CN104854096B - 钠葡萄糖协同转运蛋白1的抑制剂 - Google Patents
钠葡萄糖协同转运蛋白1的抑制剂 Download PDFInfo
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Abstract
本发明公开了钠葡萄糖协同转运蛋白1(SGLT1)的抑制剂、包含它们的组合物以及将它们用于治疗疾病和障碍例如糖尿病的方法。具体的化合物由式(I)表示,其各个取代基在本文中定义。
Description
技术领域
本发明涉及可用于抑制钠葡萄糖协同转运蛋白1(SLGT1)的化合物、包含它们的组合物以及它们的使用方法。
背景技术
2型糖尿病是一种以由肝葡萄糖生成、胰岛素分泌不足和/或外周胰岛素抗性所造成的高血糖症为特征的慢性疾病。近年中,相当多的努力已被引向发现这种疾病的治疗方式。一种相对新的方法是钠葡萄糖协同转运蛋白(SLGT)的抑制,其通过从血流中移除葡萄糖来降低血糖水平。
在正常条件下,血浆葡萄糖在肾小球中被过滤,并且在健康个体中几乎完全被重吸收。Obermeier,M.等,Drug Metabolism Disposition38(3):405-414,406(2010)。所述重吸收由两种钠依赖性葡萄糖协同转运蛋白:SGLT1和SGLT2而介导。SGLT1在肠、心脏和肾中表达,而SGLT2主要表达在肾单位的近端小管中。同上。尽管已经描述了抑制两种转运蛋白的化合物,但研究主要聚焦于发现选择性的SGLT2抑制剂。这部分是由于发现了肠中SGLT1转运蛋白的缺陷造成一些葡萄糖和半乳糖吸收障碍,以及相信SGLT1的抑制因此将伴有不可接受的副作用。同上。因此,目前在临床试验中的大多数SGLT抑制剂,包括dapagliflozin、canagliflozin和empagliflozin,是选择性的SGLT2抑制剂。
然而,最近的临床试验结果却表明,SGLT1的抑制可以提供超出仅由葡萄糖重吸收的抑制所提供的益处。参见例如美国专利申请公开号US-2011-0218159。特别是,据信SGLT1的抑制可以提高胰高血糖素样肽-1(GLP-1)的水平。参见例如Moriya,R.等,Am J Physiol Endocrinol Metab297:E1358–E1365(2009)。许多公知的糖尿病药物,包括西他列汀、维格列汀和沙格列汀,通过抑制二肽基肽酶IV(DPP-4)发挥作用,所述酶是负责GLP-1降解的酶。
发明概述
本发明是基于钠葡萄糖协同转运蛋白1(SGLT1)的新的强效抑制剂的发现。具体的抑制剂是SGLT1的选择性抑制剂。具体的抑制剂具有低的系统暴露。
本发明部分涉及包含下式的化合物及其可药用盐、二聚体或三聚体的组合物和它们的使用方法:
其中:R1是氢或任选取代的C1-10-烷基、C1-5-环烷基或5元杂环,所述任选的取代是用一个或多个R1A取代;每个R1A独立地是氨基、酯、酰胺、硫醇、羧酸、氰基、卤素、羟基或任选取代的C1-4-烷氧基、C1-5-环烷基或5元杂环,所述任选的取代是用一个或多个R1B取代;每个R1B独立地是C1-4-烷基、卤素或羟基;n是0、1或2;每个R2独立地是F或OR2A,其中每个R2A独立地是氢、C1-4-烷基或酰基;每个R3独立地是卤素、羟基或任选取代的C1-10-烷基或C1-10-烷氧基,所述任选的取代是用一个或多个R3A取代;每个R3A独立地是氨基、酯、酰胺、硫醇、羧酸、氰基、卤素、羟基或任选取代的C1-4-烷氧基、C1-5-环烷基或5元杂环,所述任选的取代是用一个或多个R3B取代;每个R3B独立地是C1-4-烷基、氨基、氰基、卤素或羟基;p是0、1或2;每个R4独立地是R4A、–N(R4A)(R4B)、–OR4A、–SR4A、-S(O)R4A或–S(O)2R4A;R4A是任选取代的C4-20-烷基或4-20元杂烷基,所述任选的取代是用一个或多个R4C取代,并且其任选地附连到另一个R4A组成部分,以提供二聚体或三聚体;R4B是氢或R4A;每个R4C独立地是氨基、氨酰基、偶氮、羰基、羧基、氰基、甲酰基、胍基、卤素、羟基、亚氨酰基、亚氨基、异硫氰酸酯、腈、硝基、亚硝基、硝酰基、氧代、硫烷基(sulfanyl)、亚磺酰基、磺酰基、硫醛、硫氰酸酯、硫酮、硫脲、脲或X1、X1-L1-X2或X1-L1-X2-L2-X3,其中每个X1、X2和X3独立地是任选取代的C1-4-烷基、C1-6-环烷基、5-或6元杂环、或芳基,所述任选的取代是用一个或多个R4D取代,并且每个L1和L2独立地是任选取代的C1-6-烷基或1-10元杂烷基,所述任选的取代是用一个或多个R4E取代;每个R4D独立地是R4E或任选地用一个或多个R4E取代的C1-6-烷基;每个R4E独立地是氨基、氨酰基、偶氮、羰基、羧基、氰基、甲酰基、胍基、卤素、羟基、亚氨酰基、亚氨基、异硫氰酸酯、腈、硝基、亚硝基、硝酰基、氧代、硫烷基、亚磺酰基、磺酰基、硫醛、硫氰酸酯、硫酮或脲;并且m是1、2或3。
具体的化合物由下式表示:
某些由下式表示:
本发明还涉及包含本文中公开的所述化合物的药物组合物,以及使用它们治疗和/或管理心血管疾病和障碍、代谢疾病和障碍、肠疾病和障碍以及某些类型的癌症的方法。
附图说明
本发明的某些方面可以参考附图来理解。
图1A示出了以1.0mg/kg(“mpk”)的剂量每日一次共4日给药的5种本发明的化合物,对在最后给药后6小时喂食含葡萄糖餐食的18周龄雄性C57/Blk6小鼠的血糖水平的影响。实验中每只动物的曲线下面积示出在图1B中。
图2示出了对于每只小鼠来说,化合物与介质相比对血浆tGLP-1的影响。
图3示出了化合物对小鼠的盲肠葡萄糖的影响。
图4示出了在给药本发明的化合物后15小时接受葡萄糖激惹给药后,葡萄糖漂移的剂量依赖性的降低。将化合物每日给药到维持在45%高脂肪饮食的12周龄雄性KKay小鼠,共22日。
图5A示出了在给药26日后,化合物对小鼠的HbA1c水平的影响。图5B示出了在第0至27日之间,小鼠的HbA1c水平的变化。
图6示出了在给药29日后,化合物对小鼠的餐后tGLP-1的影响。
详细描述
本发明是基于钠葡萄糖协同转运蛋白1(SGLT1)的新的强效抑制剂的发现。
定义
除非另有指明,否则术语“烷基”是指具有1至20(例如1至10或1至4)个碳原子的直链或支链烃类。具有1至4个碳的烷基组成部分被称为“短链烷基”。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基、异己基、庚基、4,4-二甲基戊基、2,2,4-三甲基戊基、壬基、癸基、十一烷基和十二烷基。环烷基组成部分可以是单环或多环,其实例包括环丙基、环丁基、环戊基、环己基和金刚烷基。烷基组成部分的其他实例具有直链、支链和/或环状部分(例如1-乙基-4-甲基-环己基)。术语“烷基”包括饱和烃类以及烯基和炔基组成部分。
除非另有指明,否则术语“芳基”是指由碳和氢原子构成的芳香环或芳香族或部分芳香族环系统。芳基组成部分可以包含连接或稠合在一起的多个环。特定芳基组成部分在它们的环中包含6至12个碳原子,并被称为“C6-12-芳基”。芳基组成部分的实例包括蒽基、薁基、联苯基、芴基、茚满、茚基、萘基、菲基、苯基、1,2,3,4-四氢-萘和甲苯基。
除非另有指明,否则术语“卤素”涵盖氟、氯、溴和碘。
除非另有指明,否则术语“杂烷基”是指其中至少一个碳原子已被杂原子(例如N、O或S)代替的烷基组成部分。特定杂烷基组成部分是1-4元、1-10元和4-20元的,其中“元”的数目是组成链的碳或杂原子的数目(在这种情况下,分别为1-4、1-10或4-20)。实例包括乙酸酯、胺、酰胺和酮组成部分。
除非另有指明,否则术语“杂芳基”是指其中至少一个碳原子已被杂原子(例如N、O或S)代替的芳基组成部分。其实例包括吖啶基、苯并咪唑基、苯并呋喃基、苯并异噻唑基、苯并异噁唑基、苯并喹唑啉基、苯并噻唑基、苯并噁唑基、呋喃基、咪唑基、吲哚基、异噻唑基、异噁唑基、噁二唑基、噁唑基、酞嗪基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、四唑基、噻唑基和三唑基。
除非另有指明,否则术语“杂环”是指包含碳、氢和至少一个杂原子(例如N、O或S)的芳香族、部分芳香族或非芳香族单环或多环的环或环系统。杂环可以包含稠合或连接在一起的多个(即两个或更多)环。杂环包括杂芳基。其实例包括苯并[1,3]间二氧杂环戊烯基、2,3-二氢-苯并[1,4]二氧杂芑基、噌啉基、呋喃基、海因基、吗啉基、氧杂环丁烷基、氧杂环丙烷基、哌嗪基、哌啶基、吡咯烷酮基、吡咯烷基、四氢呋喃基、四氢吡喃基、四氢吡啶基、四氢嘧啶基、四氢苯硫基、四氢硫代吡喃基和戊内酰胺基。
除非另有指明,否则术语“局部作用”是指具有不良的系统暴露的化合物。特定局部作用化合物当以10mg/kg的剂量口服给药于小鼠、大鼠或人类时,具有小于250、100、50或10nM的最高血浆浓度(Cmax)。系统暴露(例如Cmax)可以通过本领域中公知的方法,包括液相色谱质谱术来测量。
除非另有指明,否则术语“管理”涵盖在已患有指定疾病或障碍的患者中防止所述疾病或障碍的复发,和/或延长已患有所述疾病或障碍的患者保持缓解的时间。该术语涵盖调节所述疾病或障碍的阈值、发展和/或持续时间,或改变患者对所述疾病或障碍响应的方式。
除非另有指明,否则术语“可药用盐”是指从可药用的无毒性的酸或碱、包括无机酸和碱以及有机酸和碱制备的盐。适合的可药用碱加成盐包括但不限于由铝、钙、锂、镁、钾、钠和锌制成的金属盐或由赖氨酸、N,N’-二苯甲基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、甲葡胺(N-甲基葡糖胺)和普鲁卡因制成的有机盐。适合的无毒性酸包括但不限于无机和有机酸例如乙酸、海藻酸、邻氨基苯甲酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、甲酸、延胡索酸、糠酸、半乳糖醛酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、乙醇酸、氢溴酸、盐酸、羟基乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、硝酸、扑酸、泛酸、苯乙酸、磷酸、丙酸、水杨酸、硬脂酸、琥珀酸、对氨基苯磺酸、硫酸、酒石酸和对甲苯磺酸。具体的无毒性酸包括盐酸、氢溴酸、磷酸、硫酸和甲磺酸。因此,具体的盐的实例包括盐酸盐和甲磺酸盐。其他盐在本领域中是公知的。参见例如《Remington制药学》(Remington’sPharmaceutical Sciences)第18版(Mack Publishing,Easton PA:1990)和《Remington药物科学与实践》(Remington:The Science and Practice of Pharmacy)第19版(MackPublishing,Easton PA:1995)。
除非另有指明,否则术语“防止”考虑到了在患者开始患有指定疾病或障碍之前采取的抑制或降低所述疾病或障碍的严重性的行动。换句话说,该术语涵盖预防。
除非另有指明,否则化合物的“预防有效量”是足以阻止疾病或病症或与所述疾病或病症相关的一种或多种症状或阻止其复发的量。化合物的“预防有效量”是单独或与其他药剂组合时,在所述疾病的阻止中提供预防性益处的治疗药剂的量。术语“预防有效量”可以涵盖改善总体预防或提高另一种预防药剂的预防效能的量。
除非另有指明,否则术语“SGLT1IC50”是使用在下面的实施例中描述的体外人类SGLT1抑制测定法所测定的化合物的IC50。
除非另有指明,否则术语“SGLT1抑制剂”是指具有低于100nM的SGLT1IC50的化合物。特定SGLT1抑制剂具有低于50、25或10nM的SGLT1IC50。
除非另有指明,否则术语“SGLT2IC50”是使用在下面的实施例中描述的体外人类SGLT2抑制测定法所测定的化合物的IC50。
除非另有指明,否则术语“取代的”当用于描述化学结构或组成部分时,是指该结构或组成部分的衍生物,其中它的一个或多个氢原子被原子、化学组成部分或官能团取代,所述原子、化学组成部分或官能团例如但不限于醇、醛、烷氧基、烷酰氧基、烷氧基羰基、烯基、烷基(例如甲基、乙基、丙基、叔丁基)、炔基、烷基羰基氧基(-OC(O)烷基)、酰胺(-C(O)NH-烷基-或-烷基NHC(O)烷基)、脒基(-C(NH)NH-烷基或-C(NR)NH2)、胺(伯、仲和叔胺,例如烷基氨基、芳基氨基、芳基烷基氨基)、芳酰基、芳基、芳氧基、偶氮基、氨甲酰基(-NHC(O)O-烷基-或–OC(O)NH-烷基)、羧酰胺基(例如CONH2以及CONH-烷基、CONH-芳基和CONH-芳基烷基)、羰基、羧基、羧酸、羧酸酐、羧酸酰氯、氰基、酯、环氧化物、醚(例如甲氧基、乙氧基)、胍基、卤素、卤代烷基(例如-CCl3、-CF3、-C(CF3)3)、杂烷基、半缩醛、亚胺(伯和仲)、异氰酸酯、异硫氰酸酯、酮、腈、硝基、氧(即提供氧代基团)、磷酸二酯、硫化物、磺酰胺基(例如SO2NH2)、砜、磺酰基(包括烷基磺酰基、芳基磺酰基和芳基烷基磺酰基)、亚砜、硫醇(例如巯基、硫醚)和脲(-NHCONH-烷基-)。在特定实施方式中,术语“取代的”是指所述结构或组成部分的衍生物,其中它的一个或多个氢原子被醇、烷氧基、烷基(例如甲基、乙基、丙基、叔丁基)、酰胺(-C(O)NH-烷基-或-烷基NHC(O)烷基)、脒基(-C(NH)NH-烷基或-C(NR)NH2)、胺(伯、仲和叔胺,例如烷基氨基、芳基氨基、芳基烷基氨基)、芳基、氨甲酰基(-NHC(O)O-烷基-或-OC(O)NH-烷基)、羧酰胺基(例如CONH2以及CONH-烷基、CONH-芳基和CONH-芳基烷基)、卤素、卤代烷基(例如-CCl3、-CF3、-C(CF3)3)、杂烷基、亚胺(伯和仲)、异氰酸酯、异硫氰酸酯、硫醇(例如巯基、硫醚)或脲(-NHCONH-烷基-)取代。
