CN104168887B - 氨基酸脂质 - Google Patents
氨基酸脂质 Download PDFInfo
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- CN104168887B CN104168887B CN201380013769.0A CN201380013769A CN104168887B CN 104168887 B CN104168887 B CN 104168887B CN 201380013769 A CN201380013769 A CN 201380013769A CN 104168887 B CN104168887 B CN 104168887B
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Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
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- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明涉及一新型类别的脂质,更具体地说涉及具有极性头基的醚‑脂质、以及包含这些脂质的囊泡、它们的制备方法以及在医疗应用中的用途,其中醚‑脂质由通式I表示,其中Y代表O、N、S或共价键;P1代表H、Y保护基团或Y活化基团或间隔基;P2、P3彼此独立地代表H、氨基保护基团或间隔基,或P2和P3与它们所连接的N一起形成环结构;L为式(a)基团,其中虚线代表与N连接;R1代表H或式‑(CH2)2‑ORb1基团;R1'代表H或式‑(CH2)2‑ORb2基团,R2代表H或式‑CH2‑ORc基团;R2'代表H或式‑ORd或‑CH2‑ORd基团;R3代表H或式‑(CH2)2‑ORe或‑(CH2)3‑ORe基团;Ra、Rb1、Rb2,Rc、Rd,Re彼此独立地代表饱和或不饱和的、直链或分支的烃链,且m为1、2或3;条件是R1、R1'、R2、R2'、R3中至少一个不是H。
Description
发明领域
本发明涉及新类别的脂质,更具体地说涉及具有极性头基的醚- 脂质、和包含这些脂质的囊泡、它们的制备方法以及它们在医疗应用中的用途。
发明背景
分子识别,如在受体配体、抗原-抗体、DNA-蛋白质、糖-凝集素、 RNA-核糖体等之间的分子识别,是许多生物系统的一种重要的基础原理并应用于许多用于医疗应用的人工创造的生物系统中,如用于人造 (微米或纳米)颗粒系统包括聚合物珠粒、囊泡状脂质、微乳等中。
基于分子识别的应用的一个重要实例是靶向递送诊断或治疗化合物如抗病毒、化学治疗或显影剂至特定位点的使用,这可以克服与非特异性递送(如体内清除时间、潜在毒性、与试剂的膜输送相关的问题等)相关的限制并因此极大地增强它们的效力。多种基于识别的策略已经用于改善递送化合物至靶细胞的细胞内环境(即递送至特定的细胞小室)中发挥其生物活性作用,尤其是通过涉及生物或人造载体应用的特定转运子(transporters)的递送,身世载体如病毒载体、阳离子聚合物如聚赖氨酸、聚精氨酸等(参见,例如WO 79/00515、 WO 98/52614)、脂质载体、和各种其它共轭系统。
一种广泛应用的方法包括脂质囊泡作为人造载体的应用,例如脂质体、胶束、纳米颗粒,由于它们能减少生物活性剂的系统暴露已经作为药物递送载体被广泛开发和分析,从而克服与降解、溶解性等有关的问题并提供血循环时间的增加。生物活性剂的主动靶向包括用靶向配体衍生脂质囊泡中的脂质(在囊泡形成之前或在囊泡形成之后),其中靶向配体用来在体内施用之后将囊泡引导(或靶向)至特定的细胞类型如癌细胞或对特定的组织和器官特异性的细胞,如肝细胞(参见,例如,US 6,316,024和US 6,214,388;Allen等,Biochim.Biophys. Acta,1237:99-108(1995);Blume等,Biochim.Biophys.Acta, 1149:180-184(1993))。这可以通过利用在特定的细胞类型中过度表达的受体来完成,其中受体包括例如叶酸受体(在各种肿瘤组织包括乳房、卵巢、颈部、结直肠、肾、和鼻咽肿瘤中过度表达),表皮生长因子受体(EGFR)(在甲状腺未分化癌以及乳房和肺肿瘤中过度表达),转移抑制素(metastin)受体(在乳突状甲状腺癌中过度表达), ErbB族受体酪氨酸激酶(在重要的乳腺癌亚型中过度表达),人表皮生长因子受体-2(Her2/neu)(在乳腺癌中过度表达),酪氨酸激酶-18- 受体(c-Kit)(在肉瘤样肾癌中过度表达),HGF受体c-Met(在食管腺癌中过度表达),CXCR4和CCR7(在乳房癌中过度表达),内皮素 -A受体(在前列腺癌中过度表达),过氧化物酶体增殖物激活受体δ (PPAR-δ)(在大多数结直肠癌肿瘤中过度表达),PDGFR A(在卵巢癌中过度表达),BAG-1(在各种肺癌中过度表达),可溶性II型 TGFβ受体(在胰腺癌中过度表达),去唾液酸糖蛋白受体(在肝细胞中过度表达),□v□3整联蛋白受体(在生长的肿瘤脉管系统 (vascularture)中过度表达)等。
选择性结合此种待治疗或试验的特异性受体细胞或组织的任何试剂都可以附着于脂质囊泡上并充当靶向配体或受体配体。典型地,此种靶向配体通过长链(例如聚合物)连接子附着于脂质或脂质囊泡表面。例如叶酸型轭合物已经用于提供靶向递送用于治疗和/或诊断疾病的治疗化合物的方法,允许治疗化合物的所需剂量的降低(参见例如 WO02/094185、US 6,335,434、WO 99/66063、US 5,416016)。同样,应用半乳糖-和半乳糖胺-型轭合物跨细胞膜转运外源性化合物可提供针对肝病如HBV和HCV感染或肝细胞癌治疗的靶向递送的方法,同时允许对治疗所需要的治疗化合物的所需剂量的降低(参见例如US 6,030,954)。
基于分子识别的应用的另一个重要实例是抗原展示系统的使用,其包括将“自体”和“外来”这两种蛋白(抗原)呈现至免疫系统以产生T细胞激活、调节或耐受。有助于期望的免疫应答的抗原呈现系统中的受体配体相互作用或其不存在是复杂的并难以评价,受各种参数如配体密度、共同受体的存在、受体配体亲和性和表面条件的影响。因此广泛应用的方法包括应用天然存在的人类细胞(或其部分),其主要功能是抗原处理和呈递。但是,虽然基于活细胞的系统可能对实现期望的耐受或免疫应答的诱导的模拟细胞-细胞相互作用是最佳的,它们依赖于表面分子受调节的表达,包括其表面膜上其它“共刺激”分子和/或粘着分子以足够的治疗水平的可能地表达。目前已知的人工系统的范围从遗传工程亚细胞的抗原呈递囊泡(其载有对它们的表面 (WO 03/039594)上抗原呈递和T-淋巴细胞活化或抑制需要的分子) 到基于细胞大小、基于生物可降解的微球的抗原呈递系统的系统(WO 07/087341)。
清楚的是,以上基于分子识别的技术还存在缺陷,对用于基于分子识别的应用如靶向递送或抗原呈递的通用且高效的人造载体系统包括制备它们的简单和经济的方法,本领域中仍然存在需要。
本申请提供作为载体或展示系统之用的新类别的脂质和包含这些脂质的囊泡,其可以克服上面所述的限制。
发明概述
本发明涉及用于各种医疗应用中的新类别的脂质和包含这些脂质的囊泡。更具体而言本发明涉及醚-脂质化合物,其特征为至少两个醚连接的烃链和游离的、受保护的或活化形式或任选地用至少一个间隔基基团衍生化的包含具有最高6个碳原子的短直链氨基酸的头基。
具体而言,在一实施方案中,本发明涉及通式I化合物
其中
Y代表O、N、S或共价连接
P1代表H、Y保护基团或Y活化基团或间隔基,
P2、P3彼此独立地代表H、氨基保护基团或间隔基,或P2和P3与它们所连接的N一起形成环结构,
L为式(a)基团,
其中虚线代表与N连接,
R1,代表H或式-(CH2)2-ORb1基团,
R1',代表H或式-(CH2)2-ORb2基团,
R2代表H或式-CH2-ORc基团,
R2'代表H或式-ORd或-CH2-ORd基团,
R3代表H或式-(CH2)2-ORe或-(CH2)3-ORe基团,
Ra、Rb1、Rb2、Rc、Rd、Re彼此独立地代表饱和或不饱和的、直链或分支的烃链,
m为1、2或3,
条件是R1、R1'、R2、R2'、R3中至少一个不是H。
本发明的化合物包括该化合物所有可能的立体异构体,如几何异构体,例如Z和E异构体(顺式和反式异构体),和光学异构体,例如非对映异构体和对映异构体,以纯的形式或以它们的混合物形式存在。
在一实施方案中,本发明涉及非衍生化的脂质化合物,其中P1、 P2、P3中没有一个是间隔基。更具体而言,非衍生化的脂质化合物包括(i)游离形式的脂质化合物,其中P1、P2、P3中没有一个是活化基团或保护基团,(ii)受保护的脂质化合物,其中P1、P2、P3中至少一个为保护基团,且(iii)活化的脂质化合物,其中P1为活化基团。
在另一实施方案中,本发明涉及脂质-间隔基衍生物,其中P1、P2、 P3中至少一个是间隔基。
本发明的化合物包括基团R1、R1'、R2、R2'、R3及其亚结构Ra、Rb1、 Rb2、Rc、Rd、Re所有可能的变化。
