CN117500489A - 脂质纳米材料及其用途 - Google Patents
脂质纳米材料及其用途 Download PDFInfo
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- CN117500489A CN117500489A CN202280043008.9A CN202280043008A CN117500489A CN 117500489 A CN117500489 A CN 117500489A CN 202280043008 A CN202280043008 A CN 202280043008A CN 117500489 A CN117500489 A CN 117500489A
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Abstract
本文公开了可以用于药物递送和筛选的脂质制剂。
Description
相关申请的交叉引用
本申请要求2021年4月26日提交的美国临时专利申请序列号63/179,688的权益,该专利申请的公开内容明确地以引用的方式并入本文。
关于政府资助的声明
本发明是依据美国国家卫生研究院(National Institutes of Health)授予的授权号/合同号R35 GM119679在政府支持下制作的。政府对本发明享有一定权利。
技术领域
本申请总体上涉及可以用于药物递送和筛选的脂质制剂。
背景技术
治疗剂(如mRNA)的有效递送是mRNA治疗剂中的关键步骤和挑战。这些基于核酸的治疗剂已展现出作为用于保留治疗剂功能的手段的巨大潜力,但仍然需要更有效地递送至细胞或生物体内的适当部位以实现这种潜力。尽管来自正在进行的临床试验的数据很有希望,但mRNA的临床使用需要发现和开发更有效的递送系统。由于这些递送系统的功效通常源于基础脂质分子的组成结构,因此需要新的组合物和方法来将mRNA递送至细胞以治疗各种疾病状态。
然而,目前存在限制寡核苷酸在治疗和诊断背景下的广泛使用的问题。首先,游离RNA易于在血浆中被核酸酶消化,从而促进治疗剂的降解。其次,这些寡核苷酸在进入相关翻译机器所在的细胞内区室方面通常受到限制。由阳离子脂质与其它脂质组分形成的脂质纳米颗粒已被用来穿越这些屏障并增加这些寡核苷酸的细胞摄取。因此,仍然需要用于递送寡核苷酸的改进的阳离子脂质和脂质纳米颗粒。
发明内容
根据如本文所实施和广泛描述的所公开化合物和方法的目的,所公开的主题涉及化合物以及制备和使用该化合物的方法。
例如,本文公开了由式I-XIX定义的化合物或其药学上可接受的盐:
其中
R1、R2、R3和R4各自独立地为经取代的或未经取代的C1-C20烷基;
R5和R14各自独立地为氢、经取代的或未经取代的C1-C5烷基;R6、R7、R8、R9、R10、R11、R12和R13各自独立地为氢、OH、卤素或经取代的或未经取代的C1-C5烷基;
R15、R16和R17各自独立地为氢、OH、卤素或经取代的或未经取代的C1-C5烷基;并且
R18为OH或经取代的或未经取代的C1-C10烷基。
在一些方面中,R1、R2、R3和R4各自独立地选自由以下组成的组:
其中n、m和x各自独立地表示1至9,如1至5的整数。
本文还公开了制备本文公开的组合物中的任何组合物的方法。
本文还公开了包含本文公开的组合物中的任何组合物的脂质颗粒。在一些实例中,脂质颗粒的形状基本上为球形的。在一些实例中,脂质颗粒具有50纳米(nm)至500nm的平均粒度。在一些实例中,脂质颗粒具有100nm至200nm、120nm至140nm、或150nm至200nm的平均粒度。在一些实例中,脂质颗粒具有0.3或更小、0.2或更小、或者0.1或更小的多分散性指数。在一些实例中,脂质颗粒进一步包含额外的组分。在一些实例中,该额外的组分包括额外的脂质。在一些实例中,该额外的脂质包括磷脂、固醇或它们的组合。在一些实例中,该脂质颗粒进一步包含1,2-二油酰基-sn-甘油-3-磷酸乙醇胺(DOPE)、胆固醇、1,2-二肉豆蔻酰基-外消旋-甘油-3-甲基聚氧乙烯或它们的组合。
本文还公开了包含包封在本文公开的脂质颗粒中的任何脂质颗粒内的治疗剂的药物组合物。在一些实例中,该治疗剂以50%或更高、75%或更高、或90%或更高的包封效率包封在脂质颗粒内。在一些实例中,该治疗剂包括抗癌剂、抗炎剂、抗微生物剂或它们的组合。在一些实例中,该治疗剂包括化学治疗剂、免疫治疗剂或它们的组合。在一些实例中,该治疗剂包括核酸。在一些实例中,该核酸是mRNA。
本文还公开了治疗有需要的受试者的疾病或病症的方法,该方法包括向该受试者施用治疗有效量的本文公开的药物组合物中的任何药物组合物。在一些实例中,该疾病包括神经系统疾病。在其它方面,该疾病包括肝病。在其它方面,该疾病包括肌肉骨骼疾病。
所公开组合物的额外优点将部分地在下面的说明书中阐述,并且部分地将从说明书中显而易见。所公开的组合物和方法的优点将借助在所附权利要求书中特别指出的要素和组合来实现和达到。应当理解,前述一般性描述与以下详细描述两者均仅为示例性和说明性的,并且不限制所要求保护的所公开组合物和方法。
附图和下面的说明书中阐述了本发明的一个或多个实施方案的细节。本发明的其它特征、目的和优点将是从说明书和附图以及从权利要求书中显而易见的。
附图说明
并入本说明书中并且构成本说明书的一部分的附图示出本公开的若干方面,并且连同说明书一起用来解释本公开的原理。
图1描绘在CCL131细胞(使用的小鼠神经母细胞系)中包封萤火虫荧光素酶mRNA的脑靶向脂质纳米颗粒(LNP)的配制和筛选。将数据用MC3 LNP归一化。
图2描绘了用于检查使用脑靶向脂质(BL28、BL39、BL54、BL68和BL70)配制的LNP的体内mRNA递送的聚类测试方法。与PBS处理组相比,聚集的LNP-mRNA制剂在小鼠脑中显示出显著更高的生物发光强度。
图3描绘形成脂质纳米颗粒的基础的样品化合物的集合。
具体实施方式
现在将详细参考本公开的实施方案。然而,本公开可以许多不同的形式实施并且不应解读为受限于本文阐述的实施方案。
除非另外定义,否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。提供以下定义以充分理解本说明书中使用的术语。
一般定义
除非上下文另外明确规定,否则如在本说明书和权利要求书中所用,单数形式“一个/种(a/an)”和“该/所述”包括复数个提及物。例如,术语“一种剂”包括多种剂,包括其混合物。
如本文所用,术语“可以”、“任选地”和“可任选地”可互换使用并且意在包括条件发生的情况以及条件不发生的情况。因此,例如,制剂“可包含赋形剂”的陈述意在包括制剂包含赋形剂的情况以及制剂不包含赋形剂的情况。
如本文所用,向受试者“施用”剂包括向受试者引入或递送剂以执行剂的一种或多种预期功能的任何途径。施用可通过包括经口、鼻内、肠胃外(静脉内、肌内、腹膜内或皮下)、外用等在内的任何合适的途径进行。“全身施用”是指经由将剂引入或递送至受试者身体的广泛区域(例如身体的大于50%)的途径(例如通过进入循环系统、胃肠系统或淋巴系统),向该受试者引入或递送该剂。相比之下,“局部施用”是指经由将剂引入或递送至施用点局部附近的一个或多个区域并且不以治疗显著量全身性引入该剂的途径将该剂引入或递送至受试者。例如,局部施用的剂在施用点的局部附近是可容易检测到的,但在受试者身体的远端部分中是检测不到的或可以可忽略不计的量检测到。施用包括自我施用和由另一者施用。
如本文所用,术语“预防”受试者中的病症或不想要的生理事件具体是指预防症状和/或其根本原因的进展或复发,其中受试者可能或可能不表现出对病症或事件的高度易感性(例如,诱导消退或阻止进展)。
术语剂的“有效量”是指足以提供所需效果的剂的量。“有效”的剂的量将因受试者而异,这取决于许多因素,诸如受试者的年龄和一般状况、一种或多种特定剂等。因此,并不总是可以指定量化的“有效量”。然而,本领域普通技术人员可以使用常规实验确定任何受试者情况下的适当“有效量”。此外,如本文所用,并且除非另外具体说明,否则剂的“有效量”还可以指涵盖治疗有效量和预防有效量的量。
实现治疗效果所需的剂的“有效量”可根据诸如受试者的年龄、性别和体重的因素而变化。可调整剂量方案以提供最佳治疗反应。例如,可每日施用若干分开的剂量或可如治疗情况的紧急程度所指示按比例减少剂量。例如,在持续一天或数天的一次或多次剂量施用中,剂的有效量可从约0.001mg/kg至约1000mg/kg变化(取决于施用模式)。在某些实施方案中,每剂的有效量从约0.001mg/kg至约1000mg/kg、约0.01mg/kg至约750mg/kg、约0.1mg/kg至约500mg/kg、约1.0mg/kg至约250mg/kg以及约10.0mg/kg至约150mg/kg变化。
如本文所用,术语“药学上可接受的”组分可指不是生物学上或其它方面不期望的组分,例如,该组分可被并入到本发明的药物制剂中并且如本文所述施用至受试者,而不会引起任何显著的不期望的生物效应或以有害的方式与含有它的制剂的任何其它组分相互作用。当术语“药学上可接受的”用于指赋形剂时,通常意味着该组分已满足毒理学和生产测试所要求的标准,或者该组分包括在由美国食品与药品管理局制定的非活性成分指南中。
如本文所用,术语“药理学活性”(或简称为“活性”),如在“药理学活性”衍生物或类似物中,可指与母体化合物具有相同类型的药理活性且程度大致相当的衍生物或类似物(例如,盐、酯、酰胺、缀合物、代谢物、异构体、片段等)。
如本文所用,术语“受控释放”是指以受控方式从给定剂型中释放剂,以实现所需的体内药代动力学特征。“受控释放”剂递送的一个方面是操纵制剂和/或剂型以便建立所需的剂释放动力学的能力。
如本文所用,术语“受试者”或“宿主”可指活生物体,诸如哺乳动物,包括但不限于人、家畜、狗、猫和其它哺乳动物。治疗剂的施用可以对治疗受试者有效的剂量和时间段进行。在一些实施方案中,受试者是人。
范围在本文中可表示为从“约”一个特定值和/或至“约”另一个特定值。“约”意指在该值的5%内,例如该值的4%、3%、2%或1%内。当表示这样的范围时,另一方面包括从一个特定值和/或至另一特定值。类似地,当通过使用先行词“约”将值表示为近似值时,应理解,该特定值形成另一方面。应进一步理解,该范围中的每一个范围的端点相对于另一个端点以及独立于另一个端点都是有意义的。
“示例性”意指“……的实例”并且不旨在传达优选或理想实施方案的指示。“如”并非以限制性意义使用,而是出于说明性目的。
值在本文中可表示为“平均”值。“平均”一般指统计平均值。
“基本上”意指在5%以内,例如在4%、3%、2%或1%以内。
应理解,贯穿本说明书,使用标识符“第一”和“第二”仅仅是为了帮助区分公开的主题的各种组分和步骤。标识符“第一”和“第二”不希望暗含由这些术语修饰的组分或步骤的任何具体的顺序、量、优先性或重要性。
本说明书和结论性权利要求书中对组合物中特定要素或组分的重量份数的提及表示用重量份数表示的该要素或组分与组合物或物品中任何其它要素或组分之间的重量关系。因此,在含有2重量份的组分X和5重量份的组分Y的化合物中,X和Y以2:5的重量比存在,并且以这个比例存在而不管该化合物中是否包含额外的组分。
除非特别说明相反,否则组分的重量百分比(重量%)基于包含该组分的制剂或组合物的总重量。
如本文所用的术语“或它们的组合”是指该术语之前所列出的项目的所有排列和组合。例如,“A、B、C或它们的组合”旨在包括以下中的至少一者:A、B、C、AB、AC、BC或ABC,并且如果顺序在特定上下文中重要,则也包括BA、CA、CB、CBA、BCA、ACB、BAC或CAB。继续此实例,明确包括含有一个或多个项目或术语的重复的组合,诸如BB、AAA、AB、BBC、AAABCCCC、CBBAAA、CABABB等。本领域技术人员将理解,通常对任何组合中的项目或术语的数量没有限制,除非从上下文中明显看出。
术语“抑制”是指活动性(activity)、反应、疾患、疾病或其它生物学参数的降低。这可包括但不限于完全消除活动性、反应、疾患或疾病。这还可包括例如与天然或对照水平相比,活动性、反应、疾患或疾病的10%降低。因此,降低可以是与天然或对照水平相比10%、20%、30%、40%、50%、60%、70%、80%、90%、100%或其间的任何量的降低。
“降低”或该词的其它形式,例如“减少”或“减小”,意指降低事件或特性(例如,肿瘤生长)。应当理解,这通常与一些标准或预期值相关,换言之,其是相对的,但并不总是需要参考标准值或相对值。例如,“减少肿瘤生长”意指相对于标准或对照降低肿瘤的生长速率。
术语“治疗”是指对患者进行医学管理,意图是治愈、改善、稳定化或预防疾病、病理性疾患,或病症。此术语包括积极治疗,即专门针对改善疾病、病理性疾患或病症的治疗,并且还包括病因治疗,即针对去除相关疾病、病理性疾患或病症的病因的治疗。此外,此术语包括姑息治疗,即设计用于缓解症状而不是治愈疾病、病理性疾患或病症的治疗;预防性治疗,即旨在最小化或部分或完全抑制相关疾病、病理性疾患或病症的发展的治疗;和支持性治疗,即用来补充另一种旨在改善相关疾病、病理性疾患或病症的特定疗法的治疗。举例来说,在纤维化疾患的上下文中,如本文所用的“治疗(treating)”、“治疗(treat)”和“治疗(treatment)”是指部分或完全抑制或减轻受试者所患有的纤维化疾患。在一个实施方案中,此术语是指当患者患有或被诊断患有纤维化疾患时发生的作用,其降低疾患的严重性,或者延缓或减慢疾患的进展。治疗不一定带来疾患的完全治愈;此术语涵盖纤维化疾患的部分抑制或减轻。
术语“抗癌”是指在任何浓度下治疗或控制细胞增殖和/或肿瘤生长的能力。
除非另有说明,否则如本文所用,“分子量”是指如通过1H NMR光谱测量的数均分子量。
如本文所用,术语“递送”涵盖局部递送和全身递送。例如,mRNA的递送涵盖其中将mRNA递送至靶组织并且所编码的蛋白质或肽在靶组织内表达并保留的情况(也称为“局部分布”或“局部递送”),以及其中mRNA被递送至靶组织并且所编码的蛋白质或肽被表达并分泌到患者的循环系统(例如血清)中且全身性地分布并被其它组织吸收的情况(也称为“全身分布”或“全身递送)。
如本文所用,术语“包封”或语法等同物是指将单个核酸分子限制在纳米颗粒内的过程。
如本文所用,mRNA的“表达”是指将mRNA翻译成肽(例如,抗原)、多肽或蛋白质(例如,酶),并且如上下文所示,还可包括肽、多肽或完全组装的蛋白质(例如酶)的翻译后修饰。在本申请中,术语“表达”和“产生”及语法等效物可互换地使用。
如本文所用,术语“信使RNA(mRNA)”是指编码至少一种肽、多肽或蛋白质的多核苷酸。如本文所用的mRNA涵盖经修饰的和未经修饰的RNA。mRNA可含有一个或多个编码区和非编码区。mRNA可从天然来源纯化、使用重组表达系统产生并且任选地被纯化、化学合成等。在适当的情况下,例如在化学合成分子的情况下,mRNA可包含核苷类似物,如具有化学修饰的碱基或糖、主链修饰等的类似物。除非另有说明,否则mRNA序列以5'至3'方向呈现。在一些实施方案中,mRNA是或包含天然核苷(例如,腺苷、鸟苷、胞苷、尿苷);核苷类似物(例如,2-氨基腺苷、2-硫胸苷、肌苷、吡咯并嘧啶、3-甲基腺苷、5-甲基胞苷、C-5丙炔基-胞苷、C-5丙炔基-尿苷、2-氨基腺苷、C5-溴尿苷、C5-氟尿苷、C5-碘尿苷、C5-丙炔基-尿苷、C5-丙炔基-胞苷、C5-甲基胞苷、2-氨基腺苷、7-脱氮腺苷、7-脱氮鸟苷、8-氧代腺苷、8-氧代鸟苷、O(6)-甲基鸟嘌呤、2-硫胞苷、假尿苷和5-甲基胞苷);经化学修饰的碱基;经生物修饰的碱基(例如,甲基化碱基);经插入的碱基;经修饰的糖(例如,2'-氟核糖、核糖、2'-脱氧核糖、阿拉伯糖和己糖);和/或经修饰的磷酸基团(例如,硫代磷酸酯和5'-N-亚磷酰胺键联)。
如本文所用,术语“核酸”在其最广泛的意义上是指被并入或可被并入到多核苷酸链中的任何化合物和/或物质。在一些实施方案中,核酸是经由磷酸二酯键联被并入或可经由磷酸二酯键联被并入到多核苷酸链中的化合物和/或物质。在一些实施方案中,“核酸”是指单独的核酸残基(例如核苷酸和/或核苷)。在一些实施方案中,“核酸”是指包含单独的核酸残基的多核苷酸链。在一些实施方案中,“核酸”涵盖RNA以及单链和/或双链DNA和/或cDNA。此外,术语“核酸”、“DNA”、“RNA”和/或类似术语包含核酸类似物,即,不具有磷酸二酯主链的类似物。
化学定义
除非另外定义,否则本文所用的所有技术和科学术语均具有与本发明所属领域的普通技术人员通常所理解的相同的含义。
当定义本文所述通式内的可变位置时提到的有机部分(例如,术语“卤素”)是有机部分所涵盖的各个取代基的统称。基团或部分之前的前缀Cn-Cm在每种情况下表示后面的基团或部分中的碳原子的可能数目。
如本文所用的术语“离子”是指含有电荷(正电荷,负电荷,或同时存在于一个分子、分子簇、分子复合物或部分(例如,两性离子)内的两者)或者可被制成含有电荷的任何分子、分子的部分、分子簇、分子复合物、部分或原子。用于在分子、分子的部分、分子簇、分子复合物、部分或原子中产生电荷的方法在本文被公开,并且可通过本领域已知的方法,例如质子化、去质子化、氧化、还原、烷基化、乙酰化、酯化、脱酯化、水解等完成。
术语“阴离子”是一种类型的离子并且包括在术语“离子”的含义内。“阴离子”是含有净负电荷或可被制成含有净负电荷的任何分子、分子的部分(例如,两性离子)、分子簇、分子复合物、部分或原子。术语“阴离子前体”在本文中用于具体指可通过化学反应(例如,去质子化)转化为阴离子的分子。
术语“阳离子”是一种类型的离子并且包括在术语“离子”的含义内。“阳离子”是含有净正电荷或可被制成含有净正电荷的任何分子、分子的部分(例如,两性离子)、分子簇、分子复合物、部分或原子。术语“阳离子前体”在本文中用于具体指可通过化学反应(例如,质子化或烷基化)转化为阳离子的分子。
如本文所用,术语“经取代的”预期包括有机化合物的所有可允许的取代基。在广义方面,可允许的取代基包括有机化合物的无环和环状的、支化和非支化的、碳环和杂环的、以及芳族和非芳族的取代基。说明性取代基包括例如下文所述的那些取代基。对于适当有机化合物,允许的取代基可为一个或多个且相同或不同。出于本公开的目的,杂原子(例如氮)可具有氢取代基和/或本文所述有机化合物的满足杂原子化合价的任何允许的取代基。本公开并不旨在以任何方式受限于有机化合物的允许的取代基。而且,术语“取代”或“被……取代”包括隐含条件,即这种取代符合被取代原子和取代基的容许化合价,并且取代产生稳定化合物,例如不会自发地如通过重排、环化、消除等进行转化的化合物。
“Z1”、“Z2”、“Z3”和“Z4”在本文中用作通用符号以表示各种具体的取代基。这些符号可以为任何取代基,但并不限于本文公开的那些,当在一种情况下将它们定义为某些取代基时,在另一种情况下,可以将它们定义为一些其它取代基。