除非另有指明,否则化合物的“治疗有效量”是足以在疾病或病症的治疗或管理中提供治疗性益处、或延迟或最小化与所述疾病或病症相关的一种或多种症状的量。化合物的“治疗有效量”意味着单独或与其他疗法组合时,在所述疾病或病症的治疗或管理中提供治疗性益处的治疗药剂的量。术语“治疗有效量”可以涵盖改善总体治疗、减少或避免疾病或病症的症状或病因、或提高另一种治疗药剂的治疗效能的量。
除非另有指明,否则术语“治疗”考虑到了在患者患有指定疾病或障碍时采取的降低所述疾病或障碍的严重性或延迟或减慢所述疾病或障碍的进程的行动。
除非另有指明,否则术语“包括”与“包括但不限于”具有相同意义。同样地,术语“例如”与术语“例如但不限于”具有相同意义。
除非另有指明,否则紧邻一系列名词之前的一个或多个形容词应该被解释为适用于每个所述名词。例如,短语“任选取代的烷基、芳基或杂芳基”与“任选取代的烷基、任选取代的芳基或任选取代的杂芳基”具有相同意义。
应该指出,形成较大化合物的一部分的化学组成部分,在本文中可以使用当它作为单个分子存在时通常提供的名称或通常提供给它的游离基的名称来描述。例如,术语“吡啶”和“吡啶基”在用于描述附连到其他化学组成部分的组成部分时,具有相同意义。因此,两个短语“XOH,其中X是吡啶基”和“XOH,其中X是吡啶”具有相同意义,并涵盖了化合物吡啶-2-醇、吡啶-3-醇和吡啶-4-醇。
还应该指出,如果结构或结构的一部分的立体化学没有用例如粗线或虚线标明,那么所述结构或所述结构的一部分应该被解释为涵盖其所有立体异构体。此外,在图中示出的具有未满足化合价的任何原子,被假定附连有足够的氢原子以满足所述化合价。此外,用与一条虚线平行的一条实线描绘的化学键涵盖单键和双键两者(例如芳香族),如果化合价许可的话。
化合物
本发明部分涉及包含下式的化合物及其可药用盐、二聚体或三聚体的组合物以及它们的使用方法:
其中:R1是氢或任选取代的C1-10-烷基、C1-5-环烷基或5元杂环,所述任选的取代是用一个或多个R1A取代;每个R1A独立地是氨基、酯、酰胺、硫醇、羧酸、氰基、卤素、羟基或任选取代的C1-4-烷氧基、C1-5-环烷基或5元杂环,所述任选的取代是用一个或多个R1B取代;每个R1B独立地是C1-4-烷基、卤素或羟基;n是0、1或2;每个R2独立地是F或OR2A,其中每个R2A独立地是氢、C1-4-烷基或酰基;每个R3独立地是卤素、羟基或任选取代的C1-10-烷基或C1-10-烷氧基,所述任选的取代是用一个或多个R3A取代;每个R3A独立地是氨基、酯、酰胺、硫醇、羧酸、氰基、卤素、羟基或任选取代的C1-4-烷氧基、C1-5-环烷基或5元杂环,所述任选的取代是用一个或多个R3B取代;每个R3B独立地是C1-4-烷基、氨基、氰基、卤素或羟基;p是0、1或2;每个R4独立地是R4A、–N(R4A)(R4B)、–OR4A、–SR4A、-S(O)R4A或–S(O)2R4A;R4A是任选取代的C4-20-烷基或4-20元杂烷基,所述任选的取代是用一个或多个R4C取代,并且它被任选地附连到另一个R4A组成部分以提供二聚体或三聚体;R4B是氢或R4A;每个R4C独立地是氨基、氨酰基、偶氮、羰基、羧基、氰基、甲酰基、胍基、卤素、羟基、亚氨酰基、亚氨基、异硫氰酸酯、腈、硝基、亚硝基、硝酰基、氧基、硫烷基、亚磺酰基、磺酰基、硫醛、硫氰酸酯、硫酮、硫脲、脲或X1、X1-L1-X2或X1-L1-X2-L2-X3,其中每个X1、X2和X3独立地是任选取代的C1-4-烷基、C1-6-环烷基、5-或6元杂环、或芳基,所述任选的取代是用一个或多个R4D取代,并且每个L1和L2独立地是任选取代的C1-6-烷基或1-10元杂烷基,所述任选的取代是用一个或多个R4E取代;每个R4D独立地是R4E或任选地用一个或多个R4E取代的C1-6-烷基;每个R4E独立地是氨基、氨酰基、偶氮、羰基、羧基、氰基、甲酰基、胍基、卤素、羟基、亚氨酰基、亚氨基、异硫氰酸酯、腈、硝基、亚硝基、硝酰基、氧代、硫烷基、亚磺酰基、磺酰基、硫醛、硫氰酸酯、硫酮或脲;并且m是1、2或3。
本发明的一种实施方式涵盖下式的化合物及其可药用盐:
特定化合物具有下式:
参考本文中示出的结构式,本发明的特定化合物是单体。
参考本文中示出的结构式,在本发明的特定化合物中,R1是任选取代的C1-4-烷基(例如甲基、乙基、丙基)。
参考本文中示出的结构式,在本发明的特定化合物中,n为0。在其他一些化合物中,n为1。在其他一些化合物中,n为2。
参考本文中示出的结构式,在本发明的特定化合物中,R2是OR2A。在一种实施方式中,至少一个R2A是氢。在一种实施方式中,至少一个R2A是酰基。
参考本文中示出的结构式,在本发明的特定化合物中,R3是任选取代的C1-4-烷基(例如甲基、乙基、丙基)。在其他一些化合物中,R3是卤素(例如氯)。在其他一些化合物中,R3是任选取代的C1-4-烷氧基。
参考本文中示出的结构式,在本发明的特定化合物中,p为1。
参考本文中示出的结构式,在本发明的特定化合物中,R4是R4A。在其他一些化合物中,R4是–OR4A。在一种实施方式中,R4A是任选取代的C4-10-烷基。在另一种实施方式中,R4A是任选取代的4-10元杂烷基。在本发明的特定实施方式中,R4A是:–C1-10-烷基-N(R4C)2;–C1-10-烷基-N(R4C)C(O)R4C;–C1-10-烷基-C(O)N(R4C)2;–C1-10-烷基-C(O)N(R4C)-C0-6-烷基-C(O)R4C;–C1-10-烷基-C(O)N(R4C)-C0-6-烷基-C(O)N(R4C)2;–C1-10-烷基-N(R4C)C(O)-C0-6-烷基-N(R4C)2或–C1-10-烷基-N(R4C)C(O)-C0-6-烷基-N(R4C)C(O)R4C。
本发明的特定化合物是SGLT1抑制剂,并具有低于50、25或10nM的SGLT1IC50。
本发明的特定化合物局部作用于肠中,并具有低的系统暴露。低的系统暴露可以提供一些益处,包括较少的脱靶副作用和较低的SGLT2抑制。
低的系统暴露的实例包括当以150mg/kg的剂量口服给药于小鼠时低于3000nM的最高浓度(Cmax);当以50mg/kg的剂量口服给药于小鼠时低于500nM的Cmax;或当以15mg/kg的剂量口服给药于小鼠时低于100nM的Cmax。在本发明的特定实施方式中,本发明的化合物当以10mg/kg的剂量口服给药于小鼠、大鼠或人类时,具有小于250、100、50或10nM的血浆Cmax。暴露通过使用液相色谱-质谱术这种本领域中公知的技术测量血浆药物浓度来确定。
合成
本发明的化合物可以通过本领域中已知的方法、通过本文中描述的通用和特定方法、以及通过可以由本领域普通技术人员容易地实现的这些方法的改造或改良来制备。
反应路线1显示了适用于本发明的化合物的特定亚组的一种通用方法。
反应路线1
另一种通用方法由反应路线2表示:
反应路线2
参考反应路线1和2,参考实施例中公开的特定化合物,用于芳基氯的Heck反应的通用程序在下面示出:
在这里,向微波小瓶装入(2S,3S,4R,5S,6R)-2-(3-(4-氯苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(7,1.0当量)、Heck烯烃底物(3.0当量)、Pd2dba3(0.2当量),三(叔丁基)四氟硼酸膦鎓(0.8当量)、二环己基甲基胺(3.0当量)和N-甲基吡咯烷酮(0.1M)。将反应在微波中,在160℃加热20分钟。将反应在硅藻土上用过量EtOAc过滤。将有机层用H2O、饱和NaHSO4水溶液和盐水洗涤。将它用MgSO4干燥并真空浓缩。快速层析提供Heck加成物。
参考实施例中公开的特定化合物,用于苯酚的烷基化的通用程序在下面示出:
在这里,在氮气下,向(2S,3S,4R,5S,6R)-2-(3-(4-羟基苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(33,1当量)和K2CO3(5当量)在DMF中的混合物加入烷基卤(1.5当量)。将反应在室温下搅拌过夜,然后用Et2O稀释。将有机层用饱和NaHCO3水溶液和盐水洗涤(带有反萃取),在MgSO4上干燥,过滤,并在真空下浓缩。将残留物通过硅胶快速层析进行纯化。
用于HATU酰胺偶联的通用程序在下面示出:
这里,将羧酸底物(1当量)、胺(1.5当量)、HATU(1.2当量)和DIPEA(3当量)合并在CH3CN(0.2M)中,并在室温下搅拌1-16小时。将反应用饱和NaHCO3水溶液淬灭,并用EtOAc萃取两次。将合并的有机层用盐水洗涤,用MgSO4干燥,过滤并在真空下浓缩。将残留物通过制备HPLC进行纯化,以在冷冻干燥后提供所需化合物。
用于甲磺酸烷基酯的胺亲核置换的通用程序在下面示出:
在这里,将胺(2.5当量)、催化性碘化钠和甲磺酸烷基酯(1.0当量)在异丙醇/CH3CN(1:1v:v)中加热至80℃。在完全转化后,将反应冷却至室温,用MeOH稀释,并加入甲醇钠。乙酸酯去保护通常在30分钟内完成。在真空中除去挥发性组分,并将粗残留物通过制备HPLC进行纯化,以在冷冻干燥后提供所需化合物。
用于从伯胺形成脲的通用程序在下面示出:
在这里,向烷基胺(1当量)和氯甲酸4-硝基苯基酯(1.2当量)在CH2Cl2中的溶液加入三乙胺(1.4当量)。将反应搅拌4小时,然后加入胺(R2NH,1.4当量)和DIPEA(1.5当量)。将反应搅拌90分钟,然后用EtOAc稀释,用饱和NaHCO3水溶液和盐水洗涤(带有反萃取),在MgSO4上干燥,过滤,并在真空下浓缩。将粗残留物用MeOH稀释,并加入甲醇钠。乙酸酯去保护通常在30分钟内完成。在真空中除去挥发性组分,并将粗残留物通过制备HPLC进行纯化,以在冷冻干燥后提供所需化合物。
用于从伯胺形成胍的通用程序在下面示出:
在这里,向烷基胺(1当量,0.090mmol)和3,5-二甲基-1H-吡唑-1-甲脒硝酸盐(3.6当量)在CH3CN中的溶液加入DIPEA(4当量)。将反应在70℃加热2小时,然后冷却至室温并在真空下浓缩。将残留物溶解在MeOH中,并用甲醇钠处理1小时。将反应在真空下浓缩,并将残留物通过制备HPLC纯化,以在冷冻干燥后提供所需化合物。
使用方法
本发明涵盖了治疗或管理心血管疾病和障碍、代谢疾病和障碍、肠疾病和障碍以及某些类型的癌症的方法。
本发明的一种实施方式涵盖了治疗心血管或代谢疾病或障碍的方法,所述方法包括向需要的患者给药安全有效量的本发明的SGLT1抑制剂(即本文公开的化合物)。具体的心血管疾病和障碍包括动脉粥样硬化、心血管疾病、充血性心力衰竭、糖尿病(1型和2型)、与血浓缩相关的障碍(例如血色素沉着症、真性红细胞增多症)、高血糖症、高血压、低镁血症、低钠血症、脂类障碍、肥胖症、肾衰竭(例如1、2或3期肾衰竭)和X综合征。特定患者患有2型糖尿病或处于患2型糖尿病的风险中。
本发明的另一种实施方式涵盖在患者中治疗或管理便秘型肠易激综合征(IBS-C)或慢性便秘的方法,所述方法包括向需要的患者给药安全有效量的本发明的SGLT1抑制剂。
本发明的另一种实施方式涵盖在患者中治疗或管理癌症的方法,所述方法包括向需要的患者给药安全有效量的本发明的SGLT1抑制剂。特定的癌症类型是癌细胞表现出提高的SGLT基因表达的癌症。参见例如Calvo,M.B.等,Int.J.Endocrinology,vol.2010,文章ID205357。实例包括胰腺癌和肺癌。
在本发明的某些实施方式中,本发明的化合物用另一种药物或药理活性成分(“治疗药剂”)辅助给药。在心血管或代谢疾病或障碍的治疗中,第二治疗药剂的实例包括已知可用于其治疗的药剂,例如抗糖尿病药剂、降血糖药剂、降血脂/降脂药剂、减肥药剂、抗高血压药剂和食欲抑制药剂。
抗糖尿病药剂的实例包括双胍类药物(例如甲福明、苯乙双胍)、葡萄糖苷酶抑制剂(例如阿卡波糖、米格列醇)、胰岛素类药物(包括胰岛素促分泌素和胰岛素敏化剂)、美格列奈类药物(例如瑞格列奈)、磺酰脲(例如格列美脲、格列本脲、格列齐特、氯磺丙脲和格列甲嗪)、双胍类药物/格列本脲组合(例如Glucovance)、噻唑烷二酮类药物(例如曲格列酮、罗格列酮和匹格列酮)、PPAR-α激动剂、PPAR-γ激动剂、PPARα/γ双重激动剂、糖原磷酸化酶抑制剂、脂肪酸结合蛋白(aP2)的抑制剂、胰高血糖素样肽-1(GLP-1)或GLP-1受体的其他激动剂,以及二肽基肽酶IV(DPP4)抑制剂。
美格列奈类药物的实例包括那格列奈(Novartis)和KAD1229(PF/Kissei)。
噻唑二酮类药物的实例包括Mitsubishi的MCC-555(公开在美国专利号5,594,016中)、Glaxo-Welcome的GL-262570、恩格列酮(CP-68722,Pfizer)、达格列酮(CP-86325,Pfizer)、伊沙列酮(MIT/J&J)、JTT-501(JPNT/P&U)、L-895645(Merck)、R-119702(Sankyo/WL)、NN-2344(Dr.Reddy/NN)或YM-440(Yamanouchi)。
PPAR-α激动剂、PPAR-γ激动剂和PPARα/γ双重激动剂的实例包括muraglitizar、培利格列扎、AR-HO39242(Astra/Zeneca)、GW-409544(Glaxo-Wellcome)、GW-501516(Glaxo-Wellcome)、KRP297(Kyorin Merck)以及由Murakami等,Diabetes47,1841-1847(1998)、WO01/21602和美国专利号6,653,314中所公开的。
aP2抑制剂的实例包括在1999年9月7日提交的美国申请系列号09/391,053和2000年3月6日提交的美国申请系列号09/519,079中所公开的,使用其中宣布的剂量。