在式I化合物的第一实施方案中,基团R3为H。更具体而言,(i)R3为H且R1和R1'均为H,或者(ii)R3为H且R2和R2'均为H。因此,本发明涉及式Ia化合物,
其中L为式(a)基团,
且其中P1、P2、P3、Y、R1、R1'、R2、R2'、Ra、和m如上对于式I化合物的定义。
更具体而言,本发明涉及式Ia化合物,其中L为式(b)或(c)基团
其中P1、P2、P3、Y、R1、R1'、R2、R2'、Ra、和m如上定义,条件是式(b)中R2和R2'之一不是H,且式(c)中R1和R1'之一不是H。
在第二实施方案,R1、R1'、R2、R2'为H且R3为式-(CH2)2-ORe或 -(CH2)3-ORe基团。因此,本发明涉及式Ib化合物,
其中R3为式-(CH2)2-ORe或-(CH2)3-ORe基团,且
P1、P2、P3、Y、Ra、Re和m如上对式I基团的定义。
另一方面本发明涉及囊泡形式的组合物(本发明的组合物),例如脂质体、胶束、纳米颗粒等。本发明的囊泡包含至少一种本发明的化合物或本发明多种化合物的混合物,任选地与一种或多种其它形成囊泡的化合物混合。
另一方面本发明涉及制备本发明的化合物和组合物的方法。
本发明的另一方面涉及试剂盒,其包含本发明的化合物或组合物,优选以冻干形式存在。
本发明的化合物和组合物找到作为递送载体例如用于一种或多种生物活性剂靶向递送的递送载体或用于抗原展示系统的应用。本发明的化合物和组合物的此方面为同时提交的国际申请的一部分,其在此全文引入。
本发明的这些方面及其它方面由以下说明书和权利要求书将变得更显而易见。
发明详述
如上面和通篇公开所用的,某些术语,除非另有说明,要理解为具有以下含义:
如本申请所使用的术语“化合物”(单独或与“本发明”或“本发明的”或“脂质”组合)指本发明的化合物,其包含头基上的直链、双官能氨基酸,更具体地说2-氨基-链烷链烷二酸(具有最高六个碳原子),如天冬氨酸、谷氨酸等。本发明化合物包括“非衍生化(脂质)化合物”,其以游离形式(“游离的(脂质)化合物”)、以保护形式(“受保护的(脂质)化合物”)或以活化形式(“活化的(脂质)化合物”)存在并因此不带共价键连接的间隔基基团,以及“衍生化的(脂质)化合物”(或“脂质间隔基衍生物”),其为含一个或多个间隔基基团的非衍生化(脂质)化合物的轭合物。
受保护的或活化的(脂质)化合物指经改性的分别位点-特定地含有保护基团或活化基团的本发明化合物。所述改性在头基,更具体地说在氨基酸的反应位点,更优选分别在N-和/或Y-基团(例如以P1、 P2、P3的形式)上与已知于本领域合适的保护或活化基团进行。
“脂质间隔基衍生物”指经改性的分别位点-特定地含有间隔基的本发明化合物。所述改性采用已知的偶联技术在头基,更具体地说在氨基酸的反应位点,更优选在N-和/Y-基团(或如果Y是共价键,则为CO-基团)上与已知于本领域合适的间隔基(例如以P1、P2、P3的形式)进行。
术语“组合物”或“本发明的组合物”指包含本发明的至少一种化合物的组合物。示例性的组合物包括囊泡或囊泡状组合物,按其最宽泛的解释它们包括本发明的至少一种脂质化合物与其它物质和结构的任何缔合。因此,合适的囊泡状组合物包括但不限于,脂质体、胶束、微球、纳米颗粒等。在一具体的实施方案中囊泡状组合物指具有内空隙的或实心的球形实体。所述囊泡可由合成或天然存在的脂质,包括本发明的一种或多种化合物,及其混合物配制。在任何得到的囊泡中,脂质可以单层或双层的形式存在。在一个以上的单层或双层的情况下,单层或双层通常是同心的。脂质囊泡包括通常称为脂质体(即包含一个或多个含内空隙的同心排列的脂质双层)、胶束(即包含具有内空隙的单脂质单层的囊泡)、纳米球等的这种实体。因此,所述脂质可用于形成单层囊泡(包含一个单层或双层)、寡层(oligolamellar)囊泡(包含约两个或约三个单层或双层)或多层囊泡(包含约三个以上的单层或双层)。作为替代它们可用于包被先前存在的囊泡如纳米颗粒,例如纳米球。囊泡的内空隙可填充液体,包括,例如,含水液体、气体、气态前体、和/或固体物质,包括,例如,一种或多种生物活性剂。在另一具体的实施方案中,囊泡状组合物指簇(clusters)、管等形式的组合物。
本发明的组合物可包含一种或多种生物活性剂,其被嵌入或封闭于其中或与其连接(共价键和非共价键)。更具体而言,本发明的囊泡状组合物可在内空隙中包含一种或多种生物活性剂(用于递送功能) 和/或可在它们的表面上用一种或多种生物活性剂衍生化(用于靶向或展示功能)。这是同时提交的申请的一部分,其在此全文引入。
如本申请所使用的术语“辅助脂质”或“形成囊泡的(辅助)脂质”指可任选地以本发明脂质组合物中其它脂质形式存在的脂质且可包括非环状和环状的、饱和或不饱和的天然或合成来源的脂质。如本申请所用的辅助脂质可以是中性脂质、阳离子型脂质或阴离子型脂质。阳离子型脂质具有净正电荷并可包括脂质诸如N-[1-(2,3-二油酰氧基)丙基]-N,N,N-三甲基铵盐,例如硫酸甲酯(DOTAP),DDAB,二甲基双十八烷基溴化铵;1,2-二酰基氧基-3-三甲基铵丙烷,(包括但不限于:二油酰基,二肉豆蔻酰基,二月桂酰基,二棕榈酰基和二硬脂酰基;也可将两种不同的酰基链与甘油骨架连接);N-[1-(2,3-二油酰氧基)丙基]-N,N-二甲基胺(DODAP);1,2-二酰基氧基-3-二甲基铵丙烷,(包括但不限于:二油酰基,二肉豆蔻酰基,二月桂酰基,二棕榈酰基和二硬脂酰基;也可将两种不同的酰基链与甘油骨架连接);双十八烷基酰氨基甘氨酰基精胺(DOGS);3β-[N-(N',N'- 二甲基氨基-乙烷)氨甲酰基]胆固醇(DC-Chol);2,3-二油酰氧基 -N-(2-(精胺羧酰氨基)-乙基)-N,N-二甲基-1-丙铵三氟-乙酸 (DOSPA);β-丙氨酰胆固醇;十六烷基三甲基溴化铵(CTAB);二C14- 脒;N-叔丁基-N'-十四烷基-3-十四烷基氨基-丙脒;14Dea2;N-(α- 三甲基氨基乙酰基)双十二烷基-D-谷氨酸盐氯化物(TMAG);O,O'-双十四烷酰基-N-(三甲基氨基-乙酰基)二乙醇胺氯化物;1,3-二油酰氧基 -2-(6-羧基-精氨基)-丙基酰胺(DOSPER);N,N,N',N'-四甲基-N,N'-双(2-羟基乙基)-2,3-二油酰氧基-1,4-丁二铵碘化物;1-[2-(酰氧基) 乙基]2-烷基(链烯基)-3-(2-羟乙基)-咪唑啉氯化物衍生物(如 Solodin等(1995)Biochem.43:13537-13544所描述),如1-[2-(9(Z)- 十八烯酰基氧基)乙基]-2-(8(Z)-十七烯基-3-(2-羟乙基)咪唑啉氯化物(DOTIM),1-[2-(十六烷酰基氧基)乙基]-2-十五烷基-3-(2-羟乙基) 咪唑啉氯化物(DPTIM),2,3-二烷基氧基丙基季铵化合物衍生物,在季胺上含有羟烷基部分(参见例如Felgner等J.Biol.Chem.1994,269, 2550-2561),如:1,2-二油酰基-3-二甲基-羟乙基溴化铵(DORI),1,2- 二油酰氧基丙基-3-二甲基-羟乙基溴化铵(DORIE),1,2-二油酰氧基丙基-3-二甲基-羟丙基溴化铵(DORIE-HP),1,2-二油酰氧基丙基-3-二甲基-羟丁基溴化铵(DORIE-HB),1,2-二油酰氧基丙基-3-二甲基-羟戊基溴化铵(DORIE-Hpe),1,2-二肉豆蔻基氧基丙基-3-二甲基-羟基乙基溴化铵(DMRIE),1,2-二棕榈基氧基丙基-3-二甲基-羟乙基溴化铵 (DPRIE),1,2-二硬脂基氧基丙基-3-二甲基-羟乙基溴化铵(DSRIE);阳离子型酰基卡尼汀的酯(由Santaniello等美国专利号5,498,633 报道);阳离子型磷脂酰胆碱的三酯,即1,2-二酰基-sn-甘油-3-乙基磷酸胆碱,其中烃链可以是链长为C12至C24的饱和或不饱和的和分支或非分支的,两个酰基链不一定相同。中性或阴离子型脂质分别具有中性或阴离子净电荷。这些可选自甾醇类或脂质如胆固醇、磷脂、溶血脂质、溶血磷脂、神经鞘脂或带有中性或负净电荷的聚乙二醇化脂质。有用的中性和阴离子型脂质因此包括:磷脂酰丝氨酸,磷脂酰甘油,磷脂酰肌醇(不限于特定的糖),脂肪酸类,甾醇类,含有羧酸基团例如,胆固醇,胆固醇硫酸酯和胆固醇半琥珀酸酯,1,2-二酰基-sn-甘油基-3-磷酸乙醇胺,包括但不限于,DOPE,1,2-二酰基-甘油基-3-磷酸胆碱和鞘磷脂。与甘油骨架连接的脂肪酸不限于特定长度或数量的双键。磷脂也可含两种不同的脂肪酸。
本发明涉及用于各种医疗应用中的新类别的脂质和包含这些脂质的囊泡。更具体而言本发明涉及醚-脂质化合物H-L,其中L为包含至少两个醚连接的烃链的脂质基团且H为包含具有最高6个碳原子的短直链氨基酸(□-氨基酸)及其衍生物的头基。
更具体而言,本发明涉及通式I化合物
其中
Y代表O、N、S或共价连接,
P1代表H、Y保护基团或Y活化基团或间隔基,
P2、P3彼此独立地代表H、氨基保护基团或间隔基,或P2和P3与它们所连接的N一起形成环结构,
L为式(a)基团,
其中虚线代表与N连接,
R1,代表H或式-(CH2)2-ORb1基团,
R1',代表H或式-(CH2)2-ORb2基团,