如本文所用的术语“脂族”是指非芳族烃基,并且包括支化和非支化的烷基、烯基或炔基。
如本文所用,术语“烷基”是指饱和、直链或支化饱和烃基。除非另有说明,否则意指C1-C24(例如,C2-C22、C4-C22、C6-C22、C8-C22、C10-C22、C12-C22、C14-C22、C16-C22、C2-C20、C4-C20、C6-C20、C8-C20、C10-C20、C12-C20、C14-C20、C16-C20、C1-C20、C1-C18、C1-C16、C1-C14、C1-C12、C1-C10、C1-C8、C1-C6或C1-C4)烷基。烷基的实例包括甲基、乙基、丙基、1-甲基-乙基、丁基、1-甲基-丙基、2-甲基-丙基、1,1-二甲基-乙基、戊基、1-甲基-丁基、2-甲基-丁基、3-甲基-丁基、2,2-二甲基-丙基、1-乙基-丙基、己基、1,1-二甲基-丙基、1,2-二甲基-丙基、1-甲基-戊基、2-甲基-戊基、3-甲基-戊基、4-甲基-戊基、1,1-二甲基-丁基、1,2-二甲基-丁基、1,3-二甲基-丁基、2,2-二甲基-丁基、2,3-二甲基-丁基、3,3-二甲基-丁基、1-乙基-丁基、2-乙基-丁基、1,1,2-三甲基-丙基、1,2,2-三甲基-丙基、1-乙基-1-甲基-丙基、1-乙基-2-甲基-丙基、庚基、辛基、壬基、癸基、十二烷基、十四烷基、十六烷基、二十烷基、二十四烷基等。烷基取代基可以是未经取代的或者是经一个或多个化学部分取代的。烷基可被一个或多个基团取代,该基团包括但不限于如下所述的羟基、卤素、缩醛、酰基、烷基、烷氧基、烯基、炔基、芳基、杂芳基、醛、氨基、氰基、羧酸、酯、醚、碳酸酯、氨基甲酸酯、酮、硝基、膦酰基、甲硅烷基、磺基-氧代、磺酰基、砜、亚砜或硫醇,条件是取代基在空间上是相容的,并且满足化学键合和应变能的规则。
在整个说明书中,“烷基”通常用于指未经取代的烷基和经取代的烷基;然而,经取代的烷基在本文中还通过标识烷基上的一个或多个具体取代基而被具体提及。例如,术语“卤化烷基(halogenated alkyl)”或“卤代烷基(haloalkyl)”具体地指被一个或多个卤根(卤素;例如,氟、氯、溴或碘)取代的烷基。术语“烷氧基烷基”具体地指被一个或多个如下所述的烷氧基取代的烷基。术语“烷基氨基”具体是指被一个或多个如下所述的氨基等取代的烷基。当在一种情况下使用“烷基”而在另一种情况下使用诸如“烷基醇”的特定术语时,并不意味着暗示术语“烷基”也不指代诸如“烷基醇”等的特定术语。
此实践也用于本文所述的其它基团。即,尽管诸如“环烷基”的术语是指未经取代的和经取代的环烷基部分,但经取代的部分可另外在本文中被具体地标识;例如,特定的经取代的环烷基可称为例如“烷基环烷基”。类似地,经取代的烷氧基可以具体地称为例如“卤化烷氧基”,特定的经取代的烯基可以是例如“烯基醇”等。再次地,使用通用术语,诸如,“环烷基”和特定术语,诸如“烷基环烷基”的实践并不意在暗示通用术语也不包括特定术语。
如本文所用,术语“烯基”是指含有双键的不饱和直链或支化烃部分。除非另有说明,否则意指C2-C24(例如,C2-C22、C2-C20、C2-C18、C2-C16、C2-C14、C2-C12、C2-C10、C2-C8、C2-C6或C2-C4)烯基。烯基可含有多于一个不饱和键。实例包括乙烯基、1-丙烯基、2-丙烯基、1-甲基乙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-甲基-1-丙烯基、2-甲基-1-丙烯基、1-甲基-2-丙烯基、2-甲基-2-丙烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、3-甲基-1-丁烯基、1-甲基-2-丁烯基、2-甲基-2-丁烯基、3-甲基-2-丁烯基、1-甲基-3-丁烯基、2-甲基-3-丁烯基、3-甲基-3-丁烯基、1,1-二甲基-2-丙烯基、1,2-二甲基-1-丙烯基、1,2-二甲基-2-丙烯基、1-乙基-1-丙烯基、1-乙基-2-丙烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、3-甲基-1-戊烯基、4-甲基-1-戊烯基、1-甲基-2-戊烯基、2-甲基-2-戊烯基、3-甲基-2-戊烯基、4-甲基-2-戊烯基、1-甲基-3-戊烯基、2-甲基-3-戊烯基、3-甲基-3-戊烯基、4-甲基-3-戊烯基、1-甲基-4-戊烯基、2-甲基-4-戊烯基、3-甲基-4-戊烯基、4-甲基-4-戊烯基、1,1-二甲基-2-丁烯基、1,1-二甲基-3-丁烯基、1,2-二甲基-1-丁烯基、1,2-二甲基-2-丁烯基、1,2-二甲基-3-丁烯基、1,3-二甲基-1-丁烯基、1,3-二甲基-2-丁烯基、1,3-二甲基-3-丁烯基、2,2-二甲基-3-丁烯基、2,3-二甲基-1-丁烯基、2,3-二甲基-2-丁烯基、2,3-二甲基-3-丁烯基、3,3-二甲基-1-丁烯基、3,3-二甲基-2-丁烯基、1-乙基-1-丁烯基、1-乙基-2-丁烯基、1-乙基-3-丁烯基、2-乙基-1-丁烯基、2-乙基-2-丁烯基、2-乙基-3-丁烯基、1,1,2-三甲基-2-丙烯基、1-乙基-1-甲基-2-丙烯基、1-乙基-2-甲基-1-丙烯基和1-乙基-2-甲基-2-丙烯基。术语“乙烯基”是指具有结构-CH=CH2的基团;1-丙烯基是指具有结构-CH=CH-CH3的基团;并且2-丙烯基是指具有结构-CH2-CH=CH2的基团。不对称结构如(Z1Z2)C=C(Z3Z4)旨在包括E和Z异构体。这可在其中存在不对称烯烃的本文结构式中推定,或者它可由键符号C=C明确指示。烯基取代基可以是未经取代的或者是经一个或多个化学部分取代的。合适的取代基的实例包括例如如下所述的烷基、烷氧基、烯基、炔基、芳基、杂芳基、缩醛、酰基、醛、氨基、氰基、羧酸、酯、醚、碳酸酯、氨基甲酸酯、卤根、羟基、酮、硝基、膦酰基、甲硅烷基、磺基-氧代、磺酰基、砜、亚砜或硫醇,条件是取代基在空间上是相容的,并且满足化学键合和应变能的规则。
如本文所用,术语“炔基”表示含有三键的直链或支化烃部分。除非另有说明,否则意指C2-C24(例如,C2-C24、C2-C20、C2-C18、C2-C16、C2-C14、C2-C12、C2-C10、C2-C8、C2-C6或C2-C4)炔基。炔基可含有多于一个不饱和键。实例包括C2-C6-炔基,如乙炔基、1-丙炔基、2-丙炔基(或炔丙基)、1-丁炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、3-甲基-1-丁炔基、1-甲基-2-丁炔基、1-甲基-3-丁炔基、2-甲基-3-丁炔基、1,1-二甲基-2-丙炔基、1-乙基-2-丙炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、3-甲基-1-戊炔基、4-甲基-1-戊炔基、1-甲基-2-戊炔基、4-甲基-2-戊炔基、1-甲基-3-戊炔基、2-甲基-3-戊炔基、1-甲基-4-戊炔基、2-甲基-4-戊炔基、3-甲基-4-戊炔基、1,1-二甲基-2-丁炔基、1,1-二甲基-3-丁炔基、1,2-二甲基-3-丁炔基、2,2-二甲基-3-丁炔基、3,3-二甲基-1-丁炔基、1-乙基-2-丁炔基、1-乙基-3-丁炔基、2-乙基-3-丁炔基和1-乙基-1-甲基-2-丙炔基。炔基取代基可以是未经取代的或者是经一个或多个化学部分取代的。合适的取代基的实例包括例如如下所述的烷基、烷氧基、烯基、炔基、芳基、杂芳基、缩醛、酰基、醛、氨基、氰基、羧酸、酯、醚、碳酸酯、氨基甲酸酯、卤根、羟基、酮、硝基、膦酰基、甲硅烷基、磺基-氧代、磺酰基、砜、亚砜或硫醇。
如本文所用,术语“芳基”以及衍生术语如芳氧基是指包括具有3至50个碳原子的单价芳族碳环基团的基团。芳基可包括单环或多个稠合环。在一些实施方案中,芳基包括C6-C10芳基。芳基的实例包括但不限于苯、苯基、联苯基、萘基、四氢萘基、苯基环丙基、苯氧基苯和茚满基。术语“芳基”也包括“杂芳基”,杂芳基被定义为含有具有并入在芳族基团的环内的至少一个杂原子的芳族基团的基团。杂原子的实例包括但不限于氮、氧、硫和磷。术语“非杂芳基”也包括在术语“芳基”中,定义含有不含杂原子的芳族基团的基团。芳基取代基可以是未经取代的或者是经一个或多个化学部分取代的。合适的取代基的实例包括例如如本文所述的烷基、烷氧基、烯基、炔基、芳基、杂芳基、缩醛、酰基、醛、氨基、氰基、羧酸、酯、醚、碳酸酯、氨基甲酸酯、卤根、羟基、酮、硝基、膦酰基、甲硅烷基、磺基-氧代、磺酰基、砜、亚砜或硫醇。术语“联芳基”是特定类型的芳基并且包括在芳基的定义中。联芳基是指经由稠环结构结合在一起(如在萘中)或经由一个或多个碳-碳键附接(如在联苯基中)的两个芳基。
如本文所用的术语“环烷基”是由至少三个碳原子(例如,3至10个)组成的非芳族基于碳的环。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基等。术语“杂环烷基”是如上定义的环烷基,其中环的至少一个碳原子被杂原子取代,该杂原子诸如但不限于氮、氧、硫或磷。环烷基和杂环烷基可以是经取代的或未经取代的。环烷基和杂环烷基可被一个或多个基团取代,该基团包括但不限于如本文所述的烷基、烷氧基、烯基、炔基、芳基、杂芳基、缩醛、酰基、醛、氨基、氰基、羧酸、酯、醚、碳酸酯、氨基甲酸酯、卤根、羟基、酮、硝基、膦酰基、甲硅烷基、磺基-氧代、磺酰基、砜、亚砜或硫醇。
如本文所用的术语“环烯基”是由至少三个碳原子(例如,3至10个)组成且含有至少一个双键(即C=C)的非芳族基于碳的环。环烯基的实例包括但不限于环丙烯基、环丁烯基、环戊烯基、环戊二烯基、环己烯基、环己二烯基等。术语“杂环烯基”是一种类型的如上定义的环烯基,并且包括在术语“环烯基”的含义内,其中环的碳原子中的至少一个碳原子被杂原子(如但不限于氮、氧、硫或磷)取代。环烯基和杂环烯基可以是经取代的或未经取代的。环烯基和杂环烯基可被一个或多个基团取代,该基团包括但不限于如本文所述的烷基、烷氧基、烯基、炔基、芳基、杂芳基、缩醛、酰基、醛、氨基、氰基、羧酸、酯、醚、碳酸酯、氨基甲酸酯、卤根、羟基、酮、硝基、膦酰基、甲硅烷基、磺基-氧代、磺酰基、砜、亚砜或硫醇。
术语“环状基团”在本文中用于指芳基、非芳基(即,环烷基、杂环烷基、环烯基和杂环烯基)或两者。环状基团具有一个或多个可被取代或未被取代的环体系(例如,单环、双环、三环、多环等)。环状基团可含有一个或多个芳基、一个或多个非芳基、或一个或多个芳基和一个或多个非芳基。
如本文所用的术语“酰基”由式–C(O)Z1表示,其中Z1可以是上述的氢、羟基、烷氧基、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基,或杂环烯基。如本文所用,术语“酰基”可与“羰基”互换使用。贯穿本说明书,“C(O)”或“CO”是C=O的速记符号。
如本文所用的术语“缩醛”由式(Z1Z2)C(=OZ3)(=OZ4)表示,其中Z1、Z2、Z3和Z4可独立地为上述氢、卤素、羟基、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“烷醇”由式Z1OH表示,其中Z1可以是上述烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用,如本文所用的术语“烷氧基”是通过单个末端醚键联结合的烷基;即,“烷氧基”可被定义为式Z1-O-的基团,其中Z1是如上定义的未经取代的或经取代的烷基。除非另有说明,否则意指其中Z1为C1-C24(例如,C1-C22、C1-C20、C1-C18、C1-C16、C1-C14、C1-C12、C1-C10、C1-C8、C1-C6或C1-C4)烷基的烷氧基。实例包括甲氧基、乙氧基、丙氧基、1-甲基-乙氧基、丁氧基、1-甲基-丙氧基、2-甲基-丙氧基、1,1-二甲基-乙氧基、戊氧基、1-甲基-丁氧基、2-甲基-丁氧基、3-甲基-丁氧基、2,2-二甲基-丙氧基、1-乙基-丙氧基、己氧基、1,1-二甲基-丙氧基、1,2-二甲基-丙氧基、1-甲基-戊氧基、2-甲基-戊氧基、3-甲基-戊氧基、4-甲基-戊氧基、1,1-二甲基-丁氧基、1,2-二甲基-丁氧基、1,3-二甲基-丁氧基、2,2-二甲基-丁氧基、2,3-二甲基-丁氧基、3,3-二甲基-丁氧基、1-乙基-丁氧基、2-乙基丁氧基、1,1,2-三甲基-丙氧基、1,2,2-三甲基-丙氧基、1-乙基-1-甲基-丙氧基和1-乙基-2-甲基-丙氧基。
如本文所用的术语“醛”由式—C(O)H表示。在整个说明书中,“C(O)”是C=O的简写符号。
如本文所用的术语“胺”或“氨基”由式—NZ1Z2Z3表示,其中Z1、Z2和Z3可各自为如本文所述的取代基团,如上述的氢、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“酰胺”或“酰胺基”由式—C(O)NZ1Z2表示,其中Z1和Z2可各自为如本文所述的取代基团,如上述的氢、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“醛”由式Z1C(O)OC(O)Z2表示,其中Z1和Z2可独立地为上述烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“环状酸酐”由下式表示:
其中Z1可为上述的烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“叠氮根(azide)”由式-N=N=N表示。
如本文所用的术语“羧酸”由式—C(O)OH表示。
如本文所用的“羧酸根”或“羧基”由式
—C(O)O-表示。
如本文所用的“碳酸酯”基团由式Z1OC(O)OZ2表示。
如本文所用的术语“氰基”由式—CN表示。
如本文所用的术语“酯”由式—OC(O)Z1或
—C(O)OZ1表示,其中Z1可为上述烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“醚”由式Z1OZ2表示,其中Z1和Z2可独立地为上述烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“环氧基”或“环氧化物”是指具有三原子环的环状醚并且可由下式表示:
其中Z1、Z2、Z3和Z4可独立地为上述烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“酮”由式Z1C(O)Z2表示,其中Z1和Z2可独立地为上述烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“卤根”或“卤素”或“卤基”是指氟、氯、溴和碘。
如本文所用的术语“羟基”由式—OH表示。
如本文所用的术语“硝基”由式—NO2表示。
术语“膦酰基”在本文中用于指由式—P(O)(OZ1)2表示的磷氧基,其中Z1可为上述氢、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“甲硅烷基”由式—SiZ1Z2Z3表示,其中Z1、Z2和Z3可独立地为上述氢、烷基、烷氧基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“磺酰基”或“砜”是指由式—S(O)2Z1表示的硫氧基,其中Z1可为上述氢、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
如本文所用的术语“硫化物”包括式—S—。
如本文所用的术语“硫醇”由式—SH表示。
如本文所用的“R1”、“R2”、“R3”、“Rn”等(其中n是某一整数)可独立地具有一个或多个上文所列的基团。例如,如果R1是直链烷基,则烷基的一个氢原子可任选地被羟基、烷氧基、胺基团、烷基、卤化物等取代。根据所选择的基团,第一基团可被并入在第二基团内,可替代地,第一基团可被悬垂(即,附接)至第二基团。例如,对于短语“包含氨基的烷基”,氨基可被并入在烷基的主链内。可替代地,氨基可附接至烷基的主链。所选择的一个或多个基团的性质将决定第一基团是嵌入还是附接至第二基团。
除非有相反的说明,否则化学键仅以实线而非楔形或虚线显示的式涵盖每种可能的立体异构体或立体异构体的混合物(例如,每种对映异构体、每种非对映异构体、每种内消旋化合物、外消旋混合物或定比混合物(scalemic mixture))。
化合物
本文公开了各种化合物。例如,本文公开了由式I-XIX中的任一个式表示的化合物或其药学上可接受的盐:
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其中
R1、R2、R3和R4各自独立地为经取代的或未经取代的C1-C20烷基;
R5和R14各自独立地为氢、经取代的或未经取代的C1-C5烷基;R6、R7、R8、R9、R10、R11、R12和R13各自独立地为氢、OH、卤素或经取代的或未经取代的C1-C5烷基;
R15、R16和R17各自独立地为氢、OH、卤素或经取代的或未经取代的C1-C5烷基;并且
R18为OH或经取代的或未经取代的C1-C10烷基。
在一些方面,该化合物包括由式I-III中的任一个式定义的化合物或其药学上可接受的盐:
其中
R1、R2、R3和R4各自独立地为经取代的或未经取代的C1-C20烷基;
R5是氢、经取代的或未经取代的C1-C5烷基;并且
R6、R7、R8、R9、R10各自独立地为氢、OH、卤素或经取代的或未经取代的C1-C5烷基。
在一些方面,该化合物包括由式IV-VI定义的化合物或其药学上可接受的盐:
其中
R1、R2、R3和R4各自独立地为经取代的或未经取代的C1-C20烷基;
R5是氢、经取代的或未经取代的C1-C5烷基;并且
R18是OH羟基或经取代的或未经取代的C1-C10烷基。
在一个方面,该化合物包括由式VII-IX定义的化合物或其药学上可接受的盐:
其中
R1、R2、R3和R4各自独立地为经取代的或未经取代的C1-C20烷基;并且
R5和R14各自独立地为氢、经取代的或未经取代的C1-C5烷基。
在另一个方面,该化合物包括由式X-XIII定义的化合物或其药学上可接受的盐:
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其中
R1、R2、R3和R4各自独立地为经取代的或未经取代的C1-C20烷基;
R5是氢、经取代的或未经取代的C1-C5烷基;并且
R6、R7、R8、R9、R10、R11、R12和R13各自独立地为氢、OH、卤素或经取代的或未经取代的C1-C5烷基。
在另一个方面,该化合物包括由式XIV或XVII定义的化合物或其药学上可接受的盐:
其中
R1、R2、R3各自独立地为经取代的或未经取代的C1-C20烷基;
R5是氢、经取代的或未经取代的C1-C5烷基;
