CN102170939A - 酯肽及其治疗用途 - Google Patents
酯肽及其治疗用途 Download PDFInfo
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Abstract
结构(IX)或(X)的化合物或者其可药用盐,其中:X是-C(=O)N(R10)-或-CH(OPr3)-;R7、R9和R10相同或者不同,表示卤素或者来自天然或者非天然氨基酸的氨基酸侧链部分;Pr1和Pr2相同或不同,表示卤素或硫醇保护基;Pr3是卤素或醇保护基;R1、R2、R5和R6相同或不同,表示来自天然或者非天然氨基酸的氨基酸侧链部分;或者R1和R2和/或R5和R6与将它们连接的碳原子一起形成螺环部分,前提是:R1和R2各自不是氢,或者R5和R6各自不是氢。
Description
本申请要求2008年5月22日提交的发明名称为″Depsipeptides and their therapeutic use″的英国专利申请GB 0809324.7和2008年5月22日提交的发明名称为″Depsipeptides and their therapeutic use″的GB 0809328.8的优先权,其通过引用整体并入本文。
技术领域
本发明涉及用作组蛋白去乙酰化酶(HDAC)的抑制剂,因此具有治疗效用的酯肽。
背景技术
HDAC是催化乙酰化赖氨酸残基的水解的锌金属酶。在组蛋白中,这使得赖氨酸回到它们的质子化状态并且是真核细胞转录控制的完全机制,导致DNA紧密包装在核小体中。另外,可逆的赖氨酸乙酰化是非组蛋白蛋白质的重要调节过程。因此,能够调节HDAC的化合物具有重要的治疗潜力。
天然产物FK228(结构I)和Spiruchostatin A(结构II)是已被报道具有作为HDAC抑制剂潜力的酯肽。术语酯肽描述了一类链中具有酯键和肽键的寡肽或多肽。
Spiruchostatin A是结构上与FK228相关的环状酯肽:其是含有三肽、抑胃酶氨酸单元和跨环桥的酯肽。
但是,由于FK228和Spiruchostatin A都是天然产物,因此它们不容易被优化用作治疗剂。
PCT/GB2007/050709中公开了Spiruchostatin A的类似物。它们相对于Spiruchostatin A或FK228可以具有改善的HDAC抑制特性或使它们更可用作做药物的其他类药特性。这些化合物具有结构III和IV所示的一般结构,其中R1、R5、R7和R9相同或不同,表示氢或来自于天然或非天然氨基酸的氨基酸侧链部分,R2和R6是氢,各个R10相同或不同,表示氢或者C1-C6烷基、C2-C6烯基或C2-C6炔基,Pr1和Pr2相同或不同,表示氢或硫醇保护基,和Pr3是氢或醇保护基。
WO2006/129105中公开了FK228的类似物。它们相对于FK228可以具有改善的HDAC抑制特性或使它们更可用作药物的其他类药特性。这些化合物具有结构V和VI所示的一般结构,其中R1、R5、R7和R9相同或不同,表示氢或来自于天然或非天然氨基酸的氨基酸侧链部分,R2和R6是氢,各个R10相同或不同,表示氢或者C1-C6烷基、C2-C6烯基或C2-C6炔基,Pr1和Pr2相同或不同,表示氢或硫醇保护基。
WO 2008/062201中公开了含二硫桥改性的FK228和Spiruchostatin A的类似物。
不受理论限制,据信结构VII和VIII通过还原二硫键分别由结构I和II形成于细胞中,所形成的4-硫代-丁基-1-烯是该化合物作用机制的关键部分,形成能够结合HDAC活性位点中的锌的亲金属性(metallophile)。
该理论得到以下观察的支持:具有完全不同环结构的环状酯肽HDAC抑制剂FR-901375,具有与FK228和Spiruchostatin A中所示相同的跨环含二硫桥。
发明内容
本发明提供其中R1和R2、和/或R5和R6都不是氢的结构III和IV。在这些化合物中,酯肽大环的6位(IUPAC系统命名法)和/或12位(IUPAC系统命名法)是双取代的,含有两个氨基酸侧链部分(二者都不是氢)或螺环部分。
本发明还提供其中R1和R2都不是氢和/或R5和R6都不是氢的结构V和VI。在这些化合物中,酯肽大环的6位(IUPAC系统命名法)和/或12位(IUPAC系统命名法)是双取代的,含有两个氨基酸侧链部分(二者都不是氢)或螺环部分。
出乎意料地,发现这些化合物是有效的HDAC酶抑制剂,并且具有表明它们可以具有更大潜力用于人类疾病治疗的特性。下文中将这些化合物指定为称为双取代酯肽(BSD)类化合物的成员。
本发明的化合物限定为结构IX和X或其可药用盐:
其中:
X是-C(=O)N(R10)-或-CH(OPr3)-;
R7、R9和R10相同或不同,表示氢或来自于天然或非天然氨基酸的氨基酸侧链部分;
Pr1和Pr2相同或不同,表示氢或硫醇保护基;
Pr3是氢或醇保护基;
R1、R2、R5和R6相同或不同,表示氢或来自于天然或非天然氨基酸的氨基酸侧链部分,或者R1和R2、和/或R5和R6与连接它们的碳原子一起形成螺环部分,
前提是:
R1和R2各自不是氢,或
R5和R6各自不是氢。
本发明还提供上述结构IX和X的化合物或其可药用盐用于制备用作HDAC抑制剂的药物的用途。
发明的描述
结构IX和X的化合物的合成通常利用其中-(CO)-CR’R”-NH-形成大环的一部分和R’和R”是侧链部分的氨基酸进行。R1、R2、R5和R6可通过这种方法引入。R7和R9可以是氨基酸侧链部分,但是可以不是从氨基酸本身直接或间接衍生的。
结构IX或X必须包含在酯肽大环的6位(IUPAC系统命名法)或12位(IUPAC系统命名法)处的双取代碳。在这类双取代化合物中,R1和R2都不是氢,或者R5和R6都不是氢。优选地,R1和R2和/或R5和R6与连接它们的碳原子一起形成螺环分子。优选地,该螺环分子具有3、4、5、6、7或8个碳原子。或者,R1和R2、和/或R5和R6可以是C1-C6烷基。如本文中所用,术语“氨基酸侧链部分”指可存在于天然和非天然氨基酸中的任何侧链,因此不限制基团R的性质。衍生自非天然氨基酸的氨基酸侧链部分的实例,括号中显示的是衍生它们的氨基酸,包括:-(CH2)2-C(O)-O-C(CH3)3(谷氨酸叔丁酯)、-(CH2)4-NH-C(O)-O-C(CH3)3(Nε-(叔丁氧基羰基)-赖氨酸)、-(CH2)3-NH-C(O)NH2(瓜氨酸)、-CH2-CH2OH(高丝氨酸)和-(CH2)3NH2(鸟氨酸)。实例还可包括C1-C6烷基、C2-C6烯基或C2-C6炔基、芳基、饱和或不饱和杂环(官能化的和未官能化的)。
C1-C6烷基基团或部分可为直链或支链的。通常,其为C1-C4烷基基团或部分,例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基和叔丁基。优选实例包括甲基、异丙基和叔丁基.
C2-C6烯基基团或部分可为直链或支链的。通常其为C2-C4烯基基团或部分。优选烯基是单不饱和的或二不饱和的,更优选为单不饱和的。实例包括乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基和3-丁烯基。
C2-C6炔基基团或部分可以是直链或支链的。通常其为C2-C4炔基基团或部分。
优选氨基酸侧链部分是衍生自天然氨基酸的那些。衍生自天然氨基酸的氨基酸侧链部分的实例,括号中显示的是衍生它们的氨基酸,是:-H(氨基乙酸)、-CH3(丙氨酸)、-CH(CH3)2(缬氨酸)、-CH2CH(CH3)2(亮氨酸)、-CH(CH3)CH2CH3(异亮氨酸)、-(CH2)4NH2(赖氨酸)、-(CH2)3NHC(=NH)NH2(精氨酸)、-CH2-(5-1H-咪唑基)(组氨酸)、-CH2CONH2(天冬酰胺酸)、-CH2CH2CONH2(谷氨酰胺)、-CH2COOH(天门冬氨酸)、-CH2CH2COOH(谷氨酸)、-CH2-苯基(苯基丙氨酸)、-CH2-(4-OH-苯基)(酪氨酸)、-CH2-(3-1H-吲哚基)(色氨酸)、-CH2SH(半胱氨酸)、-CH2CH2SCH3(蛋氨酸)、-CH2OH(丝氨酸)和-CH(OH)CH3(苏氨酸)。
优选每个氨基酸侧链是天然氨基酸中存在的氨基酸侧链部分或者是-(CH2)2-C(O)-O-C(CH3)3(谷氨酸叔丁基酯)、-(CH2)4-NH-C(O)-O-C(CH3)3(Nε-(叔丁氧基羰基)-赖氨酸)、-(CH2)3-NH-C(O)NH2(瓜氨酸)、-CH2-CH2OH(高丝氨酸)或-(CH2)2-CH2NH2(鸟氨酸)。
优选每个氨基酸侧链是天然氨基酸中存在的氨基酸侧链部分或者是-(CR11R11)x-NR11C(O)NR11R11、-(CR11R11)x-NR11C(O)NR11R13、-(CR11R11)x-NR11C(O)OR14、-(CR11R11)x-NR11C(O)R14、-(CR11R11)x-NR11C(O)R13、-(CR11R11)x-NR11SO2NR11R11、-(CR11R11)x-NR11SO2NR11R13、-(CR11R11)x-NR11SO3R14、-(CR11R11)x-NR11SO2R14、-(CR11R11)x-NR11SO2R13、-(CR11R11)x-C(O)NR11R11、-(CR11R11)x-C(O)NR11R13、-(CR11R11)x-CO2R11、-(CR11R11)x-C(O)R13、-(CR11R11)x-SO2NR11R11、-(CR11R11)x-SO2NR11R13、-(CR11R11)x-SO2R13、-(CR11R11)x-Ar。其中x是1~10的整数,R11是氢、C1-C6烷基、C3-C7环烷基、芳基、C2-C6烯基、C2-C6炔基、杂芳基,R13是NR11-C(O)R14、NR11-SO2R14,R14是C1-C6烷基、芳基、C2-C6烯基、C2-C6炔基、杂芳基,Ar是芳基或杂芳基环,包括但不限于噻唑、四唑、咪唑、唑、异唑、噻吩、吡唑、吡啶、嘧啶、吡嗪、哒嗪和官能化衍生物。
优选侧链部分的一对或者两对(其中R1和R2形成一对,R5和R6形成另一对)与连接它们的酯肽大环的碳原子一起形成螺环部分,使得作为该酯肽大环的一部分的碳也是外部环状部分的一部分,该外部环状部分为环烷基,或优选具有3~8个原子的其他环状基团例如环丙基。
本文中所用“芳基”指单环、双环或三环一价芳基,如苯基、联苯基、萘基、蒽基,其可任选地被至多5个独立地选自如下的取代基取代:C1-C6烷基、羟基、C1-C3羟基烷基、C1-C3烷氧基、C1-C3卤代烷氧基、氨基、C1-C3单烷基氨基、C1-C3二烷基氨基、C1-C3酰基氨基、C1-C3氨基烷基、单(C1-C3烷基)氨基C1-C3烷基、双(C1-C3烷基)氨基C1-C3烷基、C1-C3-酰基氨基、C1-C3烷基磺酰基氨基、卤素、硝基、氰基、三氟甲基、羧基、C1-C3烷氧羰基、氨基羰基、单C1-C3烷基氨基羰基、双C1-C3烷基氨基羰基、-SO3H、C1-C3烷基磺酰基、氨基磺酰基、单C1-C3烷基氨基磺酰基和双C1-C3-烷基氨基磺酰基。
本文中所用“杂芳基”指含有至多四个选自氧、氮和硫的杂原子的单环、双环或三环一价芳基,例如噻唑基、四唑基、咪唑基、唑基、异唑基、噻吩基、吡唑基、吡啶基、吡嗪基、嘧啶基、吲哚基、喹啉基、异喹啉基,所述基团任选地被至多3个独立地选自如下的取代基取代:C1-C6烷基、羟基、C1-C3羟基烷基、C1-C3烷氧基、C1-C3卤代烷氧基、氨基、C1-C3单烷基氨基、C1-C3二烷基氨基、C1-C3酰基氨基、C1-C3氨基烷基、单(C1-C3烷基)氨基C1-C3烷基、双(C1-C3烷基)氨基C1-C3烷基、C1-C3-酰基氨基、C1-C3烷基磺酰基氨基、卤素、硝基、氰基、三氟甲基、羧基、C1-C3烷氧羰基、氨基羰基、单C1-C3烷基氨基羰基、双C1-C3烷基氨基羰基、-SO3H、C1-C3烷基磺酰基、氨基磺酰基、单C1-C3烷基氨基磺酰基和双C1-C3-烷基氨基磺酰基。
基团Pr1和Pr2表示氢或硫醇保护基。所述硫醇保护基通常为:
(a)形成硫醚以保护硫醇基团的保护基,例如任选被C1-C6烷氧基(如甲氧基)、C1-C6酰氧基(例如乙酰氧基)、羟基和硝基、吡啶甲基、吡啶甲基-N-氧化物、蒽基甲基、联苯基甲基、苯基、叔丁基、金刚烷基、C1-C6酰氧基甲基(例如新戊酰氧基甲基、叔丁氧羰基氧基甲基)取代的苄基;
(b)形成单硫代、双硫代或氨基硫缩醛以保护硫醇基团的保护基,例如C1-C6烷氧基甲基(例如甲氧基甲基、异丁氧基甲基)、四氢吡喃基、苄基硫代甲基、苯基硫代甲基、噻唑基、乙酰胺甲基、苯甲酰胺基甲基;
(c)形成硫酯以保护硫醇基团的保护基,例如叔丁氧基羰基(BOC)、乙酰基及其衍生物、苯甲酰基及其衍生物;或者
(d)形成氨基甲酸硫酯以保护硫醇基团的保护基,例如氨基甲酰基、苯基氨基甲酰基、C1-C6烷基氨基甲酰基(例如甲基氨基甲酰基和乙基氨基甲酰基)。
通常,Pr1和Pr2相同或不同,各自表示氢或形成硫醚,单硫代、双硫代或氨基硫缩醛,硫酯或氨基甲酸硫酯以保护硫醇基团的保护基。优选地,Pr1和Pr2相同或不同,各自表示氢或选自:被C1-C6烷氧基(如甲氧基)、C1-C6酰氧基(例如乙酰氧基)、羟基和硝基、吡啶甲基、吡啶甲基-N-氧化物、蒽基甲基、联苯基甲基、苯基、叔丁基、金刚烷基、C1-C6酰氧基甲基(例如新戊酰氧基甲基、叔丁氧羰基氧基甲基)取代的苄基;C1-C6烷氧基甲基(例如甲氧基甲基、异丁氧基甲基)、四氢吡喃基、苄基硫代甲基、苯基硫代甲基、噻唑烷、乙酰胺甲基、苯甲酰胺基甲基;叔丁氧基羰基(BOC)、乙酰基及其衍生物、苯甲酰基及其衍生物;氨基甲酰基、苯基氨基甲酰基和C1-C6烷基氨基甲酰基(例如甲基氨基甲酰基和乙基氨基甲酰基)的保护基。最优选Pr1和Pr2是氢。
基团Pr3表示氢或形成醚、缩醛或氨基缩醛、酯或氨基甲酸酯以保护羟基的保护基。优选地,Pr3表示氢或选自:被C1-C6烷氧基(如甲氧基)、C1-C6酰氧基(例如乙酰氧基)、羟基和硝基、吡啶甲基、吡啶甲基-N-氧化物、蒽基甲基、联苯基甲基、苯基、叔丁基、金刚烷基、C1-C6酰氧基甲基(例如新戊酰氧基甲基、叔丁氧羰基氧基甲基)取代的苄基;C1-C6烷氧基甲基(例如甲氧基甲基、异丁氧基甲基)、四氢吡喃基、苄基硫代甲基、苯基硫代甲基、噻唑烷基、乙酰胺甲基、苯甲酰胺基甲基;叔丁氧基羰基(BOC)、乙酰基及其衍生物、苯甲酰基及其衍生物;氨基甲酰基、苯基氨基甲酰基和C1-C6烷基氨基甲酰基(例如甲基氨基甲酰基和乙基氨基甲酰基)的保护基。最优选Pr3是氢。
优选地,X是-CH(OPr3),并且本发明的化合物具有结构IXa和Xa之一:
优选的实施方案包括化合物XI至XIII:
优选X是-C(=O)N(R10)-,并且本发明的化合物具有结构IXb或Xb:
优选的实施方案包括化合物XIV至XXXIV:
本发明还提供式IX或X的化合物、其等排体或其可药用盐和可药用载体或稀释剂。所述药用组合物通常含有至多85wt%的本发明的化合物。更典型地,其含有至多50wt%的本发明的化合物。优选的药物组合物是无菌和无热原的。另外,本发明提供的药物组合物通常含有作为基本纯的光学异构体的本发明化合物。优选地,药物组合物含有结构IX或X的化合物的可药用盐或其等排体。
如本文中所用的,可药用盐是与可药用酸或碱的盐。可药用酸包括无机酸如盐酸、硫酸、磷酸、焦磷酸、氢溴酸或硝酸,和有机酸如柠檬酸、富马酸、马来酸、苹果酸、抗坏血酸、琥珀酸、酒石酸、安息香酸、乙酸、甲磺酸、乙磺酸、苯磺酸或对甲苯磺酸。可药用碱包括碱金属(例如钠和钾)和碱土金属(例如钙和镁)的氢氧化物,和有机碱如烷基胺、芳烷基胺或杂环胺。
如本文中所用,术语“等排体”是指由一个原子或一组原子与大体相似的另一个原子或一组原子交换所得的化合物。在结构IX或X的化合物中,含有等排基团的部分优选为:-NR10-CHR1-CO-、-NR10-CHR9-CO-O-和-NR10-CO-CHR5-NR10-CO-CHR7-。这类等排体的实例是结构IX或X的化合物,其中部分-NH-被-CH2-、-O-或-S-代替,部分-CO-被-CS-或-C(=NH)-代替,部分-O-被-S-、-CH2-或-NH-代替。
为免生疑问,本发明还包括在体内反应得到本发明的化合物或其等排体或可药用盐的前药。
其中X为-CH(OPr3)-的结构IXa和Xa的本发明的化合物,可通过常规途径,例如采用下列方案1制备,其中官能团如上定义,PG表示氮保护基:
方案1
在方案1步骤(a)中,使带有侧链R1和R2的N被保护的氨基酸与带有侧链R9的酯烯醇化物缩合,然后将所得中间体1,3-二酮酯还原以提供抑胃酶氨酸单元,其中Pr3是H或可去除的醇保护基。在步骤(b)中,除去N-保护基,使抑胃酶氨酸偶联到被保护的半胱氨酸衍生物以提供肽等排体。在步骤(c)中,除去N保护基,使所述肽等排体与带有侧链R5和R6的N被保护的氨基酸偶联。在步骤(d)中,除去N保护基,使所得中间体与官能化β-羟基酸衍生物(其中R15是临时阻挡基团,其可以被除去以产生其中R15是H的化合物,X是手性助剂)偶联,如Yurek-George,A.;Habens,F.;Brimmell,M.;Packham,G.;Ganesan,A.在J.Am.Chem.Soc.2004,126,1030-1031中报道的。在步骤(e)中,酯被水解,促进步骤(f)中的环化以提供其中X是-CH(OPr3)-的结构Xa的本发明的化合物。在步骤(g)中形成二硫键,以提供其中X是-CH(OPr3)-的结构IXa的本发明的化合物。
其中X是-C(=O)N(R10)-的结构IXb和Xb的本发明的化合物可通过常规途径,例如采用下列方案2制备,其中官能团如上定义:
方案2
在方案2步骤(a)中,使带有侧链R9的氨基酸酯与另一个带有侧链R1和R2的N被保护的氨基酸(其中PG表示常规保护基)偶联,得到N被保护的二肽酯。在步骤(b)中,除去N-保护基,使得到的二肽酯与被保护的半胱氨酸偶联。在步骤(c)中,除去N保护基,使所得三肽与带有侧链R5和R6的N被保护的氨基酸偶联以产生N被保护的四肽酯。在步骤(d)中,除去N保护基,使所得四肽酯与官能化β-羟基酸衍生物(其中R15是临时阻挡基团,其可以被除去以产生其中R15是H的化合物,X是手性助剂)偶联,如Yurek-George,A.;Habens,F.;Brimmell,M.;Packham,G.;Ganesan,A.在J.Am.Chem.Soc.2004,126,1030-1031中报道的。在步骤(e)中,使酯水解,促进步骤(f)中的环化以提供其中X是-C(=O)N(R10)-的结构Xb的化合物。在步骤(g)中形成二硫键,以提供其中X是-C(=O)N(R10)-的结构IXb的本发明的化合物。
其中R10不为氢的结构IX和X的本发明化合物可通过使其中R10为氢的相应的本发明化合物或中间体进行烷基化,或者通过使用适当取代的原料来获得。
结构X的化合物可通过使上述方案1和2的步骤(g)的产物,即结构IX的化合物进行反应以使二硫键断裂而获得。二硫键的断裂通常利用一般用于具有二硫键的蛋白质的还原处理的硫醇化合物来获得,例如巯基乙醇、硫代二醇酸、2-巯基乙胺、巯基苯、对硫代甲酚和二巯基苏糖醇。优选地,使用巯基乙醇和二巯基苏糖醇。过量硫醇化合物可通过例如透析或凝胶过滤除去。或者,例如可利用电解、四氢硼酸钠、氢化锂铝或亚硫酸盐来使二硫键断裂。
其中Pr1和/或Pr2不为氢的结构X的化合物可通过将硫醇保护基引入Pr1和/或Pr2为氢的相应化合物中来制备。在这个方面,适合于将待使用的硫醇保护基引入该反应的试剂适当地根据所引入的保护基来确定。实例包括相应保护基的氯化物(例如苄基氯、甲氧基苄基氯、乙酰氧基苄基氯、硝基苄基氯、氯甲基吡啶、氯甲基吡啶-N-氧化物、蒽基甲基氯、异丁氧基甲基氯、苯基硫代甲基氯)和相应保护基的醇(例如二苯基甲基醇、金刚烷醇、乙酰胺甲基醇、苯甲酰胺基甲基醇),二硝基苯基、异丁烯、二甲氧基甲烷、二氢吡喃和氯甲酸叔丁酯。
技术人员会理解,当R1、R5、R7、R9、R10之一带有如-OH、-SH、-NH2或-COOH的官能团时,则可以优选该基团在引入后在一个或多个反应步骤中被保护。在这种情况下,所讨论的基团可以在引入后在单独步骤中被保护,或者其在引入时已经被保护。技术人员知道就此而言可使用的合适保护基。
由此获得的本发明的化合物可以通过用合适的酸或碱处理而成盐。通过任何上述方法获得的外消旋混合物可通过标准技术,例如在手性柱色谱上洗脱而拆分。
技术人员会理解多种试验适用于测试HDAC抑制作用,并且可用于测量由方案1获得的化合物的活性相对于已知的HDAC抑制剂SAHA的活性。因此,测试化合物对HDAC的IC50可例如在体外试验中确定,并且与在相同试验条件下SAHA的IC50比较。如果测试化合物具有等于或小于SAHA的IC50值,则应理解为其具有至少与SAHA所显示相等的HDAC抑制活性。
在一个优选实施方案中,本发明提供选择如上所述具有至少与SAHA所显示相等的HDAC抑制活性的化合物的方法,其中在完成方案1之后,下一步是体外HDAC试验。通常,所述试验包括使测试化合物和SAHA在不同浓度下与稀释的HeLa细胞核提取物接触,以确定测试化合物和SAHA对HeLa细胞核提取物的IC50。具有对HeLa细胞核提取物测得的等于或低于在相同试验条件下SAHA的IC50的IC50值的测试化合物应当理解为具有至少与SAHA所显示相等的抑制活性。通常所述试验利用HDAC荧光活性检测试剂盒(Biomol,UK)进行,并且在分析之前还原测试化合物。
在另一个实施方案中,本发明提供选择具有至少与SAHA所显示相等的人类癌细胞生长抑制活性的化合物的方法,所述方法包括经由上述方案1制备结构IX或X的化合物,然后筛分由此获得的化合物以测定其作为人类癌细胞生长抑制剂的活性。