DPP4抑制剂的实例包括西他列汀(Merck)、维格列汀(Novartis)、沙格列汀(BMS-477118)、利拉列汀(BI-1356)、度格列汀(PHX1149T)、gemigliptin(LG Life Sciences)、阿格列汀(SYR-322,Takeda),在WO99/38501、WO99/46272、WO99/67279(PROBIODRUG)、WO99/67278(PROBIODRUG)和WO99/61431(PROBIODRUG)中所公开的,如Hughes等,Biochemistry,38(36),11597-11603,1999所公开的NVP-DPP728A(1-[[[2-[(5-氰基吡啶-2-基)氨基]乙基]氨基]乙酰基]-2-氰基-(S)-吡咯烷)(Novartis),TSL-225(色氨酸基-1,2,3,4-四氢异喹啉-3-甲酸)(由Yamada等,Bioorg.& Med.Chem.Lett.8(1998)1537-1540所公开),由Ashworth等,Bioorg.&Med.Chem.Lett.,Vol.6,No.22,pp 1163-1166和2745-2748(1996)所公开的2-氰基吡咯烷类和4-氰基吡咯烷类,在美国申请系列号10/899,641、WO 01/868603和美国专利号6,395,767中所公开的化合物,使用在上述文献中所宣布的剂量。
降血糖药剂的实例包括胰高血糖素样肽-1(GLP-1)、GLP-1(1-36)酰胺、GLP-1(7-36)酰胺、GLP-1(7-37)(如在美国专利号5,614,492中所公开)、艾塞那肽(Amylin/Lilly)、LY-315902(Lilly)、利拉鲁肽(NovoNordisk)、ZP-10(Zealand Pharmaceuticals A/S)、CJC-1131(Conjuchem Inc)、以及在WO 03/033671中所公开的化合物。
降血脂/降脂药剂的实例包括MTP抑制剂、HMG CoA还原酶抑制剂、角鲨烯合成酶抑制剂、纤维酸衍生物、ACAT抑制剂、脂氧合酶抑制剂、胆固醇吸收抑制剂、Na+/胆汁酸协同转运蛋白抑制剂、LDL受体活性上调剂、胆汁酸多价螯合剂、胆固醇酯转移蛋白(例如CETP抑制剂,例如CP-529414(Pfizer)和JTT-705(Akros Pharma))以及烟酸及其衍生物。
MTP抑制剂的实例包括在美国专利号5,595,872、美国专利号5,739,135、美国专利号5,712,279、美国专利号5,760,246、美国专利号5,827,875、美国专利号5,885,983和美国专利号5,962,440中所公开的。
HMG CoA还原酶抑制剂的实例包括在美国专利号3,983,140中公开的美伐他汀和相关化合物,在美国专利号4,231,938中公开的洛伐他汀(mevinolin)和相关化合物,在美国专利号4,346,227中公开的普伐他汀和相关化合物,在美国专利号4,448,784和4,450,171中公开的辛伐他汀和相关化合物。可以在本发明中使用的其他HMG CoA还原酶抑制剂包括但不限于在美国专利号5,354,772中公开的氟伐他汀,在美国专利号5,006,530和5,177,080中公开的西立伐他汀,在美国专利号4,681,893、5,273,995、5,385,929和5,686,104中公开的阿托伐他汀,在美国专利号5,011,930中公开的atavastatin(Nissan/Sankyo的尼伐他汀(NK-104)),在美国专利号5,260,440中公开的visastatin(Shionogi-Astra/Zeneca(ZD-4522)),以及在美国专利号5,753,675中公开的相关他汀类化合物,美国专利号4,613,610中公开的甲羟戊酸内酯衍生物的吡唑类似物,PCT申请WO 86/03488中公开的甲羟戊酸内酯衍生物的茚类似物,美国专利号4,647,576中公开的6-[2-(取代的-吡咯-1-基)-烷基)吡喃-2-酮及其衍生物,Searle的SC-45355(3-取代的戊二酸衍生物)二氯乙酸酯,PCT申请WO 86/07054中公开的甲羟戊酸内酯的咪唑类似物,法国专利号2,596,393中公开的3-羧基-2-羟基-丙烷膦酸衍生物,欧洲专利申请号0221025中公开的2,3-二取代的吡咯、呋喃和噻吩衍生物,美国专利号4,686,237中公开的甲羟戊酸内酯的萘基类似物,在例如美国专利号4,499,289中公开的八氢萘类,欧洲专利申请号0142146 A2中公开的洛伐他汀的酮类似物,以及美国专利号5,506,219和5,691,322中公开的喹啉和吡啶衍生物。
降血脂药剂的实例包括普伐他汀、洛伐他汀、辛伐他汀、阿托伐他汀、氟伐他汀、西立伐他汀、atavastatin和ZD-4522。
可用于抑制HMG CoA还原酶的膦酸化合物的实例包括在GB2205837中所公开的。
角鲨烯合成酶抑制剂的实例包括美国专利号5,712,396中公开的α-膦酰基-磺酸酯类,由Biller等,J.Med.Chem.1988,Vol.31,No.10,pp1869-1871所公开的,包括类异戊二烯(氧膦基-甲基)膦酸酯以及其他已知的角鲨烯合成酶抑制剂,例如在美国专利号4,871,721和4,924,024以及Biller,S.A.等,Current Pharmaceutical Design,2,1-40(1996)中所公开的。
适合在本发明中使用的其他角鲨烯合成酶抑制剂的实例包括由P.Ortiz deMontellano等,J.Med.Chem.,1977,20,243-249公开的类萜焦磷酸酯,由Corey和Volante,J.Am.Chem.Soc.1976,98,1291-1293公开的法呢基二磷酸酯类似物A和原角鲨烯焦磷酸酯(PSQ-PP)类似物,由McClard,R.W.等,J.A.C.S.,1987,109,5544报道的氧膦基膦酸酯,和由Capson,T.L.(PhD论文,June,1987,Dept.Med.Chem.U of Utah,Abstract,Table ofContents,pp 16,17,40-43,48-51,Summary)报道的环丙烷类。
可以与本发明的化合物组合物使用的纤维酸衍生物的实例包括非诺贝特、吉非贝齐、氯贝特、苯扎贝特、环丙贝特、克利贝特等、普罗布考以及相关化合物,如美国专利号3,674,836中所公开的,普罗布考和吉非贝齐是优选的,胆汁酸多价螯合剂例如考来烯胺、考来替泊和DEAE-交联葡聚糖(降胆葡胺、Policexide),以及保脂妥(Rhone-Poulenc)、EisaiE-5050(一种N-取代的乙醇胺衍生物)、伊马昔尔(HOE-402)、四氢利普司他汀(THL)、豆甾烷基磷酸胆碱(SPC,Roche)、氨基环糊精(Tanabe Seiyoku)、Ajinomoto AJ-814(环戊并环庚五烯衍生物)、甲亚油酰胺(Sumitomo)、Sandoz 58-035、American Cyanamid CL-277,082和CL-283,546(双取代脲衍生物)、烟酸、阿西莫司、阿昔呋喃、新霉素、对氨基水杨酸、阿司匹林,如在美国专利号4,759,923中公开的聚二烯丙基甲基胺衍生物,如在美国专利号4,027,009中公开的季胺聚二烯丙基二甲基氯化铵和紫罗烯类,以及其他已知降血清胆固醇药剂。
可以与本发明的化合物组合使用的ACAT抑制剂的实例包括在下述文献中公开的:Drugs of the Future24,9-15(1999),(阿伐麦布);Nicolosi等,Atherosclerosis(Shannon,Irel),(1998),137(1),77-85;Ghiselli,Giancarlo,Cardiovasc.Drug Rev.(1998),16(1),16-30;Smith,C.等,Bioorg.Med.Chem.Lett.(1996),6(1),47-50;Krause等主编,Ruffolo,Robert R.,Jr.;Hollinger,Mannfred A.,Inflammation:Mediators Pathways(1995),173-98,Publisher:CRC,Boca Raton,Fla.;Sliskovic等,Curr.Med.Chem.(1994),1(3),204-25;Stout等,Chemtracts:Org.Chem.(1995),8(6),359-62或TS-962(Taisho Pharmaceutical Co.Ltd)。
降血脂药剂的实例包括LD2受体活性上调剂,例如MD-700(TaishoPharmaceutical Co.Ltd)和LY295427(Eli Lilly)。
胆固醇吸收抑制剂的实例包括SCH48461(Schering-Plough),以及在Atherosclerosis115,45-63(1995)和J.Med.Chem.41,973(1998)中所公开的。
回肠Na+/胆汁酸协同转运蛋白抑制剂的实例包括在Drugs of the Future,24,425-430(1999)中所公开的化合物。
脂氧合酶抑制剂的实例包括15-脂氧合酶(15-LO)抑制剂,例如WO 97/12615中公开的苯并咪唑衍生物,WO 97/12613中公开的15-LO抑制剂,WO 96/38144中公开的异噻唑酮类,以及Sendobry等,Brit.J.Pharmacology(1997)120,1199-1206和Cornicelli等,Current Pharmaceutical Design,1999,5,11-20所公开的15-LO抑制剂。
适合与本发明的化合物组合使用的抗高血压药剂的实例包括β-肾上腺素能阻断剂、钙通道阻断剂(L-型和T-型;例如地尔硫卓、维拉帕米、尼非地平、氨氯地平和mybefradil)、利尿剂(例如氯噻嗪、氢氯噻嗪、氟甲噻嗪、氢氟甲噻嗪、苄氟甲噻嗪、甲基氯噻嗪、三氯甲噻嗪、泊利噻嗪、苄噻嗪、利尿酸tricrynafen、氯噻酮、呋喃苯胺酸、莫唑胺、布美他尼、triamtrenene、阿米洛利、螺内酯)、肾素抑制剂、ACE抑制剂(例如卡托普利、佐芬普利、福辛普利、依那普利、ceranopril、cilazopril、地拉普利、喷托普利、喹那普利、雷米普利、赖诺普利)、AT-1受体拮抗剂(例如氯沙坦、依贝沙坦、缬沙坦)、ET受体拮抗剂(例如司他生坦、atrsentan以及美国专利号5,612,359和6,043,265中公开的化合物)、双重ET/AII拮抗剂(例如在WO 00/01389中公开的化合物)、中性内肽酶(NEP)抑制剂、血管肽酶抑制剂(双重NEP-ACE抑制剂)(例如奥马曲拉和格莫曲拉)以及硝酸酯。
减肥药剂的实例包括β3肾上腺素能激动剂,脂肪酶抑制剂,血清素(和多巴胺)再摄取抑制剂,甲状腺受体β药物,5HT2C激动剂(例如Arena APD-356),MCHR1拮抗剂例如Synaptic SNAP-7941和Takeda T-226926,黑皮质素受体(MC4R)激动剂,黑色素浓集激素受体(MCHR拮抗剂(例如Synaptic SNAP-7941和Takeda T-226926),甘丙肽受体调节剂,增食欲素拮抗剂,CCK激动剂,NPY1或NPY5拮抗剂,NPY2和NPY4调节剂,促肾上腺皮质激素释放激素激动剂,组胺受体-3(H3)调节剂,11-β-HSD-1抑制剂,缔脂素受体调节剂,单胺再摄入抑制剂或释放剂,睫状神经营养因子(CNTF,例如Regeneron的AXOKINE),BDNF(脑源神经营养因子),瘦素和瘦素受体调节剂,大麻素-1受体拮抗剂(例如SR-141716(Sanofi)或SLV-319(Solvay))和/或厌食药剂。
β3肾上腺素能激动剂的实例包括AJ9677(Takeda/Dainippon)、L750355(Merck)或CP331648(Pfizer),或美国专利号5,541,204、5,770,615、5,491,134、5,776,983和5,488,064中公开的其他已知β3激动剂。
脂肪酶抑制剂的实例包括奥利司他和ATL-962(Alizyme)。
血清素(和多巴胺)再摄取抑制剂(血清素受体激动剂)的实例包括BVT-933(Biovitrum)、西布曲明、托吡酯(Johnson&Johnson)和axokine(Regeneron)。
甲状腺受体β化合物的实例包括甲状腺受体配体例如在WO97/21993(U.Cal SF)、WO99/00353(KaroBio)和GB98/284425(KaroBio)中所公开的。
单胺再摄入抑制剂的实例包括芬氟拉明、右芬氟拉明、氟伏沙明、氟西汀、帕罗西汀、舍曲林、对氯苯丁胺、氯福雷司、氯特胺、匹西雷司、西布曲明、右旋安非他明、苯丁胺、苯丙醇胺和氯苯咪吲哚。
厌食药剂的实例包括右旋安非他明、苯丁胺、苯丙醇胺和氯苯咪吲哚。
药物配方
本发明涵盖了药物组合物,其包含本发明的化合物,并任选地与例如上面5.4部分中所描述的一种或多种第二活性成分组合。
某些药物组合物是适合于口服给药于患者的单一单位剂型。适合于口服给药的分立剂型包括片剂(例如咀嚼片剂)、囊片、胶囊和液体(例如调味糖浆)。这样的剂型含有预定量的活性成分,并可以通过本领域技术人员公知的药学方法来制备。参见例如《Remington制药学》(Remington’s Pharmaceutical Sciences)第18版(Mack Publishing,Easton PA:1990)。
典型的口服剂型通过按照常规制药配合技术将活性成分与至少一种赋形剂合并在密切混合物中来制备。由于易于给药,片剂和胶囊代表了最有利的口服单位剂型。如果需要,可以通过标准的水性或非水性技术将片剂包衣。这样的剂型可以通过常规的药学方法来制备。总的来说,通过将活性成分与液体载体、细分的固体载体或两者均匀密切地混合,然后如果需要,将产物造型成所需外观,来制备药物组合物和剂型。在固体剂型中可以掺入崩解剂以促进快速溶解。也可以掺入润滑剂以便于剂型(例如片剂)的制造。
本发明的特定化合物可以被结合于聚合物和/或球珠,所述聚合物和/或球珠可用于校准它们的递送、代谢和/或活性。例如,某些化合物可以通过R4A结合于被设计用于肠递送到患者的球珠。
实施例
(2S,3S,4R,5S,6R)-2-(3-(4-氯苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡 喃-3,4,5-三基三乙酸酯(7)的制备(6.1.)