R15、R16和R17各自独立地为氢、OH、卤素或经取代的或未经取代的C1-C5烷基。
在另一个方面,该化合物包括由式XV-XVI定义的化合物或其药学上可接受的盐:
其中
R1、R2、R3各自独立地为经取代的或未经取代的C1-C20烷基;
R5和R14各自独立地为氢、经取代的或未经取代的C1-C5烷基;并且
R6、R7、R8、R9和R10各自独立地为氢、OH、卤素或经取代的或未经取代的C1-C5烷基。
在另一个方面,该化合物包括由式XVIII定义的化合物或其药学上可接受的盐:
其中
R1和R2各自独立地为经取代的或未经取代的C1-C20烷基。
在另一个方面,该化合物包括由式XIX定义的化合物或其药学上可接受的盐:
其中
R1和R2各自独立地为经取代的或未经取代的C1-C20烷基;
R6、R7、R8各自独立地为氢、OH、卤素、或经取代的或未经取代的C1-C5烷基;并且
R15是氢、OH、卤素或经取代的或未经取代的C1-C5烷基。
在一些实施方案中,该化合物包括由式I-A至XIX-A中的任一个式定义的化合物或其药学上可接受的盐:
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其中
R1、R2、R3和R4各自独立地为经取代的或未经取代的C1-C20烷基。
在上述式I-XIX和IA-XIX-A的一些实施方案中,R1、R2、R3和R4可各自独立地表示经取代的或未经取代的C1-C20烷基,如经取代的或未经取代的C2-C18、经取代的或未经取代的C4-C16、经取代的或未经取代的C5-C15、经取代的或未经取代的C5-C12、经取代的或未经取代的C8-C12,或经取代的或未经取代的C9-C11。在一些方面,R1、R2、R3和R4可各自独立地为经取代的或未经取代的C5-C15烷基。在一些方面,R1、R2、R3和R4各自独立地为直链或支化未经取代的烷基。在其它方面,R1、R2、R3和R4各自独立地为直链或支化经取代的烷基。例如,R1、R2、R3和R4可各自独立地为直链和支化经取代的烷基的混合物。在额外的实施方案中,R1、R2、R3和R4各自独立地为直链或支化未经取代的烷基的混合物。
在上述式I-XIX和IA-XIX-A的一些实施方案中,R1、R2、R3和R4各自独立地为被一个或多个选自由以下组成的组的取代基取代的直链或支化C1-C15烷基(例如C2-C15、C3-C15、C4-C15、C5-C15、C6-C15、C7-C15、C8-C15、C9-C15 C10-C15):酯、醚、碳酸酯、缩醛、缩酮、硫缩酮、硫醇、硫化物、二硫化物、二醇、芳基、卤素、硝基、氧代基和酰胺。在一些实施方案中,R1、R2、R3和R4各自独立地为被一个或多个选自由以下组成的组的取代基取代的直链或支化C5-C15烷基:酯、醚、碳酸酯、缩醛、缩酮、硫缩酮、硫醇、硫化物、二硫化物、二醇、氧代基和酰胺。在一些特定方面,R1、R2、R3和R4各自独立地为被一个或多个选自由以下组成的组的取代基取代的直链或支化C5-C15烷基:酯、醚、碳酸酯、硫化物、二硫化物、二醇和酰胺。
在上述式I-XIX和IA-XIX-A的一些实施方案中中,R1、R2、R3和R4各自独立地选自由以下组成的组:
其中N、M和X各自独立地表示1至9,如1至5的整数。
在上述式I-XIX和IA-XIX-A的一些实施方案中中,R1、R2、R3和R4各自独立地选自由以下组成的组:
其中N和M各自独立地表示1至9,如1至5的整数。在进一步的方面,R1、R2、R3和R4中的至少一者包含:
其中N和M各自独立地表示1至9,如1至5的整数。
在甚至进一步的方面,R1、R2、R3和R4中的每一者包含:
其中N和M各自独立地表示1至9,如1至5的整数。
在上述式I-XIX和IA-XIX-A的一些实施方案中中,R1、R2、R3和R4各自独立地选自由以下组成的组:
在上述式I-XIX和IA-XIX-A的某些方面,R1、R2、R3和R4不同。如果R1、R2、R3和R4中的至少一者与其余位置不同,则R1、R2、R3和R4被认为是不同的。例如,R1可以是一个部分,而R2、R3和R4各自独立地为与R1不同的部分。在一些方面,R1、R2、R3和R4中的每一者均不同。在其它实施方案中,R1、R2、R3和R4全部相同。
尽管本申请提及如广泛应用于一组式的R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17和R18,但是权利要求解释应当仅考虑那些在式中含有相应数字的R基团。例如,包括一组式(例如式IV和式V)的权利要求:
其中R1、R2、R3和R4各自独立地为经取代的或未经取代的C1-C20烷基;R5是经取代的或未经取代的C1-C5烷基;并且R18是OH或经取代的或未经取代的C1-C10烷基;应当被解释为使得R3和R4的额外包含仅适用于式V。因此,当式中仅描绘R1和R2时,对R3和R4的额外提及将不适用。
在一些方面,该化合物包括由表1中的BL1-BL83中描绘的结构之一定义的化合物。例如,该化合物可由表1中所示的BL1、BL2、BL3、BL4、BL5、BL6、BL7、BL8、BL9、BL10、BL11、BL12、BL13、BL14、BL15、BL16、BL17、BL18、BL19、BL20、BL21、BL22、BL23、BL24、BL25、BL26、BL27、BL28、BL29、BL30、BL31、BL32、BL33、BL34、BL35、BL36、BL37、BL38、BL39、BL40、BL41、BL42、BL43、BL44、BL45、BL46、BL47、BL48、BL49、BL50、BL51、BL52、BL53、BL54、BL55、BL56、BL57、BL58、BL59、BL60、BL61、BL62、BL63、BL64、BL65、BL66、BL67、BL68、BL69、BL70、BL71、BL72、BL73、BL74、BL75、BL76、BL77、BL78、BL79、BL80、BL81、BL82或BL83中的任一者定义。例如,该化合物可由BL6、BL7、BL8、BL28、BL38、BL39、BL41、BL43、BL53、BL54、BL55、BL56、BL57、BL62、BL65、BL67、BL68、BL69、BL70中的一者或多者定义。在一些方面,该化合物由BL8、BL28、BL39、BL41、BL54、BL56、BL62、BL65、BL68、BL69或BL70中的一者或多者定义。在某些方面,该化合物由以下组成的组中的一者或多者定义:BL28、BL39、BL54、BL56、BL68,和BL70。
在一个特定方面,该化合物由BL28:
或其药学上可接受的盐定义。
在其它方面,化合物由BL39:
或其药学上可接受的盐定义。
在其它方面,化合物由BL54:
或其药学上可接受的盐定义。
在其它方面,化合物由BL56:
或其药学上可接受的盐定义。
在一个特定方面,化合物由BL68:
或其药学上可接受的盐定义。
在其它方面,化合物由BL70:
或其药学上可接受的盐定义。
脂质颗粒和使用方法
本文公开了用于基因疗法和药物递送应用的脂质纳米材料。顾名思义,“纳米材料”的尺寸在纳米级范围内。例如,如本文所用的术语“纳米颗粒”是指具有至少1nm、至少10nm、至少50nm、至少80nm、至少100nm、至少120nm、至少150nm、至少160nm、至少170nm、至少180nm、至少190nm、至少200nm、至少210nm、至少220nm、至少230nm、至少240nm、至少250nm、至少300nm、至少400nm、至少500nm、至少600nm、至少700nm、至少800nm、至少900nm或至少1000nm直径的颗粒。在一些实施方案中,纳米颗粒可具有小于1,000nm、小于900nm、小于800nm、小于700nm、小于600nm、小于500nm、小于450nm、小于400nm、小于350nm、小于320nm、小于300nm、小于280nm、小于250nm、小于200nm、小于190nm、小于180nm、小于170nm、小于160nm或小于150nm的直径。纳米颗粒的直径可在从上述最小值中的任一最小值至上述最大值中的任一最大值,例如从1nm至1,000nm、从50nm至500nm、从100nm至350nm、从100nm至300nm、从100nm至250nm、或从100nm至200nm的范围内。此列表旨在仅用于举例的目的,并且上述最小值和最大值的许多种组合中的任一组合都可用作媒介物中的纳米颗粒直径的范围。
纳米颗粒的产生可导致直径的双峰或多峰分布。可通过离心分离并收集所需的直径范围(例如单分散的直径范围)。单分散的直径范围可使用包括例如动态光散射和纳米颗粒追踪分析在内的数种方法进行分析和计数。在一些实施方案中,纳米颗粒具有单分散的平均直径分布,如100nm至200nm。如本文所用,单分散的(或均匀的)平均直径分布是指这样的纳米颗粒群体,其中大于80%的群体的直径与平均直径相差约20%或更少。在一些实例中,单分散的(或均匀的)平均直径分布是指平均多分散性指数为0.3或更小、0.25或更小、0.2或更小、0.1至0.3或0.15至0.25的纳米颗粒群体。
在一些实例中,脂质颗粒可进一步包含额外的组分,如额外的脂质。在一些实例中,该额外的脂质可包括磷脂、固醇或它们的组合。在一些实例中,脂质颗粒可进一步包含1,2-二油酰基-sn-甘油-3-磷酸乙醇胺(DOPE)、胆固醇、1,2-二肉豆蔻酰基-外消旋-甘油-3-甲基聚氧乙烯或它们的组合。
如本文所述,本文公开的脂质纳米材料包含脂质。一般而言,脂质包括这样的脂肪和脂肪衍生材料,该脂肪和脂肪衍生材料相对不溶于水但可溶于有机溶剂,实际上或潜在地与脂肪酸酯、脂肪醇、固醇、蜡等相关,并且可由动物生物体利用。脂质是活细胞的主要结构组分之一。作为实例,脂肪是高级脂肪酸的甘油酯。
在某些实施方案中,本公开涉及治疗或预防脑部疾病或病症的方法,该方法包括向有需要的受试者施用有效量的包含本文公开的脂质纳米颗粒的组合物。
含有本文所述的化合物中的一种或多种化合物的制剂可使用由被认为安全且有效的材料组成的药学上可接受的载剂来制备,并且可被施用给个体而不会引起不希望的生物副作用或不希望的相互作用。载剂是药物制剂中除一种或多种活性成分以外的所有组分。如本文通常所用,“载剂”包括但不限于稀释剂、粘合剂、润滑剂、崩解剂、填充剂、pH调节剂、防腐剂、抗氧化剂、溶解度增强剂和包衣组合物。
存在于含有药物的片剂、珠粒、微粒或颗粒中的任选药学上可接受的赋形剂包括但不限于稀释剂、粘合剂、润滑剂、崩解剂、着色剂、稳定剂和表面活性剂。通常需要稀释剂(也被称为“填充剂”),以增加固体剂型的体积以便为片剂的压缩或珠粒和颗粒的形成提供实际的尺寸。合适的稀释剂包括但不限于磷酸二钙二水合物、硫酸钙、乳糖、蔗糖、甘露糖醇、山梨糖醇、纤维素、微晶纤维素、高岭土、氯化钠、干淀粉、水解淀粉、预胶凝淀粉、二氧化硅、氧化钛、硅酸镁铝和粉末状糖。
稳定剂被用于抑制或减缓药物分解反应,药物分解反应包括,举例来说,氧化反应。
本文描述的脂质纳米材料可与其它活性化合物一起辅助施用。这些额外的活性化合物包括但不限于镇痛药、抗炎药、解热药、抗抑郁药、抗癫痫药、抗组胺药、抗偏头痛药、抗毒蕈碱药、抗焦虑药、镇静药、安眠药、抗精神病药、支气管扩张药、抗哮喘药、心血管药物、皮质类固醇、多巴胺能药、电解质、胃肠药、肌肉松弛药、营养剂、维生素、拟副交感神经药、兴奋剂、食欲抑制剂、抗嗜睡药和抗病毒药。如本文所用的“辅助施用”意指该化合物可与一种或多种其它活性剂以同一剂型或以分开的剂型施用。该一种或多种其它活性剂可被配制为立即释放、受控释放或它们的组合。
在另一方面,本发明提供治疗和/或预防有需要的受试者的疾病的方法,该疾病诸如遗传疾病、增殖性疾病、血液疾病、神经疾病、免疫疾病、胃肠疾病(例如肝病)、呼吸系统疾病(例如肺病)、疼痛性疾患、精神病症、代谢病症、肌肉骨骼病症或脾疾病。在某些实施方案中,通过本发明方法治疗和/或预防的疾病是肝癌、高胆固醇血症、难治性贫血或家族性淀粉样神经病变。在某些实施方案中,治疗和/或预防疾病的方法包括向受试者施用本发明的组合物。
术语“遗传疾病”是指由受试者基因组中的一种或多种异常引起的疾病,如从受试者出生时就存在的疾病。遗传病可能是遗传性的,并且可能从父母的基因遗传下来。遗传疾病也可由受试者的DNA和/或RNA的突变或改变引起。在此类情况下,如果遗传疾病发生在种系中,则该遗传疾病将是可遗传的。示例性遗传疾病包括但不限于阿斯科格-斯科特(Aarskog-Scott)综合征、阿瑟综合征、软骨发育不全、肢端发育不全、成瘾、肾上腺脑白质营养不良、白化病、先天性眼睑缺损-巨口综合征、阿拉吉欧综合(alagille syndrome)、尿黑酸尿症、α-1抗胰蛋白酶缺乏症、阿尔波特氏综合征(Alport's syndrome)、阿尔茨海默病、哮喘、自身免疫性多腺体综合征、雄激素不敏感综合征、天使综合征、共济失调、共济失调毛细血管扩张症、动脉粥样硬化、注意力缺陷多动病症(ADHD)、自闭症、秃发、贝敦氏症、贝克维特-威德曼综合征、贝斯特氏症(Best disease)、双向情感障碍、短指症、乳腺癌、伯基特淋巴瘤、慢性髓系白血病、恰克-马利-杜斯氏病(Charcot-Marie-Tooth disease)、克罗恩氏病、唇裂、科克因综合征、科芬-劳里综合征、结肠癌、先天性肾上腺增生症、狄兰吉氏综合征(Cornelia de Lange syndrome)、科斯特洛综合征(Costello syndrome)、考登综合征(Cowden syndrome)、颅额鼻综合征(craniofrontonasal dysplasia)、克里格勒-纳贾尔综合征(Crigler-Najjar syndrome)、克罗伊茨费尔特-雅各布病(Creutzfeldt-Jakobdisease)、囊性纤维化、耳聋、抑郁症、糖尿病、畸型发育不良、迪乔治综合征(DiGeorgesyndrome)、唐氏综合征(Down's syndrome)、阅读障碍、杜氏肌营养不良、多博维茨综合征、外胚层发育不良埃利伟氏综合征(ectodermal dysplasia Ellis-van Creveldsyndrome)、埃勒斯-当洛斯综合征(Ehlers-Danlos)、大疱性表皮松解症、癫痫、特发性震颤、家族性高胆固醇血症、家族性地中海热、脆性X综合征、弗里德希氏共济失调、戈谢病、青光眼、葡萄糖半乳糖吸收不良、戊二酸尿症、脑回状萎缩、戈德堡-什普林茨恩(GoldbergShprintzen)综合征(腭心面综合征)、基底细胞痣综合征(Gorlin syndrome)、家族性良性慢性天疱疮(Hailey-Hailey disease)、偏侧肥大、血色素沉着病、血友病、遗传性运动和感觉神经病变(HMSN)、遗传性非息肉病性结肠直肠癌(HNPCC)、亨廷顿氏病、免疫缺陷伴高IgM、青少年型糖尿病、克莱恩费尔特综合征(Klinefelter's syndrome)、歌舞伎面谱综合征(Kabuki syndrome)、利氏病(Leigh's disease)、长QT综合征、肺癌、恶性黑素瘤、躁郁症、马凡综合征、门克斯综合征(Menkes syndrome)、流产、粘多糖病、多发性内分泌赘生物形成(multiple endocrine neoplasia)、多发性硬化症、肌营养不良症、肌萎缩性侧索硬化症、强直性肌营养不良、神经纤维瘤病、尼曼-皮克病、努南综合征、肥胖症、卵巢癌、胰腺癌、帕金森病、阵发性睡眠性血红蛋白尿症、彭德雷德综合征、腓骨肌萎缩症、苯丙酮尿症(PKU)、多囊肾病、普瑞德-威利综合征、原发性胆汁性肝硬化、前列腺癌、REAR综合征、雷夫叙姆病(Refsum disease)、视网膜色素变性、视网膜母细胞瘤、雷特综合征、桑菲利波综合征、精神分裂症、严重联合免疫缺陷、镰状细胞性贫血、脊柱裂、脊髓性肌萎缩、脊髓小脑萎缩、成人猝死综合征、丹吉尔病、泰-萨二氏病、血小板减少-桡骨缺失综合征(thrombocytopenia absent radius syndrome)、唐斯-布洛克综合征(Townes-Brockssyndrome)、结节性硬化症、特纳综合征、乌谢尔综合征、希佩尔-林道综合征(von Hippel-Lindau syndrome)、瓦登堡综合征(Waardenburg syndrome)、维弗综合征(Weaversyndrome)、沃纳综合征(Werner syndrome)、威廉姆斯综合征(Williams syndrome)、威尔逊氏病(Wilson's disease)、着色性干皮病和泽尔韦格综合征(Zellweger syndrome)。
“增殖性疾病”是指由于细胞繁殖所致的异常生长或扩展而发生的疾病(Walker,Cambridge Dictionary of Biology;Cambridge University Press:Cambridge,UK,1990)。增殖性疾病可与以下相关:1)正常静止细胞的病理性增殖;2)细胞从其正常位置的病理性迁移(例如,赘生性细胞的转移);3)蛋白水解酶如基质金属蛋白酶(例如,胶原酶、明胶酶和弹性蛋白酶)的病理性表达;或4)病理性血管生成,如在增殖性视网膜病变和肿瘤转移中。示例性的增殖性疾病包括癌症(即“恶性赘生物”)、良性赘生物、血管生成、炎症性疾病和自身免疫性疾病。
术语“血管生成”是指从预先存在的血管形成新血管的生理过程。血管生成不同于血管发生,后者是从中胚层细胞前体从头形成内皮细胞。发育中的胚胎中的第一批血管通过血管发生形成,此后血管生成负责正常或异常发育期间的大多数血管生长。血管生成是生长和发育、以及伤口愈合和肉芽组织形成中的重要过程。然而,血管生成也是肿瘤从良性状态向恶性状态转变的基本步骤,从而导致了血管生成抑制剂在癌症治疗中的使用。血管生成可通过血管生成蛋白如生长因子(例如VEGF)来化学刺激。“病理性血管生成”是指等同于疾病和/或与疾病相关的异常(例如,过度或不足的)血管生成。
术语“赘生物”和“肿瘤”可互换使用,并且是指异常组织块,其中块的生长超过正常组织的生长且与正常组织的生长不协调。赘生物或肿瘤可能是“良性”或“恶性”,具体取决于以下特征:细胞分化程度(包括形态和功能)、生长速率、局部侵袭和转移。“良性赘生物”通常分化良好,具有比恶性赘生物特征性地更慢的生长,并且仍然局限于起源部位。此外,良性赘生物不具有浸润、侵入或转移至远处部位的能力。示例性良性赘生物包括但不限于脂肪瘤、软骨瘤、腺瘤、软垂疣、老年性血管瘤、脂溢性角化病、雀斑样痣和皮脂腺增生。在一些情况下,某些“良性”肿瘤随后可能会产生恶性赘生物,这可能是由于肿瘤的赘生性细胞亚群中额外的基因变化所致,并且这些肿瘤被称为“恶性前赘生物”。示例性的恶性前赘生物是畸胎瘤。相比之下,“恶性赘生物”通常分化不良(退行发育),并且具有伴随着周围组织的渐进浸润、侵入和破坏的特征性快速生长。此外,恶性赘生物通常具有转移至远处部位的能力。术语“转移”、“转移性”或“转移”是指癌性细胞从原发性或原始肿瘤扩散或迁移至另一器官或组织,并且通常可通过原发性或原始肿瘤的组织类型的“继发性肿瘤”或“继发性细胞团块”的存在来鉴定,而不是通过继发性(转移性)肿瘤所在的器官或组织的组织类型的“继发性肿瘤”或“继发性细胞团块”的存在来鉴定。例如,已经迁移至骨的前列腺癌被称为转移性前列腺癌,并且包括在骨组织中生长的癌性前列腺癌细胞。