技术人员会理解多种试验适用于测试人类癌细胞生长抑制,并且可用于测量与SAHA比较的由方案1获得的化合物的活性。因此,测试化合物对人类癌细胞生长的IC50可例如通过在体外试验中确定,并且与在相同试验条件下SAHA的IC50比较。如果测试化合物具有等于或小于SAHA的IC50值,则应理解为其具有至少与SAHA所显示相等的抑制活性。通常在该实施方案中,该步骤包括体外试验,其包括使测试化合物和SAHA在不同浓度下与MCF7乳腺、HUT78 T-细胞白血病、A2780卵巢、PC3或LNCAP前列腺癌细胞系接触,以确定测试化合物和SAHA对细胞系的IC50。具有对任何这些细胞系测得的等于或低于在相同试验条件下SAHA的IC50的IC50值的测试化合物应当理解为具有至少与SAHA所显示相等的抑制活性。通常在该实施方案中,所述试验利用CyQuantTM试验系统(Molecular Probes,Inc.USA)进行。
在另一个优选实施方案中,本发明提供选择具有至少与SAHA所显示相等的消炎活性的化合物的方法,所述方法包括经由上述方案1制备结构IX或X的化合物,然后筛分由此获得的化合物以测定其消炎活性。
技术人员会理解多种试验适用于评价化合物的消炎活性。测试化合物相对于SAHA的消炎活性可通过例如测量化合物相对于SAHA在抑制TNFα从外周血单个核细胞(PBMC)中产生的活性来确定。因此,测试化合物抑制TNFα从PBMC产生的能力可例如在试验中确定,并且与在相同试验条件下SAHA的活性比较。如果测试化合物具有等于或高于在相同试验条件下SAHA的TNFα产生的体外抑制活性,则应理解为其具有至少与SAHA所显示相等的消炎活性。通常该步骤利用QuantikineHuman-α检测试剂盒(R&D systems,Abingdon UK)进行。
在这个实施方案的另一方面,测试化合物相对于SAHA的消炎活性可通过评价化合物相对于SAHA抑制Balb/c小鼠炎性的活性。如果测试化合物具有等于或高于相同试验条件下SAHA的体内抑制活性,则应理解为其具有至少与SAHA所显示相等的消炎活性。通常,在该实施方案中,该步骤通过评价测试化合物和SAHA在抑制化学激发诱导的Balb/c小鼠炎性的体内活性来进行。通常所述化学激发包括为小鼠局部施用oxalazone或丙酮。在该实施方案中,所研究的化合物可在化学激发之前或之后施加。
在另一个优选实施方案中,本发明提供选择具有至少与SAHA所显示相等的在诱导MCF7细胞中主导G2/M相滞留或细胞死亡中的活性的化合物的方法,所述方法包括经由上述方案1制备结构I或X的化合物,然后筛分由此获得的化合物以测量其相对于SAHA在MCF7细胞中诱导主导G2/M中期停顿或细胞死亡中的活性。
发现本发明的化合物是HDAC抑制剂。因此,本发明的化合物是治疗学上可用的。
本发明的化合物和包含它们的组合物可以以多种剂型施用。在一个实施方案中,包含本发明的化合物的药物组合物可配制成适合口服、直肠、肠胃外、鼻内或透皮施用或者通过吸入或栓剂施用的形式。典型的施用途径为肠胃外、鼻内或透皮施用或者通过吸入施用。
本发明的化合物可例如以片剂、糖锭(troche)、锭剂(lozenge)、水性或油性混悬剂、可分散粉剂或颗粒剂口服施用。优选的本发明的药物组合物为适合于口服施用的组合物,例如片剂或胶囊。
本发明的化合物也可以肠胃外施用,无论是皮下的、静脉的、肌肉的、鼻内的、透皮的还是通过灌注技术。化合物也可以作为栓剂施用。
本发明的化合物还可以通过吸入施用。吸入药物的优点在于相比于很多通过口服途径摄取的药物,它们直接递送到丰富的血液供应区域。因此,由于肺泡具有巨大的表面积、丰富的血液供应和绕过首过代谢,因此吸收非常迅速。另一个优点是可以治疗肺系疾病,使得递送药物通过吸入将它们递送到需要治疗的细胞的周围。
本发明还提供含有这种药物组合物的吸入装置。通常所述装置为计量吸入器(MDI),其包含可药用化学推进剂以将药物推出吸入器。
本发明的化合物也可通过鼻内施用。鼻腔的高渗透性组织非常易于接受药物,因此吸收药物比片剂形式的药物更快且更有效。鼻药物递送比注射的痛苦性和入侵性小,在患者中产生更少的焦虑。通过这种方法,吸收非常迅速,通常绕过首过代谢,因此减少了患者间的变异性。另外,本发明还提供含有这种药物组合物的鼻内装置。
本发明的化合物还可通过透皮施用。因此,本发明还提供含有本发明的化合物或其可药用盐的透皮贴剂。
本发明的化合物还可通过舌下施用。因此,本发明还提供含有本发明的化合物或其可药用盐的舌下片剂。
本发明的化合物通常配制为与可药用载体或稀释剂一起施用。
本发明的化合物还可配制为含有通过除患者正常代谢之外的过程降低物质分解的试剂,如抗菌剂或蛋白酶抑制剂,其可存在于患者体内或者生活在患者身上或体内的共生或寄生生物中并且能够降解化合物。
用于口服施用的液体分散体可为糖浆、乳液和悬浮体。悬浮体和溶液可包含例如天然树胶、琼脂、海藻酸钠、果胶、甲基纤维素、羰甲基纤维素或聚乙烯醇作为载体。用于肌肉注射的悬浮体或溶液可包含活性化合物以及可药用载体例如无菌水、橄榄油、油酸乙酯、二醇如丙二醇,以及如果需要,适量的盐酸利多卡因。
注射或输注用溶液可包含例如无菌水作为载体,或者优选它们可以为无菌等渗盐水溶液形式。
本发明的化合物在治疗学上可用于治疗或预防由HDAC介导的症状。因此,本发明提供结构X或X的化合物或其可药用盐用于制备用于治疗或预防明显受HDAC活性影响的症状的药物的用途。还提供治疗患有或易患由HDAC介导的症状的患者的方法,所述方法包括给所述患者施用有效量的结构IX或X的化合物、其等排体或其可药用盐。
在一个实施方案中,本发明的化合物可与另一种已知的HDAC抑制剂如SAHA联用。在该实施方案中,组合产品可配制为使得其包含同时、单独或顺序使用的每种药物。
因此,本发明还提供根据结构IX或X的化合物或其等排体或可药用盐用于制备与另一种已知的HDAC抑制剂如SAHA共同施用的药物的用途。
本发明的化合物可用于治疗和预防癌症,并且可用于单独治疗或联合治疗。当用于联合治疗时,本发明的化合物通常与小的化学化合物例如铂络合物、抗代谢物、DNA拓扑异构酶抑制剂、放射、抗体疗法(如单克隆抗体和利妥昔单抗)、抗癌疫苗、基因疗法、细胞疗法、激素疗法或细胞因子疗法一起使用。
在本发明的一个实施方案中,本发明的化合物与另一种化疗剂或抗肿瘤剂联合用于治疗癌症。这种化疗剂或抗肿瘤剂的实例包括:米托蒽醌,长春花生物碱如长春新碱和长春碱,蒽环类抗生素例如阿霉素和柔红霉素,烷化剂例如苯丁酸氮芥和马法兰,紫杉烷类例如紫杉醇,叶酸拮抗剂例如甲氨蝶呤和雷替曲塞,足叶草乙甙例如依托泊苷,喜树碱例如伊立替康及其活性代谢产物SN 38,和DNA甲基化抑制剂例如WO 02/085400中公开的。
因此,根据本发明,提供包含本发明的化合物和另一种化疗剂或抗肿瘤剂作为联合制剂以同时、单独或顺序使用来缓解癌症的产品。根据本发明,还提供上述结构IX或X的化合物或其等排体或其可药用盐用于制备通过与另一种化疗剂或抗肿瘤剂共同施用来缓解癌症的药物的用途。
本发明的化合物和所述其他试剂可以以任意顺序施用。在这两种情况下,本发明的化合物和其他试剂可以一起,或者如果单独地以医师确定的任何顺序施用。
据信HDAC是几种不同疾病的病理和/或症状的成因,使得通过抑制HDAC降低对象中的HDAC活性可用于在治疗学上解决这些病症。本文中描述了可以利用本发明的HDAC抑制剂治疗的多种疾病的实例,而且本文中包括由结构IX或X描述的本发明的化合物的用途。应注意除本文中公开的那些之外的额外疾病可能以后会被认定为本发明的化合物的应用,因为HDAC在多种渠道起到的生物学作用越来越多地被发现。
可使用本发明的HDAC抑制剂来治疗的一组适应症是涉及不希望或不受控制的细胞增殖的那些。这些适应症包括良性肿瘤、各种类型的癌症例如原发性肿瘤和肿瘤转移、再狭窄(如冠状动脉、颈动脉和脑病变)、内皮细胞的异常刺激(动脉硬化)、因手术对身体组织的损伤、异常伤口愈合、异常血管生成、产生组织纤维化的疾病、重复运动障碍、不属于高度血管化的组织紊乱和与器官移植相关的增殖应答。更具体的对HDAC抑制剂的适应症包括但不限于前列腺癌、肺癌、急性白血病、多发性骨髓瘤、膀胱癌、肾癌、乳腺癌、大肠癌、神经母细胞瘤和黑色素瘤。
在一个实施方案中,提供用于治疗与不希望和不受控制的细胞增殖相关的疾病的方法。所述方法包括为患有不受控制的细胞增殖的对象施用治疗有效量的本发明的HDAC抑制剂,从而减轻所述不受控制的细胞增殖。所使用的抑制剂的特定剂量将取决于病症的严重程度、施用路径和可由主治医生确定的相关因素。一般地,可接受和有效的日剂量为足以有效地减缓或消除不受控制的细胞增殖的量。
根据本发明的HDAC抑制剂也可与其他抑制不希望和不受控制的细胞增殖的试剂联用。可与本发明的HDAC抑制剂联用的其他抗细胞增殖试剂的实例包括但不限于维甲酸及其衍生物、2-甲氧基雌二醇、ANGIOSTATIN(TM)蛋白质、ENDOSTATIN(TM)蛋白质、苏拉明、角鲨胺、金属蛋白酶-1组织抑制剂、金属蛋白酶-2组织抑制剂、纤溶酶原激活物抑制剂-1、纤溶酶原激活物抑制剂-2、软骨源性抑制剂、紫杉酚、血小板因子4、硫酸精蛋白(鲱精蛋白)、硫酸化甲壳素衍生物(由皇后蟹壳制备)、硫酸多糖肽复合物(sp-pg)、十字孢碱、基质代谢调节剂,包括例如脯氨酸类似物((1-氮杂环丁烷-2-羧酸(LACA)、顺羟基脯氨酸、d,l-3,4-脱氢脯氨酸、硫代脯氨酸)、β-氨基丙腈富马酸盐/酯、4-丙基-5-(4-吡啶基)-2(3H)-唑酮;甲氨蝶呤、米托蒽醌、肝素、干扰素、2巨球蛋白-血清、chimp-3、胰凝乳蛋白酶抑制剂、β-环糊精十四硫酸酯、eponemycin;烟曲霉素、金硫丁二钠、d-青霉胺(CDPT)、β-1-抗胶原酶-血清、α2-抗血纤维蛋白溶素、比山群、氯苯扎利二钠、n-(2-羧基苯基-2-氨基-4-氯苯甲酸二钠或″CCA″、沙利度胺;血管生成类固醇,羧基氨基咪唑;金属蛋白酶抑制剂,如BB94。其他可用的抗血管生成剂包括抗体,优选对抗这些血管生长因子的单克隆抗体:bFGF、aFGF、FGF-5、VEGF亚型、VEGF-C、HGF/SF和Ang-1/Ang-2。Ferrara N.和Alitalo、K.″Clinical application of angiogenic growth factors and their inhibitors″(1999)Nature Medicine 5:1359-1364。
一般地,良性肿瘤中的细胞保留它们的分化的5个特征,不以完全不受控制的方式分裂。良性肿瘤通常停留在一个地方并且不转移。可用本发明的HDAC抑制剂治疗的良性肿瘤的特定类型包括血管瘤、肝细胞瘤、海绵状血管瘤、局灶性结节性增生、听神经瘤、神经纤维瘤、胆管腺瘤、胆管cystanoma、纤维瘤、脂肪瘤、平滑肌瘤、间皮瘤、畸胎瘤、黏液瘤、结节性再生性增生、沙眼和化脓性肉芽肿。
在恶性肿瘤中,细胞变为未分化的,对身体的生长控制信号不响应并且以不受控制的方式繁殖。恶性肿瘤是侵入性的,能够扩散到远端部分(转移性)。恶性肿瘤一般分为两类:原发性和继发性。原发性肿瘤直接从发现它们的组织出现。继发性肿瘤或转移瘤是起源于身体的其他地方但已经扩散到远端器官的肿瘤。转移的一般路径是直接长到邻近结构中,通过血管或淋巴系统扩散并且沿着组织平面和身体空间(腹腔液、脑脊液等)追踪。
可用本发明的HDAC抑制剂治疗的特定类型的癌症或恶性肿瘤(无论是原发性还是继发性)包括但不限于:白血病、乳腺癌、皮肤癌、骨癌、前列腺癌、肝癌、肺癌、脑癌、喉、胆囊、胰腺、直肠、副甲状腺、甲状腺、肾上腺、神经组织、头部和颈部、结肠、胃、支气管、肾的癌症、基底细胞癌、溃烂和乳头状类型的鳞状细胞癌、转移性皮肤癌、骨肉瘤、尤因氏肉瘤、veticulum细胞肉瘤、多发性骨髓瘤、巨细胞瘤、小细胞肺癌、胆结石、胰岛细胞瘤,原发性脑瘤、急性和慢性淋巴细胞和粒细胞肿瘤、毛细胞瘤、腺瘤、增生、髓样癌、嗜铬细胞瘤、粘膜neuronm、肠神经节细胞、增生性角膜神经瘤、马方综合症习性肿瘤、肾母细胞瘤、精原细胞瘤、卵巢肿瘤、子宫肌瘤、宫颈不典型增生和原位癌、神经母细胞瘤、视网膜神经胶质瘤、软组织肉瘤、恶性类癌、局部皮肤损伤、蕈样肉芽肿病、横纹肌肉瘤、卡波西氏肉瘤、骨源性和其他肉瘤、恶性高钙血症、肾细胞瘤、真性红细胞增多症、腺癌、胶质母细胞瘤、白血病、淋巴瘤、恶性黑色素瘤、表皮样癌以及其他癌和肉瘤。
本发明的HDAC抑制剂也可用于治疗由手术过程中身体组织损伤引起的异常细胞增殖。这些损伤可由于多种手术过程如联合手术、肠道手术和瘢痕体伤疤而出现。产生纤维化组织的疾病包括肺气肿。可采用本发明治疗的重复运动障碍包括腕管综合征。可采用本发明治疗的细胞增生病症的实例为骨癌。
可用本发明的HDAC抑制剂治疗的与器官移植相关的增殖应答包括造成潜在器官排斥或相关并发症的增殖应答。具体地,这些增殖应答可在心、肺、肝、肾和其他身体器官或器官系统的移植过程中出现。
可采用本发明治疗的异常血管生成包括类风湿性关节炎、脑水肿及损伤相关的缺血再灌注、皮质缺血、卵巢增生和血管过多、(多囊卵巢综合症)、子宫内膜异位症、银屑病、糖尿病性视网膜病变和其他眼部血管疾病,如早产儿视网膜病变(晶状体后纤维组织形成)、黄斑变性、角膜移植排斥、neuroscular青光眼和奥斯特韦伯综合征伴随的异常血管生成。
根据本发明可治疗的与不受控制的血管生成相关的疾病的实例包括但不限于:视网膜/脉络膜新血管形成和角膜新血管形成。视网膜/脉络膜新血管形成包括但不限于:贝斯茨病、近视、视神经坑、Stargarts病、Pagets病、静脉阻塞、动脉阻塞、镰状细胞性贫血、结节病、梅毒、弹性假黄瘤颈动脉或构造性疾病、慢性葡萄膜炎/玻璃体炎、结核菌感染、莱姆病、系统性红斑狼疮、早产儿视网膜病变、Eales病、糖尿病性视网膜病变、黄斑变性、Bechets病、引起视网膜炎或chroiditis的感染、推定眼组织胞浆菌病、睫状体扁平部炎、慢性视网膜脱离、高粘滞综合征、弓形虫病、创伤后激光并发症、与红变(角的新血管形成)相关的疾病和由纤维血管或纤维组织异常增生所引起的疾病,包括所有形式的增生性玻璃体视网膜病变。角膜新血管形成疾病的实例包括但不限于流行性角结膜炎、维生素A缺乏症、隐形眼镜过度磨损、过敏性角膜炎、上缘角膜结膜炎、翼状胬肉干燥性角膜炎、干燥、痤疮酒渣鼻、泡性角膜结膜炎、糖尿病视网膜病变、早产儿视网膜病变、角膜移植排斥、蚕蚀性角膜溃疡、Terrien边缘变性、边缘角蛋白溶解、多动脉炎、韦格纳结节病、巩膜炎、periphigoid放射状角膜切除术、新血管形成性青光眼及晶状体后纤维组织形成、梅毒、分枝杆菌感染、脂质变性、化学烧伤、细菌性溃疡、真菌性溃疡、单纯疱疹病毒感染、带状疱疹感染、原虫感染和卡波西氏肉瘤。
与不受控制的血管生成相关的慢性炎性疾病也可用本发明的HDAC抑制剂治疗。慢性炎症取决于毛细血管芽的连续形成以维持炎性细胞的涌入。炎症细胞的涌入和存在产生肉芽肿,从而保持慢性炎症状态。单独使用HDAC抑制剂或与其他消炎试剂联用抑制血管生成可以阻止肉芽肿的形成,从而缓解疾病。慢性炎性疾病的实例包括但不限于,炎性肠道疾病如克罗恩病和溃疡性结肠炎、银屑病、结节病和类风湿性关节炎。
炎性肠道疾病如克罗恩病和溃疡性结肠炎的特征在于在消化道中各部位处的慢性炎症和血管生成。例如,克罗恩病发生为慢性透壁炎性疾病,其最常见的是影响远端回肠和结肠,但也可能发生在从口腔到肛门及肛周的消化道的任何部分。患有克罗恩病的患者一般有慢性腹泻,伴随腹痛、发烧、厌食、体重减轻和腹部肿胀。溃疡性结肠炎也是一种慢性、非特异性、炎症和溃疡性疾病,出现在结肠黏膜,特征在于出现出血性腹泻。这些炎性肠道疾病一般是由在整个消化道的慢性肉芽肿性炎症引起的,包括被炎性细胞柱包围的新的毛细血管芽。通过这些抑制剂抑制血管新生应该抑制芽的形成和阻止肉芽肿的形成。炎性肠道疾病也表现出额外的表现,如皮肤损伤。这类损伤的特征在于炎症和血管生成,并且可以发生在消化道之外的很多部位。通过本发明的HDAC抑制剂抑制血管生成可降低炎性细胞的涌入和阻止损伤形成。
结节病是另一种慢性炎性疾病,特征在于多系统肉芽肿性疾病。这种疾病的肉芽肿可在身体的任何地方形成。因此,症状取决于肉芽肿的位置和疾病是否是活性的。通过血管新生成毛细血管芽产生肉芽肿,从而提供持续供应的发炎细胞。通过使用根据本发明的HDAC抑制剂抑制血管生成,可以抑制这种肉芽肿形成。银屑病也是一种慢性和复发性炎性疾病,特征在于不同大小的丘疹及斑块。使用这些抑制剂单独治疗或与其他抗发炎剂联合治疗应该阻止维持特征性病变必需的新血管形成,从而缓解患者的症状。
类风湿性关节炎(RA)也是一种慢性炎性疾病,特征在于非特异性外周关节发炎。据信在关节滑膜衬里中的血管经历血管生成。除了形成新的血管网络之外,内皮细胞释放导致血管翳生长和软骨破坏的因子和活性氧物质。血管生成涉及的因素可有利于和帮助维持类风湿性关节炎的慢性发炎症状。使用根据本发明的HDAC抑制剂单独治疗或与其他抗-RA剂联合治疗可以阻止维持慢性炎症必需的新血管的形成。
本发明化合物还可以用于治疗心脏/血管疾病,如肥大、高血压、心肌梗死、再灌注、缺血性心脏病、心绞痛、心律失常、高脂血症、动脉粥样硬化和中风。该化合物还可用于治疗神经退行性紊乱/CNS紊乱,如急性和慢性神经系统疾病,包括中风、亨廷顿氏病、肌萎缩性脊髓侧索硬化症和阿尔茨海默氏病。
本发明的化合物也可用作抗菌药物,例如抗菌剂。因此,本发明还提供用于治疗细菌感染的化合物。本发明的化合物可用作抗病毒、细菌、真菌和寄生虫感染的抗感染化合物。感染的实例包括原虫寄生虫感染(包括疟原虫、隐孢子虫、弓形虫、肉孢子虫和艾美耳属球虫。)
本发明的化合物特别适用于治疗不希望或不受控制的细胞增生,优选用于治疗良性肿瘤/增生与恶性肿瘤,更优选用于治疗恶性肿瘤,最优选用于治疗CCL、乳腺癌和T-细胞淋巴瘤。
在本发明的一个优选实施方案中,本发明的化合物用于缓解癌症、心脏肥大、慢性心力衰竭、炎症、心血管疾病、血红蛋白病、地中海贫血、镰状细胞病、CNS紊乱、自身免疫性疾病、糖尿病、骨质疏松、MDS、良性前列腺增生、口白斑病、基因相关的代谢障碍、感染、Rubens-Taybi、脆性X综合征、或α-1抗胰蛋白酶缺乏症,或加快伤口愈合,保护毛囊或作为免疫抑制剂。
通常,所述炎症是皮肤炎症(例如银屑病、痤疮和湿疹)、哮喘、慢性阻塞性肺疾病(COPD)、类风湿性关节炎(RA)、炎性肠道疾病(IBD)、克罗恩病或结肠炎。
通常,所述癌症是慢性淋巴细胞白血病、乳腺癌、前列腺癌、卵巢癌、间皮瘤或T-细胞淋巴瘤。
通常,所述心血管疾病是高血压、心肌梗死(MI)、缺血性心脏病(IHD)(再灌注)、心绞痛、心律失常、高脂血症、高脂血症、动脉粥样硬化、中风、心肌炎、充血性心力衰竭、原发性和继发性,即扩张型(充血性)心肌病、肥厚性心肌病、限制性心肌病、周围血管疾病、心动过速、高血压或血栓。
通常,所述基因相关的代谢障碍是囊性纤维化(CF)、过氧化物酶合成紊乱或肾上腺脑白质营养不良。
通常,本发明的化合物用作器官移植后免疫抑制剂。
通常,所述感染是病毒、细菌、真菌或寄生虫感染,特别是由金黄色葡萄球菌、P痤疮、念珠菌或曲霉引起的感染。
通常,所述CNS紊乱是亨廷顿氏病、阿尔茨海默氏症、多发性硬化症或肌萎缩性侧索硬化症。
在该实施方案中,本发明的化合物可用于缓解癌症、心脏肥大、慢性心力衰竭、炎症、心血管疾病、血红蛋白病、地中海贫血、镰状细胞病、CNS紊乱、自身免疫性疾病、糖尿病或骨质疏松症,或用作免疫抑制剂。
本发明的化合物也可用于缓解慢性淋巴细胞白血病、乳腺癌、前列腺癌、卵巢癌、间皮瘤、T-细胞淋巴瘤、心脏肥大、慢性心力衰竭或皮肤炎症,特别是银屑病、痤疮或湿疹。
本发明的化合物可以用于治疗动物,优选治疗哺乳动物,更优选治疗人。
如果合适的话,本发明的化合物可用于预防性降低这类疾病的发生率。
将治疗有效量的本发明化合物施用给患者。典型的剂量为约0.001到50毫克每千克体重,取决于特定化合物的活性,治疗对象的年龄、体重和状况,疾病的类型和严重程度以及施用的频率和途径。
实施例
化合物XIa和XIb:3-((E)-(1S,9S,20R)-5-羟基-6,6-环丙基-3,8,18,21-四
氧代-2-氧杂-11,12-二硫杂-7,19,22-三氮杂-二环[7.7.6]二十二-15-烯-20-
基)-丙酸叔丁酯的非对映异构体
(2):3-(1-叔丁氧羰基氨基-环丙基)-3-氧代-丙酸甲酯
向在CH2Cl2(44mL)中的1-叔丁氧羰基氨基-环丙烷羧酸1(2.077g,10.3mmol)中加入DMAP(258mg,2.11mmol)、五氟苯酚(2.100g,11.4mmol)和EDAC(2.369g,12.3mmol),反应混合物在室温下搅拌1小时50分钟。加入1M HCl水溶液(40mL),分层,用饱和NaHCO3水溶液(40mL)清洗,然后用饱和盐水(40mL)清洗后,有机层干燥(MgSO4),真空浓缩,置于高真空下。在-78℃向THF(12.5mL)中以滴加的方式加入LDA(2.0M,17mL,34mmol),然后乙酸甲酯(2.6mL,32.7mmol)。反应搅拌30分钟,然后将1-叔丁氧羰基氨基-环丙烷羧酸的中间体酯加入到THF(35mL)中,所得混合物搅拌3小时20分钟。混合物用1M HCl(aq)(50mL)淬灭,分层并用饱和NaHCO3(aq)(50mL)和盐水(50mL)清洗。然后用EtOAc萃取,合并的有机层干燥(MgSO4)并真空浓缩。通过快速柱色谱在硅胶上纯化(洗脱剂3∶7-4∶6-1∶1 EtOAc/己烷),得到黄色油状物2(1.0526g,4.09mmol,40%)。
1H NMR(400MHz,CDCl3)δH:5.24(br s,1H),3.76(s,3H),3.70(s,2H),1.67-1.62(m,2H),1.47(s,9H),1.21(br s,2H).MS(ES+)279.8(100%,[M+Na]+).Rf0.40 EtOAc/己烷(6∶4).