(5-溴-2-甲基苯基)(4-氯苯基)甲酮(2)的制备。将2-甲基-4-溴苯甲酸(1,26.0g,121mmol)和草酰氯(13.2mL,152mmol)悬浮在520mL CH2Cl2中。逐滴加入催化量的DMAP(0.5mL),并将反应在室温搅拌直至反应变得均质。在真空中除去挥发物质。将粗材料溶解在200mL CH2Cl2中,并加入N,O-二甲基羟基胺盐酸盐(23.6g,242mmol)。将反应冷却至0℃并缓慢加入三乙胺(55mL,399mmol)。在三乙胺的添加完成后,将反应升温至室温并搅拌过夜。将反应用50%饱和NaHSO4水溶液淬灭。将水性层用CH2Cl2萃取两次。将合并的有机层用盐水洗涤,在Na2SO4上干燥,过滤,并在真空中除去溶剂。将得到的Weinreb酰胺(31.3g,99%得率)不需进一步纯化用于下一步中。
将所述Weinreb酰胺(31.3g,121mmol)转移到250mL无水THF中。在室温下添加4-氯溴化镁(1M,在Et2O中,182mL,182mmol),并将反应搅拌2小时。如果反应未完成,加入另外的Grignard试剂,直至LCMS指示反应完成。将反应用饱和NH4Cl水溶液/盐水(1:1v:v)淬灭,并用EtOAc萃取两次。将合并的有机层用盐水洗涤,在MgSO4上干燥,过滤,并在真空中除去溶剂。(5-溴-2-甲基苯基)(4-氯苯基)甲酮(2,37.0g,99%得率)不需进一步纯化用于下一步中。
1H NMR(400MHz,氯仿-d)δppm 7.74(d,J=8.3Hz,2H),7.53(dd,J=8.1,2.0Hz,1H),7.46(d,J=8.3Hz,2H),7.42(d,J=2.0Hz,1H),7.18(d,J=8.1Hz,1H),2.26(s,3H)。GCMS(CH4-CI)[M+H]+=309。
4-溴-2-(4-氯苯甲基)-1-甲基苯(3)的制备。将(5-溴-2-甲基苯基)(4-氯苯基)甲酮(2,37.0g,121mmol)和三乙基硅烷(77.3mL,484mmol)溶解在300mL CH3CN中并冷却至0℃。加入BF3OEt2(91mL,726mmol),并将反应加热至60℃2小时。使用GCMS来监测反应。在完成后,将反应冷却至0℃,并用500mL饱和NaHCO3水溶液淬灭。将水性相用EtOAc萃取两次。将合并的有机层用H2O和盐水洗涤,在Na2SO4上干燥,过滤,并在真空中除去溶剂。将粗固体悬浮在20%EtOAc/己烷中,并通过石英砂芯以除去残留的盐。滤液的浓缩提供作为白色固体的标题化合物(22.0g,62%得率)。1H NMR(400MHz,氯仿-d)δppm 7.22(d,J=2.0Hz,1H),7.21-7.31(m,3H),7.04(d,J=8.3Hz,2H),7.04(d,J=8.1Hz,2H),3.91(s,2H),2.17(s,3H)。GCMS(CH4-CI)[M+H]+=295。
(3-(4-氯苯甲基)-4-甲基苯基)((3aS,5R,6S,6aS)-6-羟基-2,2-二甲基四氢呋喃 并[2,3-d][1,3]间二氧杂环戊烯-5-基)甲酮(4)的制备。在氮气下,在0℃,向((3aS,5R,6S,6aS)-6-羟基-2,2-二甲基四氢呋喃并[2,3-d][1,3]间二氧杂环戊烯-5-基)(吗啉基)甲酮(25.3g,92.6mmol)在THF(200mL)中的溶液加入叔丁基氯化镁(1M,在THF中,100mL,100mmol)。将该溶液在0℃搅拌30分钟。同时,在氮气下将4-溴-2-(4-氯苯甲基)-1-甲基苯(3,32.9g,111.1mmol)在THF(330mL)中的溶液冷却至-78℃。通过注射器逐滴加入正丁基锂(2.5M,在己烷中,48mL,120mmol)并搅拌10min。在-78℃下将醇镁溶液通过插管转移到芳基锂溶液中。将反应在-78℃搅拌30min,允许其升温至室温并搅拌60min,用500mL 1:1(v:v)的饱和NH4Cl水溶液/盐水淬灭。将水性层用300mL EtOAc萃取两次。将合并的有机层用盐水洗涤,在MgSO4上干燥,过滤,并在真空下浓缩。将粗残留物转移到100mL EtOAc中并加热,直至大多数固体溶解。加入250mL己烷,并将烧瓶在冰浴中激冷2小时。过滤出白色沉淀物并用20%EtOAc/己烷洗涤,提供作为白色固体的标题化合物(26.09g,70%得率)。1H NMR(400MHz,氯仿-d)δppm7.88(dd,J=7.8,1.8Hz,1H),7.76(d,J=1.5Hz,1H),7.29(d,J=8.1Hz,1H),7.26(d,J=8.3Hz,2H),7.05(d,J=8.3Hz,2H),6.08(d,J=3.8Hz,1H),5.28(d,J=2.8Hz,1H),4.59(d,J=3.5Hz,1H),4.57(t,J=3.2Hz,1H),4.01(s,2H),3.06(d,J=4.0Hz,1H),2.30(s,3H),1.37(s,3H)。MS(ES+)[M+H]+=403。
(3aS,5S,6R,6aS)-5-((S)-(3-(4-氯苯甲基)-4-甲基苯基)(羟基)-甲基)-2,2-二 甲基四氢呋喃并[2,3-d][1,3]间二氧杂环戊烯-6-醇(5)的制备。将(3-(4-氯苯甲基)-4-甲基苯基)((3aS,5R,6S,6aS)-6-羟基-2,2-二甲基四氢呋喃并[2,3-d][1,3]间二氧杂环戊烯-5-基)甲酮(4,26.1g,64.9mmol)和CeCl3·7H2O(29.0g,77.9mmol)悬浮在520mL MeOH中。加入硼氢化钠(982mg,26.0mmol,溶解在10mL 1N NaOH水溶液中),并在约5分钟内将反应物缓慢加入到溶液中。加入另外100mg(2.6mmol)硼氢化钠以推动反应至完成。将反应搅拌10分钟,并用500mL饱和NH4Cl水溶液淬灭。在真空中除去大部分MeOH,并将残留的溶剂用1:1(v:v)饱和NH4Cl水溶液:盐水稀释。将水性层用500mL EtOAc萃取三次。将合并的有机层用盐水洗涤,在MgSO4上干燥,过滤,并在真空下浓缩。粗产物不需进一步纯化用于下一步中(26.2g,99%得率,>10:1d.r.)。1H NMR(400MHz,氯仿-d)δppm 7.14-7.31(m,5H),7.04(d,J=8.3Hz,2H),6.04(d,J=3.8Hz,1H),5.24(t,J=3.4Hz,1H),4.51(d,J=3.8Hz,1H),4.14-4.21(m,2H),4.04(d,J=1.5Hz,1H),3.97(s,2H),2.77(d,J=3.0Hz,1H),2.20-2.27(m,3H),1.46(s,3H),1.33(s,3H)。MS(ES+)[M+NH4]+=422。
(3S,4R,5S,6S)-6-(3-(4-氯苯甲基)-4-甲基苯基)四氢-2H-吡喃-2,3,4,5-四基 四乙酸酯(6)的制备。将(3aS,5S,6R,6aS)-5-((S)-(3-(4-氯苯甲基)-4-甲基苯基)(羟基)-甲基)-2,2-二甲基四氢呋喃并[2,3-d][1,3]间二氧杂环戊烯-6-醇(5,26.2g,64.8mmol)悬浮在150mL H2O和150mL冰乙酸中。将反应加热至100℃7小时。在真空中除去溶剂,并将粗残留物从甲苯共沸蒸馏三次。将粗材料置于高真空下过夜,并不需进一步纯化用于下一步中。
将所述粗材料溶解在350mL CH3CN中。加入三乙胺(57.5mL,414mmol)和乙酸酐(46.0mL,414mmol),然后加入催化量的DMAP(100mg)。将反应在室温搅拌1小时。在真空中除去约200mL CH3CN,并将残留物用600mL EtoAc稀释。将有机层用50%饱和NaHSO4水溶液洗涤两次。将酸性水性层用300mL EtOAc反萃。将合并的有机层用盐水洗涤,在MgSO4上干燥,过滤,并在真空下浓缩。将粗残留物从甲苯共沸蒸馏两次并从己烷共沸蒸馏一次,以提供作为可以容易地转移的浅棕色固体的标题化合物(34.0g,92%得率,α和β端基异构体的混合物)。
1H NMR(400MHz,氯仿-d)δppm 7.24(d,J=8.3Hz,2H),7.13-7.21(m,2H),7.09(s,1H),7.01(d,J=8.3Hz,2H),6.47(d,J=3.5Hz,1Hα),5.89(d,J=8.3Hz,1Hβ),5.59(t,J=9.8Hz,1Hα),5.37(t,J=9.6Hz,1Hβ),5.23-5.31(m,1Hα+1Hβ),5.19(t,J=9.6Hz,1Hβ),5.14(t,J=9.7Hz,1Hα),4.82(d,J=10.1Hz,1Hα),4.51(d,J=9.9Hz,1Hβ),3.94(s,2H),2.21(s,3Hα),2.20(s,3Hα),2.19(s,3Hβ),2.11(s,3Hβ),2.07(s,3Hβ),2.06(s,3Hα),2.04(s,3Hα),2.03(s,3Hβ),1.79(s,3Hα),1.77(s,3Hβ)。MS(ES+)[M+NH4]+=550。
(2S,3S,4R,5S,6R)-2-(3-(4-氯苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡 喃-3,4,5-三基三乙酸酯(7)的制备。向(3S,4R,5S,6S)-6-(3-(4-氯苯甲基)-4-甲基苯基)四氢-2H-吡喃-2,3,4,5-四基四乙酸酯(6,33.9g,63.8mmol)和硫脲(9.71g,128mmol)在340mL二噁烷中的溶液加入三氟甲磺酸三甲基甲硅烷基酯(19.7mL,108.5mmol)。将反应加热至80℃2小时,此时LCMS分析揭示出反应停止。加入另外的TMSOTf(2mL,10.8mmol),并将反应在80℃搅拌1小时。将反应冷却至室温。进行碘代甲烷(11.9mL,191mmol)然后是DIPEA(55.6mL,319mmol)的顺序添加,允许反应搅拌18小时。缓慢加入500mLH2O以淬灭反应。将水性层用300mL EtOAc萃取两次。将合并的有机层用饱和NaHSO4水溶液和盐水洗涤,在MgSO4上干燥,过滤,并在真空下浓缩。将粗固体悬浮在300mL MeOH中。超声产生浅棕色沉淀物的沉淀,将其过滤并用冷MeOH洗涤。将滤液浓缩,并将悬浮程序再重复一次,以提供并与第一批合并。产物作为纯的β端基异构体,作为浅棕色固体被分离(20.4g,60%得率)。1H NMR(400MHz,氯仿-d)δppm 7.24(d,J=8.6Hz,2H),7.10-7.18(m,2H),7.05(s,1H),7.00(d,J=8.6Hz,2H),5.34(dd,J=9.6Hz,1H),5.21(dd,J=9.6Hz,1H),5.12(dd,J=9.6Hz,1H),4.53(d,J=9.9Hz,1H),4.39(d,J=9.9Hz,1H),3.86-4.00(m,2H),2.19(s,3H),2.17(s,3H),2.10(s,3H),2.01(s,3H),1.76(s,3H)。MS(ES+)[M+NH4]+=538。
N-(1-氨基-2-甲基-1-氧丙烷-2-基)-4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4, 5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯基)丁酰胺(11)的制备(6.2)
(2S,3S,4R,5S,6R)-2-(3-(4-((E)-4-甲氧基-4-氧丁-1-烯-1-基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(8)的制备。在微波小瓶中装入(2S,3S,4R,5S,6R)-2-(3-(4-氯苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(7,1.04g,2.0mmol)、丁-5-烯酸甲酯(600mg,6.0mmol)、Pd2dba3(183mg,0.20mmol)、三(叔丁基)四氟硼酸膦鎓(235mg,0.80mmol)、二环己基甲基胺(1.27mL,6.0mmol)和N-甲基吡咯烷酮(10mL)。将反应在微波中在160℃加热20min。将反应在硅藻土上用过量EtOAc过滤。将有机层用H2O、饱和NaHSO4水溶液和盐水洗涤。将它用MgSO4干燥并真空浓缩。硅胶快速层析(梯度10-50%EtOAc/己烷)提供作为浅黄色固体的Heck加成物8(700mg,60%得率)。在1H NMR中观察到少量异构化的烯烃。1H NMR(400MHz,氯仿-d)δppm7.28-7.31(m,2H),6.97-7.19(m,5H),6.46(d,J=15.9Hz,1H),6.25(dt,J=15.9,7.1Hz,1H),5.33(dd,J=9.6Hz,1H),5.21(dd,J=9.6Hz,1H),5.12(dd,J=9.6Hz,1H),4.52(d,J=9.6Hz,1H),4.39(d,J=9.6Hz,1H),3.87-4.01(m,2H),3.72(s,2H),3.24(dd,J=7.1,1.3Hz,2H),2.21(s,3H),2.17(s,3H),2.10(s,3H),2.01(s,3H),1.75(s,3H)。MS(ES+)[M+NH4]+=602。
(2S,3S,4R,5S,6R)-2-(3-(4-(4-甲氧基-4-氧丁基)苯甲基)-4-甲基苯基)-6-(甲 基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(9)的制备。将(2S,3S,4R,5S,6R)-2-(3-(4-((E)-4-甲氧基-4-氧丁-1-烯-1-基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(8,1.74g,3.0mmol)溶解在1:1(v:v)THF/MeOH溶液中。加入Pd/C(10%湿,174mg),并将反应在40psi下氢化3小时。通过1H NMR监测反应。在完成后,将反应在硅藻土上用过量MeOH过滤。在真空中除去溶剂提供作为浅黄色固体的产物(1.65g,94%得率)。1H NMR(400MHz,氯仿-d)δppm 7.11-7.20(m,2H),7.07(t,J=7.8Hz,3H),6.99(d,J=8.1Hz,2H),5.33(dd,J=9.6Hz,1H),5.21(dd,J=9.6Hz,1H),5.12(dd,J=9.6Hz,1H),4.52(d,J=9.9Hz,1H),4.39(d,J=9.9Hz,1H),3.85-4.00(m,2H),3.67(s,3H),2.61(t,J=7.6Hz,2H),2.33(t,J=7.5Hz,2H),2.21(s,3H),2.18(s,3H),2.10(s,3H),2.01(s,3H),1.93(quin,J=7.6Hz,2H),1.75(s,3H)。MS(ES+)[M+NH4]+=604。
4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡 喃-2-基)苯甲基)苯基)丁酸(10)的制备。将(2S,3S,4R,5S,6R)-2-(3-(4-(4-甲氧基-4-氧丁基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(9,1.65g,2.81mmol)溶解在MeOH/THF/H2O溶液(25mL,2:1:2体积比)中。加入氢氧化锂(674mg,28.1mmol),并将反应在室温下搅拌1小时。将反应用饱和NaHSO4水溶液酸化到pH=1-2。将酸性水性层用EtOAc萃取三次。将合并的有机层用盐水洗涤,在MgSO4上干燥,过滤,并真空浓缩。将粗产物从己烷旋转蒸发一次,以提供作为白色可转移固体的产物(1.27g,99%得率)。1H NMR(400MHz,DMSO-d6)δppm 11.99(s,1H),6.96-7.16(m,7H),5.16(d,J=5.8Hz,1H),5.06(d,J=4.3Hz,1H),4.82(d,J=5.6Hz,1H),4.32(d,J=9.6Hz,1H),4.04(d,J=9.1Hz,1H),3.90(s,2H),2.53(t,J=7.3Hz,2H),2.19(t,J=7.3Hz,2H),2.17(s,3H),2.03(s,3H),1.76(quin,J=7.6Hz,2H)。MS(ES+)[M+NH4]+=464。
N-(1-氨基-2-甲基-1-氧丙烷-2-基)-4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4, 5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯基)丁酰胺(11)的制备。将4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯基)丁酸(10,157mg,0.35mmol)、2-氨基-2-甲基丙酰胺盐酸盐(73mg,0.53mmol)、HATU(161mg,0.42mmol)和DIPEA(0.15mL,1.06mmol)合并在DMF(2mL)中,并在室温搅拌2小时。将反应用饱和NaHCO3水溶液淬灭,并用EtOAc萃取两次。将合并的有机层用盐水洗涤,用MgSO4干燥,过滤,并在真空下浓缩。将残留物通过制备HPLC(C18 30x 100mm柱,5-100%CH3CN/10mM甲酸铵水溶液,45mL/min)进行纯化,以在冷冻干燥后提供标题化合物11(75mg,40%得率)。1H NMR(400MHz,MeOH-d4)δppm 6.96-7.23(m,7H),4.39(d,J=9.6Hz,1H),4.12(d,J=9.1Hz,1H),3.96(s,2H),3.33-3.51(m,3H),2.59(t,J=7.6Hz,2H),2.20(t,J=7.6Hz,2H),2.20(s,3H),2.14(s,3H),1.87(quin,J=7.6Hz,2H),1.45(s,6H)。MS(ES+)[M+H]+=531。
N-(2-甲基-1-(4-甲基哌嗪-1-基)-1-氧丙烷-2-基)-4-(4-(2-甲基-5-((2S,3R, 4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯基)丁酰胺(12)的 制备(6.3.)