术语“癌症”是指恶性赘生物(Stedman's Medical Dictionary,第25版;Hensyl编;Williams&Wilkins:Philadelphia,1990)。示例性癌症包括但不限于,听神经瘤;腺癌;肾上腺癌;肛门癌;血管肉瘤(例如,淋巴管肉瘤、淋巴管内皮肉瘤、血管肉瘤);阑尾癌;良性单克隆丙种球蛋白病;胆管癌(例如,胆管细胞癌);膀胱癌;乳腺癌(例如,乳房腺癌、乳房乳头状癌、乳腺癌、乳房髓样癌);脑癌(例如,脑膜瘤;胶质母细胞瘤,胶质瘤(例如,星形细胞瘤、少突神经胶质瘤)、成神经管细胞瘤);支气管癌;类癌肿瘤;宫颈癌(例如,宫颈腺癌);绒毛膜癌;脊索瘤;颅咽管瘤;结肠直肠癌(例如,结肠癌、直肠癌、结肠直肠腺癌);结缔组织癌症;上皮癌瘤;室管膜瘤;内皮肉瘤(例如,卡波济氏肉瘤、多发性特发性出血性肉瘤);子宫内膜癌(例如,子宫癌、子宫肉瘤);食道癌(例如,食道腺癌、巴雷特腺癌);尤因氏肉瘤;眼癌(例如,眼内黑素瘤、视网膜母细胞瘤);家族性嗜酸性粒细胞增多症;胆囊癌;胃癌(例如,胃腺癌);胃肠道间质瘤(GIST);生殖细胞癌;头颈癌(例如,头颈鳞状细胞癌、口腔癌(例如,口腔鳞状细胞癌)、喉癌(例如,喉癌、咽癌、鼻咽癌、口咽癌));造血细胞癌(例如,白血病,如急性淋巴细胞性白血病(ALL)(例如,B细胞性ALL、T细胞性ALL)、急性髓细胞性白血病(AML)(例如,B细胞性AML、T细胞性AML)、慢性髓细胞性白血病(CML)(例如,B细胞性CML、T细胞性CML)、以及慢性淋巴细胞性白血病(CLL)(例如,B细胞性CLL、T细胞性CLL);淋巴瘤如霍奇金氏淋巴瘤(HL)(例如,B细胞性HL、T细胞性HL)和非霍奇金氏淋巴瘤(NHL)(例如,B细胞性NHL如弥漫性大细胞淋巴瘤(DLCL)(例如,弥漫性大B细胞淋巴瘤)、滤泡性淋巴瘤、慢性淋巴细胞性白血病/小淋巴细胞性淋巴瘤(CLL/SLL)、套细胞淋巴瘤(MCL)、边缘区B细胞淋巴瘤(例如,粘膜相关淋巴组织(MALT)淋巴瘤、结节性边缘区B细胞淋巴瘤,脾边缘区B细胞淋巴瘤)、原发性纵膈B细胞淋巴瘤、伯基特氏淋巴瘤、淋巴浆细胞性淋巴瘤(即,“瓦尔登斯特伦巨球蛋白血症”)、毛细胞白血病(HCL)、免疫母细胞性大细胞淋巴瘤、前体B淋巴母细胞性淋巴瘤和原发性中枢神经系统(CNS)淋巴瘤;以及T细胞性NHL,如前体T淋巴母细胞性淋巴瘤/白血病、外周T细胞淋巴瘤(PTCL)(例如,皮肤T细胞淋巴瘤(CTCL)(例如,蕈样真菌病、塞扎莱综合征)、血管免疫母细胞性T细胞淋巴瘤、结外天然杀伤T细胞淋巴瘤、肠病型T细胞淋巴瘤、皮下脂膜炎样T细胞淋巴瘤和间变性大细胞淋巴瘤);如以上所描述的一种或多种白血病/淋巴瘤的混合;以及多发性骨髓瘤(MM))、重链病(例如,α链病、γ链病、μ链病);成血管细胞瘤;下咽癌;炎性肌纤维母细胞肿瘤;免疫细胞淀粉样变性;肾癌(例如,肾母细胞瘤又称为维尔姆斯氏肿瘤、肾细胞癌);肝癌(例如,肝细胞癌(HCC)、恶性肝细胞瘤);肺癌(例如,支气管癌、小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC)、肺腺癌);平滑肌肉瘤(LMS);肥大细胞增多症(例如,全身性肥大细胞增多症);肌肉癌症;骨髓增殖异常综合征(MDS);间皮瘤;骨髓增殖性病症(MPD)(例如,真性红细胞增多症(PV)、原发性血小板增多症(ET)、原因不明的骨髓组织异生(AMM)又称为骨髓纤维变性(MF)、慢性特发性骨髓纤维变性、慢性髓细胞性白血病(CML)、慢性嗜中性粒细胞性白血病(CNL)、嗜酸细胞过多综合征(HES));成神经细胞瘤;神经纤维瘤(例如1型或2型神经纤维瘤病(NF)、神经鞘瘤);神经内分泌癌(例如胃肠胰神经内分泌肿瘤(GEP-NET)、类癌瘤);骨肉瘤(例如,骨癌);卵巢癌(例如,囊腺癌、卵巢胚胎性癌、卵巢腺癌);乳头状腺癌;胰腺癌(例如胰腺腺癌、导管内乳头状粘液性赘生物(IPMN)、胰岛细胞肿瘤);阴茎癌(例如,阴茎和阴囊的佩吉特氏病);松果体瘤;原始神经外胚层肿瘤(PNT);浆细胞瘤形成;副肿瘤综合征;上皮内赘生物;前列腺癌(例如前列腺腺癌);直肠癌;横纹肌肉瘤;唾液腺癌;皮肤癌(例如,鳞状细胞癌(SCC)、角化棘皮瘤(KA)、黑素瘤、基底细胞癌(BCC));小肠癌(例如,阑尾癌);软组织肉瘤(例如,恶性纤维组织细胞瘤(MFH)、脂肪肉瘤、恶性周围神经鞘瘤(MPNST)、软骨肉瘤,纤维肉瘤、粘液肉瘤);皮脂腺癌瘤;小肠癌;汗腺癌;滑膜瘤;睾丸癌(例如,精原细胞瘤、睾丸胚胎性癌);甲状腺癌(例如,甲状腺乳头状癌、乳头状甲状腺癌(PTC)、甲状腺髓样癌);尿道癌;阴道癌;以及外阴癌(例如,外阴的佩吉特氏病)。
术语“炎症性疾病”是指由炎症引起、由炎症产生或导致炎症的疾病。术语“炎症性疾病”还可指失调的炎症性反应,其引起巨噬细胞、粒细胞和/或T淋巴细胞的过度反应,从而导致异常组织损伤和/或细胞死亡。炎症性疾病可以是急性或慢性炎性疾患,并且可由感染性或非感染原因引起。炎症性疾病包括但不限于动脉粥样硬化、动脉硬化、自身免疫性病症、多发性硬化症、系统性红斑狼疮、风湿性多肌痛(PMR)、痛风性关节炎、退行性关节炎、肌腱炎、滑囊炎、银屑病、囊性纤维化、关节炎、类风湿性关节炎、炎症性关节炎、干燥综合征、巨细胞动脉炎、进行性系统性硬化症(硬皮病)、强直性脊柱炎、多发性肌炎、皮肌炎、天疱疮、类天疱疮、糖尿病(例如I型)、重症肌无力、桥本氏甲状腺炎、格雷夫斯病、古德帕斯丘综合征、混合结缔组织病、硬化性胆管炎、炎症性肠病、克罗恩氏病、溃疡性结肠炎、恶性贫血、炎症性皮肤病、普通型间质性肺炎(UIP)、石棉肺、矽肺、支气管扩张、铍中毒、滑石肺、尘肺病、结节病、脱屑性间质性肺炎、淋巴性间质性肺炎、巨细胞间质性肺炎、细胞间质性肺炎、外源性过敏性肺泡炎、韦格纳氏肉芽肿病和相关形式的血管炎(颞动脉炎和结节性多动脉炎)、炎症性皮肤病、肝炎、迟发型超敏反应(例如毒漆藤皮炎)、肺炎、呼吸道炎症、成人呼吸窘迫综合征(ARDS)、脑炎、速发型超敏反应、哮喘、花粉热、过敏、急性过敏反应、风湿热、肾小球肾炎、肾盂肾炎、蜂窝组织炎、膀胱炎、慢性胆囊炎、缺血(缺血性损伤)、再灌注损伤、同种异体移植排斥、宿主抗移植物排斥、阑尾炎、动脉炎、睑炎、细支气管炎、支气管炎、宫颈炎、胆管炎、绒毛膜炎、结膜炎、泪腺炎、皮肌炎、心内膜炎、结膜炎、肠炎、小肠结肠炎、上髁炎、附睾炎、筋膜炎、纤维组织炎、胃炎、胃肠炎、牙龈炎、回肠炎、虹膜炎、喉炎、脊髓炎、心肌炎、肾炎、脐炎、卵巢炎、睾丸炎、骨炎、耳炎、胰腺炎、腮腺炎、心包炎、咽炎、胸膜炎、静脉炎、肺炎、直肠炎、前列腺炎、鼻炎、输卵管炎、鼻窦炎、口腔炎、滑膜炎、睾丸炎、扁桃体炎、尿道炎、膀胱炎、葡萄膜炎、阴道炎、血管炎、外阴炎、外阴阴道炎、脉管炎、慢性支气管炎、骨髓炎、视神经炎、颞动脉炎、横贯性脊髓炎、坏死性筋膜炎和坏死性小肠结肠炎。眼部炎症性疾病包括但不限于手术后炎症。
“自身免疫性疾病”是指由受试者的身体对身体内正常存在的物质和组织的不适当的免疫反应引起的疾病。换言之,免疫系统将身体的一些部分误认为是病原体,并攻击其自身细胞。这可能仅限于某些器官(例如,在自身免疫性甲状腺炎中)或涉及不同部位的特定组织(例如,古德帕斯丘病,其可能影响肺和肾的基底膜)。自身免疫性疾病的治疗通常采用免疫压制,例如降低免疫反应的药物。示例性自身免疫性疾病包括但不限于肾小球肾炎、古德帕斯丘综合征(Goodpasture'ssyndrome)、坏死性血管炎、淋巴结炎、结节性动脉周围炎、系统性红斑狼疮、类风湿性关节炎、银屑病性关节炎、系统性红斑狼疮、银屑病、溃疡性结肠炎、系统性硬化症、皮肌炎/多发性肌炎、抗磷脂抗体综合征、硬皮病、寻常型天疱疮、ANCA相关血管炎(例如韦格纳氏肉芽肿病、显微镜下多血管炎)、葡萄膜炎、干燥综合征、克罗恩氏病、莱特尔氏综合征、强直性脊柱炎、莱姆病、格林-巴利综合征、桥本氏综合征甲状腺炎和心肌病。
术语“肝病”或“肝脏疾病”是指肝脏的损伤或疾病。肝病的非限制性实例包括肝内胆汁淤积(例如,阿拉吉欧综合征、胆汁性肝硬化)、脂肪肝(例如,酒精性脂肪肝、雷氏综合征)、肝静脉血栓形成、肝豆状核变性(即,威尔逊氏病)、肝肿大、肝脓肿(例如阿米巴肝脓肿)、肝硬化(例如,酒精性、胆汁性和实验性肝硬化)、酒精性肝病(例如脂肪肝、肝炎、肝硬化)、寄生虫性肝病(例如肝包虫病、片形吸虫病、阿米巴肝脓肿)、黄疸(例如溶血性、肝细胞性、胆汁淤积性黄疸)、胆汁淤积、门静脉高压、肝脏肿大、腹水、肝炎(例如酒精性肝炎、动物肝炎、慢性肝炎(例如自身免疫性、乙型肝炎、丙型肝炎、丁型肝炎、药物引起的慢性肝炎)、中毒性肝炎、病毒性人类肝炎(例如甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、戊型肝炎)、肉芽肿性肝炎、继发性胆汁性肝硬化、肝性脑病、静脉曲张、原发性胆汁性肝硬化、原发性硬化性胆管炎、肝细胞腺瘤、血管瘤、胆结石、肝衰竭(例如,肝性脑病、急性肝衰竭)、血管平滑肌脂肪瘤、钙化性肝转移、囊性肝转移、纤维板层肝癌、肝腺瘤、肝癌、肝囊肿(例如单纯性囊肿、多囊肝病、肝胆管囊腺瘤、胆总管囊肿)、间叶性肿瘤(间叶性错构瘤、婴儿血管内皮瘤、血管瘤、紫癜性肝病、脂肪瘤、炎症性假瘤)、上皮性肿瘤(例如胆管错构瘤、胆管腺瘤)、局灶性结节性增生、结节性再生增生、肝母细胞瘤、肝细胞癌、胆管癌、囊腺癌、血管肿瘤、血管肉瘤、卡波济氏肉瘤、血管内皮瘤、胚胎肉瘤、纤维肉瘤、平滑肌肉瘤、横纹肌肉瘤、癌肉瘤、畸胎瘤、类癌、鳞状细胞癌、原发性淋巴瘤、紫癜样肝病、红细胞肝性卟啉症、肝卟啉症(例如急性间歇性卟啉症、迟发性皮肤卟啉症)和泽尔韦格综合征。
术语“脾疾病”是指脾的疾病。脾疾病的实例包括但不限于脾肿大、脾癌、无脾、脾损伤、特发性紫癜、费尔蒂综合征、霍奇金病和免疫介导的脾破坏。
术语“肺病”或“肺部疾病”是指肺的疾病。肺病的实例包括但不限于支气管扩张、支气管炎、支气管肺发育不良、间质性肺病、职业性肺病、肺气肿、囊性纤维化、急性呼吸窘迫综合征(ARDS)、严重急性呼吸综合征(SARS)、哮喘(例如,间歇性哮喘、轻度持续性哮喘、中度持续性哮喘、重度持续性哮喘)、慢性支气管炎、慢性阻塞性肺病(COPD)、肺气肿、间质性肺病、结节病、石棉肺、曲霉肿、曲霉病、肺炎(例如大叶性肺炎、多叶性肺炎、支气管肺炎、间质性肺炎)、肺纤维化、肺结核、类风湿性肺病、肺栓塞和肺癌(例如非小细胞肺癌(例如腺癌、鳞状细胞肺癌、大细胞肺癌)、小细胞肺癌)。
“血液疾病”包括影响造血细胞或组织的疾病。血液疾病包括与异常的血液含量和/或功能相关的疾病。血液疾病的实例包括由骨髓辐射或癌症的化疗疗法治疗引起的疾病、疾病如恶性贫血、失血性贫血、溶血性贫血、再生障碍性贫血、镰状细胞贫血、铁粒幼细胞贫血、与慢性感染相关的贫血如疟疾、锥虫病、HTV、肝炎病毒或其它病毒、由骨髓缺陷引起的骨髓病性贫血、由贫血引起的肾衰竭、贫血、红细胞增多症、传染性单核细胞增多症(EVI)、急性非淋巴细胞性白血病(ANLL)、急性髓系白血病(AML)、急性早幼粒细胞白血病(APL)、急性粒单核细胞性白血病(AMMoL)、真性红细胞增多症、淋巴瘤、急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病、威尔姆斯肿瘤、尤因氏肉瘤、视网膜母细胞瘤、血友病、与血栓形成的风险增加相关的病症、疱疹、地中海贫血、抗体介导的病症如输血反应和骨髓成红细胞增多症、红细胞的机械性损伤如微血管病性溶血性贫血、血栓性血小板减少性紫癜和弥散性血管内凝血、由寄生虫如疟原虫引起的感染、来自例如铅中毒的化学损伤,以及脾功能亢进。
术语“神经系统疾病”是指神经系统的任何疾病,包括涉及中枢神经系统(脑、脑干和小脑)、周围神经系统(包括脑神经)和自主神经系统(其部分位于中枢和周围神经系统中)的疾病。神经变性疾病还指以神经细胞损失为特征的一类神经系统疾病,包括但不限于阿尔茨海默病、帕金森氏病、肌萎缩性侧索硬化症、tau蛋白病(包括额颞叶痴呆)和亨廷顿氏病。神经系统疾病的实例包括但不限于头痛,木僵和昏迷,痴呆,癫痫,睡眠障碍,外伤,感染,赘生物,神经眼科学(neuroophthalmology),运动障碍,脱髓鞘疾病,脊髓病症,以及周围神经、肌肉和神经肌肉接点的病症。成瘾和精神疾患包括但不限于双相型障碍和精神分裂症,也包括于神经系统疾病的定义中。神经系统疾病的此外的实例包括获得性癫痫性失语症;疾病播散性脑脊髓炎;肾上腺脑白质营养不良;胼胝体发育不全;失认症;艾卡迪综合征(Aicardi syndrome);亚历山大病(Alexander disease);阿尔帕斯病(Alpers'disease);交叉性肢体瘫痪;阿尔茨海默病;肌萎缩性侧索硬化;无脑畸形;天使综合征(Angelman syndrome);血管瘤病;缺氧症;失语症;失用症;蛛网膜囊肿;蛛网膜炎;安诺儿-基亚里畸形(Anronl-Chiari malformation);动静脉畸形;阿斯佩各综合征(Aspergersyndrome);共济失调性毛细血管扩张;注意力缺乏过动症;孤独症;自主机能障碍;背痛;贝敦氏症(Batten disease);白塞氏病(Behcet'sdisease);贝尔氏麻痹(Bell's palsy);良性特发性眼睑痉挛;良性局灶性病变;肌萎缩;良性颅内高压;宾斯万格病(Binswanger'sdisease);眼睑痉挛;布洛赫苏兹贝格综合征(Bloch Sulzberger syndrome);臂丛神经损伤;脑脓肿;脑损伤;脑肿瘤(包括多形性成胶质细胞瘤);脊髓肿瘤;布朗-希夸得综合征(Brown-Sequard syndrome);卡纳万病(Canavan disease);腕隧道综合征(CTS);灼性神经痛;中枢性疼痛综合征;脑桥中央髓鞘溶解症;头部病症;脑动脉瘤;脑动脉硬化症;脑萎缩;大脑性巨人症;脑性麻痹;夏科-玛丽-图斯病(Charcot-Marie-Tooth disease);化学疗法诱发的神经病变和神经痛;基亚里畸形(Chiari malformation);舞蹈症;慢性炎症性脱髓鞘性多神经病变(CIDP);慢性疼痛;慢性区域性疼痛综合征;科芬劳里综合征(CoffinLowry syndrome);昏迷,包括持续性植物人状态;先天性面瘫;皮质基底退化;颅动脉炎;颅缝早闭;克罗伊茨费尔特-雅格布病(Creutzfeldt-Jakob disease);累积性损伤病症;库欣氏综合征(Cushing's syndrome);巨细胞包涵体病(CIBD);巨细胞病毒感染;舞蹈眼-舞蹈足综合征(dancing eyes-dancing feet syndrome);丹迪-沃克综合征(DandyWalkersyndrome);道森病(Dawson disease);德莫西尔综合征(De Morsier's syndrome);德热里纳-克隆普克麻痹(Dejerine-Klumke palsy);痴呆;皮肌炎;糖尿病性肾病;弥漫性硬化症;家族性自主神经异常;书写困难;读写困难;张力障碍;早期幼儿癫痫性脑病;空蝶鞍综合征;脑炎;脑突出;脑三叉神经血管瘤病;癫痫;欧泊氏麻痹(Erb's palsy);特发性震颤;法布里病(Fabry's disease);华氏综合征(Fahr's syndrome);昏厥;家族性痉挛性瘫痪;热性癫痫发作;费希尔综合征(Fisher syndrome);弗里德希氏共济失调(Friedreich'sataxia);额颞性痴呆和其它“tau蛋白病”;高歇氏病(Gaucher's disease);格斯特曼综合征(Gerstmann's syndrome);巨细胞性动脉炎;巨细胞性包涵体病;球形细胞脑白质营养不良;格林-巴利综合征(Guillain-Barre syndrome);HTLV-1相关性脊髓病;哈勒沃登-施帕茨病(Hallervorden-Spatz disease);头部损伤;头痛;半面痉挛;遗传性痉挛性截瘫;多神经炎型遗传性共济失调;耳部带状疱疹;带状疱疹;平山综合征(Hirayama syndrome);HIV相关性痴呆和神经病变(也参见AIDS的神经表现);前脑无裂畸形;亨廷顿氏病(Huntington's disease)和其它聚谷氨酰胺重复序列疾病;水脑畸形;脑积水;皮质醇增多症;低氧症;免疫介导的脑脊髓炎;包涵体性肌炎;色素失调症;婴儿植烷酸储积症;婴儿雷夫叙姆病(infantile refsum disease);婴儿痉挛;炎症性肌病;颅内囊肿;颅内高压;朱伯特综合征(Joubert syndrome);基姆-赛耶综合征(Keams-Sayre syndrome);肯尼迪病(Kennedy disease);金斯波姆综合征(Kinsboume syndrome);克利佩尔费尔综合征(Klippel Feil syndrome);克拉伯病(Krabbe disease);库格尔贝格-韦兰德病(Kugelberg-Welander disease);库鲁病(kuru);拉福拉病(Lafora disease);兰伯特-伊顿肌无力综合征(Lambert-Eaton myasthenic syndrome);兰道-克莱夫勒综合征(Landau-Kleffner syndrome);侧髓(瓦伦贝格(Wallenberg))综合征;学习不能;利氏病(Leigh'sdisease);伦诺克斯-古斯塔特综合征(Lennox-Gustaut syndrome);莱施-奈恩综合征(Lesch-Nyhan syndrome);脑白质营养不良;路易体痴呆(Lewy body dementia);无脑回畸形;闭锁综合征;路格瑞氏病(Lou Gehrig's disease)(又称为运动神经元病或肌萎缩性侧索硬化);腰椎间盘病;莱姆病(Lyme disease)-神经后遗症;马查度-约瑟夫病(Machado-Joseph disease);巨脑;巨脑症;梅尔克逊-罗森塔尔综合征(Melkersson-Rosenthalsyndrome);美尼尔病(Menieres disease);脑膜炎;门克斯病(Menkes disease);异染性脑白质营养不良;头小畸形;偏头痛;米勒费希尔综合征(Miller Fisher syndrome);小中风(mini-strokes);线粒体肌病;莫比乌斯综合征(Mobius syndrome);单肢肌萎缩;运动神经元病;烟雾病(Moyamoya