R2代表H或式-CH2-ORc基团,
R2'代表H或式-ORd或-CH2-ORd基团,
R3代表H或式-(CH2)2-ORe或-(CH2)3-ORe基团,
Ra、Rb1、Rb2、Rc、Rd、Re彼此独立地代表饱和或不饱和的、直链或分支的烃链,
m为1、2或3,
条件是R1、R1'、R2、R2'、R3中至少一个不是H。
在式I化合物的第一实施方案中,基团R3为H。更具体而言,(i)R3为H且R1和R1'为H,或者(ii)R3为H且R2和R2'为H。
因此,在该第一实施方案本发明涉及式Ia化合物,
其中L为式(a)基团,
且其中P1、P2、P3、Y、R1、R1'、R2、R2'、Ra、和m如上对于式I化合物的定义。
更具体而言,本发明涉及式Ia化合物,其中L为式(b)或(c)基团
其中P1、P2、P3、Y、R1、R1'、R2、R2'、Ra如上定义,条件是式(b) 中R2和R2'之一不是H,且式(c)中R1和R1'之一不是H。
在基团(b)的一个优选的实施方案中R2为H且R2'为-ORd或 -CH2-ORd。在基团(b)的另一优选的实施方案中R2为-CH2-ORc且R2'为-ORd或R2'为-CH2-ORd。
因此,本发明优选涉及式Ia化合物,其中L为式(b1)、(b2)、(b3) 或(b4)基团:
其中虚线代表与N连接,且
其中Ra、Rc和Rd彼此独立地为饱和或不饱和的、直链或分支的烃链。
在基团(c)的一个优选的实施方案中,其中R1和R1'之一为H。在基团(c)的另一优选的实施方案中R1和R1'没有一个是H。
因此,本发明优选地还涉及化合物,其中L为式(c1)或(c2)基团:
其中Ra、Rb1、Rb2如上定义。
在式I化合物的第二实施方案中,基团R1、R1'、R2、R2'为H且R3为式-(CH2)2-ORe或-(CH2)3-ORe基团。
因此,在该第二实施方案中本发明涉及式Ib化合物,
其中R3为式-(CH2)2-ORe或-(CH2)3-ORe基团,且
P1、P2、P3、Y、Ra、Re和m如上对式I基团的定义。
因此本发明的优选实施方案为式II或III化合物代表的式I(或式Ia)化合物
其中
Y代表O、N、S或共价连接,
P1代表H、Y保护基团或Y活化基团或间隔基,
P2、P3彼此独立地代表H、氨基保护基团或间隔基,或P2和P3与它们所连接的N一起形成环结构,
R1代表H或式-(CH2)2-ORb1基团,
R1'代表H或式-(CH2)2-ORb2基团,
R2代表H或式-CH2-ORc基团,
R2'代表H或式-ORd或-CH2-ORd基团,
Ra、Rb1、Rb2,Rc、Rd彼此独立地代表饱和或不饱和的、直链或分支的烃链,
m为1、2或3,
条件是式II中R2和R2'之一不是H,且式III中R1和R1'之一不是 H。
式II化合物的更具体的实施方案为式IIa、IIb、IIc或IId化合物,
其中
Y代表O、N、S或共价连接,
P1代表H、Y保护基团或Y活化基团或间隔基,
P2、P3彼此独立地代表H、氨基保护基团或间隔基,或P2和P3与它们所连接的N一起形成环结构,
Ra、Rc、Rd彼此独立地代表饱和或不饱和的、直链或分支的烃链,
m为1、2或3。
式III化合物的更具体的实施方案为式IIIa或IIIb化合物,
其中
Y代表O、N、S或共价连接,
P1代表H、Y保护基团或Y活化基团或间隔基,
P2、P3彼此独立地代表H、氨基保护基团或间隔基,或P2和P3与它们所连接的N一起形成环结构,
Ra、Rb1、Rb2彼此独立地代表饱和或不饱和的、直链或分支的烃链,
m为1、2或3。
式I(或式Ib)化合物的其它优选的实施方案由式IVa或IVb化合物代表,
其中
Y代表O、N、S或共价连接,
P1代表H、Y保护基团或Y活化基团或间隔基,
P2、P3彼此独立地代表H、氨基保护基团或间隔基,或P2和P3与它们所连接的N一起形成环结构,
Ra、Re彼此独立地代表饱和或不饱和的、直链或分支的烃链,且
m为1、2或3。
本领域技术人员将理解本发明的化合物含有一个或多个手性中心和/或双键,因此可以立体异构体,如双键异构体(即,几何异构体,例如Z/E异构体或顺式/反式异构体)、对映异构体或非对映异构体的形式存在。因此,当手性中心上的立体化学未标明时,本申请描述的化学结构包括在那些手性中心的所有可能的构型包括立体异构纯的形式(例如,几何纯、对映体纯或非对映体纯的)富集形式(例如,几何富集的、对映体富集的或非对映体富集的)以及对映体和立体异构体混合物。各种异构体可使用起始原料相应的异构形式来获得。作为替代,对映体和立体异构体混合物可采用技术人员熟知的分离技术或手性合成技术拆分成它们的组分对映异构体或立体异构体。本申请描述的本发明化合物也可以若干互变异构形式存在,包括烯醇形式、酮形式及其混合物。因此,本申请描述的结构包括举例说明的化合物的所有可能的互变异构形式。
本申请所用的术语“饱和或不饱和的、直链或分支的烃链”指具有6至30个、优选10至22个碳原子的饱和或不饱和的、直链或分支的烃链。
术语“饱和”与烃链结合指含有6至30个、优选10至22个碳原子的、直链或分支的烷基链。实例包括但不限于,辛基(癸基)、十一烷基、月桂基(dodedecyl)、肉豆蔻基(十四烷基)、鲸蜡基(十六烷基)、硬脂基(十八烷基)、十九基、花生基(arachidyl)(二十烷基)、二十一烷基、山嵛基(二十二烷基)、二十三烷基、二十四烷基、二十五烷基,包括其分支的异构体,例如异月桂基、反异月桂基、异肉豆蔻基、反异肉豆蔻基、异棕榈基、反异棕榈基、异硬脂基、反异硬脂基或植烷基(3,7,11,15-四甲基-十六烷基)。
术语“不饱和”与烃链结合表示比最大可能的数目少的氢原子与链中各个碳键合产生一个或多个碳-碳双键或三键。在优选的实施方案中,不饱和烃链中不饱和键的数目为1、2、3或4,优选为1或2。
链烯基的实例包括但不限于,单不饱和的链烯基,如癸烯基、十一碳烯基、十二烯基、棕榈油基、十七烯基、十八烯基(反油基、油基、蓖麻油烯基)、十九烯基、二十烯基、二十一烯基、二十二烯基 (erucyl)、二十三烯基、二十四烯基、二十五烯基、及其分支链异构体,以及多不饱和链烯基如十八-9,12-二烯基(亚油基、 elaidolinoleyl)、十八-9,12,15-三烯基(亚麻基、 elaidolinolenyl)、9(Z),11(E),13(E)-十八碳三烯基(桐酸基(eleostearyl))、和二十-5,8,ll,14-四烯基。
炔基的实例包括但不限于十六-7-炔基和十八-9-炔基。
术语“分支的”与烃结合指具有线性系列的碳原子作为主链、一个或多个碳原子的至少一个取代基作为次链(或分支基团)的烃链。次链的实例包括一种或多种(C1-6)烷基基团,如甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、己基等,一种或多种(C1-6)链烯基基团,如乙烯基、烯丙基、丙烯基、异丙烯基、2-丁烯基等,或一种或多种(C1-6)炔基基团,如乙炔基、丙炔基、丁炔基等。优选的次链为(C1-6)烷基基团,最优选为甲基和乙基。
本发明的化合物优选包含至少两个烃链,优选2、3、4、5或6 个烃链,最优选2或3个烃链,其中烃链的主链相同或不同,优选相同,且选自烷基链、链烯基链、和炔基链,优选烷基和链烯基链。在一优选的实施方案中,本发明的化合物载有两个烷基链,它们可以相同或不同,优选相同。
在本发明化合物的一具体实施方案中烃链Ra、Rb1、Rb2、Rc、Rd、 Re优选选自肉豆蔻基、棕榈基、硬脂基、油基、亚油基和植烷酰基。
涉及基团P1、P2、P3时本申请所使用的术语“烷基”、“烷氧基”、“链烯基”、“炔基”具有以下含义:
术语“烷基”指含有1至12、优选1至8个碳原子的、直链或分支的烷基链。烷基基团的实例包括但不限于,甲基、乙基、正丙基、异丙基、正丁基、异丁基、和叔丁基。术语“烷氧基”指-O-烷基基团。烷氧基基团的实例包括但不限于,甲氧基、乙氧基、和丁氧基。术语“链烯基”指具有一个或多个碳-碳双键的直链或分支的不饱和烷基基团。以上烷基、链烯基、和烷氧基基团可任选地被其它基团取代。取代基的实例包括但不限于,卤代、羟基、氨基、氰基、硝基、巯基、烷氧羰基、酰氨基、羧基、烷基磺酰基、烷基羰基、脲基、氨甲酰基、羧基、硫脲基、氰硫基、亚磺酰氨基、芳基、杂芳基、环基(cyclyl)、和杂环基。
术语“芳基”指含有约6至约10个、优选5至7个碳原子的芳族碳环基团。芳基基团可任选地被一个或多个可相同或不同的芳基基团取代基取代,其中“芳基基团取代基”包括烷基、链烯基、炔基、芳基、芳烷基、羟基、烷氧基、芳氧基、芳烷氧基、羧基、芳酰基、卤代、硝基、三卤代甲基、氰基、烷氧羰基、芳氧基羰基、芳烷氧羰基、酰氧基、酰基氨基、芳酰氨基(aroylamino)、氨甲酰基、烷基氨甲酰基、二烷基氨甲酰基、芳基硫基、烷硫基、亚烷基和-NRR',其中R 和R'各自独立地为氢、烷基、芳基和芳烷基。示例性的芳基基团包括取代或未取代的苯基、萘基、芘基、蒽基、和菲基。
术语“杂芳基”指具有至少一个杂原子(例如,N、O或S)的如上定义的芳基部分。杂芳基部分的实例包括呋喃基、furylene、芴基、吡咯基、噻吩基、噁唑基、咪唑基、噻唑基、吡啶基、嘧啶基、喹唑啉基、喹啉基、异喹啉基和吲哚基。
