CN115175894B - 纳米材料 - Google Patents
纳米材料 Download PDFInfo
- Publication number
- CN115175894B CN115175894B CN202180016840.5A CN202180016840A CN115175894B CN 115175894 B CN115175894 B CN 115175894B CN 202180016840 A CN202180016840 A CN 202180016840A CN 115175894 B CN115175894 B CN 115175894B
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- CN
- China
- Prior art keywords
- oxy
- bis
- butanoyl
- propyl ester
- acid
- Prior art date
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- 239000000203 mixture Substances 0.000 claims abstract description 100
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 40
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- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 5
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- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 370
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- 125000000217 alkyl group Chemical group 0.000 description 124
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 121
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 117
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 113
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 77
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- 125000003118 aryl group Chemical group 0.000 description 64
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 46
- 239000000243 solution Substances 0.000 description 42
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 38
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 35
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- UFFXQKBVALLYQW-UHFFFAOYSA-N (1-ethylpiperidin-3-yl)methanol Chemical compound CCN1CCCC(CO)C1 UFFXQKBVALLYQW-UHFFFAOYSA-N 0.000 description 26
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 23
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- 238000006243 chemical reaction Methods 0.000 description 20
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- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 17
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- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 16
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- 125000001424 substituent group Chemical group 0.000 description 16
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- 239000011734 sodium Substances 0.000 description 15
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- 239000003795 chemical substances by application Substances 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
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- 125000003545 alkoxy group Chemical group 0.000 description 9
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Abstract
描述了用于递送核酸的脂质纳米颗粒组合物。在各种实施方案中,所述脂质纳米颗粒包含式(I)的可电离脂质。还提供了在不需要靶向配体的情况下使用这种脂质纳米颗粒组合物以实现治疗性运载物的靶向递送的方法。
Description
相关申请信息
本申请要求于2020年1月9日提交的第62/958,876号美国临时申请的优先权,所述美国临时申请通过引用整体据此并入本文。
背景技术
技术领域
本申请涉及化学、生物和医学领域。本文公开了药物递送系统及其使用方法。更具体地,本文公开了用于将核酸递送至细胞的纳米颗粒组合物。
描述
肝细胞有助于维持体内平衡并产生许多分泌蛋白,因此涉及许多遗传疾病。尽管携带RNA的纳米颗粒已被导向肝细胞,但在没有靶向配体的情况下全身递送至肝细胞仍然具有挑战性。
发明内容
本文所述的一些实施方案涉及式(I)的化合物:
其中:
R1是C9-C20烷基或具有1至3个不饱和度的C9-C20烯基;
X1和X2各自独立地不存在或选自-O-、-NR2-和其中每个R2独立地是氢或C1-C6烷基;
每个a独立地是1至6的整数;
X3和X4各自独立地不存在或选自:任选地被1或2个C1-C6烷基取代的4至8元杂环基、任选地被1或2个C1-C6烷基取代的5至6元杂芳基、任选地被1或2个C1-C6烷基取代的5至6元芳基、任选地被1或2个C1-C6烷基取代的4至7元环烷基、-O-和-NR3-,其中每个R3是氢原子或C1-C6烷基,并且其中X1-X2-X3-X4不包含任何氧-氧、氧-氮或氮-氮键;
X5是-(CH2)b-,其中b是0至6的整数;
X6是氢、C1-C6烷基、任选地被1或2个C1-C6烷基取代的5至6元杂芳基、或-NR4R5,其中R4和R5各自独立地是氢或C1-C6烷基;或者替代地,R4和R5与它们键合的氮连接在一起以形成任选地被1或2个C1-C6烷基取代的4至7元杂环基,其中所述杂环基任选地包括选自氧、硫和氮的另外的杂原子;
每个X7独立地是氢、羟基或-NR6R7,其中R6和R7各自独立地是氢或C1-C6烷基;或者替代地,R6和R7与它们键合的氮连接在一起以形成任选地被1或2个C1-C6烷基取代的4至7元杂环基,其中所述杂环基任选地包括选自氧、硫和氮的另外的杂原子;
X1、X2、X3、X4和X5中的至少一个是存在的;
A1和A2各自独立地选自:C5-C12卤代烷基,C5-C12烯基,C5-C12炔基,(C5-C12烷氧基)-(CH2)n2-,环任选地被一个或两个卤素、C1-C6烷基、C1-C6卤代烷基或C1-C6烷氧基取代的(C5-C10芳基)-(CH2)n3-,以及环任选地被1或2个C1-C6烷基取代的(C3-C8环烷基)-(CH2)n4-;或者替代地,A1和A2与它们键合的原子连接在一起以形成被1或2个C4-C10烷基取代的5至6元环状缩醛;
n1、n2和n3各自独立地是1至4的整数;以及
n4是0至4的整数。
一些实施方案的特征在于脂质纳米颗粒组合物,其包含:如本文所述的可电离脂质;磷脂;聚乙二醇-脂质;胆固醇;以及任选地核酸。其它实施方案涉及将核酸递送至有需要的个体的方法,所述方法包括向有需要的个体施用脂质纳米颗粒组合物。
下面将更详细地描述这些和其它实施方案。
附图说明
图1例示了制备式(I)的化合物的反应方案。
图2总结了实施例1至实施例148的化合物的结构。
具体实施方案
定义
除非另有定义,本文使用的所有技术和科学术语具有与本领域普通技术人员通常理解相同的含义。除非另有说明,本文引用的所有专利、申请、公开的申请和其它出版物均通过引用整体并入。在本文中对术语存在多个定义的情况下,除非另有说明,否则以本章节中的那些为准。
如本文使用,任何“R”或“X”基团,例如但不限于R1、R2、R3、R4、R5、R6、R7、X1、X2、X3、X4、X5、X6、X7、A1和A2表示可以连接至所示原子的取代基。此类R、X和A基团可以在本文中通称为“R”基团。R基团可以是取代或未取代的。如果两个“R”基团被称为“连接在一起”,则应理解,R基团和它们键合的原子可以形成环状结构,例如环烷基、环烯基、芳基、杂芳基或杂环。例如,但不限于,如果NRaRb基团的Ra和Rb被指示为“连接在一起”,则这意味着它们彼此共价键合以形成环:
此外,作为替代,如果两个“R”基团与它们附接的原子“连接在一起”以形成环,则R基团不限于先前定义的变量或取代基。
每当基团被描述为“任选取代的”时,基团可以是未取代的或者被一个或多个所示取代基取代。同样地,当基团被描述为“未取代或取代的”时,如果是取代的,则取代基可选自所示取代基中的一个或多个。如果未示出取代基,则意指所示“任选取代的”或者“取代的”基团可以被一个或多个单独且独立地选自以下的基团取代:烷基、烯基、炔基、环烷基、环烯基、酰基烷基、羟基、烷氧基、烷氧基烷基、氨基烷基、氨基酸、芳基、杂芳基、杂环基、芳基(烷基)、杂芳基(烷基)、杂环基(烷基)、羟基烷基、酰基、氰基、卤素、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-磺酰氨基、N-磺酰氨基、C-羧基、O-羧基、异氰酸基、氰硫基、异氰硫基、叠氮基、硝基、甲硅烷基、硫基、亚磺酰基、磺酰基、卤代烷基、卤代烷氧基、三卤代甲磺酰基、三卤代甲磺酰氨基、氨基、单取代的氨基和二取代的氨基。
如本文使用,“Ca至Cb”(其中“a”和“b”是整数)是指烷基、烯基或炔基中的碳原子数,或环烷基、环烯基、芳基、杂芳基或杂脂环基的环中的碳原子数。即,烷基、烯基、炔基、环烷基的环、环烯基的环、芳基的环、杂芳基的环或杂脂环基的环可以包含“a”至“b”(包括端值)个碳原子。因此,例如,“C1至C4烷基”是指具有1至4个碳原子的所有烷基基团,即,CH3-、CH3CH2-、CH3CH2CH2-、(CH3)2CH-、CH3CH2CH2CH2-、CH3CH2CH(CH3)-和(CH3)3C-。如果对于烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基或杂脂环基没有指定“a”和“b”,则假定在这些定义中描述的最宽范围。
如本文使用,“烷基”是指包含完全饱和的(无双键或叁键)烃基团的直链或支链烃链。烷基可以具有1至20个碳原子(每当在本文中出现时,诸如“1至20”的数值范围是指给定范围内的每个整数;例如,“1至20个碳原子”意指烷基可以由1个碳原子、2个碳原子、3个碳原子等,至多且包括20个碳原子构成,然而本定义还涵盖未指定数值范围的术语“烷基”的存在)。烷基还可以是具有1至10个碳原子的中等大小的烷基。烷基还可以是具有1至6个碳原子的低级烷基。化合物的烷基可以被指定为“C1-C4烷基”或类似指定。仅举例而言,“C1-C4烷基”表示在烷基链中存在一个至四个碳原子,即,烷基链选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。典型的烷基包括但决不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基和己基。烷基可以是取代或未取代的。
如本文使用,“烯基”是指在直链或支链烃链中含有一个或多个双键的烃基。烯基的实例包括丙二烯基、乙烯基甲基和乙烯基。烯基可以是未取代或取代的。
如本文使用,“炔基”是指在直链或支链烃链中含有一个或多个叁键的烃基。炔基的实例包括乙炔基和丙炔基。炔基可以是未取代或取代的。
如本文使用,“环烷基”是指完全饱和的(无双键或者叁键)单环烃环系或者多环烃环系。当由两个或更多个环组成时,所述环可以以稠合、桥接或者螺接的方式连接在一起。如本文使用,术语“稠合”是指共同具有两个原子和一个键的两个环。如本文使用,术语“桥接的环烷基”是指其中环烷基含有一个或多个原子连接非相邻原子的键的化合物。如本文使用,术语“螺”是指共同具有一个原子的两个环,并且所述两个环不通过桥连接。环烷基可以在环中含有3至30个原子、在环中含有3至20个原子、在环中含有3至10个原子、在环中含有3至8个原子或在环中含有3至6个原子。环烷基可以是未取代或取代的。典型的单环烷基包括但决不限于环丙基、环丁基、环戊基、环己基、环庚基和环辛基。稠合环烷基的实例是十氢萘基、十二氢-1H-非那烯基和十四氢蒽基;桥接的环烷基的实例是双环[1.1.1]戊基、双环[2.1.1]庚烷、金刚烷基和降冰片烷基;并且螺环烷基的实例包括螺[3.3]庚烷和螺[4.5]癸烷。
如本文使用,“环烯基”是指在至少一个环中包含一个或多个双键的单环烃环系或者多环烃环系;然而,如果存在一个以上的环,则遍及所有环双键无法形成完全离域的π电子体系(否则该基团将为如本文所定义的“芳基”)。环烯基可在环中包含3至10个原子或者在环中包含3至8个原子。当由两个或更多个环组成时,所述环可以以稠合方式连接在一起。环烯基可以是未取代或取代的。
如本文使用,“芳基”是指遍及所有环具有完全离域的π电子体系的碳环(全碳)单环芳香族环系或者多环芳香族环系(包括其中两个碳环共用化学键的稠合环系)。芳基中的碳原子数可以变化。例如,芳基可以是C6-C14芳基、C6-C10芳基或者C6芳基。芳基的实例包括但不限于苯、萘和甘菊环。芳基可以是取代或未取代的。
如本文使用,“杂芳基”是指包含一个、两个、三个或更多个杂原子(即除了碳之外的元素,包括但不限于氮、氧和硫)的单环芳香族环系或多环芳香族环系(具有完全离域的π电子体系的环系)。杂芳基中的环中的原子数量可以变化。例如,杂芳基可在环中包含4至14个原子、在环中包含5至10个原子或者在环中包含5至6个原子。此外,术语“杂芳基”包括两个环(例如至少一个芳环和至少一个杂芳环,或者至少两个杂芳环)共用至少一个化学键的稠合环系。杂芳基环的实例包括但不限于本文所述的那些和以下:呋喃、呋咱、噻吩、苯并噻吩、酞嗪、吡咯、噁唑、苯并噁唑、1,2,3-噁二唑、1,2,4-噁二唑、噻唑、1,2,3-噻二唑、1,2,4-噻二唑、苯并噻唑、咪唑、苯并咪唑、吲哚、吲唑、吡唑、苯并吡唑、异噁唑、苯并异噁唑、异噻唑、三唑、苯并三唑、噻二唑、四唑、吡啶、哒嗪、嘧啶、吡嗪、嘌呤、蝶啶、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉和三嗪。杂芳基可以是取代或未取代的。
如本文使用,“杂环基”或者“杂脂环基”是指三元、四元、五元、六元、七元、八元、九元、十元、多至18元的单环、双环和三环环系,其中碳原子与1至5个杂原子一起构成所述环系。然而,杂环可任选地包含以遍及所有环不出现完全离域的π电子体系的方式设置的一个或多个不饱和键。杂原子是除碳之外的元素,包括但不限于氧、硫和氮。杂环可进一步包含一个或多个羰基或者硫代羰基官能团,以便使所述定义包括氧代体系和硫代体系,例如内酰胺、内脂、环状酰亚胺、环状硫代酰亚胺和环状氨基甲酸酯。当由两个或更多个环组成时,环可以以稠合或螺方式连接在一起,如本文关于“环烷基”所述。另外,杂环基中的任何氮可以被季铵化。杂环基或者杂脂环基可以是未取代或者取代的。此类“杂环基”或“杂脂环基”的实例包括但不限于本文所述的那些和以下:1,3-二氧杂环己烯、1,3-二氧杂环己烷、1,4-二氧杂环己烷、1,2-二氧杂环戊环、1,3-二氧杂环戊环、1,4-二氧杂环戊烷、1,3-氧硫杂环己烷、1,4-氧硫杂环己二烯、1,3,4-噁二唑-2(3H)-酮、1,2,3-噁二唑-5(2H)-酮、1,3-氧硫杂环戊烷、1,3-二硫杂环戊二烯、1,3-二硫杂环戊环、1,4-氧硫杂环戊烷、四氢-1,4-噻嗪、1,3-噻嗪烷、2H-1,2-噁嗪、马来酰亚胺、琥珀酰亚胺、巴比妥酸、硫代巴比妥酸、二氧代哌嗪、乙内酰脲、二氢尿嘧啶、三噁烷、六氢-1,3,5-三嗪、咪唑啉、咪唑烷、异噁唑啉、异噁唑烷、噁唑啉、噁唑烷、噁唑烷酮、噻唑啉、噻唑烷、吗啉、环氧乙烷、哌啶N-氧化物、哌啶、哌嗪、吡咯烷、吡咯烷酮、吡咯烷二酮、4-哌啶酮、吡唑啉、吡唑烷、2-氧代吡咯烷、四氢吡喃、4H-吡喃、四氢噻喃、硫吗啉、硫吗啉亚砜、硫吗啉砜和它们的苯并稠合类似物(例如,苯并咪唑烷酮、四氢喹啉和3,4-亚甲基二氧基苯基)。
如本文使用,“芳烷基”和“芳基(烷基)”是指作为取代基通过低级亚烷基连接的芳基。芳烷基的低级亚烷基和芳基可以是取代或未取代的。实例包括但不限于苄基、2-苯基烷基、3-苯基烷基和萘基烷基。
如本文使用,“杂芳烷基”和“杂芳基(烷基)”是指作为取代基通过低级亚烷基连接的杂芳基。杂芳烷基的低级亚烷基和杂芳基可以是取代或未取代的。实例包括但不限于2-噻吩基烷基、3-噻吩基烷基、呋喃基烷基、噻吩基烷基、吡咯基烷基、吡啶基烷基、异噁唑基烷基、咪唑基烷基和它们的苯并稠合类似物。
“杂脂环基(烷基)”和“杂环基(烷基)”是指作为取代基通过低级亚烷基连接的杂环基或杂脂环基。杂脂环基(烷基)的低级亚烷基和杂环基可以是取代或未取代的。实例包括但不限于四氢-2H-吡喃-4-基(甲基)、哌啶-4-基(乙基)、哌啶-4-基(丙基)、四氢-2H-噻喃-4-基(甲基)和1,3-噻嗪烷-4-基(甲基)。
“低级亚烷基”为直链的-CH2-束缚基团,其形成经由其末端碳原子连接分子片段的键。实例包括但不限于亚甲基(-CH2-)、亚乙基(-CH2CH2-)、亚丙基(-CH2CH2CH2-)和亚丁基(-CH2CH2CH2CH2-)。低级亚烷基可以通过用在“取代的”的定义下列出的取代基替换低级亚烷基的一个或多个氢来进行取代。
如本文使用,“烷氧基”是指式-OR的基团,其中R是如本文定义的烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。烷氧基的非限制性列表为甲氧基、乙氧基、正丙氧基、1-甲基乙氧基(异丙氧基)、环丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、环丁氧基、苯氧基和苄氧基。烷氧基可以是取代或未取代的。
如本文使用,“酰基”是指作为取代基通过羰基连接的氢、烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。实例包括甲酰基、乙酰基、丙酰基、苯甲酰基和丙烯酰基。酰基可以是取代或未取代的。
如本文使用,“酰基烷基”是指作为取代基通过低级亚烷基连接的酰基。实例包括芳基-C(=O)-(CH2)n-和杂芳基-C(=O)-(CH2)n-,其中n为1至6的整数。
如本文使用,“烷氧基烷基”是指作为取代基通过低级亚烷基连接的烷氧基。实例包括C1-4烷基-O-(CH2)n-,其中n为1至6的整数。
如本文使用,“氨基烷基”是指作为取代基通过低级亚烷基连接的任选取代的氨基。实例包括H2N(CH2)n-,其中n为1至6的整数。
如本文使用,“羟烷基”是指一个或多个氢原子被羟基替代的烷基。示例性羟烷基包括但不限于2-羟乙基、3-羟丙基、2-羟丙基和2,2-二羟乙基。羟烷基可以是取代或未取代的。
如本文使用,“卤代烷基”是指一个或多个氢原子被卤素替代的烷基(例如,单卤代烷基、双卤代烷基和三卤代烷基)。此类基团包括但不限于氯甲基、氟甲基、二氟甲基、三氟甲基、氯-氟代烷基、氯-二氟代烷基和2-氟异丁基。卤代烷基可以是取代或未取代的。
如本文使用,“卤代烷氧基”是指其中一个或多个氢原子被卤素替代的烷氧基(例如,单卤代烷氧基、双卤代烷氧基和三卤代烷氧基)。此类基团包括但不限于氯甲氧基、氟甲氧基、二氟甲氧基、三氟甲氧基、氯-氟代烷基、氯-二氟烷氧基和2-氟异丁氧基。卤代烷氧基可以是取代或未取代的。
“硫基”是指“-SR”基团,其中R可以是氢、烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。硫基可以是取代或未取代的。
“亚磺酰基”是指“-S(=O)-R”基团,其中R可以与关于硫基定义的相同。亚磺酰基可以是取代或未取代的。
“磺酰基”是指“SO2R”基团,其中R可以与关于硫基定义的相同。磺酰基可以是取代或未取代的。
“O-羧基”是指“RC(=O)O-”基团,其中R可以是如本文定义的氢、烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。O-羧基可以是取代或未取代的。
术语“酯”和“C-羧基”是指“-C(=O)OR”基团,其中R可以与关于O-羧基定义的相同。酯和C-羧基可以是取代或未取代的。
“硫代羰基”是指“-C(=S)R”基团,其中R可以与关于O-羧基定义的相同。硫代羰基可以是取代或未取代的。
“三卤代甲磺酰基”是指“X3CSO2-”基团,其中每个X是卤素。
“三卤代甲磺酰氨基”是指“X3CS(O)2N(RA)-”基团,其中每个X是卤素,并且RA是氢、烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。
如本文使用的术语“氨基”是指-NH2基团。
如本文使用,术语“羟基”是指-OH基团。
“氰基”是指“-CN”基团。
如本文使用的术语“叠氮基”是指-N3基团。
“异氰酸基”是指“-NCO”基团。
“氰硫基”是指“-CNS”基团。
“异氰硫基”是指“-NCS”基团。
“羰基”是指C=O基团。
“S-磺酰氨基”是指“-SO2N(RARB)”基团,其中RA和RB可以独立地是氢、烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。S-磺酰氨基可以是取代或未取代的。
“N-磺酰氨基”是指“RSO2N(RA)-”基团,其中R和RA可以独立地是氢、烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。N-磺酰氨基可以是取代或未取代的。
“O-氨基甲酰基”是指“-OC(=O)N(RARB)”基团,其中RA和RB可以独立地是氢、烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。O-氨基甲酰基可以是取代或未取代的。
“N-氨基甲酰基”是指“ROC(=O)N(RA)-”基团,其中R和RA可以独立地是氢、烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。N-氨基甲酰基可以是取代或未取代的。
“O-硫代氨基甲酰基”是指“-OC(=S)-N(RARB)”基团,其中RA和RB可以独立地是氢、烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。O-硫代氨基甲酰基可以是取代或未取代的。
“N-硫代氨基甲酰基”是指“ROC(=S)N(RA)-”基团,其中R和RA可以独立地是氢、烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。N-硫代氨基甲酰基可以是取代或未取代的。
“C-酰氨基”是指“-C(=O)N(RARB)”基团,其中RA和RB可以独立地是氢、烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。C-酰氨基可以是取代或未取代的。
“N-酰氨基”是指“RC(=O)N(RA)-”基团,其中R和RA可以独立地是氢、烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。N-酰氨基可以是取代或未取代的。
“脲”基团是指“N(R)-C(=O)-NRARB”基团,其中R可以是氢或烷基,并且RA和RB可以独立地是氢、烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。脲可以是取代或未取代的。
“肟”基团是指“-C(=N-OH)RA”,其中RA可以独立地是烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。肟可以是取代或未取代的。
“酰基腙”是指“-C(=N-NH-酰基)-RA”,其中酰基部分具有如本文提供的“酰基”的结构,并且RA可以独立地是烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。酰基腙可以是取代或未取代的。
“肼”是指“-NHNRARB”,其中RA和RB可以独立地是氢、烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基(烷基)、芳基(烷基)、杂芳基(烷基)或杂环基(烷基)。肼可以是取代或未取代的。
如本文使用的术语“卤原子”或“卤素”意指元素周期表中第7列的辐射稳定的原子中的任一个,例如氟、氯、溴和碘。
如本文使用,“------”表示单键或双键,除非另有说明。
在未指定取代基的数量的情况下(例如卤代烷基),可存在一个或多个取代基。例如“卤代烷基”可包括一个或多个相同或不同的卤素。作为另一实例,“C1-C3烷氧基苯基”可包括含有一个、两个或三个原子的一个或多个相同或不同的烷氧基。
如本文使用,除非另有说明,任何保护基团、氨基酸和其它化合物的缩写与其常用、公认的缩写或IUPAC-IUB生化命名委员会(参见Biochem.11:942-944(1972))一致。
如本文使用的术语“保护基团”(protecting group/protecting groups)(和缩写“PG”)是指添加到分子中以防止分子中的现有基团经历不希望的化学反应的任何原子或原子团。保护基团部分的实例描述于T.W.Greene和P.G.M.Wuts,Protective Groups inOrganic Synthesis,第3版.John Wiley&Sons,1999,以及.F.W.McOmie,ProtectiveGroups in Organic Chemistry Plenum Press,1973中,为了公开适合的保护基团的有限目的,通过引用据此并入这两篇文献。保护基团部分可以以这样的方式选择,即它们对某些反应条件是稳定的,并且在方便的阶段使用本领域已知的方法容易地去除。保护基团的非限制性列表包括苄基;取代的苄基;烷基羰基和烷氧基羰基(例如,叔丁氧基羰基(BOC)、乙酰基或异丁酰基);芳基烷基羰基和芳基烷氧基羰基(例如,苄氧基羰基);取代的甲基醚(例如甲氧基甲基醚);取代的乙醚;取代的苄基醚;四氢吡喃基醚;甲硅烷基(例如,三甲基甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基、叔丁基二甲基甲硅烷基、三异丙基甲硅烷基氧基甲基、[2-(三甲基甲硅烷基)乙氧基]甲基或叔丁基二苯基甲硅烷基);酯(例如苯甲酸酯);碳酸酯(例如,甲氧基甲基碳酸酯);磺酸酯(例如甲苯磺酸酯或甲磺酸酯);非环状缩酮(例如二甲基缩醛);环状缩酮(例如,1,3-二氧杂环己烷、1,3-二氧杂环戊烷和本文所述的那些);非环状缩醛;环状缩醛(例如,本文所述的那些);非环状半缩醛;环状半缩醛;环状二硫代缩酮(例如,1,3-二硫杂环己烷或1,3-二硫杂环戊烷);原酸酯(例如,本文所述的那些)和三芳基甲基(例如,三苯甲基;单甲氧基三苯甲基(MMTr);4,4'-二甲氧基三苯甲基(DMTr);4,4',4”-三甲氧基三苯甲基(TMTr);以及本文所述的那些)。
如本文使用的术语“离去基团”(和缩写“LG”)是指在化学反应中能够被其它原子或者部分替代的任何原子或部分。更具体地,在一些实施方案中,“离去基团”是指在亲核取代反应中被替换的原子或者部分。在一些实施方案中,“离去基团”为强酸的共轭碱的任何原子或部分。适合的离去基团的实例包括但不限于甲苯磺酸酯、甲磺酸酯、三氟乙酸酯和卤素(例如,I、Br和Cl)。离去基团的非限制性特性和实例可见于,例如Organic Chemistry,第2版,Francis Carey(1992),第328-331页;Introduction to Organic Chemistry,第2版,Andrew Streitwieser和Clayton Heathcock(1981),第169-171页;以及OrganicChemistry,第5版,John McMurry(2000),第398页和第408页;为了离去基团的公开特性和实例的有限目的,所有以上文献通过引用并入本文。
术语“药物可接受的盐”是指化合物的盐,其不会对其所施用的生物体造成显著刺激并且不会消除化合物的生物活性和性质。在一些实施方案中,盐是化合物的酸加成盐。药用盐可以通过使化合物与无机酸例如氢卤酸(例如,盐酸或氢溴酸)、硫酸、硝酸和磷酸反应来获得。药用盐也可以通过使化合物与有机酸例如脂肪族或芳香族羧酸或磺酸,例如甲酸、乙酸、琥珀酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、烟碱酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸或萘磺酸反应来获得。药用盐也可以通过使化合物与碱反应形成盐来获得,所述盐例如铵盐、碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如钙盐或镁盐)、有机碱(例如二环己胺、N-甲基-D-葡糖胺、三(羟甲基)甲胺、C1-C7烷基胺、环己胺、三乙醇胺、乙二胺)的盐、以及与氨基酸如精氨酸和赖氨酸形成的盐。
除非另有明确说明,本申请中使用的术语和短语及其变体,尤其是所附权利要求书中使用的术语和短语及其变体应被解释为是开放式的,而不是限制性的。作为前述的实例,术语“包括”应被理解为意指“不受限制地包括”、“包括但不限于”等;如本文使用的术语“包含”与“包括”、“含有”或“特征在于”同义,并且是包含性的或开放式的,并且不排除另外的未列举的要素或方法步骤;术语“具有”应被解释为“至少具有”;术语“包括”应被解释为“包括但不限于”;术语“实例”用于提供讨论中的项目的示例性实例,而不是其穷尽性或限制性列表;并且术语如“优选地”、“优选地”、“期望的”或“可期望的”和具有类似含义的词语的使用不应被理解为暗示某些特征对于结构或功能是关键的、必要的或甚至是重要的,而仅旨在突出在具体实施方案中可能使用或可能不使用的替代或附加特征。此外,术语“包括”应解释为与短语“至少具有”或“至少包括”同义。当在方法的上下文中使用时,术语“包括”意指该方法至少包括所述步骤,但可以包括另外的步骤。当在化合物、组合物或装置的上下文中使用时,术语“包括”意指化合物、组合物或装置至少包括所述特征或组分,但也可以包括另外的特征或组分。同样,用连接词“和”连接的一组项目不应被理解为要求这些项目中的每一种和每一个都存在于分组中,而应被理解为“和/或”,除非上下文另外指明。类似地,用连接词“或”连接的一组项目不应被理解为要求在该组中相互排他,而应被理解为“和/或”,除非上下文另外指明。
关于本文使用的基本上任何复数和/或单数术语,本领域技术人员视上下文和/或应用的情况而定可将复数翻译为单数和/或将单数翻译为复数。出于清楚的目的,本文明确地阐述各种单数/复数置换。不定冠词“一(a)”或“一(an)”不排除多个。某些措施在互不相同的从属权利要求中陈述,但这一事实并不表示这些措施的组合不能被有利地使用。本发明的任何参考标记不应解释为限制范围。
应理解,在具有一个或多个手性中心的本文所述的任何化合物中,如果未明确指出绝对立体化学,则每个中心可独立地具有R构型或S构型或其混合物。因此,本文提供的化合物可以是对映体纯的、富含对映体的外消旋混合物,或者非对映体纯、富含非对映体的立体异构混合物。此外,应理解,在具有产生可以定义为E或者Z的几何异构体的一个或多个双键的本文所述的任何化合物中,每个双键可以独立地为E或Z或其混合物。
同样,应理解,在所述的任何化合物中,也旨在包括所有互变异构形式。
应理解,在本公开的化合物具有未充满的化合价的情况下,则用氢或其同位素(例如,氢-1(氕)和氢-2(氘))填充化合价。