disease);粘多糖贮积症;多梗塞性痴呆;多灶性运动神经病变;多发性硬化症和其它脱髓鞘病症;伴有体位性低血压的多系统萎缩;肌肉萎缩症;重症肌无力;脱髓鞘性弥漫性硬化症;婴儿肌阵挛性脑病;肌阵挛;肌病;先天性肌强直;发作性睡病;神经纤维瘤病;神经抑制药恶性综合征;AIDS的神经表现;狼疮神经后遗症;神经性肌强直;神经元蜡样脂褐质沉积症;神经元迁移病症;尼曼-匹克病(Niemann-Pick disease);奥沙利文-麦克劳德综合征(O'Sullivan-McLeod syndrome);枕神经痛;隐性脊柱神经管闭合不全序列症;大田原综合征(Ohtahara syndrome);橄榄体脑桥小脑萎缩症;斜视眼阵挛肌阵挛;视神经炎;直立性低血压;过度使用综合征;感觉异常;帕金森氏病(Parkinson'sdisease);先天性肌强直;副肿瘤病;阵发性发作;帕里龙贝格综合征(Parry Rombergsyndrome);佩利措伊斯-梅茨巴赫病(Pelizaeus-Merzbacher disease);周期性瘫痪;周围神经病变;疼痛性神经病变和神经痛;持续性植物人状态;广泛性发育障碍;光喷嚏反射;植烷酸贮积病;匹克病(Pick's disease);神经挟捏;垂体肿瘤;多肌炎;脑穿通畸形;小儿麻痹症后综合征;疱疹后神经痛(PHN);感染后脑脊髓炎;体位性低血压;普拉德-威利综合征(Prader-Willi syndrome);原发性侧索硬化;朊病毒疾病;进行性面部单侧萎缩;进行性多灶性白质脑病;进行性硬化性灰质营养不良;进行性核上性麻痹;假性脑瘤;拉姆齐-亨特综合征(Ramsay-Hunt syndrome)(I型和II型);拉斯马森脑炎(Rasmussen's encephalitis);反射性交感神经营养不良综合征(reflex sympathetic dystrophy syndrome);雷夫叙姆病(Refsum disease);重复运动障碍;重复应激损伤;不宁腿综合征;逆转录病毒相关性脊髓病;雷特综合征(Rett syndrome);雷氏综合征(Reye's syndrome);圣维特斯舞蹈病(Saint Vitus dance);桑德霍夫病(Sandhoff disease);希尔德病(Schilder'sdisease);脑裂;中隔-眼发育不良;惊吓婴儿综合征;带状疱疹;夏伊-德雷格综合征(Shy-Drager syndrome);干燥综合征(Sjogren's syndrome);睡眠呼吸暂停;索托综合征(Soto's syndrome);痉挛状态;脊柱裂;脊髓损伤;脊髓肿瘤;脊髓性肌萎缩;斯蒂夫-珀森综合征(Stiff-Person syndrome);中风;斯特奇-韦伯综合征(Sturge-Weber syndrome);亚急性硬化性全脑炎;蛛网膜下腔出血;皮层下动脉硬化性脑病;西登哈姆舞蹈病(Sydenhamchorea);晕厥;脊髓空洞症;迟发性运动障碍;泰-萨二氏病(Tay-Sachs disease);颞动脉炎;脊髓栓系综合征;汤姆森病(Thomsen disease);胸出口综合征;三叉神经痛(TicDouloureux);托德氏麻痹(Todd's paralysis);图雷特综合征(Tourette syndrome);短暂缺血发作;播散性海绵状脑病;横贯性脊髓炎;外伤性脑损伤;震颤;三叉神经痛(trigeminal neuralgia);热带痉挛性截瘫;结节性脑硬化;血管性痴呆(多梗塞性痴呆);血管炎,包括颞动脉炎;范希佩尔-林道病(Von Hippel-Lindau disease)(VHL);瓦伦贝格综合征(Wallenberg'ssyndrome);韦德尼希-霍夫曼病(Werdnig-Hoffman disease);维斯特综合征(West syndrome);急性颈部扭伤;威廉姆斯综合征(Williams syndrome);威尔逊病(Wilson's disease);和泽尔韦格综合征(Zellweger syndrome)。
“肌肉骨骼疾病”或肌肉骨骼病症”可互换使用,包括引起或导致肌肉萎缩的疾患。肌肉萎缩可由使用糖皮质激素如皮质醇、地塞米松、倍他米松、泼尼松、甲基泼尼松龙或泼尼松龙治疗引起。肌肉萎缩也可能是神经创伤所致的去神经支配的结果,或者是退行性、代谢性或炎症性神经病变的结果。例如,肌肉萎缩可能是成人运动神经元疾病、格林-巴利综合征、婴儿脊髓性肌萎缩症、肌萎缩性侧索硬化症、青少年脊髓性肌萎缩症、伴有多灶性传导阻滞的自身免疫性运动神经病变、中风或脊髓损伤所致的麻痹、外伤所致的骨骼固定、长时间卧床、自愿不活动、非自愿不活动以及代谢应激或营养不足的结果。肌肉萎缩可能是肌病的结果,该肌病包括例如肌强直;先天性肌病,包括杆状体肌病、多核/小核肌病和肌管(中心核)肌病;线粒体肌病;家族性周期性麻痹;炎症性肌病;代谢性肌病,如由糖原或脂质贮积病引起;皮肌炎;多发性肌炎;包涵体肌炎;骨化性肌炎;横纹肌溶解症和肌红蛋白尿。肌病可由肌营养不良综合征引起,如杜氏肌营养不良(DMD)、贝克肌营养不良(也称为良性假肥大性肌营养不良症)、强直性肌营养不良、肩胛肱型和筋膜肩胛肱型肌营养不良、埃-德二氏肌营养不良、眼咽型肌营养不良、肢带型肌营养不良、福山先天性肌营养不良或遗传性远端肌病。
肌肉骨骼疾病或病症或者导致肌肉骨骼疾病或病症的疾患的此外的实例包括少肌症、皮肤萎缩、肌肉萎缩、脑萎缩、动脉粥样硬化、动脉硬化、肺气肿、骨质疏松症、骨关节炎、免疫机能不全、高血压、痴呆、亨廷顿氏病、阿尔茨海默病、白内障、年龄相关性黄斑变性、癌症、中风、虚弱、记忆力减退、肾功能受损、代谢病症(包括II型糖尿病、代谢综合征、高血糖、肥胖症、甲状腺病症)、恶病质(包括与类风湿性关节炎相关的恶病质和与癌症相关的恶病质)、急性和/或慢性肾病或衰竭、肝病(实例如纤维化、肝硬化)、癌症(包括横纹肌肉瘤、前列腺癌、乳腺癌、肝细胞癌和胃肠癌)、帕金森氏病;贫血、暴露于环境毒素或药物、HIV/AIDS、禁食、良性先天性肌张力低下、中央轴空病(central core disease)、烧伤、慢性阻塞性肺病、败血症、充血性心力衰竭、衰老或年龄相关性疾患以及太空旅行或在零重力环境中度过的时间。
“疼痛性疾患”包括但不限于,神经性疼痛(例如,周围神经性疼痛)、中枢性疼痛、传入阻滞性疼痛(deafferentiation pain)、慢性疼痛(例如,慢性伤害性疼痛,和其它形式的慢性疼痛如手术后疼痛,诸如在髋、膝或其它关节置换手术之后产生的疼痛)、手术前疼痛、伤害性受体的刺激(伤害性疼痛)、急性疼痛(例如,幻痛和瞬态急性疼痛)、非炎性疼痛、炎性疼痛、与癌症相关的疼痛、伤口疼痛、烧伤疼痛、手术后疼痛、与医疗程序相关的疼痛、由瘙痒症引起的疼痛、疼痛性膀胱综合征、与月经前焦虑症和/或经前综合症相关的疼痛、与慢性疲劳综合征相关的疼痛、与早产相关的疼痛、与药物成瘾戒断症状相关的疼痛、关节疼痛、关节炎疼痛(例如,与结晶性关节炎、骨关节炎、银屑病性关节炎、痛风性关节炎、反应性关节炎,类风湿性关节炎或莱特尔氏关节炎相关的疼痛)、腰骶疼痛、肌肉骨骼疼痛、头痛、偏头痛、肌肉疼痛、下背疼痛、颈疼痛、齿疼痛、牙齿/上颌面疼痛、内脏疼痛等。本文考虑的疼痛性疾患中的一种或多种疼痛疾患可包括以上和本文提供的各种类型的疼痛(例如伤害性疼痛、炎征性疼痛、神经性疼痛等)的混合物。在一些实施方案中,特定疼痛可能占主导地位。在其它实施方案中,疼痛性疾患包括两种或更多种类型的疼痛,而无一种占据主导地位。熟练的临床医师可基于疼痛性疾患确定对特定受试者达到治疗有效量的剂量。
术语“精神病症”是指心理疾病,并且包括由华盛顿特区美国精神病学协会(American Psychiatric Association,Washington D.C.)(1994)出版的精神病症诊断和统计手册—第四版(Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition)(DSM-IV)中列出的疾病和病症。精神病症包括但不限于焦虑症(例如,急性应激病症广场恐惧症、广泛性焦虑症、强迫症、惊恐病症、创伤后应激障碍、分离焦虑症、社交恐惧症和特定恐惧症)、儿童期障碍(例如,注意力缺陷/多动障碍、品行障碍和对立违抗性障碍)、饮食障碍(例如,神经性厌食症和神经性贪食症)、情绪障碍(例如,抑郁症、双相情感障碍、循环情感性精神病症、恶劣心境障碍和重度抑郁症)、人格障碍(例如,反社会型人格障碍、回避型人格障碍、边缘型人格障碍、依赖型人格障碍、表演型人格障碍、自恋型人格障碍、强迫型人格障碍、偏执型人格障碍、精神分裂型人格障碍和分裂型人格障碍)、精神病症(例如,短暂性精神病症、妄想性障碍、分裂情感性障碍、精神分裂症样障碍、精神分裂症和共有型精神病症)、物质相关障碍(例如,酒精依赖、安非他明依赖、大麻依赖、可卡因依赖、致幻剂依赖、吸入剂依赖、尼古丁依赖、阿片类药物依赖、苯环己哌啶依赖和镇静剂依赖)、适应障碍、孤独症、谵妄、痴呆、多梗塞性痴呆、学习和记忆障碍(例如健忘症和年龄相关性记忆丧失)和图雷特氏障碍。
术语“代谢病症”是指涉及碳水化合物、脂质、蛋白质、核酸或它们的组合的正常代谢的改变的任何病症。代谢病症与导致核酸、蛋白质、脂质和/或碳水化合物代谢失衡的代谢途径的不足或过量相关。影响代谢的因素包括但不限于内分泌(激素)控制系统(例如胰岛素途径、肠内分泌激素,包括GLP-1、PYY等)、神经控制系统(例如脑中的GLP-1)等。代谢病症的实例包括但不限于糖尿病(例如,1型糖尿病、2型糖尿病、妊娠糖尿病)、高血糖症、高胰岛素血症、胰岛素抵抗和肥胖症。
在一些方面,治疗剂是以下中的一种或多种:单克隆抗体、嵌合抗体、人源化抗体、纳米抗体、抗体片段、胆固醇、激素、肽、蛋白质、化学治疗剂、抗赘生物剂、低分子量药物、维生素、辅因子、核苷、核苷酸、寡核苷酸、多核苷酸、酶核酸、反义核酸、三链体形成寡核苷酸、反义DNA或RNA组合物、嵌合DNA:RNA组合物、同工酶、适体、核酶、诱饵、类似物、质粒、表达载体、小核酸分子、mRNA、RNAi剂、短干扰核酸(siNA)、短干扰RNA(siRNA)、双链RNA(dsRNA)、微小RNA(miRNA)、短发夹RNA(shRNA)、肽核酸(PNA)、锁核酸核糖核苷酸(LNA)、吗啉代核苷酸、苏糖核酸(TNA)、乙二醇核酸(GNA)、sisiRNA(小内部片段化干扰RNA)、aiRNA(不对称干扰RNA)以及在相关细胞或组织的有义链与反义链之间存在具有1个、2个或更多个错配的siRNA。
例如,治疗剂可包含用于治疗或预防疾病状态的核酸,如mRNA。具体地,该疾病可包括上面提到的疾病之一(例如神经系统疾病、肝脏疾病、肌肉骨骼疾病)。本公开的脂质颗粒可提供更大的穿过血脑屏障的渗透性,从而增加某些治疗剂的递送有效性。
所公开的化合物和含有该化合物的组合物的体内应用可通过本领域技术人员目前或未来已知的任何合适的方法和技术来完成。例如,所公开的化合物可配制成生理学或药学上可接受的形式并通过包括例如经口、经鼻、直肠、外用和肠胃外施用途径在内的本领域已知的任何合适的途径施用。如本文所用,术语肠胃外包括皮下、皮内、静脉内、肌肉内、腹膜内和胸骨内施用,诸如通过注射。在某些方面,该施用可包括静脉内、鞘内、颅内、还有肌内、瘤内、气管内、皮下应用。所公开的化合物或组合物的施用可以是单次施用,或以连续或不同的间隔施用,这可由本领域技术人员容易地确定。
本文公开的化合物和包含该化合物的组合物还可利用脂质体技术、缓释胶囊、可植入泵和可生物降解的容器来施用。这些递送方法可有利地在长时间段内提供均一的剂量。该化合物也可以其盐衍生物形式或结晶形式施用。
本文公开的化合物可根据已知的用于制备药学上可接受的组合物的方法来配制。制剂在本领域技术人员熟知且容易获得的许多来源中进行了详细描述。例如,E.W.Martin(1995)的Remington’sPharmaceutical Science描述了可与所公开的方法结合使用的制剂。通常,本文公开的化合物可被配制成使得有效量的该化合物与合适的赋形剂组合以便促进该化合物的有效施用。所使用的组合物也可呈多种形式。这些形式包括例如固体、半固体和液体剂型,如片剂、丸剂、粉末、液体溶液或悬浮液、栓剂、可注射和可输注溶液以及喷雾剂。优选的形式取决于预期的施用模式和应用。该组合物还可包含本领域技术人员已知的常规药学上可接受的载剂和稀释剂。
用于与该化合物一起使用的载剂或稀释剂的实例包括乙醇、二甲基亚砜、甘油、氧化铝、淀粉、盐水和等效的载剂和稀释剂。为了提供用于所需应用的此类剂量的施用,本文公开的组合物可包含基于包含载剂或稀释剂的总组合物的重量的约0.1重量%与100重量%之间的一种或多种主题化合物的总量。
所采用的药物载剂可以是例如,固体、液体或气体。固体载剂的实例包括乳糖、石膏粉、蔗糖、滑石、明胶、琼脂、果胶、阿拉伯树胶、硬脂酸镁和硬脂酸。液体载剂的实例是糖浆、花生油、橄榄油和水。气体载剂的实例包括二氧化碳和氮气。
适合于施用的制剂包括例如无菌注射水溶液,其可含有抗氧化剂、缓冲剂、抑菌剂以及使制剂与预期接受者的血液等渗的溶质;以及水性和非水性无菌悬浮液,其可包含助悬剂和增稠剂。该制剂可呈现于单位剂量或多剂量容器(例如密封安瓿和小瓶)中,并且可存储于冷冻干燥(冻干)条件下,只需要在使用前添加无菌液体载剂,例如注射用水即可。临时注射溶液和悬浮液可由无菌粉末、颗粒和片剂等制备。应当理解,除上文特别提到的赋形剂之外,考虑到所讨论制剂的类型,本文公开的组合物还可包含本领域中常规的其它剂。
本文公开的化合物和包含该化合物的组合物可通过与细胞直接接触或经由载剂手段递送至细胞。用于将化合物和组合物递送至细胞的载剂手段是本领域已知的。
为了治疗肿瘤学病症,可将本文公开的化合物或组合物与其它抗肿瘤或抗癌物质和/或与放射和/或光动力疗法和/或与手术治疗组合施用给需要治疗的患者以除去肿瘤。这些其它物质或治疗可与本文公开的化合物或组合物在同一时间或不同时间给予。例如,可将本文公开的化合物或组合物与有丝分裂抑制剂(如紫杉醇或长春碱)、烷基化剂(如环磷酰胺或异环磷酰胺)、抗代谢物(如5-氟尿嘧啶或羟基脲)、DNA嵌入剂(如阿霉素或博来霉素)、拓扑异构酶抑制剂(如依托泊苷或喜树碱)、抗血管生成剂(如血管抑制素)、抗雌激素(如他莫昔芬)和/或其它抗癌药物或抗体(分别如例如格列卫(Novartis PharmaceuticalsCorporation)和赫赛汀(Genentech,Inc.)),或免疫治疗剂(如伊匹单抗和硼替佐米)组合使用。
在某些实例中,本文公开的化合物和组合物可在一个或多个解剖部位,如不期望的细胞生长的部位(如肿瘤部位或良性皮肤生长物,例如注射或外用施加至肿瘤或皮肤生长物)处局部施用,任选地与药学上可接受的载剂如惰性稀释剂组合。本文公开的化合物和组合物可全身施用,如静脉内或经口施用,任选地与药学上可接受的载剂(如惰性稀释剂)或用于经口递送的可同化的可食用载剂组合。它们可封闭在硬质或软质外壳明胶胶囊中,可压制成片剂,或者可直接与患者膳食的食物合并。对于经口治疗性施用,活性化合物可与一种或多种赋形剂组合并以可摄取片剂、经颊片剂、锭剂、胶囊、酏剂、悬浮液、糖浆、糯米纸囊剂(wafer)、气溶胶喷雾等形式使用。
片剂、锭剂、丸剂、胶囊等也可含有以下各物:粘合剂,如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;稀释剂,如磷酸二钙;崩解剂,如玉米淀粉、马铃薯淀粉、海藻酸等;润滑剂,如硬脂酸镁;以及甜味剂,如蔗糖、果糖、乳糖或阿斯巴甜(aspartame)或调味剂,例如胡椒薄荷、冬青油,或者可添加樱桃调味剂。当单位剂型是胶囊时,它除了含有以上类型的物质之外,还可含有液体载剂,如植物油或聚乙二醇。各种其它物质可作为包衣存在或者可为了以其他方式改良固体单位剂型的物理形式而存在。举例来说,片剂、丸剂或胶囊可用明胶、蜡、虫胶或糖等包覆。糖浆或酏剂可含有活性化合物、作为甜味剂的蔗糖或果糖、作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、染料和调味剂(如樱桃或橙调味剂)。当然,用于制备任何单位剂型的任何物质都应为药学上可接受的且在所用量下基本上无毒。此外,活性化合物可被并入到持续释放制品和装置中。
本文公开的化合物和组合物(包括其药学上可接受的盐)可通过经由输注或注射静脉内、肌内或腹膜内施用。可在任选地与无毒表面活性剂混合的水中制备活性化合物或其盐的溶液。也可在甘油、液体聚乙二醇、三乙酸甘油酯和它们的混合物中以及在油中制备分散体。在普通的存储和使用条件下,这些制品可含有防腐剂以防止微生物的生长。
适于注射或输注的药物剂型可包括无菌水溶液或分散体;或包含活性成分的无菌粉末,该无菌粉末适合于临时制备无菌可注射或可输注溶液或分散体,该无菌粉末任选地包封于脂质体中。最终剂型在制造和存储条件下都应为无菌的、流动的且稳定的。液体载剂或媒介物可为溶剂或液体分散介质,其包含例如水、乙醇、多元醇(例如甘油、丙二醇、液体聚乙二醇等)、植物油、无毒甘油酯以及它们的合适的混合物。适当流动性可例如通过形成脂质体、在分散体的情况下通过维持所需粒度或通过使用表面活性剂加以维持。任选地,可通过各种抗细菌剂和抗真菌剂(例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞(thimerosal)等)来防止微生物作用。在许多情况下,优选的是包括等张剂,例如糖、缓冲剂或氯化钠。可通过包含延迟吸收的剂,例如单硬脂酸铝和明胶来延长可注射组合物的吸收。
本文公开的适合于可注射用途的药物组合物包括无菌水溶液或分散体。此外,该组合物可呈用于临时制备此类无菌可注射溶液或分散体的无菌粉末形式。在一些实例中,最终可注射形式可以是无菌的,并且可以有效地为易于注射的流体。在一些实例中,药物组合物在制造和储存条件下可以是稳定的;因此,可保藏它们以防诸如细菌和真菌的微生物污染作用。载剂可以是溶剂和分散介质,其含有例如水、乙醇、多元醇(例如,甘油、丙二醇和液态聚乙二醇)、植物油及它们的合适的混合物。
无菌可注射溶液是通过将本文公开的化合物和/或剂以所需量与以上列举的各种其它成分一起并入在适当溶剂中,在必要时随后进行过滤灭菌来制备。在用于制备无菌可注射溶液的无菌粉末的情况下,优选制备方法是真空干燥和冷冻干燥技术,其产生活性成分外加存在于先前经无菌过滤的溶液中的任何额外所需成分的粉末。
本文公开的药物组合物可呈适于外用使用的形式,诸如例如气溶胶、乳膏、软膏、洗剂、细粉、漱口剂、含漱剂、溶液、酊剂等。在一些实例中,该组合物可呈适合用于透皮装置的形式。在一些实例中,将希望将它们以与皮肤病学上可接受的载剂(其可为固体或液体)组合的组合物形式外用施用于皮肤。本文公开的化合物和剂及组合物可外用施用于受试者的皮肤。这些制剂可利用本文公开的化合物中的任何化合物或其药学上可接受的盐经由常规加工方法来制备。
有用的固体载剂包括细粉状固体,如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等。适用液体载剂包括水、醇或二醇或水-醇/二醇掺合物,化合物可任选地借助于无毒表面活性剂在有效水平下溶解或分散于其中。可添加如芳香剂和其它抗微生物剂的佐剂来使性质最优化以用于给定用途。所得液体组合物可例如自吸收垫施用,用于浸渍绷带和其它敷料,或使用泵型喷雾器或气溶胶喷雾器喷雾于受影响区域上。