(3):3-(1-叔丁氧羰基氨基-环丙基)-3-羟基-丙酸甲酯在-78℃向在HPLC MeOH(20mL)中的2(1.053g,4.09mmol)分部分加入KBH4(764.3mg,14.2mmol),所得反应混合物搅拌45分钟,然后温热到-20℃,在该温度再搅拌30分钟。然后混合物温热到0℃,再搅拌2h,然后用AcOH淬灭反应直到pH低于7。然后混合物在真空下浓缩,加入EtOAc(70mL),然后加入水(40mL)。分层,水相用EtOAc(60mL)萃取。合并有机萃取物,用饱和盐水(60mL)清洗,干燥(MgSO4)和真空浓缩。通过快速柱色谱在硅胶上纯化(洗脱剂3∶7-4∶6-1∶1 EtOAc/己烷),得到白色固体3(436mg,1.68mmol,41%)(非对映异构体1∶1比例)。
1H NMR(400MHz,CDCl3)δH:5.08(br s,1H),4.37(d,J=4.27Hz,1H),3.71(s,3H),3.47(m,1H),2.65(dd,J=6.71,3.33Hz,2H),1.45(s,9H),1.01(m,1H),0.92(m,1H),0.86-0.73(m,2H).MS(ES+)281.8(100%,[M+Na]+).Rf 0.55EtOAc/己烷(6∶4).
(4):3-{1-[(S)-2-(9H-芴-9-基甲氧基羰基氨基)-3-三苯甲基硫烷基-丙酰基氨基]-环丙基}-3-羟基-丙酸甲酯
在0℃和Ar(g)下向3(431.3mg,1.66mmol)在CH2Cl2(20mL)的溶液中逐滴加入TFA(4mL,20%v/v),然后反应混合物搅拌2小时35分钟。在30℃以下真空除去溶剂,然后置于高真空下2h。在0℃和Ar(g)下向PyBOP(734mg,1.41mmol)和Fmoc-D-Cys(STrt)-OH(825mg,1.41mmol)在CH2Cl2(15mL)中的溶液中加入二异丙基乙胺(1.2mL,6.89mmol),混合物搅拌2分钟。然后加入3的粗胺在MeCN(15mL)中的溶液,然后反应在0℃搅拌1h,然后在室温搅拌2h,然后真空除去溶剂。通过快速柱色谱在硅胶上纯化(洗脱剂4∶6-4.5∶5.5-5.5∶4.5 EtOAc/己烷),得到白色固体4(924mg,1.27mmol,90%),非对映异构体的混合物不能用1H NMR拆分。
1H NMR(400MHz,CDCl3)δH:7.75(t,J=6.78Hz,2H),7.55(d,J=6.65Hz,2H),7.44-7.35(m,8H),7.32-7.17(m,11H),6.36(d,J=7.65Hz,1H),4.98(m,1H),4.41-4.35(m,2H),4.21-4.15(m,1H),3.71(m,1H),3.60(s,3H),3.49-3.43(m,2H),2.72-2.60(m,J=13.72,13.72,6.90,6.68Hz,1H),2.60-2.49(m,3H),1.01(m,1H),0.83-0.73(m,3H).MS(ES+)749.5(100%,[M+Na]+).Rf 0.41EtOAc/己烷(6∶4).
(5):(R)-4-(9H-芴-9-基甲氧基羰基氨基)-4-{(S)-1-[1-(1-羟基-2-甲氧基羰基-乙基)-环丙基氨基甲酰基]-2-三苯甲基硫烷基-乙基氨基甲酰基}-丁酸叔丁酯
向在MeCN(10mL)中的4(908mg,1.28mmol)中加入二乙胺(1mL,10%v/v),反应混合物搅拌2h。然后混合物真空浓缩,加入MeCN(3×20mL),然后真空除去,粗胺置于高真空下2h。然后,在0℃和Ar(g)下向PyBOP(705mg,1.35mmol)和Fmoc-D-Glu(OtBu)-OH(577.8mg,1.36mmol)在CH2Cl2(15mL)中的溶液中加入二异丙基乙胺(0.70mL,4.02mmol),混合物搅拌2分钟。加入4的粗胺衍生物在MeCN(15mL)中的溶液,并且混合物在室温下搅拌16h,然后真空除去溶剂。通过快速柱色谱在硅胶上纯化(洗脱剂4∶6-6∶4 EtOAc/己烷),得到白色固体5(1.099g,1.20mmol,94%):Rf 0.54 EtOAc/己烷(6∶4),非对映异构体的混合物不能用1H NMR拆分。
1H NMR(400MHz,CDCl3+ 10% MeOD)δH:7.70(d,J=7.44Hz,2H),7.50(br s,2H),7.38-7.28(m,6H),7.26-7.07(m,12H),4.35-4.21(m,2H),4.10-3.92(m,3H),3.55(d,J=5.84Hz,3H),3.45(m,1H),2.69-2.36(m,4H),2.32-2.22(m,2H),1.92(m,1H),1.79(m,1H),1.38(s,9H),0.91(br s,1H),0.82-0.67(m,4H).MS(ES+)933.5(100%,[M+Na]+).
(7):(R)-4-{(S)-1-[1-(1-羟基-2-甲氧基羰基-乙基)-环丙基氨基甲酰基]-2-三苯甲基硫烷基-乙基氨基甲酰基}-4-((E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酰基氨基)-丁酸叔丁酯
向在MeCN/CH2Cl2(20mL)中的5(1.088g,1.19mmol)中加入二乙胺(1.5mL,7.5%v/v),所得混合物搅拌1.5h。然后混合物真空浓缩,加入MeCN(4×20mL),然后真空除去,粗胺置于真空中2h。然后在Ar(g)下向PyBOP(650mg,1.25mmol)和羧酸6(506.5mg,1.21mmol(根据Yurek-George,A.等人在J.Am.Chem.Soc.2004,126,1030中指出的步骤制备)在CH2Cl2(15mL)中的溶液中加入二异丙基乙胺(0.65mL,3.73mmol),混合物搅拌3分钟。加入得到的5的去保护的胺在MeCN(15mL)中的溶液,混合物在室温下搅拌16h,然后真空除去溶液。通过快速柱色谱在硅胶上纯化(洗脱剂4∶6-1∶1-6∶4-7∶3-8∶2 EtOAc/己烷),得到白色固体7(940mg,0.862mmol,72%),非对映异构体的混合物不能用1H NMR拆分。
1H NMR(400MHz,CDCl3)δH:7.39-7.29(m,10H),7.28-7.11(m,20H),5.47(m,1H),5.35(m,1H),4.34(m,1H),4.12(m,1H),3.97(td,J=6.85,3.53Hz,1H),3.57(s,3H),3.49-3.31(m,2H),2.54-1.79(m,14H),1.37(s,9H),0.96-0.63(m,4H).MS(ES+)1111.5(100%,[M+Na]+).Rf 0.17 EtOAc/己烷(6∶4).
(8):(R)-4-{(S)-1-[1-(2-羧基-1-羟基-乙基)-环丙基氨基甲酰基]-2-三苯甲基硫烷基-乙基氨基甲酰基}-4-((E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酰基氨基)-丁酸叔丁酯
在0℃向在THF(12mL)中的7(927.1mg,0.850mmol)中加入在水(3mL)中的LiOH(30.6mg,1.28mmol),反应混合物搅拌3.25h。然后混合物用1M HCl(aq)(20mL)淬灭,用水(20mL)稀释,用EtOAc(60mL)处理。分层,产物用EtOAc(3×60mL)萃取。合并有机层,用饱和盐水(50mL)清洗,干燥(MgSO4),真空浓缩得到白色固体产品8(789.1mg,86%)(非对映异构体比例1∶1)。化合物8经进一步纯化用于下一步骤[MS(ES+)1097.4(100%,[M+Na]+)]。
(9):3-[(6S,9R,13S)-17-羟基-5,8,11,15-四氧代-13-((E)-4-三苯甲基硫烷基-丁-1-烯基)-6-三苯甲基硫烷基甲基-14-氧杂-4,7,10-三氮杂-螺[2.14]十七烷-9-基]-丙酸叔丁酯
向MNBA(303.7mg,0.882mmol)和DMAP(215.6mg,1.76mmol)在CH2Cl2(135mL)中的溶液中经过3h逐滴加入酸8(787mg,0.731mmol)在CH2Cl2(550mL)中的溶液,然后混合物搅拌16h;然后混合物真空浓缩得到褐色固体。通过柱色谱在硅胶上纯化(洗脱剂0∶1-1∶99-2∶98-3∶97 MeOH/CH2Cl2)得到白色固体9(430.2mg,0.407mmol,56%)。非对映异构体可通过快速柱色谱分离,不过后续反应用混合物。
1H NMR(400MHz,CDCl3)δH:7.90(d,J=3.26Hz,1H),7.85(d,J=3.39Hz,1H),7.44(t,23H),7.37-7.17(m,37H),7.11(s,1H),6.49-6.37(m,2H),5.73-5.57(m,3H),5.42-5.28(m,3H),4.63-4.54(m,2H),4.45(m,1H),4.00(m,1H),3.50-3.37(m,2H),3.12(dd,J=11.98,5.84Hz,1H),2.91-2.33(m,14H),2.29-1.88(m,15H),1.47(s,9H),1.47(s,9H),1.16-0.99(m,4H),0.92-0.81(m,3H),0.79-0.67(m,2H).Rf 0.39+0.35(MeOH/CH2Cl2(5∶95).
化合物XIa和XIb:3-((E)-(1S,9S,20R)-5-羟基-6,6-环丙基-3,8,18,21-四氧代-2-氧杂-11,12-二硫杂-7,19,22-三氮杂-二环[7.7.6]二十二-15-烯-20基)-丙酸叔丁酯
向碘(1.045g,4.12mmol)在CH2Cl2/MeOH(9∶1)(0.84L)中的溶液中经过4小时40分钟逐滴加入9(430.2mg,0.410mmol)在CH2Cl2/MeOH(9∶1)(0.22L)中的溶液。然后反应混合物再搅拌30分钟,之后加入硫代硫酸钠(300mL,100eq)。然后分离所得层,产物用EtOAc(3×250ml)萃取。然后分离有机层,合并和干燥(MgSO4),真空除去溶剂。然后通过柱色谱在硅胶上进行纯化(洗脱剂1∶99-2∶98-3∶97 MeOH/CH2Cl2),得到白色固体的异构体1,化合物XIa(73.8mg,0.129mmol,32%)和白色固体的异构体2,化合物XIa(60.27mg,0.105mmol,26%)。
异构体1(化合物XIa):
1H NMR(400MHz,CDCl3)δH:8.35(d,J=2.51Hz,1H),7.59(br s,1H),6.82(d,J=8.66Hz,1H),6.46(br s,1H),5.80(d,J=15.18Hz,1H),5.47(br s,1H),5.17(d,J=10.16Hz,1H),4.93(br s,1H),4.01(ddd,J=10.89,3.92,3.64Hz,1H),3.59(br s,1H),3.40(td,J=10.60,5.77Hz,1H),3.22(dd,J=13.18,6.78Hz,2H),3.08(br s,1H),2.90(dd,J=13.30,5.77Hz,1H),2.71(ddd,J=18.26,7.28,2.45Hz,3H),2.56(d,J=11.29Hz,2H),2.50(dd,J=13.24,1.32Hz,1H),2.38(ddd,J=18.35,9.76,2.51Hz,1H),2.15-2.02(m,2H),1.48(s,9H),1.39-1.33(m,1H),1.13-1.07(m,1H),0.87-0.77(m,2H).MS(ES+)593.7(100%,[M+Na]+).Rf 0.46CH2Cl2/MeOH(95∶5).
异构体2(化合物XIb):
1H NMR(400MHz,CDCl3)δH:8.57(d,J=3.14Hz,1H),7.32(s,1H),6.85(d,J=9.79Hz,1H),6.22(m,1H),5.82(br s,1H),5.77(m,1H),4.92(m,1H),4.39(d,J=10.04Hz,1H),4.11(m,1H),3.80(td,J=9.25,3.58Hz,1H),3.42(dd,J=14.81,8.41Hz,1H),3.17(ddd,J=7.75,5.74,5.58Hz,1H),3.07(dd,J=14.87,3.45Hz,1H),2.98(dd,J=13.05,6.78Hz,1H),2.88(dd,J=14.12,3.70Hz,1H),2.79-2.63(m,4H),2.52(dd,J=13.11,1.32Hz,2H),2.47-2.37(m,1H),2.17-2.10(m,2H),1.48(s,9H),1.19(m,1H),0.99-0.81(m,3H).MS(ES+)593.7(100%,[M+Na]+).Rf 0.38 CH2Cl2/MeOH(95∶5)
化合物XII:3-((E)-(1S,9S,20R)-5-羟基-6,6-环丙基-3,8,18,21-四氧代-2-氧杂-11,12-二硫杂-7,19,22-三氮杂-二环[7.7.6]二十二-15-烯-20基)-丙酸
在室温下向化合物XIa(35.94mg,0.0629mmol)中加入TFA(2mL)和三乙基硅烷(100μL,0.626mmol),然后反应混合物搅拌1小时40分钟。然后混合物真空浓缩,然后通过快速柱色谱在硅胶上进行纯化(洗脱剂1∶99-2∶98-3∶97-4∶96 MeOH/CH2Cl2),得到白色固体化合物XII(14.1mg,0.0343mmol,44%)。
1H NMR(400MHz,CDCl3+10% MeOD)δH:8.48(d,J=2.51Hz,1H),7.68(s,1H),6.84(d,J=8.78Hz,1H),6.27(m,1H),5.76(d,J=15.18Hz,1H),5.40(br s,1H),4.83(br s,1H),3.98(td,J=7.22,3.14Hz,1H),3.45-3.27(m,6H),3.13(dd,J=13.05,6.90Hz,2H),2.83(dd,J=13.36,5.71Hz,1H),2.75-2.38(m,6H),2.10-2.03(m,2H),1.31(m,1H),1.04(m,1H),0.84-0.73(m,2H).MS(ES+)538.2(100%,[M+Na]+).Rf 0.17 CH2Cl2/MeOH(95∶5).
化合物XIII:3-((E)-(1S,9S,20R)-5-羟基-6,6-环丙基-3,8,18,21-四氧代-2-氧杂-11,12-二硫杂-7,19,22-三氮杂-二环[7.7.6]二十二-15-烯-20基)-N-(2,2,2-三氟-乙基)-丙酰胺
向化合物XII(14.1mg,0.0273mmol)、EDC(21.23mg,0.111mmol)和HOBt(4.40mg,0.0326mmol)中加入THF(0.32mL),然后加入CHCl3(1.3mL),反应混合物搅拌2分钟。加入2,2,2-三氟乙胺(25μL,0.314mmol),然后混合物搅拌18h。然后混合物真空浓缩,加入CH2Cl2,然后加入1M HCl(aq),分层并用EtOAc萃取粗产物。合并有机物并干燥(MgSO4),然后通过快速柱色谱在硅胶上进行纯化(洗脱剂1∶99-2∶98-3∶97-4∶96 MeOH/CH2Cl2),得到白色固体XIII(9.49mg,0.0159mmol,58%)。
1H NMR(400MHz,CDCl3+10% MeOD)δH:8.97(br s,1H),7.72(s,1H),6.89(d,J=7.40Hz,1H),6.25(br s,1H),5.87(d,J=15.31Hz,1H),5.45(br s,1H),4.85(br s,1H),3.97(m,1H),3.94-3.76(m,2H),3.40(dd,J=10.85,5.83Hz,1H),3.17(dd,J=13.05,6.90Hz,1H),2.88(dd,J=13.43,5.77Hz,1H),2.71-2.56(m,3H),2.56-2.45(m,3H),2.43-2.32(m,6H),2.19-2.02(m,2H),1.34(m,1H),1.08(m,1H),0.87-0.76(m,2H).MS(ES+)619.2(100%,[M+Na]+).Rf 0.17 CH2Cl2/MeOH(94∶6).
化合物XIV 3-((E)-(1S,10S,21R)-7,7-二甲基-3,6,9,19,22-五氧代-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-21-基)-丙酸叔丁酯,和
化合物XV:3-((E)-(1S,10S,21R)-7,7-二甲基-3,6,9,19,22-五氧代-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-21-基)-丙酸
(3):[2-(9H-芴-9-基甲氧基羰基氨基)-2-甲基-丙酰基氨基]-乙酸甲酯
在0℃向市售2(1.29g,3.96mmol,1.1eq)和PyBOP(2.06g,3.96mmol,1.1eq)在MeCN(60mL)中的溶液中逐滴加入二异丙基乙胺(1.88mL,10.8mmol,3.0eq)。5分钟后,向反应混合物中逐滴加入H-Gly-(OMe).HCl,1(452mg,3.6mmol,1eq)在CH2Cl2(60mL)中的溶液。然后溶液温热到室温过夜,随后真空除去溶剂。通过柱色谱在硅胶上纯化(利用己烷/EtOAc,1∶3),得到白色固体3(1.42g,3.59mmol,99%)。
1H NMR(300MHz,CDCl3+10% MeOD)δH:H 7.72(d,J=7.4Hz,2H),7.57(d,J=7.3Hz,2H),7.23-7.40(m,4H),4.30-4.48(m,2H),4.12-4.22(m,3H),3.67(s,3H),1.44(br.s.,6H).MS(ES+)419.7(100%,[M+Na]+).Rf(己烷/EtOAc,1∶3)=0.35.
(4):{2-[(S)-2-(9H-芴-9-基甲氧基羰基氨基)-3-三苯甲基硫烷基-丙酰基氨基]-2-甲基-丙酰基氨基}-乙酸甲酯
室温下向3(1.60g,4.04mmol,1eq)在MeCN(80mL)中的溶液中逐滴加入二乙胺(8mL,10%v/v)。1h后,真空浓缩溶液并用MeCN(2×20mL)然后CH2Cl2/己烷(10mL)共同蒸发。然后所得油状物在高真空下干燥3h。在0℃向Fmoc-D-Cys-(Trt)-OH(2.60g,4.44mmol,1.1eq)和PyBOP(2.31g,4.44mmol,1.1eq)在MeCN(60mL)中的溶液中逐滴加入二异丙基乙胺(1.76mL,10.1mmol,2.5eq)。5分钟后,向反应混合物中逐滴加入粗胺的CH2Cl2(60mL)溶液。然后溶液温热到室温过夜。真空除去溶剂。通过柱色谱在硅胶上纯化(己烷/EtOAc,1∶1)得到白色固体4(2.79g,3.76mmol,93%)。
1H NMR(400MHz,CDCl3+10% MeOD)δH:7.69-7.74(m,2H),7.53-7.59(m,2H),7.31-7.38(m,8H),7.16-7.27(m,11H),4.26-4.38(m,2H),4.15-4.19(m,2H),3.75(d,J=6.0Hz,2H),3.59(s,3H),2.46-2.62(m,2H),1.45(s,3H),1.44(s,3H).MS(ES+)764.6(100%,[M+Na]+).Rf (己烷/EtOAc,1∶3)=0.45.
(5):(R)-4-(9H-芴-9-基甲氧基羰基氨基)-4-{(S)-1-[1-(甲氧基羰基甲基-氨基甲酰基)-1-甲基-乙基氨基甲酰基]-2-三苯甲基硫烷基-乙基氨基甲酰基}-丁酸叔丁酯
在室温下向4(1.29g,1.74mmol,1eq)在MeCN(35mL)中的溶液中逐滴加入二乙胺(3.5mL,10%v/v)。1h后,真空浓缩溶液并用MeCN(2×10mL)然后CH2Cl2/己烷(5mL)共同蒸发。然后所得油状物在高真空下干燥3h。在0℃向FmOC-D-GIu-(OtBu)-OH(814mg,1.91mmol,1.1eq)和PyBOP(996mg,1.91mmol,1.1eq)在MeCN(25mL)中的溶液中逐滴加入二异丙基乙胺(0.76mL,4.4mmol,2.5eq)。5分钟后,向反应混合物中逐滴加入粗胺的CH2Cl2(25mL)溶液。然后溶液温热到室温过夜。真空除去溶剂。通过柱色谱在硅胶上纯化(用己烷/EtOAc,2∶3洗脱)得到白色固体5(1.60g,1.73mmol,95%)。
1H NMR(300MHz,CDCl3+10% MeOD)δH:7.06-7.79(m,23H),4.16-4.41(m,2H),3.95-4.12(m,2H),3.77-3.90(m,2H),3.59(br.s.,5H),2.46-2.67(m,1H),2.22-2.34(m,1H),1.74-1.98(m,2H),1.37(s,9H),1.20(br.s.,6H).MS(ES+)949.4(100%,[M+Na]+).Rf(己烷/EtOAc,2∶3)=0.25.