利用与用于酰胺11的相同的程序,使用2-氨基-2-甲基-1-(4-甲基哌嗪-1-基)丙-1-酮盐酸盐,提供作为双甲酸盐的产物12。1H NMR(400MHz,MeOH-d4)δppm 8.40(s,2H),7.11-7.21(m,3H),7.02-7.11(m,4H),4.39(d,J=9.6Hz,1H),4.13(d,J=9.1Hz,1H),3.96(s,2H),3.74(br.s.,4H),3.34-3.52(m,3H),2.67(t,J=4.6Hz,4H),2.60(t,J=7.6Hz,2H),2.47(s,3H),2.19(t,J=7.6Hz,2H),2.21(s,3H),2.14(s,3H),1.88(quin,J=7.5Hz,2H),1.44(s,6H)。MS(ES+)[M+H]+=614。
N-(1-((2-(二甲基氨基)乙基)氨基)-2-甲基-1-氧丙烷-2-基)-4-(4-(2-甲基-5- ((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯基)丁酰 胺(13)的制备(6.4.)
利用与用于酰胺11的相同的程序,使用2-氨基-2-甲基-1-(4-甲基哌嗪-1-基)丙-1-酮盐酸盐,提供作为甲酸盐的产物13。1H NMR(400MHz,MeOH-d4)δppm 8.52(s,1H),7.12-7.21(m,3H),7.03-7.12(m,4H),4.39(d,J=9.6Hz,1H),4.13(d,J=9.3Hz,1H),3.96(s,2H),3.51(t,J=5.6Hz,2H),3.33-3.47(m,3H),3.07(t,J=4.8Hz,2H),2.79(s,6H),2.60(t,J=7.6Hz,2H),2.21(s,3H),2.22(t,J=7.6Hz,2H),2.14(s,3H),1.88(quin,J=7.5Hz,2H),1.41(s,6H)。MS(ES+)[M+H]+=602。
(S,R,R,S,R)-N,N'-((甲基氮烷二基)双(丙烷-3,1-二基))双(4-(4-(2-甲基-5- ((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯基)丁酰 胺)(14)的制备(6.5.)
利用与用于酰胺11的相同的程序,使用N1-(3-氨基丙基)-N1-甲基丙烷-1,3-二胺(0.5当量),提供作为甲酸盐的产物14。1H NMR(400MHz,MeOH-d4)δppm 8.50(s,1H),7.15(q,J=7.8Hz,6H),7.02-7.09(m,8H),4.38(d,J=9.6Hz,2H),4.12(d,J=9.1Hz,2H),3.94(s,4H),3.34-3.51(m,6H),3.21(t,J=6.6Hz,4H),2.86(t,J=7.3Hz,4H),2.63(s,3H),2.57(t,J=7.6Hz,4H),2.18(t,J=7.6Hz,4H),2.20(s,6H),2.14(s,6H),1.88(quin,J=7.6Hz,4H),1.82(quin,J=7.3Hz,4H)。MS(ES+)[M+H]+=1002。
(2S,3S,4R,5S,6R)-2-(3-(4-(5-氨基戊基)苯甲基)-4-甲基苯基)-6-(甲基硫基) 四氢-2H-吡喃-3,4,5-三基三乙酸酯(16)的制备(6.6.)
在微波小瓶中装入(2S,3S,4R,5S,6R)-2-(3-(4-氯苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(7,520mg,1.0mmol)、戊-4-烯-1-基氨基甲酸叔丁基酯(555mg,3.0mmol.)、Pd2dba3(183mg,0.20mmol)、三(叔丁基)四氟硼酸膦鎓(232mg,0.80mmol)、二环己基甲基胺(0.64mL,3.0mmol)和N-甲基吡咯烷酮(15mL)。将反应在微波中在160℃下加热20min。将反应在硅藻土上,用过量EtOAc过滤。将有机层用H2O、饱和NaHSO4水溶液和盐水洗涤。将它用MgSO4干燥并真空浓缩。硅胶快速层析(梯度10-50%EtOAc/己烷)提供作为浅黄色固体的Heck加成物15(360mg,54%得率)。
将Heck产物(15,360mg,0.63mmol)溶解在10mL MeOH中。加入Pd/C(10%水分,100mg),并将反应在50psi氢化4小时。在完全转化后,将反应在硅藻土上过滤以除去催化剂,并在真空中除去溶剂。将粗残留物转移到4mL CH2Cl2中,并加入2mL TFA。在室温下搅拌3小时后,将反应用饱和NaHCO3水溶液淬灭,并用EtOAc萃取三次。将合并的有机萃取物用盐水洗涤,在MgSO4上干燥,过滤并在真空下浓缩,以提供标题化合物16(260mg,85%得率)。1HNMR(400MHz,DMSO-d6)δppm 7.49(br.s.,1H),6.94-7.22(m,2H),5.37(t,J=9.6Hz,2H),5.12(t,J=9.6Hz,1H),5.07(t,J=9.6Hz,1H),4.90(d,J=9.6Hz,1H),4.66(d,J=9.6Hz,1H),3.81-3.99(m,2H),2.62-2.80(m,4H),2.18(s,3H),2.10(s,3H),2.05(s,3H),1.95(s,3H),1.71(s,3H),1.48-1.61(m,4H),1.28-1.34(m,2H)。MS(ES+)[M+H]+=572。
(2S,3R,4R,5S,6R)-2-(3-(4-(5-(双((S)-2,3-二羟基丙基)氨基)戊基)苯甲基)- 4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三醇(17)的制备(6.7.)
将(2S,3S,4R,5S,6R)-2-(3-(4-(5-氨基戊基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(16,75mg,0.13mmol)和(R)-2,2-二甲基-1,3-二氧戊环-4-甲醛(26mg,0.20mmol)溶解在1mL二氯乙烷中。加入三乙酰氧基硼氢化钠(55mg,0.26mmol),并将反应在室温搅拌过夜。将反应用饱和NaHCO3水溶液淬灭,并将水性相用EtOAc萃取三次。将合并的有机层用盐水洗涤,在MgSO4上干燥,过滤,并在真空中除去溶剂。
将粗残留物转移到1mL H2O和1mL MeOH中。加入氢氧化锂(26mg,1.1mmol)。加入1mL THF以辅助起始原料的溶解。在16小时后,将反应用H2O稀释并用EtOAc萃取三次。将合并的有机层用盐水洗涤,在MgSO4上干燥,过滤,并在真空中除去溶剂。
将粗产物溶解在1mL MeOH中。加入TFA(1mL),并将反应搅拌2小时,在所述时间后,发生的反应可以忽略。加入H2O(0.5mL),并将反应在室温下搅拌过夜。在真空中除去溶剂。将残留物通过制备HPLC(C18 30x 100mm柱,5-100%CH3CN/10mM甲酸铵水溶液,45mL/min)进行纯化,以在冷冻干燥后提供作为双甲酸盐的标题化合物17。1H NMR(400MHz,MeOH-d4)δppm 8.50(s,2H),6.98-7.21(m,7H),4.39(d,J=9.3Hz,1H),4.12(d,J=9.1Hz,1H),3.87-4.01(m,2H),3.95(s,2H),3.47-3.62(m,4H),3.36-3.47(m,3H),3.02-3.25(m,4H),3.20(td,J=13.6,3.0Hz,2H),2.60(t,J=7.5Hz,2H),2.21(s,3H),2.14(s,3H),1.59-1.79(m,2H),1.67(quin,J=7.6Hz,2H),1.39(sxt,J=7.1Hz,2H)。MS(ES+)[M+H]+=594。
2-甲基-2-(3-(5-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫 基)四氢-2H-吡喃-2-基)苯甲基)苯基)戊基)脲基)丙酰胺(18)的制备(6.8.)
向(2S,3S,4R,5S,6R)-2-(3-(4-(5-氨基戊基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(16,100mg,0.18mmol)和氯甲酸4-硝基苯基酯(43mg,0.22mmol)在CH2Cl2(4mL)中的溶液加入三乙胺(35μL,0.25mmol)。将反应搅拌4小时,然后加入2-氨基-2-甲基丙酰胺盐酸盐(17mg,0.25mmol)和DIPEA(23μL,0.27mmol)。将反应搅拌90min.,然后用EtOAc稀释,用饱和NaHCO3水溶液和盐水洗涤(带有反萃取),在MgSO4上干燥,过滤,并在真空下浓缩。
将该材料用NaOMe(50μL,25重量%,在MeOH中,0.22mmol)在MeOH(2mL)中处理2小时。将反应在真空下浓缩,并将残留物通过制备HPLC(C18 30x 100mm柱,10-70%CH3CN/10mM甲酸铵水溶液,45mL/min)进行纯化,以在冷冻干燥后给出10mg作为白色固体的标题化合物18。1H NMR(400MHz,MeOH-d4)δppm 7.00-7.20(m,7H),4.39(d,J=9.6Hz,1H),4.12(d,J=9.1Hz,1H),3.95(s,2H),3.34-3.50(m,3H),3.06(t,J=6.9Hz,2H),2.57(t,J=7.6Hz,2H),2.21(s,3H),2.14(s,3H),1.53-1.67(m,2H),1.48(quin,J=7.3Hz,2H),1.43(s,3H),1.42(s,3H),1.34(spt,J=7.3Hz,1H)。MS(ES+)[M+H]+=574。
1-(4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H- 吡喃-2-基)苯甲基)苯基)丁基)胍(20)的制备(6.9.)
(2S,3S,4R,5S,6R)-2-(3-(4-(4-氨基丁基)苯甲基)-4-甲基苯基)-6-(甲基硫基) 四氢-2H-吡喃-3,4,5-三基三乙酸酯(19)的制备。利用与用于(2S,3S,4R,5S,6R)-2-(3-(4-(5-氨基戊基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(16)的合成相同的程序,使用丁-3-烯-1-基氨基甲酸叔丁酯作为用于Heck反应的试剂。
1-(4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H- 吡喃-2-基)苯甲基)苯基)丁基)胍(20)的制备。向(2S,3S,4R,5S,6R)-2-(3-(4-(4-氨基丁基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(19,50mg,0.090mmol)和3,5-二甲基-1H-吡唑-1-甲脒硝酸盐(66mg,0.33mmol)在CH3CN中的溶液加入DIPEA(62μL,0.35mmol)。将反应在70℃加热2小时,然后冷却至室温,并在真空下浓缩。将残留物溶解在MeOH中,并用几滴NaOMe(25重量%,在MeOH中)处理1小时。将反应在真空下浓缩,将残留物通过制备HPLC(C18 30x 100mm柱,5-40%CH3CN/10mM甲酸铵水溶液,45mL/min)进行纯化,以给出作为甲酸盐的标题化合物20(22mg,43%得率)。1H NMR(400MHz,MeOH-d4)δppm 8.55(s,1H),7.00-7.24(m,7H),4.39(d,J=9.6Hz,1H),4.12(d,J=9.1Hz,1H),3.92-4.02(m,2H),3.34-3.51(m,3H),3.17(t,J=6.8Hz,2H),2.62(t,J=7.3Hz,2H),2.21(s,3H),2.14(s,3H),1.63-1.73(m,2H),1.59(s,2H)。MS(ES+)[M+H]+=474。
3-羟基-2,2-二甲基-N-(4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6- (甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯基)丁基)丙酰胺(21)的制备(6.10.)
将(2S,3S,4R,5S,6R)-2-(3-(4-(4-氨基丁基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(19,55mg,0.10mmol)、3-羟基-2,2-二甲基丙酸(18mg,0.15mmol)、HATU(57mg,0.15mmol)和DIPEA(52μL,0.30mmol)的溶液合并在DMF(1mL)中,并在室温下搅拌4小时。将反应用饱和NaHCO3水溶液淬灭,并用EtOAc萃取两次。将合并的有机层用盐水洗涤,用MgSO4干燥,过滤,并在真空下浓缩。将残留物溶解在MeOH中,并用几滴NaOMe(25重量%,在MeOH中)处理1小时。将反应在真空下浓缩,并将残留物通过制备HPLC(C18 30x 100mm柱,5-40%CH3CN/10mM甲酸铵水溶液,45mL/min)进行纯化,以给出作为白色固体的标题化合物21(22mg,41%得率)。1H NMR(400MHz,MeOH-d4)δppm 6.98-7.22(m,7H),4.39(d,J=9.6Hz,1H),4.13(d,J=9.1Hz,1H),3.90-3.99(m,2H),3.49(s,2H),3.35-3.46(m,3H),3.19(t,J=6.9Hz,2H),2.58(t,J=7.5Hz,2H),2.18-2.23(m,3H),2.14(s,3H),1.60(s,2H),1.46-1.57(m,2H),1.11(s,6H)。MS(ES+)[M+H]+=532。
(2S,3R,4R,5S,6R)-2-(3-(4-(4-((1-羟基-2-甲基丙-2-基)氨基)丁基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三醇(24)的制备(6.11.)