诸如合成聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、经修饰的纤维素或经修饰的矿物材料的增稠剂也可与液体载剂一起被用于形成用于直接施加至使用者的皮肤的可涂敷糊剂、凝胶剂、软膏、皂剂等。
本文公开的药物组合物可呈适合于直肠施用的形式,其中载剂为固体。在一些实例中,混合物形成单位剂量栓剂。合适的载剂包括可可脂和本领域中常用的其它材料。栓剂可通过首先将组合物与软化的或熔化的载剂混合,随后通过在模具中冷却和成形而方便地形成。
除了前面提到的载剂成分之外,上述药物制剂还可在适当时包含一种或多种额外的载剂成分诸如稀释剂、缓冲剂、调味剂、粘合剂、表面活性剂、增稠剂、润滑剂、防腐剂(包括抗氧化剂)等。此外,可包含其它佐剂以使制剂与预期接受者的血液等渗。含有本文公开的化合物中的任何化合物和/或其药学上可接受的盐的组合物也可以粉末或液体浓缩物形式制备。
制造方法
本文提供了制备本文公开的脂质纳米材料的方法。该脂质纳米材料优选具有在10至1000nm范围内的粒度并且表现出增强的靶向性,例如,这是由于脂质纳米颗粒的形态和性质而实现的。脂质纳米颗粒可根据本公开来制备。
虽然已经参考各种和优选实施方案描述了本发明,但是本领域技术人员应理解,在不脱离本发明的基本范围的情况下,可做出各种改变并且可使用等效物来取代本发明的要素。另外,在不背离本发明的基本范围的情况下,可做出许多修改来使具体的情况或材料适应本发明的教义。
因此,意图是本发明不限于本文公开的考虑用于实施本发明的一个或多个特定实施方案,而是本发明将包括落入权利要求书范围内的所有实施方案。
本文引用的出版物的全文以及至少该出版物被引用所针对的资料特此以引用的方式明确地并入。
实施例
实施例1:脑靶向脂质纳米颗粒及其用途
mRNA的有效递送是mRNA治疗剂的关键步骤和挑战。尽管来自正在进行的临床试验的数据很有希望,但mRNA的临床使用需要发现和开发更有效的递送系统。
概述
本实施例中描述了用于基因疗法和药物递送应用的脑靶向脂质纳米材料。
用于合成脑靶向脂质的一般程序:
(1)向(Fmoc保护的)脑靶向配体、DMF和N,N-二异丙基乙胺的溶液中添加N,N,N',N'-四甲基-O-(3,4-二氢-4-氧代-1,2,3-苯并三嗪-3-基)四氟硼酸铀)。将所得混合物在室温下搅拌20分钟。然后添加Boc保护的胺,并将溶液在室温下搅拌过夜。将产物混合物逐滴添加至200mL的5%NaHCO3中,并且用乙酸乙酯萃取,并用去离子水洗涤3次。将所得固体通过Combiflash柱色谱法使用RediSep Gold Resolution硅胶柱用100%CH2Cl2至CH2Cl2/MeOH(85/15,v/v/v)梯度洗脱进一步纯化,从而得到Boc保护的脑靶向胺。
(2)将Boc保护的脑靶向胺溶解于10mL的CH2Cl2和1mL的CF3COOH中,并将混合物搅拌2.5小时。通过TLC检查反应完成后,在减压下除去溶剂从而得到脑靶向胺。
(3)向该胺(0.2mmol)和三乙胺(1.0mmol)于THF(5mL)中的溶液中添加醛(1.0mmol)和三乙酰氧基硼氢化钠(1.2mmol)。然后将所得混合物在室温下搅拌过夜。将所得产物用NaHCO3(50ml)和盐水(50ml)洗涤,通过Combiflash柱色谱法使用RediSep GoldResolution硅胶柱(Teledyne Isco)使用100%CH2Cl2至CH2Cl2/MeOH/NH4OH(80/20/0.5,v/v/v)的梯度洗脱纯化从而得到最终产物。通过在CH2Cl2中添加哌啶来除去Fmoc。
用于产生示例性类别的脂质的合成策略在下面的方案1-4中详细描述。
方案1.基于L-DOPA的脂质的一般合成途径。
1.L-DOPA-脂质
(1)
(2)
(3)。
方案2.基于D-丝氨酸的脂质的一般合成途径。
D-丝氨酸-脂质
(1)
(2)
(3)
方案3.基于替莫唑胺的脂质的一般合成途径。
替莫唑胺-脂质
(1)
(2)
(3)
方案4.基于Aβ结合部分的脂质的一般合成途径。
Aβ结合部分-脂质
(1)
(2)
(3)
(4)
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脂质表征:
下文包括示例性脂质的表征。
L-DOPA-脂质-1-R9:1H NMR(400MHz,CDCl3)δ6.71(s,2H),6.50(s,1H),4.19(s,1H),3.01(d,J=38.3Hz,11H),1.63(s,6H),1.47–1.01(m,45H),0.89(t,J=6.8Hz,6H)。ESI-MS[M+H+]实测值632.8。
L-DOPA-脂质-2-R9:1H NMR(400MHz,CDCl3)δ6.93–6.65(m,2H),6.53(d,J=6.0Hz,1H),4.31–4.03(m,1H),3.45–2.78(m,20H),2.01–1.43(m,10H),1.28(d,J=11.6Hz,71H),0.90(t,J=6.8Hz,12H)。ESI-MS[M+2H+]实测值521.2。
D-丝氨酸-脂质-1-R9:1H NMR(300MHz,CDCl3)δ4.22(s,1H),4.06(s,1H),3.77(s,1H),3.40–3.15(m,2H),3.04(m,6H),1.60(m,6H),1.30(m,40H),0.89(t,J=6.7Hz,6H)。MALDI-MS[M+H+]实测值540.449。
D-丝氨酸-脂质-2-R9:1H NMR(300MHz,CDCl3)δ4.20(s,1H),4.00(s,1H),3.77(s,1H),3.40-3.05(m,17H),1.57(d,J=49.7Hz,10H),1.27(s,70H),0.89(t,J=6.6Hz,12H)。MALDI-MS[M+H+]实测值907.082。
TMZ-脂质-1-R9:1H NMR(300MHz,CDCl3)δ8.39(s,1H),4.04(s,3H),3.71–3.21(m,2H),2.56(m,6H),1.81–1.01(m,56H),0.88(t,J=6.6Hz,6H)。MALDI-MS[M+H+]实测值630.653。
TMZ-脂质-2-R9:1H NMR(400MHz,CDCl3)δ8.49–8.15(m,1H),4.21–3.81(m,3H),3.78–3.54(m,2H),2.76(m,10H),2.50(m,8H),1.59–1.04(m,73H),0.90(t,J=6.8Hz,12H)。MALDI-MS[M+H+]实测值996.899。
Aβ结合部分-脂质-1-R9:1H NMR(300MHz,CDCl3)δ7.26(m,4H),6.74(m,4H),6.49(dd,2H),6.25–5.87(m,2H),3.27(t,J=19.7Hz,4H),2.94(d,J=15.3Hz,12H),2.48(m,10H),1.35(d,J=43.5Hz,59H),0.90(t,J=6.6Hz,9H)。MALDI-MS[M+H+]实测值926.838。
Aβ结合部分-脂质-2-R9:1H NMR(300MHz,CDCl3)δ7.28(t,2H),6.69(d,2H),6.42(d,J=15.7Hz,1H),6.17–5.85(m,1H),3.28(t,2H),2.94(m,6H),2.69–2.09(m,16H),1.35(d,J=44.4Hz,82H),1.05–0.71(m,12H)。MALDI-MS[M+H+]实测值961.923。
Aβ结合部分-脂质-3-R9:1H NMR(400MHz,CDCl3)δ7.29(m,4H),6.67(m,4H),6.52(dd,2H),6.22–5.88(m,2H),3.45(t,2H),2.98(s,10H),2.75(m,6H),1.64(s,6H),1.43–1.09(m,36H),0.90(t,J=6.8Hz,6H)。MALDI-MS[M+H+]实测值771.680。
实施例2:脂质BL1-BL83的评价
用于合成脑靶向脂质的一般程序:
(1)向(Fmoc保护的)脑靶向配体、DMF和N,N-二异丙基乙胺的溶液中添加N,N,N',N'-四甲基-O-(3,4-二氢-4-氧代-1,2,3-苯并三嗪-3-基)四氟硼酸铀)。将所得混合物在室温下搅拌20分钟。然后添加Boc保护的胺,并将溶液在室温下搅拌过夜。将产物混合物逐滴添加至200mL的5%NaHCO3中,并且用乙酸乙酯萃取,并用去离子水洗涤3次。将所得固体通过Combiflash柱色谱法使用RediSep Gold Resolution硅胶柱用100%CH2Cl2至CH2Cl2/MeOH(85/15,v/v/v)梯度洗脱进一步纯化,从而得到Boc保护的脑靶向胺。
(2)将Boc保护的脑靶向胺溶解于10mL的CH2Cl2和1mL的CF3COOH中,并将混合物搅拌2.5小时。通过TLC检查反应完成后,在减压下除去溶剂从而得到脑靶向胺。
(3)向该胺(0.2mmol)和三乙胺(1.0mmol)于THF(5mL)中的溶液中添加醛(1.0mmol)和三乙酰氧基硼氢化钠(1.2mmol)。然后将所得混合物在室温下搅拌过夜。将所得产物用NaHCO3(50ml)和盐水(50ml)洗涤,通过Combiflash柱色谱法使用RediSep GoldResolution硅胶柱(Teledyne Isco)使用100%CH2Cl2至CH2Cl2/MeOH/NH4OH(80/20/0.5,v/v/v)的梯度洗脱纯化从而得到最终产物。通过在CH2Cl2中添加哌啶来除去Fmoc。
下文的方案中详细描述了用于获取特定脂质的合成策略。
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脂质表征:
下文包括示例性脂质的表征。
BL1:1H NMR(400MHz,CDCl3)δ6.71(m,2H),6.50(d,1H),4.19(m,1H),3.01(m,10H),1.63–1.01(m,50H),0.89(t,J=6.8Hz,6H)。C39H74N3O3([M+H]+)的ESI-MS实测值:632.8。
BL2:1H NMR(400MHz,CDCl3)δ6.93–6.65(m,2H),6.53(d,J=6.0Hz,1H),4.31–4.03(m,1H),3.45–2.78(m,20H),2.01–1.43(m,10H),1.28(m,71H),0.90(t,J=6.8Hz,12H)。C66H129N5O3([M+2H]2+)的ESI-MS实测值521.2。
BL3:1H NMR(400MHz,CDCl3)δ6.75(m,2H),6.60(d,1H),4.57–4.20(m,4H),4.16(m,8H),2.97(m,12H),1.95–1.06(m,33H),0.91(t,J=6.8Hz,6H)。
BL4:1H NMR(400MHz,CDCl3)δ6.88–6.35(m,2H),6.21–5.96(m,1H),4.83–4.51(m,4H),4.53–4.20(m,4H),3.31–2.29(m,12H),1.93–1.02(m,46H),0.90(t,J=6.8Hz,6H)。
BL5:1H NMR(400MHz,CDCl3)δ6.75(m,2H),6.60(s,1H),4.57–4.20(m,4H),4.16(m,6H),2.97(m,12H),1.95–1.06(m,33H),0.91(t,J=6.8Hz,6H)。
BL6:1H NMR(400MHz,CDCl3)δ6.88–6.48(m,3H),4.47–4.24(m,3H),4.15(m,10H),2.93–2.21(m,11H),1.89–1.10(m,43H),0.81(t,J=6.8Hz,9H)。C52H96N4O12([M+2H]2+)的ESI-MS实测值484.5。
BL7:1H NMR(400MHz,CDCl3)δ6.76(m,3H),4.63(m,3H),4.47–4.14(m,4H),3.77–2.29(m,30H),1.96–0.99(m,55H),0.96–0.74(t,J=6.8Hz,9H)。C55H106N4O9([M+2H]2+)的ESI-MS实测值484.5。
BL8:1H NMR(400MHz,CDCl3)δ6.99–6.45(m,4H),4.64(m,4H),4.44–3.86(m,7H),3.74–2.25(m,33H),1.85–1.04(m,78H),0.89(t,J=6.8Hz,9H)。
BL9:1H NMR(400MHz,CDCl3)δ7.02–6.44(m,4H),4.81–4.54(m,7H),4.45–4.13(m,4H),3.67–3.37(m,14H),3.18–2.21(m,16H),1.95–1.06(m,49H),0.91(t,J=6.5Hz,9H)。
BL10:1H NMR(400MHz,CDCl3)δ6.76(t,1H),6.72–6.59(m,1H),6.56–6.42(m,1H),2.91–2.77(m,2H),2.68(m,6H),1.78–1.06(m,46H),0.90(t,J=6.8Hz,6H)。
BL11:1H NMR(300MHz,CDCl3)δ6.75(t,1H),6.63(d,1H),6.50(m,1H),4.13(m,8H),2.94–2.28(m,8H),1.96–1.03(m,51H),0.89(t,J=6.7Hz,6H)。
BL12:1H NMR(300MHz,CDCl3)δ6.90–6.62(m,1H),6.49(m,1H),3.68–3.40(m,8H),3.20–2.71(m,4H),2.32(t,J=7.6Hz,2H),1.90–1.05(m,47H),0.89(t,J=6.7Hz,6H)。C34H64NO6([M+H]+)的ESI-MS实测值582.5。
BL13:1H NMR(400MHz,CDCl3)δ6.96–6.74(m,1H),6.74–6.61(m,1H),6.61–6.33(m,1H),3.77(m,7H),3.00–2.54(m,8H),2.01–1.75(m,6H),1.43(m,50H),0.90(t,J=6.8Hz,6H)。
BL14:1H NMR(400MHz,CDCl3)δ7.20–6.34(m,3H),3.90–3.63(m,6H),3.18–2.73(m,4H),1.98–1.07(m,49H),0.90(t,J=6.8Hz,6H)。
BL15:1H NMR(400MHz,CDCl3)δ6.60(m,3H),4.85–4.51(m,3H),4.16–3.91(m,3H),3.84–3.67(m,5H),3.67–3.52(m,4H),3.50–3.32(m,4H),2.69(t,9H),2.20–1.03(m,56H),0.97–0.72(m,6H)。
BL16:1H NMR(400MHz,CDCl3)δ8.39(s,1H),4.09–3.98(s,3H),3.62–3.51(m,2H),2.76(m,10H),2.50(m,8H),1.62–1.04(m,84H),0.90(t,J=6.8Hz,12H)。C60H117N9O2([M+H]+)的MALDI-MS实测值996.9。
BL17:1H NMR(300MHz,CDCl3)δ8.40(s,1H),4.05(s,3H),3.66–3.38(m,2H),2.68–2.30(m,6H),1.77–1.12(m,53H),0.88(t,J=6.7Hz,6H)。C36H67N7O2([M+H]+)的MALDI-MS实测值630.6。
BL18:1H NMR(400MHz,CDCl3)δ8.40(s,1H),4.05(s,3H),3.66–3.38(m,2H),2.68–2.30(m,6H),1.77–1.12(m,60H),0.88(t,J=6.7Hz,6H)。
BL19:1H NMR(300MHz,CDCl3)δ8.41(s,1H),4.67(s,4H),4.06(s,3H),3.57(m,14H),2.98–2.42(m,7H),1.86–1.12(m,38H),0.90(t,J=6.7Hz,6H)。C38H72N7O6([M+H]+)的ESI-MS实测值722.7。
BL20:1H NMR(400MHz,CDCl3)δ8.39(s,1H),4.37–4.04(m,8H),4.04(s,3H),3.66–3.37(m,2H),2.64–2.18(m,7H),1.81–1.07(m,44H),0.88(t,J=6.8Hz,6H)。C38H68N7O8([M+H]+)的ESI-MS实测值750.7。
BL21:1H NMR(400MHz,CDCl3)δ8.40(s,1H),4.63(t,J=21.0Hz,2H),4.15–3.87(m,4H),3.70–3.26(m,16H),2.72–2.29(m,8H),1.81–1.02(m,65H),0.89(t,J=6.4Hz,6H)。C44H84N7O6([M+H]+)的ESI-MS实测值806.8。
BL22:1H NMR(300MHz,CDCl3)δ8.46(s,1H),4.10(s,3H),3.89–3.52(m,4H),2.85–2.30(m,13H),2.18(s,3H),1.93–1.04(m,64H),0.89(t,J=6.5Hz,6H)。C37H71N8O2([M+H]+)的ESI-MS实测值659.7。
BL23:1H NMR(400MHz,CDCl3)δ8.36(s,1H),4.67(s,4H),4.17(s,3H),3.60–3.36(m,18H),2.68–2.31(m,17H),2.31–2.16(m,4H),1.90–1.01(m,71H),0.90(t,J=6.7Hz,6H)。
BL24:1H NMR(400MHz,CDCl3)δ8.13(s,1H),4.81–4.61(s,3H),3.50(m,7H),3.12–2.20(m,24H),2.17(s,3H),1.89–1.02(m,56H),0.89(t,J=6.8Hz,6H)。C45H87N8O2([M+H]+)的ESI-MS实测值771.8。
BL25:1H NMR(300MHz,CDCl3)δ4.20(s,1H),4.00(s,2H),3.31(m,8H),3.05(m,10H),1.46(m,93H),0.89(t,J=6.6Hz,12H)。C57H120N5O2([M+H]+)的MALDI-MS实测值907.0。
BL26:1H NMR(400MHz,CDCl3)δ4.25–3.82(m,2H),3.78–3.60(m,1H),3.28(m,2H),2.50(m,6H),1.74–1.09(m,46H),0.90(t,J=6.7Hz,6H)。C33H70N3O2([M+H]+)的MALDI-MS实测值540.5。