(6):(R)-4-((E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酰基氨基)-4-{(S)-1-[1-(甲氧基羰基甲基-氨基甲酰基)-1-甲基-乙基氨基甲酰基]-2-三苯甲基硫烷基-乙基氨基甲酰基}-丁酸叔丁酯
在室温下向5(1.60g,1.73mmol,1eq)在MeCN(35mL)中的溶液中逐滴加入二乙胺(3.5mL,10%v/v)。一小时后,真空浓缩溶液,并用MeCN(2×10mL)然后CH2Cl2/己烷(5mL)共同蒸发。然后所得油状物在高真空下干燥3h。在0℃向(E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酸(758mg,1.81mmol,1.05eq)和PyBOP(988mg,1.90mmol,1.1eq)在MeCN(25mL)中的溶液中逐滴加入二异丙基乙胺(0.75mL,4.3mmol,2.5eq)。5分钟后,向反应混合物中逐滴加入粗胺的CH2Cl2(25mL)溶液。然后溶液温热到室温过夜。真空除去溶剂。通过柱色谱在硅胶上纯化(用己烷/EtOAc,1∶4洗脱)得到白色固体6(1.61g,1.46mmol,85%)。
1H NMR(300MHz,CDCl3+10% MeOD)δH:7.09-7.44(m,30H),5.28-5.58(m,2H),4.23-4.38(m,1H),4.02-4.14(m,1H),3.73-3.94(m,3H),3.64(s,3H),3.60(s,2H),2.01-2.59(m,10H),1.43(s,3H),1.39(s,3H),1.37(s,9H).MS(ES+)1127.7(100%,[M+Na]+).Rf (己烷/EtOAc,1∶4)=0.25.
(7):3-[(9S,12R,16S)-6,6-二甲基-2,5,8,11,14-五氧代-16-((E)-4-三苯甲基硫烷基-丁-1-烯基)-9-三苯甲基硫烷基甲基-1-氧杂-4,7,10,13-四氮杂-环十六烷-12-基]-丙酸叔丁酯
在0℃向6(1.61g,1.46mmol,1eq)在THF(49mL)中的溶液中逐滴加入LiOH(52.4mg,2.19mmol,1.5eq)在H2O(9mL)中的溶液。混合物搅拌1.5h,然后用1N HCl(12mL)和盐水(10mL)淬灭。分离有机层,所得水溶液进一步用EtOAc(2×15mL)和CH2Cl2(15mL)萃取。合并的有机物用MgSO4干燥。真空除去溶剂。然后所得羧酸在高真空下干燥2h。向MNBA(603mg,1.75mmol,1.2eq)和DMAP(428mg,3.5mmol,2.4eq)在CH2Cl2(1.3L)中的溶液中经过3h逐滴加入粗羧酸在CH2Cl2(220mL)和THF(30mL)中的溶液。然后所得反应混合物搅拌过夜。真空除去溶剂。通过柱色谱在硅胶上纯化(己烷/EtOAc,1∶4洗脱)获得淡黄色固体7(982mg,0.92mmol,63%)。
1H NMR(400MHz,CDCl3+10% MeOD)δH:7.09-7.40(m,30H),5.51-5.62(m,1H),5.37-5.45(m,1H),5.27-5.37(m,1H),4.03-4.10(m,1H),3.94-4.02(m,1H),3.75-3.84(m,1H),3.59(t,J=6.8Hz,1H),2.49-2.59(m,3H),2.35-2.44(m,2H),2.07-2.31(m,4H),1.66-2.02(m,4H),1.49(s,3H),1.35(s,9H),1.31(s,3H).MS(ES+)1095.7(100%,[M+Na]+).Rf(己烷/EtOAc,1∶5)=0.25.
化合物XIV:3-((E)-(1S,10S,21R)-7,7-二甲基-3,6,9,19,22-五氧代-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-21-基)-丙酸叔丁酯
本反应分两批等量进行。
在室温下向I2(1.16g,4.55mmol,10eq)在CH2Cl2/MeOH(1.30L,9∶1)中的溶液中经2h逐滴加入7(490mg,0.45mmol,1eq)的溶液。混合物用Na2S2O3(0.1M,250mL)和盐水(50mL)淬灭。两个水层合并并用CH2Cl2(2×100mL)和EtOAc(100mL)萃取。合并的有机萃取物用MgSO4干燥。真空除去溶剂。通过柱色谱在硅胶上纯化(CH2Cl2/MeOH,49∶1)获得白色固体的化合物XIV(433mg,0.74mmol,81%)。
1H NMR(400MHz,CDCl3+10% MeOD)δH:5.79-5.90(m,1H),5.66-5.77(m,2H),4.59-4.68(m,1H),4.33(d,J=17.8Hz,1H),4.04-4.09(m,1H),3.77(d,J=17.7Hz,1H),3.11-3.22(m,1H),2.98-3.10(m,2H),2.93(dd,J=15.7,3.9Hz,1H),2.82(dd,J=13.1,7.3Hz,1H),2.52-2.75(m,3H),2.38-2.51(m,2H),1.96-2.16(m,2H),1.49(s,3H),1.43(s,9H),1.38(s,3H);13C NMR(100MHz,CDCl3+5% MeOD)δH 174.6,173.8,173.7,170.7,170.0,168.5,130.9,130.7,82.1,70.3,57.1,56.5,56.3,43.5,38.7,37.2,32.7,31.9,31.5,28.3,27.8,25.5,23.0.MS(ES+)609.7(100%,[M+Na]+).Rf(CH2Cl2/MeOH,49∶1)=0.35.
化合物XV:3-((E)-(1S,10S,21R)-7,7-二甲基-3,6,9,19,22-五氧代-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-21-基)-丙酸
在0℃向化合物XIV(387.4mg,0.66mmol,1eq)在CH2Cl2(5mL)中的溶液中加入TFA(11mL,96mmol,150eq),然后加入三乙基硅烷(0.51mL,3.17mmol,4.8eq)。反应混合物搅拌2h,然后温热到室温。真空除去溶剂。通过柱色谱在硅胶上纯化(CH2Cl2∶MeOH,19∶1->12∶1)/AcOH:0.1%得到白色固体化合物XV(290mg,0.55mmol,83%)。
1H NMR(400MHz,CDCl3+10% MeOD)d H 7.59(d,J=7.3Hz,1H),7.44(s,1H),7.10(d,J=4.1Hz,1H),5.81-5.92(m,1H),5.67-5.77(m,2H),4.60-4.69(m,1H),4.27-4.40(m,3H),4.11(dd,J=8.5,6.3Hz,1H),3.78(dd,J=17.7,2.2Hz,1H),3.17(dd,J=15.7,11.4Hz,1H),2.96-3.09(m,2H),2.92(dd,J=15.7,3.9Hz,1H),2.81(dd,J=13.1,7.2Hz,1H),2.49-2.74(m,5H),1.49(s,3H),1.38(s,3H);13C NMR(100MHz,CDCl3+5% MeOD)δH 176.1,174.8,174.0,170.9,170.1,168.5,130.83,130.79,70.4,57.2,56.7,56.4,43.7,38.7,37.2,34.2,31.5,31.3,27.8,25.4,23.0.MS(ES+)553.7(100%,[M+Na]+).Rf(CH2Cl2/MeOH,15∶1)=0.30.
化合物XVI:3-((E)-(1S,10S,21R)-7,7-环丙基-3,6,9,19,22-五氧代-2-氧杂 -12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-21-基)-丙酸 叔丁酯,和
化合物XVII:3-((E)-(1S,10S,21R)-7,7-环丙基-3,6,9,19,22-五氧代-2-氧
杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-21-基)-丙
酸
(3):{[1-(9H-芴-9-基甲氧基羰基氨基)-环丙烷羰基]-氨基}-乙酸甲酯
在0℃向市售的Fmoc-1-氨基环丙烷羧酸2(850mg,2.63mmol,1.1eq)和PyBOP(1.37g,2.63mmol,1.1eq)在MeCN(40mL)中的溶液中逐滴加入二异丙基乙胺(1.25mL,7.17mmol,3.0eq)。5分钟后,向反应混合物中逐滴加入H-Gly-(OMe)·HCl,1(300mg,2.39mmol,1eq)在CH2Cl2(40mL)中的溶液。然后溶液温热到室温过夜。真空除去溶剂。通过柱色谱在硅胶上纯化(己烷/EtOAc,2∶3洗脱)得到白色固体3(940mg,2.38mmol,99%)。1H NMR(300MHz,CDCl3+10% MeOD)δH:7.46-7.78(m,4H),7.35(t,J=7.4Hz,2H),7.21-7.30(m,2H),4.43(d,J=6.3Hz,2H),4.16(t,J=6.2Hz,1H),3.91(br.s.,2H),3.68(br.s.,3H),1.29-1.57(m,2H),0.84-1.10(m,2H).MS(ES+)417.6(100%,[M+Na]+).Rf(己烷/EtOAc,2∶3)=0.25.
(4):({1-[(S)-2-(9H-芴-9-基甲氧基羰基氨基)-3-三苯甲基硫烷基-丙酰基氨基]-环丙烷羰基}-氨基)-乙酸甲酯
在室温下向3(0.94g,2.38mmol,1eq)在MeCN(50mL)中的溶液中逐滴加入二乙胺(5mL,10%v/v)。1h后,真空浓缩溶液,并用MeCN(2×20mL)然后CH2Cl2/己烷(10mL)共同蒸发。然后所得油状物在高真空下干燥3h。在0℃向Fmoc-D-Cys-(Trt)-OH(1.60g,2.70mmol,1.1eq)和PyBOP(1.35g,2.70mmol,1.1eq)在MeCN(45mL)中的溶液中逐滴加入二异丙基乙胺(1.03mL,6.2mmol,2.5eq)。5分钟后,向反应混合物中逐滴加入粗胺在CH2Cl2(25mL)中的溶液。然后溶液温热到室温过夜。真空除去溶剂。通过柱色谱在硅胶上纯化(己烷/EtOAc,2∶3相同)获得白色固体4(2.79g,3.76mmol,93%)。
1H NMR(400MHz,CDCl3+10% MeOD)δH:8.49(s,1H),7.13-7.81(m,23H),4.25-4.40(m,2H),4.13-4.23(m,1H),3.63-3.85(m,3H),3.58(s,3H),2.51-2.69(m,2H),1.37-1.56(m,2H),0.95-1.08(m,2H).MS(ES+)762.9(100%,[M+Na]+).Rf(己烷/EtOAc,2∶3)=0.32.
(5):(R)-4-(9H-芴-9-基甲氧基羰基氨基)-4-{(S)-1-[1-(甲氧基羰基甲基-氨基甲酰基)-环丙基氨基甲酰基]-2-三苯甲基硫烷基-乙基氨基甲酰基}-丁酸叔丁酯
在室温下向4(0.83g,1.12mmol,1eq)在MeCN(22mL)中的溶液中逐滴加入二乙胺(2.0mL,10%v/v)。1h之后,真空浓缩溶液,并用MeCN(2×10mL)然后CH2Cl2/己烷(5mL)共同蒸发。然后所得油状物在高真空下干燥3h。在0℃向Fmoc-D-Glu-(OtBu)-OH(522mg,1.23mmol,1.1eq)和PyBOP(638mg,1.23mmol,1.1eq)在MeCN(20mL)中的溶液中逐滴加入二异丙基乙胺(0.49mL,2.8mmol,2.5eq)。5分钟之后,向反应混合物中逐滴加入粗胺在CH2Cl2(20mL)中的溶液。然后溶液温热到室温过夜。真空除去溶剂。通过柱色谱在硅胶上纯化(己烷/EtOAc,2∶3)获得白色固体5(0.97g,1.05mmol,94%)。
1H NMR(300MHz,CDCl3+10% MeOD)δH:7.09-7.74(m,23H),4.20-4.37(m,2H),3.94-4.13(m,2H),3.71-3.84(m,3H),3.60(s,3H),2.48-2.72(m,2H),2.18-2.36(m,2H),1.73-1.98(m,2H),1.41-1.51(m,2H),1.38(br.s.,9H),0.96(br.s.,2H).MS(ES+)948.0(100%,[M+Na]+).Rf(己烷/EtOAc,2∶3)=0.20.
(6):(R)-4-((E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酰基氨基)-4-{(S)-1-[1-(甲氧基羰基甲基-氨基甲酰基)-环丙基氨基甲酰基]-2-三苯甲基硫烷基-乙基氨基甲酰基}-丁酸叔丁酯
在室温下向5(0.97g,1.05mmol,1eq)在MeCN(21mL)中的溶液中逐滴加入二乙胺(2.1mL,10%v/v)。一小时后,真空浓缩溶液,并用MeCN(2×5mL)然后CH2Cl2/己烷(5mL)共同蒸发。然后所得油状物在高真空下干燥3h。
在0℃向(E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酸(461mg,1.10mmol,1.05eq)和PyBOP(601mg,1.16mmol,1.1eq)在MeCN(20mL)中的溶液中逐滴加入二异丙基乙胺(0.46mL,2.6mmol,2.5eq)。5分钟之后,向反应混合物中逐滴加入粗胺在CH2Cl2(20mL)中的溶液。然后溶液温热到室温过夜。真空除去溶剂。通过柱色谱在硅胶上纯化(己烷/EtOAc,1∶4),获得白色固体6(1.06g,0.96mmol,91%)。
1H NMR(400MHz,CDCl3+10% MeOD)δH:7.14-7.39(m,30H),5.46-5.56(m,1H),5.35-5.43(m,1H),4.29-4.37(m,1H),4.14-4.21(m,1H),3.85-3.95(m,1H),3.71-3.83(m,2H),3.63(s,3H),2.51-2.63(m,2H),2.25-2.35(m,4H),2.15-2.23(m,2H),2.00-2.11(m,3H),1.78-1.93(m,1H),1.42-1.52(m,2H),1.40(s,9H),0.95-1.04(m,2H).MS(ES+)1125.6(100%,[M+Na]+).Rf(己烷/EtOAc,1∶4)=0.20.
(7):3-[(6S,9R,13S)-5,8,11,15,18-五氧代-13-((E)-4-三苯甲基硫烷基-丁-1-烯基)-6-三苯甲基硫烷基甲基-14-氧杂-4,7,10,17-四氮杂-螺[2.15]十八烷-9-基]-丙酸叔丁酯
在0℃向6(1.06g,0.96mmol,1eq)在THF(32mL)中的溶液中逐滴加入LiOH(34.5mg,1.44mmol,1.5eq)在H2O(6mL)中的溶液。混合物搅拌1.5h,然后用1N HCl(6mL)和盐水(5mL)淬灭。分离有机层,所得水层进一步用EtOAc(2×10mL)和CH2Cl2(10mL)萃取。合并的有机萃取物用MgSO4干燥。真空除去溶剂。然后所得羧酸在高真空中干燥2h。向MNBA(397mg,1.13mmol,1.2eq)和DMAP(281mg,2.3mmol,2.4eq)在CH2Cl2(0.80L)中的溶液中经3h逐滴加入粗羧酸在CH2Cl2(320mL)和THF(15mL)中的溶液。然后反应混合物在在室温下搅拌过夜。然后真空除去溶剂。通过柱色谱在硅胶上纯化(CH2Cl2/MeOH,32∶1->19∶1)得到淡黄色固体7(300mg,0.28mmol,29%)。
1H NMR(400MHz,CDCl3)δH:7.18-7.46(m,30H),5.58-5.70(m,1H),5.39-5.50(m,2H),4.23-4.40(m,2H),3.73(dd,J=16.3,3.8Hz,1H),2.96-3.18(m,2H),2.84(dd,J=13.2,4.5Hz,1H),2.51-2.62(m,2H),2.34-2.43(m,2H),2.17-2.30(m,2H),1.76-2.13(m,4H),1.46-1.63(m,3H),1.45(s,9H),1.03-1.14(m,1H).MS(ES+)1094.0(100%,[M+Na]+).Rf(CH2Cl2/MeOH,19∶1)=0.25.
化合物XVI:3-((E)-(1S,10S,21R)-7,7-环丙基-3,6,9,19,22-五氧代-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-21-基)-丙酸叔丁酯
在室温下向I2(0.71g,2.80mmol,10eq)在CH2Cl2/MeOH(700mL,9∶1)中的溶液中经过2h逐滴加入7(300mg,0.28mmol,1eq)。混合物用Na2S2O3(0.1M,250mL)和盐水(50mL)淬灭。合并两个水层并用CH2Cl2(2×100mL)和EtOAc(100mL)萃取。合并的有机萃取物用MgSO4干燥。真空除去溶剂。通过柱色谱在硅胶上纯化(CH2Cl2/MeOH,32∶1->19∶1)得到白色固体化合物XVI(107mg,0.18mmol,65%)。
1H NMR(400MHz,CDCl3+10% MeOD)δH:8.38(d,J=3.7Hz,1H),7.38-7.49(m,2H),6.81-6.90(m,1H),5.85-5.97(m,1H),5.74-5.83(m,2H),4.74(ddd,J=10.2,7.8,3.8Hz,1H),4.09-4.27(m,3H),3.36(dd,J=15.4,10.3Hz,1H),3.10(dd,J=15.5,3.8Hz,1H),3.00-3.06(m,2H),2.96(dd,J=13.2,7.0Hz,1H),2.64(dd,J=7.8,2.5Hz,1H),2.55(d,J=13.1Hz,1H),2.43(s,1H),2.08-2.28(m,2H),1.80(ddd,J=10.2,7.2,4.4Hz,1H),1.49(s,9H),0.95-1.16(m,2H).MS(ES+)607.9(100%,[M+Na]+).Rf(CH2Cl2/MeOH,19∶1)=0.30.
化合物XVII:3-((E)-(1S,10S,21R)-7,7-环丙基-3,6,9,19,22-五氧代-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-21-基)-丙酸
在0℃向化合物XVI(105mg,0.18mmol,1eq)在TFA(1.35mL,18mmol,100eq)中的溶液中加入三乙基硅烷(86μL,0.54mmol,3.0eq)。反应混合物搅拌3h,然后温热到室温。真空除去溶剂。通过柱色谱在硅胶上纯化((CH2Cl2/MeOH,13∶1->9∶1)/AcOH:0.1%洗脱)获得白色固体的化合物XVII(90.3mg,0.17mmol,95%)。
1H NMR(400MHz,CDCl3)δH:7.56(s,1H),7.39(d,J=7.5Hz,1H),6.88(br.s.,1H),5.73-5.87(m,1H),5.57-5.69(m,2H),4.51-4.63(m,1H),4.00-4.12(m,2H),3.85-3.95(m,1H),3.11-3.27(m,1H),2.82-3.00(m,2H),2.76(dd,J=13.1,6.9Hz,1H),2.56(br.s.,2H),2.34-2.50(m,2H),1.92-2.11(m,2H),1.57-1.66(m,1H),1.07-1.21(m,2H),0.87-1.00(m,2H);13C NMR(100MHz,CDCl3)δC:177.7,174.6,173.10,173.08,172.4,169.1,132.4,131.9,72.0,58.0,57.2,45.0,40.7,38.7,37.2,36.7,33.7,32.7,26.6,18.2,17.9.MS(ES+)551.7(100%,[M+Na]+).Rf(CH2Cl2/MeOH,9∶1)=0.20.
化合物XVIII:((E)-(1S,10S,21R)-7,7-环丙基-21-(3-吗啉-4-基-3-氧代-丙
基)-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯
-3,6,9,19,22-五酮
在0℃和Ar气下,向化合物XVII(20.4mg,0.039mmol,1eq)在MeCN(700μL)中的溶液中加入PyBOP(22.0mg,0.042mmol,1.1eq)和二异丙基乙胺(18μL,0.096mmol,2.5eq)。反应混合物搅拌5分钟,然后向混合物中逐滴加入吗啉(3.7μL,0.042mmol,1.05eq)在CH2Cl2(700μL)中的溶液。溶液温热至室温过夜。真空除去溶剂。通过柱色谱(CH2Cl2/MeOH,1∶0->32∶1)、然后使用SCX3筒(CH2Cl2/MeOH,1∶0->99∶1)纯化,获得白色固体化合物XVIII(6.1mg,27%)。
1H NMR(400MHz,CDCl3)δH:9.27(d,J=3.1Hz,1H),7.48(s,1H),7.41(d,J=8.0Hz,1H),6.92(t,J=3.9Hz,1H),5.84-5.94(m,1H),5.75-5.82(m,2H),4.77(ddd,J=10.3,8.0,4.0Hz,1H),4.20(t,J=3.6Hz,1H),4.17(d,J=4.3Hz,2H),3.58-3.76(m,5H),3.50(t,J=4.8Hz,2H),3.23-3.34(m,2H),3.16(dd,J=15.5,3.9Hz,1H),2.95-3.11(m,2H),2.92(dd,J=13.2,6.9Hz,1H),2.48-2.77(m,5H),2.33-2.44(m,1H),2.15-2.25(m,1H),1.92-1.97(m,1H),1.81(m,1H),1.30-1.38(m,2H),1.09-1.17(m,2H),0.98-1.05(m,1H);13C NMR(100MHz,CDCl3)δH 174.9,172.2,170.8,170.3,170.2,167.3,130.6,129.6,70.6,66.6,60.6,56.3,47.2,43.4,38.9,35.1,34.9,33.2,32.7,30.8,16.6,16.5.MS(ES+)620.9(100%,[M+Na]+).Rf(CH2Cl2/MeOH,11∶1)=0.35.
化合物XIX:3-((E)-(1S,10S,21R)-7,7-环丙基-3,6,9,19,22-五氧代-2-氧杂
-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-21-基)-N-(2-
甲氧基-乙基)-丙酰胺
在0℃和Ar(g)下向化合物XVII(26mg,0.05mmol,1eq)在MeCN(1mL)中的溶液中加入PyBOP(28.0mg,0.05mmol,1.1eq)和N-二异丙基乙胺(22μL,0.12mmol,2.5eq)。然后向混合物中逐滴加入2-甲氧基乙胺(4.7μL,0.05mmol,1.1eq)溶于CH2Cl2(1mL)的溶液。然后反应混合物温热到室温过夜。然后混合物真空浓缩,残余物通过硅胶柱色谱CH2Cl2/MeOH(1∶0->19∶1),然后通过SCX-3筒CH2Cl2/MeOH(1∶0->32∶1)进一步纯化,获得白色固体化合物XIX(13.5mg,47%)。
1H NMR(400MHz,CDCl3)δH:7.46(d,J==7.7Hz,1H),5.86-5.96(m,1H),5.66-5.78(m,2H),4.61(ddd,J=10.8,7.5,3.6Hz,1H),4.11-4.19(m,1H),4.05(dd,J=9.2,5.1Hz,1H),3.95-4.02(m,1H),3.40(d,J=4.7Hz,2H),3.33-3.38(m,2H),3.30(s,3H),3.20(dd,J=15.5,10.7Hz,1H),3.02(d,J=3.7Hz,1H),2.97(dd,J=6.7,4.9Hz,2H),2.83(dd,J=13.2,6.8Hz,1H),2.69(d,J=13.0Hz,1H),2.59-2.66(m,2H),2.33-2.50(m,2H),2.00-2.17(m,2H),1.71(ddd,J=10.2,7.2,4.5Hz,1H),1.20-1.28(m,2H)0.92-1.07(m,2H).MS(ES+)608.9(100%,[M+Na]+).
