连同它们连接的氮原子,一起形成包含一个氮原子的5元、6元或7元杂环;
a和d各自独立地为0至24的整数;
b和c各自独立地为1至24的整数;并且
e为1或2,
条件是:
R1a、R2a、R3a或R4a中的至少一个为C1-C12烃基,或者L1或L2中的至少一个为-O(C=O)-或–(C=O)O-;并且
R1a和R1b当a为6时不为不为异丙基,或当a为8时不为正丁基。
实施方案2.如实施方案1的化合物,其中L1或L2之一为-O(C=O)-。
实施方案3.如实施方案1或2中任一项的化合物,其中L1或L2之一为-(C=O)O-。
实施方案4.如实施方案1-3中任一项的化合物,其中L1或L2之一为碳-碳双键。
实施方案5.如实施方案1的化合物,其中所述化合物具有以下结构(Ia)、(Ib)或(Ic)之一:
实施方案6.如实施方案1-5中任一项的化合物,其中a、b、c和d各自独立地为2至12的整数。
实施方案7.如实施方案1-5中任一项的化合物,其中a、b、c和d各自独立地为5至9的整数。
实施方案8.如实施方案1-7中任一项的化合物,其中R1a、R2a、R3a和R4a中的至少一个为H。
实施方案9.如实施方案1-7中任一项的化合物,其中R1a、R2a、R3a和R4a在每次出现时为H。
实施方案10.如实施方案1-7中任一项的化合物,其中R1a、R2a、R3a和R4a中的至少一个为C1-C8烃基。
实施方案11.如实施方案10的化合物,其中C1-C8烃基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正己基或正辛基。
实施方案12.如实施方案1-11中任一项的化合物,其中R1b、R2b、R3b和R4b中的至少一个为H。
实施方案13.如实施方案1-11中任一项的化合物,其中R1b、R2b、R3b和R4b在每次出现时为H。
实施方案14.如实施方案1-11中任一项的化合物,其中R1b连同其连接的碳原子结合相邻的R1b及其连接的碳原子,以形成碳-碳双键。
实施方案15.如实施方案1-11或14中任一项的化合物,其中R4b连同其连接的碳原子结合相邻的R4b及其连接的碳原子,以形成碳-碳双键。
实施方案16.如实施方案1-15中任一项的化合物,其中R5或R6之一为甲基。
实施方案17.如实施方案1-15中任一项的化合物,其中各个R5和R6为甲基。
实施方案18.如实施方案1-15中任一项的化合物,其中R5或R6之一为环烃基。
实施方案19.如实施方案1-15中任一项的化合物,其中各个R5和R6为环烃基。
实施方案20.如实施方案18或19中任一项的化合物,其中所述环烃基是未取代的。
实施方案21.如实施方案18或19中任一项的化合物,其中所述环烃基是取代的。
实施方案22.如实施方案18或19中任一项的化合物,其中所述环烃基被C1-C6烃基取代。
实施方案23.如实施方案22的化合物,其中C1-C6烃基为叔丁基。
实施方案24.如实施方案18-23中任一项的化合物,其中环烃基为环己基。
实施方案25.如实施方案1-24中任一项的化合物,其中至少一个R7为H。
实施方案26.如实施方案25的化合物,其中各个R7为H。
实施方案27.如实施方案1-25中任一项的化合物,其中至少一个R7为C1-C6烃基。
实施方案28.如实施方案1-27中任一项的化合物,其中e为2。
实施方案29.如实施方案1-28中任一项的化合物,其中R8或R9中的至少一个为甲基。
实施方案30.如实施方案1-29的化合物,其中各个R8和R9为甲基。
实施方案31.如实施方案1的化合物,其中所述化合物选自表1中的化合物。
实施方案32.包含实施方案1-31中任一项的化合物和治疗剂的组合物。
实施方案33.如实施方案32的组合物,其还包含一种或多种选自中性脂质、甾族化合物和聚合物缀合的脂质的赋形剂。
实施方案34.如实施方案33的组合物,其中所述组合物包含一种或多种选自DSPC、DPPC、DMPC、DOPC、POPC、DOPE和SM的中性脂质。
实施方案35.如实施方案34的组合物,其中所述中性脂质为DSPC。
实施方案36.如实施方案33-35中任一项的组合物,其中所述化合物与所述中性脂质的摩尔比为约2:1至约8:1。
实施方案37.如实施方案32-36中任一项的组合物,其中所述甾族化合物为胆甾醇。
实施方案38.如实施方案37的组合物,其中所述化合物与胆甾醇的摩尔比为约2:1至1:1。