(2S,3S,4R,5S,6R)-2-(3-(4-(4-羟基丁基)苯甲基)-4-甲基苯基)-6-(甲基硫基) 四氢-2H-吡喃-3,4,5-三基三乙酸酯(22)的制备。在20mL微波小瓶中装入(2S,3S,4R,5S,6R)-2-(3-(4-氯苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(7,520mg,1.0mmol)、3-丁烯醇(0.26mL,3.0mmol)、Pd2dba3(183mg,0.20mmol)、三(叔丁基)四氟硼酸膦鎓(232mg,0.80mmol)、二环己基甲基胺(0.64mL,3.0mmol)和10mL N-甲基吡咯烷酮。将反应在微波中在160℃加热20min。将反应在硅藻土上用过量EtOAc过滤。将有机层用H2O、饱和NaHSO4水溶液和盐水洗涤。将它用MgSO4干燥并真空浓缩。快速层析(梯度10–80%EtOAc/己烷)提供Heck加成物(257mg)。将该纯化的产物溶解在5mL 1:1(v:v)的MeOH/THF混合物中。加入Pd/C(10%水分,26mg)并经历40psi氢压力5小时。将反应在硅藻土上用过量MeOH过滤并真空浓缩,以提供标题化合物22(247mg,44%得率)。1H NMR(400MHz,氯仿-d)δppm 7.11-7.18(m,2H),7.09(d,J=8.1Hz,2H),6.95-7.06(m,3H),5.33(dd,J=9.6Hz,1H),5.20(dd,J=9.6Hz,1H),5.10(dd,J=9.7Hz,1H),4.52(d,J=9.9Hz,1H),4.38(d,J=9.9Hz,1H),3.93(d,J=4.5Hz,2H),3.66(t,J=5.9Hz,2H),2.61(t,J=7.3Hz,2H),2.22(s,3H),2.17(s,3H),2.10(s,3H),2.01(s,3H),1.74(s,3H),1.64-1.73(m,2H),1.56-1.64(m,2H)。MS(ES+)[M+NH4]+=576。
(2S,3S,4R,5S,6R)-2-(4-甲基-3-(4-(4-((甲基磺酰基)氧基)丁基)-苯甲基)苯 基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(23)的制备。向(2S,3S,4R,5S,6R)-2-(3-(4-(4-羟基丁基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(22,247mg,0.44mmol)在5mL CH2Cl2中的溶液加入甲磺酰氯(41μL,0.53mmol)和三乙胺(80μL,0.58mmol),并在室温搅拌2小时。将反应用1N HCl水溶液淬灭。将水性层用EtOAc萃取两次。将合并的有机层用H2O和盐水洗涤,用MgSO4干燥,过滤并真空浓缩,以提供产物23(279mg,99%得率),其不需进一步纯化用于下一步中。1H NMR(400MHz,氯仿-d)δppm7.14(s,2H),7.02-7.11(m,3H),7.00(d,J=7.8Hz,2H),5.33(dd,J=9.6Hz,1H),5.21(dd,J=9.6Hz,1H),5.12(dd,J=9.6Hz,1H),4.48-4.56(m,1H),4.39(d,J=9.9Hz,1H),4.24(t,J=6.1Hz,1H),3.93(d,J=3.8Hz,2H),2.99(s,3H),2.62(t,J=7.2Hz,2H),2.22(s,3H),2.15-2.20(m,3H),2.10(s,3H),2.01(s,3H),1.70-1.81(m,4H)。MS(ES+)[M+NH4]+=654。
(2S,3R,4R,5S,6R)-2-(3-(4-(4-((1-羟基-2-甲基丙-2-基)氨基)丁基)苯甲基)- 4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三醇(24)的制备。将2-氨基-2-甲基丙-1-醇(23mg,0.25mmol)、催化性碘化钠和(2S,3S,4R,5S,6R)-2-(4-甲基-3-(4-(4-((甲基磺酰基)氧基)丁基)苯甲基)苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(65mg,0.10mmol)在0.5mL异丙醇/CH3CN(1:1v:v)中加热至80℃64小时。将反应冷却至室温,用2mLMeOH稀释,并加入NaOMe(25重量%,在MeOH中,0.5mL)。乙酸酯去保护在30min内完成。在真空中除去挥发物,并将粗残留物通过制备HPLC(C18 30x 100mm柱,5-100%CH3CN/10mM甲酸铵水溶液,45mL/min)进行纯化,以在冷冻干燥后提供作为双甲酸盐的产物(17mg,34%得率)。1H NMR(400MHz,MeOH-d4)δppm8.53(s,2H),7.01-7.25(m,7H),4.39(d,J=9.6Hz,1H),4.13(d,J=9.1Hz,1H),3.90-4.02(m,2H),3.50(s,2H),3.35-3.48(m,3H),2.87-2.97(m,2H),2.65(t,J=6.9Hz,2H),2.20(s,3H),2.15(s,3H),1.59-1.78(m,4H),1.27(s,6H)。MS(ES+)[M+H]+=504。
(2S,3R,4R,5S,6R)-2-(3-(4-(4-((1,3-二羟基-2-(羟基甲基)丙-2-基)氨基)丁 基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三醇(25)的制备(6.12.)
利用与用于胺24的相同的程序,使用2-氨基-2-(羟基-甲基)丙烷-1,3-二醇,提供作为双甲酸盐的产物25。1H NMR(400MHz,MeOH-d4)δppm 8.53(s,2H),6.98-7.23(m,7H),4.39(d,J=9.3Hz,1H),4.13(d,J=9.1Hz,1H),3.94-4.03(m,2H),3.69(s,6H),3.34-3.50(m,3H),3.03-3.13(m,2H),2.58-2.69(m,2H),2.20(s,3H),2.12-2.18(m,3H),1.70(m,4H)。[M+H]+=537。
1-((4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢- 2H-吡喃-2-基)苯甲基)苯基)丁基)氨基)环戊烷甲酰胺(26)的制备(6.13.)
利用与用于胺24的相同的程序,使用1-氨基环戊烷甲酰胺,提供含有0.5当量甲酸的产物26。1H NMR(400MHz,MeOH-d4)δppm 8.52(s,0.5H,甲酸盐),6.98-7.22(m,7H),4.39(d,J=9.6Hz,1H),4.13(d,J=9.3Hz,1H),3.91-4.01(m,2H),3.34-3.51(m,3H),2.50-2.68(m,4H),2.21(s,3H),2.14(s,3H),2.10(d,J=7.3Hz,2H),1.73-1.87(m,6H),1.63-1.72(m,2H),1.58(d,J=7.1Hz,2H)。MS(ES+)[M+H]+=543。
1-((4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢- 2H-吡喃-2-基)苯甲基)苯基)丁基)氨基)环戊烷甲酰胺(27)的制备(6.14.)
利用与用于胺24的相同的程序,使用3-氨基-2,2-二甲基丙酰胺,提供含有1.5当量甲酸的产物27。1H NMR(400MHz,MeOH-d4)δppm8.52(s,1.5H,甲酸盐),7.00-7.22(m,7H),4.39(d,J=9.3Hz,1H),4.13(d,J=9.3Hz,1H),3.96(s,2H),3.35-3.52(m,3H),2.95-3.06(m,4H),2.65(t,J=6.4Hz,2H),2.21(s,3H),2.14(s,3H),1.64-1.78(m,4H),1.30(s,6H)。MS(ES+)[M+H]+=531。
四唑衍生物(30和31)的制备(6.15.)
(2S,3S,4R,5S,6R)-2-(3-(4-((E)-3-氰基丙-1-烯-1-基)苯甲基)-4-甲基苯基)- 6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(28)的制备。在5mL微波小瓶中装入(2S,3S,4R,5S,6R)-2-(3-(4-氯苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(7,208mg,0.40mmol)、丁-3-烯腈(0.10mL,1.2mmol)、Pd2dba3(37mg,0.040mmol)、三(叔丁基)四氟硼酸膦鎓(46mg,0.16mmol)、二环己基甲基胺(0.25mL,1.2mmol)和2mL N-甲基吡咯烷酮。将反应在微波中在160℃加热20min。将反应在硅藻土上用过量EtOAc过滤。将有机层用H2O、饱和NaHSO4水溶液和盐水洗涤。将它用MgSO4干燥并真空浓缩。快速层析(梯度10–80%EtOAc/己烷)提供Heck加成物28(140mg,64%得率)。1H NMR(400MHz,氯仿-d)δppm 7.24-7.31(m,2H),7.11-7.20(m,2H),7.02-7.09(m,3H),6.70(dt,J=15.9,1.6Hz,1H),6.01(dt,J=15.8,5.7Hz,1H),5.33(t,J=9.3Hz,1H),5.21(t,J=9.7Hz,1H),5.12(t,J=9.6Hz,1H),4.52(d,J=9.9Hz,1H),4.39(d,J=9.9Hz,1H),3.95(d,J=3.5Hz,2H),3.28(dd,J=5.8,1.8Hz,2H),2.20(s,3H),2.16(s,3H),2.09(s,3H),2.01(s,3H),1.75(s,3H)。MS(ES+)[M+NH4]+=567。
(2S,3S,4R,5S,6R)-2-(3-(4-(3-(2H-四唑-5-基)丙基)苯甲基)-4-甲基苯基)-6- (甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(29)的制备。将(2S,3S,4R,5S,6R)-2-(3-(4-((E)-3-氰基丙-1-烯-1-基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(28,140mg,0.25mmol)溶解在6mL MeOH中。加入Pd/C(10%水分,14mg)并经受40psi氢压力5小时。将反应在硅藻土上用过量MeOH过滤并真空浓缩。粗产物不需进一步纯化直接使用(120mg,87%得率)。MS(ES+)[M+NH4]+=569。
将60mg该氢化产物(0.108mmol)转移到甲苯(1.1mL,0.1M)中。加入三甲基甲硅烷基叠氮化物(43μL,0.324mmol)和二丁基锡氧化物(8mg,0.0324mmol)。将反应加热至90℃18小时。将反应冷却至室温,并用H2O淬灭。将水性层用EtOAc萃取两次。将合并的有机层用盐水洗涤,在Na2SO4上干燥,并真空浓缩。硅胶快速层析(梯度5-80%EtOAc/己烷,然后10%MeOH/CH2Cl2)提供四唑29(32mg,50%得率)。MS(ES+)[M+NH4]+=597。
2-(5-(3-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢- 2H-吡喃-2-基)苯甲基)苯基)丙基)-2H-四唑-2-基)-1-(4-甲基哌嗪-1-基)乙酮(30)和2- (5-(3-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2- 基)苯甲基)苯基)丙基)-1H-四唑-1-基)-1-(4-甲基哌嗪-1-基)乙酮(31)的制备。将(2S,3S,4R,5S,6R)-2-(3-(4-(3-(2H-四唑-5-基)丙基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(29,32mg,0.0537mmol)与2-氯-1-(4-甲基哌嗪-1-基)乙酮(14mg,0.0644mmol)和三乙胺(22μL,0.161mmol)合并在0.5mL CH3CN中。将反应在60℃搅拌18小时,提供两种区域异构体的混合物。将反应用H2O稀释,过滤,并通过制备HPLC(C1830x 100mm柱,5-100%CH3CN/10mM甲酸铵水溶液,45mL/min)进行纯化。所述区域异构体被干净地分离。将相应的产物残留物在氮气下用MeOH(2mL)中的甲醇钠(0.10mL,25重量%,在MeOH中)处理30min。将反应在真空下浓缩,并将反应通过制备HPLC(C18 30x 100mm柱,5-100%CH3CN/10mM甲酸铵水溶液,45mL/min)进行纯化,并冷冻干燥以给出烷基化四唑的区域异构体30和31(分别为4.3mg和3.1mg,作为双甲酸盐)。区域化学通过NOESY相关性来验证。
1,2-双取代的四唑30:1H NMR(400MHz,MeOH-d4)δppm 8.39(s,2H,甲酸盐),7.01-7.21(m,8H),5.45(s,2H),4.39(d,J=9.6Hz,1H),4.13(d,J=9.1Hz,1H),3.97(s,2H),3.60(q,J=4.8Hz,4H),3.33-3.50(m,3H),2.79(t,J=7.5Hz,2H),2.68(t,J=7.5Hz,2H),2.62(t,J=5.1Hz,2H),2.53(t,J=5.1Hz,2H),2.41(s,3H),2.21(s,3H),2.14(s,3H),2.09(quin,J=7.6Hz,2H)。MS(ES+)[M+H]+=611。
1,3-双取代的四唑31:1H NMR(400MHz,MeOH-d4)δppm 8.38(s,2H),6.99-7.20(m,7H),5.74(s,2H),4.38(d,J=9.3Hz,1H),4.12(d,J=9.1Hz,1H),3.96(s,2H),3.65(t,J=5.3Hz,4H),3.33-3.49(m,3H),2.88(t,J=7.5Hz,2H),2.60-2.69(m,4H),2.57(t,J=5.1Hz,2H),2.41(s,3H),2.21(s,3H),2.10-2.14(m,3H),2.07(quin,J=7.3Hz,2H)。MS(ES+)[M+H]+=611。
(2S,3S,4R,5S,6R)-2-(3-(4-羟基苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H- 吡喃-3,4,5-三基三乙酸酯(37)的制备(6.16.)