BL27:1H NMR(400MHz,CDCl3)δ4.71(m,3H),4.30–4.01(m,3H),3.99(m,2H),3.74–3.44(m,13H),3.39–3.17(m,12H),2.42–1.11(m,80H),1.03–0.79(t,J=6.7Hz,9H)。C49H103N4O8([M+H]+)的ESI-MS实测值:875.9。
BL28:1H NMR(400MHz,CDCl3)δ4.13(t,J=6.8Hz,12H),3.96–3.78(m,1H),3.78–3.57(m,1H),3.49–3.24(m,3H),2.52(m,14H),1.85–1.06(m,76H),0.90(t,J=6.8Hz,9H)。C58H116N4O11([M+2H]2+)的ESI-MS实测值:522.7。
BL29:1H NMR(400MHz,CDCl3)δ4.14(t,J=6.7Hz,8H),3.97–3.83(m,1H),3.80–3.61(m,1H),3.33(m,3H),2.66–2.38(m,6H),1.78–1.10(m,57H),0.90(t,J=6.8Hz,6H)。C43H86N3O8([M+H]+)的ESI-MS实测值:772.7。
BL30:1H NMR(400MHz,CDCl3)δ4.68(s,4H),3.88(m,1H),3.78–3.60(m,1H),3.53(m,8H),3.35(m,3H),2.65–2.33(m,5H),1.83–1.09(m,52H),0.90(t,J=6.8Hz,6H)。C43H91N3O6([M+2H]2+)的ESI-MS实测值:373.1。
BL31:1H NMR(400MHz,CDCl3)δ4.68(s,4H),3.94–3.82(m,1H),3.77–3.68(m,1H),3.67(m,4H),3.60–3.49(m,4H),3.45–3.16(m,3H),2.81(t,J=6.0Hz,4H),2.68–2.51(m,2H),1.69–1.07(m,40H),0.90(t,J=6.8Hz,6H)。C35H75N3O6([M+2H]2+)的ESI-MS实测值:317.0。
BL32:1H NMR(300MHz,CDCl3)δ7.26(m,4H),6.69(d,J=8.7Hz,4H),6.45(d,J=15.8Hz,2H),6.24–5.99(m,2H),3.27(t,J=19.7Hz,4H),2.94(s,12H),2.71–2.30(m,13H),1.35(m,59H),0.90(t,J=6.6Hz,9H)。C62H112N5([M+H]+)的MALDI-MS实测值:926.8。
BL33:1H NMR(400MHz,CDCl3)δ7.29(m,4H),6.67(m,4H),6.50(t,J=16.4Hz,2H),6.27–6.02(m,2H),3.45(m,4H),2.98(s,12H),2.67(m,8H),1.90–1.09(m,45H),0.90(t,J=6.8Hz,6H)。C52H91N4([M+H]+)的MALDI-MS实测值:771.7。
BL34:1H NMR(300MHz,CDCl3)δ7.53(d,J=15.5Hz,1H),7.37(d,J=8.8Hz,2H),6.71–6.51(m,2H),6.23(d,J=15.5Hz,1H),4.23–3.99(m,8H),3.44–3.23(m,2H),2.97(s,6H),2.67–2.37(m,4H),1.76–1.09(m,38H),0.86(t,J=6.6Hz,6H)。C43H76N3O7([M+H]+)的ESI-MS实测值:746.7。
BL35:1H NMR(400MHz,CDCl3)δ7.53(d,1H),7.41(d,J=8.8Hz,2H),6.70(m,2H),6.21(d,J=15.5Hz,1H),4.68(m,2H),3.64–3.54(m,4H),3.46–3.35(m,6H),3.02(s,6H),1.75–1.07(m,56H),0.89(t,J=6.7Hz,6H)。C45H84N3O5([M+H]+)的ESI-MS实测值:746.6。
BL36:1H NMR(400MHz,CDCl3)δ7.56(d,J=15.5Hz,1H),7.40(d,2H),6.77–6.55(m,2H),6.19(d,1H),4.66(m,4H),3.62–3.45(m,8H),3.38(m,2H),3.09–2.93(m,6H),2.42(d,J=49.0Hz,6H),1.71–1.04(m,49H),0.89(t,J=6.5Hz,6H)。C47H88N3O5([M+H]+)的ESI-MS实测值:774.8。
BL37:1H NMR(400MHz,CDCl3)δ7.65–7.45(m,1H),7.41(d,J=8.7Hz,2H),6.75–6.54(m,2H),6.25(d,J=15.6Hz,1H),3.12–2.93(s,6H),2.68–2.31(m,14H),1.64–1.05(m,59H),0.97–0.75(t,J=6.8Hz,9H)。C51H98N4O([M+2H]2+)的ESI-MS实测值:391.7。
BL38:1H NMR(400MHz,CDCl3)δ7.55(d,J=15.5Hz,1H),7.42(d,J=8.5Hz,2H),6.64(d,2H),6.23(d,J=15.3Hz,1H),4.14(m,12H),3.40(d,J=19.8Hz,2H),3.19–2.84(m,6H),2.53(dd,J=30.3,23.1Hz,11H),1.83–1.06(m,49H),0.89(t,J=6.5Hz,9H)。C54H98N4O10([M+2H]2+)的ESI-MS实测值:481.7。
BL39:1H NMR(400MHz,CDCl3)δ7.55(d,J=7.5Hz,1H),7.42(d,J=7.9Hz,2H),6.70(d,J=11.3Hz,2H),6.21(d,J=15.3Hz,1H),4.74–4.53(m,3H),3.67–3.26(m,14H),3.16–2.88(m,6H),2.54(m,8H),1.74–1.08(m,52H),0.90(t,J=6.6Hz,9H)。C54H98N4O10([M+2H]2+)的ESI-MS实测值:481.7。
BL40:1H NMR(400MHz,CDCl3)δ7.55(d,J=15.5Hz,1H),7.43(d,J=14.7Hz,2H),6.65(d,J=21.3Hz,2H),6.22(d,J=15.5Hz,1H),4.86–4.54(m,6H),3.89–3.13(m,17H),3.07–2.89(m,6H),2.82–2.54(m,4H),1.43(m,55H),0.96–0.77(t,9H)。C54H104N4O7([M+2H]2+)的ESI-MS实测值:460.5。
BL41:1H NMR(400MHz,CDCl3)δ7.52(d,1H),7.40(d,J=8.7Hz,2H),6.70(d,J=12.0Hz,2H),6.22(d,J=14.3Hz,1H),4.11(m,11H),3.12–2.80(m,6H),2.48(dd,J=86.3,57.9Hz,11H),1.79–1.06(m,66H),0.89(t,J=6.8Hz,9H)。C66H122N4O10([M+2H]2+)的ESI-MS实测值:565.8。
BL42:1H NMR(400MHz,CDCl3)δ7.68–7.47(d,1H),7.41(d,J=8.8Hz,2H),6.68(d,J=8.8Hz,2H),6.24(d,J=15.5Hz,1H),3.83–3.49(m,2H),3.46–3.24(m,2H),3.01(s,6H),2.64(m,6H),1.74–1.00(m,63H),0.98–0.74(t,6H)。C49H93N3O([M+2H]2+)的ESI-MS实测值:370.2。
BL43:1H NMR(400MHz,CDCl3)δ7.53(t,J=19.4Hz,1H),7.40(t,J=12.5Hz,2H),6.80–6.59(m,2H),6.25(d,J=15.5Hz,1H),3.76–3.55(m,2H),3.47–3.32(m,3H),3.05–2.97(s,6H),1.77–1.11(m,72H),0.90(t,J=6.8Hz,6H)。C45H85N3O([M+2H]2+)的ESI-MS实测值:342.1。
BL44:1H NMR(400MHz,CDCl3)δ7.58–7.45(d,1H),7.39(d,J=8.7Hz,2H),6.68(d,J=8.8Hz,2H),6.29–6.10(d,1H),4.76–4.53(m,2H),3.68–3.52(m,4H),3.47–3.29(m,6H),2.97(d,J=19.4Hz,6H),2.61–2.30(m,13H),2.30–2.17(m,4H),1.84–1.15(m,55H),0.88(t,J=6.8,6H)。C50H95N4O5([M+H]+)的ESI-MS实测值:831.8。
BL45:1H NMR(400MHz,CDCl3)δ7.63–7.47(d,1H),7.39(d,J=14.1Hz,2H),6.70(d,2H),6.22(d,J=15.6Hz,1H),3.58–3.35(m,2H),3.08–2.95(m,5H),2.62–2.34(m,11H),2.34–2.15(m,5H),1.84–1.11(m,45H),0.90(t,J=6.8Hz,6H)。C42H79N4O([M+H]+)的ESI-MS实测值:655.8。
BL46:1H NMR(400MHz,CDCl3)δ7.48(d,J=14.3Hz,1H),7.39(d,J=8.8Hz,2H),6.76–6.55(d,2H),6.20(d,J=15.6Hz,1H),4.66(s,4H),3.59–3.36(m,10H),2.97(s,6H),2.61–2.30(m,13H),2.30–2.12(s,3H),1.82–1.13(m,37H),0.89(t,J=6.8Hz,6H)。C44H83N4O5([M+H]+)的ESI-MS实测值:747.8。
BL47:1H NMR(400MHz,CDCl3)δ7.57–7.44(d,1H),7.41(d,2H),6.75–6.62(d,2H),6.20(d,J=15.6Hz,1H),4.28–3.99(m,8H),3.60–3.39(m,2H),2.99(s,6H),2.58–2.38(m,9H),2.29(s,3H),1.80–1.17(m,36H),0.89(t,J=6.8Hz,6H)。C44H79N4O7([M+H]+)的ESI-MS实测值:775.7。
BL48:1H NMR(400MHz,CDCl3)δ7.53(d,1H),7.39(d,J=12.7Hz,2H),6.73–6.56(d,2H),6.22(d,J=15.5Hz,1H),4.90–4.75(m,2H),3.35(m,2H),3.05–2.97(m,6H),2.40–2.20(m,6H),1.80–1.11(m,61H),1.02–0.70(t,12H)。C51H93N3O5([M+2H]2+)的ESI-MS实测值:414.2。
BL49:1H NMR(400MHz,CDCl3)δ7.53(d,J=15.5Hz,1H),7.40(d,J=12.8Hz,2H),6.70(d,J=8.8Hz,2H),6.21(d,J=14.5Hz,1H),4.92–4.72(m,2H),4.14(m,2H),3.61–3.34(m,4H),3.02(s,6H),2.68–2.16(m,17H),2.07(s,3H),1.84–1.08(m,50H),0.97–0.78(t,12H)。C52H95N4O5([M+H]+)的ESI-MS实测值:855.9。
BL50:1H NMR(400MHz,CDCl3)δ7.62(d,J=7.8Hz,1H),7.38(d,J=8.1Hz,1H),7.17(m,2H),7.04(d,1H),4.36–3.94(m,8H),3.30–2.99(m,4H),2.68–2.26(m,8H),1.87–1.08(m,43H),0.90(t,J=6.7Hz,6H)。C43H74N3O7([M+H]+)的ESI-MS实测值:744.7。
BL51:1H NMR(400MHz,CDCl3)δ7.69–7.52(d,1H),7.37(d,J=12.3Hz,1H),7.25–7.06(m,2H),7.02(d,J=8.4Hz,1H),4.68(s,4H),3.54(m,8H),3.28–3.03(m,4H),2.66–2.35(m,8H),1.70–1.03(m,42H),0.90(t,J=6.8Hz,6H)。C43H78N3O5([M+H]+)的ESI-MS实测值:716.7。
BL52:1H NMR(400MHz,CDCl3)δ7.69–7.49(m,1H),7.35(d,J=8.0Hz,1H),7.22–7.04(m,2H),7.01(d,J=14.0Hz,1H),4.80–4.54(m,2H),3.69–3.52(m,4H),3.48–3.33(m,4H),3.24–3.03(m,4H),2.68–2.30(m,8H),1.68–1.04(m,49H),0.89(t,J=6.7Hz,6H)。C45H82N3O5([M+H]+)的ESI-MS实测值:744.8。
BL53:1H NMR(400MHz,CDCl3)δ7.59(d,J=16.0Hz,1H),7.34(d,J=9.8Hz,1H),7.13(m,2H),7.04(d,J=1.5Hz,1H),4.12(m,12H),3.21(m,4H),2.70–2.21(m,14H),1.82–1.11(m,47H),0.89(t,J=6.7Hz,9H)。C54H96N4O10([M+2H]2+)的ESI-MS实测值:480.7。
BL54:1H NMR(400MHz,CDCl3)δ7.57(d,1H),7.37(d,J=10.4Hz,1H),7.23–6.96(m,3H),4.66(m,3H),3.72–3.30(m,13H),3.30–3.07(m,4H),2.72–2.23(m,13H),1.97–1.01(m,59H),0.89(t,J=6.7Hz,9H)。C57H107N4O7([M+H]+)的ESI-MS实测值:959.9。
BL55:1H NMR(400MHz,CDCl3)δ7.70–7.44(m,1H),7.37(d,1H),7.18–6.93(m,2H),3.10(t,J=6.5Hz,2H),2.89–2.63(m,4H),2.57(m,2H),1.70–0.95(m,44H),0.92–0.77(t,6H)。C49H90N3O([M+H]+)的ESI-MS实测值:736.8。
BL56:1H NMR(400MHz,CDCl3)δ7.58(d,J=7.6Hz,1H),7.35(d,J=8.1Hz,1H),7.21–7.06(m,2H),7.02(t,J=7.2Hz,1H),3.21–3.06(m,4H),2.77–2.27(m,9H),1.82–1.04(m,64H),0.90(t,J=6.8Hz,6H)。C45H82N3O([M+H]+)的ESI-MS实测值:680.7。
BL57:1H NMR(400MHz,CDCl3)δ7.62(d,J=7.8Hz,1H),7.49–7.31(m,1H),7.16(m,2H),7.03(t,J=10.9Hz,1H),3.41–3.21(m,2H),3.06(m,2H),2.71–2.41(m,8H),2.38–2.19(m,4H),2.19–1.98(m,3H),1.77–1.09(m,45H),0.90(t,J=6.8Hz,6H)。C42H77N4O([M+H]+)的ESI-MS实测值:653.7。
BL58:1H NMR(400MHz,CDCl3)δ7.59(d,1H),7.47–7.29(d,1H),7.13(m,2H),7.04(t,1H),4.68(s,4H),3.67–3.44(m,8H),3.23(m,2H),2.67–1.95(m,15H),1.79–1.16(m,33H),0.91(t,J=6.8Hz,6H)。C44H81N4O5([M+H]+)的ESI-MS实测值:745.8。
BL59:1H NMR(300MHz,CDCl3)δ7.60(d,J=7.7Hz,1H),7.34(d,J=10.5Hz,1H),7.24–7.04(m,2H),7.03(d,J=1.8Hz,1H),4.26–4.00(m,8H),3.28(m,2H),3.12(m,2H),2.68–2.51(m,2H),2.50–2.20(m,11H),2.12(s,3H),1.75–1.08(m,40H),0.89(t,J=6.6Hz,6H)。C44H77N4O7([M+H]+)的ESI-MS实测值:773.7。
BL60:1H NMR(300MHz,CDCl3)δ7.58(d,1H),7.34(d,J=7.8Hz,1H),7.15(m,2H),7.04(s,1H),4.75–4.55(m,2H),3.70–3.01(m,12H),2.67–2.15(m,14H),2.14–1.99(m,4H),1.79–1.12(m,50H),0.89(t,J=6.7Hz,6H)。C50H93N4O5([M+H]+)的ESI-MS实测值:829.9。
BL61:1H NMR(300MHz,CDCl3)δ7.61(d,J=7.7Hz,1H),7.42–7.30(m,1H),7.23–7.07(m,2H),7.03(d,J=2.2Hz,1H),4.67(s,4H),4.13(m,2H),3.63–3.37(m,9H),3.22(m,4H),2.69–2.19(m,14H),2.08(d,J=9.9Hz,3H),2.06(s,3H),1.72–1.05(m,51H),0.89(t,J=6.7Hz,6H)。C48H89N4O5([M+H]+)的ESI-MS实测值:801.8。
BL62:1H NMR(300MHz,CDCl3)δ7.62(d,J=7.7Hz,1H),7.43–7.32(m,1H),7.15(m,2H),7.04(d,J=2.1Hz,1H),3.39–3.18(m,2H),3.13(t,J=7.2Hz,2H),2.71–2.36(m,9H),2.36–2.17(m,4H),2.08(s,3H),1.78–1.08(m,61H),0.93–0.84(t,6H)。C46H85N4O([M+H]+)的ESI-MS实测值:709.8。