化合物XX:N-(2-氰基-乙基)-3-((E)-(1S,10S,21R)-7,7-环丙基
-3,6,9,19,22-五氧代-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]
二十三-16-烯-21-基)-丙酰胺
在0℃和Ar(g)下向化合物XVII(25mg,0.05mmol,1eq)在MeCN(1mL)中的溶液中加入PyBOP(27mg,0.05mmol,1.1eq)和N-二异丙基乙胺(21μL,0.12mmol,2.5eq)。然后向混合物中逐滴加入3-氨基丙腈(3.6μL,0.05mmol,1.1eq)溶于CH2Cl2(1mL)的溶液。然后反应混合物温热至室温过夜。然后混合物真空浓缩,残余物通过硅胶柱色谱CH2Cl2/MeOH(19∶1),然后通过SCX-3筒CH2Cl2/MeOH(1∶0->9∶1)进一步纯化,获得白色固体化合物XX(8.0mg,29%)。
1H NMR(400MHz,CDCl3+10% MeOH)δH:7.46(d,J=7.2Hz,1H),5.82-5.93(m,1H),5.67-5.77(m,2H),4.61(ddd,J=10.8,7.5,3.7Hz,1H),4.10-4.18(m,1H),4.04(dd,J=8.4,6.1Hz,1H),3.95-4.02(m,1H),3.36-3.44(m,2H),3.21(dd,J=15.5,10.8Hz,1H),2.94-3.04(m,3H),2.83(dd,J=13.2,7.0Hz,1H),2.59-2.69(m,3H),2.55(t,J=6.5Hz,2H),2.40-2.49(m,1H),2.29-2.38(m,1H),2.02-2.11(m,2H),1.66-1.75(m,1H),1.20-1.27(m,2H),0.92-1.07(m,2H).MS(ES+)603.6(100%,[M+Na]+).
化合物XXI:3-((E)-(1S,10S,21R)-7,7-二甲基-3,6,9,19.22-五氧代-2-氧代
-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-21-
基)-N-(2,2,2-三氟乙基)-丙酰胺
在0℃和Ar(g)下向化合物XVII(26.7mg,0.05mmol,1eq)在中的溶液中MeCN(1mL)加入PyBOP(29mg,0.05mmol,1.1eq)和N-二异丙基乙胺(22μL,0.12mmol,2.5eq).然后向混合物中逐滴加入3,3,3-三氟丙胺(4.8μL,0.05mmol,1.1eq)溶于CH2Cl2(1mL)的溶液。然后反应混合物放至室温过夜。然后混合物真空浓缩,残余物通过硅胶柱色谱CH2Cl2/MeOH(19∶1)然后SCX-3筒CH2Cl2/MeOH(1∶0->19∶1)进一步纯化,获得白色固体的化合物XXI(6.6mg,22%)。
1H NMR(400MHz,CDCl3)δH:7.39(d,J=7.0Hz,2H),5.74-5.86(m,1H),5.59-5.69(m,2H),4.54(td,J=7.0,2.9Hz,1H),4.02-4.10(m,1H),3.97(dd,J=5.8,2.2Hz,1H),3.86-3.94(m,1H),3.63-3.79(m,2H),3.14(ddd,J=15.3,10.9,1.9Hz,1H),2.97-3.04(m,1H),2.85-2.96(m,3H),2.70-2.79(m,1H),2.50-2.60(m,3H),2.37-2.46(m,1H),2.24-2.35(m,1H),1.95-2.08(m,2H),1.56-1.65(m,1H),1.22-1.30(m,1H),1.12-1.19(m,2H),0.85-0.96(m,2H).MS(ES+)632.9(100%,[M+Na]+).
化合物XXII:3-((E)-(1S,10S,21R)-7,7-环丙基-3,6,9,19,22-五氧代-2-氧
杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-21-
基)-N,N-二乙基-丙酰胺
在0℃和Ar(g)下向化合物XVII(25.8mg,0.05mmol,1eq)在MeCN(1mL)中的溶液中加入PyBOP(28mg,0.05mmol,1.1eq)和N-二异丙基乙胺(21μL,0.12mmol,2.5eq)。然后向混合物中逐滴加入二乙胺(5.3μL,0.05mmol,1.1eq)溶于CH2Cl2(1mL)中的溶液。然后反应混合物放至室温过夜。然后混合物真空浓缩,残余物通过硅胶柱色谱CH2Cl2/MeOH(49∶1->24∶1)进一步纯化获得白色固体化合物XXII(13.1mg,46%)。
1H NMR(400MHz,CDCl3+10%MeOH)δH:7.58(s,1H),7.44(d,J=7.8Hz,1H),5.84-5.94(m,1H),5.70-5.79(m,2H),4.63-4.71(m,1H),4.15(dd,J=18.4,4.9Hz,1H),4.08-4.11(m,1H),4.04(dd,J=18.5,3.7Hz,1H),3.57-3.69(m,3H),3.19-3.43(m,4H),3.05-3.15(m,4H),2.96-3.04(m,2H),2.60-2.69(m,3H),2.39-2.49(m,1H),2.17-2.29(dddd,J=13.8,9.1,9.1,4.4Hz,1H),2.05-2.15(m,1H),1.83(ddd,J=6.4,3.5,3.3Hz,2H),1.73(ddd,J=10.2,7.4,4.6Hz,1H),1.23-1.30(m,2H),1.14(t,J=7.2Hz,3H),1.10(t,J=7.1Hz,3H),1.03-1.07(m,1H),0.94-1.02(m,1H);MS(ES+)607.0(100%,[M+Na]+).
化合物XXIII:3-((E)-(1S,10S,21R)-7,7-环丙基-3,6,9,19,22-五氧代-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-21-基)-N-(2-吗啉-4-基-乙基)-丙酰胺
在0℃和Ar(g)下向化合物XVII(20.7mg,0.04mmol,1eq)在MeCN(1mL)中的溶液中加入PyBOP(22mg,0.04mmol,1.1eq)和N-二异丙基乙胺(17μL,0.10mmol,2.5eq)。然后向混合物中逐滴加入2-氨基乙基吗啉(5.7μL,0.04mmol,1.1eq)溶于CH2Cl2(1mL)中的溶液。然后反应混合物放至室温过夜。然后混合物真空浓缩,残余物通过硅胶柱色谱CH2Cl2/MeOH(12∶1->9∶1),然后SCX-3筒CH2Cl2/MeOH(1∶0->9∶1)进一步纯化,得到白色固体化合物XXIII(8.5mg,34%)。
1H NMR(400MHz,CDCl3+10% MeOH)δH:7.52-7.57(m,1H),7.40-7.47(m,1H),6.88-6.94(m,1H),5.82-5.92(m,1H),5.59-5.76(m,3H),5.54(dd,J=15.8,4.5Hz,1H),4.59(ddd,J=10.8,7.6,3.7Hz,1H),4.39(dd,J=10.5,3.4Hz,1H),4.10-4.18(m,2H),4.00-4.07(m,1H),3.91(dd,J=5.7,2.5Hz,2H),3.64-3.67(m,4H),2.79-2.87(m,2H),2.56-2.68(m,6H),2.44-2.50(m,4H),2.23-2.29(m,3H),1.91-1.99(m,1H),1.66-1.76(m,1H),1.48(dd,J=10.4,3.6Hz,1H),1.42(dd,J=9.8,3.0Hz,1H),1.18-1.25(m,2H),0.98-1.04(m,1H),0.91-0.95(m,1H).MS(ES+)664.0(100%,[M+Na]+).
化合物XXIV:(E)-(1S,10S,21R)-7,7-环丙基-21-[3-(4-甲基-哌嗪-1-基)-3-
氧代-丙基]-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三
-16-烯-3,6,9,19,22-五酮
在0℃和Ar(g)下向化合物XVII(27.6mg,0.05mmol,1eq)在MeCN(1mL)中的溶液中加入PyBOP(30mg,0.05mmol,1.1eq)和N-二异丙基乙胺(23μL,0.13mmol,2.5eq)。然后向混合物中逐滴加入1M-甲基哌嗪(6.0μL,0.05mmol,1.1eq)溶于CH2Cl2(1mL)的溶液。然后反应混合物放至室温过夜。然后混合物真空浓缩,残余物通过硅胶柱色谱CH2Cl2/MeOH(19∶1->9∶1),然后SCX-3筒CH2Cl2/MeOH(1∶0->0∶1)和MeOH/H2O/NH3(9∶1∶0.1)进一步纯化,得到白色固体化合物XXIV(15.0mg,47%)。
1H NMR(400MHz,CDCl3+10% MeOH)δH:8.90(d,J=3.2Hz,1H),7.54(s,1H),7.40(d,J=7.7Hz,1H),6.89(t,J=3.8Hz,1H),5.71-5.82(m,1H),5.59-5.67(m,2H),4.49-4.58(m,1H),4.07(d,J=5.2Hz,1H),3.95-4.00(m,1H),3.85-3.93(m,1H),3.56(s,1H),3.37-3.45(m,3H),3.10(dd,J=15.5,10.9Hz,1H),2.87-2.97(m,3H),2.70-2.78(m,1H),2.48-2.58(m,4H),2.33-2.44(m,4H),2.24(br.s.,3H),2.03-2.13(m,1H),1.94(s,1H),1.56-1.64(m,1H),1.13-1.17(m,1H),0.87-0.98(m,3H).MS(ES+)633.6(100%,[M+Na]+).
化合物XXV:3-((1S,10S,21R,E)-3,6,9,19,22-五氧代-2-氧杂-12,13-二硫
杂-5,8,20,23-四氮杂螺[二环[8.7.6]二十三[16]烯-7,1′-环丁烷]-21-基)丙
酸叔丁酯
(3):{[1-(9H-芴-9-基甲氧基羰基氨基)-环丁烷羰基]-氨基}-乙酸甲酯
在室温和Ar(g)下将N,N-二异丙基乙胺(2.60mL,14.82mmol)加入到1-(9H-芴-9-基甲氧基羰基氨基)-环丁烷甲酸、1(2.0g,5.93mmol)和PyBOP(3.393g,6.52mmol)在CH2Cl2(150mL)中的溶液中。10分钟之后,加入MeCN(150mL)和HCl.GIyOMe,2(819mg,6.52mmol)。16h之后,减压浓缩反应混合物,残余物通过硅胶柱色谱以己烷/EtOAc(2∶1 to 1∶3)洗脱纯化,得到白色固体3(2.373g,98%)。
1H NMR(300MHz,CDCl3)δH:7.78(d,J=7.4Hz,2H),7.59(d,J=6.5Hz,2H),7.41(t,J=7.3Hz,2H),7.32(td,J=7.3,0.7Hz,2H),7.01(br.s.,1H),5.37(br.s.,1H),4.49(d,J=5.8Hz,2H),4.17-4.27(m,1H),4.02(br.s.,2H),3.72(s,3H),2.69(br.s.,2H),2.17(br.s.,2H),1.98(t,J=6.6Hz,2H).MS(ES):431.8(100%,[M+Na]+),840.1(80%,[2M+Na]+).
(4):({1-[(S)-2-(9H-芴-9-基甲氧基羰基氨基)-3-三苯甲基硫烷基-丙酰基氨基]-环丁烷羰基}-氨基)-乙酸甲酯
在室温和Ar(g)下将Et2NH(2mL)加入到3(2.202g,5.39mmol,)在MeCN(18mL)中的溶液中。搅拌1h之后,减压除去溶剂,然后残余物用MeCN(4×20mL)和己烷(2×20mL)再溶解和蒸发。粗产品在高真空下干燥至少3h。在-10℃和Ar(g)下,将N,N-二异丙基乙胺(2.35mL,13.47mmol)加入到Fmoc-D-Cys(Trt)OH(3.473g,5.93mmol)和PyBOP(3.086g,5.93mmol)在CH2Cl2(150mL)中的溶液中。搅拌10分钟之后,在-10℃和Ar(g)下将混合物转移到溶于MeCN(150mL)中的粗胺中。然后反应混合物温热到室温。16h之后,减压浓缩反应混合物,残余物通过硅胶柱色谱用己烷/EtOAc(80∶20然后40∶60)洗脱以获得白色固体4(1.467g,36%)。
1H NMR(400MHz,CDCl3)δH:7.77(dd,J=7.5,3.5Hz,2H),7.57(d,J=7.5Hz,2H),7.38-7.45(m,7H),7.17-7.33(m,13H),6.24(s,1H),5.01(d,J=6.7Hz,1H),4.44(dd,J=10.7,6.9Hz,1H),4.40(dd,J=10.7,6.5Hz,1H),4.19(t,J=6.4Hz,1H),3.92(dd,J=18.4,5.9Hz,1H),3.84(dd,J=18.3,6.1Hz,1H),3.65-3.69(m,1H),3.64(s,3H),2.62-2.78(m,4H),2.06-2.17(m,2H),1.84-2.05(m,2H).MS(ES):777.2(100%,[M+Na]+).
(5):(R)-4-(9H-芴-9-基甲氧基羰基氨基)-4-{(S)-1-[1-(甲氧基羰基甲基-氨基甲酰基)-环丁基氨基甲酰基]-2-三苯甲基硫烷基-乙基氨基甲酰基}-丁酸叔丁酯
在室温和Ar(g)下将Et2NH(2mL)加入到4(1.467g,1.95mmol,)在MeCN(28mL)中的溶液中。搅拌1h之后,低压除去溶剂,然后用MeCN(4×20mL)和己烷(2×20mL)再溶解和蒸发。粗产品在高真空下干燥3小时,然后在下一步使用。在0℃和Ar(g)下将N,N-二异丙基乙胺(0.85mL,4.87mmol)加入到Fmoc-D-Glu(tBu)OH(910mg,2.14mmol)和PyBOP(1.114g,2.14mmol)在CH2Cl2(100mL)中的溶液中。搅拌10分钟之后,在0℃和Ar(g)下将混合物转移到溶于MeCN(100mL)的由去保护的4得到的粗胺中。然后反应混合物温热到室温。16h之后,减压浓缩反应混合物,残余物通过硅胶柱色谱用己烷/EtOAc(70∶30至35∶65)洗脱纯化以获得白色固体5(1.485g,81%)。
1H NMR(400MHz,CDCl3)δH:7.77(d,J=7.4Hz,2H),7.54(t,J=6.8Hz,2H),7.37-7.44(m,8H),7.10-7.34(m,13H),6.68(d,J=6.5Hz,1H),6.44(d,J=4.0Hz,1H),4.33(dd,J=10.4,7.7Hz,1H),4.24(dd,J=9.9,7.2Hz,1H),4.08(t,J=6.9Hz,1H),3.94(d,J=5.6Hz,2H),3.65(s,3H),3.02(dd,J=13.1,5.8Hz,1H),2.74-2.84(m,1H),2.63-2.73(m,2H),2.52(dd,J=12.8,5.0Hz,2H),2.37(ddd,J=17.1,8.7,4.1Hz,2H),2.18-2.31(m,2H),1.83-2.03(m,4H),1.49(s,9H).MS(ES):961.8(100%,[M+Na]+).
(6):(E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酸
At 0℃向(S,E)-3-羟基-1-((R)-4-异丙基-2-硫酮噻唑烷-3-基)-7-(三苯甲基硫烷基)庚-4-烯-1-酮(934mg,1.66mmol,根据Yurek-George,A.等人在J.Am.Chem.Soc.2004,126,1030中的步骤制备)在THF(30mL)中的溶液中加入LiOH(196.1mg,8.19mmol)在H2O(10mL)中的溶液。反应混合物经过1h温热到室温,向其中加入1M HCl直至pH达到2。然后加入EtOAc(30mL),分层。用EtOAc(20mL)萃取水层。合并有机层,干燥(MgSO4)和真空浓缩。快速柱色谱纯化(洗脱剂3∶7-1∶1-1∶0 EtOAc/己烷)得到白色固体6(600mg,1.43mmol,86%)。
1H NMR(300MHz,CDCl3)δH:7.48-7.38(m,6H),7.35-7.18(m,9H),5.60(m,1H),5.43(m,1H),4.46(q,J=6.28,1H),2.59-2.51(m,2H),2.28-2.19(m,2H),2.09(q,J=6.47Hz,2H).MS(ES-)417(100%,[M-H]-).Rf 0.52 EtOAc+2 drops AcOH;[α]D 27-4.15(c 0.975,CH2Cl2).
(7)(R)-4-((E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酰基氨基)-4-{(S)-1-[1-(甲氧基羰基甲基-氨基甲酰基)-环丁基氨基甲酰基]-2-三苯甲基硫烷基-乙基氨基甲酰基}-丁酸叔丁酯
在室温和Ar(g)下,将Et2NH(3mL)加入到5(1.480g,1.57mmol)在MeCN(27mL)中的溶液中。搅拌1h之后,低压除去溶剂,然后用MeCN(4×20mL)和己烷(2×20mL)再溶解和蒸发。粗产品在高真空下干燥3小时,然后在下一步使用。在0℃和Ar(g)下将N,N-二异丙基乙胺(0.685mL,3.92mmol)加入到6(724mg,1.73mmol)和PyBOP(899mg,1.73mmol)在CH2Cl2(100mL)中的溶液中。搅拌10分钟之后,在0℃和Ar(g)下将混合物转移到溶于MeCN(100mL)的由去保护的5得到的粗胺中。然后反应混合物温热到室温。18.5h之后反应结束,减压浓缩反应混合物。残余物通过硅胶柱色谱用己烷/EtOAc(80∶20至20∶80)洗脱纯化以获得白色固体7(1.322g,75%)。
1H NMR(400MHz,CDCl3)δH:7.66(d,J=5.0Hz,1H),7.39-7.44(m,6H),7.34-7.39(m,6H),7.27-7.33(m,8H),7.16-7.27(m,12H),5.52(dt,J=15.2,6.5Hz,1H),5.36(dd,J=15.4,6.7Hz,1H),4.45(sxt,J=4.4Hz,1H),4.28-4.35(m,1H),4.19(dt,J=7.6,4.8Hz,1H),4.08(d,J=6.9Hz,1H),3.69(d,J=4.8Hz,1H),3.65(d,J=4.8Hz,1H),3.51(s,3H),2.69-2.77(m,1H),2.67(d,J=8.5Hz,1H),2.64(d,J=8.3Hz,1H),2.60(dd,J=8.4,4.3Hz,1H),2.56(dd,J=9.2,4.3Hz,1H),2.54(t,J=4.5Hz,1H),2.43(dd,J=7.9,4.4Hz,1H),2.38(dd,J=7.4,4.5Hz,1H),2.27-2.35(m,3H),2.14-2.26(m,4H),2.06-2.12(m,2H),1.87-2.00(m,2H),1.41(s,9H).MS(ES):1140.5(100%,[M+Na]+).
(8)3-[(7R,10R,14R)-6,9,12,16,19-五氧代-14-((E)-4-三苯甲基硫烷基-丁-1-烯基)-7-三苯甲基硫烷基甲基-15-氧杂-5,8,11,18-四氮杂-螺[3.15]十九烷-10-基]-丙酸叔丁酯
在0℃将LiOH(42mg,1.77mmol)在水(4mL)中的溶液加入到7(1.322g,1.18mmol)在THF(16mL)中的溶液中。在0℃搅拌1.5h之后,用0.5M HCl水溶液中和反应混合物,然后加入(50mL)和EtOAc(50mL)。分离相并用EtOAc(4×25mL)萃取。合并有机相,干燥MgSO4,过滤然后减压浓缩。粗产品在高真空下干燥,然后在下一步使用。在室温和Ar(g)下经过3h将粗羧酸在CH2Cl2/THF(740mL,12∶1v/v)中的溶液中加入到2-甲基-6-硝基苯酐(487mg,1.42mmol)和4-(二甲基氨基)吡啶(346mg,2.83mmol)在CH2Cl2(300mL)中的溶液中。16h后,减压浓缩反应混合物,残余物通过硅胶柱色谱用CH2Cl2/异丙醇(100∶4然后100∶8)获得白色固体8(648mg,51%)。
1H NMR(400MHz,CDCl3)δH:7.42(dd,J=16.0,8.2Hz,12H),7.27-7.33(m,8H),7.25-7.27(m,5H),7.18-7.25(m,6H),7.06(t,J=5.3Hz,1H),6.83(d,J=5.4Hz,1H),6.79(d,J=6.8Hz,1H),6.67(s,1H),5.58-5.69(m,1H),5.36-5.47(m,2H),4.18(dd,J=17.0,6.7Hz,1H),3.98-4.12(m,2H),3.86(dd,J=17.3,4.2Hz,1H),3.34(q,J=7.8Hz,1H),2.93(dd,J=13.6,8.3Hz,1H),2.82(d,J=5.6Hz,1H),2.78(d,J=5.3Hz,1H),2.54(dd,J=14.8,4.1Hz,1H),2.47(dd,J=14.8,6.1Hz,1H),2.37(d,J=6.4Hz,1H),2.34(d,J=7.0Hz,1H),2.17-2.30(m,3H),2.08(d,J=6.9Hz,1H),2.05(d,J=6.8Hz,1H),1.84-1.98(m,2H),1.72-1.84(m,2H),1.44(s,9H).MS(ES):1107.8(100%,[M+Na]+).
化合物XXV:3-((E)-(1S,10S,21R)-7-环丁基-3,6,9,19,22-五氧代-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-21-基)-丙酸叔丁酯
在室温和Ar(g)下将化合物8(648mg,0.60mmol)在CH2Cl2/CH3OH(472mL,9∶1,v/v)中的溶液经过30分钟加入到I2(1.515mg,6.0mmol)在CH2Cl2/CH3OH(828mL,9∶1v/v)中的溶液中。搅拌2h之后加入0.1M Na2S2O3(500mL)和盐水(150mL)。分离相然后用CH2Cl2(200mL)和EtOAc(2×100mL)萃取。合并有机相,用MgSO4干燥,过滤然后减压浓缩。残余物通过硅胶柱色谱用CH2Cl2/CH3OH(100∶3)洗脱纯化以获得白色固体化合物XXV(335mg,93%)。
1H NMR(400MHz,CDCl3)δH:8.33(d,J=3.4Hz,1H),7.41(s,1H),7.35(d,J=7.9Hz,1H),6.81(d,J=3.9Hz,1H),5.82-5.94(m,1H),5.71-5.80(m,2H),4.83(ddd,J=10.4,7.9,3.7Hz,1H),4.37(dd,J=18.1,6.4Hz,1H),4.16(m,J=9.8,4.3,4.3Hz,1H),3.96(dd,J=18.1,2.6Hz,1H),3.30(dd,J=15.6,10.4Hz,1H),2.95-3.10(m,4H),2.90(dd,J=13.1,7.1Hz,1H),2.59-2.78(m,3H),2.47-2.55(m,2H),2.42(ddd,J=18.3,9.5,2.9Hz,1H),2.08-2.26(m,4H),1.91-2.07(m,2H),1.48(s,9H).(100MHz,CDCl3)δC:175.55,172.53,172.20,169.62,169.51,168.07,130.33,130.26,82.41,69.31,59.13,57.24,55.07,42.98,38.56,38.21,35.97,32.80,32.15,32.08,30.14,28.02,24.35(3C),15.65.MS(ES):621.4(100%,[M+Na]+).