应理解,本文所述的化合物可以是同位素标记的。用同位素(例如氘)取代可以提供某些治疗优势,产生较高的代谢稳定性,例如,体内半衰期增加或剂量需求降低。如化合物结构中表示的每种化学元素均可以包括所述元素的任何同位素。例如,在化合物结构中,氢原子可以被明确地公开或理解为存在于化合物中。在可以存在氢原子的化合物的任何位置处,氢原子可以是氢的任何同位素,包括但不限于氢-1(氕)和氢-2(氘)。因此,本文对化合物的引用涵盖所有可能的同位素形式,除非上下文另外明确规定。
应理解,本文所述的方法和组合包括结晶形式(也称为多晶型物,其包括化合物的相同元素组成的不同晶体堆积排列)、无定形相、盐、溶剂化物和水合物。在一些实施方案中,本文所述的化合物以与药物可接受的溶剂如水、乙醇等的溶剂化形式存在。在其它实施方案中,本文所述的化合物以非溶剂化形式存在。溶剂化物含有化学计量或非化学计量的量的溶剂,并且可以在用药物可接受的溶剂如水、乙醇等结晶的过程中形成。当溶剂是水时形成水合物,或者当溶剂是醇时形成醇化物。此外,本文提供的化合物可以以非溶剂化形式以及溶剂化形式存在。通常,出于本文提供的化合物和方法的目的,溶剂化形式被认为等同于非溶剂化形式。
在提供数值范围的情况下,应理解,上限和下限以及在所述范围的上限与下限之间的每个中间值均涵盖在实施方案内。
如本文使用,“RNA”是指可以天然或非天然存在的核糖核酸。例如,RNA可以包括修饰的和/或非天然存在的组分,例如一种或多种核碱基、核苷、核苷酸或连接基。RNA可以包括帽结构、链终止核苷、茎环、polyA序列和/或多腺苷酸化信号。RNA可以具有编码目标多肽的核苷酸序列。例如,RNA可以是信使RNA(mRNA)。编码特定多肽的mRNA的翻译,例如哺乳动物细胞内mRNA的体内翻译,可以产生编码的多肽。RNA可以选自由小干扰RNA(siRNA)、微小RNA(miRNA)、Dicer底物RNA(dsRNA)、小发夹RNA(shRNA)、mRNA、单向导RNA(sgRNA)、cas9mRNA及其混合物组成的非限制性组。
术语“多肽”、“肽”和“蛋白质”可以互换使用,是指通过肽键连接在一起的至少三个氨基酸的串。肽可以是指单个肽或肽的集合。肽可以含有天然氨基酸、非天然氨基酸(即,在自然界中不存在但可掺入多肽链中的化合物)和/或氨基酸类似物。此外,肽中的一个或多个氨基酸可以被修饰,例如,通过添加化学实体,如碳水化合物基团,磷酸基团,法呢基,异法呢基,脂肪酸基团,用于缀合、功能化或其它修饰的连接基等。修饰可以包括肽的环化、D-氨基酸的掺入等。
如本文使用,术语“治疗(treat)”、“治疗(treatment)”和“治疗用途”是指消除、减轻或改善疾病或病症的一种或多种症状。如本文使用,“治疗有效量”是指足以介导这种症状的临床相关消除、减轻或改善的治疗剂的量。如果其大小足以影响接受者个体的健康或预后,则效果在临床上是相关的。治疗有效量可以是指足以延迟或最小化疾病发作(例如,延迟或最小化癌症扩散)的治疗剂的量。治疗有效量还可以是指在疾病的治疗或管理中提供治疗益处的治疗剂的量。
本文所述的组合物优选以单位剂型提供。如本文使用,“单位剂型”是包含根据良好医学实践适于以单剂量向动物(优选哺乳动物个体)施用的量的化合物或组成的组合物。然而,单一或单位剂型的制备并不意味着该剂型每天施用一次或每疗程施用一次。预期此类剂型每天施用一次、两次、三次或更多次,并且可以作为输注在一段时间(例如,约30分钟至约2-6小时)内施用,或作为连续输注施用,且可以在治疗过程中给予多于一次,尽管不特别排除单次施用。本领域技术人员将认识到,制剂不具体考虑整个疗程,并且这样的决定留给治疗领域的技术人员而不是制剂领域的技术人员。如本文使用,术语“预防剂”是指可以用于在检测到病症或疾病的任何症状之前预防此类病症或疾病的试剂。“预防有效”量是足以介导这种保护的预防剂的量。预防有效量也可以是指在预防疾病中提供预防益处的预防剂的量。
如以上所述有用的组合物可以是用于各种给药途径的各种合适的形式中的任一种,例如用于口服、鼻用、直肠、局部(包括透皮)、眼、脑内、颅内、鞘内、动脉内、静脉内、肌内或其它肠胃外给药途径。本领域技术人员将理解,口服和鼻用组合物包含通过吸入施用并使用可用方法制备的组合物。根据所需的具体给药途径,可以使用本领域熟知的多种药物可接受的载体。药物可接受的载体包括,例如,固体或液体填充剂、稀释剂、助溶剂、表面活性剂和包封物质。可以包括任选的药物活性材料,其基本上不干扰化合物的抑制活性。与所述化合物结合使用的载体的量足以为每单位剂量的所述化合物提供用于施用的实际量的材料。用于制备可用于本文所述方法的剂型的技术和组合物描述于以下参考文献中,其全部通过引用并入本文:Modern Pharmaceutics,第4版,第9章和第10章(Banker&Rhodes,editors,2002);Lieberman等人,Pharmaceutical Dosage Forms:Tablets(1989);以及Ansel,Introduction to Pharmaceutical Dosage Forms第8版(2004)。
如本文使用,术语“个体”、“宿主”、“受试者”和“患者”在本文可互换使用,并且是指哺乳动物,包括但不限于人、啮齿动物(例如小鼠和大鼠)以及其它实验动物。
如本文使用,术语“药物可接受的载体”涵盖任何标准药物载体,例如磷酸盐缓冲盐水溶液、水和乳液,例如油/水或水/油乳液,和各种类型的润湿剂。
术语“PEG-脂质”是指用聚乙二醇修饰的脂质。示例性PEG-脂质包括但不限于C14PEG350、C14PEG1000、C14PEG2000、C14PEG3000和C18PEG2000。
术语“寡核苷酸”是指含有相对少量核苷酸的短DNA、RNA或DNA/RNA分子或寡聚物。
A.脂质纳米颗粒
生物活性物质如小分子药物、蛋白质和核酸的有效靶向递送是医学领域的持续挑战。核酸的相对不稳定性和低细胞渗透性使得核酸的特异性递送变得困难。已经发现,如本文所述的具有可电离脂质的脂质纳米颗粒可以更有效地将核酸递送至体内的特定组织。在一个实施方案中,可以通过将核酸与可电离脂质、PEG-脂质、磷脂、胆固醇和任选的核酸混合来配制脂质纳米颗粒。在一些实施方案中,脂质纳米颗粒不包含靶向配体。在一些实施方案中,所公开的脂质纳米颗粒在不存在靶向配体的情况下相对于肝细胞优先靶向T细胞。
脂质纳米颗粒的尺寸是不同的。在一个实施方案中,脂质纳米颗粒可以具有约30至约170nm的平均流体动力学直径。脂质纳米颗粒可以具有约30nm、35nm、40nm、45nm、50nm、55nm、60nm、65nm、70nm、75nm、80nm、85nm、90nm、95nm、100nm、105nm、110nm、115nm、120nm、125nm、130nm、135nm、140nm、145nm、150nm、155nm、160nm、165nm、170nm或具有由上述值中的任两个定义的端点的任何范围的平均流体动力学直径。例如,在实施方案中,纳米颗粒具有50nm至100nm的平均流体动力学直径。
1.化合物
本文所述的一些实施方案涉及式(I)的化合物:
在各种实施方案中,式(I)的化合物是如本文别处所述的可电离脂质。在各种实施方案中,式(I)中的R1为C9-C20烷基或具有1至3个不饱和度的C9-C20烯基。例如,在一些实施方案中,式(I)中的R1为具有2个不饱和度的C9-C20烯基,例如式的C17烯基。
在各种实施方案中,式(I)中的X1和X2各自独立地不存在或选自-O-、-NR2-和其中R2为氢或C1-C6烷基,a为1至6的整数,X7独立地是氢、羟基或-NR6R7,并且R6和R7各自独立地是氢或C1-C6烷基;或者替代地,R6和R7与它们键合的氮连接在一起以形成任选地被1或2个C1-C6烷基取代的4至7元杂环基,其中所述杂环基任选包括选自氧、硫和氮的另外的杂原子。在一些实施方案中,X1不存在,X2不存在,或X1和X2两者都不存在。如本文别处所述,X1-X2-X3-X4彼此不包含任何氧-氧、氧-氮或氮-氮键。因此,X1和X2不能两者均是-O-,也不能两者均是-NR2-。类似地,X1和X2不能分别是-O-和-NR2-,也不能分别是-NR2-和-O-。
在各种实施方案中,X1是-O-。在各种实施方案中,X2是-O-。在一些实施方案中,X1为例如-(CH2)a-、-CH(OH)-或-(CH2)a-1CH(OH)-。在一些实施方案中,X2是例如-(CH2)a-、-CH(OH)-或-(CH2)a-1CH(OH)-。在各种实施方案中,每个a独立地是1、2、3、4、5或6。在各种实施方案中,X1是-NR6R7。在各种实施方案中,X2是-NR6R7。在一些实施方案中,R6是氢或C1-C6烷基。在一些实施方案中,R7是氢或C1-C6烷基。在其它实施方案中,R6和R7与它们键合的氮连接在一起以形成任选地被1或2个C1-C6烷基取代的4至7元杂环基。在一些实施方案中,通过将R6和R7连接在一起形成的4至7元杂环基任选地包含选自氧、硫和氮的另外的杂原子。
在各种实施方案中,式(I)中的X3和X4各自独立地不存在或选自:
(1)任选地被1或2个C1-C6烷基取代的4至8元杂环基;
(2)任选地被1或2个C1-C6烷基取代的5至6元杂芳基;
(3)任选地被1或2个C1-C6烷基取代的5至6元芳基;
(4)任选地被1或2个C1-C6烷基取代的4至7元环烷基;
(5)-O-;或者
(6)-NR3-,其中每个R3独立地是氢原子或C1-C6烷基。
在一些实施方案中,X3不存在,X4不存在,或X3和X4两者都不存在。如本文别处所述,X1-X2-X3-X4彼此不包含任何氧-氧、氧-氮或氮-氮键。因此,X2和X3不能两者均是-O-。当X2是-O-或-NR2-时,则X3不能是-NR3-。类似地,当X3是-O-或-NR3-时,则X2不能是-NR2-。同样地,X3和X4不能两者均是-O-,也不能两者均是-NR3-。类似地,X3和X4不能分别是-O-和-NR3-,也不能分别是-NR3-和-O-。
在各种实施方案中,式(I)中的X3和X4各自独立地是任选地被1或2个C1-C6或C1-C3烷基取代的4至8元杂环基。例如,在各种实施方案中,X3和X4各自独立地是氮杂环丁烷基、甲基氮杂环丁烷基、吡咯烷基、甲基吡咯烷基、哌啶基、甲基哌啶基、哌嗪基、甲基哌嗪基、二甲基哌嗪基、吗啉基、二氮杂环庚烷基、甲基二氮杂环庚烷基、八氢-2H-喹嗪基、氮杂双环[3.2.1]辛基、甲基-氮杂双环[3.2.1]辛基、二氮杂螺[3.5]壬基或甲基二氮杂螺[3.5]壬基。
在各种实施方案中,式(I)中的X3和X4各自独立地是任选地被1或2个C1-C6或C1-C3烷基取代的5至6元杂芳基。例如,在各种实施方案中,X3和X4各自独立地是吡咯基、甲基吡咯基、咪唑基、甲基咪唑基、吡啶基或甲基吡啶基。
在各种实施方案中,式(I)中的X3和X4各自独立地是任选地被1或2个C1-C6或C1-C3烷基取代的5至6元芳基。例如,在各种实施方案中,X3和X4各自独立地是苯基、甲基苯基、萘基或甲基萘基。
在各种实施方案中,式(I)中的X3和X4各自独立地是任选地被1或2个C1-C6或C1-C3烷基取代的4至7元环烷基。例如,在各种实施方案中,X3和X4各自独立地是环戊基、甲基环戊基、环己基或甲基环己基。
在各种实施方案中,式(I)中的X3是-O-。在各种实施方案中,式(I)中的X4是-O-。在各种实施方案中,X3是-NR3-,其中R3是氢原子或C1-C6烷基,例如C1-C3烷基。例如,在各种实施方案中,X3是-N(CH3)-、-N(CH2CH3)-或N(CH2CH2CH3)-。在其它实施方案中,X4是-NR3-,其中R3是氢原子或C1-C6烷基,例如C1-C3烷基。例如,在各种实施方案中,X4是-N(CH3)-、-N(CH2CH3)-或N(CH2CH2CH3)-。
在各种实施方案中,式(I)中的X5是-(CH2)b-,其中b是0至6的整数。在一些实施方案中,b为0,在这种情况下,X5不存在。在其它实施方案中,b为1、2、3、4、5或6。
在各种实施方案中,式(I)中的X6是氢、C1-C6烷基、任选地被1或2个C1-C6烷基取代的5至6元杂芳基或-NR4R5。在一些实施方案中,R4和R5各自独立地是氢或C1-C6烷基。替代地,在其它实施方案中,R4和R5与它们键合的氮连接在一起以形成任选地被1或2个C1-C6烷基取代的4至7元杂环基,其中所述4至7元杂环基任选地包括选自氧、硫和氮的另外的杂原子。
在式(I)的各种实施方案中,X1、X2、X3、X4和X5中的至少一个是存在的。例如,在各种实施方案中,在式(I)中,X1、X2、X3、X4和X5中的至少两个是存在的。在其它实施方案中,在式(I)中,X1、X2、X3、X4和X5中的至少三个是存在的。例如,在一些实施方案中,在式(I)中,X1、X2、X3、X4和X5中的至少四个是存在的。在其它实施方案中,在式(I)中,所有X1、X2、X3、X4和X5是存在的。
在一些实施方案中,X6为氢。在其它实施方案中,X6是C1-C6烷基,例如C1-C3烷基(例如,甲基、乙基或丙基)。在其它实施方案中,X6是任选地被1或2个C1-C6烷基取代的5至6元杂芳基。例如,在各种实施方案中,X6是吡咯基、甲基吡咯基、咪唑基、甲基咪唑基、吡啶基或甲基吡啶基。在其它实施方案中,X6是-NR4R5。例如,在一些实施方案中,X6是-NH2、-NHCH3、-NHCH2CH3、-NHCH2CH2CH3、-N(CH3)2、-N(CH2CH3)2或-N(CH2CH2CH3)2。替代地,在其它实施方案中,R4和R5与它们键合的氮连接在一起以形成4至7元杂环基。4至7元杂环基可以任选地被1或2个C1-C6烷基(例如C1-C3烷基)取代,和/或4至7元杂环基可以任选地包括选自氧、硫和氮的另外的杂原子。例如,在一些实施方案中,X6是氮杂环丁烷基、甲基氮杂环丁烷基、吡咯烷基、甲基吡咯烷基、哌啶基、甲基哌啶基、哌嗪基、甲基哌嗪基、二甲基哌嗪基、吗啉基、二氮杂环庚烷基或甲基二氮杂环庚烷基。
在各种实施方案中,式(I)中的每个X7是氢。在其它实施方案中,每个X7是羟基。在其它实施方案中,每个X7是-NR6R7。对于其中a为2至6的实施方案,每个X7可以相同或不同。例如,在各种实施方案中,X7是(CH2)a-1CH(X7)-,其中a是2、3、4、5或6。在其中X7是-NR6R7的一些实施方案中,R6和R7各自独立地是氢或C1-C6烷基,例如C1-C3烷基。例如,在一些实施方案中,X7是-NH2、-NHCH3、-NHCH2CH3、-NHCH2CH2CH3、-N(CH3)2、-N(CH2CH3)2或-N(CH2CH2CH3)2。替代地,在其中X7是-NR6R7的一些实施方案中,R6和R7与它们键合的氮连接在一起以形成任选地被1或2个C1-C6烷基取代的4至7元杂环基。替代地,在其中X7是-NR6R7的其它实施方案中,R6和R7可以与它们键合的氮连接在一起以形成4至7元杂环基。4至7元杂环基可以任选地被1或2个C1-C6烷基(例如C1-C3烷基)取代,和/或4至7元杂环基可以任选地包括选自氧、硫和氮的另外的杂原子。例如,在一些实施方案中,X6是氮杂环丁烷基、甲基氮杂环丁烷基、吡咯烷基、甲基吡咯烷基、哌啶基、甲基哌啶基、哌嗪基、甲基哌嗪基、二甲基哌嗪基、吗啉基、二氮杂环庚烷基或甲基二氮杂环庚烷基。
在各种实施方案中,式(I)中的A1和A2各自独立地选自:
(1)C5-C12卤代烷基;
(2)C5-C12烯基;
(3)C5-C12炔基;
(4)(C5-C12烷氧基)-(CH2)n2-;
(5)环任选地被一个或两个卤素、C1-C6烷基、C1-C6卤代烷基或C1-C6烷氧基取代的(C5-C10芳基)-(CH2)n3-;以及
(6)环任选地被1或2个C1-C6烷基取代的(C3-C8环烷基)-(CH2)n4-;
或者替代地,A1和A2与它们键合的原子连接在一起以形成被1或2个C4-C10烷基取代的5至6元环状缩醛。
在式(I)的各种实施方案中,n1、n2和n3各自独立地是1至4的整数(即,1、2、3或4),并且n4是0至4的整数(即,0、1、2、3或4)。在各种实施方案中,A1和A2具有相同的化学结构。
在式(I)的各种实施方案中,A1和A2各自独立地是C5-C12卤代烷基。例如,在各种实施方案中,C5-C12卤代烷基是C5-C12氟代烷基,例如C6氟代烷基、C7氟代烷基、C8氟代烷基、C9氟代烷基、C10氟代烷基、C11氟代烷基或C12氟代烷基。连接至C5-C12卤代烷基的卤素原子的数量可以在宽范围内变化,这取决于烷基链的长度和卤化程度。例如,在各种实施方案中,C5-C12卤代烷基含有1至25个卤素原子,例如1、2、3、4、5、6、7、8、9、10或11个卤素原子。在各种实施方案中,C5-C12卤代烷基是包含氟化端基的C5-C12氟代烷基,例如CF3(CF2)n5-,其中n5是0至5的整数。例如,在各种实施方案中,C5-C12氟代烷基是CF3(CF2)n5(CH2)n6-,其中n5是0至5的整数,n6是0至11的整数,并且n5+n6+1等于C5-C12氟代烷基中的碳数。
在式(I)的各种实施方案中,A1和A2各自独立地是C5-C12烯基。烯基双键的位置可以变化。例如,在各种实施方案中,C5-C12烯基是CH3CH2CH=CH(CH2)n7-,其中n7是1至8的整数,例如CH3CH2CH=CH(CH2)4-。在一些实施方案中,C5-C12烯基是支化的,例如(CH3)2C=CH(CH2)n8-CH(CH3)-(CH2)n9-,其中n8和n9各自独立地是1、2或3。
在式(I)的各种实施方案中,A1和A2各自独立地是C5-C12炔基。炔基叁键的位置可以变化。例如,在各种实施方案中,C5-C12炔基是CH3CH2C≡C(CH2)n10-,其中n10是1至8的整数,例如CH3CH2C≡C(CH2)4-。在一些实施方案中,C5-C12炔基是支化的,例如(CH3)2CHC≡C(CH2)n11-CH(CH3)-(CH2)n12-,其中n11和n12各自独立地是1、2或3,并且n11+n12是2至5。
在式(I)的各种实施方案中,A1和A2各自独立地是(C5-C12烷氧基)-(CH2)n2-。在各种实施方案中,每个n2独立地是1至4的整数(即,1、2、3或4)。氧的位置可以变化。例如,在各种实施方案中,(C5-C12烷氧基)-(CH2)n2-是CH3O(CH2)n13-(CH2)n2-,其中n13是1至11的整数,例如CH3O(CH2)7-。在其它实施方案中,(C5-C12烷氧基)-(CH2)n2-是CH3(CH2)n14-O-(CH2)n15-(CH2)n2-,其中n14和n15各自独立地是1至8的整数,并且n14+n15是4至11的整数,例如CH3(CH2)7-O-(CH2)2-(CH2)n2-。在一些实施方案中,C5-C12烷氧基是支化的,例如,CH3O(CH2)n16-CH(CH3)-(CH2)n17--(CH2)n2-,其中n16和n17各自独立地是1、2、3、4或5,并且n16+n17是2至9的整数。
在式(I)的各种实施方案中,A1和A2各自独立地是任选地被一个或两个卤素、C1-C6烷基、C1-C6卤代烷基或C1-C6烷氧基取代的(C5-C10芳基)-(CH2)n3-。在各种实施方案中,每个n3独立地是1至4的整数(即,1、2、3或4)。在一些实施方案中,C5-C10芳基是苯基。例如,在各种实施方案中,(C5-C10芳基)-(CH2)n3-是环任选地被一个或两个卤素、C1-C6烷基、C1-C6卤代烷基或C1-C6烷氧基取代的C6H5-(CH2)n3-。在实施方案中,环任选地被取代的(C5-C10芳基)-(CH2)n3-是CF3-C6H4-(CH2)n3-,例如CF3-C6H4-CH2-或CF3-C6H4-(CH2)2-。在另一个实施方案中,环任选地被取代的(C5-C10芳基)-(CH2)n3-是CH3-(CH2)n18-C6H4-(CH2)n2-,其中n18是1、2或3,并且n2是1、2、3或4,例如CH3(CH2)3-C6H4-CH2-或CH3(CH2)3-C6H4-(CH2)2-。
在式(I)的各种实施方案中,A1和A2各自独立地是环任选地被1或2个C1-C6烷基取代的(C3-C8环烷基)-(CH2)n4-。在各种实施方案中,每个n4独立地是0至4的整数(即,0、1、2、3或4)。在一些实施方案中,C3-C8环烷基是环己基或环戊基。例如,在各种实施方案中,(C3-C8环烷基)-(CH2)n4-是环任选地被1或2个C1-C6烷基取代的C6H11-(CH2)n4-,例如C6H11-(CH2)2-、C6H11-(CH2)3-或CH3-C6H10-(CH2)3-。
替代地,在式(I)的其它实施方案中,A1和A2与它们键合的原子连接在一起以形成被1或2个C4-C10烷基取代的5至6元环状缩醛。例如,在实施方案中,A1和A2与它们键合的原子连接在一起形成6元环状缩醛,所述6元环状缩醛是被2个C8烷基取代的环,如下所示:在另一个实施方案中,A1和A2与它们键合的原子连接在一起以形成5元环状缩醛,所述5元环状缩醛是被2个C8烷基取代的环,如下所示:
2.可电离脂质
在一个实施方案中,公开的脂质纳米颗粒包含可电离脂质。可电离脂质通常包括头部基团上的含胺基团。在各种实施方案中,可电离脂质是式(I)的化合物。在一些实施方案中,基于脂质纳米颗粒的组分的总摩尔数,可电离脂质以35摩尔%、45摩尔%、50摩尔%或65摩尔%存在于脂质纳米颗粒中。在另一个实施方案中,基于脂质纳米颗粒的组分的总摩尔数,可电离脂质以约33mol%至约36mol%存在。在又一个实施方案中,基于脂质纳米颗粒的组分的总摩尔数,可电离脂质以约35mol%存在。
另外的实施方案涉及脂质纳米颗粒组合物,包含:可电离脂质;磷脂;聚乙二醇-脂质;胆固醇;以及任选的核酸。在一些实施方案中,可电离脂质包含根据式(I)、(Ia)、(II)、(IIa)、(IIb)和(IIc)中的任一个的结构。在一些实施方案中,基于脂质纳米颗粒的组分的总摩尔数,可电离脂质的量以约35摩尔%至65摩尔%的范围存在。
3.甾醇
在一些实施方案中,公开的脂质纳米颗粒包含一种或多种甾醇。在一个实施方案中,甾醇是胆固醇、或其变体或衍生物。在一些实施方案中,胆固醇被修饰,例如被氧化。未修饰的胆固醇可以被酶作用以形成侧链或环被氧化的变体。胆固醇可以在β-环结构上或在烃末端结构上被氧化。被认为用于所公开的脂质纳米颗粒的示例性胆固醇包括但不限于25-羟基胆固醇(25-OH)、20α-羟基胆固醇(20α-OH)、27-羟基胆固醇、6-酮-5α-羟基胆固醇、7-酮胆固醇、7β-羟基胆固醇、7α-羟基胆固醇、7β-25-二羟基胆固醇、β-谷甾醇、豆甾醇、菜子甾醇、菜油甾醇或其组合。在一个实施方案中,相对于其它胆固醇变体,侧链氧化的胆固醇可以增强运载物递送。在一个实施方案中,胆固醇是未修饰的胆固醇。
4.PEG-脂质
在一些实施方案中,公开的纳米颗粒组合物还包括一种或多种PEG或PEG-修饰的脂质。此类脂质也可以被称为PEG化脂质或PEG-脂质。包含PEG化脂质可以用于增强脂质纳米颗粒胶体的体外稳定性和体内循环时间。在一些实施方案中,PEG化是可逆的,因此PEG部分在血液循环中逐渐释放。示例性PEG-脂质包括但不限于与长度为C6-C20的饱和或不饱和烃基链缀合的PEG。PEG-修饰的磷脂酰乙醇胺、PEG-修饰的磷脂酸、PEG-修饰的神经酰胺(PEG-CER)、PEG-修饰的二烷基胺、PEG-修饰的二酰基甘油(PEG-DAG)、PEG-修饰的二烷基甘油及其混合物。例如,PEG脂质可以是PEG-c-DOMG、PEG-DMG、PEG-DLPE、PEG-DMPE、PEG-DPPE、PEG-DSG或PEG-DSPE脂质。
5.磷脂
纳米颗粒的磷脂组分可以包括一种或多种磷脂,例如一种或多种(多)不饱和脂质。磷脂可以组装成一个或多个脂质双层。在一些实施方案中,磷脂可以包括磷脂部分和一个或多个脂肪酸部分。
在一些实施方案中,磷脂部分包括但不限于磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰甘油、磷脂酰丝氨酸、磷脂酸、2-溶血磷脂酰胆碱和鞘磷脂。在一些实施方案中,脂肪酸部分包括但不限于月桂酸、肉豆蔻酸、肉豆蔻油酸、棕榈酸、棕榈油酸、硬脂酸、油酸、亚油酸、α-亚麻酸、芥酸、植烷酸、花生酸、花生四烯酸、二十碳五烯酸、二十二烷酸、二十二碳五烯酸和二十二碳六烯酸。也考虑了包括具有包括支化、氧化、环化和炔烃在内的修饰和取代的天然物质的非天然物质。例如,磷脂可以用一个或多个炔烃(例如,烯基基团中的一个或多个双键被叁键替代)官能化或交联。在合适的反应条件下,炔烃基团在暴露于叠氮化物时可以经历铜催化的环加成。此类反应可用于功能化纳米颗粒组合物的脂质双层以促进膜渗透或细胞识别,或用于将纳米颗粒组合物缀合至有用的组分如靶向或成像部分(例如,染料)。
示例性磷脂包括但不限于1,2-二硬脂酰基-sn-甘油基-3-磷酸胆碱(DSPC)、1,2-二油酰基-sn-甘油基-3-磷酸乙醇胺(DOPE)、1,2-二亚油酰基-sn-甘油基-3-磷酸胆碱(DLPC)、1,2-二肉豆蔻酰基-sn-甘油基-磷酸胆碱(DMPC)、1,2-二油酰基-sn-甘油基-3-磷酸胆碱(DOPC)、1,2-二棕榈酰基-sn-甘油基-3-磷酸胆碱(DPPC)、1,2-二十一酰基-sn-甘油基-磷酸胆碱(DUPC)、l-棕榈酰基-2-油酰基-sn-甘油基-3-磷酸胆碱(POPC)、1,2-二-0-十八烯基-sn-甘油基-3-磷酸胆碱(18:0二醚PC)、1-油酰基-2-胆甾醇基半琥珀酰基-sn-甘油基-3-磷酸胆碱(OChemsPC)、1-十六烷基-sn-甘油基-3-磷酸胆碱(C16 Lyso PC)、1,2-二亚麻酰基-sn-甘油基-3-磷酸胆碱、1,2-二花生四烯酰基-sn-甘油基-3-磷酸胆碱、1,2-二(二十二碳六烯酰基)-sn-甘油基-3-磷酸胆碱、1,2-二植烷酰基-sn-甘油基-3-磷酸乙醇胺(ME16.0PE)、1,2-二硬脂酰基-sn-甘油基-3-磷酸乙醇胺、1,2-二亚油酰基-sn-甘油基-3-磷酸乙醇胺、1,2-二亚麻酰基-sn-甘油基-3-磷酸乙醇胺、1,2-二花生酰基-sn-甘油基-3-磷酸乙醇胺、1,2-二(二十二碳六烯酰基)-sn-甘油基-3-磷酸乙醇胺、1,2-二油酰基-sn-甘油基-3-磷-rac-(1-甘油)钠盐(DOPG)、二棕榈酰基磷脂酰甘油(DPPG)、棕榈酰基油酰基磷脂酰乙醇胺(POPE)、二硬脂酰基-磷脂酰基-乙醇胺(DSPE)、二棕榈酰基磷脂酰乙醇胺(DPPE)、二肉豆蔻酰基磷酸乙醇胺(DMPE)、1-硬脂酰基-2-油酰基-磷脂酰乙醇胺(SOPE)、1-硬脂酰基-2-油酰基-磷脂酰胆碱(SOPC)、鞘磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇、磷脂酸、棕榈酰基油酰基磷脂酰胆碱、溶血磷脂酰胆碱、溶血磷脂酰乙醇胺(LPE)。在优选实施方案中,磷脂是DSPC。在另一个实施方案中,磷脂是DMPC。
E.运载物
在一个实施方案中,公开的脂质纳米颗粒组合物包含用于递送至个体的治疗剂或预防剂。在一些实施方案中,治疗剂或预防剂被脂质纳米颗粒包封。在一个实施方案中,脂质纳米颗粒负载有一种或多种核酸。
代表性核酸包括但不限于脱氧核糖核酸(DNA)、核糖核酸(RNA)RNA、DNA、单链RNA、单链DNA、双链RNA、双链DNA、三链DNA、siRNA、shRNA、sgRNA、mRNA、miRNA和反义DNA。在实施方案中,核酸是siRNA、miRNA、mRNA、表达DNA、反义寡核苷酸或免疫刺激性寡核苷酸。
基于CRISPR(成簇的规律间隔的短回文重复序列)的基因编辑需要两个组分:向导RNA和CRISPR相关的内切核酸酶蛋白(Cas)。向导RNA将Cas核酸酶引导至特定靶DNA序列。然后Cas在该位点的DNA中产生双链断裂。在一个实施方案中,公开的脂质纳米颗粒可用于携带基于CRISPR的基因编辑所需的组分。在一种脂质纳米颗粒中,核酸运载物是向导RNA。在此类实施方案中,第二脂质纳米颗粒可以含有编码RNA引导的内切核酸酶的核酸运载物。两种脂质纳米颗粒可以一起施用。示例性RNA引导的内切核酸酶包括但不限于Cas9、CasX、CasY、Cas13或Cpf1。
在一个实施方案中,运载物是siRNA。短干扰RNA(siRNA)是可以诱导序列特异性转录后基因沉默,从而降低或甚至抑制基因表达的双链RNA。在一个实施例中,siRNA触发在siRNA与靶RNA两者之间的序列同一性区域内的同源RNA分子如mRNA的特异性降解。例如,WO02/44321公开了当与3'悬垂端碱基配对时能够序列特异性降解靶mRNA的siRNA,制备这些siRNA的方法通过引用并入本文。序列特异性基因沉默可以在哺乳动物细胞中使用模拟由酶dicer产生的siRNA的合成的、短的双链RNA来实现(Elbashir等人,(2001)Nature,411:494 498)(Ui-Tei等人,(2000)FEBS Lett 479:79-82)。
在一个实施方案中,运载物是信使RNA(mRNA)。信使RNA是单链RNA,一旦运载物到达细胞质,其可以使用细胞蛋白合成机制被翻译成其编码的蛋白质。mRNA的翻译和稳定性可以受到负责募集RNA结合蛋白和微小RNA的5'和3'UTR的修饰的影响,其可以均对翻译活性具有影响(Sahin等人,(2014)Nat Rev Drug Disco 13:759-580)(Kariko等人,(2008)Mol Ther 11:1833-1840)。
在一个实施方案中,脂质纳米颗粒含有少于1.0mg/kg的抑制性核酸。纳米颗粒可以含有1.0mg/kg、0.9mg/kg、0.8mg/kg、0.7mg/kg、0.6mg/kg或0.5mg/kg的抑制性核酸。在另一个实施方案中,脂质纳米颗粒含有0.5mg/kg的抑制性核酸。这是优于现有技术的优点,在现有技术中,纳米颗粒需要高剂量的核酸(>1mg/kg)来实现基因沉默,该剂量未被批准用于人类递送。公开的技术可以在不包含靶向配体的脂质纳米颗粒中使用0.5mg/kg的抑制性核酸实现基因沉默。
在一些实施方案中,核酸,包括但不限于寡核苷酸,被修饰或包括一个或多个修饰的核苷酸以增加稳定性、半衰期和/或核酸酶稳定性。为了限制核酸酶敏感性,天然磷酸二酯寡脱氧核糖核苷酸、天然磷酸二酯寡核糖核苷酸、核糖核苷酸聚合物和脱氧核糖核苷酸聚合物可以包括一种或多种不同的修饰。示例性修饰包括但不限于硫代磷酸酯(PS)键、2"-O-甲基(2'OMe)、2'氟碱基、反向dT和ddT、寡核苷酸的3'端的磷酸化、锁核酸,并且包括亚磷酰胺C3间隔基。
硫代磷酸酯键在寡核苷酸的磷酸骨架中用硫原子代替非桥接氧。约50%的时间(由于可形成的2种所得立体异构体),PS修饰使核苷酸间连接基更耐核酸酶降解。在一些实施方案中,核酸包括一个或多个PS键,例如在5'和3'寡核苷酸末端的至少3个PS键以抑制外切核酸酶降解。一些核酸包括遍及整个寡核苷酸的PS键以帮助减少内切核酸酶的攻击。
在tRNA和其它小RNA中发现了RNA、2'OMe的天然存在的转录后修饰。在一些实施方案中,直接合成核酸或寡核苷酸以含有2'OMe。这种修饰增加了RNA:RNA双链体的Tm,但仅导致RNA:DNA稳定性的微小变化。它防止单链核酸内切酶攻击,但不防止核酸外切酶消化。在一些实施方案中,这些核酸或寡核苷酸也被末端封闭。包括这种修饰的DNA寡核苷酸通常比未修饰的DNA对于DNases的敏感性低5至10倍。2'OMe修饰通常用于反义寡核苷酸作为增加稳定性和与靶转录物的结合亲和力的手段。
2'-氟碱基具有氟修饰的核糖,其增加结合亲和力(Tm),并且与天然RNA相比还赋予一些相对核酸酶抗性。在一些实施方案中,核酸或寡核苷酸包括与PS-修饰的键结合的2'氟碱基。
可以在寡核苷酸的3'端掺入反向dT,形成3'-3'键,其将抑制3'外切核酸酶的降解和DNA聚合酶的延伸。此外,在寡核苷酸的5'末端放置反向2',3'双脱氧-dT碱基(5'反向ddT)防止假连接,并可以防止一些形式的酶降解。
一些实施方案提供了包括亚磷酰胺C3间隔基的核酸或寡核苷酸。亚磷酰胺C3间隔基可以在内部引入,或者在寡聚物的任一端引入用于连接荧光团或其它侧基的长亲水间隔基臂。C3间隔基也可用于抑制3'外切核酸酶的降解。
在一些实施方案中,核酸或寡核苷酸包括锁核酸。锁核酸包括修饰的RNA核苷酸,其中核糖的2'-O和4'-C原子通过亚甲基桥连接。这种附加的桥限制了通常与环相关的灵活性,基本上将结构锁定为刚性结构。可以将LNA插入RNA和DNA寡核苷酸中。
可通过所公开的纳米颗粒递送的其它类型的运载物包括但不限于化疗剂、细胞毒性剂、放射性离子、小分子、蛋白质、多核苷酸和核酸。
代表性化疗剂包括但不限于安吖啶、博来霉素、白消安、卡培他滨、卡铂、卡莫司汀、苯丁酸氮芥、顺铂、克拉屈滨、氯法拉滨、克瑞他酶、环磷酰胺、阿糖胞苷、达卡巴嗪、放线菌素、柔红霉素、多西他赛。多柔比星、表柔比星、依托泊苷、氟达拉滨、氟尿嘧啶、吉西他滨、羟基脲、伊达比星、异环磷酰胺、伊立替康、亚叶酸、脂质体多柔比星、脂质体柔红霉素、洛莫司汀、美法仑、巯嘌呤、美司钠、氨甲蝶呤、丝裂霉素、米托蒽醌、奥沙利铂、紫杉醇、培美曲塞、喷司他丁、丙卡巴肼、雷替曲塞、沙拉铂、链脲菌素、替加氟尿嘧啶、替莫唑胺、替尼泊苷、塞替派、噻鸟嘌呤、托泊替康、曲索丹、长春碱、长春新碱、长春地辛、长春瑞滨或其组合。代表性的促凋亡剂包括但不限于氟达拉滨牛磺菌素、放线菌素D、乳糖神经酰胺、15d-PGJ(2)及其组合。
一些实施方案涉及将核酸递送至有需要的个体的方法,包括向所述个体施用如本文所述的脂质纳米颗粒组合物。在一些实施方案中,核酸是siRNA、miRNA、mRNA、表达DNA、反义寡核苷酸或免疫刺激性寡核苷酸。
B.示例性脂质纳米颗粒制剂
在一个实施方案中,脂质纳米颗粒制剂包含约30mol%至约70mol%的可电离脂质、约5mol%至约25mol%的磷脂、约25mol%至约45mol%的胆固醇和约0mol%至约5mol%的PEG-脂质。在另一个实施方案中,脂质纳米颗粒制剂包含约45mol%的可电离脂质、约9mol%的磷脂、约44mol%的胆固醇和约2mol%的PEG-脂质。在另一个实施方案中,脂质纳米颗粒制剂包含约50mol%的可电离脂质、约9mol%的磷脂、约38mol%的胆固醇和约3mol%的PEG-脂质。