术语“(杂)芳氧基”指(杂)芳基-O-基团,其中(杂)芳基基团如前所述。示例性的芳氧基包括苯氧基和萘氧基。术语“(杂)芳烷基”指(杂) 芳基-烷基-基团,其中(杂)芳基和烷基如前所述。示例性的芳烷基基团包括苄基、苯基乙基和萘基甲基。术语“(杂)芳烷氧基”指(杂)芳烷基-O-基团,其中(杂)芳烷基如前所述。示例性的芳烷氧基基团是苄氧基。
术语“环烷基”指具有6至10个碳原子的饱和或不饱和的、非芳香环烃部分,如环己基或环己烯-3-基。术语“杂环烷基”指具有至少一个环杂原子(例如,N、O或S)的如本申请定义的环烷基,如4-四氢吡喃基或4-吡喃基。
本申请提及的芳基、杂芳基、环烷基、杂环烷基既包括取代又包括未取代的部分,除非另有说明。环烷基、杂环烷基、芳基和杂芳基上可能的取代基包括(C1-C10)烷基、(C2-C10)链烯基、(C2-C10)炔基、 (C3-C8)环烷基、(C5-C8)环烯基、(C1-C10)烷氧基、芳基、芳氧基、杂芳基、杂芳氧基、氨基、(C1-C10)烷基氨基、(C1-C20)二烷基氨基、芳基氨基、二芳基氨基、羟基、卤素、硫基、(C1-C10)烷硫基、芳基硫基、(C1-C10)烷基磺酰基、芳基磺酰基、酰基氨基、氨酰基、脒基、胍、脲基、氰基、硝基、酰基、酰氧基、羧基、和羧酸酯。环烷基、杂环烷基、芳基、和杂芳基也可以也相互稠合。
基团Y为O、N、S或共价连接,优选为O或N,最优选为N。应当理解如果基团Y为共价连接,那么-S1-X1与CO-基团直接连接。
“保护基”为能选择性与分子中特定的化学反应性官能团连接且能从该官能团上除去以阻止该官能团参与不期望的化学反应的部分。所述保护基将取决于被保护的化学反应性基团的类型以及采用的反应条件和分子中其它反应性或保护基团的存在而变化。应当理解术语“保护基”如果相对于化合物之一中的N-基团(如Y为N时的P1,P2或P3) 使用时则为氨基保护基团,如果相对于化合物之一中的COO-基团(如 Y为O时的P1)使用时则为羧基保护基,如果相对于化合物之一中的 CO-基团(如Y为共价连接时的P1)使用时则为羰基-保护基,如果相对于化合物之一中的S-基团(如Y为S时的P1)使用则为硫保护基。
各种官能团,诸如羧酸基、氨基、羟基、硫醇基、羰基等的代表性保护基,为本领域技术人员熟知,描述于,例如T.W.Greene和G. M.Wuts,Protecting Groups in OrganicSynthesis,Third Edition, Wiley,N.Y.,1999及其中引用参考文献中。
对于本发明的化合物,“羧基保护基”(例如Y为O时的基团P1) 包括但不限于二苯甲基、苄基酯,如苄基、和邻或对硝基苄基、对甲氧苄基,烷基酯,如甲基、叔丁基、4-吡啶甲基2-萘基甲基、2,2-三氯乙基、甲硅烷基的酯,如2-三甲基硅烷基、叔丁基二甲基甲硅烷基、叔丁基二苯基硅烷基、2-(三甲基硅烷基)乙基;原酸酯,如原乙酸三甲酯或原乙酸三乙酯;噁唑啉、烯丙基、2-氯烯丙基、苯酰基、丙酮基、对甲氧苯基。优选的基团包括苄基、叔丁基。
酰胺保护基(例如Y为N时的基团P1)包括但不限于邻苯二甲酰亚胺或三氟乙酰胺保护基。
“氨基保护基团”既包括非环状的保护基又包括环状保护基(P2和P3),例如基团P2和P3中的各基团可代表可以相同或不同的保护基或者P2和P3与它们所连接的N一起形成环状保护基。典型的基团包括但不限于,氨基甲酸酯类,如Boc(叔丁氧羰基、Cbz(羧苄基)、Fmoc(芴甲基氧基羰基)、alloc(烯丙基氧羰基)、氨基甲酸甲酯和氨基甲酸乙酯;三苯甲基、苄基、苯亚甲基、甲苯磺酰基等;环状酰亚胺衍生物,如琥珀酰亚胺和邻苯二甲酰亚胺;酰胺类,如甲酰基、(未)取代的乙酰基、和苯甲酰基;和三烷基甲硅烷基,如叔丁基二甲基甲硅烷基和三异丙基甲硅烷基。优选的氨基保护基团包括Boc、Cbz、Fmoc、苄基、乙酰基、苯甲酰基、三苯甲基等。
术语“活化的”或“活化”,例如,与术语“基团”、“胺基”、“羧基”、“间隔基”连结使用时,指使化学官能团对在某些反应条件下的改变更敏感以致活化的化学官能团能在适宜的条件下与另一化学基团反应从而形成共价键的化学部分。
例如,活化基团可将不易离去的基团(poor leaving group)转变为易离去的基团(good leaving group)或增加(或降低)对亲核攻击或其它化学转化的敏感性。
因此,“羧基活化基团”意指置换羧基的氢或羟基、从而改变羧基的化学和电子性质使得羧基对亲核攻击或取代更敏感的部分。
在其中羧基的氢被置换的实施方案中,示例性的羧基活化基团包括,例如,烷基、芳基、芳烷基、杂芳基、杂环基、烷基羰基、芳基羰基、芳烷基羰基、杂芳基羰基、杂环基羰基、C(S)O-芳基、C(S)O- 烷基、甲硅烷基或取代的烷基羰基。芳基羧基活化基团的实例为五卤代苯基,如五氟苯基,烷基羰基羧基活化基团的实例为乙酰基或三氟乙酰基。羧基活化基团可任选地被取代。取代的羧基活化基团的实例为取代的烷基羰基,例如,羧基取代的烷基羰基,如琥珀酰(3-羧基丙酰基)。
其中-C(=O)-OH基团的氢被置换的羧基活化还可涉及使用偶联剂,其为促进亲核加成反应的部分,即对羰基具有吸引净电子作用的取代基。此种基团起作用帮助或促进羧酸酯基团与具有反应性官能团的化合物偶联、或改善偶联的速率,其中具有反应性官能团的化合物例如,亲核试剂,包括氨基基团如酰氨基官能团形成中的氨基基团。偶联剂为本领域普通技术人员熟知,描述于,例如,Larock,R.C., Comprehensive OrganicTransformations,VCH Publishers,Inc., NY(1989)、和Carey,F.A.,和Sundberg,R.J.,Advanced Organic Chemistry,第3版,Plenum Press,NY(1990)中,各自公开的内容在此全文引入作为参考。
其中-C(=O)-OH基团的羟基基团被置换的羧基活化包括例如以诸如卤代基团的部分,如氟、氯、溴或碘,置换羟基,得到羧酸卤化物,其对亲核攻击或取代更敏感。
因此,典型的活化或偶联基团包括但不限于,酯类和酰胺类如羟基苯并三唑、咪唑、硝基苯酚、五氯苯酚、N-羟基琥珀酰亚胺、二环己基碳二亚胺、N-羟基-N-甲氧胺等;酸酐类如乙酸、甲酸、磺酸、甲磺酸、乙磺酸、苯磺酸、或对甲苯基磺酸酸酐等;和酰基卤如酰氯、酰溴、或酰碘。
活化的羰基化合物通过采用标准程序使所选择的反应性部分与羰基化合物反应而获得。适当时,活化的羰基化合物可原位产生,或可以分离的形式提供。获得上述活化的化合物的示例性的反应性部分包括含有异硫氰酸离子、异氰酸离子、一氯三嗪、二氯三嗪、单-或二- 卤素取代的吡啶、单-或二-卤素取代的二嗪、马来酰亚胺、氮丙啶、磺酰卤、酰基卤、羟基琥珀酰亚胺酯、羟基硫代琥珀酰亚胺酯、酰亚胺酯、肼、叠氮基硝基苯基、叠氮化物、3-(2-吡啶基二硫代)丙酰胺、乙二醛和醛的各个基团。
术语“间隔基”或“间隔基基团”与基团P1、P2、P3结合用于本申请中指二价有支链的或无支链的化学基团,其可以将本发明化合物与其它部分,即生物活性基团以足够的距离连接以消除化合物与其它部分之间的任何不期望的相互作用和/或减少可能影响其它部分的生物学活性(如配体与它们的受体结合的亲和性)的任何位阻(由化合物本身或任何其它邻近的分子引起的)。依赖于醚-脂质和生物活性配体的轭合物的应用,间隔基基团可具有不同的长度且可被(水解、酶解和化学)稳定的或可包括可裂解的连接。本发明的可裂解的连接可选择为经任何形式的可裂解化学过程,例如化学、酶解、水解等来裂解。示例性的可裂解的连接子包括但不限于,蛋白酶裂解的肽连接子、核酸酶敏感性核酸连接子、脂肪酶敏感性脂质连接子、糖苷酶敏感性碳水化合物连接子、pH敏感性连接子、低氧敏感性连接子、光裂解的连接子、热不稳定的连接子、酶可裂解的连接子、超声-敏感性连接子、 x射线可裂解的连接子等。
基团P1、P2、P3可彼此独立地代表H、保护基或间隔基基团。更具体而言P1代表H、Y-保护基或Y-活化基团或间隔基基团S1;P2代表H、氨基保护基团或间隔基基团S2;且P3代表H、氨基保护基团或间隔基基团S3;或P2和P3与它们所连接的N一起形成环结构。
应当理解间隔基可以是或可以不是端基活化的,所述端基活化允许间隔基改性的本发明化合物与其它部分(如生物活性基团)的连接。
在具体的实施方案中,“间隔基基团”(亦称基团S1、S2、S3)代表选自亚烷基链的短间隔基基团或长链间隔基基团,其任选地包含一个或多个选自酮、酯、醚、氨基、酰胺、脒、酰亚胺、氨基甲酸酯或硫代氨基甲酸酯官能团、甘油、脲、硫脲、双键或芳香环的基团。
更具体而言,短间隔基基团(或基团S1、S2、S3)可选自(C1-C12) 烷基、(C2-C12)链烯基、芳基、芳烷基、杂芳基。
长链间隔基基团(或基团S1、S2、S3)可选自式-W-(CH2-)k-W′- 的聚合物基团,其中k为13至3000之间的整数,且W和W′为能与氨基、羧基、羟基或硫基基团起反应的反应基团且其中一个或多个不相邻的CH2基团可独立地被芳基、杂芳基、-CH=CH-、-C≡C-、或选自 -O-、-CO-、-CO-O-、-O-CO-、-NR'-、-NR'-CO-、-CO-NR'-、-NR'-CO-O-、 -O-CO-NR'-、-NR'-CO-NR'-、和-O-CO-O-的亲水性(或极性)基团置换,其中R'代表氢或(C1-C12)烷基。应当理解以相同的基团置换一个以上的不相邻的CH2基团可在具有特定重复单元的聚合链(例如聚酯、聚醚、聚酰亚胺等)中产生。