化合物XXVI:3-((E)-(1S,10S,21R)-7-环丁基-3,6,9,19,22-五氧代-2-氧杂
-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-21基)-丙酸
向化合物XXV(273mg,0.416mmol)中加入Et3SiH(0.37mL,2.3mmol),然后加入三氟乙酸(1mL)。反应混合物在室温下搅拌1小时15分钟,然后减压浓缩。剩余三氟乙酸通过用甲苯(4×5mL)减压共蒸发粗产品而除去。然后残余物通过硅胶柱色谱用CH2Cl2/CH3OH(100∶5)洗脱纯化以获得白色固体化合物XXVI(191mg,76%)。
1H NMR(400MHz,9/1 CDCl3/CD3OD)δH:7.65(s,1H),7.49(d,J=7.7Hz,1H),6.94(d,J=5.5Hz,1H),5.82-5.95(m,1H),5.68-5.80(m,2H),4.78(ddd,J=10.9,7.6,3.7Hz,1H),4.40(dd,J=18.0,6.6Hz,1H),4.17(dd,J=8.7,5.8Hz,1H),3.88(dd,J=17.9,2.3Hz,4H),3.25(dd,J=15.6,10.8Hz,1H),2.95-3.10(m,4H),2.86(dd,J=13.2,7.0Hz,1H),2.64-2.75(m,2H),2.61(dt,J=17.6,6.9Hz,1H),2.54(dt,J=17.4,6.8Hz,1H),2.37-2.47(m,1H),2.07-2.25(m,4H),1.98(quin,J=8.5Hz,2H).(100MHz,9/1 CDCl3/CD3OD)δC:175.93,172.80,172.71,170.11,169.59,167.90,130.27,130.09,69.74,58.97,56.03,55.19,42.69,38.46,36.76,34.68,32.02,31.46,30.82,29.81,24.55,15.31.
化合物XXVII:((E)-(1S,7R,10S)-7-异丙基-21,21-二甲基-2-氧杂-12,13-
二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-3,6,9,19,22-五酮
(2)((R)-2-{(S)-2-[2-(9H-芴-9-基甲氧基羰基氨基)-2-甲基-丙酰基氨基]-3-三苯甲基硫烷基-丙酰基氨基}-3-甲基-丁酰氨基)-乙酸甲酯在室温和Ar(g)下将Et2NH(3mL)加入到{(R)-2-[(S)-2-(9H-芴-9-基甲氧基羰基氨基)-3-三苯甲基硫烷基-丙酰基氨基]-3-甲基-丁酰氨基}-乙酸甲酯1(500mg,0.66mmol,根据WO 2006/129105制备)在MeCN(27mL)中的溶液中。搅拌1h之后,低压除去溶剂,然后残余物用MeCN(4×20mL)和己烷(2×2mL)重新溶解和蒸发。粗产品在高真空下干燥3小时,然后在下一步使用。在0℃和Ar(g)下将N,N-二异丙基乙胺(0.29mL,1.65mmol)加入到Fmoc-Me-Ala-OH(237mg,0.73mmol)和PyBOP(378mg,0.73mmol)在CH2Cl2(30mL)中的溶液中。搅拌10分钟之后,在0℃和Ar(g)下将混合物转移到溶于MeCN(30mL)的由去保护的{(R)-2-[(S)-2-(9H-芴-9-基甲氧基羰基氨基)-3-三苯甲基硫烷基-丙酰基氨基]-3-甲基-丁酰氨基}-乙酸甲酯1得到的粗胺中。然后反应混合物温热到室温。16h之后,减压浓缩反应混合物,残余物通过硅胶柱色谱用己烷/EtOAc(50∶50然后20∶80)洗脱纯化以获得白色固体2(410mg,74%)。
1H NMR(400MHz,CDCl3)δH:7.69(d,J=7.5Hz,2H),7.00-7.58(m,23H),6.77(d,J=5.4Hz,1H),4.46-4.60(m,1H),4.30-4.35(m,1H),4.24(dd,J=9.7,7.9Hz,1H),3.98-4.18(m,3H),3.73(d,J=17.4Hz,1H),3.59(s,3H),2.83-3.03(m,1H),2.35-2.42(m,1H),2.31(dd,J=12.5,4.1Hz,1H),1.97(d,J=1.8Hz,1H),1.32(s,3H),1.26(s,3H),0.97(t,J=7.5Hz,6H).MS(ES):863.7(100%,[M+Na]+).
(3):(E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酸
在0℃向(S,E)-3-羟基-1-((R)-4-异丙基-2-硫代噻唑烷-3-基)-7-(三苯甲基硫代)庚-4-烯-1-酮(934mg,1.66mmol,根据Yurek-George,A.等人在J.Am.Chem.Soc.2004,126,1030中指出的步骤制备)在THF(30mL)中的溶液中加入LiOH(196.1mg,8.19mmol)在H2O(10mL)中的溶液。反应混合物经过1h温热到室温,然后加入1M HCl加入直至pH达到2。然后加入EtOAc(30mL),分层。水相用EtOAc(20mL)萃取,合并有机层,干燥(MgSO4)和真空浓缩。快速柱色谱纯化(洗脱剂3∶7-1∶1-1∶0 EtOAc/己烷)得到白色固体3(600mg,1.43mmol,86%)。
1H NMR(300MHz,CDCl3)δH:7.48-7.38(m,6H),7.35-7.18(m,9H),5.60(m,1H),5.43(m,1H),4.46(q,J=6.28,1H),2.59-2.51(m,2H),2.28-2.19(m,2H),2.09(q,J=6.47Hz,2H).MS(ES-)417(100%,[M-H]-).Rf 0.52 EtOAc+2 dropsAcOH;[α]D 27-4.15(c 0.975,CH2Cl2).
(4):((R)-2-{(S)-2-[2-((E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酰基氨基)-2-甲基-丙酰基氨基]-3-三苯甲基硫烷基-丙酰基氨基}-3-甲基-丁酰氨基)-乙酸甲酯
在室温和Ar(g)下将Et2NH(4mL)加入到2(410mg,0.49mmol)在MeCN(36mL)中的溶液中。搅拌1小时15分钟之后,低压除去溶剂,然后残余物用MeCN(4×20mL)和己烷(2×20mL)重新溶解和蒸发。粗产品在高真空下干燥至少3h,然后用于下一步骤。在0℃和Ar(g)下将N,N-二异丙基乙胺(0.214mL,1.22mmol)加入到3(226mg,0.54mmol)和PyBOP(279mg,0.54mmol)在CH2Cl2(40mL)中的溶液中。搅拌10分钟之后,在0℃和Ar(g)下将混合物转移到溶于MeCN(40mL)中的保护2所得的粗胺中,然后反应混合物放置温热到室温。2.5h之后,反应混合物减压浓缩。残余物进一步用EtOAc洗脱的通过柱色谱在硅胶上纯化得到白色固体4(257mg,51%)。
1H NMR(400MHz,9/1 CDCl3/CD3OD)δH:7.09-7.44(m,33H)5.39(dt,J=15.4,5.9Hz,1H)5.30(dd,J=15.3,5.9Hz,1H)4.21-4.29(m,1H)4.19(d,J=6.0Hz,1H)3.95-3.99(m,1H)3.92(d,J=17.6Hz,1H)3.61(s,3H)2.69(d,J=8.0Hz,1H)2.66(d,J=8.0Hz,1H)2.48(d,J=4.9Hz,1H)2.45(d,J=5.0Hz,1H)2.33-2.42(m,2H)2.29(quin,J=6.7Hz,2H)2.11-2.22(m,4H)1.40(s,3H)1.32(s,3H)0.92(d,J=1.4Hz,3H)0.90(d,J=1.5Hz,3H).MS(ES):1042.0(100%,[M+Na]+).
(5):(6R,9S,16R)-6-异丙基-12,12-二甲基-16-((E)-4-三苯甲基硫烷基-丁-1-烯基)-9-三苯甲基硫烷基甲基-1-氧杂-4,7,10,13-四氮杂-环十六烷-2,5,8,11,14-五酮
在0℃将LiOH(9mg,0.37mmol)在水(2mL)中的溶液加入到4(255mg,0.25mmol)在THF(8mL)中的溶液中。在0℃下搅拌45分钟之后,,反应混合物用0.5M HCl水溶液中和,然后加入盐水(40mL)和EtOAc(40mL)。分离相并用EtOAc(20mL)萃取水相。合并有机萃取物,干燥MgSO4,过滤然后减压浓缩,然后直接用于下一步骤。在室温和Ar(g)下CH2Cl2/THF(200mL,12∶1v/v)中的粗羧酸经过3h逐滴加入到2-甲基-6-硝基苯酸酐(103mg,0.30mmol)和4-(二甲基氨基)吡啶(73mg,0.60mmol)的CH2Cl2(50mL)溶液。15h之后,减压浓缩反应混合物。残余物用CH2Cl2/异丙醇(100∶2.5然后100∶5)洗脱的通过柱色谱在硅胶上纯化得到白色固体5(117mg,47%)。
1H NMR(400MHz,CDCl3)δH:7.36-7.47(m,10H),7.14-7.36(m,21H),7.02(d,J=10.0Hz,1H),6.45(d,J=4.6Hz,1H),5.80-5.91(m,1H),5.62(dt,J=14.9,6.7Hz,1H),5.31-5.38(m,1H),5.26(ddd,J=10.7,7.0,3.9Hz,1H),4.73(dd,J=16.7,10.0Hz,1H),4.68(dd,J=10.9,3.8Hz,1H),3.98-4.00(m,1H),3.39(dd,J=15.4,1.3Hz,1H),2.95(dd,J=12.5,7.3Hz,1H),2.63-2.73(m,2H),2.59(dd,J=12.5,4.3Hz,1H),2.52(dd,J=14.2,3.9Hz,1H),2.36(dd,J=14.2,10.9Hz,1H),2.14-2.23(m,2H),1.94-2.14(m,2H),1.55(s,3H),1.32(s,3H),0.99(t,J=8.0Hz,6H).MS(ES):1009.8(100%,[M+Na]+).
化合物XXVII:(E)-(1S,7R,10S)-7-异丙基-21,21-二甲基-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-3,6,9,19,22-五酮
在室温和Ar(g)下,将化合物5(115mg,0.117mmol)在CH2Cl2/CH3OH(80mL,9∶1,v/v)中的溶液经过30分钟逐滴加入到I2(295mg,1.16mmol)在CH2Cl2/CH3OH(170mL,9∶1,v/v)中的溶液中。搅拌2h之后,加入0.1M Na2S2O3(500mL)水溶液和盐水(150mL)。分离相并用CH2Cl2(2×40mL)和EtOAc(2×40mL)萃取水相。合并有机萃取物,用MgSO4干燥,过滤然后减压浓缩。残余物用CH2Cl2/CH3OH(100∶1至100∶5)洗脱的通过柱色谱在硅胶上纯化得到白色固体化合物XXVII(41mg,70%)。
1H NMR(400MHz,9/1 CDCl3/CD3OD)δH:7.33(d,J=7.7Hz,1H),5.68-5.80(m,1H),5.57-5.67(m,2H),4.69(ddd,J=10.0,7.7,4.0Hz,1H),4.16(d,J=17.4Hz,1H),3.85(d,J=17.3Hz,1H),3.26(dd,J=15.3,10.0Hz,1H),2.94-3.05(m,2H),2.80-2.92(m,2H),2.57-2.68(m,1H),2.52-2.57(m,2H),2.36-2.49(m,1H),1.50(s,3H),1.43(s,3H),0.91(t,J=6.8Hz,6H).13C NMR(100MHz,9/1 CDCl3/CD3OD)□C:174.88,172.31,170.57,169.71,168.18,129.05,129.02,69.67,64.93,57.12,55.47,42.04,39.73,37.42,31.72,26.95,26.37,22.66,20.38,20.00.MS(ES):523.4(100%,[M+Na]+),1024.0(70%,[2M+Na]+).
化合物XXIX:(E)-(1S,10S)-7-异丙基-21,21-环丙基-2-氧杂-12,13-二硫
杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-3,6,9,19,22-五酮
(2):[2-((S)-2-{[1-(9H-芴-9-基甲氧基羰基氨基)-环丙烷羰基]-氨基}-3-三苯甲基硫烷基-丙酰基氨基)-3-甲基-丁酰氨基]-乙酸甲酯
在室温和Ar(g)下向1(300mg,0.40mmol,1eq)在MeCN(8mL)中的溶液中逐滴加入0.8mL of Et2NH(10%v/v)。溶液在室温下搅拌2h,然后真空除去溶剂。过量的胺用MeCN(3×5mL)然后用1∶5的CH2Cl2/己烷(10mL)混合物共蒸发除去。获得白色固体,并且烧瓶在高真空下干燥2h。在0℃和Ar(g)下,向Fmoc-环丙基氨基酸(141mg,0.44mmol,1.1eq)在MeCN(6mL)中的溶液中加入PyBOP(227mg 0.44mmol,1.1eq)和N-二异丙基乙胺(173μL,0.99mmol,2.5eq)。溶解于CH2Cl2(6mL)中的粗胺逐滴加入到混合物中。然后反应混合物放至室温过夜。然后混合物真空浓缩,残余物通过硅胶柱色谱进一步用己烷/EtOAc(1∶3->0∶1)纯化获得白色固体2(344mg,98%)。
1H NMR(400MHz,CDCl3+10% MeOD)δH:7.70(d,J=7.5Hz,2H),7.44-7.51(m,1H),7.42(d,J=7.4Hz,1H),7.31-7.36(m,2H),7.20-7.27(m,8H),7.12-7.18(m,7H),7.05-7.10(m,3H),4.32(dd,J=10.5,6.8Hz,1H),4.14-4.22(m,2H),3.99-4.05(m,1H),3.83-3.93(m,1H),3.63(s,3H),2.66-2.80(m,1H),2.37-2.49(m,1H),2.18-2.31(m,1H),1.38-1.49(m,2H),1.22-1.28(m,1H),1.03-1.12(m,1H),0.87-0.97(m,6H).MS(ES+)862.1(100%,[M+Na]+).
(4):[2-((S)-2-{[1-((E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酰基氨基)-环丙烷羰基]-氨基}-3-三苯甲基硫烷基-丙酰基氨基)-3-甲基-丁酰氨基]-乙酸甲酯
在室温和Ar(g)下向2(344mg,0.41mmol,1eq)在MeCN(9mL)中的溶液中逐滴加入Et2NH(0.9mL,10%v/v)。溶液在室温下搅拌2h,然后真空除去溶剂。过量的胺用MeCN(3×5mL)然后用1∶5的CH2Cl2/己烷(10mL)混合物共蒸发除去。获得白色固体,并且烧瓶在高真空下干燥2h。在0℃和Ar(g)下,向α-羟基酸3(189mg,0.45mmol,1.1eq)在MeCN(8mL)中的溶液中逐滴加入PyBOP(235mg,0.45mmol,1.1eq)和N-二异丙基乙胺(179μL.1.02mmol,2.5eq)中。然后反应混合物放至室温过夜。然后混合物真空浓缩,残余物通过硅胶柱色谱进一步用己烷/EtOAc(1∶4)纯化,获得白色固体4(171mg,41%)。
1H NMR(400MHz,CDCl3+10% MeOD)δH:7.31-7.38(m,8H),7.28-7.30(m,3H),7.06-7.25(m,22H),5.36-5.45(m,1H),5.32(dd,J=15.6,6.1Hz,1H),4.26-4.33(m,1H),4.03-4.13(m,2H),3.62(s,3H),2.55(dd,J=12.7,7.9Hz,1H),2.46(dd,J=12.4,6.1Hz,1H),2.07-2.26(m,6H),1.96-2.06(m,3H),1.49-1.57(m,1H),1.25-1.33(m,1H),0.92-1.00(m,1H),0.88(dd,J=6.8,2.8Hz,6H),0.75-0.80(m,1H).MS(ES+)1039.8(100%,[M+Na]+).
(5):(7S,16S)-13-异丙基-7-((E)-4-三苯甲基硫烷基-丁-1-烯基)-16-三苯甲基硫烷基甲基-8-氧杂-4,11,14,17-四氮杂-螺[2.15]十八烷-5,9,12,15,18-五酮
在0℃向4(171mg,0.17mmol,1eq)在THF(6mL)中的溶液中逐滴加入LiOH(6.0mg,0.25mmol,1.5eq)在H2O(2mL)中的溶液。混合物搅拌2h,然后用1N HCl(2mL)和盐水(10mL)淬灭。分离有机层,所得水层进一步用EtOAc(2×15mL)和CH2Cl2(15mL)萃取。合并的有机萃取物用MgSO4干燥。真空除去溶剂。然后所得羧酸在高真空中干燥2h。向MNBA(69mg,0.21mmol,1.2eq)和DMAP(49.3mg,0.40mmol,2.4eq)在CH2Cl2(150mL)的溶液中经3h逐滴加入粗羧酸在CH2Cl2(60mL)和THF(10mL)中的溶液。然后反应混合物在在室温下搅拌过夜。然后真空除去溶剂。残余物通过硅胶柱色谱用己烷/EtOAc(2∶3)进一步纯化得到白色固体5(83mg,50%)。
1H NMR(400MHz,CDCl3)δH:7.36-7.45(m,13H),7.27-7.35(m,15H),7.18-7.27(m,8H),5.54-5.64(m,1H),5.49(dd,J=15.5,7.2Hz,1H),5.28-5.36(m,1H),4.65(dd,J=17.2,9.6Hz,1H),4.55(dd,J=9.6,3.8Hz,1H),3.87-3.96(m,1H),3.43-3.53(m,1H),2.93(dd,J=12.7,7.2Hz,1H),2.61-2.70(m,1H),2.58(dd,J=14.9,4.7Hz,1H),2.51(dd,J=12.6,4.5Hz,1H),2.44(dd,J=14.7,8.5Hz,1H),2.14-2.22(m,2H),1.94-2.11(m,2H),1.04-1.14(m,1H),0.92-1.03(m,9H).MS(ES+)1008.2(100%,[M+Na]+).
化合物XXIX:(E)-(1S,10S)-7-异丙基-21,21-环丙基-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-3,6,9,19,22-五酮
在室温下向I2(216mg,0.85mmol,10eq)在CH2Cl2/MeOH(200mL,9∶1)中的溶液中经过2h逐滴加入5(84mg,0.085mmol,1eq)。混合物用Na2S2O3(0.1M,200mL)和盐水(10mL)淬灭。分离有机层,并且所得水层进一步用CH2Cl2(2×50mL)和EtOAc(50mL)萃取。合并的有机萃取物用MgSO4干燥。真空除去溶剂。通过柱色谱在硅胶上纯化(CH2Cl2/MeOH(19∶1->9∶1))得到白色固体化合物XXIX(34.0mg,0.07mmol,76%)。
1H NMR(400MHz,CDCl3)δH:7.11(d,J=8.9Hz,1H),6.57-6.70(m,1H),6.03-6.16(m,1H),5.65-5.85(m,2H),5.01(t,J=8.2Hz,1H),4.18(dd,J=17.6,4.8Hz,1H),4.07(dd,J=17.6,5.8Hz,1H),3.61(dd,J=13.7,8.8Hz,1H),3.26(dd,J=10.0,6.7Hz,1H),2.93-3.03(m,1H),2.77-2.91(m,5H),2.67-2.75(m,2H),2.57(d,J=13.4Hz,1H),1.35-1.44(m,1H),1.14-1.22(m,1H),0.89-1.00(m,8H).MS(ES+)521.3(100%,[M+Na]+).
化合物XXX:(E)-(1S,10S)-7,7-环丙基-2-氧杂-12,13-二硫杂-5,8,20,23-
四氮杂-二环[8.7.6]二十三-16-烯-3,6,9,19,22-五酮
(2):{[1-((S)-2-甲酰基氨基-3-三苯甲基硫烷基-丙酰基氨基)-环丙烷羰基]-氨基}-乙酸甲酯;具有乙基-氨基甲酸9H-芴-9-基甲酯的化合物
在Ar(g)下向1(310.5mg,0.420mmol)在MeCN/CH2Cl2(10mL/19mL)中的溶液中加入二乙胺(2.9mL,10%v/v),反应混合物在室温下搅拌1小时50分钟。真空除去溶剂,粗混合物用MeCN(3×20mL)处理和低压除去溶剂。然后在高真空干燥粗胺1h。然后在Ar(g)下一边搅拌一边在3分钟内向PyBOP(234.9mg,0.451mmol)和FmocGly-OH(133.86mg,0.450mmol)在CH2Cl2(20mL)中的溶液中加入二异丙基乙胺(0.25mL,1.44mmol)。加入所得的1的去保护胺在MeCN(20mL)中的溶液,所得混合物在室温下搅拌16h。然后真空除去溶剂。通过快速柱色谱在硅胶上纯化(洗脱剂1∶99-3∶97-5∶95 MeOH/CH2Cl2)得到白色固体。材料用1M HCl(aq)清洗,干燥(MgSO4)和真空浓缩得到白色固体2(228.6mg,0.289mmol,68%)。
1H NMR(400MHz,CDCl3)δH:7.76(d,J=7.53Hz,2H),7.55(t,J=6.78Hz,2H),7.43-7.35(m,7H),7.33-7.24(m,9H),7.24-7.18(m,3H),6.96(br s,1H),6.50(d,J=6.27Hz,1H),5.70(br s,1H),4.37(dd,J=6.90,1.63Hz,2H),4.17(t,J=6.84Hz,1H),3.92(m,1H),3.86-3.73(m,3H),3.61(s,3H),2.80(m,1H),2.63(dd,J=13.11,5.84Hz,1H),1.54(q,J=3.97Hz,2H),1.27(s,2H),1.00(d,J=2.51Hz,2H).MS(ES+)820.2(100%,[M+Na]+).Rf 0.35 MeOH/CH2Cl2(5∶95).
(4):[(1-{(S)-2-[2-((E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酰基氨基)-乙酰基氨基]-3-三苯甲基硫烷基-丙酰基氨基}-环丙烷羰基)-氨基]-乙酸甲酯
在Ar(g)下向2(228.6mg,0.287mmol)在MeCN(20mL)中的溶液中加入二乙胺(2.0mL,10%v/v),反应混合物在室温下搅拌2h。真空除去溶剂,粗混合物用MeCN(3×20mL)处理和低压除去溶剂。然后在高真空干燥粗胺。然后在Ar(g)下向PyBOP(150.37mg,0.289mmol)和手性酸3(121.49mg,0.290mmol)在CH2Cl2(15mL)中的溶液中加入二异丙基乙胺(0.18mL,1.03mmol)。加入所得的2的去保护胺在MeCN(15mL)中的溶液,所得混合物在室温下搅拌16h。然后真空除去溶剂,形成的固体用通过快速柱色谱在硅胶上纯化(洗脱剂1∶99-3∶97-5∶95 MeOH/CH2Cl2)得到白色固体4(157.3mg,0.161mmol,56%)。
1H NMR(300MHz,CDCl3)δH:7.45-7.32(m,11H),7.32-7.16(m,20H),7.11(d,J=7.44Hz,1H),6.94(t,J=5.27Hz,1H),5.52(m,1H),5.39(m,1H),4.39(m,1H),4.06(m,1H),3.98-3.52(m,7H),2.78(dd,J=12.57,6.73Hz,1H),2.57(dd,J=12.53,5.27Hz,1H),2.45-2.15(m,4H),2.11-1.99(m,2H),1.56-1.46(m,2H),1.43-1.35(m,2H),1.09-0.94(m,2H).MS(ES+)998.2(100%,[M+Na]+).Rf 0.26MeOH/CH2Cl2(5∶95).