一个实施方案提供了脂质纳米颗粒制剂,其包含约40mol%至约60mol%的式(I)的可电离脂质、约5mol%至约15mol%的1-2-二硬脂酰基-sn-甘油基-3-磷酸胆碱、约1mol%至约5mol%的C14PEG2000和约30mol%至约47mol%的胆固醇,基于这四种成分的总摩尔数。
另一个实施方案提供了脂质纳米颗粒制剂,其包含50mol%的式(I)的可电离脂质、9mol%的1-2-二硬脂酰基-sn-甘油基-3-磷酸胆碱和3mol%的C14PEG2000、38mol%的胆固醇,基于这四种成分的总摩尔数。
另一个实施方案提供了脂质纳米颗粒制剂,其中(可电离脂质、胆固醇、脂质-PEG和磷脂):mRNA的质量比为约2:1至50:1。
C.药物组合物
提供了包含公开的脂质纳米颗粒的药物组合物。脂质纳米颗粒组合物可以全部或部分配制为药物组合物。药物组合物可以包括一种或多种纳米颗粒组合物。例如,药物组合物可以包括一种或多种纳米颗粒组合物,所述纳米颗粒组合物包括一种或多种不同的治疗和/或预防剂,所述治疗和/或预防剂包括但不限于一种或多种不同类型的核酸或编码不同的试剂。在一些实施方案中,药物组合物包括一种或多种药物可接受的赋形剂或辅助成分,包括但不限于药物可接受的载体。
含有纳米颗粒的药物组合物可配制成通过肠胃外(肌内、腹膜内、静脉内(IV)或皮下注射)、透皮(被动或使用离子电渗或电穿孔)或经粘膜(鼻、阴道、直肠或舌下)给药途径或使用可生物溶蚀的插入物来施用,并且可以配制成适于每种给药途径的剂型。
在一些体内方法中,本文公开的纳米颗粒组合物以治疗有效量施用于个体。如本文使用,术语“有效量”或“治疗有效量”是指足以治疗、抑制或缓解所治疗的病症的一种或多种症状或以其它方式提供所需的药理学和/或生理学作用的剂量。精确剂量将根据多种因素而变化,例如个体依赖性变量(例如,年龄、免疫系统健康等)、疾病和进行的治疗。
对于所公开的纳米颗粒,如进行进一步的研究时,将出现关于在各种患者中治疗各种病症的适当剂量水平的信息,并且考虑接受者的治疗背景、年龄和一般健康状况,普通技术人员将能够确定适当的剂量。所选择的剂量取决于所需的治疗效果、给药途径和所需治疗的持续时间。对于所公开的纳米颗粒,通常每日对哺乳动物施用0.001mg至5mg核酸/kg体重的剂量水平。更具体地,所公开的纳米颗粒的优选剂量为0.01mg/kg至0.25mg/kg。对于所公开的纳米颗粒,通常将0.2mg至100mg的四种组分(可电离脂质、胆固醇、PEG-脂质和磷脂)/kg体重的剂量水平施用于哺乳动物。更具体地,所公开的纳米颗粒的优选剂量是0.05mg/kg至0.5mg/kg四种组分/kg体重。
在某些实施方案中,脂质纳米颗粒组合物例如通过直接注射到待治疗的部位而局部施用。通常,注射引起脂质纳米颗粒组合物的局部浓度增加,其大于通过全身施用可以实现的浓度。脂质纳米颗粒组合物可以与如上所述的基质组合,从而通过降低多肽被动扩散到待治疗部位之外来辅助多肽组合物的局部浓度增加。
1.用于肠胃外给药的制剂
在一些实施方案中,本文公开的纳米颗粒组合物,包括含有脂质纳米颗粒的那些,在水溶液中通过肠胃外注射施用。制剂也可以是悬浮液或乳液的形式。通常,提供包含有效量的脂质纳米颗粒的药物组合物,并且任选地包括药物可接受的稀释剂、防腐剂、增溶剂、乳化剂、佐剂和/或载体。此类组合物任选地包括以下中的一种或多种:稀释剂、无菌水、具有各种缓冲液含量的缓冲盐水(例如Tris-HCl、乙酸盐、磷酸盐)、pH和离子强度;以及添加剂,例如洗涤剂和增溶剂(例如,TWEEN 20(聚山梨醇酯-20)、TWEEN 80(聚山梨醇酯-80))、抗氧化剂(例如,抗坏血酸、焦亚硫酸钠)和防腐剂(例如,硫柳汞、苄醇)和填充物质(例如,乳糖、甘露糖醇)。非水溶剂或媒介物的实例是丙二醇、聚乙二醇、植物油(例如橄榄油和玉米油)、明胶和可注射的有机酯(例如油酸乙酯)。制剂可以在使用前立即冻干和再溶解/再悬浮。制剂可以通过例如通过细菌截留过滤器过滤,通过向组合物中加入杀菌剂,通过照射组合物,或通过加热组合物来灭菌。
2.受控递送聚合物基质
本文公开的脂质纳米颗粒也可以以受控释放制剂的形式施用。可以在植入聚合物装置(棒、圆柱体、膜、盘)或注射(微粒)后,制备用于全身长期释放的受控释放聚合物装置。基质可以是微粒如微球体的形式,其中药剂分散在固体聚合物基质或微胶囊中,其中核具有与聚合物壳不同的材料,并且肽分散或悬浮在核中,其在性质上可以是液体或固体。除非本文具体定义,微粒、微球和微胶囊可互换使用。替代地,可以将聚合物流延成纳米至4厘米的薄板或薄膜,通过研磨或其它标准技术生产的粉末,或甚至凝胶如水凝胶。
不可生物降解的或可生物降解的基质可用于递送脂质纳米颗粒,尽管在一些实施方案中可生物降解的基质是优选的。这些可以是天然的或合成的聚合物,尽管由于降解和释放曲线的更好表征,合成聚合物在一些实施方案中是优选的。基于期望释放的时间段选择聚合物。在一些情况下,线性释放可能是最有用的,尽管在其它情况下脉冲释放或“整体释放”可提供更有效的结果。聚合物可以是水凝胶的形式(通常吸收至多约90重量%的水),并且可以任选地与多价离子或聚合物交联。
基质可以通过溶剂蒸发、喷雾干燥、溶剂萃取和本领域技术人员已知的其它方法形成。可生物溶蚀的微球可以使用为制备用于药物递送的微球而开发的任何方法来制备,例如,如Mathiowitz和Langer,J.Controlled Release,5:13-22(1987);Mathiowitz等人,Reactive Polymers,6:275-283(1987);以及Mathiowitz等人,J.Appl.Polymer Sci.,35:755-774(1988)描述的。
所述装置可以配制用于局部释放以治疗植入或注射区域,其通常递送的剂量远小于用于治疗整个身体的剂量-或全身递送。这些可以植入或皮下注射进入肌肉、脂肪,或吞咽。
D.制造脂质纳米颗粒的方法
制造脂质纳米颗粒的方法在本领域是已知的。在一个实施方案中,所公开的脂质纳米颗粒是使用微流体制造的。对于使用微流体形成脂质纳米颗粒的示例性方法,参见Leung,A.K.K等人,J Phys Chem,116:18440-18450(2012),Chen,D.等人,J Am Chem Soc,134:6947-6951(2012),以及Belliveau,N.M.等人,Molecular Therapy-Nucleic Acids,1:e37(2012)。简而言之,在一种缓冲液中制备运载物,例如寡核苷酸或siRNA。在另一种缓冲液中制备其它脂质纳米颗粒组分(可电离脂质、PEG-脂质、胆固醇和DSPC)。注射泵将这两种溶液引入到微流体装置中。两种溶液在微流体装置内接触以形成包封运载物的脂质纳米颗粒。
在国际专利申请号PCT/US/2018/058171中讨论了筛选公开的脂质纳米颗粒的方法,其通过引用整体并入本文。筛选方法表征了媒介物递送制剂以鉴定具有所需向性的制剂,并且将功能性运载物递送至特定细胞的细胞质。筛选方法使用具有在递送至细胞时可检测到的功能的报道子。检测细胞中报道子的功能表明递送媒介物的制剂将向细胞递送功能性运载物。在每种不同的递送媒介物制剂中包括化学组成标识物,以跟踪对于每种不同的递送媒介物制剂特定的化学组成。在一个实施方案中,化学组成标识物是核酸条形码。核酸条形码的序列与用于配制装载核酸条形码的递送媒介物的化学组分配对,使得当核酸条形码被测序时,递送条形码的递送媒介物的化学组成被标识。代表性报道子包括但不限于siRNA、mRNA、核酸酶蛋白、核酸酶mRNA、小分子、表观遗传修饰剂和表型修饰剂。
E.使用方法
本文公开了使用所公开的脂质纳米颗粒将运载物(例如核酸)递送至特定细胞或器官的方法。在一些实施方案中,纳米颗粒在不存在靶向配体的情况下将治疗剂或预防剂递送至有需要的个体的特定细胞或器官。在另一个实施方案中,所公开的脂质纳米颗粒可用于治疗或预防有需要的个体的疾病。
在一些实施方案中,所公开的纳米颗粒被直接递送至个体。在其它实施方案中,脂质纳米颗粒与细胞离体接触,并且将经处理的细胞施用于个体。细胞可以是自体细胞,例如免疫细胞,包括但不限于T细胞或分化成T细胞的细胞。在一些实施方案中,所公开的脂质纳米颗粒可以用作过继细胞转移的媒介物。
1.向细胞递送运载物的方法
本文提供了将治疗性和/或预防性核酸递送至有需要的个体的方法。
在一些实施方案中,所公开的脂质纳米颗粒组合物靶向特定类型或类别的细胞(例如,其特定器官或系统的细胞)。例如,可以将包含目标治疗剂和/或预防剂的纳米颗粒组合物特异性递送至个体的免疫细胞。示例性免疫细胞包括但不限于CD8+、CD4+或CD8+CD4+细胞。在其它实施方案中,脂质纳米颗粒可以配制成在不存在靶向配体的情况下递送至哺乳动物肝脏肝细胞、肝脏免疫细胞、脾T细胞或肺内皮细胞。对特定类别或类型的细胞的特异性递送表明更高比例的脂质纳米颗粒被递送至目标类型或类别的细胞。在一些实施方案中,特异性递送可以导致每1g靶向终点的组织的治疗剂和/或预防剂的量增加超过2倍、5倍、10倍、15倍或20倍。
2.基因调节方法
本文提供了使用所公开的脂质纳米颗粒进行基因调节的方法。在一个实施方案中,脂质纳米颗粒可以用于降低有需要的个体的靶细胞中的基因表达。脂质纳米颗粒可以在没有靶向配体的情况下将抑制性核酸递送至个体的靶细胞。抑制性核酸可以是siRNA。
另一个实施方案提供了使用所公开的脂质纳米颗粒编辑有需要的个体的细胞中的基因的方法。
在一个实施方案中,靶向基因调节的细胞是免疫细胞。免疫细胞可以是T细胞,例如CD8+T细胞、CD4+T细胞或T调节细胞。用于基因编辑的其它示例性免疫细胞包括但不限于巨噬细胞、树突细胞、B细胞或天然杀伤细胞。在一些实施方案中,靶向基因调节的细胞是肝细胞。
可以靶向的示例性基因包括但不限于T细胞受体、B细胞受体、CTLA4、PD1、FOXO1、FOXO3、AKT、CCR5、CXCR4、LAG3、TIM3、杀伤免疫球蛋白样受体、GITR、BTLA、LFA-4、T4、LFA-1、Bp35、CD27L受体、TNFRSF8、TNFRSF5、CD47、CD52、ICAM-1、LFA-3、L-选择蛋白、Ki-24、MB1、B7、B70、M-CSFR、TNFR-II、IL-7R、OX-40、CD137、CD137L、CD30L、CD40L、FasL、TRAIL、CD257、LIGHT、TRAIL-R1、TRAILR2、TRAIL-R4、TWEAK-R、TNFR、BCMA、B7DC、BTLA、B7-H1、B7-H2、B7-H3、ICOS、VEGFR2、NKG2D、JAG1、GITR、CD4、CCR2、GATA-3、MTORC1、MTORC2、RAPTOR、GATOR、FOXP3、NFAT、IL2R和IL7。可以靶向的其它示例性基因包括但不限于OCT、G6Pase、Mut、PCCA、PCCB和PAH。
可以被T细胞识别并预期靶向的示例性肿瘤相关抗原包括但不限于MAGE1、MAGE3、MAGE6、BAGE、GAGE、NYESO-1、MART1/Melan A、MC1R、GP100、酪氨酸酶、TRP-1、TRP-2、PSA、CEA、Cyp-B、Her2/Neu、hTERT、MUC1、PRAME、WT1、RAS、CDK-4、MUM-1、KRAS、MSLN和β-连环蛋白。
3.待治疗的个体
在一些实施方案中,所治疗的个体是罹患癌症、自身免疫性疾病、感染病、器官移植、器官衰竭、蛋白质缺乏或其组合的哺乳动物。在实施方案中,个体是人。在一些实施方案中,本文所述的方法可引起肝细胞翻译某些蛋白质。在一些实施方案中,本文所述的方法可以用于将一种或多种DNA、mRNA、sgRNA或siRNA递送至肝细胞。
实施例
一般注释:除非另有说明,否则所有反应均在氮气气氛下在烧瓶或小瓶中在磁力搅拌下使用无水级溶剂进行。无水溶剂购自Sigma-Aldrich并原样使用。使用BiotageSelekt或Teledyne-Isco Combiflash Nextgen300+与预填充Biotage Sfar硅胶柱进行快速柱色谱。使用Merck硅胶60板进行薄层色谱,并且使用碘使化合物可视化。使用VarianINOVA 500MHz光谱仪进行核磁共振(NMR)光谱;化学位移以四甲基硅烷高场的δ百万分率(ppm)报告,参考CHCl3在δ=7.26ppm处的残留溶剂峰。使用配备有Waters Acquity UPLCBEH C18柱(1.7μM,2.1mm×50mm)的具有QDa检测器(ESI)的Waters Acquity UPLCH-class Plus进行液相色谱-质谱(LCMS)分析。使用以下一般LCMS方法之一分析化合物。方法A:溶剂A=水+0.1%甲酸,溶剂B=乙腈;从90%A、10%B至5%A、95%B的梯度历时3分钟,然后在95%B保持2分钟,然后回升至10%B历时1分钟;流速=0.5mL/min。方法B:柱-XTERRARP 18(4.6×50mm),5μ,(流动相:初始50%[0.1%HCOOH在水中]和50%[0.1%HCOOH在(70:30)ACN:THF中];然后在2.65分钟内,至2%[0.1%HCOOH在水中]和98%[0.1%HCOOH在(70:30)ACN:THF中],保持该流动相组成直至3.75分钟,最后回到初始条件,即,在4.90分钟内,50%[0.1%HCOOH在水中]和50%[0.1%HCOOH在(70:30)ACN:THF中],保持该流动相组成直至5.10分钟。流速=1.2ml/min
缩写列表
DCM:二氯甲烷
DIPEA:N,N-二异丙基乙胺
DMAP:4-(二甲基氨基)吡啶
DMPC:1,2-二肉豆蔻酰基-sn-甘油基-3-磷酸胆碱
DSPC:1,2-二硬脂酰基-sn-甘油基-3-磷酸胆碱
EDC:N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐
Eq:当量
ESI:电喷雾离子化
LCMS:液相色谱-质谱
LNP:脂质纳米颗粒
NMR:核磁共振
PPTS:对甲苯磺酸吡啶鎓
RT:保留时间
根据图1所示的合成方案制备实施例脂质。
使用实施例1的制备来说明代表性合成程序:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:4,4-双(((Z)-辛-5-烯-1-基)氧基)丁腈(中间体Ia)
以下是一般程序A的代表:向含有对甲苯磺酸吡啶鎓(0.12g,0.48mmol,0.05当量)的小瓶中添加4,4-二乙氧基丁腈(1.5g,9.5mmol,1当量)和顺式-5-辛烯-1-醇(3.7g,29mmol,3当量)。将小瓶盖紧,并且将所得混合物在105℃加热72小时。此后,使混合物冷却至室温。通过快速柱色谱法(100g二氧化硅,在己烷中的0%至100%二氯甲烷,持续20分钟)纯化粗制材料。获得呈无色油状物的4,4-双(((Z)-辛-5-烯-1-基)氧基)丁腈(1.14g,37%)。1H NMR(500MHz,氯仿-d)δ5.43-5.27(m,4H),4.56(t,J=5.3Hz,1H),3.61(dt,J=9.3,6.6Hz,2H),3.44(dt,J=9.3,6.6Hz,2H),2.42(t,J=7.4Hz,2H),2.12-1.91(m,9H),1.66-1.54(m,5H),1.49-1.36(m,4H),0.96(t,J=7.6Hz,6H)。
步骤2:4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酸(中间体IIa)
以下是一般程序B的代表:向含有4,4-双(((Z)-辛-5-烯-1-基)氧基)丁腈(中间体Ia,1.14g,3.54mmol,1当量)的小瓶中添加氢氧化钾(0.60g,10.6mmol,3当量),然后添加乙醇(3.5mL)和水(3.5mL)。将小瓶盖紧,并且将反应混合物加热至110℃持续18小时。此后,使混合物冷却至室温。将混合物用乙酸乙酯(20mL)稀释,并且通过添加1M HCl将pH调节至~5。分离所得的两相混合物,并且将水相用乙酸乙酯(2×20mL)再萃取两次。将有机萃取物合并,经硫酸钠干燥,过滤并浓缩,得到呈粘性白色固体状的4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酸(1.16g,96%产率)。1H NMR(400MHz,氯仿-d)δ5.41-5.24(m,4H),4.45(t,J=5.6Hz,1H),3.51(dt,J=9.0,6.7Hz,2H),3.39(dt,J=9.0,6.7Hz,2H),2.17(t,J=7.6Hz,2H),2.08-1.98(m,8H),1.81(q,J=7.3Hz,2H),1.59-1.52(m,4H),1.44-1.32(m,4H),0.94(t,J=7.5Hz,6H)。
步骤3:(9Z,12Z)-十八碳-9,12-二烯酸3-羟基-2-(羟甲基)丙酯(中间体III)
向三羟甲基甲烷(3.0g,1当量,28mmol)在二氯甲烷(100mL)中的混合物中添加亚油酸(7.9g,1当量,28mmol)、DIPEA(5.5g,7.4mL,1.5当量,42mmol)和DMAP(0.69g,0.2当量,5.7mmol)。最后添加EDC(8.1g,1.5当量,42mmol),并且在23℃下搅拌18小时。此后,将反应混合物浓缩并通过快速柱色谱法(200g二氧化硅,在己烷中的0%至90%乙酸乙酯,持续20分钟)纯化。获得呈无色油状物的(9Z,12Z)-十八碳-9,12-二烯酸3-羟基-2-(羟甲基)丙酯(2.6g,25%)。1H NMR(500MHz,氯仿-d)δ5.43-5.27(m,5H),4.24(d,J=6.3Hz,2H),3.76(ddt,J=21.1,11.1,5.3Hz,4H),2.77(d,J=6.8Hz,2H),2.61-2.55(m,2H),2.36-2.29(m,2H),2.10-1.98(m,6H),1.66-1.58(m,2H),1.41-1.21(m,12H),0.92-0.85(m,3H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯(中间体IVa)。
以下是一般程序C的代表:向4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酸(中间体IIa,591mg,1当量,1.74mmol)在二氯甲烷(10mL)中的混合物中添加(9Z,12Z)-十八碳-9,12-二烯酸3-羟基-2-(羟甲基)丙酯(中间体III,640mg,1当量,1.74mmol)、DIPEA(673mg,904μL,3当量,5.21mmol)和DMAP(42.4mg,0.2当量,347μmol)。最后添加EDC(666mg,2当量,3.47mmol),在23℃下搅拌18小时。此后,将反应混合物浓缩并通过快速柱色谱法(50g二氧化硅,在己烷中的0%至40%乙酸乙酯,经12个柱体积)纯化。获得呈无色油状物的(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯(450mg,38%)。1H NMR(500MHz,氯仿-d)δ5.43-5.27(m,8H),4.49(t,J=5.5Hz,1H),4.23-4.12(m,4H),3.65-3.60(m,2H),3.58(dt,J=9.3,6.6Hz,2H),3.41(dt,J=9.3,6.6Hz,2H),2.81-2.73(m,2H),2.41(t,J=7.5Hz,2H),2.32(dd,J=7.9,7.2Hz,2H),2.25-2.15(m,2H),2.12-1.97(m,12H),1.94(ddd,J=8.0,7.2,5.5Hz,2H),1.67-1.53(m,8H),1.45-1.26(m,17H),0.96(t,J=7.6Hz,5H),0.92-0.87(m,3H)。
步骤5:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例1)
以下是一般程序D的代表:向(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯(中间体IVa,100mg,1当量,145μmol)在二氯甲烷(1mL)中的溶液中添加吡啶(22.9mg,23.3μL,2当量,289μmol)、DMAP(4.42mg,0.25当量,36.2μmol)和氯甲酸4-硝基苯酯(58.3mg,2当量,289μmol)。将所得混合物在23℃下搅拌1小时。此后,向其中添加DIPEA(74.8mg,101μL,4当量,579μmol)和3-(二乙基氨基)丙-1-醇(76.0mg,85.9μL,4当量,579μmol)。将所得混合物在23℃下再搅拌18小时。此后,将反应混合物用二氯甲烷(10mL)稀释,用0.75M碳酸钠水溶液(3×10mL)、水(10mL)和饱和氯化钠水溶液(10mL)洗涤。将所得有机层经硫酸钠干燥,浓缩,并将残余物通过快速柱色谱法(10g二氧化硅,0%至25%甲醇在二氯甲烷中,持续12分钟)纯化。获得呈淡黄色油状物的(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(81mg,66%)。1H NMR(500MHz,氯仿-d)δ5.43-5.27(m,8H),4.49(t,J=5.5Hz,1H),4.22-4.11(m,8H),3.57(dt,J=9.3,6.6Hz,2H),3.41(dt,J=9.3,6.6Hz,2H),2.81-2.74(m,2H),2.51(q,J=7.1Hz,6H),2.45-2.36(m,3H),2.31(dd,J=8.0,7.2Hz,2H),2.11-1.97(m,14H),1.92(ddd,J=8.2,7.1,5.5Hz,2H),1.86-1.77(m,2H),1.65-1.53(m,8H),1.49-1.23(m,14H),1.01(t,J=7.1Hz,6H),0.95(t,J=7.5Hz,6H),0.92-0.86(m,3H)。LCMS(方法A):实测值m/z(M+H)=848.7,RT=3.73分钟。
实施例2:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((4-(吡咯烷-1-基)丁酰基)氧基)甲基)丙酯
以下是一般程序E的代表:向(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯(中间体IVa,78mg,1当量,0.11mmol)在二氯甲烷(1mL)中的混合物中添加4-(吡咯烷-1-基)丁酸盐酸盐(26mg,1.2当量,0.14mmol)、DIPEA(73mg,98μL,5当量,0.56mmol)和DMAP(2.8mg,0.2当量,23μmol)。最后添加EDC(43mg,2当量,0.23mmol),在23℃下搅拌18小时。此后,将反应混合物浓缩并通过快速柱色谱法(10g二氧化硅,0%至20%甲醇在DCM中,经12个柱体积)纯化。获得呈无色油状物的(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((4-(吡咯烷-1-基)丁酰基)氧基)甲基)丙酯(74mg,78%)。1HNMR(500MHz,氯仿-d)δ5.42-5.28(m,8H),4.49(t,J=5.6Hz,1H),4.15-4.10(m,6H),3.57(dt,J=9.3,6.6Hz,2H),3.41(dt,J=9.3,6.6Hz,2H),2.77(tdq,J=7.1,1.4,0.8Hz,2H),2.57-2.43(m,6H),2.43-2.35(m,5H),2.30(dd,J=8.0,7.2Hz,2H),2.11-1.97(m,12H),1.92(ddd,J=8.3,7.2,5.6Hz,2H),1.89-1.73(m,6H),1.68-1.52(m,8H),1.48-1.24(m,16H),0.95(t,J=7.6Hz,6H),0.92-0.85(m,3H)。LCMS(方法A):实测值m/z(M+H)=830.7,RT=3.75分钟。
根据一般程序A制备以下中间体Ib-Ih,但改变醇构建单元。
中间体Ib,4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁腈:由rac-香茅醇以9.5mmol规模制备,产量0.87g(24%)。
中间体Ic,4,4-双((4,4,5,5,5-五氟戊基)氧基)丁腈:由4,4,5,5,5-五氟戊-1-醇以9.5mmol规模制备,产量1.8g(45%)。
中间体Id,4,4-双((5,5,6,6,6-五氟己基)氧基)丁腈:由5,5,6,6,6-五氟己-1-醇以9.5mmol规模制备,产量0.70g(16%)。
中间体Ie,4,4-双((4,4,5,5,6,6,7,7,7-九氟庚基)氧基)丁腈:由4,4,5,5,6,6,7,7,7-九氟庚-1-醇以9.5mmol规模制备,产量2.0g(34%)。
中间体If,4,4-双((7,7,8,8,8-五氟辛基)氧基)丁腈:由7,7,8,8,8-五氟辛-1-醇以9.5mmol规模制备,产量1.6g(33%)。1H NMR(500MHz,氯仿-d)δ4.57(t,J=5.3Hz,1H),3.61(dt,J=9.2,6.5Hz,2H),3.45(dt,J=9.3,6.5Hz,2H),2.43(t,J=7.3Hz,2H),2.09-1.91(m,6H),1.65-1.53(m,8H),1.47-1.35(m,8H)。
中间体Ig,4,4-双(4-(三氟甲基)苯乙氧基)丁腈:由(4-三氟甲基苯基)乙醇以9.5mmol规模制备,产量2.2g(52%)。
中间体Ih,4,4-双(3-环己基丙氧基)丁腈:由3-环己基丙-1-醇以9.5mmol规模制备,产量2.3g(68%)。
根据一般程序B由相应的中间体Ib-IIh制备以下中间体IIb-IIh。
中间体IIb,4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酸:由4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁腈(中间体Ib)以2.3mmol规模制备,产量0.88g(97%)。1H NMR(500MHz,氯仿-d)δ5.09(dddd,J=7.1,5.7,2.9,1.4Hz,2H),4.51(t,J=5.5Hz,1H),3.62(dddd,J=16.2,14.0,6.9,1.5Hz,2H),3.45(ddt,J=16.7,9.2,6.7Hz,2H),2.45(t,J=7.3Hz,2H),2.06-1.89(m,6H),1.68(d,J=1.4Hz,6H),1.66-1.52(m,8H),1.42-1.29(m,5H),1.16(dddd,J=13.4,9.8,7.8,5.8Hz,3H),0.89(dd,J=6.6,1.7Hz,6H)。
中间体IIc,4,4-双((4,4,5,5,5-五氟戊基)氧基)丁酸:由4,4-双((4,4,5,5,5-五氟戊基)氧基)丁腈(中间体Ic)以4.3mmol规模制备,产量1.6g(83%)。1H NMR(500MHz,氯仿-d)δ4.55(t,J=5.4Hz,1H),3.65(dt,J=9.5,6.1Hz,2H),3.49(dt,J=9.5,6.1Hz,2H),2.43(t,J=7.2Hz,2H),2.22-2.06(m,4H),1.92-1.82(m,6H)。
中间体IId,4,4-双((5,5,6,6,6-五氟己基)氧基)丁酸:由4,4-双((5,5,6,6,6-五氟己基)氧基)丁腈(中间体Id)以1.6mmol规模制备,产量0.53g(73%)。
中间体IIe,4,4-双((4,4,5,5,6,6,7,7,7-九氟庚基)氧基)丁酸:由4,4-双((4,4,5,5,6,6,7,7,7-九氟庚基)氧基)丁腈(中间体Ie)以3.3mmol规模制备,产量1.9g(91%)。1HNMR(500MHz,氯仿-d)δ4.55(t,J=5.5Hz,1H),3.65(dt,J=9.5,6.1Hz,2H),3.50(dt,J=9.5,6.1Hz,2H),2.43(td,J=7.2,3.5Hz,2H),2.18(tt,J=18.5,7.8Hz,4H),2.02-1.83(m,6H)。
中间体IIf,4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酸:由4,4-双((7,7,8,8,8-五氟辛基)氧基)丁腈(中间体If)以3.1mmol规模制备,产量1.6g(96%)。1H NMR(500MHz,氯仿-d)δ4.50(t,J=5.5Hz,1H),3.57(dt,J=9.4,6.6Hz,2H),3.41(dt,J=9.4,6.6Hz,2H),2.38(t,J=7.5Hz,2H),2.08-1.87(m,6H),1.69-1.51(m,8H),1.41-1.38(m,J=3.5Hz,8H)。
中间体IIg,4,4-双(4-(三氟甲基)苯乙氧基)丁酸:由4,4-双(4-(三氟甲基)苯乙氧基)丁腈(中间体Ig)以5.0mmol规模制备,产量1.7g(74%)。1H NMR(500MHz,氯仿-d)δ7.52(d,J=7.6Hz,4H)7.27(d,J=7.6Hz,4H),4.49(t,J=5.5Hz,1H),3.66(dt,J=9.4,6.6Hz,2H),3.53(dt,J=9.4,6.6Hz,2H),2.84(t,J=6.6Hz,4H),2.31(t,J=7.3Hz,2H),1.88(td,J=7.4,5.6Hz,2H)。
中间体IIh,4,4-双(3-环己基丙氧基)丁酸:由4,4-双(3-环己基丙氧基)丁腈(中间体Ih)以6.5mmol规模制备,产量1.9g(79%)。1H NMR(500MHz,氯仿-d)δ4.50(t,J=5.5Hz,1H),3.55(dt,J=9.3,6.8Hz,2H),3.40(dt,J=9.3,6.8Hz,2H),2.41(t,J=7.3Hz,2H),1.92(td,J=7.4,5.4Hz,2H),1.76-1.49(m,14H),1.33-1.06(m,12H),0.94-0.73(m,4H)。
根据一般程序C由相应的中间体IIb-IIh和中间体III制备以下中间体IVb-IVh。
中间体IVb,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯:由4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酸(中间体IIb)以1.1mmol规模制备,产量0.37g(45%)。1H NMR(500MHz,氯仿-d)δ5.43-5.28(m,4H),5.13-5.06(m,2H),4.49(t,J=5.5Hz,1H),4.23-4.12(m,4H),3.68-3.55(m,4H),3.50-3.38(m,2H),2.80-2.74(m,2H),2.41(t,J=7.5Hz,2H),2.35-2.29(m,2H),2.25-2.15(m,2H),2.10-1.89(m,10H),1.74-1.66(m,6H),1.66-1.51(m,12H),1.44-1.23(m,18H),1.22-1.11(m,2H),0.96-0.84(m,9H)。
中间体IVc,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((4,4,5,5,5-五氟戊基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯:由4,4-双((4,4,5,5,5-五氟戊基)氧基)丁酸(中间体IIc)以1.4mmol规模制备,产量0.40g(37%)。1H NMR(500MHz,氯仿-d)δ5.43-5.28(m,4H),4.53(t,J=5.5Hz,1H),4.23-4.08(m,4H),3.68-3.57(m,4H),3.49(dt,J=9.5,6.0Hz,2H),2.80-2.74(m,2H),2.40(t,J=7.4Hz,2H),2.32(dd,J=7.9,7.2Hz,2H),2.23-2.00(m,11H),1.99-1.81(m,6H),1.68-1.55(m,4H),1.40-1.24(m,11H),0.91-0.86(m,3H)。
中间体IVd,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((5,5,6,6,6-五氟己基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯:由4,4-双((5,5,6,6,6-五氟己基)氧基)丁酸(中间体IId)以1.1mmol规模制备,产量0.20g(23%)。
中间体IVe,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((4,4,5,5,6,6,7,7,7-九氟庚基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯:由4,4-双((4,4,5,5,6,6,7,7,7-九氟庚基)氧基)丁酸(中间体IIe)以1.4mmol规模制备,产量0.50g(37%)。1H NMR(500MHz,氯仿-d)δ5.43-5.28(m,4H),4.54(t,J=5.5Hz,1H),4.24-4.08(m,4H),3.68-3.60(m,4H),3.51(dt,J=9.5,6.1Hz,2H),2.80-2.74(m,2H),2.41(t,J=7.4Hz,2H),2.32(dd,J=8.0,7.2Hz,2H),2.26-2.11(m,5H),2.10-2.01(m,5H),1.99-1.84(m,6H),1.65-1.59(m,2H),1.57(s,2H),1.40-1.23(m,12H),0.92-0.86(m,3H)。