优选的间隔基基团包括亲水性聚合物基团(对水溶液具有增强的亲和性),即含有在它们的亚烷基骨架中包含一个或多个上述亲水性 (或极性)基团的重复结构单位的聚合物。亲水性聚合物基团的典型实例包括聚氧(C2-C3)亚烷基(例如聚乙二醇(PEG)或聚丙二醇(PPG))、多糖(例如右旋糖酐、芽霉菌糖、壳聚糖、透明质酸)、聚酰胺(例如聚氨基酸、半合成的肽和多聚核苷酸);聚唾液酸、聚酯(例如聚乳酸(PLA)、聚乳酸-乙醇酸共聚物(PLGA))、聚碳酸酯、聚乙烯亚胺 (PEI)、聚酰亚胺、聚乙酸乙烯酯(PVA)。
优选的间隔基为“PEG”或“聚乙二醇”,其包括任何水溶性聚(氧化乙烯)。典型地,“PEG”指含有多数,例如>50%,的亚单位—CH2CH2O —的聚合物。不同形式的PEG可在分子量、结构或几何形状方面不同 (例如,分支的、直链的、分叉的PEGs、多功能的等)。用于本发明中的PEGs优选地可包含两个以下结构之一:“—O(CH2CH2O)m—”或“— CH2CH2O(CH2CH2O)m—CH2CH2—”,其中m为3至3000,且整体PEG的端基和结构可变化。如上所述,依赖于其应用,PEG可以是封端的形式。当PEG被定义为“—O(CH2CH2O)m—”时封端基团通常为典型地由1-20 个碳构成的含碳基团,优选为烷基(例如,甲基、乙基或苄基),尽管还想象它们的饱和和不饱和形式、以及芳基、杂芳基、环基、杂环基、和任何前述的取代形式。当PEG被定义为“—CH2CH2O(CH2CH2O)m—CH2CH2—”时,封端基团通常为典型地由1-20个碳原子和以共价键结合的氧原子构成的含碳基团,且对与PEG的一端共价键键合是有效的。在这种情况下,该基团典型地为烷氧基(例如,甲氧基、乙氧基或苄氧基)且就含碳基团而言可任选是饱和和不饱和的、以及芳基、杂芳基、环基、杂环基、和任何前述的取代形式。当PEG被定义为“— CH2CH2O(CH2CH2O)m—CH2CH2—”时其它(“非封端的”)端典型地为羟基、胺或可经受其它化学改性的活化基团。此外,封端基团也可是硅烷。
关于各种端基官能化或活化的PEG的综述是本领域已知的(例如参见ZalipskyS.,Bioconjug.Chem.,6,150-165(1995))。
在优选的实施方案中本发明涉及下式V、VI和VII的化合物:
其中
Y代表O、N、S或共价连接,
P1代表H、Y保护基团或Y活化基团或间隔基,
P2、P3彼此独立地代表H、氨基保护基团或间隔基,或P2和P3与它们所连接的N一起形成环结构,
p1、q1、p2、q2、p3、q3彼此独立地为1至23,条件是p1和q1、 p2和q2、p3和q3的和为12至24。
在其它方面本发明涉及制备本发明化合物的方法。
本发明化合物特别适用于制备囊泡状组合物,如脂质体、胶束和 (脂质包被的)纳米颗粒。
因此,另一方面本发明涉及由本发明的至少一种化合物构成的囊泡状组合物。此种囊泡包含含间隔基的非衍生化化合物或衍生化化合物或它们的混合物。任选地囊泡状组合物可包含一种或多种其它的形成囊泡的脂质。
在一实施方案中囊泡可包含本发明的脂质-间隔基衍生物和其它形成囊泡的脂质(辅助脂质),优选地为1:200至200:1的比例。
本领域的技术人员将认识到,一旦置于本发明的控制 (possession)中,脂质包被的纳米颗粒、脂质体、胶束、或其它囊泡形式的囊泡状组合物可采用本领域已知的标准条件由本发明的化合物容易制备。
依赖于期望的物理性质,囊泡状组合物可由本发明的化合物任选地与一种或多种辅助脂质包括稳定化的脂质组合制备。最后与本发明化合物组合的具体的稳定化的化合物可根据期望进行选择以使所得组合物的性质最佳化(且容易由本领域技术人员不经过度的实验可鉴别)。
本发明的囊泡状组合物作为递送生物活性剂的载体或作为呈递抗原的载体特别有效。
如本申请所使用的术语“生物活性剂”指具有生物学活性的任何合成或天然存在的化合物(为游离形式、盐形式或溶剂合物或水合物形式),如靶向剂、抗原剂、治疗剂或诊断剂,优选为治疗剂或诊断剂。
如本申请所使用的术语“抗原呈递系统”(亦称“抗原展示系统”) 指天然存在的或合成的系统,其(i)可呈递至少一种抗原(或其一部分) 使得至少一种抗原(或其一部分)能被免疫效应分子,例如T细胞表面上的T细胞抗原受体识别或结合,或(ii)能呈递至少一种可被免疫系统的特异性效应细胞识别的抗原-MHC复合体形式的抗原(或其一部分),从而诱导有效的针对呈递的抗原(或其一部分)的细胞免疫应答。
本发明的胶束囊泡状组合物可采用各种对本领域技术人员显而易见的常规的胶束制备方法中的任何一种方法来制备。这些方法典型地包括将脂质化合物悬浮于有机溶剂中、蒸发溶剂、再悬浮于水介质中、超声处理和离心。前述方法、以及其它方法,例如,在Canfield等, Methods in Enzymology,第189卷,第418-422页(1990);El-Gorab 等,Biochem.Biophys.Acta,第306卷,第58-66页(1973); Colloidal Surfactant,Shinoda,等,Academic Press,N.Y.(1963) (尤其是"The Formation of Micelles",Shinoda,第1章,第1-88 页);Catalysis in Micellar和Macromolecular Systems,Fendler 和Fendler,Academic Press,N.Y.(1975)中有论述。前述各出版物的公开内容在此全文引入作为参考。
任选的与本发明化合物组合以使由此制备的胶束组合物稳定的稳定化物质包括溴化月桂基三甲基铵、溴化鲸蜡基三甲基铵、溴化肉豆蔻基三甲基铵、(C12-C16)烷基二甲基-苄基氯化铵、十六烷基吡啶溴化物和氯化物、月桂基硫酸盐等。除上面示例的那些外,其它用于稳定胶束组合物的物质,基于本申请的公开对本领域技术人员将是显而易见的。
脂质体囊泡状组合物可包含一种或多种非衍生化的化合物和/或一种或多种衍生化的化合物(载有间隔基),任选地与一种或多种其它辅助脂质和/或一种或多种稳定化的化合物组合。本发明的化合物(任选地与辅助脂质组合)可以单层或双层的形式存在。在一个以上的单层或双层的情况下,单层或双层通常是同心的。因此,本发明的化合物(和任选的辅助脂质)可用于形成单层脂质体(包含一个单层或双层)、寡层脂质体(包含两个或三个单层或双层)或多层脂质体 (包含三个以上的单层或双层)。
可以与本发明的化合物组合使用和在本发明的脂质体囊泡状组合物的形成中使用的(辅助)脂质优选地包括阳离子型脂质、磷脂酰胆碱(PC)、磷脂酰基-DL-甘油(PG)、L-α-磷脂酰乙醇胺(PE)、胆固醇、胆固醇基半琥珀酸酯三盐(CHEMS)、1,2-二油酰基-3-三甲基铵-丙烷(DOTAP)。
除上面示例的那些外,其它用于制备本发明的脂质体囊泡状组合物的物质,基于本申请的公开对本领域技术人员将是显而易见的。
稳定化物质诸如与本发明化合物组合的其它两亲性化合物的量可随多种因素而变化,包括所选择的本发明的化合物的特定结构、所选择的特定的稳定化物质、使用它的具体应用、递送模式等。与本发明化合物组合的稳定化物质的量和稳定化物质与本发明化合物的比例,将会变化并基于本申请的公开可由本领域技术人员容易地确定。典型地本发明的化合物与稳定化脂质高于约4:1、3:1或2:1的比例为优选。
基于本申请的公开,在本发明的脂质体囊泡状组合物的制备中选择合适的辅助脂质和稳定化化合物对本领域技术人员将是显而易见的且不需过度的实验能获得。
各式各样与本发明脂质体囊泡状组合物的制备有关的方法都可利用。因此,脂质体可采用各种对本领域技术人员来说将是显而易见的常规的脂质体制备技术中的任何一种方法来制备。这些技术包括采用例如常规的微乳化装置,进行乙醇注入、薄膜技术、匀化、溶剂透析、加压水合(forced hydration)、反相蒸发、微乳化和简易冻-融。其它由本发明的化合物制备本发明的脂质体囊泡状组合物的方法包括,例如,超声处理、螯合透析、匀化、溶剂输注、自发形成、溶剂气化、受控制的洗涤剂透析等,各种方法都涉及以不同的方式制备脂质体。典型地,在由本发明的化合物制备本发明的脂质体组合物方面优选包括乙醇注入、薄膜技术、匀化和挤压的方法。
脂质体的尺寸可通过各种技术进行调整,如果期望,包括挤压、过滤、超声处理和匀化。其它的调整脂质体的尺寸和调节所得脂质体体内分布和脂质体的清除的方法基于本申请的公开对本领域技术人员将是显而易见的。优选地,脂质体的尺寸通过所定义尺寸的孔通过在压力下挤压调整。本发明的脂质体组合物可以是任意尺寸,优选外径小于约200纳米(nm)。