(5):[(1-{(S)-2-[2-((E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酰基氨基)-乙酰基氨基]-3-三苯甲基硫烷基-丙酰基氨基}-环丙烷羰基)-氨基]-乙酸
在0℃向4(157.3mg,0.154mmol)在THF(2.45mL)中的溶液中逐滴加入LiOH(9.19mg,0.384mmol)在H2O(0.65mL)中的溶液,反应搅拌55分钟。反应混合物然后用1M HCl(10mL)淬灭然后用水(10mL)稀释。向分离的层中加入EtOAc(30mL),水层用EtOAc(3×30mL)萃取。合并有机层,用饱和盐水(20mL)洗,分离,干燥(MgSO4)和真空浓缩得到白色固体5(153mg,0.154mmol,100%),其不经进一步纯化直接使用[MS(ES-)959.2(100%,[M-H]-)]。
(6):(6S,13S)-13-((E)-4-三苯甲基硫烷基-丁-1-烯基)-6-三苯甲基硫烷基甲基-14-氧杂-4,7,10,17-四氮杂-螺[2,15]十八烷-5,8,11,15,18-五酮
经3小时55分钟向MNBA(65.48mg,0.190mmol)和DMAP(46.24mg,0.378mmol)在CH2Cl2(38mL)中的溶液中逐滴加入酸5(153mg,0.159mmol)在CH2Cl2(148mL)中的溶液,然后反应混合物在室温下搅拌过夜。然后真空浓缩反应混合物得到橙色/黄色固体。通过柱色谱在硅胶上纯化(洗脱剂1∶99-2∶98 MeOH/CH2Cl2)得到橙色/黄色固体6(68.2mg,0.0723mmol,45%)。
1H NMR(400MHz,CDCl3)δH:7.55(br s,1H)7.49(d,J=7.40Hz,1H),7.45-7.36(m,12H),7.32-7.17(m,18H),7.02(br s,1H),5.57(m,1H),5.50(m,1H),5.36(dd,J=15.50,6.34Hz,1H),4.08(br s,1H),3.87(d,J=13.88Hz,1H),3.74(m,1H),3.46(dd,J=15.75,3.70Hz,1H),2.81(dd,J=12.80,7.03Hz,1H),2.60(m,1H),2.53(d,J=2.89Hz,1H),2.49-2.40(m,2H),2.19(t,J=7.09Hz,2H),2.07-1.99(m,2H),1.87(br s,1H),1.55(br s,2H),1.08-0.97(m,2H).MS(ES+)966.1(100%,[M+Na]+).Rf 0.27(MeOH/CH2Cl2(5∶95).
化合物XXX:(E)-(1S,10S)-7,7-环丙基-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-3,6,9,19,22-五酮
向I2(188.95mg,0.744mmol)在CH2Cl2/MeOH(9∶1)(248mL)中的溶液中经过30分钟逐滴加入6(68.2mg,0.0723mmol)CH2Cl2/MeOH(9∶1)(122.5mL)的溶液。然后反应混合物再搅拌30分钟,然后加入饱和硫代硫酸钠(10mL),然后加水(30mL)。分层,产物用EtOAc(3×100ml)和然后用CH2Cl2(100mL)萃取,干燥(MgSO4)。然后真空除去溶剂。通过快速硅胶柱色谱进行纯化(洗脱剂5∶95-7∶93MeOH/CH2Cl2)得到白色固体化合物XXX(17.6mg,0.0386mmol,53%)。Rf 0.48
CH2Cl2/MeOH(9∶1);1H NMR(400MHz,CDCl3+10% MeOD)δH:8.45(br s,1H),7.60(br s,1H),7.32(d,J=7.65Hz,1H),6.93(br s,1H),5.97(m,1H),5.80-5.68(m,2H),4.72(m,1H),4.19(m,1H),4.11-3.94(m,2H),3.65(m,1H),3.36(m,1H),3.05-2.92(m,2H),2.90-2.74(m,2H),2.66(br s,2H),1.70(m,1H),1.29-1.16(m,2H),1.09-0.96(m,2H).MS(ES+)479.8(100%,[M+Na]+).
化合物XXXI:(E)-(1S,10S,21R)-7,7-环丙基-21-吡啶3-基甲基-2-氧杂
-12,
13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三16-烯-3,6,9,19,22-五
酮
(2):(2-{(S)-2-[(R)-2-(9H-芴-9-基甲氧基羰基氨基)-3-吡啶-3-基-丙酰基氨基]-3-三苯甲基硫烷基-丙酰基氨基}-2-甲基-丙酰氨基)-乙酸甲酯
在室温和Ar(g)下向1(300mg,0.40mmol,1eq)在MeCN(8mL)中的溶液中逐滴加入Et2NH(0.8mL,10%v/v)。溶液在在室温下搅拌2h,然后真空除去溶剂。过量的胺用MeCN(3×5mL)然后用1∶5的CH2Cl2/己烷(10mL)混合物共蒸发除去。获得白色固体,并且烧瓶在高真空下干燥2h。在0℃和Ar下,向Fmoc-D-3-吡啶丙氨酸(173mg,0.45mmol,1.1eq)在MeCN(7mL)中的溶液中加入PyBOP(232mg,0.45mmol,1.1eq)和N-二异丙基乙胺(176μL,1.01mmol,2.5eq)。溶解于CH2Cl2(6mL)中的粗胺逐滴加入到混合物中。然后反应混合物放至室温过夜。然后混合物真空浓缩,残余物通过硅胶柱色谱进一步用EtOAc/MeOH(1∶0->19∶1)纯化获得黄色油状物(316mg,88%)。
1H NMR(400MHz,CDCl3+10% MeOD)δH:8.32(d,J=4.8Hz,2H),7.74-7.79(m,1H),7.70(d,J=7.5Hz,2H),7.55(t,J=5.5Hz,2H),7.43-7.48(m,2H),7.33(t,J=7.4Hz,2H),7.12-7.29(m,18H),4.17-4.36(m,3H),4.07(t,J=6.8Hz,1H),3.67-3.72(m,3H),3.61(s,3H),2.98-3.09(m,1H),2.76-2.92(m,1H),2.41-2.59(m,2H),1.41-1.53(m,2H),0.87-1.05(m,2H).MS(ES+)910.7(100%,[M+Na]+).
(4):(2-{(S)-2-[(R)-2-((E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酰基氨基)-3-吡啶-3-基-丙酰基氨基]-3-三苯甲基硫烷基-丙酰基氨基}-2-甲基-丙酰基氨基)-乙酸甲酯
在室温和Ar(g)下向2(316mg,0.36mmol,1eq)在MeCN(8mL)中的溶液中逐滴加入Et2NH(10%v/v)。溶液在在室温下搅拌2h,然后真空除去溶剂。过量的胺用MeCN(3×5mL)然后用1∶5的CH2Cl2/己烷(5mL)混合物共蒸发除去。获得白色固体,并且烧瓶在高真空下干燥2h。在0℃和Ar下,向β-羟基酸3(157mg,0.37mmol,1.1eq)在MeCN(6mL)中的溶液中加入PyBOP(204mg,0.37mmol,1.1eq)和N-二异丙基乙胺(155μL,0.89mmol,2.5eq)。溶解于CH2Cl2(6mL)中的粗胺逐滴加入到混合物中。然后反应混合物放至室温过夜。然后混合物真空浓缩,残余物通过硅胶柱色谱进一步用CH2Cl2/MeOH(49∶1->13∶1)纯化得到白色固体4(375mg,95%)。
1H NMR(400MHz,CDCl3)δH:8.42-8.49(m,2H),7.67(d,J=7.9Hz,1H),7.38-7.43(m,7H),7.33-7.37(m,5H),7.27-7.31(m,8H),7.25-7.27(m,4H),7.18-7.24(m,7H),7.07(s,1H),6.67(d,J=6.8Hz,1H),5.45(dt,J=15.4,6.6Hz,1H),5.34(d,J=6.2Hz,1H),4.52-4.60(m,1H),4.29-4.37(m,1H),4.01(dd,J=17.9,6.4Hz,1H),3.85-3.92(m,1H),3.66-3.76(m,3H),3.60(s,3H),3.18-3.23(m,1H),3.00(dd,J=14.6,8.9Hz,1H),2.70(dd,J=12.9,7.5Hz,1H),2.63(dd,J=12.9,5.6Hz,1H),2.26-2.32(m,1H),2.16-2.26(m,3H),2.00-2.06(m,3H),1.53-1.58(m,1H),1.48-1.52(m,1H),0.92-1.10(m,2H).MS(ES+)1089.4(100%,[M+Na]+).
(5):(9S,12R,16S)-6,6-环丙基-12-吡啶-3-基甲基-16-((E)-4-三苯甲基硫烷基-丁-1-烯基)-9-三苯甲基硫烷基甲基-1-氧杂-4,7,10,13-四氮杂-环十六烷-2,5,8,11,14-五酮
在0℃向4(375mg,0.35mmol,1eq)在THF(15mL)中的溶液逐滴加入LiOH(12.3mg,0.51mmol,1.5eq)在水(3mL)中的溶液。混合物搅拌2h,然后用1N HCl(4mL)和盐水(10mL)淬灭。分离有机相,所得水层进一步用EtOAc(2×15mL)和CH2Cl2(15mL)萃取。合并的有机萃取物用MgSO4干燥并真空除去溶剂。然后所得羧酸在高真空下干燥2h。向MNBA(141mg,0.41mmol,1.2eq)和DMAP(100.2mg,0.82mmol,2.4eq)在CH2Cl2(350mL)中的溶液中经过3h逐滴加入CH2Cl2(150mL)和THF(20mL)中的粗羧酸。然后反应混合物放置在室温下搅拌过夜。然后真空除去溶剂,并且残余物通过硅胶柱色谱用CH2Cl2/MeOH(24∶1)进一步纯化得到白色固体5(357mg,96%)。
1H NMR(400MHz,CDCl3)δH:8.39-8.46(m,2H),8.06(d,J=7.5Hz,1H),7.31-7.43(m,15H),7.13-7.26(m,17H),6.79(d,J=7.5Hz,1H),6.71-6.77(m,1H),5.41-5.57(m,2H),5.30(dd,J=15.6,6.6Hz,1H),4.65-4.75(m,1H),4.20(dd,J=16.4,7.4Hz,1H),3.72(dd,J=16.8,3.9Hz,1H),2.88(dd,J=14.2,9.0Hz,1H),2.72-2.83(m,1H),2.42-2.52(m,1H),2.32-2.40(m,1H),2.13-2.19(m,3H),1.96-2.03(m,5H),1.39-1.52(m,3H),1.01-1.10(m,1H).MS(ES+)1057.4(100%,[M+Na]+).
化合物XXXI:(E)-(1S,10S,21R)-7,7-环丙基-21-吡啶-3-基甲基-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-3,6,9,19,22-五酮
在室温下向I2(877mg,3.46mmol,10eq)在CH2Cl2/MeOH(1.0L,9∶1)中的溶液中经2h逐滴加入5(357mg,0.35mmol,1eq)。混合物用Na2S2O3(0.1M,300mL)和盐水(10mL)淬灭。分离有机层,所得水层进一步用CH2Cl2(2×50mL)和EtOAc(50mL)萃取。合并的有机萃取物用MgSO4干燥。真空除去溶剂。用CH2Cl2/MeOH(16∶1->12∶1)通过柱色谱在硅胶上纯化获得白色固体的化合物XXXI(45.0mg,24%)。
1H NMR(400MHz,CDCl3+10% MeOD)δH:8.40(br.s.,2H),7.66(d,J=8.0Hz,1H),7.52-7.58(m,2H),7.31(dd,J=7.7,5.0Hz,1H),6.89-6.95(m,1H),5.82-5.92(m,1H),5.70(d,J=16.5Hz,1H),5.63-5.68(m,1H),4.63(ddd,J=11.2,7.5,3.9Hz,1H),4.52(dd,J=9.7,4.9Hz,1H),4.24(dd,J=18.5,5.9Hz,1H),3.92(dd,J=18.5,2.6Hz,1H),3.19-3.31(m,2H),2.94-3.09(m,3H),2.80-2.92(m,2H),2.59-2.71(m,3H),1.71-1.78(m,1H),1.21-1.27(m,2H),0.94-1.03(m,2H).MS(ES+)570.6(100%,[M+Na]+).
化合物XXXII:(E)-(1S,10S,21R)-21-(3-氯-苄基)-7,7-环丙基-2-氧杂
-12,
13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-3,6,9,19,22-五
酮
(2)[(1-{(S)-2-[(R)-3-(3-氯-苯基)-2-(9H-氟-9-基甲氧基羰基氨基)-丙酰基氨基]-3-三苯甲基硫烷基-丙酰基氨基}-环丙烷羰基)-氨基]-乙酸甲酯
在Ar(g)下向1(299.75mg,0.405mmol)在MeCN/CH2Cl2(10mL/20mL)中的溶液中加入二乙胺(2.5mL,8.3%v/v),反应混合物在室温下搅拌2小时20分钟。真空除去溶剂,用MeCN(3×25mL)处理,然后减压除去溶剂。然后粗胺在高真空下干燥2h。然后在0℃和Ar(g)下向PyBOP(222.4mg,0.427mmol)和Fmoc-D 3-chloroPhe-OH(179.94mg,0.425mmol)在CH2Cl2(15mL)中的溶液中边搅拌边用2分钟加入二异丙基乙胺(0.22mL,1.26mmol)。加入所得1的去保护的胺的MeCN(15mL)溶液,然后反应混合物在室温下搅拌16h。然后通过快速硅胶柱色谱进行纯化(洗脱剂4∶6-6∶4-7∶3EtOAc/己烷)得到白色固体2(201.6mg,0.219mmoi,54%)。
1H NMR(400MHz,CDCl3)δH:7.74(d,J=7.40Hz,2H),7.48(d,J=7.53Hz,2H),7.41-7.11(m,23H),7.04(br s,1H),4.38(m,1H),4.30-4.22(m,2H),4.11(m,1H),3.79(br s,1H),3.65(s,2H),3.64-3.58(m,2H),3.02(br s,1H),2.88(br s,1H),2.61(br s,2H),1.51(br s,2H),0.95(br s,2H).MS(ES+)943.0(100%,[M+Na]+).Rf 0.35 CH2Cl2/MeOH(95∶5).
(4):[(1-{(S)-2-[(R)-3-(3-氯-苯基)-2-((E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酰基氨基)-丙酰基氨基]-3-三苯甲基硫烷基-丙酰基氨基}-环丙烷羰基)-氨基]-乙酸甲酯
在Ar(g)和室温下向2(200mg,0.217mmol)在MeCN/CH2Cl2(10mL/5mL)中的溶液中加入二乙胺(1.0mL,7%v/v),反应混合物搅拌1小时30分钟。真空除去溶剂,用MeCN(4×20mL)处理,然后减压除去溶剂。粗胺在高真空下干燥。然后在Ar(g)下向PyBOP(121.7mg,0.234mmol)和手性酸3(105.4mg,0.252mmol)在CH2Cl2(15mL)中的溶液中加入二异丙基乙胺(0.13mL,0.746mmol)。加入所得的去保护胺在MeCN(15mL)中的溶液,然后所得混合物在室温下搅拌16h。然后真空除去溶剂,形成的固体用通过快速柱色谱在硅胶上纯化(洗脱剂1∶1-7∶3 EtOAc/己烷)得到白色固体4(190mg,0.173mmol,80%)。
1H NMR(400MHz,CDCl3+ 10% MeOD)δH:7.37-7.10(m,37H),7.01(d,J=7.03Hz,1H),5.42(m,1H),5.28(m,1H),4.44(m,1H),4.24(m,1H),3.85-3.67(m,3H),3.59(s,3H),3.37(s,1H),3.33(dt,J=3.17,1.62Hz,1H),3.02(d,J=5.14Hz,2H),2.80(dd,J=14.31,8.78Hz,1H),2.53(dd,J=6.90,2.01Hz,1H),2.24-2.10(m,5H),2.01(q,J=7.19Hz,2H),1.52-1.40(m,2H),0.95(d,J=2.76Hz,2H).MS(ES+)1121.7(100%,[M+Na]+).Rf 0.22 MeOH/CH2Cl2(5∶95).
(5):[(1-{(S)-2-[(R)-3-(3-氯-苯基)-2-((E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酰基氨基)-丙酰基氨基]-3-三苯甲基硫烷基-丙酰基氨基}-环丙烷羰基)-氨基]-乙酸
在0℃向4(188.5mg,0.172mmol)在THF(2.9mL)中的溶液中逐滴加入LiOH(8.5mg,0.355mmol)在H2O(0.70mL)中的溶液,反应搅拌1小时30分钟。反应混合物然后用1M HCl(10mL)淬灭然后加入水(10mL)和EtOAc(30mL)稀释。分离层,产品用EtOAc(3×25mL)萃取。合并有机层,用饱和盐水(20mL)洗,干燥(MgSO4)和真空浓缩得到白色固体5(182mg,98%)。产品不作进一步纯化而使用[MS(ES-)1083.6(100%,[M-H]-)]。
(6):(6S,9R,13S)-9-(3-氯-苄基)-13-((E)-4-三苯甲基硫烷基-丁-1-烯基)-6-三苯甲基硫烷基甲基-14-氧杂-4,7,10,17-四氮杂-螺[2.15]十八烷-5,8,11,15,18-五酮
经3小时向MNBA(69.29mg,0.201mmol)和DMAP(48.76mg,0.40mmol)在CH2Cl2(31mL)中的溶液中逐滴加入酸5(180mg,0.166mmol)在CH2Cl2(125mL)中的溶液,然后反应混合物在室温下搅拌过夜。然后真空浓缩反应混合物得到褐色固体。通过柱色谱在硅胶上纯化(洗脱剂0∶1-0.5∶99.5-1∶99-1.5∶98.5-2∶98-3∶97MeOH/CH2Cl2)得到橙色/黄色固体6(70.0mg,0.0656mmol,40%)。
1H NMR(400MHz,CDCl3)δH:7.41-7.35(m,10H),7.31-7.03(m,23H),6.96(d,J=7.65Hz,1H),6.82(br s,1H),6.26(br s,1H),5.61-5.52(m,1H),5.44-5.32(m,2H),4.39(br s,1H),4.23(dd,J=16.63,7.47Hz,1H),3.84-.75(m,1H),3.50(s,2H),3.01,(br s,1H),2.97-2.90(m,1H),2.88-2.79(m,2H),2.71-2.78(m,1H),2.52-2.39(m,2H),2.26-2.16(m,2H),2.05(br s,2H),1.49(d,J=4.02Hz,2H),1.05(dd,J=9.79,3.64Hz,1H),0.86(dd,J=10.04,3.89Hz,1H).MS(ES+)1089.3(100%,[M+Na]+).Rf 0.42 MeOH/CH2Cl2(5∶95).
化合物XXXII:(E)-(1S,10S,21R)-21-(3-氯代-苄基)-7,7-环丙基-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-3,6,9,19,22-五酮
在室温下向碘(171.3mg,0.155mmol)在CH2Cl2/MeOH(9∶1)(113.5mL)中的溶液中经过40分钟逐滴加入6(70.0mg,0.0656mmol)。反应混合物再搅拌50分钟,之后加入Na2S2O3(100mL,0.05M)。分层,产物用EtOAc(3×65mL)萃取。合并有机层,干燥(MgSO4),真空除去溶剂。通过柱色谱在硅胶上纯化(洗脱剂1∶99-2∶98-3∶97-4∶96-5∶95 MeOH/CH2Cl2)得到白色固体化合物XXXII(17.6mg,0.0343mmol,32%)。
1H NMR(400MHz,CDCl3+ 10% MeOD)δH:7.77(d,J=3.89Hz,1H),7.62(s,1H),7.47(d,J=7.53Hz,1H),7.21(dd,J=5.52,1.76Hz,2H),7.08(m,1H),6.92(br s,1H),5.84(m,1H),5.70-5.61(m,2H),4.64(ddd,J=10.76,7.31,3.89Hz,1H),4.48(m,1H),4.18(dd,J=18.45,5.65Hz,1H),3.94(dd,J=18.45,3.14Hz,1H),3.37-3.29(m,2H),3.17(dd,J=14.68,5.27Hz,1H),3.04-2.95(m,2H),2.90(dd,J=15.50,3.83Hz,1H),2.85-2.71(m,2H),2.66-2.57(m,3H),1.71(m,1H),1.21(m,1H),0.98(q,J=3.05Hz,2H).MS(ES+)603.2(100%,[M+Na]+).Rf 0.34 CH2Cl2/MeOH(94∶6).
化合物XXXIII:(E)-(1S,10S,21R)-21-苄基-7,7-环丙基-2-氧杂-12,13-二
硫杂-5,8,20,23-四氮杂-二环[8.7.6]-二十三-16-烯-3,6,9,19,22-五酮
(2):[(1-{(S)-2-[(R)-2-(9H-芴-9-基甲氧基羰基氨基)-3-苯基-丙酰基氨基]-3-三苯甲基硫烷基-丙酰基氨基}-环丙烷羰基)-氨基]-乙酸甲酯
在室温和Ar(g)下向1(300mg,0.40mmol,1eq)在MeCN(8mL)中的溶液中逐滴加入Et2NH(0.8mL,10%v/v)。溶液在在室温下搅拌2h,然后真空除去溶剂。过量的胺用MeCN(3×5mL)然后用1∶5的CH2Cl2/己烷(10mL)混合物共蒸发除去。获得白色固体,并且烧瓶在高真空下干燥2h。在0℃和Ar下,向Fmoc-D-3-吡啶丙氨酸(173mg,0.45mmol,1.1eq)在MeCN(7mL)中的溶液中加入PyBOP(233mg,0.45mmol,1.1eq)和N-二异丙基乙胺(176μL,1.01mmol,2.5eq)。溶解于CH2Cl2(6mL)中的粗胺逐滴加入到混合物中。然后反应混合物放至室温过夜。然后混合物真空浓缩,残余物通过硅胶柱色谱进一步用己烷/EtOAc(1∶2->0∶1)纯化获得白色固体2(294mg,82%)。
1H NMR(400MHz,CDCl3+10% MeOD)δH:7.70(d,J=7.3Hz,2H),7.45(d,J=7.0Hz,2H),7.34(t,J=7.4Hz,2H),7.05-7.29(m,25H),4.15-4.37(m,3H),4.08(t,J=6.8Hz,2H),3.66-3.74(m,3H),3.60(s,3H),2.80-3.06(m,2H),2.38-2.56(m,2H),1.41-1.51(m,2H),0.88-0.99(m,2H).MS(ES+)909.2(100%,[M+Na]+).