中间体IVf,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯:由4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酸(中间体IIf)以1.1mmol规模制备,产量0.39g(41%)。1H NMR(500MHz,氯仿-d)δ5.43-5.28(m,4H),4.49(t,J=5.5Hz,1H),4.23-4.12(m,4H),3.62(t,J=5.9Hz,2H),3.57(dt,J=9.3,6.5Hz,2H),3.41(dt,J=9.3,6.6Hz,2H),2.81-2.74(m,2H),2.41(t,J=7.5Hz,2H),2.32(dd,J=7.9,7.2Hz,2H),2.24-2.16(m,2H),2.10-1.89(m,12H),1.66-1.57(m,9H),1.46-1.24(m,21H),0.92-0.86(m,3H)。
中间体IVg,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(4-(三氟甲基)苯乙氧基)丁酰基)氧基)-2-(羟甲基)丙酯:由4,4-双(4-(三氟甲基)苯乙氧基)丁酸(中间体IIg)以1.4mmol规模制备,产量0.38g(35%)。1H NMR(500MHz,氯仿-d)δ7.54-7.50(m,4H),7.29-7.26(m,4H),5.43-5.28(m,4H),4.48(t,J=5.5Hz,1H),4.22-4.06(m,5H),3.69-3.62(m,2H),3.60(t,J=5.7Hz,2H),3.57-3.47(m,2H),2.85(t,J=6.7Hz,4H),2.80-2.74(m,2H),2.38-2.23(m,4H),2.23-2.12(m,2H),2.10-2.01(m,4H),1.95-1.85(m,2H),1.65-1.56(m,4H),1.41-1.23(m,11H),0.92-0.86(m,3H)。
中间体IVh,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(3-环己基丙氧基)丁酰基)氧基)-2-(羟甲基)丙酯:由4,4-双(3-环己基丙氧基)丁酸(中间体IIh)以1.4mmol规模制备,产量0.40g(41%)。1H NMR(500MHz,氯仿-d)δ5.43-5.28(m,4H),4.49(t,J=5.5Hz,1H),4.23-4.11(m,4H),3.62(t,J=5.8Hz,2H),3.55(dt,J=9.3,6.8Hz,2H),3.39(dt,J=9.3,6.8Hz,2H),2.77(ttd,J=7.0,1.4,0.7Hz,2H),2.41(t,J=7.5Hz,2H),2.32(dd,J=7.9,7.2Hz,2H),2.25-2.16(m,1H),2.09-2.01(m,4H),1.93(ddd,J=7.9,7.2,5.5Hz,2H),1.74-1.50(m,18H),1.42-1.09(m,25H),0.92-0.83(m,7H)。
根据一般程序D由中间体IVa制备以下实施例3至11。
实施例3,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:由中间体IVa和(1-乙基哌啶-3-基)甲醇以0.15mmol规模制备,产量0.082g(66%)。1H NMR(500MHz,氯仿-d)δ5.43-5.27(m,8H),4.49(t,J=5.6Hz,1H),4.22-4.12(m,6H),4.09-3.93(m,1H),3.57(dt,J=9.3,6.6Hz,2H),3.41(dt,J=9.4,6.6Hz,2H),2.80-2.74(m,2H),2.47-2.36(m,4H),2.31(dd,J=8.0,7.2Hz,2H),2.12-1.96(m,12H),1.96-1.85(m,3H),1.82-1.67(m,3H),1.67-1.51(m,10H),1.48-1.24(m,21H),1.08(t,J=7.2Hz,3H),0.96(t,J=7.6Hz,6H),0.92-0.85(m,3H)。LCMS(方法A):实测值m/z(M+H)=860.6,RT=3.75分钟。
实施例4,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二丙基氨基)丙氧基)羰基)氧基)甲基)丙酯:由中间体IVa和3-(二丙基氨基)丙-1-醇以0.072mmol规模制备,产量0.057g(90%)。LCMS(方法A):实测值m/z(M+H)=876.6,RT=3.76分钟。
实施例5,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((2-(1-甲基吡咯烷-2-基)乙氧基)羰基)氧基)甲基)丙酯:由中间体IVa和2-(1-甲基吡咯烷-2-基)乙-1-醇以0.072mmol规模制备,产量0.042g(69%)。LCMS(方法A):实测值m/z(M+H)=846.7,RT=3.72分钟。
实施例6,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((1-乙基吡咯烷-3-基)甲氧基)羰基)氧基)甲基)丙酯:由中间体IVa和(1-乙基吡咯烷-3-基)甲醇以0.072mmol规模制备,产量0.039g(64%)。LCMS(方法A):实测值m/z(M+H)=846.6,RT=3.72分钟。
实施例7,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)-2-羟基丙氧基)羰基)氧基)甲基)丙酯:由中间体IVa和3-(二乙基氨基)丙烷-1,2-二醇以0.072mmol规模制备,产量0.002g(3%)。LCMS(方法A):实测值m/z(M+H)=864.6,RT=3.66分钟。
实施例8,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二甲基氨基)丙氧基)羰基)氧基)甲基)丙酯:由中间体IVa和3-(二甲基氨基)丙-1-醇以0.077mmol规模制备,产量0.022g(35%)。LCMS(方法A):实测值m/z(M+H)=820.7,RT=3.77分钟。
实施例9,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-(吡咯烷-1-基)丙氧基)羰基)氧基)甲基)丙酯:由中间体IVa和3-(吡咯烷-1-基)丙-1-醇以0.077mmol规模制备,产量0.027g(41%)。LCMS(方法A):实测值m/z(M+H)=846.7,RT=3.76分钟。
实施例10,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((2-(1-甲基哌啶-2-基)乙氧基)羰基)氧基)甲基)丙酯:由中间体IVa和2-(1-甲基哌啶-2-基)乙-1-醇以0.087mmol规模制备,产量0.039g(52%)。LCMS(方法A):实测值m/z(M+H)=860.6,RT=3.83分钟。
实施例11,(9Z,12Z)-十八碳-9,12-二烯酸3-(((3-(氮杂环丁烷-1-基)丙氧基)羰基)氧基)-2-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)甲基)丙酯:由中间体IVa和3-(氮杂环丁烷-1-基)丙-1-醇以0.087mmol规模制备,产量0.041g(57%)。LCMS(方法A):实测值m/z(M+H)=832.5,RT=3.74分钟。
根据一般程序E由中间体IVa制备以下实施例12和13。
实施例12,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-(4-甲基哌嗪-1-基)丙酰基)氧基)甲基)丙酯:由中间体IVa和3-(4-甲基哌嗪-1-基)丙酸二盐酸盐以0.072mmol规模制备,产量0.056g(91%)。1H NMR(500MHz,氯仿-d)δ5.42-5.27(m,8H),4.49(t,J=5.6Hz,1H),4.21-4.10(m,6H),3.64-3.53(m,2H),3.41(dt,J=9.3,6.6Hz,2H),2.80-2.74(m,2H),2.72-2.65(m,2H),2.62-2.46(m,6H),2.46-2.35(m,7H),2.35-2.23(m,4H),2.12-1.96(m,13H),1.96-1.89(m,2H),1.67-1.52(m,9H),1.48-1.23(m,15H),0.95(t,J=7.6Hz,6H),0.92-0.86(m,3H)。LCMS(方法A):实测值m/z(M+H)=845.6,RT=3.67分钟。
实施例13,1,3-二甲基吡咯烷-3-甲酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((9Z,12Z)-十八碳-9,12-二烯酰基)氧基)甲基)丙酯:由中间体IVa和1,3-二甲基吡咯烷-3-甲酸以0.077mmol规模制备,产量0.007g(11%)。LCMS(方法A):实测值m/z(M+H)=816.6,RT=3.76分钟。
根据一般程序D由中间体IVb制备以下实施例14至22。
实施例14,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯:由中间体IVb和3-(二乙基氨基)丙-1-醇以0.13mmol规模制备,产量0.056g(46%)。1H NMR(500MHz,氯仿-d)δ5.43-5.28(m,4H),5.13-5.06(m,2H),4.48(t,J=5.5Hz,1H),4.22-4.10(m,8H),3.66-3.55(m,2H),3.50-3.38(m,2H),2.80-2.74(m,2H),2.51(q,J=7.1Hz,6H),2.48-2.37(m,3H),2.31(dd,J=8.0,7.2Hz,2H),2.05(dd,J=7.2,1.1Hz,3H),2.02-1.89(m,3H),1.81(p,J=6.7Hz,2H),1.73-1.50(m,23H),1.45-1.23(m,17H),1.22-1.11(m,2H),1.01(t,J=7.1Hz,6H),0.95-0.82(m,9H)。LCMS(方法A):实测值m/z(M+H)=904.8,RT=4.06分钟。
实施例15,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:由中间体IVb和(1-乙基哌啶-3-基)甲醇以0.13mmol规模制备,产量0.070g(57%)。LCMS(方法A):实测值m/z(M+H)=916.7,RT=4.06分钟。
实施例16,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-((((1-乙基吡咯烷-3-基)甲氧基)羰基)氧基)甲基)丙酯:由中间体IVb和(1-乙基吡咯烷-3-基)甲醇以0.08mmol规模制备,产量0.040g(55%)。LCMS(方法A):实测值m/z(M+H)=902.7,RT=4.00分钟。
实施例17,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-((((2-(1-甲基哌啶-3-基)乙氧基)羰基)氧基)甲基)丙酯:由中间体IVb和2-(1-甲基哌啶-3-基)乙-1-醇以0.08mmol规模制备,产量0.038g(52%)。LCMS(方法A):实测值m/z(M+H)=916.8,RT=3.94分钟。
实施例18,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-((((4-吗啉代丁氧基)羰基)氧基)甲基)丙酯:由中间体IVb和4-吗啉代丁-1-醇以0.08mmol规模制备,产量0.039g(52%)。LCMS(方法A):实测值m/z(M+H)=932.6,RT=3.95分钟。
实施例19,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((((1r,4r)-4-吗啉代环己基)氧基)羰基)氧基)甲基)丙酯:由中间体IVb和反式-4-吗啉代环己-1-醇以0.08mmol规模制备,产量0.036g(47%)。LCMS(方法A):实测值m/z(M+H)=958.6,RT=3.95分钟。
实施例20,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((4-(4-甲基哌嗪-1-基)丁氧基)羰基)氧基)甲基)丙酯:由中间体IVb和4-(4-甲基哌嗪-1-基)丁-1-醇以0.08mmol规模制备,产量0.027g(36%)。LCMS(方法A):实测值m/z(M+H)=945.7,RT=3.95分钟。
实施例21,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((((1R,3s,5S)-8-甲基-8-氮杂双环[3.2.1]辛-3-基)氧基)羰基)氧基)甲基)丙酯:由中间体IVb和假托品碱以0.08mmol规模制备,产量0.019g(26%)。LCMS(方法A):实测值m/z(M+H)=914.6,RT=3.88分钟。
实施例22,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-((((2-((二甲基氨基)甲基)苄基)氧基)羰基)氧基)甲基)丙酯:由中间体IVb和(2-((二甲基氨基)甲基)苯基)甲醇以0.08mmol规模制备,产量0.030g(40%)。LCMS(方法A):实测值m/z(M+H)=938.8,RT=4.28分钟。
根据一般程序E由中间体IVb制备以下实施例23至30。
实施例23,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((4-(吡咯烷-1-基)丁酰基)氧基)甲基)丙酯:由中间体IVb和4-(吡咯烷-1-基)丁酸盐酸盐以0.09mmol规模制备,产量0.052g(64%)。LCMS(方法A):实测值m/z(M+H)=886.7,RT=3.98分钟。
实施例24,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((3-(4-甲基哌嗪-1-基)丙酰基)氧基)甲基)丙酯:由中间体IVb和3-(4-甲基哌嗪-1-基)丙酸二盐酸盐以0.09mmol规模制备,产量0.060g(72%)。LCMS(方法A):实测值m/z(M+H)=901.8,RT=4.08分钟。
实施例25,1'-乙基-[1,4'-联哌啶]-4-甲酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-((((9Z,12Z)-十八碳-9,12-二烯酰基)氧基)甲基)丙酯:由中间体IVb和1'-乙基-[1,4'-联哌啶]-4-甲酸二盐酸盐以0.08mmol规模制备,产量0.021g(27%)。LCMS(方法A):实测值m/z(M+H)=969.8,RT=3.60分钟。
实施例26,1-(吡啶-4-基)哌啶-4-甲酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((9Z,12Z)-十八碳-9,12-二烯酰基)氧基)甲基)丙酯:由中间体IVb和1-(吡啶-4-基)哌啶-4-甲酸以0.08mmol规模制备,产量0.020g(27%)。LCMS(方法A):实测值m/z(M+H)=935.5,RT=3.88分钟。
实施例27,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((5-(二甲基氨基)戊酰基)氧基)甲基)丙酯:由中间体IVb和5-(二甲基氨基)戊酸盐酸盐以0.08mmol规模制备,产量0.057g(81%)。LCMS(方法A):实测值m/z(M+H)=874.8,RT=3.95分钟。
实施例28,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((4-(二丙基氨基)丁酰基)氧基)甲基)丙酯:由中间体IVb和4-(二丙基氨基)丁酸盐酸盐以0.08mmol规模制备,产量0.062g(84%)。LCMS(方法A):实测值m/z(M+H)=916.8,RT=4.00分钟。
实施例29,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((5-吗啉代戊酰基)氧基)甲基)丙酯:由中间体IVb和5-吗啉代戊酸盐酸盐以0.08mmol规模制备,产量0.064g(87%)。LCMS(方法A):实测值m/z(M+H)=916.8,RT=3.96分钟。
实施例30,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-((2-(1-甲基哌啶-4-基)乙酰氧基)甲基)丙酯:由中间体IVb和2-(1-甲基哌啶-4-基)乙酸以0.08mmol规模制备,产量0.040g(56%)。LCMS(方法A):实测值m/z(M+H)=886.7,RT=3.96分钟。
根据一般程序D由中间体IVc制备以下实施例31和32。
实施例31,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((4,4,5,5,5-五氟戊基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯:由中间体IVc和3-(二乙基氨基)丙-1-醇以0.13mmol规模制备,产量0.042g(35%)。LCMS(方法A):实测值m/z(M+H)=948.5,RT=3.49分钟。
实施例32,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((4,4,5,5,5-五氟戊基)氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:由中间体IVc和(1-乙基哌啶-3-基)甲醇以0.13mmol规模制备,产量0.050g(41%)。LCMS(方法A):实测值m/z(M+H)=960.6,RT=3.52分钟。
根据一般程序D由中间体IVd制备以下实施例33和34。
实施例33,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((5,5,6,6,6-五氟己基)氧基)丁酰基)氧基)-2-(((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯:由中间体IVd和3-(二乙基氨基)丙-1-醇以0.12mmol规模制备,产量0.044g(37%)。1H NMR(500MHz,氯仿-d)δ5.43-5.29(m,4H),4.50(t,J=5.5Hz,1H),4.22-4.09(m,8H),3.60(dt,J=9.2,5.8Hz,2H),3.44(dt,J=9.3,5.8Hz,2H),2.77(t,J=6.7Hz,2H),2.51(q,J=7.2Hz,6H),2.46-2.37(m,3H),2.31(t,J=7.6Hz,2H),2.13-1.99(m,9H),1.93(td,J=7.5,5.4Hz,2H),1.86-1.76(m,2H),1.73-1.56(m,11H),1.41-1.24(m,12H),1.01(t,J=7.1Hz,6H),0.92-0.83(m,3H)。LCMS(方法A):实测值m/z(M+H)=976.6,RT=3.52分钟。
实施例34,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((5,5,6,6,6-五氟己基)氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:由中间体IVd和(1-乙基哌啶-3-基)甲醇以0.12mmol规模制备,产量0.035g(29%)。1H NMR(500MHz,氯仿-d)δ5.43-5.29(m,4H),4.51(t,J=5.5Hz,1H),4.21-4.11(m,6H),4.05(dd,J=10.6,5.8Hz,1H),3.96(dd,J=10.6,7.2Hz,1H),3.60(dt,J=9.3,5.8Hz,2H),3.44(dt,J=9.3,5.8Hz,2H),2.89(dd,J=35.3,11.1Hz,2H),2.77(t,J=6.7Hz,2H),2.47-2.36(m,5H),2.31(t,J=7.6Hz,2H),2.13-1.83(m,9H),1.78-1.55(m,15H),1.42-1.23(m,17H),1.08(t,J=7.2Hz,3H),0.89(t,J=6.9Hz,3H)。LCMS(方法A):实测值m/z(M+H)=988.4,RT=3.52分钟。
根据一般程序D由中间体IVe制备以下实施例35和36。
实施例35,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((4,4,5,5,6,6,7,7,7-九氟庚基)氧基)丁酰基)氧基)-2-(((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯:由中间体IVe和3-(二乙基氨基)丙-1-醇以0.12mmol规模制备,产量0.050g(36%)。LCMS(方法A):实测值m/z(M+H)=1148.4,RT=3.72分钟。
实施例36,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((4,4,5,5,6,6,7,7,7-九氟庚基)氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:由中间体IVe和(1-乙基哌啶-3-基)甲醇以0.12mmol规模制备,产量0.072g(51%)。LCMS(方法A):实测值m/z(M+H)=1160.4,RT=3.73分钟。
根据一般程序D由中间体IVf制备以下实施例37至45。
实施例37,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯:由中间体IVf和3-(二乙基氨基)丙-1-醇以0.11mmol规模制备,产量0.084g(71%)。1H NMR(500MHz,氯仿-d)δ5.43-5.28(m,4H),4.48(t,J=5.5Hz,1H),4.22-4.10(m,8H),3.57(dt,J=9.3,6.5Hz,2H),3.41(dt,J=9.3,6.5Hz,2H),2.80-2.74(m,2H),2.51(q,J=7.2Hz,6H),2.45-2.36(m,3H),2.31(dd,J=8.0,7.2Hz,2H),2.09-1.88(m,10H),1.86-1.76(m,2H),1.73-1.49(m,12H),1.46-1.23(m,20H),1.01(t,J=7.1Hz,6H),0.92-0.86(m,3H)。LCMS(方法A):实测值m/z(M+H)=1032.5,RT=3.69分钟。
实施例38,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:由中间体IVf和(1-乙基哌啶-3-基)甲醇以0.11mmol规模制备,产量0.081g(68%)。1H NMR(500MHz,氯仿-d)δ5.43-5.28(m,4H),4.49(t,J=5.5Hz,1H),4.19(d,J=6.0Hz,2H),4.17-4.12(m,4H),4.05(dd,J=10.6,5.8Hz,1H),3.96(dd,J=10.7,7.2Hz,1H),3.57(dt,J=9.3,6.6Hz,2H),3.41(dt,J=9.3,6.5Hz,2H),2.90(dd,J=35.1,11.3Hz,2H),2.80-2.74(m,2H),2.47-2.36(m,5H),2.31(dd,J=8.0,7.2Hz,2H),2.11-1.79(m,11H),1.79-1.66(m,3H),1.66-1.49(m,12H),1.49-1.23(m,24H),1.08(t,J=7.2Hz,3H),0.94-0.86(m,2H)。LCMS(方法A):实测值m/z(M+H)=1044.6,RT=3.67分钟。
实施例39,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酰基)氧基)-2-((((1-甲基哌啶-4-基)甲氧基)羰基)氧基)甲基)丙酯:由中间体IVf和(1-甲基哌啶-4-基)甲醇以0.09mmol规模制备,产量0.055g(63%)。LCMS(方法A):实测值m/z(M+H)=1030.5,RT=3.68分钟。
实施例40,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酰基)氧基)-2-(((3-(哌啶-1-基)丙氧基)羰基)氧基)甲基)丙酯:由中间体IVf和3-(哌啶-1-基)丙-1-醇以0.09mmol规模制备,产量0.052g(58%)。LCMS(方法A):实测值m/z(M+H)=1044.5,RT=3.70分钟。
实施例41,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酰基)氧基)-2-((((八氢-2H-喹嗪-1-基)甲氧基)羰基)氧基)甲基)丙酯:由中间体IVf和(八氢-2H-喹嗪-1-基)甲醇以0.09mmol规模制备,产量0.050g(55%)。LCMS(方法A):实测值m/z(M+H)=1070.6,RT=3.65分钟。
实施例42,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酰基)氧基)-2-(((3-(4-甲基哌嗪-1-基)丙氧基)羰基)氧基)甲基)丙酯:由中间体IVf和3-(4-甲基哌嗪-1-基)丙-1-醇以0.09mmol规模制备,产量0.049g(54%)。LCMS(方法A):实测值m/z(M+H)=1059.5,RT=3.66分钟。
实施例43,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酰基)氧基)-2-(((4-(二乙基氨基)丁氧基)羰基)氧基)甲基)丙酯:由中间体IVf和4-(二乙基氨基)丁-1-醇以0.09mmol规模制备,产量0.049g(55%)。LCMS(方法A):实测值m/z(M+H)=1046.5,RT=3.62分钟。
实施例44,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酰基)氧基)-2-(((3-(3-(哌啶-1-基)丙氧基)丙氧基)羰基)氧基)甲基)丙酯:由中间体IVf和3-(3-(哌啶-1-基)丙氧基)丙-1-醇以0.09mmol规模制备,产量0.044g(46%)。LCMS(方法A):实测值m/z(M+H)=1102.5,RT=3.66分钟。
实施例45,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酰基)氧基)-2-((((1,3-二甲基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:由中间体IVf和(1,3-二甲基哌啶-3-基)甲醇以0.06mmol规模制备,产量0.042g(70%)。LCMS(方法A):实测值m/z(M+H)=1044.5,RT=3.68分钟。
实施例46,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酰基)氧基)-2-(((4-(吡咯烷-1-基)丁酰基)氧基)甲基)丙酯:根据一般程序E,由中间体IVf和4-(吡咯烷-1-基)丁酸盐酸盐以0.09mmol规模制备,产量0.079g(91%)。1H NMR(500MHz,氯仿-d)δ5.43-5.28(m,4H),4.51-4.46(m,1H),4.22-4.10(m,6H),3.57(dtd,J=9.3,6.6,1.3Hz,2H),3.41(dt,J=9.3,6.5Hz,2H),2.80-2.74(m,2H),2.55-2.27(m,12H),2.11-1.72(m,15H),1.69-1.52(m,16H),1.47-1.23(m,18H),0.92-0.86(m,3H)。LCMS(方法A):实测值m/z(M+H)=1014.4,RT=3.68分钟。
根据一般程序D由中间体IVg制备以下实施例47和48。
实施例47,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(4-(三氟甲基)苯乙氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯:由中间体IVg和3-(二乙基氨基)丙-1-醇以0.12mmol规模制备,产量0.067g(56%)。LCMS(方法A):实测值m/z(M+H)=972.5,RT=3.58分钟。
实施例48,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(4-(三氟甲基)苯乙氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:由中间体IVg和(1-乙基哌啶-3-基)甲醇以0.12mmol规模制备,产量0.045g(37%)。LCMS(方法A):实测值m/z(M+H)=984.5,RT=3.56分钟。
根据一般程序D由中间体IVh制备以下实施例49和50。
实施例49,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(3-环己基丙氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯:由中间体IVh和3-(二乙基氨基)丙-1-醇以0.14mmol规模制备,产量0.059g(48%)。LCMS(方法A):实测值m/z(M+H)=876.6,RT=4.08分钟。
实施例50,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(3-环己基丙氧基)丁酰基)氧基)-2-(((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:由中间体IVh和(1-乙基哌啶-3-基)甲醇以0.14mmol规模制备,产量0.048g(39%)。LCMS(方法A):实测值m/z(M+H)=888.7,RT=4.04分钟。
根据一般程序E由中间体IVh制备以下实施例51和52。
实施例51,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(3-环己基丙氧基)丁酰基)氧基)-2-(((4-(吡咯烷-1-基)丁酰基)氧基)甲基)丙酯:由中间体IVh和4-(吡咯烷-1-基)丁酸盐酸盐以0.14mmol规模制备,产量0.104g(87%)。LCMS(方法A):实测值m/z(M+H)=858.8,RT=4.06分钟。
实施例52,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(3-环己基丙氧基)丁酰基)氧基)-2-(((3-(4-甲基哌嗪-1-基)丙酰基)氧基)甲基)丙酯:由中间体IVh和3-(4-甲基哌嗪-1-基)丙酸二盐酸盐以0.14mmol规模制备,产量0.074g(61%)。LCMS(方法A):实测值m/z(M+H)=873.7,RT=4.17分钟。
实施例53,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-((((1-乙基吡咯烷-3-基)甲氧基)羰基)氧基)甲基)丙基酯:根据一般程序D,由中间体IVb和(1-乙基吡咯烷-3-基)甲醇以0.08mmol规模制备,产量40mg(55%)。LCMS(方法A):实测值m/z(M+H)=902.7,RT=3.99分钟。
实施例54,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((((1r,4r)-4-吗啉代环己基)氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由中间体IVb和反式-4-吗啉代环己-1-醇以0.08mmol规模制备,产量36mg(47%)。LCMS(方法A):实测值m/z(M+H)=958.6,RT=4.56分钟。
实施例55,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((4-(4-甲基哌嗪-1-基)丁氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由中间体IVb和4-(4-甲基哌嗪-1-基)丁-1-醇以0.08mmol规模制备,产量27mg(36%)。LCMS(方法A):实测值m/z(M+H)=945.7,RT=3.95分钟。
实施例56,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((((1r,3s,5s)-8-甲基-8-氮杂双环[3.2.1]辛-3-基)氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由中间体IVb和伪托品碱以0.08mmol规模制备,产量19mg(26%)。LCMS(方法A):实测值m/z(M+H)=914.8,RT=3.88分钟。