(4-(苯甲基氧基)苯基)(5-溴-2-甲基苯基)甲醇(33)的制备。在-78℃下,在氮气下,向4-苯甲氧基溴苯(2.63g,10mmol)在THF(50mL)中的溶液缓慢加入正丁基锂(2.5M,在己烷中,4.4mL,11mmol)。将反应搅拌30分钟。缓慢加入THF(4mL加上1mL冲洗)中的5-溴-2-甲基苯甲醛(32,1.99g,10mmol)。允许反应在超过2小时下缓慢升温至约0℃,然后用饱和NH4Cl水溶液淬灭,用乙醚稀释,用H2O和盐水洗涤,在MgSO4上干燥,过滤,并在真空下浓缩。将残留物通过硅胶快速层析(梯度0-25%EtOAc/己烷)进行纯化,以给出3.12g(82%得率)作为透明油状物的标题化合物33。1H NMR(400MHz,氯仿-d)δppm 7.80(d,J=2.3Hz,1H),7.36-7.47(m,4H),7.29-7.36(m,2H),7.18-7.24(m,2H),6.99(d,J=8.1Hz,1H),6.88-6.97(m,2H),5.89(d,J=3.5Hz,1H),5.06(s,2H),2.12(s,3H),2.06(d,J=3.5Hz,1H);MS(ES+)[M-OH]+=365,367。
(4-(苯甲基氧基)苯基)(5-溴-2-甲基苯基)甲醇(34)的制备。在0℃和氮气下,向(4-(苯甲基氧基)苯基)(5-溴-2-甲基苯基)甲醇(33,3.12g,8.2mmol)和三乙基甲硅烷(1.6mL,9.8mmol)在CH2Cl2(40mL)中的溶液缓慢添加BF3OEt2(1.4mL,11.4mmol)。将反应在室温搅拌过夜,随后将它用饱和NaHCO3水溶液淬灭,并搅拌30分钟。将反应用乙醚稀释,用另外的饱和NaHCO3水溶液和盐水洗涤(带有反萃取),在MgSO4上干燥,过滤,并在真空下浓缩。将残留物通过硅胶快速层析(梯度0-10%EtOAc:己烷)进行纯化,给出2.71g(91%得率)作为白色固体的产物34。1H NMR(400MHz,氯仿-d)δppm 7.30-7.49(m,5H),7.27(dd,J=8.0,2.1Hz,1H),7.22(d,J=2.0Hz,1H),6.98-7.09(m,3H),6.86-6.97(m,2H),5.05(s,2H),3.88(s,2H),2.19(s,3H);MS(ES+)[M+NH4]+=384,386。
(3-(4-(苯甲基氧基)苯甲基)-4-甲基苯基)((3aS,5R,6S,6aS)-6-羟基-2,2-二甲 基四氢呋喃并[2,3-d][1,3]间二氧杂环戊烯-5-基)甲酮(35)的制备。在氮气下,在-78℃,向2-(4-(苯甲基氧基)苯甲基)-4-溴-1-甲基苯(34,2.71g,7.4mmol)在THF(37mL)中的溶液缓慢添加正丁基锂(3.3mL在己烷中的2.5M溶液,8.1mmol),并将反应搅拌30min。同时,在氮气下,在0℃,向((3aS,5R,6S,6aS)-6-羟基-2,2-二甲基四氢呋喃并[2,3-d][1,3]间二氧杂环戊烯-5-基)(吗啉基)甲酮(2.02g,7.4mmol)在THF(37mL)中的溶液添加叔丁基氯化镁(8.1mL在THF中的1M溶液,8.1mmol)。将反应搅拌20min,然后在-78℃通过插管缓慢添加到芳基锂溶液。允许反应在超过3小时下逐渐升温至室温,然后用饱和NH4Cl水溶液淬灭,用EtOAc稀释,用H2O和盐水洗涤(带有反萃取),在MgSO4上干燥,过滤,并在真空下浓缩。将残留物通过硅胶快速层析(梯度0-50%EtOAc/己烷)进行纯化,以给出2.44g(70%得率)作为白色泡沫的产物35。1H NMR(400MHz,氯仿-d)δppm 7.86(dd,J=7.8,1.8Hz,1H),7.75-7.80(m,1H),7.27-7.49(m,6H),7.04(d,J=8.6Hz,2H),6.86-6.96(m,2H),6.09(d,J=3.5Hz,1H),5.32(d,J=2.8Hz,1H),5.04(s,2H),4.60(d,J=3.5Hz,1H),4.53-4.58(m,1H),3.98(s,2H),3.03(d,J=4.3Hz,1H),2.31(s,3H),1.56(s,3H),1.36(s,3H);MS(ES+)[M+H]+=475。
(3S,4R,5S,6S)-6-(3-(4-(苯甲基氧基)苯甲基)-4-甲基苯基)四氢-2H-吡喃-2, 3,4,5-四基四乙酸酯(36)的制备。在0℃下,向(3-(4-(苯甲基氧基)苯甲基)-4-甲基苯基)((3aS,5R,6S,6aS)-6-羟基-2,2-二甲基四氢呋喃并[2,3-d][1,3]间二氧杂环戊烯-5-基)甲酮(35,2.44g,5.1mmol)和CeCl3·7H2O(2.30g,6.2mmol)在MeOH中的溶液缓慢添加硼氢化钠(78mg,2.1mmol,在1mL 1M NaOH水溶液中)。将反应在0℃搅拌15min并在室温搅拌15min,然后用饱和NH4Cl水溶液淬灭。将反应在真空下部分浓缩,用EtOAc稀释,用H2O洗涤并用盐水洗涤两次(带有反萃取),在Na2SO4上干燥并在真空下浓缩,给出2.4g作为白色固体的二醇。
在100℃,在氮气下,将该材料用1:1AcOH/H2O(20mL)处理22小时。将反应冷却至室温,在真空下浓缩,与甲苯共沸蒸馏两次,并置于高真空下。在氮气下,在0℃,将残留物以及DMAP(61mg,0.5mmol)溶解在CH2Cl2(25mL)中,并加入三乙胺(6.2mL,45mmol),然后加入乙酸酐(3.8mL,40mmol)。将反应在室温搅拌18小时,然后用饱和NaHCO3水溶液(60mL)淬灭,搅拌50min,并用EtOAc萃取两次。将合并的有机萃取物用盐水洗涤,在MgSO4上干燥,过滤,并在真空下浓缩。将残留物通过硅胶快速层析(梯度0-50%EtOAc/己烷)进行纯化,给出2.80g(90%得率)作为白色泡沫的产物36的1:1的α:β端基异构体混合物。1H NMR(400MHz,氯仿-d)δppm 7.29-7.47(m,5H),7.10-7.18(m,2H),7.06(s,1H),6.98(d,J=8.6Hz,2H),6.83-6.94(m,2H),6.46(d,J=3.5Hz,0.5H),5.87(d,J=8.3Hz,0.5H),5.57(t,J=10.1Hz,0.5H),5.35(t,J=9.6Hz,0.5H),5.21-5.30(m,1H),5.18(t,J=9.6Hz,0.5H),5.12(t,J=9.9Hz,0.5H),4.80(d,J=10.1Hz,0.5H),4.48(d,J=9.9Hz,0.5H),3.83-3.97(m,2H),2.21(s,1.5H),2.20(s,3H),2.10(s,1.5H),2.07(s,1.5H),2.05(s,1.5H),2.03(s,1.5H),2.02(s,1.5H),1.76(s,1.5H),1.74(s,1.5H);MS(ES+)[M+NH4]+=622。
(2S,3S,4R,5S,6R)-2-(3-(4-羟基苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H- 吡喃-3,4,5-三基三乙酸酯(37)的制备。将(3S,4R,5S,6S)-6-(3-(4-(苯甲基氧基)苯甲基)-4-甲基苯基)四氢-2H-吡喃-2,3,4,5-四基四乙酸酯(36,5.29g,8.8mmol)在THF(44mL)中的10%Pd/C(50%水分)(0.93g,0.44mmol)上,在氢气下,在大气压加氢1小时。将反应通过硅藻土过滤,在真空下浓缩,与甲苯共沸蒸馏两次,并置于高真空下以充分干燥。得到的酚不需进一步纯化用于下一步。将它与硫脲(2.01g,26mmol)合并并溶解在二噁烷(44mL)中。加入TMSOTf(4.8mL,26mmol)。将反应在80℃加热3小时,然后冷却至室温。加入碘代甲烷(2.2mL,35mmol),然后加入DIPEA(12mL,70mmol)。将反应搅拌过夜,然后用饱和NaHSO4水溶液(150mL)淬灭,剧烈搅拌2小时,用EtOAc稀释,用H2O和盐水洗涤(带有反萃取),在MgSO4上干燥,过滤,并在真空下浓缩。将残留物通过硅胶层析(梯度0-50%EtOAc/己烷)进行纯化,给出3.88g(88%得率)作为白色泡沫的产物37。1H NMR(400MHz,氯仿-d)δppm 7.10-7.19(m,2H),7.03(s,1H),6.94(d,J=8.6Hz,2H),6.68-6.77(m,2H),5.33(t,J=9.3Hz,1H),5.21(t,J=9.6Hz,1H),5.12(t,J=9.6Hz,1H),4.59(s,1H),4.52(d,J=9.9Hz,1H),4.38(d,J=9.9Hz,1H),3.82-3.96(m,2H),2.21(s,3H),2.18(s,3H),2.10(s,3H),2.01(s,3H),1.75(s,3H);MS(ES+)[M+NH4]+=520。
(2S,3S,4R,5S,6R)-2-(4-氯-3-(4-羟基苯甲基)苯基)-6-(甲基硫基)四氢-2H-吡 喃-3,4,5-三基三乙酸酯(38)的制备(6.17.)
酚38以与(2S,3S,4R,5S,6R)-2-(3-(4-羟基苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(37)类似的方式制备。1H NMR(400MHz,氯仿-d)δppm7.36(d,J=8.3Hz,1H),7.18(dd,J=8.3,2.3Hz,1H),7.07(d,J=2.3Hz,1H),7.03(d,J=8.6Hz,2H),6.73-6.78(m,2H),5.32(t,J=9.3Hz,1H),5.19(t,J=9.6Hz,1H),5.04(t,J=9.6Hz,1H),4.77(s,1H),4.51(d,J=9.9Hz,1H),4.37(d,J=9.9Hz,1H),3.95-4.07(m,2H),2.16(s,3H),2.09(s,3H),2.01(s,3H),1.73(s,3H);MS(ES+)[M+NH4]+=540。
N-(2-甲基-1-(4-甲基哌嗪-1-基)-1-氧丙烷-2-基)-4-(4-(2-甲基-5-((2S,3R, 4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯氧基)丁酰胺(40) 的制备(6.18.)
4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡 喃-2-基)苯甲基)苯氧基)丁酸(39)的制备。在氮气下,向(2S,3S,4R,5S,6R)-2-(3-(4-羟基苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(37,2.01g,4.0mmol)和K2CO3(2.76g,20mmol)在DMF(8mL)中的混合物添加4-碘代丁酸甲酯(0.81mL,6.0mmol)。将反应在室温搅拌过夜,然后用Et2O稀释。将有机层用饱和NaHCO3水溶液和盐水洗涤(带有反萃取),在MgSO4上干燥,过滤,并在真空下浓缩。将残留物通过硅胶快速层析(梯度0-50%EtOAc/己烷)进行纯化,给出2.18g(90%得率)作为白色泡沫的酯。
将该材料在氮气下,在60℃,用MeOH(14mL)和THF(29mL)中的LiOH(29mL,1M aq,29mmol)处理1小时。将反应冷却至室温,倾倒在1M NaHSO4水溶液中,并用EtOAc萃取。将有机萃取物用H2O和盐水洗涤(带有反萃取),在MgSO4上干燥,过滤,并在真空下浓缩,以给出1.71g(100%得率)酸39。1H NMR(400MHz,MeOH-d4)δppm 7.10-7.21(m,3H),7.04(d,J=8.6Hz,2H),6.76-6.85(m,2H),4.38(d,J=9.3Hz,1H),4.12(d,J=9.1Hz,1H),3.97(t,J=6.2Hz,2H),3.92(s,2H),3.34-3.50(m,3H),2.47(t,J=7.3Hz,2H),2.20(s,3H),2.14(s,3H),1.98-2.08(m,2H);MS(ES-)[M-H]-=461。
N-(2-甲基-1-(4-甲基哌嗪-1-基)-1-氧丙烷-2-基)-4-(4-(2-甲基-5-((2S,3R, 4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯氧基)丁酰胺(40) 的制备。将4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯氧基)丁酸(39,1.47g,3.2mmol)、2-氨基-2-甲基-1-(4-甲基哌嗪-1-基)丙-1-酮(1.07g,2HCl盐,4.1mmol)、HATU(1.45g,3.8mmol)和DIPEA(2.2mL,13mmol)合并在CH3CN(32mL)中,并在室温搅拌过夜。向反应加入DMAP(39mg,0.32mmol)、DIPEA(3.3mL,19mmol)和乙酸酐(1.5mL,16mmol)。将反应搅拌1小时,然后用饱和NaHCO3水溶液淬灭,搅拌1小时,并用EtOAc萃取两次。将合并的有机相用盐水洗涤,在MgSO4上干燥,过滤,并在真空下浓缩。将残留物通过硅胶层析(梯度2-10%MeOH/CH2Cl2)进行纯化,得到2.27g(94%得率)作为黄色泡沫的三乙酸酯。
在氮气下,将该材料用中MeOH(30mL)的甲醇钠(0.55mL,25重量%,在MeOH中,2.4mmol)处理18小时。将反应在真空下浓缩,并将残留物通过C18柱进行纯化(0-25-75%MeOH/H2O)并冷冻干燥,给出1.40g(74%得率)作为白色固体的标题化合物40。1H NMR(400MHz,MeOH-d4)δppm 7.09-7.21(m,3H),7.04(d,J=8.6Hz,2H),6.77-6.84(m,2H),4.39(d,J=9.3Hz,1H),4.12(d,J=9.1Hz,1H),3.96(t,J=6.2Hz,2H),3.92(s,2H),3.65(br.s.,4H),3.34-3.50(m,3H),2.39(t,J=7.6Hz,2H),2.34(br.s.,4H),2.203(s,3H),2.198(s,3H),2.14(s,3H),1.97-2.07(m,2H),1.42(s,6H);MS(ES+)[M+H]+=630。
1-(4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H- 吡喃-2-基)苯甲基)苯氧基)丁氨酰基)环戊烷甲酰胺(41)的制备(6.19.)
将4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯氧基)丁酸(39,46mg,0.10mmol)、1-氨基环戊烷甲酰胺(26mg,0.20mmol)、HATU(57mg,0.15mmol)和DIPEA(52μL,0.30mmol)合并在DMF(0.5mL)中,并在室温搅拌过夜。将反应用EtOAc稀释,用饱和NaHCO3水溶液和盐水洗涤(带有反萃取),在MgSO4上干燥,过滤,并在真空下浓缩。将材料通过制备HPLC(C18 30x 100mm柱,20-60%CH3CN/10mM甲酸铵水溶液,45mL/min)进行纯化并冷冻干燥,给出35mg(61%得率)作为白色固体的酰胺41。1H NMR(400MHz,MeOH-d4)δppm 7.10-7.19(m,3H),7.04(d,J=8.6Hz,2H),6.81(m,J=8.6Hz,2H),4.39(d,J=9.3Hz,1H),4.12(d,J=9.1Hz,1H),3.96(t,J=6.2Hz,2H),3.92(s,2H),3.34-3.50(m,3H),2.41(t,J=7.5Hz,2H),2.12-2.22(m,8H),2.04(quin,J=6.9Hz,2H),1.93(dt,J=12.8,5.1Hz,2H),1.64-1.75(m,4H);MS(ES+)[M+H]+=573。
4-(4-(2-氯-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃- 2-基)苯甲基)苯氧基)-N-(1-羟基-2-甲基丙-2-基)丁酰胺(42)的制备(6.20.)
利用与用于酰胺41的相同的程序,使用2-氨基-2-甲基丙-1-醇,以提供产物42。1HNMR(400MHz,MeOH-d4)δppm 7.36(d,J=8.8Hz,1H),7.20-7.29(m,2H),7.10(d,J=8.6Hz,2H),6.79-6.86(m,2H),4.38(d,J=9.6Hz,1H),4.13(d,J=9.6Hz,1H),3.98-4.09(m,2H),3.96(t,J=6.3Hz,2H),3.56(s,2H),3.44(t,J=8.6Hz,1H),3.33-3.39(m,2H),2.35(t,J=7.5Hz,2H),2.13(s,3H),1.96-2.08(m,2H),1.25(s,6H);MS(ES+)[M+H]+=554。
2-甲基-2-(2-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基) 四氢-2H-吡喃-2-基)苯甲基)苯氧基)乙氨酰基)丙酰胺(43)的制备(6.21.)
利用与用于酰胺41的相同的程序,使用2-氨基-2-甲基丙酰胺,以提供产物43。1HNMR(400MHz,MeOH-d4)δppm 7.12-7.21(m,3H),7.09(d,J=8.6Hz,2H),6.86-6.94(m,2H),4.45(s,2H),4.39(d,J=9.6Hz,1H),4.13(d,J=9.1Hz,1H),3.95(s,2H),3.35-3.50(m,3H),2.20(s,3H),2.15(s,3H),1.55(s,6H);MS(ES+)[M+H]+=519。
1-(1-羟基-2-甲基丙-2-基)-3-(2-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯氧基)乙基)脲(45)的制备(6.22.)