BL63:1H NMR(300MHz,CDCl3)δ7.62(d,J=7.8Hz,1H),7.43–7.31(m,1H),7.23–7.08(m,2H),7.05(d,J=2.1Hz,1H),3.27(m,2H),3.13(t,J=7.2Hz,2H),2.68–2.37(m,9H),2.35–2.14(m,4H),2.16–1.96(m,4H),1.74–1.06(m,61H),0.90(t,J=6.7Hz,6H)。C50H93N4O([M+H]+)的ESI-MS实测值:765.9。
BL64:1H NMR(400MHz,CDCl3)δ7.60(d,J=13.8Hz,1H),7.37(d,J=8.1Hz,1H),7.24–7.09(m,2H),7.04(t,J=6.0Hz,1H),4.95–4.67(m,2H),3.29–3.01(m,4H),2.69–2.51(m,3H),2.51–2.20(m,10H),1.80–1.04(m,60H),1.02–0.79(m,12H)。C51H90N3O5([M+H]+)的ESI-MS实测值:824.8。
BL65:1H NMR(400MHz,CDCl3)δ7.42–7.31(m,4H),7.16–6.96(m,2H),6.92–6.73(m,1H),3.37–3.14(m,2H),2.43(m,9H),2.23–2.13(m,2H),1.93–1.10(m,54H),0.89(t,J=6.8Hz,6H)。
BL66:1H NMR(300MHz,CDCl3)δ7.44–7.29(m,4H),7.09–6.95(m,2H),6.83(m,1H),4.66(s,4H),3.51(m,9H),3.36–3.14(m,2H),2.82–2.11(m,12H),1.91–1.05(m,51H),0.89(t,J=6.8Hz,6H)。C53H88ClF2N2O7S([M+H]+)的ESI-MS实测值:969.8。
BL67:1H NMR(300MHz,CDCl3)δ7.46–7.29(m,4H),7.17–6.94(m,2H),6.96–6.66(m,1H),3.25(m,2H),2.74(m,4H),2.51–2.27(m,4H),2.31–2.11(m,2H),1.94–1.00(m,65H),0.89(t,J=6.7Hz,6H)。C59H100ClF2N2O3S([M+H]+)的ESI-MS实测值:989.9。
BL68:1H NMR(300MHz,CDCl3)δ7.42–7.30(m,4H),7.16–6.96(m,2H),6.92–6.70(m,1H),4.31–3.93(m,9H),3.36–3.09(m,2H),2.62–2.08(m,13H),1.94–1.17(m,53H),0.89(t,J=6.7Hz,6H)。C53H84ClF2N2O9S([M+H]+)的ESI-MS实测值:997.8。
BL69:1H NMR(400MHz,CDCl3)δ7.34(m,4H),7.11–6.94(m,2H),6.83(m,1H),3.94–3.60(m,4H),3.37–3.11(m,2H),2.57–2.25(m,10H),2.25–2.08(m,2H),1.95–1.03(m,71H),0.89(t,J=6.8Hz,6H)。C55H92ClF2N2O3S([M+H]+)的ESI-MS实测值:933.8。
BL70:1H NMR(400MHz,CDCl3)δ7.47–7.31(m,4H),7.11–6.95(m,2H),6.92–6.74(m,1H),4.75–4.57(m,2H),3.68–3.52(m,4H),3.46–3.31(m,4H),3.31–3.13(m,2H),2.67–1.98(m,13H),1.87–1.06(m,58H),0.89(t,J=6.8Hz,6H)。C59H100ClF2N2O7S([M+H]+)的ESI-MS实测值:1053.7。
BL71:1H NMR(400MHz,CDCl3)δ7.43–7.31(m,4H),7.12–7.01(m,2H),6.89–6.76(m,1H),4.92–4.69(m,2H),3.45–3.22(m,2H),2.58–2.06(m,23H),1.88–1.16(m,56H),1.00–0.79(t,12H)。C62H103ClF2N3O7S([M+H]+)的ESI-MS实测值:1106.8。
BL72:1H NMR(400MHz,CDCl3)δ7.41–7.29(m,4H),7.06(m,2H),6.84(m,1H),3.39–3.23(m,2H),2.62–2.31(m,12H),2.16(m,2H),1.91–1.00(m,58H),1.00–0.74(t,6H)。C52H87ClF2N3O3S([M+H]+)的ESI-MS实测值:906.8。
BL73:1H NMR(400MHz,CDCl3)δ7.48–7.27(m,4H),7.14–7.00(m,3H),6.88–6.73(m,1H),3.45–3.27(m,2H),2.63–2.30(m,12H),2.19(m,2H),1.88–1.09(m,53H),0.90(t,J=6.8Hz,6H)。C54H87ClF2N3O9S([M+H]+)的ESI-MS实测值:962.9。
BL74:1H NMR(400MHz,CDCl3)δ7.48–7.31(m,4H),7.06(m,2H),6.91–6.68(m,1H),3.43–3.15(m,2H),2.43(m,12H),2.21–2.02(m,2H),1.95–1.01(m,62H),0.90(t,J=6.8Hz,6H)。C60H103ClF2N3O3S([M+H]+)的ESI-MS实测值:1018.8。
BL75:1H NMR(300MHz,CDCl3)δ7.49–7.30(m,4H),7.06(m,2H),6.92–6.74(m,1H),4.14(m,8H),3.44–3.23(m,2H),2.58–2.03(m,16H),1.90–1.06(m,40H),0.90(t,J=6.6Hz,6H)。C54H87ClF2N3O9S([M+H]+)的ESI-MS实测值:1026.7。
BL76:1H NMR(300MHz,CDCl3)δ7.46–7.27(m,4H),7.13–6.96(m,2H),6.89–6.74(m,1H),4.67(s,4H),3.68–3.45(m,8H),3.32(m,2H),2.63–2.30(m,14H),2.20(s,3H),1.88–1.14(m,45H),0.90(t,J=6.8Hz,6H)。C54H91ClF2N3O7S([M+H]+)的ESI-MS实测值:998.8。
BL77:1H NMR(400MHz,CDCl3)δ2.64–2.31(m,4H),2.24–2.05(m,2H),1.69–1.04(m,53H),0.89(m,12H)。C36H70N([M+H]+)的ESI-MS实测值:516.8。
BL78:1H NMR(400MHz,CDCl3)δ2.66–2.47(m,4H),2.23–2.04(m,2H),1.58–0.99(m,65H),0.94–0.77(m,12H)。C44H86N([M+H]+)的ESI-MS实测值:628.8。
BL79:1H NMR(300MHz,CDCl3)δ7.37(dd,J=8.3,7.5Hz,1H),6.53(dd,J=15.4,7.9Hz,2H),2.91–2.64(m,4H),2.57–2.29(m,5H),1.97–1.03(m,58H),0.90(t,J=6.7Hz,6H)。C34H63ClN3([M+H]+)的ESI-MS实测值:548.5。
BL80:1H NMR(300MHz,CDCl3)δ7.44–7.35(m,1H),6.54(m,2H),4.17(m,10H),3.06–2.83(m,4H),2.83–2.53(m,5H),2.09–1.01(m,40H),0.89(t,J=6.7Hz,6H)。C36H63ClN3O6([M+H]+)的ESI-MS实测值:668.5。
BL81:1H NMR(400MHz,CDCl3)δ7.32(dd,J=16.4,8.6Hz,1H),6.56–6.40(m,2H),4.63(d,J=1.6Hz,4H),3.60–3.28(m,8H),2.86–2.61(m,4H),2.54–2.24(m,5H),1.88–1.18(m,33H),0.87(t,J=6.8Hz,6H)。C36H67ClN3O4([M+H]+)的ESI-MS实测值:640.6。
BL82:1H NMR(400MHz,CDCl3)δ7.41(dd,J=14.6,7.6Hz,1H),
6.56(m,2H),4.14(m,8H),3.76(m,6H),3.01–2.84(m,4H),2.84–2.55(m,5H),2.06–1.09(m,43H),0.91(t,J=6.9Hz,6H)。
BL83:1H NMR(300MHz,CDCl3)δ7.45–7.31(m,1H),6.53(dd,J=14.9,7.9Hz,2H),2.76(m,4H),2.62–2.33(m,5H),1.35(m,57H),0.89(t,J=6.7Hz,6H)。
独立地形成表1中所描绘的包含化合物BL1-BL83的脂质纳米颗粒以包封萤火虫荧光素酶mRNA以用于筛选CCL131细胞中的活性。所筛选颗粒的MC3 LNP归一化数据在图1中示出。使用聚类测试方法检查与PBS处理组相比使用表1中所描绘的脑靶向脂质中的几种脑靶向脂质(BL28、BL39、BL54、BL68和BL70)的体内mRNA递送。各组的生物发光强度比较在图2中示出。
表1
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Claims (52)
1.一种由式I至XIX中的任一个式表示的化合物或其药学上可接受的盐:
其中
R1、R2、R3和R4各自独立地为经取代的或未经取代的C1-C20烷基;
R5和R14各自独立地为氢、经取代的或未经取代的C1-C5烷基;R6、R7、R8、R9、R10、R11、R12和R13各自独立地为氢、OH、卤素或经取代的或未经取代的C1-C5烷基;
R15、R16和R17各自独立地为氢、OH、卤素或经取代的或未经取代的C1-C5烷基;并且
R18为OH或经取代的或未经取代的C1-C10烷基。
2.如权利要求1所述的化合物,其中所述化合物由式I-XIII中的任一个式或其药学上可接受的盐表示:
3.如权利要求1所述的化合物,其中所述化合物由权利要求XIV-XIX中的任一个或其药学上可接受的盐表示:
4.如权利要求1-2中任一项所述的化合物,其中所述化合物由式I-III中的任一个式或其药学上可接受的盐表示:
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5.如权利要求1-2中任一项所述的化合物,其中所述化合物由式IV-VI中的任一个式或其药学上可接受的盐表示:
6.如权利要求1-2中任一项所述的化合物,其中所述化合物由式VII-IX中的任一个式或其药学上可接受的盐表示:
7.如权利要求1-2中任一项所述的化合物,其中所述化合物由式X-XIII中的任一个式或其药学上可接受的盐表示:
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8.如权利要求1或3中任一项所述的化合物,其中所述化合物由式XIV或XVII中的任一个式或其药学上可接受的盐表示:
9.如权利要求1或3中任一项所述的化合物,其中所述化合物由式XV-XVI中的任一个式或其药学上可接受的盐表示:
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10.如权利要求1或3中任一项所述的化合物,其中所述化合物由式XVIII或其药学上可接受的盐定义:
11.如权利要求1或3中任一项所述的化合物,其中所述化合物由式XIX或其药学上可接受的盐定义:
12.如权利要求1-11中任一项所述的化合物,其中所述化合物由式I-A至XIX-A中的任一个式或其药学上可接受的盐表示:
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13.如权利要求1-12中任一项所述的化合物,其中R1、R2、R3和R4各自独立地为经取代的或未经取代的C5-C15烷基。
14.如权利要求1-13中任一项所述的化合物,其中R1、R2、R3和R4各自独立地为直链或支化未经取代的烷基。
15.如权利要求1-14中任一项所述的化合物,其中R1、R2、R3和R4各自独立地为直链或支化经取代的烷基。
16.如权利要求1-15中任一项所述的化合物,其中R1、R2、R3和R4各自独立地为被一个或多个选自由以下组成的组的取代基取代的直链或支化C5-C15烷基:酯、醚、碳酸酯、缩醛、缩酮、硫缩酮、硫醇、硫化物、二硫化物、二醇、氧代基和酰胺。
17.如权利要求1-16中任一项所述的化合物,其中R1、R2、R3和R4各自独立地选自由以下组成的组:
其中N、M和X各自独立地表示1至9的整数。
18.如权利要求1-17中任一项所述的化合物,其中R1、R2、R3和R4各自独立地选自由以下组成的组:
其中N和M各自独立地表示1至9,如1至5的整数。
19.如权利要求1-18中任一项所述的化合物,其中R1、R2、R3和R4中的至少一者包含:
其中N和M各自独立地表示1至9,如1至5的整数。
20.如权利要求1-19中任一项所述的化合物,其中R1、R2、R3和R4各自包含
其中N和M各自独立地表示1至9,如1至5的整数。
21.如权利要求1-20中任一项所述的化合物,其中R1、R2、R3和R4各自独立地选自由以下组成的组:
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22.如权利要求1-19和21中任一项所述的化合物,其中R1、R2、R3和R4不同。
23.如权利要求1-21中任一项所述的化合物,其中R1、R2、R3和R4全部相同。
24.如权利要求1-23中任一项所述的化合物,其中所述化合物选自BL1-BL83中描绘的结构中的任一结构。
25.如权利要求1-24中任一项所述的化合物,其中所述化合物选自由以下组成的组:
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或其药学上可接受的盐。
26.如权利要求1-25中任一项所述的化合物,其中所述化合物选自由以下组成的组:
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或其药学上可接受的盐。
27.如权利要求1-26中任一项所述的化合物,其中所述化合物选自由以下组成的组:
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或其药学上可接受的盐。
28.如权利要求1-27中任一项所述的化合物,其中所述化合物包括:
或其药学上可接受的盐。
29.如权利要求1-27中任一项所述的化合物,其中所述化合物包括:
或其药学上可接受的盐。
30.如权利要求1-27中任一项所述的化合物,其中所述化合物包括:
或其药学上可接受的盐。
31.如权利要求1-27中任一项所述的化合物,其中所述化合物包括:
或其药学上可接受的盐。
32.如权利要求1-27中任一项所述的化合物,其中所述化合物包括:
或其药学上可接受的盐。
33.如权利要求1-27中任一项所述的化合物,其中所述化合物包括:
或其药学上可接受的盐。
34.一种制备权利要求1-33中任一项所述的化合物的方法。
35.一种脂质颗粒,所述脂质颗粒包含权利要求1-33中任一项所述的化合物。
36.如权利要求35所述的脂质颗粒,其中所述脂质颗粒的形状基本上为球形。
37.如权利要求35-36中任一项所述的脂质颗粒,其中所述脂质颗粒具有30纳米(nm)至800nm的平均粒度。
38.如权利要求35-37中任一项所述的脂质颗粒,其中所述脂质颗粒进一步包含额外的组分。
39.如权利要求38所述的脂质颗粒,其中所述额外的组分包括额外的脂质。
40.如权利要求39所述的脂质颗粒,其中所述额外的脂质包括磷脂、固醇或它们的组合,如1,2-二油酰基-sn-甘油-3-磷酸乙醇胺(DOPE)、胆固醇、1,2-二肉豆蔻酰基-rac-甘油-3-甲基聚氧乙烯或它们的组合。
41.一种药物组合物,所述药物组合物包含包封在权利要求35-40中任一项所述的脂质颗粒内的治疗剂。
42.如权利要求41所述的药物组合物,其中所述治疗剂是抗癌剂、抗微生物剂、免疫调节剂、抗炎剂或调节细胞代谢活性的剂。
43.如权利要求41-42中任一项所述的药物组合物,其中所述治疗剂包含病毒抗原、细菌抗原、癌抗原、肿瘤抗原、基因编辑组分、蛋白质替代组分、免疫调节剂、免疫调控剂或它们的组合。
44.如权利要求41-43中任一项所述的药物组合物,其中所述治疗剂是以下中的一种或多种:单克隆抗体、嵌合抗体、人源化抗体、纳米抗体、抗体片段、胆固醇、激素、肽、蛋白质、化学治疗剂、抗赘生物剂、低分子量药物、维生素、辅因子、核苷、核苷酸、寡核苷酸、多核苷酸、酶核酸、反义核酸、三链体形成寡核苷酸、反义DNA或RNA组合物、嵌合DNA:RNA组合物、同工酶、适体、核酶、诱饵、类似物、质粒、表达载体、小核酸分子、mRNA、RNAi剂、短干扰核酸(siNA)、短干扰RNA(siRNA)、双链RNA(dsRNA)、微小RNA(miRNA)、短发夹RNA(shRNA)、肽核酸(PNA)、锁核酸核糖核苷酸(LNA)、吗啉代核苷酸、苏糖核酸(TNA)、乙二醇核酸(GNA)、sisiRNA(小内部片段化干扰RNA)、aiRNA(不对称干扰RNA)以及在相关细胞或组织的有义链与反义链之间存在具有1个、2个或更多个错配的siRNA。
45.如权利要求41-44中任一项所述的药物组合物,其中所述治疗剂包含核酸。
46.如权利要求41-45中任一项所述的药物组合物,其中所述治疗剂包含mRNA。
47.一种治疗有需要的受试者的疾病的方法,所述方法包括向所述受试者施用治疗有效量的权利要求41-46中任一项所述的药物组合物。
48.如权利要求47所述的方法,其中所述药物组合物通过静脉内施用。
49.如权利要求47-48中任一项所述的方法,其中所述疾病是增殖性疾病、炎症性疾病、移植排斥、组织排斥、自身免疫性疾病、年龄相关性疾病、神经系统疾病、神经变性疾病、呼吸系统疾病、心血管疾病、眼部疾病、代谢疾病、肌肉骨骼疾病、皮肤病、听觉疾病、肝病、肾病和肾脏疾病中的一种或多种。
50.如权利要求47-49中任一项所述的方法,其中所述疾病是神经系统疾病。
51.如权利要求47-49中任一项所述的方法,其中所述疾病是肝病。
52.如权利要求47-49中任一项所述的方法,其中所述疾病是肌肉骨骼疾病。
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