实施例57,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-((((4-吗啉代丁氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由中间体IVb和4-吗啉代丁-1-醇以0.08mmol规模制备,产量39mg(52%)。LCMS(方法A):实测值m/z(M+H)=932.7,RT=4.58分钟。
实施例58,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((2-(1-甲基哌啶-3-基)乙氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由中间体IVb和2-(1-甲基哌啶-3-基)乙-1-醇以0.08mmol规模制备,产量38mg(52%)。LCMS(方法A):实测值m/z(M+H)=916.8,RT=3.94分钟。
实施例59,1'-乙基-[1,4'-联哌啶]-4-甲酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((9Z,12Z)-十八碳-9,12-二烯酰基)氧基)甲基)丙酯:根据一般程序E,由中间体IVb和1'-乙基-[1,4'-联哌啶]-4-甲酸二盐酸盐以0.08mmol规模制备,产量21mg(27%)。LCMS(方法A):实测值m/z(M+H)=969.7,RT=3.41分钟。
实施例60,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((4-(二丙基氨基)丁酰基)氧基)甲基)丙酯:根据一般程序E,由中间体IVb和4-(二丙基氨基)丁酸盐酸盐以0.08mmol规模制备,产量62mg(84%)。LCMS(方法A):实测值m/z(M+H)=916.8,RT=4.00分钟。
实施例61,1-(吡啶-4-基)哌啶-4-甲酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-((((9Z,12Z)-十八碳-9,12-二烯酰基)氧基)甲基)丙酯:根据一般程序E,由中间体IVb和1-(吡啶-4-基)哌啶-4-甲酸盐酸盐以0.08mmol规模制备,产量20mg(27%)。LCMS(方法A):实测值m/z(M+H)=935.7,RT=3.87分钟。
实施例62,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-((2-(1-甲基哌啶-4-基)乙酰氧基)甲基)丙酯:根据一般程序E,由中间体IVb和2-(1-甲基哌啶-4-基)乙酸以0.08mmol规模制备,产量40mg(56%)。LCMS(方法A):实测值m/z(M+H)=886.7,RT=3.95分钟。
实施例63,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((5-吗啉代戊酰基)氧基)甲基)丙酯:根据一般程序E,由中间体IVb和5-吗啉代戊酸盐酸盐以0.08mmol规模制备,产量64mg(87%)。LCMS(方法A):实测值m/z(M+H)=916.9,RT=4.50分钟。
实施例64,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((5-(二甲基氨基)戊酰基)氧基)甲基)丙酯:实施例63,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-(((5-吗啉代戊酰基)氧基)甲基)丙酯:根据一般程序E,从中间体IVb和5-(二甲基氨基)戊酸盐酸盐以0.08mmol规模制备,产量57mg(81%)。LCMS(方法A):实测值m/z(M+H)=874.8,RT=3.95分钟。
实施例65,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((2-(1-甲基哌啶-2-基)乙氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由中间体IVa和2-(1-甲基哌啶-2-基)乙-1-醇以0.087mmol规模制备,产量39mg(52%)。LCMS(方法A):实测值m/z(M+H)=860.7,RT=3.83分钟。
实施例66,(9Z,12Z)-十八碳-9,12-二烯酸3-(((3-(氮杂环丁烷-1-基)丙氧基)羰基)氧基)-2-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)甲基)丙酯:根据一般程序D,由中间体IVa和3-(氮杂环丁烷-1-基)丙-1-醇以0.087mmol规模制备,产量41mg(57%)。LCMS(方法A):实测值m/z(M+H)=832.6,RT=3.74分钟。
实施例67,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((3,7-二甲基辛-6-烯-1-基)氧基)丁酰基)氧基)-2-((((2-((二甲基氨基)甲基)苄基)氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由中间体IVb和(2-((二甲基氨基)甲基)苯基)甲醇以0.087mmol规模制备,产量30mg(40%)。LCMS(方法A):实测值m/z(M+H)=938.7,RT=4.28分钟。
实施例68,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酰基)氧基)-2-((((4-(二乙基氨基)丁氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由中间体IVf和4-(二乙基氨基)丁-1-醇以0.086mmol规模制备,产量49mg(55%)。LCMS(方法A):实测值m/z(M+H)=1046.5,RT=3.63分钟。
实施例69,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酰基)氧基)-2-(((3-(3-(哌啶-1-基)丙氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由中间体IVf和3-(3-(哌啶-1-基)丙氧基)丙-1-醇以0.086mmol规模制备,产量44mg(46%)。LCMS(方法A):实测值m/z(M+H)=1102.5,RT=3.66分钟。
实施例70,1,3-二甲基吡咯烷-3-甲酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((9Z,12Z)-十八碳-9,12-二烯酰基)氧基)甲基)丙酯:根据一般程序E,由中间体IVa和1,3-二甲基吡咯烷-3-甲酸以0.077mmol规模制备,产量7mg(11%)。LCMS(方法A):实测值m/z(M+H)=816.6,RT=3.74分钟。
实施例71,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二甲基氨基)丙氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由中间体IVa和3-(二甲基氨基)丙-1-醇以0.077mmol规模制备,产量22mg(35%)。LCMS(方法A):实测值m/z(M+H)=820.7,RT=3.76分钟。
实施例72,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(吡咯烷-1-基)丙氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由中间体IVa和3-(吡咯烷-1-基)丙-1-醇以0.077mmol规模制备,产量27mg(41%)。LCMS(方法A):实测值m/z(M+H)=846.7,RT=3.73分钟。
实施例73,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酰基)氧基)-2-((((1,3-二甲基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由中间体IVf和(1,3-二甲基哌啶-3-基)甲醇以0.057mmol规模制备,产量42mg(70%)。LCMS(方法A):实测值m/z(M+H)=1044.5,RT=3.69分钟。
实施例74,(9Z,12Z)-十八碳-9,12-二烯酸2-(((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)甲基)-4-(((3-(二乙基氨基)丙氧基)羰基)氧基)丁酯
步骤1:2-(羟甲基)丁烷-1,4-二醇
在氩气气氛下在25℃向乙烷-1,1,2-三甲酸三乙酯(5g,20.3mmol)在叔丁醇(80mL)中的搅拌溶液中添加NaBH4(2.3g,60.9mmol)。将所得悬浮液加热至回流,并且在30分钟内分三份逐滴添加甲醇(3mL)。将所得溶液加热至回流再持续3小时。然后将反应混合物冷却至25℃并且用5N HCl(2.5mL)中和。将沉淀物过滤并将滤液蒸发以得到粗制材料,将其通过组合快速(combiflash)柱色谱法纯化,用10%至15%MeOH/DCM洗脱,得到呈黄色液体状的2-(羟甲基)丁烷-1,4-二醇(1.7g,69%)。1H NMR(400MHz,DMSO-d6):δ1.34-1.46(m,2H),1.49-1.63(m,1H),3.27-3.48(m,6H),4.34(t,J=5.2Hz,2H),4.40(t,J=5.1Hz,1H)。
步骤2:2-(2,2-二甲基-1,3-二氧杂环己烷-5-基)乙-1-醇
在氩气气氛下在25℃向2-(羟甲基)丁烷-1,4-二醇(1.7g,14.1mmol)和2,2-二甲氧基丙烷(4.3mL,35.3mmol)在THF(10mL)中的搅拌溶液中添加对甲苯磺酸一水合物(0.36g,3.1mmol)。将反应混合物在25℃下搅拌16小时。此后,用三乙胺(5mL)中和反应。在减压下去除溶剂,得到粗制材料,将其通过组合快速柱色谱法纯化,用15%乙酸乙酯-己烷洗脱,得到呈淡黄色液体状的2-(2,2-二甲基-1,3-二氧杂环己烷-5-基)乙-1-醇(1.2g,53%)。1H NMR(400MHz,CDCl3):δ1.41(s,6H),1.50-1.60(m,2H),1.88-1.98(m,1H),3.63(dd,J=7.9,11.8Hz,2H),3.70(t,J=6.4Hz,2H),3.93(dd,J=4.5,11.8Hz,2H)。
步骤3:(4-硝基苯基)碳酸2-(2,2-二甲基-1,3-二氧杂环己烷-5-基)乙酯
向2-(2,2-二甲基-1,3-二氧杂环己烷-5-基)乙-1-醇(400mg,2.5mmol)在DCM(10mL)中的溶液中添加吡啶(0.4mL,5.0mmol)、DMAP(30.5mg,0.25mmol),最后添加氯甲酸4-硝基苯酯(604mg,2.9mmol)。使反应在25℃下搅拌7小时。此后,用水(20mL)和DCM(30mL)稀释反应混合物。分离有机层并且用DCM(10mL×2)萃取水层。将合并的有机层用Na2SO4干燥。在减压下去除溶剂,得到粗制材料,将其通过组合快速柱色谱法纯化,用30%乙酸乙酯-己烷洗脱,得到呈无色液体状的(4-硝基苯基)碳酸2-(2,2-二甲基-1,3-二氧杂环己烷-5-基)乙酯(0.302g,37%)。1H NMR(400MHz,CDCl3)δ1.29-1.34(m,6H),1.62(q,J=6.7Hz,2H),1.80(bs,1H),3.54(q,J=8.8Hz,2H),3.83(dd,J=11.4Hz,4.0Hz,2H),4.28(t,J=6.4Hz,2H),7.57(d,J=9.0Hz,2H),8.31(d,J=9.0Hz,2H)。
步骤4:(2-(2,2-二甲基-1,3-二氧杂环己烷-5-基)乙基)碳酸3-(二乙基氨基)丙酯
在25℃下向(4-硝基苯基)碳酸2-(2,2-二甲基-1,3-二氧杂环己烷-5-基)乙酯(150mg,0.46mmol)在5mL DCM中的搅拌溶液中添加DMAP(5.6mg,0.04mmol)和吡啶(0.07mL,0.9mmol)并且搅拌5分钟。然后在25℃下添加3-(二乙基氨基)-1-丙醇(78.7mg,0.6mmol)。将反应物质在25℃下搅拌9小时。通过TLC(5%MeOH-DCM)判断反应完成。将反应混合物用水稀释并用DCM(3×15mL)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥,过滤并在减压下浓缩。将由此获得的粗制材料通过组合快速柱色谱法纯化,用10%MeOH-DCM洗脱,得到呈淡黄色液体状的(2-(2,2-二甲基-1,3-二氧杂环己烷-5-基)乙基)碳酸3-(二乙基氨基)丙酯(98mg,67%)。1H NMR(400MHz,CDCl3)δ1.03(t,J=7.0Hz,3H),1.40(s,3H),1.63(q,J=6.7Hz,1H),1.80-1.87(m,1H),2.54(t,J=7.0Hz,3H),3.58(q,J=8.2Hz,1H),3.91(dd,J=11.8Hz,4.2Hz,1H),4.13(q,J=6.2Hz,2H)。
步骤5:(4-羟基-3-(羟甲基)丁基)碳酸3-(二乙基氨基)丙酯
在25℃下向(2-(2,2-二甲基-1,3-二氧杂环己烷-5-基)乙基)碳酸3-(二乙基氨基)丙酯(92mg,0.3mmol)在MeOH(1mL)中的搅拌溶液中添加1N HCl(0.9mL,0.9mmol)。将反应物质搅拌2小时。通过TLC(5%MeOH-DCM)判断反应完成。将反应混合物浓缩并且与甲苯共沸两次,得到粗产物(4-羟基-3-(羟甲基)丁基)碳酸3-(二乙基氨基)丙酯(120mg),其不经纯化直接用于下一步骤。
步骤6:(9Z,12Z)-十八碳-9,12-二烯酸4-(((3-(二乙基氨基)丙氧基)羰基)氧基)-2-(羟甲基)丁酯
在25℃下向亚油酸(0.08mL,0.26mmol)在3mL DCM中的搅拌溶液中添加EDC(82.9mg,0.43mmol)和DMAP(7.2mg,0.06mmol)并且搅拌5分钟。在25℃添加DIPEA(0.147mL,0.86mmol)和(4-羟基-3-(羟甲基)丁基)碳酸3-(二乙基氨基)丙酯(80mg,0.29mmol)。然后将反应混合物在25℃搅拌16小时。通过粗反应混合物的LCMS判断反应完成。将反应混合物用水(10mL)稀释并且用DCM(15mL×3)萃取。将合并的有机层用盐水(10mL)洗涤,经无水Na2SO4干燥,过滤并且在减压下浓缩。由此获得的粗制材料通过组合快速柱色谱法纯化,用10%MeOH-DCM洗脱,得到呈淡黄色液体状的(9Z,12Z)-十八碳-9,12-二烯酸4-(((3-(二乙基氨基)丙氧基)羰基)氧基)-2-(羟甲基)丁酯(42mg,27%)。1H NMR(400MHz,CDCl3)δ0.87(d,J=6.6Hz,3H),1.00-1.10(m,5H),1.24-1.29(m,20H),1.69-1.83(m,4H),2.02(t,J=6.6Hz,5H),2.30(t,J=7.3Hz,2H),2.50-2.55(m,5H),2.75(d,J=7.3Hz,2H),3.54-3.61(m,2H),4.13-4.23(m,5H),5.34(t,J=4.5Hz,4H)。
步骤7:(9Z,12Z)-十八碳-9,12-二烯酸2-(((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)甲基)-4-(((3-(二乙基氨基)丙氧基)羰基)氧基)丁酯(实施例74):在25℃下向4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酸(中间体IIa)(24.1mg,0.07mmol)在2mL DCM中的搅拌溶液添加EDC(22.3mg,0.12mmol)和DMAP(1.9mg,0.015mmol)并且搅拌5分钟。然后在25℃下添加DIPEA(0.04mL,0.23mmol)和(9Z,12Z)-十八碳-9,12-二烯酸4-(((3-(二乙基氨基)丙氧基)羰基)氧基)-2-(羟甲基)丁酯(42mg,0.08mmol)。将反应混合物在25℃下搅拌6小时。通过粗反应混合物的LCMS判断反应完成。将反应混合物用NaHCO3溶液(5mL)稀释并且用DCM(10mL×3)萃取。将合并的有机层用盐水(10mL)洗涤,经无水Na2SO4干燥,过滤并且在减压下浓缩。通过制备型-HPLC纯化由此获得的粗制材料,得到呈淡黄色液体状的(9Z,12Z)-十八碳-9,12-二烯酸2-(((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)甲基)-4-(((3-(二乙基氨基)丙氧基)羰基)氧基)丁酯(24mg,36%)。LCMS(方法B):实测值m/z(M+H)=867.7,RT=2.04分钟。
实施例75,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-(4-乙基哌嗪-1-基)丙酰基)氧基)甲基)丙酯
步骤1:(9Z,12Z)-十八碳-9,12-二烯酸3-(丙烯酰氧基)-2-(((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)甲基)丙酯(中间体V)
向(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯(中间体IVa)(1.0g,1.4mmol)在DCM(20mL)中的搅拌溶液中添加DMAP(18.0mg,0.1mmol)和DIPEA(0.50mL,2.8mmol)。将所得混合物在冰浴中冷却,然后在10分钟内滴加丙烯酰氯(0.2mL,2.9mmol)。将混合物在室温下搅拌1小时。此后,将反应混合物用DCM(20mL×2)萃取。将合并的有机层用水(20mL×2)和盐水(20mL×2)洗涤,经无水Na2SO4干燥,过滤并且在减压下浓缩。将粗制材料通过组合快速柱色谱法纯化,用10%乙酸乙酯-己烷洗脱,得到呈无色液体状的(9Z,12Z)-十八碳-9,12-二烯酸3-(丙烯酰氧基)-2-(((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)甲基)丙酯(860mg,79%)。1H NMR(400MHz,氯仿-d)δ0.84-0.91(m,3H),0.94(t,J=7.5Hz,6H),1.17-1.47(m,20H),1.53-1.65(m,4H),1.86-1.95(m,2H),1.97-2.09(m,12H),2.30(t,J=7.4Hz,2H),2.34-2.47(m,3H),2.76(t,J=6.4Hz,2H),3.34-3.45(m,2H),3.56(q,J=7.4Hz,2H),4.11-4.18(m,4H),4.22(d,J=6.0Hz,2H),4.47(t,J=5.6Hz,1H),5.22-5.45(m,8H),5.85(d,J=11.3Hz,1H),6.11(dd,J=10.5,17.3Hz,1H),6.36-6.45(m,1H)。
步骤2:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-(4-乙基哌嗪-1-基)丙酰基)氧基)甲基)丙酯(实施例75):以下是一般程序F的代表。将(9Z,12Z)-十八碳-9,12-二烯酸3-(丙酰基氧基)-2-(((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)甲基)丙酯(中间体V)(50mg,0.067mmol,1当量)和1-乙基哌嗪(38mg,0.34mmol,5当量)在没有溶剂的情况下加热至50℃持续16小时。在冷却至室温后,将粗反应混合物通过柱色谱法纯化,用9:1DCM/MeOH洗脱,得到(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-(4-乙基哌嗪-1-基)丙酰基)氧基)甲基)丙酯(26mg,44%)。LCMS(方法B):实测值m/z(M+H)=859.9,RT=1.67分钟。
实施例76,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-(4-乙基-1,4-二氮杂环庚烷-1-基)丙酰基)氧基)甲基)丙酯:根据一般程序F,由中间体V和1-乙基-1,4-二氮杂环庚烷制备,产量16mg(46%)。LCMS(方法B):实测值m/z(M+H)=873.9,RT=1.56分钟。
实施例77,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-(4-(2-甲氧基乙基)哌嗪-1-基)丙酰基)氧基)甲基)丙酯:根据一般程序F,由中间体V和1-(2-甲氧基乙基)哌嗪制备,产量34mg(57%)。LCMS(方法B):实测值m/z(M+H)=889.9,RT=1.69分钟。
实施例78,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-(3,5-二甲基哌嗪-1-基)丙酰基)氧基)甲基)丙酯:根据一般程序F,由中间体V和2,6-二甲基哌嗪制备,产量38mg(65%)。LCMS(方法B):实测值m/z(M+H)=859.9,RT=1.71分钟。
实施例79,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-((2-(二乙基氨基)乙基)(乙基)氨基)丙酰基)氧基)甲基)丙酯:根据一般程序F,由中间体V和N1,N1,N2-三乙基乙烷-1,2-二胺制备,产量24mg(48%)。LCMS(方法B):实测值m/z(M+H)=889.9,RT=2.29分钟。
实施例80,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-((1-异丙基哌啶-4-基)氨基)丙酰基)氧基)甲基)丙酯:根据一般程序F,由中间体V和1-异丙基哌啶-4-胺制备,产量18mg(37%)。LCMS(方法B):实测值m/z(M+H)=887.9,RT=1.34分钟。
实施例81,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-((吡啶-3-基甲基)氨基)丙酰基)氧基)甲基)丙酯:根据一般程序F,由中间体V和吡啶-3-基甲胺制备,产量20mg(43%)。LCMS(方法B):实测值m/z(M+H)=854.0,RT=1.34分钟。
实施例82,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-(甲基(2-(吡啶-2-基)乙基)氨基)丙酰基)氧基)甲基)丙酯:根据一般程序F,由中间体V和N-甲基-2-(吡啶-2-基)乙-1-胺制备,产量34mg(49%)。LCMS(方法B):实测值m/z(M+H)=882.0,RT=1.07分钟。
实施例83,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-(3-(二甲基氨基)吡咯烷-1-基)丙酰基)氧基)甲基)丙酯:根据一般程序F,由中间体V和3-(二甲基氨基)吡咯烷制备,产量27mg(58%)。LCMS(方法B):实测值m/z(M+H)=859.9,RT=1.62分钟。
实施例84,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-((2-(吡咯烷-1-基)乙基)氨基)丙酰基)氧基)甲基)丙酯:根据一般程序F,由中间体V和2-(吡咯烷-1-基)乙-1-胺制备,产量26mg(56%)。LCMS(方法B):实测值m/z(M+H)=859.9,RT=1.34分钟。
实施例85,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-((3-吗啉代丙基)氨基)丙酰基)氧基)甲基)丙酯:根据一般程序F,由中间体V和2-(1-甲基吡咯烷-2-基)乙-1-胺制备,产量17mg(35%)。LCMS(方法B):实测值m/z(M+H)=873.8,RT=2.28分钟。
实施例86,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-((2-(吡啶-4-基)乙基)氨基)丙酰基)氧基)甲基)丙酯:根据一般程序F,由中间体V和2-(吡啶-4-基)乙-1-胺制备,产量18mg(39%)。LCMS(方法B):实测值m/z(M+H)=867.9,RT=1.34分钟。
实施例87,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((3-((2-(1-甲基吡咯烷-2-基)乙基)氨基)丙酰基)氧基)甲基)丙酯:根据一般程序F,由中间体V和2-(吡啶-4-基)乙-1-胺制备,产量26mg(43%)。LCMS(方法B):实测值m/z(M+H)=867.9,RT=1.34分钟。
实施例88,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-3-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:4,4-双(((Z)-壬-3-烯-1-基)氧基)丁腈
根据一般程序A,使用(Z)-壬-3-烯-1-醇制备,产量280mg(41%)。1H NMR(400MHz,氯仿-d):δ0.88(t,J=6.7Hz,6H),1.21-1.41(m,12H),1.94(q,J=7.2Hz,2H),2.03(q,J=7.2Hz,4H),2.32(q,J=7.0Hz,4H),2.41(t,J=7.4Hz,2H),3.39-3.50(m,2H),3.56-3.66(m,2H),4.58(t,J=5.3Hz,1H),5.29-5.40(m,2H),5.41-5.53(m,2H)。
步骤2:4,4-双(((Z)-壬-3-烯-1-基)氧基)丁酸
根据一般程序B,由4,4-双(((Z)-壬-3-烯-1-基)氧基)丁腈制备,产量230mg(78%)。1H NMR(400MHz,DMSO-d6):δ0.85(t,J=6.6Hz,6H),1.13-1.38(m,13H),1.72(q,J=7.1Hz,2H),2.00(q,J=7.0Hz,4H),2.16-2.29(m,5H),3.33-3.42(m,2H),3.43-3.54(m,2H),4.49(t,J=5.6Hz,1H),5.30-5.47(m,4H),12.06(s,1H)。
步骤3:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-3-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由4,4-双(((Z)-壬-3-烯-1-基)氧基)丁酸制备,产量340mg(58%)。1H NMR(400MHz,氯仿-d):δ0.82-0.92(m,9H),1.21-1.40(m,26H),1.61(t,J=7.1Hz,2H),1.88-2.09(m,10H),2.13-2.23(m,2H),2.30(q,J=7.0Hz,6H),2.41(t,J=7.5Hz,2H),2.76(t,J=6.4Hz,2H),3.36-3.47(m,2H),3.52-3.65(m,4H),4.13-4.23(m,4H),4.52(t,J=5.5Hz,1H),5.26-5.51(m,8H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-3-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例88)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-3-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)丙-1-醇制备,产量79mg(83%)。LCMS(方法B):实测值m/z(M+H)=876.9,RT=1.91分钟。
实施例89,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-3-烯-1-基)氧基)丁酰基)氧基)-2-(((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-3-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量50mg(69%)。LCMS(方法B):实测值m/z(M+H)=889.0,RT=1.77分钟。
实施例90,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((4-丁基苄基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:4,4-双((4-丁基苄基)氧基)丁腈
根据一般程序A,使用(4-丁基苯基)甲醇制备,产量1.1g(36%)。1H NMR(400MHz,氯仿-d):δ0.92(t,J=7.3Hz,6H),1.28-1.40(m,4H),1.51-1.65(m,4H),1.97-2.07(m,2H),2.41(t,J=7.4Hz,2H),2.60(t,J=7.7Hz,4H),4.51(d,J=11.5Hz,2H),4.64(d,J=11.5Hz,2H),4.79(t,J=5.3Hz,1H),7.16(d,J=7.9Hz,4H),7.20-7.28(m,4H)。
步骤2:4,4-双((4-丁基苄基)氧基)丁酸
根据一般程序B,由4,4-双((4-丁基苄基)氧基)丁腈制备,产量1.1g(91%)。1HNMR(400MHz,DMSO-d6):δ0.89(t,J=7.3Hz,6H),1.22-1.36(m,4H),1.47-1.60(m,4H),1.87(q,J=7.2Hz,2H),2.27(t,J=7.4Hz,2H),2.56(t,J=7.6Hz,4H),4.45(d,J=11.7Hz,2H),4.56(d,J=11.7Hz,2H),4.72(t,J=5.5Hz,1H),7.15(d,J=7.9Hz,4H),7.22(d,J=7.6Hz,4H),12.09(s,1H)。
步骤3:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((4-丁基苄基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由4,4-双((4-丁基苄基)氧基)丁酸制备,产量400mg(64%)。1HNMR(400MHz,氯仿-d):δ0.83-0.96(m,9H),1.21-1.42(m,17H),1.52-1.66(m,7H),1.99-2.19(m,8H),2.30(t,J=7.6Hz,2H),2.44(t,J=7.4Hz,2H),2.59(t,J=7.7Hz,4H),2.76(t,J=6.4Hz,2H),3.55(t,J=5.7Hz,2H),4.04-4.19(m,4H),4.50(d,J=11.5Hz,2H),4.61(d,J=11.5Hz,2H),4.74(t,J=5.4Hz,1H),5.26-5.42(m,4H),7.15(d,J=7.9Hz,4H),7.22(d,J=7.8Hz,4H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((4-丁基苄基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例90)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((4-丁基苄基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)丙-1-醇制备,得到62mg(83%)。LCMS(方法B):实测值m/z(M+H)=920.9,RT=1.81分钟。
实施例91,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((4-丁基苄基)氧基)丁酰基)氧基)-2-(((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((4-丁基苄基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量50mg,69%。LCMS(方法B):实测值m/z(M+H)=889.0,RT=1.77分钟。
实施例92,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-癸-4-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:4,4-双(((Z)-癸-4-烯-1-基)氧基)丁腈