(4):[(1-{(S)-2-[(R)-2-((E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酰基氨基)-3-苯基-丙酰基氨基]-3-三苯甲基硫烷基-丙酰基氨基}-环丙烷羰基)-氨基]-乙酸甲酯
在室温和Ar(g)下向2(294mg,0.33mmol,1eq)在MeCN(7mL)中的溶液中逐滴加入Et2NH(0.7mL,10%v/v)。溶液在在室温下搅拌2h,然后真空除去溶剂。过量的胺用MeCN(3×5mL)然后用1∶5的CH2Cl2/己烷(5mL)混合物共蒸发除去。获得白色固体,并且烧瓶在高真空下干燥2h。在0℃和Ar下,向β-羟基酸3(145mg,0.35mmol,1.1eq)在MeCN(5mL)中的溶液中加入PyBOP(189mg,0.36mmoi,1.1eq)和N-二异丙基乙胺(143μL,0.83mmol,2.5eq)。溶解于CH2Cl2(5mL)中的粗胺逐滴加入到混合物中。然后反应混合物放至室温过夜。然后混合物真空浓缩,残余物通过硅胶柱色谱进一步用己烷/EtOAc(2∶3->0∶1)纯化得到白色固体4(305mg,87%)。
1H NMR(400MHz,CDCl3+10%MeOD)δH:7.49(s,1H),7.33-7.39(m,7H),7.28-7.33(m,4H),7.12-7.28(m,27H),5.39-5.49(m,1H),5.26-5.35(m,1H),4.27(q,J=6.3Hz,1H),3.86(r,J=6.8Hz,1H),3.72(d,J=5.9Hz,2H),3.62(s,3H),3.05(dd,1H),2.85(dd,J=14.1,8.6Hz,1H),2.57(dd,J=12.4,6.9Hz,1H),2.50(dd,J=12.3,7.1Hz,1H),2.22(d,J=6.8Hz,2H),2.16(t,J=7.2Hz,2H),1.97-2.07(m,2H),1.39-1.52(m,2H),0.94-1.03(m,2H).MS(ES+)1087.8(100%,[M+Na]+).
(5):(6S,9R,13S)-9-苄基-13-((E)-4-三苯甲基硫烷基-丁-1-烯基)-6-三苯甲基硫烷基甲基-14-氧杂-4,7,10,17-四氮杂-螺[2.15]十八烷-5,8,11,15,18-五酮
在0℃向4(305mg,0.29mmol,1eq)在THF(10mL)中的溶液逐滴加入LiOH(10.3mg,0.43mmol,1.5eq)在水(2mL)中的溶液。混合物搅拌2h,然后用1N HCl(3mL)和盐水(10mL)淬灭。分离有机相,所得水层进一步用EtOAc(2×15mL)和CH2Cl2(15mL)萃取。合并的有机萃取物用MgSO4干燥并真空除去溶剂。然后所得羧酸在高真空下干燥2h。向MNBA(118mg,0.34mmol,1.2eq)和DMAP(84mg,0.69mmol,2.4eq)在CH2Cl2(200mL)中的溶液中经过3h逐滴加入CH2Cl2(130mL)和THF(20mL)中的粗羧酸。然后反应混合物放置在室温下搅拌过夜。然后真空除去溶剂,残余物通过硅胶柱色谱用己烷/EtOAc(1∶9->0∶1)进一步纯化得到白色固体5(171mg,58%)。
1H NMR(400MHz,CDCl3+10% MeOD)δH:7.50(br.s.,1H),7.34-7.40(m,7H),7.18-7.33(m,30H),5.42-5.52(m,1H),5.40(d,J=16.5Hz,1H),5.33-5.39(m,1H),4.61(m,1H),4.51(m,1H),4.19(m,1H),3.82(m,1H),3.17-3.21(m,2H),2.84-2.99(m,3H),2.70-2.82(m,2H),2.49-2.60(m,2H),1.65-1.58(m,1H),1.39-1.52(m,2H),0.94-1.03(m,2H).MS(ES+)1056.7(100%,[M+Na]+).
化合物XXXIII:(E)-(1S,10S,21R)-21-苄基-7,7-环丙基-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-3,6,9,19,22-五酮
在室温下向I2(420mg,1.65mmol,10eq)在CH2Cl2/MeOH(400mL,9∶1)中的溶液中经2h逐滴加入5(171mg,0.17mmol,1eq)。混合物用Na2S2O3(0.1M,200mL)和盐水(10mL)淬灭。分离有机层,所得水层进一步用CH2Cl2(2×50mL)和EtOAc(50mL)萃取。合并的有机萃取物用MgSO4干燥。真空除去溶剂。用CH2Cl2/MeOH(32∶1->12∶1)通过柱色谱在硅胶上纯化获得白色固体的化合物XXXI(73.0mg,81%)。
1H NMR(400MHz,CDCl3)δH:7.50(s,1H),7.44(d,J=7.7Hz,1H),7.36-7.42(m,2H),7.30-7.35(m,1H),7.23(d,J=6.9Hz,2H),6.82(t,J=3.9Hz,1H),6.00(d,J=3.8Hz,1H),5.80-5.91(m,1H),5.74(d,J=5.6Hz,1H),5.65(dd,J=16.0,1.2Hz,1H),4.78(ddd,J=10.0,7.7,4.0Hz,1H),4.59(dt,J=9.5,4.7Hz,1H),4.19(dd,J=18.4,5.0Hz,1H),4.11(dd,J=18.5,4.0Hz,1H),3.51(dd,J=15.4,10.0Hz,1H),3.33(dd,J=14.6,5.0Hz,1H),2.88-3.10(m,4H),2.64-2.81(m,2H),2.53-2.63(m,1H),2.45(d,J=13.3Hz,1H),1.79(ddd,J=10.2,7.2,4.4Hz,1H),1.35(ddd,J=10.2,7.2,4.0Hz,1H),1.07-1.14(m,J=10.2,7.7,4.7Hz,1H),0.99-1.06(m,J=10.2,7.2,3.9Hz,1H).MS(ES+)579.7(100%,[M+Na]+).
化合物XXXIV:(E)-(1S,10S,21R)-7-环丙基-21-吡啶-4-基甲基-2-氧杂
-12,
13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-3,6,9,19,22-五
酮
(2):[(1-{(S)-2-[(R)-2-(9H-芴-9-基甲氧基羰基氨基)-3-吡啶-4-基-丙酰基氨基]-3-三苯甲基硫烷基-丙酰基氨基}-环丙烷羰基)-氨基]-乙酸甲酯在室温和Ar(g)下将Et2NH(2mL)加入到({1-[(S)-2-(9H-芴-9-基甲氧基羰基氨基)-3-三苯甲基硫烷基-丙酰基氨基]-环丙烷羰基}-氨基)-乙酸甲酯1(548mg,0.72mmol)在MeCN(18mL)中的溶液中。搅拌3h之后,低压除去溶剂,然后残余物用MeCN(4×20mL)和己烷(2×20mL)重新溶解和蒸发。粗产品在高真空下干燥3小时,然后在下一步使用。在0℃和Ar(g)下将N,N-二异丙基乙胺(0.26mL,1.50mmol)加入到(R)-2-(9H-芴-9-基甲氧基羰基氨基)-3-吡啶-4-基-丙酸(254mg,0.65mmol)和PyBOP(338mg,0.65mmol)在CH2Cl2(20mL)中的溶液中。搅拌10分钟之后,在0℃和Ar(g)下将混合物转移到溶于MeCN(20mL)的由去保护的({1-[(S)-2-(9H-芴-9-基甲氧基羰基氨基)-3-三苯甲基硫烷基-丙酰基氨基]-环丙烷羰基}-氨基)-乙酸甲酯1得到的粗胺中。然后反应混合物温热到室温。17h之后,减压浓缩反应混合物,残余物通过硅胶柱色谱用EtOAc/CH3OH(100∶0然后100∶0.5至100∶4)洗脱纯化以获得白色固体2(522mg,99%)。
1H NMR(400MHz,400MHz,9/1 CDCl3/CD3OD)δH:8.46(d,J=6.0Hz,1H),7.69(d,J=4.8Hz,1H),7.64(m,J=7.2Hz,2H),7.38-7.51(m,2H),7.24-7.34(m,10H),7.05-7.23(m,15H),4.33-4.39(m,1H),4.21-4.31(m,2H),3.65-3.78(m,2H),3.62(t,J=6.9Hz,1H),3.54(s,3H),2.96-3.14(m,2H),2.44(d,J=6.9Hz,1H),1.36-1.49(m,2H),1.34(d,J=6.8Hz,1H),1.29(d,J=6.8Hz,1H),0.80-0.96(m,2H).MS(ES):888.7(100%,[M+H]+).
(4):[(1-{(S)-2-[(R)-2-((E)-(S)-3-羟基-7-三苯甲基硫烷基-庚-4-烯酰基氨基)-3-吡啶-4-基-丙酰基氨基]-3-三苯甲基硫烷基-丙酰基氨基}-环丙烷羰基)-氨基]-乙酸甲酯
在室温和Ar(g)下将Et2NH(2mL)加入到2(523mg,0.59mmol)在MeCN(18mL)中的溶液中。搅拌4h之后,低压除去溶剂,然后残余物用MeCN(4×20mL)和己烷(2×20mL)重新溶解和蒸发。粗产品在高真空下干燥至少3h,然后用于下一步骤。在0℃和Ar(g)下将N,N-二异丙基乙胺(0.247mL,1.47mmol)加入到3(272mg,0.65mmol)和PyBOP(338mg,0.65mmol)在CH2Cl2(20mL)中的溶液中。搅拌10分钟之后,在0℃和Ar(g)下将混合物转移到溶于MeCN(10mL)中的保护2所得的粗胺中,然后反应混合物放置温热到室温。2.5h之后,反应混合物减压浓缩。残余物进一步用CH2Cl2/CH3OH(100∶1至100∶4)洗脱的通过柱色谱在硅胶上纯化得到白色固体4(384mg,61%)。
1H NMR(400MHz,CDCl3)δH:8.50(d,J=6.5Hz,2H),8.03(d,J=6.9Hz,1H),7.83-7.89(m,2H),7.10-7.42(m,34H),5.42(dt,J=14.1,6.1Hz,1H),5.32(dd,J=15.7,6.3Hz,1H),4.64-4.73(m,1H),4.21-4.28(m,1H),3.83(d,J=17.7Hz,1H),3.74(d,J=17.8Hz,1H),3.61-3.68(m,2H),3.59(s,3H),3.22-3.29(m,1H),2.60(d,J=7.4Hz,2H),2.19-2.31(m,2H),2.08-2.19(m,2H),2.01(q,J=6.9Hz,2H),1.35-1.54(m,4H).MS(ES):1066.9(40%,[M+H]+),1088.8(100%,[M+Na]+).
(5):(6S,9R,13R)-9-吡啶-4-基甲基-13-((E)-4-三苯甲基硫烷基-丁-1-烯基)-6-三苯甲基硫烷基甲基-14-氧杂-4,7,10,17-四氮杂-螺[2.15]十八烷-5,8,11,15,18-五酮
在0℃将LiOH(13mg,0.54mmol)在水(2mL)中的溶液加入到4(384mg,0.36mmol)在THF(8mL)中的溶液中。在0℃下搅拌1.5小时之后,,反应混合物用0.5M HCl水溶液中和,然后加入盐水(50mL)和EtOAc(50mL)。分离相并用EtOAc(3×10mL)萃取水相。合并有机萃取物,用MgSO4干燥,过滤然后减压浓缩,然后直接用于下一步骤。在室温和Ar(g)下CH2Cl2/THF(250mL,12∶1v/v)中的粗羧酸经过3h逐滴加入到2-甲基-6-硝基苯酸酐(149mg,0.43mmol)和4-(二甲基氨基)吡啶(105mg,0.86mmol)的CH2Cl2(120mL)溶液。19h之后,减压浓缩反应混合物。残余物用CH2Cl2/CH3OH(100∶2然后100∶10)洗脱的通过柱色谱在硅胶上纯化得到白色固体5(203mg,54%)。
1H NMR(400MHz,9/1 CDCl3/CD3OD)δH:8.37(d,J=6.5Hz,2H),7.75(d,J=6.7Hz,2H),6.90-7.22(m,33H),5.34(dt,J=14.8,6.8Hz,1H),5.08-5.21(m,2H),4.50(dd,J=10.8,4.5Hz,1H),3.84(d,J=15.9Hz,1H),3.57(d,J=15.9Hz,1H),3.22(dd,J=14.1,4.5Hz,1H),3.15(dd,J=9.4,5.1Hz,1H),2.59(d,J=9.4Hz,1H),2.56(d,J=9.3Hz,1H),2.45(d,J=5.0Hz,1H),2.42(d,J=5.1Hz,1H),2.38(d,J=10.7Hz,1H),2.34(d,J=10.8Hz,1H),2.02(dd,J=14.8,2.1Hz,1H),1.89-1.96(m,2H),1.74-1.83(m,2H),1.24-1.35(m,2H),1.19(ddd,J=9.8,7.9,4.0Hz,2H).MS(ES):1056.8(100%,[M+Na]+).
化合物XXXIV:(E)-(1S,10S,21R)-7-环丙基-21-吡啶-4-基甲基-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂-二环[8.7.6]二十三-16-烯-3,6,9,19,22-五酮
在室温和Ar(g)下将化合物5(201mg,0.19mmol)在CH2Cl2/CH3OH(143mL,9∶1v/v)中的溶液经过30分钟逐滴加入到I2(502mg,1.94mmol)在CH2Cl2/CH3OH(297mL,9∶1v/v)中的溶液中。搅拌3小时之后,加入0.5M Na2S2O3(500mL)和盐水(150mL)。分离相,水相用CH2Cl2(2×50mL)和EtOAc(50mL)萃取。合并有机相,用MgSO4干燥,过滤然后减压浓缩。残余物通过以CH2Cl2/CH3OH(100∶3)洗脱的通过柱色谱在硅胶上纯化得到白色固体化合物XXXIV(2mg,2%)。
1H NMR(400MHz,9/1 CDCl3/CD3OD)δH:8.88(d,J=3.4Hz,1H),8.49(d,J=6.5Hz,2H),8.07(d,J=6.5Hz,1H),7.96(d,J=6.5Hz,2H),7.51-7.59(m,1H),6.86(d,J=6.0Hz,1H),5.83-5.94(m,1H),5.75(dd,J=18.6,15.8Hz,1H),5.53-5.65(m,1H),4.82(ddd,J=9.6,4.0,2.5Hz,1H),4.51-4.58(m,1H),4.48(dt,J=8.8,4.6Hz,1H),4.25(d,J=18.6Hz,1H),4.14-4.21(m,1H),3.79(dd,J=14.8,2.3Hz,1H),3.76(d,J=18.3Hz,1H),3.70(d,J=18.4Hz,1H),3.48-3.59(m,2H),3.39(dd,J=15.6,5.0Hz,2H),3.23-3.33(m,2H),1.55-1.70(m,2H),1.16-1.25(m,2H).MS(ES):570.8(100%,[M+Na]+).
Claims (20)
1.一种结构IX或X的化合物或其可药用盐:
其中:
X是-C(=O)N(R10)-或-CH(OPr3)-;
R7、R9和R10相同或不同,表示氢或来自于天然或非天然氨基酸的氨基酸侧链部分;
Pr1和Pr2相同或不同,表示氢或硫醇保护基;
Pr3是氢或醇保护基;
R1、R2、R5和R6相同或不同,表示氢或来自于天然或非天然氨基酸的氨基酸侧链部分,或者R1和R2、和/或R5和R6与连接它们的碳原子一起形成螺环部分,
前提是:
R1和R2各自不是氢,或
R5和R6各自不是氢。
2.根据权利要求1的化合物,其中R1和R2、和/或R5和R6与连接它们的碳原子一起形成具有3-8个碳原子的环烷基。
3.根据前述权利要求中任一项的化合物,其中所述天然或非天然氨基酸侧链部分为:-CH3(丙氨酸)、-CH(CH3)2(缬氨酸)、-CH2CH(CH3)2(亮氨酸)、-CH(CH3)CH2CH3(异亮氨酸)、-(CH2)4NH2(赖氨酸)、-(CH2)3NHC(=NH)NH2(精氨酸)、-CH2-(5-1H-咪唑基)(组氨酸)、-CH2CONH2(天冬酰胺酸)、-CH2CH2CONH2(谷氨酰胺)、-CH2COOH(天门冬氨酸)、-CH2CH2COOH(谷氨酸)、-CH2-苯基(苯基丙氨酸)、-CH2-(4-OH-苯基)(酪氨酸)、-CH2-(3-1H-吲哚基)(色氨酸)、-CH2SH(半胱氨酸)、-CH2CH2SCH3(蛋氨酸)、-CH2OH(丝氨酸)和-CH(OH)CH3(苏氨酸)、-(CH2)2-C(O)-O-C(CH3)3(谷氨酸叔丁基酯)、-(CH2)4-NH-C(O)-O-C(CH3)3(Nε-(叔丁氧基羰基)-赖氨酸)、-(CH2)3-NH-C(O)NH2(瓜氨酸)、-CH2-CH2OH(高丝氨酸)和-(CH2)3NH2(鸟氨酸)、-H(氨基乙酸)、C1-C6烷基、C2-C6烯基、C2-C6炔基、芳基、或可官能化或未官能化的饱和或不饱和杂环。
4.根据权利要求3的化合物,其中所述天然或非天然氨基酸侧链部分为:-H(氨基乙酸)、-CH3(丙氨酸)、-CH(CH3)2(缬氨酸)、-CH2CH(CH3)2(亮氨酸)、-CH(CH3)CH2CH3(异亮氨酸)、-(CH2)4NH2(赖氨酸)、-(CH2)3NHC(=NH)NH2(精氨酸)、-CH2-(5-1H-咪唑基)(组氨酸)、-CH2CONH2(天冬酰胺酸)、-CH2CH2CONH2(谷氨酰胺)、-CH2COOH(天门冬氨酸)、-CH2CH2COOH(谷氨酸)、-CH2-苯基(苯基丙氨酸)、-CH2-(4-OH-苯基)(酪氨酸)、-CH2-(3-1H-吲哚基)(色氨酸)、-CH2SH(半胱氨酸)、-CH2CH2SCH3(蛋氨酸)、-CH2OH(丝氨酸)和-CH(OH)CH3(苏氨酸)。
5.根据前述权利要求中任一项的化合物,其中X为-CH(=O)N(R10)-。
7.根据权利要求1-4中任一项所述的化合物,其中X是-CH(OPr3)-。
9.根据前述权利要求中任一项的化合物,用于治疗。
10.根据前述权利要求中任一项的化合物,用于治疗或预防由组蛋白去乙酰化酶(HDAC)介导的病症。
11.根据权利要求10的化合物类似物,其中所述病症为癌症、心脏肥大、慢性心力衰竭、炎症、心血管疾病、血红蛋白病、地中海贫血、镰状细胞病、CNS紊乱、自身免疫性疾病、糖尿病、骨质疏松、MDS、良性前列腺增生、子宫内膜异位、口白斑病、基因相关的代谢障碍、感染、Rubens-Taybi、脆性X综合征、或α-1抗胰蛋白酶缺乏症。
12.根据权利要求10或11的化合物,其中所述病症为慢性淋巴细胞白血病、乳腺癌、前列腺癌、卵巢癌、间皮瘤、T-细胞淋巴瘤、心脏肥大、慢性心力衰竭或皮肤炎症,特别是银屑病、痤疮或湿疹。
13.根据权利要求1-8中任一项的化合物,用于加快伤口愈合、保护毛囊或者作为免疫抑制剂。
14.一种药物组合物,含有根据权利要求1-8中任一项的化合物和可药用载体或稀释剂。
15.根据权利要求14的组合物,其为适合于口服、直肠、肠胃外、鼻内或透皮施用或者通过吸入或栓剂施用的形式。
16.根据权利要求15的组合物,其为颗粒剂或片剂,例如舌下片剂、胶囊、糖锭、锭剂、水性或油性混悬剂或可分散粉末剂的形式。
17.一种产品,含有(a)根据权利要求1-8中任一项的化合物和(b)另一种HDAC抑制剂,在治疗中同时、单独或顺序使用。
18.根据权利要求17的产品,其中所述治疗针对由HDAC介导的病症。
19.一种产品,含有(a)根据权利要求1-8中任一项的化合物和(b)化疗剂或抗肿瘤剂,在治疗中同时、单独或顺序使用。
20.根据权利要求19的产品,其中所述治疗针对癌症。
Applications Claiming Priority (5)
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GB0809328.8 | 2008-05-22 | ||
GB0809328A GB0809328D0 (en) | 2008-05-22 | 2008-05-22 | Depsipeptides and their therapeutic use |
GB0809324.7 | 2008-05-22 | ||
GB0809324A GB0809324D0 (en) | 2008-05-22 | 2008-05-22 | Depsipeptides and their therapeutic use |
PCT/GB2009/050554 WO2009141658A1 (en) | 2008-05-22 | 2009-05-22 | Depsipeptides and their therapeutic use |
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US (1) | US8614193B2 (zh) |
EP (1) | EP2293846B1 (zh) |
JP (1) | JP5579703B2 (zh) |
CN (1) | CN102170939A (zh) |
CA (1) | CA2725278A1 (zh) |
DK (1) | DK2293846T3 (zh) |
ES (1) | ES2428817T3 (zh) |
GB (1) | GB2460181B (zh) |
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GB0905970D0 (en) | 2009-04-06 | 2009-05-20 | Karus Therapeutics Ltd | Depsipeptides and their therapeutic use |
EP2624832B1 (en) | 2010-10-08 | 2017-09-27 | Vib Vzw | Hdac inhibitors to treat charcot-marie-tooth disease |
ITRM20120405A1 (it) | 2012-08-09 | 2014-02-10 | C N C C S Scarl Collezione Naziona Le Dei Compost | Compounds for use in the treatment of disorders that are ameliorated by inhibition of hdac |
KR102022631B1 (ko) | 2017-02-09 | 2019-09-19 | 중앙대학교 산학협력단 | 고리형 펜타뎁시펩타이드를 유효성분으로 함유하는 혈관신생 억제용 약학적 조성물 |
WO2018147615A1 (ko) * | 2017-02-09 | 2018-08-16 | 중앙대학교 산학협력단 | 고리형 펜타뎁시펩타이드를 유효성분으로 함유하는 혈관신생 억제용 약학적 조성물 |
WO2020018888A1 (en) | 2018-07-20 | 2020-01-23 | The Board Of Regents Of The University Of Oklahoma | Antimicrobial peptides and methods of use |
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EP1547617A1 (en) * | 2002-08-20 | 2005-06-29 | Yamanouchi Pharmaceutical Co. Ltd. | Arthrodial cartilage extracellular matrix degradation inhibitor |
WO2006129105A1 (en) * | 2005-06-02 | 2006-12-07 | University Of Southampton | Fk 228 derivates as hdac inhibitors |
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ATE353663T1 (de) * | 1999-12-08 | 2007-03-15 | Cyclacel Pharmaceuticals Inc | Verwendung von depsipeptide und deren analoge als immunosuppressiva zur behandlung von infektionskrankheiten, autoimmunerkrankungen, allergien und hyperproliferativer hautkrankheiten |
GB0623388D0 (en) * | 2006-11-23 | 2007-01-03 | Univ Southampton | Chemical compounds |
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EP1547617A1 (en) * | 2002-08-20 | 2005-06-29 | Yamanouchi Pharmaceutical Co. Ltd. | Arthrodial cartilage extracellular matrix degradation inhibitor |
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Also Published As
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EP2293846B1 (en) | 2013-07-10 |
CA2725278A1 (en) | 2009-11-26 |
GB0908875D0 (en) | 2009-07-01 |
GB2460181B (en) | 2010-08-18 |
EP2293846A1 (en) | 2011-03-16 |
GB2460181A (en) | 2009-11-25 |
ES2428817T3 (es) | 2013-11-11 |
US8614193B2 (en) | 2013-12-24 |
DK2293846T3 (da) | 2013-10-14 |
WO2009141658A1 (en) | 2009-11-26 |
US20110112090A1 (en) | 2011-05-12 |
JP2011529023A (ja) | 2011-12-01 |
JP5579703B2 (ja) | 2014-08-27 |
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