纳米颗粒囊泡状组合物或纳米颗粒典型地为小颗粒,直径典型地小于1微米,优选在约25-1000nm的范围内,更优选在约50-300nm 的范围内,最优选在约60-200nm的范围内。纳米颗粒可具有任何形状和任何形态。纳米颗粒的实例包括纳米粉、纳米簇(nanoclusters)、纳米晶体、纳米球、纳米纤维、及其它几何形状。纳米聚合物指在聚合装配时形成纳米颗粒,诸如,纳米棒、纳米纤维、或纳米球的聚合物。纳米球指一类在形状上大致为球形的纳米颗粒且可具有空心芯或实心芯。
在一实施方案中,纳米颗粒具有基质芯结构,其可使用各种类型的物质和结构,包括无机物,如金属,和有机物如聚合物包括生理学可接受的聚合物形成。此种聚合物的非限制性实例包括,例如,聚酯 (如聚(乳酸),聚(L-赖氨酸),聚(乙醇酸)和聚(乳酸-乙醇酸)共聚物),聚(乳酸-赖氨酸)共聚物,聚(乳酸-赖氨酸)接枝聚合物,聚酐类(如聚(脂肪酸二聚体),聚(富马酸),聚(皮脂酸),聚(羧基苯氧基丙烷),聚(羧基苯氧基己烷),这些单体的共聚物等),聚(酸酐-酰亚胺)共聚物,聚(酰胺),聚(原酸酯),聚(亚氨基碳酸酯),聚(尿烷),聚(organopha sphazenes),聚(磷酸酯),聚(乙烯乙酸乙烯酯)和其它酰基取代的醋酸纤维素及其衍生物,聚(己内酯),聚(碳酸酯),聚(氨基酸),聚(丙烯酸酯),聚缩醛,聚(氰基丙烯酸酯),聚(苯乙烯),聚 (氯乙烯),聚氟乙烯),聚乙烯咪唑),氯磺化聚烯烃,聚氧乙烯,共聚物,聚苯乙烯,和它们的混合物或共聚物。纳米颗粒还可以包括羟丙基纤维素(HPC)、N-异丙基丙烯酰胺(NIPA)、聚乙二醇、聚乙烯醇 (PVA)、聚乙烯亚胺、壳聚糖、壳多糖、硫酸右旋糖酐、肝素、硫酸软骨素、明胶等以及它们的衍生物、共聚物、及其混合物。制备纳米颗粒的非限制性方法描述于例如美国公开号2003/0138490。在另一实施方案中芯材可选自金属、合金、类金属、金属化合物如金属氧化物、无机化合物、和碳-基材,特别是碳纳米管、富勒烯C60的一维纳米颗粒、和富勒烯C70的三维纳米颗粒。
金属的合适实例包括但不限于,贵重金属或铂族金属如Ag、Au、 Pd、Pt、Rh、Ir、Ru和Os,过渡金属元素如Ti、Cr、Mn、Fe、Co、 Ni、Cu、Zn、Zr、Nb、Mo、Ta、W、Re,主族金属如Al、Ga、In、Si、 Ge、Sn、Sb、Bi、Te。应当理解一些主族金属,特别是Si和Ge,通常也称为类金属。合金的合适实例包括但不限于,贵重金属或铂族金属和过渡金属元素的合金,特别是银和过渡金属元素的合金如Ag/Ni、 Ag/Cu、Ag/Co,和铂和过渡金属元素的合金如Pt/Cu,或贵重金属合金或铂合金如Ru/Pt。无机化合物的非限制性实例包括,但不限于, SiO2、金属化合物,特别是金属氧化物如TiO2和氧化铁。
技术人员将知道材料的选择依赖于纳米颗粒的使用意图。
纳米颗粒任选地包含官能团诸如羧基、巯基(sulhydryl)、羟基、或氨基基团,用于将其它化合物,如连接子,与纳米颗粒的表面共价键连接。在其它实施方案中化合物,如连接子,可通过其它分子间力如范德华力、离子相互作用、疏水性相互作用与纳米颗粒缔合。
在某些实施方案中,纳米颗粒可与生物活性剂(例如,卷入、嵌入、掺入、囊化、结合至表面,或以其它方式与纳米颗粒缔合)缔合。优选地此种生物活性剂通过本发明的化合物与纳米颗粒缔合,其中本发明的化合物充当生物活性剂和纳米颗粒之间的连接子。本发明化合物及其组合物的这些方面是同时提交的国际申请的一部分,其在此全文引入。
纳米颗粒也可集合在一起(任选地与分散剂)形成纳米簇。在团簇形成之前各种纳米颗粒类型的独立制剂和团簇内纳米颗粒的特定排列可以控制生物活性成分的持续时间和浓度。
在本发明的一实施方案中,一种或多种非衍生化或衍生化的本发明化合物可掺入、连接或吸附于纳米颗粒。优选地,脂质包被的纳米颗粒(LCN)可由纳米尺寸的芯颗粒和本发明的一种或多种化合物和任选的一种或多种辅助脂质形成。在任何得到的脂质包被的纳米颗粒中,脂质可以单层或双层的形式存在。在一个以上的单层或双层的情况下,单层或双层通常是同心的。纳米颗粒的包被优选在包含本发明化合物的溶液中和通过提供允许化合物包被纳米颗粒的足够时间来进行(采用本领域已知的技术,参见例如Journal ofControlled Release,Vol 137(1),69-77,2009)。在任何得到的脂质包被的纳米颗粒中,脂质可以单层或双层的形式存在。在一个以上的单层或双层的情况下,单层或双层通常是同心的。
各种方法都可用于制造合适尺寸的纳米颗粒。这些方法包括汽化法(例如,自由射流膨胀,激光汽化,电火花腐蚀,电爆炸和化学气相沉积)、包括机械磨碎的物理方法(例如,珠磨技术,Elan Nanosystems,Ireland)、和溶剂置换之后的界面沉积。
本领域的技术人员将认识到,任何本发明的化合物和含有本发明化合物的囊泡状组合物,含或不含生物活性剂,可被冻干用于储存、和在例如,水介质(如无菌水或磷酸盐缓冲溶液、或盐水溶液)中,优选在剧烈搅动下重建。如有必要,可包含添加剂以阻止脂质由于冷冻干燥的凝集或融合。有用的添加剂非限制性地包括山梨醇、甘露醇、氯化钠、葡萄糖、海藻糖、聚乙烯吡咯烷酮和聚(乙二醇),例如,PEG 400。
如上所述,本发明的化合物特别是本发明的脂质体组合物特别适于用作生物活性剂靶向递送或用作抗原展示系统的载体。因此,本发明的化合物特别适用于在治疗疾病的方法中的体外和/或体内应用(其中一种或多种特定生物活性剂的靶向递送是期望的或需要的)、以及适用于体外/体内诊断应用的方法。本发明化合物及其组合物的这些方面是同时提交的国际申请的一部分,其在此全文引入。
在其它方面,本发明涉及包含容器的试剂盒,所述容器被区室化用于存贮试剂盒的各种元件。一个区室可含有预定量的本发明化合物或其囊泡状组合物。在囊泡状组合物的情况下,这些可含或不含调节组合物pH至约7至约8的生理范围的pH缓冲剂、或其它在冻干形式中用于在使用时重建的物质。在试剂盒内还包含其它试剂和使用说明书。
本发明在以下实施例中进一步描述。
实施例
材料∶胆固醇和POPC购自Avanti Polar Lipids(Alabaster, AL)。所有保护的氨基酸得自Novabiochem。二苯基重氮甲烷树脂 D-2230得自Bachem AG。所有其它的化学药品和溶剂都是A.R.级或A.R. 级以上。
2,3-双(十四烷基氧基)丙-1-胺根据Kokotos等Chemistry-A European Journal,2000,第6卷,#22,4211-4217合成。双(3-((Z)- 十八-9-烯氧基)丙基)胺以类似的方式由油基甲磺酸酯和双(3-羟丙基) 胺获得(参见MaGee等,J.Journal of Organic Chemistry,2000, 第65卷,#24,8367-8371)。
实施例1:(2S)-2-(((9H-芴-9-基)甲氧基)羰基氨基)-谷氨酸-α-叔丁基酯-γ-2,
3-双(十四烷基氧基)丙基-酰胺的合成
在室温下将15g的Fmoc-Glu(OSu)OtBu((2S)-N□-(9-芴甲基氧基羰基)-谷氨酸α-叔丁基-酯γ-N-羟基琥珀酰亚胺酯)溶解于二氯甲烷中。加入15.3g的2,3-双(十四烷基氧基)丙-1-胺之后,将混合物搅拌17小时并蒸干。将残余物溶解于最小量的二氯甲烷中并用SiO2作为固相和甲基叔丁基醚/己烷/7:3作为洗脱剂进行柱层析纯化。将产物级分蒸发之后得到无色固体形式的25.5g的(2S)-2-(((9H-芴-9- 基)甲氧基)羰基氨基)-谷氨酸-α-叔丁基酯-γ-2,3-双(十四烷基氧基)丙基-酰胺。在CDCl3中进行1H-NMR(TMS作为内标),以ppm为单位的化学位移:7.76(d,2H,Fmoc),7.61(d,2H,Fmoc),7.25-7.43 (m,4H,Fmoc),6.13(bs,NH,1H),5.60(bs,NH,1H),4.39, 4.18-4.25(d和m,4H),3.21-3.62(m,9H),1.97-2.23(m,4H), 1.51-1.60(m,4H),1.47(s,9H),1.25(m,44H,CH2),0.84-0.91 (m,6H,2x alkyl-CH3)。
实施例2:(2S)-2-(((9H-芴-9-基)甲氧基)羰基氨基)-谷氨酸-γ-2,3-双(十四烷
基氧基)丙基-酰胺的合成
将4.6g(5.1mmol)的(2S)-2-(((9H-芴-9-基)甲氧基)羰基氨基)-谷氨酸-α-叔丁基酯-γ-2,3-双(十四烷基氧基)丙基-酰胺溶解于100ml烧瓶中的25ml二氯甲烷中并用25ml三氟乙酸处理。在1h 之后将酯基完全裂解并将溶液倒在50ml的冷水上。将有机层萃取,用水洗至中性pH并经Na2SO4干燥。将有机层滤出并蒸发溶剂得到4.2g 期望的产物(5.0mmol,98%产率,TLC:MtBE/己烷7:3;Rf=0.43。
实施例3:(2S)-谷氨酸-γ-(2,3-双(十四烷基氧基)丙基)酰胺的合成
将5g的(2S)-2-(((9H-芴-9-基)甲氧基)羰基氨基)-谷氨酸-α- 叔丁基酯-γ-2,3-双(十四烷基氧基)丙基-酰胺加入到85ml的N,N- 二甲基甲酰胺中。将2.6ml的哌啶加入到混合物中。将混合物于室温搅拌三小时然后在真空下蒸干得到5.2g的无色固体形式的(2S)-谷氨酸-γ-(2,3-双(十四烷基氧基)丙基)酰胺,其可用于制备脂质囊泡或用于用活性剂或间隔基基团的先前衍生化。