根据一般程序A,使用(Z)-癸-4-烯-1-醇制备,产量750mg(51%)。1H NMR(400MHz,DMSO-d6):δ0.86(t,J=6.8Hz,6H),1.18-1.37(m,12H),1.48-1.60(m,4H),1.74-1.86(m,2H),1.94-2.10(m,8H),2.46(t,J=7.2Hz,2H),3.33-3.44(m,2H),3.47-3.60(m,2H),4.51(t,J=5.4Hz,1H),5.28-5.42(m,4H)。
步骤2:4,4-双(((Z)-癸-4-烯-1-基)氧基)丁酸
根据一般程序B,由4,4-双(((Z)-癸-4-烯-1-基)氧基)丁腈制备,产量300mg(71%)。1H NMR(400MHz,DMSO-d6):δ0.85(t,J=6.7Hz,6H),1.19-1.36(m,12H),1.53(q,J=6.9Hz,4H),1.73(q,J=7.0Hz,2H),1.91-2.09(m,8H),2.22(t,J=7.5Hz,2H),3.29-3.40(m,2H),3.44-3.55(m,2H),4.45(t,J=5.5Hz,1H),5.27-5.42(m,4H),12.05(s,1H)。
步骤3:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-癸-4-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由4,4-双(((Z)-癸-4-烯-1-基)氧基)丁酸制备,产量270mg(47%)。1H NMR(400MHz,氯仿-d):δ0.83-0.92(m,9H),1.07-1.15(m,2H),1.20-1.41(m,23H),1.47-1.76(m,9H),1.88-2.13(m,10H),2.17-2.23(m,2H),2.31(t,J=7.5Hz,2H),2.41(t,J=7.4Hz,2H),2.76(t,J=6.6Hz,2H),3.35-3.50(m,3H),3.52-3.65(m,4H),3.97-4.06(m,1H),4.10-4.22(m,4H),4.48(t,J=5.4Hz,1H),5.26-5.44(m,8H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-癸-4-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例92)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-癸-4-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)-1-丙醇制备,产量40mg(61%)。LCMS(方法B):实测值m/z(M+H)=905.0,RT=1.90分钟。
实施例93,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-癸-4-烯-1-基)氧基)丁酰基)氧基)-2-(((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-癸-4-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量50mg(68%)。LCMS(方法B):实测值m/z(M+H)=917.0,RT=1.91分钟。
实施例94,(9Z,12Z)-十八碳-9,12-二烯酸3-(((3-(二乙基氨基)丙氧基)羰基)氧基)-2-((3-(5,5-二辛基-1,3-二氧杂环己烷-2-基)丙酰基)氧基)甲基)丙酯
步骤1:3-(5,5-二辛基-1,3-二氧杂环己烷-2-基)丙腈
根据一般程序A,使用2,2-二辛基丙烷-1,3-二醇制备,产量500mg(70%)。1H NMR(400MHz,氯仿-d):δ0.83-0.91(m,6H),0.92-1.02(m,2H),1.05-1.35(m,24H),1.53-1.63(m,2H),1.89-1.99(m,2H),2.47(t,J=7.4Hz,2H),3.37(d,J=11.1Hz,2H),3.76(d,J=11.1Hz,2H),4.55(t,J=4.6Hz,1H)。
步骤2:3-(5,5-二辛基-1,3-二氧杂环己烷-2-基)丙酸
根据一般程序B,由3-(5,5-二辛基-1,3-二氧杂环己烷-2-基)丙腈制备,产量400mg(70%)。1H NMR(400MHz,DMSO-d6):δ0.78-0.97(m,8H),1.02-1.35(m,24H),1.47-1.57(m,2H),1.67-1.76(m,2H),2.26(t,J=7.5Hz,2H),3.33(d,J=10.3Hz,2H),3.67(d,J=10.9Hz,2H),4.44(t,J=4.8Hz,1H),12.05(s,1H)。
步骤3:(9Z,12Z)-十八碳-9,12-二烯酸3-((3-(5-己基-5-辛基-1,3-二氧杂环己烷-2-基)丙酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由3-(5,5-二辛基-1,3-二氧杂环己烷-2-基)丙酸制备,产量80mg(40%)。1H NMR(400MHz,氯仿-d):δ0.79-1.01(m,11H),1.02-1.45(m,38H),1.56-1.65(m,4H),1.89-1.99(m,2H),1.99-2.09(m,4H),2.12-2.26(m,2H),2.31(t,J=7.6Hz,2H),2.47(t,J=7.5Hz,2H),2.76(t,J=6.3Hz,2H),3.34(d,J=11.0Hz,2H),3.60(t,J=6.0Hz,2H),3.74(d,J=11.1Hz,2H),4.17(t,J=7.1Hz,4H),4.42-4.54(m,1H),5.30-5.39(m,4H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-(((3-(二乙基氨基)丙氧基)羰基)氧基)-2-((3-(5,5-二辛基-1,3-二氧杂环己烷-2-基)丙酰基)氧基)甲基)丙酯(实施例94)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((3-(5-己基-5-辛基-1,3-二氧杂环己烷-2-基)丙酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)-1-丙醇制备,产量27mg(73%)。LCMS(方法B):实测值m/z(M+H)=892.9,RT=1.93分钟。
实施例95,(9Z,12Z)-十八碳-9,12-二烯酸3-((3-(5,5-二辛基-1,3-二氧杂环己烷-2-基)丙酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((3-(5-己基-5-辛基-1,3-二氧杂环己烷-2-基)丙酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量27mg(59%)。LCMS(方法B):实测值m/z(M+H)=905.0,RT=1.94分钟。
实施例96,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(2-(辛氧基)乙氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:4,4-双(2-(辛氧基)乙氧基)丁腈
根据一般程序A,使用2-(辛氧基)乙-1-醇制备,产量340mg(21%)。1H NMR(400MHz,氯仿-d):δ0.87(t,J=6.7Hz,6H),1.23-1.37(m,20H),1.53(d,J=7.7Hz,2H),1.58(d,J=7.8Hz,2H),1.93-2.03(m,2H),2.44(t,J=7.4Hz,2H),3.43(t,J=6.8Hz,4H),3.55(t,J=4.8Hz,4H),3.58-3.69(m,2H),3.70-3.80(m,2H),4.70(t,J=5.4Hz,1H)。
步骤2:4,4-双(2-(辛氧基)乙氧基)丁酸
根据一般程序B,由4,4-双(2-(辛氧基)乙氧基)丁腈制备,产量136mg(81%)。1HNMR(400MHz,DMSO-d6):δ0.85(t,J=6.7Hz,6H),1.07-1.36(m,20H),1.47(t,J=6.9Hz,4H),1.68-1.79(m,2H),2.23(t,J=7.5Hz,2H),3.36(t,J=6.5Hz,4H),3.42-3.56(m,6H),3.58-3.63(m,2H),4.55(t,J=5.6Hz,1H),12.04(s,1H)。
步骤3,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(2-(辛氧基)乙氧基)丁酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由4,4-双(2-(辛氧基)乙氧基)丁酸制备,产量147mg(53%)。1HNMR(400MHz,氯仿-d):δ0.83-0.92(m,9H),1.13-1.41(m,37H),1.55-1.65(m,3H),1.92-2.09(m,6H),2.13-2.22(m,1H),2.27-2.36(m,3H),2.42(t,J=7.4Hz,2H),2.76(t,J=6.5Hz,2H),3.43(t,J=6.8Hz,4H),3.55(t,J=4.8Hz,4H),3.56-3.66(m,4H),3.67-3.77(m,2H),4.08-4.23(m,4H),4.64(t,J=5.5Hz,1H),5.28-5.41(m,4H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(2-(辛氧基)乙氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例96)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(2-(辛氧基)乙氧基)丁酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)-1-丙醇制备,产量36mg(62%)。LCMS(方法B):实测值m/z(M+H)=941.0,RT=1.80分钟。
实施例97,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(2-(辛氧基)乙氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(2-(辛氧基)乙氧基)丁酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量27mg(58%)。LCMS(方法B):实测值m/z(M+H)=953.0,RT=1.81分钟。
实施例98,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-壬-2-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:4,4-双(((Z)-壬-2-烯-1-基)氧基)丁腈
根据一般程序A,使用(Z)-壬-2-烯-1-醇制备,产量610mg(38%)。1H NMR(400MHz,氯仿-d)δ0.87(t,J=6.7Hz,6H),1.19-1.41(m,18H),1.97(q,J=7.3Hz,2H),2.05(q,J=7.2Hz,4H),2.42(t,J=7.4Hz,2H),4.04-4.21(m,4H),4.65(t,J=5.3Hz,1H),5.45-5.65(m,4H)。
步骤2:4,4-双(((Z)-壬-2-烯-1-基)氧基)丁酸
根据一般程序B,由4,4-双(((Z)-壬-2-烯-1-基)氧基)丁腈制备,产量550mg,87%。1H NMR(400MHz,DMSO-d6)δ0.85(t,J=6.4Hz,6H),1.09-1.39(m,16H),1.76(q,J=6.9Hz,2H),2.02(q,J=6.8Hz,4H),2.22(t,J=7.4Hz,2H),3.95-4.11(m,4H),4.53(t,J=5.6Hz,1H),5.41-5.57(m,4H),12.06(s,1H)。
步骤3:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-2-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由4,4-双(((Z)-壬-2-烯-1-基)氧基)丁酸制备,产量390mg,71%。1H NMR(400MHz,氯仿-d)δ0.80-0.94(m,9H),1.19-1.40(m,29H),1.56-1.67(m,2H),1.90-2.10(m,10H),2.12-2.27(m,2H),2.31(t,J=7.6Hz,2H),2.41(t,J=7.4Hz,2H),2.76(t,J=6.4Hz,2H),3.60(t,J=5.9Hz,2H),4.01-4.23(m,8H),4.58(t,J=5.5Hz,1H),5.26-5.43(m,4H),5.44-5.62(m,4H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-2-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例98)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-2-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)-1-丙醇制备,产量70mg(71%)。LCMS(方法B):实测值m/z(M+H)=876.9,RT=1.81分钟。
实施例99,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-2-烯-1-基)氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-2-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量45mg(81%)。LCMS(方法B):实测值m/z(M+H)=860.9,RT=1.56分钟。
实施例100,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-己-3-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:4,4-双(((Z)-己-3-烯-1-基)氧基)丁腈
根据一般程序A,使用(Z)-己-3-烯-1-醇制备,产量350mg(51%)。
步骤2:4,4-双(((Z)-己-3-烯-1-基)氧基)丁酸
根据一般程序B,由4,4-双(((Z)-己-3-烯-1-基)氧基)丁腈制备,产量310mg(82%)。1H NMR(400MHz,DMSO-d6)δ0.92(t,J=7.5Hz,6H),1.72(q,J=7.0Hz,2H),1.95-2.07(m,4H),2.17-2.27(m,6H),3.31-3.42(m,2H),3.44-3.55(m,2H),4.49(t,J=5.6Hz,1H),5.27-5.38(m,2H),5.36-5.47(m,2H),12.05(s,1H)。
步骤3:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-己-3-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由4,4-双(((Z)-己-3-烯-1-基)氧基)丁酸制备,产量165mg(37%)。1H NMR(400MHz,氯仿-d)δ0.88(t,J=6.7Hz,3H),0.95(t,J=7.5Hz,6H),1.30(s,16H),1.56-1.66(m,2H),1.88-1.98(m,2H),2.04(q,J=7.2Hz,8H),2.18(t,J=6.8Hz,2H),2.31(t,J=7.3Hz,6H),2.41(t,J=7.5Hz,2H),2.76(t,J=6.4Hz,2H),3.42(q,J=7.4Hz,2H),3.52-3.65(m,4H),4.17(t,J=5.3Hz,4H),4.52(t,J=5.6Hz,1H),5.27-5.41(m,4H),5.41-5.50(m,2H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-己-3-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例100)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-己-3-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)-1-丙醇制备,产量29mg(52%)。LCMS(方法B):实测值m/z(M+H)=792.8,RT=1.49分钟。
实施例101,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-己-3-烯-1-基)氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-己-3-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量29mg(51%)。LCMS(方法B):实测值m/z(M+H)=804.8,RT=1.50分钟。
实施例102,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-庚-3-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:4,4-双(((Z)-庚-3-烯-1-基)氧基)丁腈
根据一般程序A,使用(Z)-庚-3-烯-1-醇制备,产量310mg(41%)。1H NMR(400MHz,氯仿-d)δ0.90(t,J=7.4Hz,6H),1.30-1.44(m,4H),1.89-1.99(m,2H),2.02(q,J=7.3Hz,4H),2.32(q,J=7.0Hz,4H),2.41(t,J=7.4Hz,2H),3.40-3.48(m,2H),3.54-3.66(m,2H),4.58(t,J=5.3Hz,1H),5.31-5.42(m,2H),5.42-5.53(m,2H)。
步骤2:4,4-双(((Z)-庚-3-烯-1-基)氧基)丁酸
根据一般程序B,由4,4-双(((Z)-庚-3-烯-1-基)氧基)丁腈制备,产量320mg(83%)。1H NMR(400MHz,DMSO-d6)δ0.86(t,J=7.3Hz,6H),1.21-1.40(m,4H),1.72(q,J=7.2Hz,2H),1.99(q,J=6.9Hz,4H),2.18-2.28(m,6H),3.31-3.42(m,2H),3.44-3.55(m,2H),4.49(t,J=5.6Hz,1H),5.31-5.47(m,4H),12.05(s,1H)。
步骤3:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-庚-3-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由4,4-双(((Z)-庚-3-烯-1-基)氧基)丁酸制备,产量295mg,45%。1H NMR(400MHz,氯仿-d)δ0.83-0.93(m,9H),1.22-1.44(m,18H),1.57-1.67(m,2H),1.88-2.09(m,10H),2.19(q,J=5.9Hz,2H),2.25-2.35(m,6H),2.41(t,J=7.5Hz,2H),2.76(t,J=6.5Hz,2H),3.36-3.47(m,2H),3.52-3.65(m,4H),4.10-4.23(m,4H),4.52(t,J=5.5Hz,1H),5.26-5.51(m,8H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-庚-3-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例102)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-庚-3-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)-1-丙醇制备,产量40mg(72%)。LCMS(方法B):实测值m/z(M+H)=820.8,RT=1.60分钟。
实施例103,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-庚-3-烯-1-基)氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-己-3-烯-1-基)氧基))丁酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量46mg(83%)。LCMS(方法B):实测值m/z(M+H)=832.8,RT=1.61分钟。
实施例104,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(辛-3-炔-1-基氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:4,4-双(辛-3-炔-1-基氧基)丁腈
根据一般程序A,使用辛-3-炔-1-醇制备,产量410mg(28%)。1HNMR(400MHz,氯仿-d)δ0.89(t,J=7.1Hz,6H),1.31-1.51(m,8H),1.92-2.02(m,2H),2.09-2.19(m,4H),2.38-2.49(m,6H),3.50-3.61(m,2H),3.64-3.74(m,2H),4.67(t,J=5.4Hz,1H)。
步骤2:4,4-双(辛-3-炔-1-基氧基)丁酸
根据一般程序B,由4,4-双(辛-3-炔-1-基氧基)丁腈制备,产量310mg(82%)。1HNMR(400MHz,DMSO-d6)δ0.86(t,J=7.0Hz,6H),1.26-1.45(m,8H),1.74(q,J=7.0Hz,2H),2.07-2.17(m,4H),2.25(t,J=7.5Hz,2H),2.30-2.41(m,4H),3.40-3.51(m,2H),3.52-3.62(m,2H),4.56(t,J=5.7Hz,1H),12.06(s,1H)。
步骤3:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(辛-3-炔-1-基氧基)丁酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由4,4-双(辛-3-炔-1-基氧基)丁酸制备,产量390mg(60%)。1HNMR(400MHz,氯仿-d)δ0.83-0.93(m,9H),1.22-1.51(m,22H),1.57-1.65(m,2H),1.90-2.00(m,2H),2.04(q,J=6.9Hz,4H),2.08-2.23(m,6H),2.31(t,J=7.6Hz,2H),2.36-2.47(m,6H),2.76(t,J=6.4Hz,2H),3.48-3.71(m,6H),4.08-4.23(m,4H),4.60(t,J=5.6Hz,1H),5.26-5.42(m,4H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(辛-3-炔-1-基氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例104)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(辛-3-炔-1-基氧基)丁酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)-1-丙醇制备,产量62mg(67%)。LCMS(方法B):实测值m/z(M+H)=844.9,RT=1.56分钟。
实施例105,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(辛-3-炔-1-基氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-己-3-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量43mg(51%)。LCMS(方法B):实测值m/z(M+H)=856.9,RT=1.57分钟。
实施例106,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-3-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:4,4-双(((Z)-辛-3-烯-1-基)氧基)丁腈
根据一般程序A,使用(Z)-辛-3-烯-1-醇制备,产量100mg(40%)。1H NMR(400MHz,氯仿-d)δ0.79-0.99(m,7H),1.16-1.39(m,9H),1.90-1.98(m,2H),2.03(d,J=6.9Hz,4H),2.32(q,J=7.0Hz,4H),2.41(t,J=7.4Hz,2H),3.39-3.49(m,2H),3.56-3.66(m,2H),4.57(t,J=5.4Hz,1H),5.29-5.40(m,2H),5.41-5.52(m,2H)。
步骤2:4,4-双(((Z)-辛-3-烯-1-基)氧基)丁酸
根据一般程序B,由4,4-双(((Z)-辛-3-烯-1-基)氧基)丁腈制备,产量320mg,83%。1H NMR(400MHz,DMSO-d6)δ0.83-0.89(m,6H),1.18-1.36(m,8H),1.72(q,J=7.0Hz,2H),2.01(q,J=6.7Hz,4H),2.15-2.29(m,6H),3.31-3.42(m,2H),3.44-3.54(m,2H),4.49(t,J=5.5Hz,1H),5.30-5.47(m,4H),12.06(s,1H)。
步骤3:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-3-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由4,4-双(((Z)-辛-3-烯-1-基)氧基)丁酸制备,产量310mg,48%。1H NMR(400MHz,氯仿-d)δ0.84-0.93(m,9H),1.20-1.42(m,25H),1.55-1.69(m,2H),1.89-1.98(m,2H),1.98-2.08(m,7H),2.13-2.22(m,2H),2.31(t,J=7.2Hz,5H),2.41(t,J=7.5Hz,2H),2.76(t,J=6.0Hz,2H),3.42(q,J=7.6Hz,2H),3.52-3.65(m,4H),4.09-4.28(m,4H),4.48-4.56(m,1H),5.27-5.41(m,5H),5.39-5.53(m,2H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-3-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例106)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-3-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)-1-丙醇制备,产量47mg(82%)。LCMS(方法B):实测值m/z(M+H)=848.9,RT=1.72分钟。
实施例107,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-3-烯-1-基)氧基)丁酰基)氧基)-2-(((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-3-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量45mg(81%)。LCMS(方法B):实测值m/z(M+H)=860.9,RT=1.56分钟。
实施例108,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-6-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:4,4-双(((Z)-壬-6-烯-1-基)氧基)丁腈
根据一般程序A,使用(Z)-壬-6-烯-1-醇制备,产量610mg(37%)。1H NMR(400MHz,氯仿-d)δ0.94(t,J=7.5Hz,6H),1.29-1.43(m,8H),1.53-1.63(m,4H),1.89-1.97(m,2H),1.96-2.11(m,8H),2.41(t,J=7.4Hz,2H),3.36-3.47(m,2H),3.53-3.65(m,2H),4.54(t,J=6.9Hz,1H),5.18-5.52(m,4H)。
步骤2:4,4-双(((Z)-壬-6-烯-1-基)氧基)丁酸
根据一般程序B,由4,4-双(((Z)-壬-6-烯-1-基)氧基)丁腈制备,产量280mg,73%。1H NMR(400MHz,DMSO-d6)δ0.91(t,J=7.5Hz,6H),1.21-1.34(m,13H),1.40(t,J=6.7Hz,2H),1.43-1.52(m,2H),1.72(q,J=7.1Hz,1H),1.91-2.07(m,8H),2.21(t,J=7.4Hz,1H),3.32-3.41(m,3H),3.42-3.53(m,1H),4.32(s,1H),5.24-5.39(m,4H)。
步骤3:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-6-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由4,4-双(((Z)-壬-6-烯-1-基)氧基)丁酸制备,产量318mg,49%。1H NMR(400MHz,氯仿-d)δ0.86-0.90(m,4H),0.94(t,J=7.5Hz,9H),1.30-1.41(m,15H),1.56-1.67(m,2H),1.92(q,J=7.3Hz,3H),2.01-2.04(m,5H),2.19(q,J=6.5Hz,3H),2.31(t,J=7.6Hz,3H),2.40(t,J=7.5Hz,3H),2.76(t,J=6.4Hz,3H),3.34-3.44(m,3H),3.50-3.65(m,6H),4.06-4.23(m,7H),4.48(t,J=5.5Hz,2H),5.17-5.50(m,12H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-6-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例108)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-6-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)-1-丙醇制备,产量36mg(69%)。LCMS(方法B):实测值m/z(M+H)=876.9,RT=1.78分钟。
实施例109,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-6-烯-1-基)氧基)丁酰基)氧基)-2-(((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-壬-6-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇,产量37mg(67%)。LCMS(方法B):实测值m/z(M+H)=888.9,RT=1.77分钟。
实施例110,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((8-氟辛基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:4,4-双((8-溴辛基)氧基)丁腈
根据一般程序,使用8-溴辛烷-1-醇制备,产量750mg(33%)。1HNMR(400MHz,氯仿-d)δ1.22-1.41(m,12H),1.37-1.48(m,4H),1.56(t,J=7.3Hz,4H),1.78-1.91(m,4H),1.88-1.98(m,2H),2.41(t,J=7.3Hz,2H),3.33-3.47(m,6H),3.51-3.64(m,2H),4.54(t,J=5.3Hz,1H)。
步骤2:4,4-双((8-氟辛基)氧基)丁腈