实施方案39.如实施方案32-38中任一项的组合物,其中所述聚合物缀合的脂质为聚乙二醇化的脂质。
实施方案40.如实施方案39的组合物,其中所述化合物与所述聚乙二醇化的脂质的摩尔比为约100:1至约25:1。
实施方案41.如实施方案39或40中任一项的组合物,其中所述聚乙二醇化的脂质为PEG-DMG。
实施方案42.如实施方案39或40中任一项的组合物,其中所述聚乙二醇化的脂质具有以下结构(II):
或其药物可接受的盐、互变异构体或立体异构体,其中:
R10和R11各自独立地为含有10至30个碳原子的直链或支链、饱和或不饱和的烃基链,其中所述烃基链任选地被一个或多个酯键中断;并且
z具有30至60的平均值。
实施方案43.如实施方案42的组合物,其中R10和R11各自独立地为含有12至16个碳原子的直链的、饱和的烃基链。
实施方案44.如实施方案42或43中任一项的组合物,其中平均值z为约45。
实施方案45.如实施方案32-44中任一项的组合物,其中所述治疗剂包含核酸。
实施方案46.如实施方案45的组合物,其中所述核酸选自反义RNA和信使RNA。
实施方案47.向由此需要的患者施用治疗剂的方法,所述方法包括制备或提供实施方案32-46中任一项的组合物,并向所述患者施用该组合物。
实施方案48.具有以下结构(II)的聚乙二醇化的脂质:
或其药物可接受的盐、互变异构体或立体异构体,其中:
R10和R11各自独立地为含有10至30个碳原子的直链或支链、饱和或不饱和的烃基链,其中所述烃基链任选地被一个或多个酯键中断;并且
z具有30至60的平均值;
条件是,R10和R11当z为42时不均为正十八烷基。
实施方案49.如实施方案48的聚乙二醇化的脂质,其中R10和R11各自独立地为含有12至16个碳原子的直链的、饱和的烃基链。
实施方案50.如实施方案48或49中任一项的聚乙二醇化的脂质,其中z为约45。
实施方案51.如实施方案48的聚乙二醇化的脂质,其具有以下结构之一:
其中n具有40至50的平均值。
实施方案52.包含实施方案48-51中任一项的聚乙二醇化的脂质和阳离子脂质的组合物。
实施方案53.如实施方案52的组合物,其中所述阳离子脂质为实施方案1-31中任一项的化合物。
可以合并上述各种实施方案以提供其他实施方案。本说明书中提及的和/或申请数据单中列出的所有美国专利、美国专利申请公开、美国专利申请、外国专利、外国专利申请和非专利出版物,包括但不限于2014年6月25日提交的美国临时申请第62/016,839号,通过引用整体并入本文。如果有必要,可使用各种专利、申请和出版物的概念修改各实施方案的方面,来提供其他的实施方案。根据上文详细的描述,可以对实施方案进行这些和其他的改变。通常,在以下权利要求中,不应将所使用的术语解释为将权利要求限定于本说明书中公开的特定实施方案,并且应当将权利要求解释为包括所有可能的实施方案,以及这些权利要求有权享有的等价物的全部范围。因此,权利要求不受本公开内容限定。
Claims (47)
1.具有式I结构的化合物:
或其药物可接受的盐、互变异构体、前药或立体异构体,其中:
L1和L2各自独立地为–O(C=O)-、-(C=O)O-或碳-碳双键;
R1a和R1b在每次出现时独立地(a)为H或C1-C12烃基,或(b)R1a为H或C1-C12烃基,并且R1b连同其连接的碳原子与相邻的R1b连同其连接的碳原子一起形成碳-碳双键;
R2a和R2b在每次出现时独立地(a)为H或C1-C12烃基,或(b)R2a为H或C1-C12烃基,并且R2b连同其连接的碳原子结合相邻的R2b及其连接的碳原子,以形成碳-碳双键;
R3a和R3b在每次出现时独立地(a)为H或C1-C12烃基,或(b)R3a为H或C1-C12烃基,并且R3b连同其连接的碳原子结合相邻的R3b及其连接的碳原子,以形成碳-碳双键;
R4a和R4b在每次出现时独立地(a)为H或C1-C12烃基,或(b)R4a为H或C1-C12烃基,并且R4b连同其连接的碳原子结合相邻的R4b及其连接的碳原子,以形成碳-碳双键;
R5和R6各自独立地为甲基或环烃基;
R7在每次出现时独立地为H或C1-C12烃基;
R8和R9各自独立地为未取代的C1-C12烃基;或者R8和R9,连同它们连接的氮原子,一起形成包含一个氮原子的5元、6元或7元杂环;
a和d各自独立地为0至24的整数;
b和c各自独立地为1至24的整数;并且