实施例4:(R)-2-氨基-N1-(2-(4-甲氧基苯甲酰氨基)乙基)-N4,N4-双(3-((Z)-十
八-9-烯氧基)丙基)琥珀酰胺的合成
(a)N-(2-氨基乙基)-4-甲氧基苯甲酰胺的合成
将3.0g4-甲氧基苯甲酰氯于-78℃加入到30mL在二氯甲烷中的1,2-二氨基乙烷中随后让其温热至23℃。以含水的酸-碱精制并在真空下蒸干得到1.65g浅黄色油状的N-(2-氨基乙基)-4-甲氧基苯甲酰胺。在CDCl3中进行1H-NMR(TMS作为内标),以ppm为单位的化学位移:8.53(t,1H,NH),7.91(d,2H,Benz),6.99(d,2H,Benz), 4.75(bs,2H,NH2),3.81(s,3H,CH3),3.39,(dd,2H,CH2),2.82 (t,2H,CH2)。
(b)(R)-叔丁基3-(((9H-芴-9-基)甲氧基)羰基氨基)-4-(2-(4- 甲氧基苯甲酰氨基)乙氨基)-4-氧丁酸酯的合成
将3.0g的2N-(2-氨基乙基)-4-甲氧基苯甲酰胺(步骤(a)中获得)和1.70mL在DMF(0℃)中的N-甲基吗啉加入到6.35g Fmoc-Asp(OtBu)-OH、1.70mLN-甲基吗啉和2.00mL异丁基氯甲酸酯在乙酸乙酯(-12℃)中的溶液中并搅拌3h同时让其温热至23℃。用乙酸乙酯稀释所得悬浮液,之后以含水的酸-碱精制并在真空下蒸干产生9.55g(R)-叔丁基3-(((9H-芴-9-基)甲氧基)羰基氨基)-4-(2-(4-甲氧基苯甲酰氨基)乙基氨基)-4-氧代丁酸酯。将此粗品悬浮于异丙醚中23h,然后滤出并干燥提供4.47g白色晶体形式的 (R)-叔丁基3-(((9H-芴-9-基)甲氧基)羰基氨基)-4-(2-(4-甲氧基苯甲酰氨基)乙基氨基)-4-氧丁酸酯。
在CDCl3中进行1H-NMR(TMS作为内标),以ppm为单位的化学位移:8.28(t,1H,NH),8.07(t,1H,NH),7.89(d,2H,Fmoc),7.81 (d,2H,Benz),7.71-7.60(m,2H,Fmoc和1H,NH),7.46-7.27(m, 4H,Fmoc),6.96(d,2H,Benz),4.35-4.20(m,3H,Fmoc,和1H CH),3.78(s,3H,CH3),3.40-3.20,(m,4H,2xCH2),2.69(dd,1H, CH2),2.46(dd,1H,CH2),1.37(s,9H,3xCH3)。
(c)(R)-3-(((9H-芴-9-基)甲氧基)羰基氨基)-4-(2-(4-甲氧基苯甲酰氨基)乙基氨基)-4-氧丁酸钠乙酸酯的合成
在23℃下将30.0mL的三氟乙酸加入到3.0g在二氯甲烷中的 (R)-叔丁基3-(((9H-芴-9-基)甲氧基)羰基氨基)-4-(2-(4-甲氧基苯甲酰氨基)乙基氨基)-4-氧丁酸酯(步骤(b)中获得)中。在反应完毕时加入NaHCO3水溶液中提供白色沉淀,将其以二氯甲烷洗涤并干燥产生白色粉末形式的2.55g的(R)-3-(((9H-芴-9-基)甲氧基)羰基氨基)-4-(2-(4-甲氧基苯甲酰氨基)乙基氨基)-4-氧丁酸钠乙酸酯。在 SO(CD3)/CD3OD,1:1中进行1H-NMR(TMS作为内标),以ppm为单位的化学位移:7.85-7.79(m,2H,Fmoc和2H,Benz),7.68(d,2H,Fmoc),7.45-7.29(m,4H,Fmoc),6.93(d,2H,Benz),4.51-4.17 (m,3H,Fmoc和1H,CH),3.78(s,3H,CH3),3.47-3.34,(m,4H, 2xCH2),2.82(dd,1H,CH2),2.63(dd,1H,CH2)。
(d)(9H-芴-9-基)甲基(R,Z)-1-(4-甲氧苯基)-10-(3-((Z)-十八-9-烯氧基)丙基)-1,6,9-三氧代-14-氧杂-2,5,10-三氮杂三十二 -23-烯-7-基氨基甲酸酯的合成
将0.48g在二甲基甲酰胺中的(R)-3-(((9H-芴-9-基)甲氧基)羰基氨基)-4-(2-(4-甲氧基苯甲酰氨基)乙基氨基)-4-氧丁酸钠乙酸酯 (步骤(c)中获得)冷却至10℃然后随后加入0.46g双(3-((Z)-十八 -9-烯氧基)丙基)胺、0.37g COMU和0.20g DIPEA。于23℃搅拌20h 之后将溶液通过Alox垫料过滤并将此用少许二甲基甲酰胺冲洗。滤液用乙酸乙酯稀释,用水洗涤并在真空下蒸干得到1.12g橙色油,其经柱层析纯化产生0.41g的(9H-芴-9-基)甲基(R,Z)-1-(4-甲氧苯基)-10-(3-((Z)-十八-9-烯氧基)丙基)-1,6,9-三氧代-14-氧杂 -2,5,10-三氮杂三十二-23-烯-7-基-氨基甲酸酯。在CDCl3中进行1H-NMR(TMS作为内标),以ppm为单位的化学位移:7.86(d,2H,Benz), 7.69(d,2H,Fmoc),7.55(d,2H,Fmoc),7.42-7.23(m,4H,Fmoc 和1H,NH),6.88(d,2H,Benz和1H,NH),6.12(bd,1H,NH), 5.41-5.26(m,4H,4xCH),4.60-4.33(m,3H,Fmoc),4.17(t,1H, CH),3.82(s,3H,CH3),3.62-3.23,(m,16H,8xCH2和1H,CH2), 2.73(dd,1H,CH2),2.05-1.95(m,8H,4xCH2),1.85-1.65(m,4H,2xCH2),1.57-1.45(m,4H,2xCH2),1.24(bs,44H,22xCH2),0.88 (t,6H,2xCH3)。
(e)(R)-2-氨基-N1-(2-(4-甲氧基苯甲酰氨基)乙基)-N4,N4-双 (3-((Z)-十八-9-烯氧基)丙基)琥珀酰胺的合成
将0.75g的二乙胺加入到2.12g在二氯乙烷中的(9H-芴-9-基) 甲基(R,Z)-1-(4-甲氧苯基)-10-(3-((Z)-十八-9-烯氧基)丙基)-1,6,9-三氧代-14-氧杂-2,5,10-三氮杂三十二-23-烯-7-基-氨基甲酸酯(步骤(d)中获得)中,搅拌26h之后在真空下蒸干得到1.90 g粗品,其通过吸附至20g Dowex Monosphere和随后通过在乙醇中的氨解吸附纯化产生1.09g的(R)-2-氨基-N1-(2-(4-甲氧基苯甲酰氨基)乙基)-N4,N4-双(3-((Z)-十八-9-烯氧基)丙基)琥珀酰胺。在CDCl3中进行1H-NMR(TMS作为内标),以ppm为单位的化学位移:7.88(d, 2H,Benz和1H,NH),7.64(t,1H,NH),6.89(d,2H,Benz), 5.42-5.26(m,4H,4xCH),3.82(s,3H,CH3),3.65-3.49,(m,4H, 2xCH2),3.42-3.28(m,12H,6xCH2和1H,CH),2.99(dd,1H,CH2), 2.71(dd,1H,CH2),2.10-1.92(m,8H,4xCH2和2H,NH2),1.85-1.67 (m,4H,2xCH2),1.60-1.47(m,4H,2xCH2),1.28(bs,44H,22xCH2), 0.90(t,6H,2xCH3).MS:947.9[M+Na]+。
实施例5:(41S)-1-氨基-41-(3-((2,3-双(十四烷基氧基)丙基)氨基)-3-氧代丙
基)-39-氧代-3,6,9,12,15,18,21,24,27,30,33,36-十二氧杂-40-氮杂四十二烷-42-酸的
合成
(a)Fmoc-Glu(DMA)-OtBu树脂的合成:
3.85g的二苯基重氮甲烷树脂(3.3mmol)在100ml SPPS反应器中用30ml DCM洗涤两次并用4.2g的2S)-2-(((9H-芴-9-基)甲氧基) 羰基氨基)-谷氨酸-γ-2,3-双(十四烷基氧基)丙基-酰胺(参见实施例 2,1.5当量,5.0mmol)在30ml DCM中的溶液处理过夜。将溶液滤出并将树脂用DCM洗涤四次。为了破坏最终未反应的二苯基重氮甲烷将树脂用125μl在30ml DCM中的乙酸(0.5当量,2.2mmol)处理 15分钟,之后交替以30ml二甲基甲酰胺和异丙醇洗涤三次。树脂用二异丙醚洗涤两次并在真空中干燥过夜。得到6.7g的期望的产物 (>100%的理论值,理论上产生6.5g)。通过在304nm下进行UV测量Fmoc裂解产物测定树脂的载荷为0.49mmol/g(理论上最大载荷为 0.51mmol/g)。
(b)H-Glu-OtBu-NH-PEG11-Glu(DMA)-二苯基甲基树脂的合成:
H-Glu-OtBu-NH-PEG11-Glu(DMA)-联苯甲基树脂通过常规的固相合成获得,包括以下反应顺序:
1)用在DMF中的哌啶裂解Fmoc-Glu(DMA)-OtBu树脂的Fmoc基团,
(2)与Fmoc-NH-PEG11-COOH缩合(在DMF和DIPEA中使用HTBU),
(3)用在DMF中的哌啶裂解Fmoc-NH-PEG11-Glu(DMA)-OtBu树脂的Fmoc基团,
(c)H-Glu-OtBu-NH-PEG11-Glu(DMA)-二苯基甲基树脂的裂解和脱保护:
期望的化合物可通过自树脂裂解例如通过用三氟乙酸 (trifluaroacetic acid)和三异丙基硅烷处理来获得。
实施例6:茴香(anis)酰胺修饰的脂质体的制备
在55℃下将470mg POPC、60mg胆固醇(Chol)和13.5mg茴香酰胺脂质(参见实施例4)溶解于750μL乙醇(96%)并注射入4.25mL 的PBS pH 7.4中。所用脂质的摩尔比为77.99:18.83:1.02:0.27。通过100nm聚碳酸酯膜挤压之后脂质体的平均尺寸为110nm,PDI为0.068。根据HPLC分析茴香酰胺脂质含量为理论值的72%。
实施例7:NH2-PEG8-PA-Glu(DMA)-酰胺的合成
(a)Fmoc-Glu(DMA)-Sieber树脂的合成:(参见实施例16)。
(b)NH2-PEG8-PA-Glu(DMA)-Sieber树脂的合成:
NNH2-PEG8-PA-Glu(DMA)-Sieber树脂通过常规的固相合成获得,包括以下反应顺序:
(1)用在DMF中的哌啶裂解Fmoc-Glu(DMA)-Sieber树脂的Fmoc 基团,
(2)与Fmoc-NH-PEG8-PA缩合(在DMF和DIPEA中使用HBTU)和 最后
(3)用在DMF中的哌啶裂解Fmoc-NH-PEG8-PA-Glu(DMA)-Sieber树脂的Fmoc基团。
(c)NH2-PEG8-PA-Glu(DMA)-酰胺的合成:
产物用在二氯甲烷中的三氟乙酸(trifluaroacetic acid)自 NH2-PEG8-PA-Glu(DMA)-Sieber树脂裂解。ESI-MS:计算的单同位素的 Mw=1034.8,MW[M+H]+=1035.9。
Claims (19)
1.通式I化合物
其中
Y代表O、N、S或共价键,
P1代表H、Y保护基团或Y活化基团或间隔基,
P2、P3彼此独立地代表H、氨基保护基团或间隔基,或P2和P3与它们所连接的N一起形成环结构,
L为式(a)基团,
其中虚线代表与N连接,
R1代表H或式-(CH2)2-ORb1基团,
R1'代表H或式-(CH2)2-ORb2基团,
R2代表H或式-CH2-ORc基团,
R2'代表H或式-ORd或-CH2-ORd基团,
R3代表H或式-(CH2)2-ORe或-(CH2)3-ORe基团,
Ra、Rb1、Rb2、Rc、Rd、Re彼此独立地代表饱和或不饱和的、直链或分支的烃链,
m为1、2或3,
条件是R1、R1'、R2、R2'、R3中至少一个不是H。
2.根据权利要求1的化合物,其中R3为H,且L为式(b)或(c)基团
其中虚线代表与N连接,
且P1、P2、P3、Y、R1、R1'、R2、R2'、Ra和m如权利要求1中定义,
条件是式(b)中R2和R2'之一不是H,且式(c)中R1和R1'之一不是H。
3.根据权利要求2的化合物,其中L为式(b1)、(b2)、(b3)或(b4)基团:
其中虚线代表与N连接,且
其中Ra、Rc和Rd彼此独立地为饱和或不饱和的、直链或分支的烃链。
4.根据权利要求2的化合物,其中L为式(c1)或(c2)基团:
其中虚线代表与N连接,且
其中Ra、Rb1、Rb2彼此独立地为饱和或不饱和的、直链或分支的烃链。
5.根据权利要求1的化合物,其中
R1、R1'、R2、R2'为H,
R3为式-(CH2)2-ORe或-(CH2)3-ORe基团,且
P1、P2、P3、Y、Ra、Re和m如权利要求1中定义。
6.根据权利要求1的化合物,其具有式II或III
其中
Y代表O、N、S或共价连接,
P1代表H、Y保护基团或Y活化基团或间隔基,
P2、P3彼此独立地代表H、氨基保护基团或间隔基,或P2和P3与它们所连接的N一起形成环结构,
R1代表H或式-(CH2)2-ORb1基团,
R1'代表H或式-(CH2)2-ORb2基团,
R2代表H或式-CH2-ORc基团,
R2'代表H或式-ORd或-CH2-ORd基团,
Ra、Rb1、Rb2,Rc、Rd彼此独立地代表饱和或不饱和的、直链或分支的烃链,
m为1、2或3,
条件是式II中R2和R2'之一不是H,且式III中R1和R1'之一不是H。
7.根据权利要求6的化合物,其具有IIa、IIb、IIc或IId,
其中
Y代表O、N、S或共价连接,
P1代表H、Y保护基团或Y活化基团或间隔基,
P2、P3彼此独立地代表H、氨基保护基团或间隔基,或P2和P3与它们所连接的N一起形成环结构,
Ra、Rc、Rd彼此独立地代表饱和或不饱和的、直链或分支的烃链,
m为1、2或3。
8.根据权利要求6的化合物,其具有式IIIa或IIIb,
其中
Y代表O、N、S或共价连接,
P1代表H、Y保护基团或Y活化基团或间隔基,
P2、P3彼此独立地代表H、氨基保护基团或间隔基,或P2和P3与它们所连接的N一起形成环结构,
Ra、Rb1、Rb2彼此独立地代表饱和或不饱和的、直链或分支的烃链,
m为1、2或3。
9.根据权利要求1的化合物,其具有式IVa和IVb,
其中
Y代表O、N、S或共价连接,
P1代表H、Y保护基团或Y活化基团或间隔基,
P2、P3彼此独立地代表H、氨基保护基团或间隔基,或P2和P3与它们所连接的N一起形成环结构,
Ra、Re彼此独立地代表饱和或不饱和的、直链或分支的烃链,且
m为1、2或3。
10.根据权利要求1至9中任一项的化合物,其中Ra、Rb1、Rb2、Rc、Rd、Re彼此独立地为直链或分支的C(10-22)烷基、C(10-22)链烯基或C(10-22)炔基。
11.根据权利要求10的化合物,其中C(10-22)链烯基和C(10-22)炔基具有1、2、3或4个不饱和键。
12.根据权利要求11的化合物,其中C(10-22)链烯基和C(10-22)炔基具有1或2个不饱和键。
13.根据权利要求1至9中任一项的化合物,其中P1、P2、P3中至少一个为间隔基。
14.根据权利要求13的化合物,其中间隔基选自亚烷基链,其进一步包含一个或多个选自下列的基团:酮、酯、醚、氨基、酰胺、脒、氨基甲酸酯或硫代氨基甲酸酯官能团、甘油、脲、硫脲、双键或芳香环。
15.根据权利要求14的化合物,间隔基为聚乙二醇或封端的聚乙二醇。
16.根据权利要求1的化合物,用于药物递送系统或用作抗原展示系统。
17.囊泡状组合物,包含至少一种权利要求1至15中任一项的化合物,任选地与一种或多种其它形成囊泡的化合物混合。
18.根据权利要求17的囊泡状组合物,其中囊泡状组合物为脂质体、胶束或纳米颗粒。
19.试剂盒,包含权利要求1至15中任一项的化合物或权利要求17或18的囊泡状组合物。
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MX359736B (es) | 2018-10-09 |
SG11201405536YA (en) | 2014-10-30 |
JP2015514692A (ja) | 2015-05-21 |
HK1199819A1 (zh) | 2015-07-24 |
AU2013231819B2 (en) | 2017-07-20 |
EP2825157B1 (en) | 2018-09-05 |
PL2825157T3 (pl) | 2019-05-31 |
RU2014141547A (ru) | 2016-05-10 |
CN104168887A (zh) | 2014-11-26 |
SI2825157T1 (sl) | 2019-01-31 |
SG10201610402VA (en) | 2017-02-27 |
TWI606030B (zh) | 2017-11-21 |
TW201343615A (zh) | 2013-11-01 |
ES2700742T3 (es) | 2019-02-19 |
MX2014010810A (es) | 2014-12-08 |
JP6457816B2 (ja) | 2019-01-23 |
BR112014022847A2 (zh) | 2017-06-20 |
ZA201407491B (en) | 2015-12-23 |
US9796666B2 (en) | 2017-10-24 |
BR112014022847B1 (pt) | 2022-08-23 |
US20150030670A1 (en) | 2015-01-29 |
KR20140135832A (ko) | 2014-11-26 |
RU2670618C2 (ru) | 2018-10-24 |
EP2825157A1 (en) | 2015-01-21 |
WO2013135360A1 (en) | 2013-09-19 |
CA2867184A1 (en) | 2013-09-19 |
NZ630990A (en) | 2016-04-29 |
AU2013231819A1 (en) | 2014-10-30 |
CA2867184C (en) | 2020-09-01 |
DK2825157T3 (da) | 2019-01-02 |
KR102081046B1 (ko) | 2020-02-25 |
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