将四丁基氟化铵在THF(1M,4.65mL,4.65mmol,3当量)中的溶液添加至4,4-双((8-溴辛基)氧基)丁腈(750mg,1.55mmol)中。将混合物在80℃搅拌24小时。此后,将反应物质倒入冰冷的水中,然后将有机层用乙酸乙酯(30mL×3)萃取。将有机层用盐水(5mL×3)洗涤,然后经硫酸钠干燥。将有机层蒸发以得到粗产物。将粗产物进行柱色谱法(使用乙酸乙酯/己烷),得到呈淡黄色胶状物的4,4-双((8-氟辛基)氧基)丁腈(210mg,37%)。1H NMR(400MHz,氯仿-d)δ1.30-1.45(m,18H),1.56-1.77(m,6H),1.88-1.98(m,2H),2.41(t,J=7.3Hz,2H),3.32-3.47(m,2H),3.54-3.64(m,2H),4.37(t,J=6.2Hz,2H),4.48(t,J=6.1Hz,2H),4.54(t,J=5.3Hz,1H)。
步骤3:4,4-双((8-氟辛基)氧基)丁酸
根据一般程序B,由4,4-双((8-氟辛基)氧基)丁腈制备,产量200mg(92%)。1H NMR(400MHz,DMSO-d6)δ1.21-1.37(m,14H),1.48(t,J=6.6Hz,4H),1.53-1.77(m,6H),2.22(t,J=7.4Hz,2H),3.27-3.40(m,3H),3.43-3.54(m,2H),4.36(t,J=6.1Hz,2H),4.41-4.52(m,3H),12.05(s,1H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((8-氟辛基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由4,4-双((8-氟辛基)氧基)丁酸制备,产量160mg,37%。1H NMR(400MHz,氯仿-d)δ0.88(t,J=6.9Hz,3H),1.21-1.44(m,34H),1.58-1.77(m,6H),1.87-1.97(m,2H),2.04(q,J=6.8Hz,4H),2.13-2.24(m,2H),2.31(t,J=7.6Hz,2H),2.40(t,J=7.5Hz,2H),2.76(t,J=6.4Hz,2H),3.34-3.44(m,2H),3.50-3.65(m,4H),4.10-4.23(m,4H),4.36(t,J=6.1Hz,2H),4.44-4.52(m,3H),5.25-5.44(m,4H)。
步骤5:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((8-氟辛基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例110)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((8-氟辛基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)-1-丙醇制备,产量18mg(21%)。LCMS(方法B):实测值m/z(M+H)=888.9,RT=1.40分钟。
实施例111,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((8-氟辛基)氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((8-氟辛基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量41mg(48%)。LCMS(方法B):实测值m/z(M+H)=900.9,RT=1.41分钟。
实施例112,(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((((Z)-辛-3-烯-1-基)氧基)己酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:2-甲氧基环己-1-酮肟
向2-甲氧基环己-1-酮(5g,39.0mmol)在MeOH-H2O(150ml,1:2)中的搅拌溶液中添加乙酸钠(6.41g,78.1mmol),然后添加盐酸羟胺(5.43g,78.1mmol)。将所得混合物在密封管中在70℃加热16小时。此后,蒸发MeOH,并将混合物用水稀释,用乙酸乙酯(3×50mL)萃取,用盐水洗涤,经硫酸钠干燥,并且在减压下浓缩。将由此获得的粗产物通过快速柱色谱法纯化,用3%乙酸乙酯/己烷洗脱,得到呈无色油状物的2-甲氧基环己-1-酮肟(4.1g,88%)。1H NMR(400MHz,DMSO-d6)δ1.17-1.32(m,1H),1.40-1.56(m,2H),1.59-1.82(m,3H),1.92-1.99(m,1H),2.93-3.01(m,1H),3.11(s,3H),3.63(s,1H),10.61(s,1H)。
步骤2:6,6-二甲氧基己腈
在0℃下向2-甲氧基环己-1-酮肟(2.0g,14.0mmol)在CCl4(20ml)中的搅拌溶液中滴加亚硫酰氯(1.2ml,16.8mmol)并搅拌10分钟。此后,在5-10℃下向反应混合物中添加无水MeOH(20ml)。添加完成后,使反应混合物达到室温并放置2小时。然后将混合物用乙酸乙酯稀释并用盐水洗涤,经硫酸钠干燥并浓缩,得到呈淡黄色油状物的6,6-二甲氧基己腈(1.6g,81%)。1H NMR(400MHz,氯仿-d)δ1.44-1.56(m,2H),1.57-1.75(m,4H),2.34(t,J=7.0Hz,2H),3.31(s,6H),4.34(t,J=5.5Hz,1H)。
步骤3:6,6-双(((Z)-辛-3-烯-1-基)氧基)己腈
根据一般程序A,由6,6-二甲氧基己腈和(Z)-辛-3-烯-1-醇制备,产量280mg(50%)。1H NMR(400MHz,DMSO-d6)δ0.83-0.89(m,6H),1.21-1.32(m,8H),1.31-1.43(m,2H),1.47-1.61(m,4H),2.01(q,J=6.7Hz,4H),2.23(q,J=6.8Hz,4H),2.47(d,J=7.1Hz,2H),3.32-3.42(m,2H),3.44-3.54(m,2H),4.47(t,J=5.6Hz,1H),5.30-5.47(m,4H)。
步骤4:6,6-双(((Z)-辛-3-烯-1-基)氧基)己酸
根据一般程序B,由6,6-二甲氧基己腈制备,产量260mg(80%)。1H NMR(400MHz,DMSO-d6)δ0.86(q,J=3.8,5.1Hz,6H),1.21-1.34(m,10H),1.48(t,J=7.6Hz,4H),2.00(t,J=6.7Hz,4H),2.14-2.27(m,6H),3.30-3.41(m,2H),3.42-3.53(m,2H),4.44(t,J=5.6Hz,1H),5.30-5.46(m,4H),11.97(s,1H)。
步骤5:(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双(((Z)-辛-3-烯-1-基)氧基)己酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由6,6-双(((Z)-辛-3-烯-1-基)氧基)己酸制备,产量70mg(55%)。1H NMR(400MHz,氯仿-d)δ0.83-0.95(m,9H),1.17-1.42(m,25H),1.57-1.70(m,5H),2.04(d,J=7.0Hz,8H),2.18(t,J=6.2Hz,2H),2.31(t,J=6.7Hz,8H),2.76(t,J=6.5Hz,2H),3.41(q,J=7.5Hz,2H),3.50-3.64(m,4H),4.09-4.20(m,4H),4.48(t,J=5.6Hz,1H),5.32-5.37(m,5H),5.33-5.48(m,3H)。
步骤6:(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((((Z)-辛-3-烯-1-基)氧基)己酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例112)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((((Z)-辛-3-烯-1-基)氧基)己酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)-1-丙醇制备,产量37mg(64%)。LCMS(方法B):实测值m/z(M+H)=877.0,RT=1.70分钟。
实施例113,(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-二(((Z)-辛-3-烯-1-基)氧基)己酰基)氧基)-2-(((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-二((Z)-辛-3-烯-1-基))氧基)己酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量89mg(70%)。LCMS(方法B):实测值m/z(M+H)=889.0,RT=1.79分钟。
实施例114,(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((((Z)-己-3-烯-1-基)氧基)己酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:6,6-双(((Z)-己-3-烯-1-基)氧基)己腈
根据一般程序A,由6,6-二甲氧基己腈和(Z)-己-3-烯-1-醇制备,产量190mg,42%。1H NMR(400MHz,氯仿-d)δ0.96(t,J=7.5Hz,6H),1.58-1.74(m,6H),1.99-2.11(m,4H),2.20-2.38(m,6H),3.36-3.47(m,2H),3.52-3.62(m,2H),4.48(t,J=5.5Hz,1H),5.27-5.39(m,2H),5.46(q,J=7.6Hz,2H)。
步骤2:6,6-双(((Z)-己-3-烯-1-基)氧基)己酸
根据一般程序B,由6,6-双(((Z)-己-3-烯-1-基)氧基)己腈制备,产量170mg,82%。1H NMR(400MHz,DMSO-d6)δ0.92(t,J=7.5Hz,6H),1.21-1.32(m,2H),1.42-1.55(m,4H),1.95-2.07(m,4H),2.14-2.27(m,6H),3.31-3.42(m,2H),3.43-3.54(m,2H),4.45(t,J=5.6Hz,1H),5.27-5.38(m,2H),5.36-5.47(m,2H),11.96(s,1H)。
步骤3:(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((((Z)-己-3-烯-1-基)氧基)己酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由6,6-双(((Z)-己-3-烯-1-基)氧基)己酸制备,产量60mg(45%)。1H NMR(400MHz,氯仿-d)δ0.88(t,J=6.7Hz,3H),0.95(t,J=7.5Hz,6H),1.18-1.44(m,15H),1.56-1.70(m,7H),1.99-2.11(m,8H),2.13-2.23(m,2H),2.23-2.37(m,8H),2.76(t,J=6.4Hz,2H),3.36-3.47(m,2H),3.50-3.64(m,4H),4.09-4.24(m,4H),4.48(t,J=5.6Hz,1H),5.26-5.51(m,8H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((((Z)-己-3-烯-1-基)氧基)己酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例114)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((((Z)-己-3-烯-1-基)氧基)己酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)-1-丙醇制备,产量36mg(62%)。LCMS(方法B):实测值m/z(M+H)=820.9,RT=1.70分钟。
实施例115,(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双(((Z)-己-3-烯-1-基)氧基)己酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双(((Z)-己-3-烯-1-基)氧基)己酰基)氧基)-2-(羟甲基甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量69mg(72%)。LCMS(方法B):实测值m/z(M+H)=833.0,RT=1.60分钟。
实施例116,(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((((Z)-辛-5-烯-1-基)氧基)己酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:6,6-双(((Z)-辛-5-烯-1-基)氧基)己腈
根据一般程序A,由6,6-二甲氧基己腈和(Z)-辛-5-烯-1-醇制备,产量210mg(47%)。1H NMR(400MHz,氯仿-d)δ0.94(t,J=7.5Hz,6H),1.34-1.52(m,4H),1.47-1.74(m,10H),1.95-2.10(m,8H),2.33(t,J=7.1Hz,2H),3.34-3.45(m,2H),3.51-3.61(m,2H),4.44(t,J=5.5Hz,1H),5.25-5.42(m,4H)。
步骤2:6,6-双(((Z)-辛-5-烯-1-基)氧基)己酸
根据一般程序B,自6,6-双(((Z)-辛-5-烯-1-基)氧基)己腈制备,产量150mg,94%。1H NMR(400MHz,DMSO-d6)δ0.91(t,J=7.5Hz,6H),1.24-1.41(m,6H),1.42-1.53(m,8H),1.93-2.06(m,8H),2.18(t,J=7.3Hz,2H),3.31-3.40(m,2H),3.43-3.53(m,2H),4.40(t,J=5.6Hz,1H),5.19-5.45(m,4H),11.97(s,1H)。
步骤3:(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双(((Z)-辛-5-烯-1-基)氧基)己酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由6,6-双(((Z)-辛-5-烯-1-基)氧基)己酸制备,产量90mg(45%)。1H NMR(400MHz,氯仿-d)δ0.88(t,J=6.8Hz,3H),0.94(t,J=7.5Hz,6H),1.20-1.47(m,23H),1.50-1.70(m,9H),1.94-2.11(m,12H),2.10-2.23(m,2H),2.27-2.37(m,4H),2.76(t,J=6.4Hz,2H),3.34-3.44(m,2H),3.50-3.58(m,2H),3.60(t,J=5.6Hz,2H),4.09-4.24(m,4H),4.44(t,J=5.6Hz,1H),5.25-5.43(m,8H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((((Z)-辛-5-烯-1-基)氧基)己酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例116)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((((Z)-辛-5-烯-1-基)氧基)己酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)-1-丙醇制备,产量24mg(57%)。LCMS(方法B):实测值m/z(M+H)=876.8,RT=1.70分钟。
实施例117,(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((((Z)-辛-5-烯-1-基)氧基)己酰基)氧基)-2-(((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双(((Z)-辛-5-烯-1-基)氧基)己酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量50mg(50%)。LCMS(方法B):实测值m/z(M+H)=889.2,RT=1.73分钟。
实施例118,(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((((Z)-癸-4-烯-1-基)氧基)己酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:6,6-双(((Z)-癸-4-烯-1-基)氧基)己腈
根据一般程序A,由6,6-二甲氧基己腈和(Z)-癸-4-烯-1-醇制备,产量150mg(38%)。1H NMR(400MHz,氯仿-d)δ0.88(t,J=6.7Hz,6H),1.17-1.41(m,12H),1.45-1.57(m,2H),1.59-1.74(m,8H),1.87-2.20(m,8H),2.33(t,J=7.1Hz,2H),3.35-3.45(m,2H),3.50-3.70(m,2H),4.44(t,J=5.5Hz,1H),5.28-5.45(m,4H)
步骤2:6,6-双(((Z)-癸-4-烯-1-基)氧基)己酸
根据一般程序B,由6,6-双(((Z)-癸-4-烯-1-基)氧基)己腈制备,产量150mg,95%。1H NMR(400MHz,DMSO-d6)δ0.85(t,J=6.7Hz,6H),1.18-1.37(m,14H),1.45-1.56(m,8H),1.91-2.10(m,8H),2.18(t,J=7.4Hz,2H),3.32-3.41(m,2H),3.43-3.53(m,2H),4.37-4.44(m,1H),5.25-5.46(m,4H),11.96(s,1H)。
步骤3:(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双(((Z)-癸-4-烯-1-基)氧基)己酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由6,6-双(((Z)-癸-4-烯-1-基)氧基)己酸制备,产量87mg(42%)。1H NMR(400MHz,氯仿-d)δ0.88(t,J=6.8Hz,9H),1.17-1.45(m,24H),1.51-1.71(m,10H),1.96-2.17(m,12H),2.32(q,J=7.3Hz,4H),2.76(t,J=6.5Hz,2H),3.35-3.45(m,2H),3.51-3.64(m,4H),4.09-4.24(m,4H),4.44(t,J=5.6Hz,1H),5.28-5.44(m,8H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((((Z)-癸-4-烯-1-基)氧基)己酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((((Z)-癸-4-烯-1-基)氧基)己酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)-1-丙醇制备,产量32mg(59%)。LCMS(方法B):实测值m/z(M+H)=932.9,RT=1.70分钟。
实施例119,(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((((Z)-癸-4-烯-1-基)氧基)己酰基)氧基)-2-(((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双(((Z)-癸-4-烯-1-基)氧基)己酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量51mg(52%)。LCMS(方法B):实测值m/z(M+H)=945.2,RT=1.70分钟。
实施例120,(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((3,7-二甲基辛-6-烯-1-基)氧基)己酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:6,6-双((3,7-二甲基辛-6-烯-1-基)氧基)己腈
根据一般程序A,由6,6-二甲氧基己腈和3,7-二甲基辛-6-烯-1-醇制备,产量220mg(42%)。1H NMR(400MHz,氯仿-d)δ0.88(d,J=6.4Hz,6H),1.11-1.22(m,3H),1.25-1.43(m,6H),1.45-1.77(m,19H),1.87-2.04(m,4H),2.33(t,J=7.1Hz,2H),3.35-3.50(m,2H),3.52-3.66(m,2H),4.44(t,J=5.5Hz,1H),5.08(t,J=7.3Hz,2H)。
步骤2:6,6-双((3,7-二甲基辛-6-烯-1-基)氧基)己酸
根据一般程序B,由6,6-双((3,7-二甲基辛-6-烯-1-基)氧基)己腈制备,产量220mg(95%)。1H NMR(400MHz,DMSO-d6)δ0.85(d,J=5.9Hz,6H),1.13-1.03(m,2H),1.40-1.17(m,8H),1.58-1.44(m,12H),1.70-1.59(m,6H),2.03-1.87(m,5H),2.18(t,J=7.3Hz,1H),3.44-3.33(m,2H),3.60-3.44(m,2H),4.40(t,J=5.4Hz,1H),5.07(t,J=7.3Hz,2H),11.97(s,1H)。
步骤3:(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((3,7-二甲基辛-6-烯-1-基)氧基)己酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由6,6-双((3,7-二甲基辛-6-烯-1-基)氧基)己酸制备,产量90mg(42%)。1H NMR(400MHz,氯仿-d)δ0.88(d,J=6.1Hz,10H),1.18-1.45(m,15H),1.51-1.57(m,22H),1.67(s,5H),1.83-2.09(m,8H),2.16-2.23(m,2H),2.32(q,J=7.5Hz,4H),2.75(d,J=6.1Hz,2H),3.32-3.69(m,7H),4.10-4.21(m,4H),4.40-4.48(m,1H),5.03-5.16(m,2H),5.28-5.42(m,4H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((3,7-二甲基辛-6-烯-1-基)氧基)己酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例120)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((3,7-二甲基辛-6-烯-1-基)氧基)己酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)-1-丙醇制备,产量32mg(59%)。LCMS(方法B):实测值m/z(M+H)=933.0,RT=1.70分钟。
实施例121,(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((3,7-二甲基辛-6-烯-1-基)氧基)己酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((3,7-二甲基辛-6-烯-1-基)氧基)己酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量32mg(59%)。LCMS(方法B):实测值m/z(M+H)=945.2,RT=1.96分钟。
实施例122,(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((7,7,8,8,8-五氟辛基)氧基)己酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:6,6-双((7,7,8,8,8-五氟辛基)氧基)己腈
根据一般程序A,由6,6-二甲氧基己腈和7,7,8,8,8-五氟辛-1-醇制备,产量300mg(44%)。1H NMR(400MHz,氯仿-d)δ1.35-1.45(m,8H),1.45-1.56(m,2H),1.54-1.74(m,12H),1.91-2.09(m,4H),2.34(t,J=7.0Hz,2H),3.34-3.45(m,2H),3.51-3.61(m,2H),4.44(t,J=5.5Hz,1H)。
步骤2:6,6-双((7,7,8,8,8-五氟辛基)氧基)己酸
根据一般程序B,由6,6-双((7,7,8,8,8-五氟辛基)氧基)己腈制备,产量296mg(95%)。1H NMR(400MHz,DMSO-d6)δ1.18-1.40(m,10H),1.38-1.55(m,12H),2.04-2.23(m,6H),3.29-3.38(m,2H),3.40-3.51(m,2H),4.39(t,J=5.6Hz,1H),11.93(s,1H)。
步骤3:(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((7,7,8,8,8-五氟辛基)氧基)己酰基)氧基)-2-(羟甲基)丙酯
根据一般程序C,由6,6-双((7,7,8,8,8-五氟辛基)氧基)己酸制备,产量140mg(57%)。1H NMR(400MHz,氯仿-d)δ0.87(d,J=7.3Hz,3H),1.22-1.46(m,27H),1.56-1.70(m,9H),1.88-2.10(m,9H),2.11-2.25(m,2H),2.26-2.37(m,4H),2.76(t,J=7.3Hz,2H),3.36-3.44(m,2H),3.49-3.58(m,2H),3.60(t,J=5.7Hz,2H),3.91-4.10(m,1H),4.09-4.26(m,4H),4.36-4.53(m,1H),5.22-5.52(m,4H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((7,7,8,8,8-五氟辛基)氧基)己酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例122)。根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((7,7,8,8,8-五氟辛基)氧基)己酰基)氧基)-2-(羟甲基)丙酯和3-(二乙基氨基)-1-丙醇制备,产量51mg(61%)。LCMS(方法B):实测值m/z(M+H)=1060.7,RT=1.70分钟。
实施例123,(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((7,7,8,8,8-五氟辛基)氧基)己酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由(9Z,12Z)-十八碳-9,12-二烯酸3-((6,6-双((7,7,8,8,8-五氟辛基)氧基)己酰基)氧基)-2-(羟甲基)丙酯和(1-乙基哌啶-3-基)甲醇制备,产量80mg(74%)。LCMS(方法B):实测值m/z(M+H)=1073.2,RT=1.81分钟。
实施例124,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((((1-(2-羟乙基)哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯
步骤1:1-(2-羟乙基)哌啶-3-甲酸乙酯
向哌啶-3-甲酸乙酯(2g,12.74mmol)在无水丙酮(10mL)中的搅拌溶液中添加2-溴乙烷-1-醇(1.89g,15.28mmol)、干燥的粉末K2CO3(3.5g,25.47mmol)和KI(0.42g,2.55mmol)。将反应混合物在25℃下搅拌18小时。将反应混合物过滤,并将滤液在减压下蒸发。将由此获得的粗制材料通过组合快速柱色谱法纯化,用30%乙酸乙酯-己烷洗脱,得到呈无色油状物的1-(2-羟乙基)哌啶-3-甲酸乙酯(2.2g,85%)。1HNMR(400MHz,氯仿-d)δ1.17-1.29(m,3H),1.46-1.62(m,2H),1.60-1.76(m,1H),1.81-1.95(m,1H),2.14-2.19(m,1H),2.38(t,J=10.4Hz,1H),2.42-2.59(m,4H),2.62-2.71(m,1H),2.80-2.89(m,1H),3.52-3.63(m,2H),4.10(q,J=7.1Hz,2H)。
步骤2:1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-3-甲酸乙酯
在0℃下向1-(2-羟乙基)哌啶-3-甲酸乙酯(200mg,0.99mmol)在DCM(2mL)中的搅拌溶液中添加三乙胺(0.35mL,2.48mmol)和叔丁基二甲基甲硅烷基氯(225mg,1.49mmol)。将反应混合物在25℃下搅拌14小时。然后将反应混合物用水淬灭并用DCM(50mL)萃取,用盐水溶液(25mL)洗涤。将有机层经无水Na2SO4干燥,过滤并在减压下浓缩。由此获得的粗制材料通过组合快速色谱法纯化,用5%乙酸乙酯-己烷洗脱,得到呈粘性固体状的1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-3-甲酸乙酯(160mg,51%)。1H NMR(400MHz,氯仿-d)δ0.04(s,6H),0.87(s,9H),1.23(t,J=7.1Hz,3H),1.32-1.48(m,1H),1.47-1.64(m,1H),1.63-1.77(m,1H),1.87-1.98(m,1H),2.00-2.13(m,1H),2.22(t,J=10.9Hz,1H),2.48-2.59(m,3H),2.78(d,J=11.2Hz,1H),3.04(d,J=13.4Hz,1H),3.73(t,J=6.4Hz,2H),4.11(q,J=7.1Hz,2H)。
步骤3:(1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-3-基)甲醇
在0℃下,向1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-3-甲酸乙酯(500mg,1.58mmol)在THF(5mL)中的搅拌溶液中添加氢化铝锂(1M在THF中)(3.2mL,3.17mmol),并将反应混合物在25℃下搅拌1小时。完成后,将反应物质在0℃下用饱和Na2SO4水溶液(10mL)淬灭并过滤。将滤液在减压下浓缩,得到呈无色油状物的(1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-3-基)甲醇(400mg,92%),其不经进一步纯化即用于下一步骤。1H NMR(400MHz,氯仿-d)δ0.04(s,6H),0.87(s,9H),1.07-1.22(m,1H),1.49-1.62(m,1H),1.62-1.72(m,1H),1.72-1.85(m,3H),2.11(d,J=10.5Hz,1H),2.23(d,J=11.6Hz,1H),2.48(t,J=6.5Hz,2H),2.55-2.72(m,1H),2.82(d,J=10.8Hz,1H),3.53(dd,J=5.8,10.6Hz,1H),3.57-3.70(m,1H),3.73(t,J=6.4Hz,2H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯
向(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯(中间体IVa)(100mg,0.14mmol)在DCM(1mL)中的搅拌溶液中添加吡啶(0.03mL,0.29mmol)、N,N-二甲基吡啶-4-胺(5.3mg,0.04mmol)和氯甲酸4-硝基苯酯(72.36mg,0.29mmol)并且在25℃下搅拌1小时。然后添加(1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-3-基)甲醇(158mg,0.58mmol)和DIPEA(0.1mL,0.58mmol)并且再搅拌16小时。将反应混合物用DCM(10mL)稀释,用1M Na2CO3溶液(3×10mL)洗涤并且用水(10mL)和盐水洗涤。将合并的有机部分经无水Na2SO4干燥,过滤并且在减压下浓缩。将由此获得的粗制材料通过组合快速柱色谱法纯化,用2%MeOH-DCM洗脱,得到呈淡黄色油状物的(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯(50mg,35%)。LCMS(方法B):实测值m/z(M+H)=991.1,RT=1.14分钟。