e为1或2,
条件是:
R1a、R2a、R3a或R4a中的至少一个为C1-C12烃基,或者L1或L2中的至少一个为-O(C=O)-或–(C=O)O-;并且
R1a和R1b当a为6时不为异丙基,或者当a为8时不为正丁基。
2.如权利要求1所述的化合物,其中L1或L2之一为-O(C=O)-。
3.如权利要求1所述的化合物,其中L1或L2之一为-(C=O)O-。
4.如权利要求1所述的化合物,其中L1或L2之一为碳-碳双键。
6.如权利要求1所述的化合物,其中a、b、c和d各自独立地为2至12的整数。
7.如权利要求1所述的化合物,其中a、b、c和d各自独立地为5至9的整数。
8.如权利要求1所述的化合物,其中R1a、R2a、R3a和R4a中的至少一个为H。
9.如权利要求1所述的化合物,其中R1a、R2a、R3a和R4a在每次出现时为H。
10.如权利要求1所述的化合物,其中R1a、R2a、R3a和R4a中的至少一个为C1-C8烃基。
11.如权利要求10所述的化合物,其中C1-C8烃基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正己基或正辛基。
12.如权利要求1所述的化合物,其中R1b、R2b、R3b和R4b中的至少一个为H。
13.如权利要求1所述的化合物,其中R1b、R2b、R3b和R4b在每次出现时为H。
14.如权利要求1所述的化合物,其中R1b连同其连接的碳原子结合相邻的R1b及其连接的碳原子,以形成碳-碳双键。
15.如权利要求1所述的化合物,其中R4b连同其连接的碳原子结合相邻的R4b及其连接的碳原子,以形成碳-碳双键。
16.如权利要求1所述的化合物,其中R5或R6之一为甲基。
17.如权利要求1所述的化合物,其中各个R5和R6为甲基。
18.如权利要求1所述的化合物,其中R5或R6之一为环烃基。
19.如权利要求1所述的化合物,其中各个R5和R6为环烃基。
20.如权利要求18所述的化合物,其中所述环烃基是未取代的。
21.如权利要求18所述的化合物,其中所述环烃基是取代的。
22.如权利要求18所述的化合物,其中所述环烃基被C1-C6烃基取代。
23.如权利要求22所述的化合物,其中C1-C6烃基为叔丁基。
24.如权利要求18所述的化合物,其中环烃基为环己基。
25.如权利要求1所述的化合物,其中至少一个R7为H。
26.如权利要求25所述的化合物,其中各个R7为H。
27.如权利要求1所述的化合物,其中至少一个R7为C1-C6烃基。
28.如权利要求1所述的化合物,其中e为2。
29.如权利要求1所述的化合物,其中R8或R9中的至少一个为甲基。
30.如权利要求1所述的化合物,其中各个R8和R9为甲基。
32.包含权利要求1至31中任一项所述的化合物和治疗剂的组合物。
33.如权利要求32所述的组合物,其还包含一种或多种选自中性脂质、甾族化合物和聚合物缀合的脂质的赋形剂。
34.如权利要求33所述的组合物,其中所述组合物包含一种或多种选自DSPC、DPPC、DMPC、DOPC、POPC、DOPE和SM的中性脂质。
35.如权利要求34所述的组合物,其中所述中性脂质为DSPC。
36.如权利要求33所述的组合物,其中所述化合物与所述中性脂质的摩尔比为约2:1至约8:1。
37.如权利要求32所述的组合物,其中所述甾族化合物为胆甾醇。
38.如权利要求37所述的组合物,其中所述化合物与胆甾醇的摩尔比为约2:1至1:1。
39.如权利要求32所述的组合物,其中所述聚合物缀合的脂质为聚乙二醇化的脂质。
40.如权利要求39所述的组合物,其中所述化合物与所述聚乙二醇化的脂质的摩尔比为约100:1至约25:1。
41.如权利要求39所述的组合物,其中所述聚乙二醇化的脂质为PEG-DMG。
43.如权利要求42所述的组合物,其中R10和R11各自独立地为含有12至16个碳原子的直链的、饱和的烃基链。
44.如权利要求42所述的组合物,其中所述平均值z为约45。
45.如权利要求32所述的组合物,其中所述治疗剂包含核酸。
46.如权利要求45所述的组合物,其中所述核酸选自反义RNA和信使RNA。
47.向有此需要的患者施用治疗剂的方法,所述方法包括制备或提供权利要求32所述的组合物,并向所述患者施用所述组合物。
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