步骤5:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((1-(2-羟乙基)哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯(实施例124)。在0℃下向(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯(60mg,0.061mmol)在无水THF(1mL)中的搅拌溶液中添加四正丁基氟化铵(TBAF)(0.12mL,0.12mmol)(在四氢呋喃中的1M溶液)。使混合物温热至室温后,将所得溶液搅拌4小时。将所得溶液用DCM(5mL)稀释并用水(5mL)淬灭。将有机层用DCM(2×5mL)、盐水(5mL)萃取,并经无水Na2SO4干燥,在减压下过滤浓缩。将由此获得的粗制材料通过组合快速柱色谱法纯化,用2%MeOH-DCM洗脱,得到呈棕色粘性胶状的(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((1-(2-羟乙基)哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯(35mg,66%)。LCMS(方法B):实测值m/z(M+H)=876.7,RT=1.58分钟。
实施例125,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((((1-(3-羟丙基)哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯
步骤1:1-(3-羟丙基)哌啶-3-甲酸乙酯
向哌啶-3-甲酸乙酯(2g,12.74mmol)在无水丙酮(10mL)中的搅拌溶液中添加3-溴丙-1-醇(2.12g,15.28mmol)、干燥的粉末K2CO3(3.5g,25.47mmol)和KI(0.42g,2.55mmol)。将反应混合物在25℃下搅拌16小时。将反应混合物过滤,并将滤液在减压下蒸发。将由此获得的粗制材料通过组合快速柱色谱法纯化,用25%乙酸乙酯-己烷洗脱,得到呈无色油状物的1-(3-羟丙基)哌啶-3-甲酸乙酯(2.0g,73%)。1H NMR(400MHz,氯仿-d)δ1.23(t,J=7.1Hz,3H),1.37-1.59(m,2H),1.62-1.79(m,3H),1.88-1.95(m,1H),1.96-2.08(m,1H),2.11-2.22(m,2H),2.47-2.56(m,1H),2.58(t,J=5.7Hz,2H),2.84(d,J=11.3Hz,1H),3.06(d,J=9.7Hz,1H),3.76(t,J=5.2Hz,2H),4.10(q,J=7.1Hz,2H)。
步骤2:1-(3-((叔丁基二甲基甲硅烷基)氧基)丙基)哌啶-3-甲酸乙酯
在0℃下向1-(3-羟丙基)哌啶-3-甲酸乙酯(200mg,0.93mmol)在DCM(2mL)中的搅拌溶液中添加三乙胺(0.3mL,3.31mmol)和叔丁基二甲基甲硅烷基氯(211mg,1.39mmol)。将反应混合物缓慢温热至25℃并搅拌14小时。然后将反应混合物用水淬灭并用DCM萃取,用盐水溶液洗涤。将合并的有机层经无水Na2SO4干燥,过滤并在减压下浓缩。将由此获得的粗制材料通过组合快速柱色谱法纯化,用5%乙酸乙酯-己烷洗脱,得到呈粘性固体状的1-(3-((叔丁基二甲基甲硅烷基)氧基)丙基)哌啶-3-甲酸乙酯(160mg,52%)。1H NMR(400MHz,氯仿-d)δ0.03(s,6H),0.87(s,9H),1.24(t,J=7.1Hz,3H),1.34-1.63(m,2H),1.63-1.75(m,3H),1.87-2.01(m,2H),2.11(t,J=10.7Hz,1H),2.35-2.44(m,2H),2.47-2.59(m,1H),2.75(d,J=11.2Hz,1H),2.96(d,J=10.1Hz,1H),3.63(t,J=6.3Hz,2H),4.11(q,J=7.1Hz,2H)。
步骤3:(1-(3-((叔丁基二甲基甲硅烷基)氧基)丙基)哌啶-3-基)甲醇
在0℃下向1-(3-((叔丁基二甲基甲硅烷基)氧基)丙基)哌啶-3-甲酸酯(100mg,0.30mmol)在THF(2mL)中的搅拌溶液中添加氢化铝锂(1M在THF中)(0.6mL,0.60mmol),并将反应物质在0℃下搅拌1小时。完成后,将反应物质在0℃下用饱和Na2SO4水溶液(10mL)淬灭并过滤。蒸发滤液,得到呈无色油状物的(1-(3-((叔丁基二甲基甲硅烷基)氧基)丙基)哌啶-3-基)甲醇(80mg,92%),其不经进一步纯化用于下一步骤。1H NMR(400MHz,氯仿-d)δ0.03(s,6H),0.88(s,9H),1.10-1.23(m,1H),1.49-1.87(m,7H),1.95-2.24(m,2H),2.32-2.41(m,2H),2.50-2.67(m,1H),2.77(d,J=11.0Hz,1H),3.54(dd,J=5.7,10.5Hz,1H),3.59-3.71(m,3H)。
步骤4:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((1-(3-((叔丁基二甲基甲硅烷基)氧基)丙基)哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯
向(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-二((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(羟甲基)丙酯(中间体IVa)(50mg,0.07mmol)在DCM(1.0mL)中的搅拌溶液中添加吡啶(0.01mL,0.14mmol)、N,N-二甲基吡啶-4-胺(2.65mg,0.02mmol)和氯甲酸4-硝基苯酯(36.18mg,0.14mmol)并且在室温下搅拌1小时。1小时后,添加(1-(3-((叔丁基二甲基甲硅烷基)氧基)丙基)哌啶-3-基)(83.06mg,0.28mmol)和DIPEA(0.05mL,0.28mmol),并且在25℃下搅拌16小时。完成后,将反应混合物用DCM(10mL)稀释,用1M碳酸钠溶液(3×10mL)洗涤,并用水(10mL)和盐水洗涤。将合并的有机部分经Na2SO4干燥、过滤并且子啊减压下浓缩以及通过组合快速柱色谱法纯化,用2%MeOH-DCM洗脱,得到呈淡黄色油状物的(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((1-(3-((叔丁基二甲基甲硅烷基)氧基)丙基)哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯(50mg,30%)。LCMS(方法B):实测值m/z(M+H)=1005.1,RT=1.12分钟。
步骤5:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((1-(3-羟丙基)哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯(实施例125)。在0℃下向(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((1-(3-((叔丁基二甲基甲硅烷基)氧基)丙基)哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯(85mg,0.085mmol)在无水THF(1.0mL)中的溶液中添加四正丁基氟化铵(TBAF)(0.17mL,0.17mmol)(在四氢呋喃中的1M溶液)。使混合物温热至25℃之后,将所得溶液搅拌4小时。将所得溶液用DCM(10mL)稀释并用水(5mL)淬灭。将有机层用DCM(2x5mL)、盐水(5mL)萃取并且经无水Na2SO4干燥,过滤并且在减压下浓缩。将由此获得的粗制材料通过组合快速柱色谱法纯化,用1.5%MeOH-DCM洗脱,得到呈淡黄色粘性胶状的(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((1-(3-羟丙基)哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯(36mg,52%)。LCMS(方法B):实测值m/z(M+H)=891.0,RT=1.61分钟。
实施例126,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((3-((3-羟丙基)(甲基)氨基)丙氧基)羰基)氧基)甲基)丙酯
步骤1:3,3'-(甲基氮烷二基)双(丙-1-醇)
在氩气气氛下,向3-(甲基氨基)丙-1-醇(100mg,1.12mmol)在EtOH(2mL)中的搅拌溶液中添加Na2CO3(260mg,2.24mmol)和3-氯丙醇(0.1mL,1.12mmol)。将反应混合物在80℃下搅拌4小时。完成后,将反应混合物在减压下浓缩。将由此获得的粗制材料通过组合快速柱色谱法纯化,用2%丙酮-己烷洗脱,得到呈无色油状物的3,3'-(甲基氮烷二基)双(丙-1-醇)(90mg,55%)。1H NMR(400MHz,DMSO-d6)δ1.53-1.67(m,2H),1.68-1.78(m,1H),1.84(t,J=6.2Hz,1H),2.26(s,2H),2.52(d,J=6.7Hz,3H),2.90(t,J=7.5Hz,1H),3.39-3.51(m,6H),3.68(t,J=6.5Hz,1H)。
步骤2:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((3-((3-羟丙基)(甲基)氨基)丙氧基)羰基)氧基)甲基)丙酯(实施例126)。根据一般程序D,由中间体IVa和3,3'-(甲基氮烷二基)双(丙-1-醇)制备,产量18mg(23%)。LCMS(方法B):实测值m/z(M+H)=864.7,RT=1.55分钟。
实施例127,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙基)氨基甲酰基)氧基)甲基)丙酯:根据一般程序D,由中间体IVa和N1,N1-二乙基丙烷-1,3-二胺制备,产量32mg(53%)。LCMS(方法B):实测值m/z(M+H)=848.0,RT=1.55分钟。
实施例128,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((2-(1-乙基吡咯烷-2-基)乙氧基)羰基)氧基)甲基)丙酯
步骤1:2-(1-乙基吡咯烷-2-基)乙-1-醇
以下是一般程序G的代表。在氮气气氛下,向2-(吡咯烷-2-基)乙-1-醇(20mg,0.21mmol)在乙腈(1mL)中的搅拌溶液中添加K2CO3(72mg,0.65mmol)和EtI(0.01mL,0.21mmol)。将所得混合物在56℃下搅拌16小时。将反应物质冷却至室温并将其通过硅藻土床过滤,将滤液在减压下蒸发,得到呈无色液体状的2-(1-乙基吡咯烷-2-基)乙-1-醇(18mg,58%)。1H NMR(400MHz,氯仿-d)δ1.08(t,J=7.2Hz,3H),1.37-1.48(m,1H),1.65-1.96(m,5H),1.92-2.05(m,1H),2.04-2.18(m,2H),2.72-2.83(m,1H),2.87-3.04(m,1H),3.10-3.20(m,1H),3.62-3.72(m,1H),3.89-4.05(m,1H)。
(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双((((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((2-(1-乙基吡咯烷-2-基)乙氧基)羰基)氧基)甲基)丙酯(实施例128)。根据一般程序D,由中间体IVa和2-(1-乙基吡咯烷-2-基)乙-1-醇制备,产量28mg(52%)。LCMS(方法B):实测值m/z(M+H)=860.8,RT=1.55分钟。
实施例129,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((((1R,3s,5S)-8-乙基-8-氮杂双环[3.2.1]辛-3-基)氧基)羰基)氧基)甲基)丙酯
步骤1:(1R,3r,5S)-8-乙基-8-氮杂双环[3.2.1]辛-3-醇
根据一般程序G,由(1R,3r,5S)-8-氮杂双环[3.2.1]辛-3-醇制备,产量180mg,73%。
步骤2:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((((1R,3s,5S)-8-乙基-8-氮杂双环[3.2.1]辛-3-基)氧基)羰基)氧基)甲基)丙酯(实施例129)。根据一般程序D,由中间体IVa和(1R,3r,5S)-8-乙基-8-氮杂双环[3.2.1]辛-3-醇制备,产量16mg(51%)。LCMS(方法B):实测值m/z(M+H)=872.8,RT=1.70分钟。
实施例130,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((((1R,3r,5S)-8-乙基-8-氮杂双环[3.2.1]辛-3-基)氧基)羰基)氧基)甲基)丙酯
步骤1:(1R,3R,5S)-8-乙基-8-氮杂双环[3.2.1]辛-3-醇
根据一般程序G,由(1R,3r,5S)-8-氮杂双环[3.2.1]辛-3-醇制备,产量80mg(92%)。
步骤2:(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-(((((1R,3r,5S)-8-乙基-8-氮杂双环[3.2.1]辛-3-基)氧基)羰基)氧基)甲基)丙酯(实施例130)。根据一般程序D,由中间体IVa和(1R,3r,5S)-8-乙基-8-氮杂双环[3.2.1]辛-3-醇制备,产量16mg(51%)。LCMS(方法B):实测值m/z(M+H)=872.9,RT=1.64分钟。
实施例131,1'-乙基-[1,4'-联哌啶]-4-甲酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((9Z,12Z)-十八碳-9,12-二烯酰基)氧基)甲基)丙酯:根据一般程序E,由中间体IVa和1'-乙基-[1,4'-联哌啶]-4-甲酸二盐酸盐制备,产量138mg(52%)。LCMS(方法A):实测值m/z(M+H)=913.7,RT=3.21分钟。
实施例132,1'-乙基-[1,4'-联哌啶]-4-甲酸3-((4,4-双((7,7,8,8,8-五氟辛基)氧基)丁酰基)氧基)-2-(((9Z,12Z)-十八碳-9,12-二烯酰基)氧基)甲基)丙酯:根据一般程序E,由中间体IVf和1'-乙基-[1,4'-联哌啶]-4-甲酸二盐酸盐制备,产量195mg(78%)。LCMS(方法A):实测值m/z(M+H)=1097.5,RT=3.19分钟。
实施例133,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((((2-(1-乙基哌啶-2-基)乙氧基)羰基)氧基)甲基)丙酯:根据一般程序D,由中间体IVa和2-(1-乙基哌啶-2-基)乙-1-醇制备,产量38mg(40%)。LCMS(方法A):实测值m/z(M+H)=874.7,RT=3.98分钟。
实施例134,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((Z)-辛-5-烯-1-基)氧基)丁酰基)氧基)-2-((2-(1-乙基哌啶-4-基)乙酰氧基)甲基)丙酯:根据一般程序E,由中间体IVa和2-(1-乙基哌啶-4-基)乙酸制备,产量66mg(72%)。LCMS(方法A):实测值m/z(M+H)=844.7,RT=3.95分钟。
实施例135,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(辛-2-炔-1-基氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:使用与实施例3类似的程序,在一般程序A中,用辛-2-炔-1-醇代替(Z)-辛-5-烯-1-醇来制备。最后步骤的产量:91mg(92%)。LCMS(方法A):实测值m/z(M+H)=856.7,RT=3.63分钟。
实施例136,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(辛-2-炔-1-基氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯:使用与实施例1类似的程序,在一般程序A中,用辛-2-炔-1-醇代替(Z)-辛-5-烯-1-醇来制备。最后步骤的产量:80mg(82%)。LCMS(方法A):实测值m/z(M+H)=844.7,RT=3.66分钟。
实施例137,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(壬-2-炔-1-基氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙基酯:使用与实施例3类似的程序,在一般程序A中,用壬-2-炔-1-醇代替(Z)-辛-5-烯-1-醇来制备。最后步骤的产量:86mg(88%)。LCMS(方法A):实测值m/z(M+H)=884.7,RT=3.73分钟。
实施例138,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(壬-2-炔-1-基氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯:使用与实施例1类似的程序,在一般程序A中,用壬-2-炔-1-醇代替(Z)-辛-5-烯-1-醇来制备。最后步骤的产量:87mg(90%)。LCMS(方法A):实测值m/z(M+H)=872.7,RT=3.69分钟。
实施例139,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(辛-7-炔-1-基氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:使用与实施例3类似的程序,在一般程序A中,用辛-7-炔-1-醇代替(Z)-辛-5-烯-1-醇来制备。最后步骤的产量:111mg(84%)。LCMS(方法A):实测值m/z(M+H)=856.7,RT=3.74分钟。
实施例140,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(辛-7-炔-1-基氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯:使用与实施例1类似的程序,在一般程序A中,用辛-7-炔-1-醇代替(Z)-辛-5-烯-1-醇来制备。最后步骤的产量:108mg(83%)。LCMS(方法A):实测值m/z(M+H)=844.7,RT=3.76分钟。
实施例141,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(癸-2-炔-1-基氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:使用与实施例3类似的程序,在一般程序A中,用癸-2-炔-1-醇代替(Z)-辛-5-烯-1-醇来制备。最后步骤的产量:122mg(88%)。LCMS(方法A):实测值m/z(M+H)=912.8,RT=4.13分钟。
实施例142,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(癸-2-炔-1-基氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯:使用与实施例1类似的程序,在一般程序A中,用癸-2-炔-1-醇代替(Z)-辛-5-烯-1-醇来制备。最后步骤的产量:115mg(84%)。LCMS(方法A):实测值m/z(M+H)=900.8,RT=4.04分钟。
实施例143,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(癸-3-炔-1-基氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:使用与实施例3类似的程序,在一般程序A中,用癸-3-炔-1-醇代替(Z)-辛-5-烯-1-醇来制备。最后步骤的产量:104mg(89%)。LCMS(方法A):实测值m/z(M+H)=912.8,RT=3.97分钟。
实施例144,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(癸-3-炔-1-基氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯:使用与实施例1类似的程序,在一般程序A中,用癸-3-炔-1-醇代替(Z)-辛-5-烯-1-醇来制备。最后步骤的产量:108mg(94%)。LCMS(方法A):实测值m/z(M+H)=900.8,RT=3.93分钟。
实施例145,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((E)-辛-2-烯-1-基)氧基)丁酰基)氧基)-2-(((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:使用与实施例3类似的程序,在一般程序A中,用(E)-辛-2-烯-1-醇代替(Z)-辛-5-烯-1-醇来制备。最后步骤的产量:74mg(89%)。LCMS(方法A):实测值m/z(M+H)=860.7,RT=3.87分钟。
实施例146,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((E)-辛-2-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯:使用与实施例1类似的程序,在一般程序A中,用(E)-辛-2-烯-1-醇代替(Z)-辛-5-烯-1-醇来制备。最后步骤的产量:68mg(83%)。LCMS(方法A):实测值m/z(M+H)=848.8,RT=3.89分钟。
实施例147,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((E)-壬-2-烯-1-基)氧基)丁酰基)氧基)-2-((((1-乙基哌啶-3-基)甲氧基)羰基)氧基)甲基)丙酯:使用与实施例3类似的程序制备,在一般程序A中,用(E)-壬-2-烯-1-醇代替(Z)-辛-5-烯-1-醇来制备。最后步骤的产量:68mg(81%)。LCMS(方法A):实测值m/z(M+H)=888.8,RT=4.01分钟。
实施例148,(9Z,12Z)-十八碳-9,12-二烯酸3-((4,4-双(((E)-壬-2-烯-1-基)氧基)丁酰基)氧基)-2-((((3-(二乙基氨基)丙氧基)羰基)氧基)甲基)丙酯:使用与实施例1类似的程序制备,在一般程序A中,用(E)-壬-2-烯-1-醇代替(Z)-辛-5-烯-1-醇来制备。最后步骤的产量:34mg(41%)。LCMS(方法A):实测值m/z(M+H)=877.9,RT=4.07分钟。
脂质纳米颗粒
F.LNP制剂
脂质纳米颗粒组分以特定的脂质组分摩尔比溶解在100%乙醇中。将核酸(NA)运载物溶解在10mM柠檬酸盐、100mM NaCl、pH 4.0中,得到约0.22mg/mL的NA运载物浓度。在一些实施方案中,NA运载物由功能性NA(例如,siRNA,反义、表达DNA,mRNA)以及以1:10至10:1功能性NA与条形码的质量比混合的报道子DNA条形码(如先前由Sago,2018PNAS描述)组成。
将LNP配制成总脂质与NA的质量比为11.7。根据制造商的方案,使用PrecisionNanosystems NanoAssemblr Spark或Benchtop仪器通过脂质和NA溶液的微流体混合来形成LNP。在使用不同的流速混合期间保持水与有机溶剂的2:1比率。在混合后,收集LNP,在PBS(约1:1v/v)中稀释,并且使用在PBS中在4℃下对于20kDa过滤器透析8至24小时进行进一步的缓冲液交换。在该初始透析之后,通过DLS表征每种单独的LNP制剂以测量尺寸和多分散性,并且通过TNS测定测量LNP亚群的pKa。合并落入特定直径和多分散性范围内的LNP,并且在100kDa透析盒上在4℃下对PBS进一步透析1至4小时。在第二次透析之后,使用0.22μM过滤器无菌过滤LNP,并在4℃下储存以供进一步使用。
G.LNP表征
DLS-使用高通量动态光散射(DLS)(DynaPro读板器II,Wyatt)测量LNP流体动力学直径和多分散性百分比(PDI%)。将LNP用1×PBS稀释至合适的浓度并分析。
通过Qubit microRNA试剂盒(对于siRNA)或HS RNA试剂盒(对于mRNA)根据制造商的说明书测定NA的浓度和包封效率-浓度。通过测量未裂解和裂解的LNP来测定包封效率。
pKa-制备10mM HEPES(Sigma Aldrich)、10mM MES(Sigma Aldrich)、10mM乙酸钠(Sigma)和140nM氯化钠(Sigma Aldrich)的储备溶液,并使用氯化氢和氢氧化钠将pH调节至pH 4-10。对于每种pH重复4次,将140μL pH调节的缓冲液添加至96孔板中,然后添加5μL的2-(对甲苯胺基)-6-萘磺酸(60μg/mL)。向每个孔中添加5μL的LNP。在温和摇动下孵育5分钟后,使用325nm的激发波长和435nm的发射波长(BioTek Synergy H4 Hybrid)测量荧光。
LNP施用-将约8-12周龄的雄性和雌性小鼠用于所有研究。暂时限制每只小鼠,并且经由尾静脉注射将汇集的LNP通过IV施用至每个实验多达5只动物。还使用年龄匹配的小鼠经由尾静脉注射施用媒介物(1×PBS),每个实验至多3只动物。在给药后72小时,收集包括肝、脾、骨髓和血液的组织用于分析。
流动-将肝组织机械地消化并且然后使用蛋白酶的混合物通过酶来消化,然后通过70μM过滤器以产生单细胞悬浮液。机械消化脾组织以产生单细胞悬浮液。用ACK缓冲液处理所有组织以裂解红细胞,然后用荧光标记的抗体染色用于流式细胞术和荧光激活细胞分选(FACS)。所有抗体均是市售的抗体。使用BD FACSMelody(Becton Dickinson),通过流式细胞计获得所有样品,以在分选之前产生门。通常,门控结构是目标的尺寸→单细胞→活细胞→细胞。T细胞定义为CD45+CD3+,单核细胞定义为CD45+CD11b+,B细胞定义为CD45+CD19+。在肝脏中,内皮细胞定义为CD31+,枯否细胞定义为CD45+CD11b+,肝细胞定义为CD31-/CD45-。对于siRNA研究,我们选择下调靶基因,而对于mRNA研究,我们选择上调靶基因。来自施用媒介物的小鼠的组织被用于设置门以进行分选。将具有正确表型的每个细胞亚组的多至20,000个细胞分选到1×PBS中。分选后,通过离心沉淀细胞,并根据制造商的方案使用快速提取DNA提取溶液(Lucigen)提取DNA。将DNA储存在-20℃。
条形码测序-使用QuickExtract(Lucigen)分离DNA(基因组和DNA条形码),并使用如前所述的Illumina MiniSeq(Sago等人,PNAS 2018,Sago等人,JACs 2018,Sago,Lokugamage等人,Nano Letters 2018)测序,将FACS分离的样品中的DNA条形码计数归一化为注射输入的频率。这些数据被绘制为“归一化的折叠顶部输入”。
H.确认
LNP制剂
脂质纳米颗粒组分以特定的脂质组分摩尔比溶解在100%乙醇中。将核酸(NA)运载物溶解在10mM柠檬酸盐、100mM NaCl、pH 4.0中,得到约0.22mg/mL的NA运载物浓度。在一些实施方案中,NA运载物由功能性NA(例如,siRNA,反义、表达DNA,mRNA)组成。将LNP配制成总脂质与NA质量比为11.7。根据制造商的方案,使用Precision NanosystemsNanoAssemblr Spark或Benchtop仪器通过脂质和NA溶液的微流体混合来形成LNP。在使用不同的流速混合期间保持水与有机溶剂的3:1比率。在混合后,收集LNP,在PBS(约1:1v/v)中稀释,并且使用在PBS中在4℃下对于20kDa过滤器透析8至24小时进行进一步的缓冲液交换。在该初始透析之后,通过DLS表征每种单独的LNP制剂以测量尺寸和多分散性,并且通过TNS测定测量LNP亚群的pKa。在透析之后,使用0.22μM无菌过滤器无菌过滤LNP,并在4℃下储存以供进一步使用。
LNP表征
DLS-使用高通量动态光散射(DLS)(DynaPro读板器II,Wyatt)测量LNP流体动力学直径和多分散性百分比(PDI%)。将LNP用1×PBS稀释至合适的浓度并分析。
通过Qubit microRNA试剂盒(对于siRNA)或HS RNA试剂盒(对于mRNA)根据制造商的说明书测定NA的浓度和包封效率-浓度。通过测量未裂解和裂解的LNP来测定包封效率。
pKa-制备10mM HEPES(Sigma Aldrich)、10mM MES(Sigma Aldrich)、10mM乙酸钠(Sigma)和140nM氯化钠(Sigma Aldrich)的储备溶液,并使用氯化氢和氢氧化钠将pH调节至pH 4-10。对于每种pH重复4次,将140μL pH调节的缓冲液添加至96孔板中,然后添加5μL的2-(对甲苯胺基)-6-萘磺酸(60μg/mL)。向每个孔中添加5μL的LNP。在温和摇动下孵育5分钟后,使用325nm的激发波长和435nm的发射波长(BioTek Synergy H4 Hybrid)测量荧光。
LNP施用-将约8-12周龄的雄性和雌性小鼠用于所有研究。暂时限制每只小鼠,并且经由尾静脉注射将汇集的LNP通过IV施用至每个实验多达5只动物。还使用年龄匹配的小鼠经由尾静脉注射施用媒介物(1×PBS),每个实验至多3只动物。在给药后72小时,收集包括肝、脾、骨髓和血液的组织用于分析。
hEPO表达-对于人EPO(hEPO)蛋白表达,小鼠在施用后6小时(通过尾静脉)被暂时限制和放血。将血液收集在肝素管中,加工成血浆,并在-80℃下储存直至备用。使用R&D系统ELISA试剂盒(DuoSet;DY286-05)根据制造商的说明,将合适稀释的血浆用于测量hEPO蛋白质。使用以下摩尔比将各种示例性的可电离脂质配制成LNP A1至LNP A17:45%可电离脂质/9%二硬脂酰磷脂酰胆碱(DSPC)/44%胆固醇/2%PEG脂质或50%可电离脂质/9%二硬脂酰磷脂酰胆碱(DSPC)/38%胆固醇/3%PEG脂质,其中脂质与核酸(人EPO mRNA)的质量比为11.7:1、18:1或25:1。如所述,以0.1 5mg/kg的核酸剂量通过尾静脉注射施用后6小时测量血浆中hEPO的表达来测定活性。表1中提供了LNP包封效率、流体动力学直径、多分散性(PDI)的代表性数据,并测量了LNP制剂在施用后6小时的血浆中的hEPO。
表1
虽然本文已经公开了各种方面和实施方案,但其它方面和实施方案对于本领域技术人员来说是显而易见的。本文公开的各个方面和实施方案是出于说明的目的,而不是为了限制,真正的范围和主旨由所附权利要求说明。
Claims (7)
1.具有以下结构的化合物:
2.脂质纳米颗粒组合物,包含:
权利要求1所述的化合物;
磷脂;
聚乙二醇-脂质;
胆固醇;以及任选地
核酸。
3.如权利要求2所述的脂质纳米颗粒组合物,其中所述核酸是siRNA、miRNA、mRNA、表达DNA、反义寡核苷酸或免疫刺激性寡核苷酸。
4.如权利要求2所述的脂质纳米颗粒组合物,其中所述核酸是向导RNA。
5.如权利要求2所述的脂质纳米颗粒组合物,其中基于总摩尔数,所述化合物以35摩尔%至65摩尔%的范围存在。
6.如权利要求2所述的脂质纳米颗粒组合物,其中所述磷脂是DSPC或DMPC。
7.权利要求2所述的脂质纳米颗粒组合物在制备用于将核酸递送至有需要的个体的药物中的用途。
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CN115175894A (zh) | 2022-10-11 |
EP4103542A4 (en) | 2024-02-14 |
CA3163161A1 (en) | 2021-07-15 |
WO2021141969A1 (en) | 2021-07-15 |
AU2021205837A1 (en) | 2022-08-11 |
BR112022013599A2 (pt) | 2022-09-13 |
KR20220123536A (ko) | 2022-09-07 |
IL294318A (en) | 2022-08-01 |
US20210230112A1 (en) | 2021-07-29 |
EP4103542A1 (en) | 2022-12-21 |
JP2023510778A (ja) | 2023-03-15 |
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