(2S,3S,4R,5S,6R)-2-(3-(4-(2-氨基乙氧基)苯甲基)-4-甲基苯基)-6-(甲基硫 基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(44)的制备。在氮气下,将(2S,3S,4R,5S,6R)-2-(3-(4-羟基苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(37,0.50g,1.0mmol)、(2-溴乙基)氨基甲酸叔丁基酯(0.62g,3.0mmol)和K2CO3(0.64g,5.0mmol)合并在DMF(2mL)中,并在室温搅拌过夜。加入另外的(2-溴乙基)氨基甲酸叔丁基酯(0.62g,3.0mmol),并将反应搅拌另外3天。将反应用Et2O稀释,用饱和NaHCO3水溶液和盐水洗涤(带有反萃取),在MgSO4上干燥,过滤,并在真空下浓缩。将残留物通过硅胶层析(梯度0-50%EtOAc/己烷)进行纯化,给出0.37g(58%得率)作为白色泡沫的烷基化产物。
将一部分该材料(0.34g,0.53mmol)用CH2Cl2(4.5mL)中的TFA(0.5mL)处理2小时。将反应在真空下浓缩。将粗残留物用EtOAc稀释,用饱和NaHCO3水溶液和盐水洗涤(带有反萃取),在MgSO4上干燥,并在真空下浓缩,给出0.30g(100%得率)作为棕褐色泡沫的胺44。1HNMR(400MHz,氯仿-d)δppm 7.10-7.17(m,2H),7.02(s,1H),6.99(d,J=8.8Hz,2H),6.79-6.84(m,2H),5.33(t,J=9.6Hz,1H),5.21(t,J=9.6Hz,1H),5.11(t,J=9.7Hz,1H),4.52(d,J=9.9Hz,1H),4.38(d,J=9.9Hz,1H),4.03(t,J=5.2Hz,2H),3.84-3.95(m,2H),3.16(t,J=5.2Hz,2H),2.20(s,3H),2.17(s,3H),2.09(s,3H),2.01(s,3H),1.76(s,3H);MS(ES+)[M+H]+=546。
1-(1-羟基-2-甲基丙-2-基)-3-(2-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三 羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯氧基)乙基)脲(45)的制备。向(2S,3S,4R,5S,6R)-2-(3-(4-(2-氨基乙氧基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(44,55mg,0.10mmol)和4-硝基苯基氯甲酸酯(24mg,0.12mmol)在CH2Cl2(1mL)中的溶液加入三乙胺(19μL,0.14mmol)。将反应搅拌4小时,然后加入2-氨基-2-甲基丙-1-醇(19μL,0.20mmol)。将反应搅拌90min.,然后用EtOAc稀释,用饱和NaHCO3水溶液和盐水洗涤(带有反萃取),在MgSO4上干燥,过滤,并在真空下浓缩。
将该材料用MeOH(1mL)中的甲醇钠(23μL,25重量%,在MeOH中,0.10mmol)处理2小时。将反应在真空下浓缩,并将残留物通过制备HPLC(C18 30x 100mm柱,10-70%CH3CN/10mM甲酸铵水溶液,45mL/min)进行纯化,给出21mg(40%得率)作为白色固体的脲45。1HNMR(400MHz,MeOH-d4)δppm 7.10-7.19(m,3H),7.04(d,J=8.8Hz,2H),6.79-6.86(m,2H),4.38(d,J=9.6Hz,1H),4.12(d,J=9.1Hz,1H),3.95(t,J=5.3Hz,2H),3.93(s,2H),3.52(s,2H),3.33-3.49(m,5H),2.20(s,3H),2.14(s,3H),1.24(s,6H);MS(ES+)[M+H]+=535。
1-(2-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯氧基)乙基)胍(46)的制备(6.23.)
向(2S,3S,4R,5S,6R)-2-(3-(4-(2-氨基乙氧基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(44,31mg,0.057mmol)和3,5-二甲基-1H-吡唑-1-甲脒硝酸盐(23mg,0.11mmol)在CH3CN中的溶液加入DIPEA(30μL,0.17mmol)。将反应在60℃加热4小时,然后冷却至室温并在真空下浓缩。将残留物溶解在MeOH中,并用几滴NaOMe(25重量%,在MeOH中)处理1小时。将反应在真空下浓缩,并将残留物通过制备HPLC(C1830x 100mm柱,5-40%CH3CN/10mM甲酸铵水溶液,45mL/min)进行纯化,给出作为甲酸盐的脲46(9mg,34%得率)。1H NMR(400MHz,MeOH-d4)δppm 7.11-7.20(m,3H),7.07(d,J=8.6Hz,2H),6.81-6.89(m,2H),4.39(d,J=9.3Hz,1H),4.12(d,J=9.1Hz,1H),4.08(t,J=4.9Hz,2H),3.94(s,2H),3.58(t,J=5.1Hz,2H),3.34-3.48(m,3H),2.20(s,3H),2.14(s,3H);MS(ES+)[M+H]+=462。
(2S,3R,4R,5S,6R)-2-(3-(4-(3-((1-羟基-2-甲基丙-2-基)氨基)丙氧基)苯甲 基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三醇(49)的制备(6.24.)
(2S,3S,4R,5S,6R)-2-(3-(4-(3-(苯甲基氧基)丙氧基)苯甲基)-4-甲基苯基)-6- (甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(47)的制备。在氮气下,将(2S,3S,4R,5S,6R)-2-(3-(4-羟基苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(37,2.01g,4.0mmol)、((3-溴丙氧基)甲基)苯(1.41mL,8.0mmol)、Bu4NI(148mg,0.40mmol)和K2CO3(2.76g,20mmol)合并在DMF(8mL)中,并在室温搅拌过夜。将反应用Et2O稀释,用饱和NaHCO3水溶液和盐水洗涤(带有反萃取),在MgSO4上干燥,过滤,并在真空下浓缩。将残留物通过硅胶层析(梯度0-50%EtOAc/己烷)进行纯化,给出作为玻璃状固体的烷基化产物47(2.36g,91%得率)。1H NMR(400MHz,氯仿-d)δppm7.28-7.36(m,5H),7.10-7.18(m,2H),7.03(s,1H),6.97(d,J=8.6Hz,2H),6.77-6.84(m,2H),5.33(t,J=9.6Hz,1H),5.21(t,J=9.6Hz,1H),5.12(t,J=9.6Hz,1H),4.48-4.54(m,3H),4.38(d,J=9.9Hz,1H),4.06(t,J=6.3Hz,2H),3.83-3.96(m,2H),3.66(t,J=6.2Hz,2H),2.21(s,3H),2.17(s,3H),2.10(s,3H)2.04-2.12(m,2H),2.01(s,3H),1.75(s,3H);MS(ES+)[M+NH4]+=668。
(2S,3S,4R,5S,6R)-2-(4-甲基-3-(4-(3-((甲基磺酰基)氧基)丙氧基)苯甲基)苯 基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(48)的制备。在大气压下,在氢气下,将(2S,3S,4R,5S,6R)-2-(3-(4-(3-(苯甲基氧基)丙氧基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(47,2.36g,3.6mmol)在THF(36mL)中的10%Pd/C(50%水分,0.38g,0.18mmol)上加氢18小时。将反应通过硅藻土过滤,并在真空下浓缩。将残留物通过硅胶层析(梯度0-70%EtOAc/己烷)进行纯化,给出作为白色固体的相应的醇(1.90g,93%得率)。
在氮气下,将该材料溶解在CH2Cl2(34mL)中。加入三乙胺(0.61mL,4.4mmol),随后加入甲磺酰氯(0.32mL,4.1mmol)。将反应搅拌2小时。将它用EtOAc稀释,用1M HCl水溶液、H2O和盐水洗涤(带有反萃取),在MgSO4上干燥,过滤,并在真空下浓缩,给出作为白色泡沫的甲磺酸盐48(2.20g,100%得率)。1H NMR(400MHz,氯仿-d)δppm 7.10-7.18(m,2H),7.03(s,1H),6.99(d,J=8.6Hz,2H),6.75-6.85(m,2H),5.33(t,J=9.3Hz,1H),5.21(t,J=9.6Hz,1H),5.12(t,J=9.6Hz,1H),4.52(d,J=9.9Hz,1H),4.45(t,J=6.1Hz,2H),4.39(d,J=9.9Hz,1H),4.06(t,J=5.9Hz,2H),3.83-3.96(m,2H),3.00(s,3H),2.20(s,3H),2.18-2.28(m,2H),2.17(s,3H),2.10(s,3H),2.01(s,3H),1.76(s,3H);MS(ES+)[M+NH4]+=656。
(2S,3R,4R,5S,6R)-2-(3-(4-(3-((1-羟基-2-甲基丙-2-基)氨基)丙氧基)苯甲 基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三醇(49)的制备。在氮气下,将(2S,3S,4R,5S,6R)-2-(4-甲基-3-(4-(3-((甲基磺酰基)氧基)丙氧基)苯甲基)苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(48,1.23g,1.9mmol)和2-氨基-2-甲基丙-1-醇(0.52g,5.8mmol)溶解在异丙醇(3.9mL)和CH3CN(3.9mL)中。将反应在90℃加热过夜,然后冷却至室温。将它用EtOAc稀释,用饱和NaHCO3水溶液和盐水洗涤(带有反萃取),在MgSO4上干燥,过滤,并在真空下浓缩。将残留物通过硅胶层析(梯度0-10%[10%NH4OH/MeOH]CH2Cl2)进行纯化,给出1.04g作为白色固体的受保护的糖。
在氮气下,将该材料溶解在MeOH(16mL)中,并用NaOMe(0.19mL,25重量%,在MeOH中,0.8mmol)处理2小时。将反应在真空下浓缩,并将残留物通过C18柱进行纯化(0-25-80%MeOH/H2O)。将材料通过制备HPLC(C18 30x 250mm柱,5-80%CH3CN/10mM甲酸铵水溶液,45mL/min)再次纯化,溶解在H2O中并冷冻干燥,给出作为白色固体的氨基醇49的甲酸盐(710mg,68%得率)。1H NMR(400MHz,MeOH-d4)δppm 7.11-7.21(m,3H),7.07(d,J=8.6Hz,2H),6.86(m,J=8.6Hz,2H),4.39(d,J=9.3Hz,1H),4.06-4.15(m,3H),3.88-3.98(m,2H),3.55(s,2H),3.34-3.50(m,3H),3.18(t,J=7.5Hz,2H),2.20(s,3H),2.14(s,3H),2.08-2.18(m,2H),1.32(s,6H);MS(ES+)[M+H]+=506。
(2S,3R,4R,5S,6R)-2-(3-(4-(3-((3-(二甲基氨基)-2,2-二甲基丙基)氨基)丙氧基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三醇(50)的制备(6.25.)
在氮气下,将(2S,3S,4R,5S,6R)-2-(4-甲基-3-(4-(3-((甲基磺酰基)氧基)丙氧基)苯甲基)苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(48,1.28g,2.0mmol)和N1,N1,2,2-四甲基丙烷-1,3-二胺(0.64mL,4.0mmol)溶解在异丙醇(4mL)和CH3CN(4mL)中。将反应在90℃加热过夜,然后冷却至室温。加入MeOH(8mL)和甲醇钠(0.69mL,25重量%,在MeOH中,3.0mmol),并将反应搅拌2小时,然后用乙酸中和并在真空下浓缩。将残留物通过制备HPLC(C18 30x 250mm柱,5-60%CH3CN/10mM甲酸铵水溶液,45mL/min和C18 30x 100mm柱,5-92%MeOH/H2O(含0.1%甲酸),45mL/min)纯化两次,并冷冻干燥,以给出作为白色固体的产物50的甲酸盐(0.52g,44%得率)。1H NMR(400MHz,MeOH-d4)δppm 7.11-7.20(m,3H),7.08(d,J=8.6Hz,2H),6.86(d,J=8.6Hz,2H),4.39(d,J=9.6Hz,1H),4.08-4.15(m,3H),3.94(s,2H),3.34-3.49(m,3H),3.20(t,J=6.8Hz,2H),3.04(s,2H),2.62(s,2H),2.32(s,6H),2.19(s,3H),2.15(s,3H)2.10-2.18(m,2H),1.05(s,6H);MS(ES+)[M+H]+=547。
2,2-二甲基-3-((3-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基 硫基)四氢-2H-吡喃-2-基)苯甲基)苯氧基)丙基)-氨基)丙酰胺(51)的制备(6.26.)
利用与用于胺50的相同的程序,使用3-氨基-2,2-二甲基丙酰胺,以提供产物51。将材料通过制备HPLC(C18 30x 100mm柱,5-60%CH3CN/10mM甲酸铵水溶液,45mL/min)进行纯化并冷冻干燥,以给出作为白色固体的产物的甲酸盐。1H NMR(400MHz,MeOH-d4)δppm7.11-7.21(m,3H),7.06(d,J=8.1Hz,2H),6.88(m,J=8.3Hz,2H),4.39(d,J=9.3Hz,1H),4.05-4.16(m,3H),3.94(s,2H),3.35-3.53(m,3H),3.23(t,J=6.9Hz,2H),3.07(s,2H),2.20(s,3H),2.16-2.24(m,2H),2.14(s,3H),1.33(s,6H);MS(ES+)[M+H]+=533。
1-((2-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢- 2H-吡喃-2-基)苯甲基)苯氧基)乙基)氨基)环戊烷甲酰胺(52)的制备(6.27.)
利用与用于胺50的相同的程序,使用1-氨基环戊烷甲酰胺,以提供产物52。1H NMR(400MHz,MeOH-d4)δppm 7.11-7.21(m,3H),7.06(d,J=8.3Hz,2H),6.85(m,J=8.6Hz,2H),4.39(d,J=9.6Hz,1H),4.12(d,J=9.3Hz,1H),4.06(t,J=4.9Hz,2H),3.94(s,2H),3.34-3.54(m,3H),2.92(t,J=4.8Hz,2H),2.20(s,3H),2.14(s,3H),2.06-2.13(m,2H),1.75-1.83(m,6H);MS(ES+)[M+H]+=531。
(2S,3R,4R,5S,6R)-2-(3-(4-(2,3-二羟基丙氧基)苯甲基)-4-甲基苯基)-6-(甲 基硫基)四氢-2H-吡喃-3,4,5-三醇(53)的制备(6.28.)
在氮气下,向(2S,3S,4R,5S,6R)-2-(3-(4-羟基苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(37,50mg,0.10mmol)在EtOH(1mL)中的溶液加入三乙胺(1.4μL,0.010mmol)和缩水甘油(10μL,0.15mmol)。将反应在80℃加热过夜,然后再次装入三乙胺和缩水甘油,在90℃加热5小时。将反应冷却至室温,用EtOAc稀释,用饱和NaHCO3水溶液和盐水洗涤(带有反萃取),在MgSO4上干燥,过滤,并在真空下浓缩。将材料通过制备HPLC(C1830x 100mm柱,20-60%CH3CN/10mM甲酸铵水溶液,45mL/min)纯化两次并冷冻干燥,以提供作为白色固体的二醇53(12mg,27%得率)。1H NMR(400MHz,MeOH-d4)δppm7.10-7.19(m,3H),7.05(d,J=8.8Hz,2H),6.81-6.88(m,2H),4.39(d,J=9.3Hz,1H),4.12(d,J=9.1Hz,1H),3.89-4.05(m,5H),3.59-3.71(m,2H),3.35-3.49(m,3H),2.20(s,3H),2.14(s,3H);MS(ES+)[M+NH4]+=468。
2-氨基-2-甲基-1-(4-甲基哌嗪-1-基)丙-1-酮(55)的合成(6.29.)
将2-((叔丁氧基羰基)氨基)-2-甲基丙酸(Boc-Aib-OH,54,10.0g,49.2mol)、EDC·HCl(11.3g,59.0mmol)、HOBt(9.97g,73.8mmol)和DIPEA(25.6mL,148mmol)在250mLTHF中搅拌,直至所有固体溶解。加入N-甲基-哌嗪(10.9mL,98.4mmol),并将反应在室温搅拌18小时。将混合物用300mL EtOAc稀释,并用饱和NaHCO3水溶液洗涤两次。然后将有机层用盐水洗涤,在MgSO4上干燥,过滤,并在真空中除去溶剂。将该粗材料溶解在300mL CH3CN中。在超过10分钟下加入HCl(4N,在二噁烷中,49mL,196mmol)。将反应搅拌8小时,在此期间产物形成白色沉淀物。将产物过滤,用CH2Cl2洗涤,并在高真空下干燥过夜,以提供作为双盐酸盐的产物55(10.4g,82%得率)。1H NMR(400MHz,DMSO-d6)δppm 8.30(br.s.,3H),4.35(d,J=13.6Hz,2H),3.52(br.s.,2H),3.41(d,J=11.1Hz,2H),3.01(q,J=11.1Hz,2H),2.77(d,J=3.5Hz,3H),1.56(s,6H)。MS(ES+)[M+H]+=186。
(1-氨基环戊基)(4-甲基哌嗪-1-基)甲酮(56)的制备(6.30.)
利用与用于酰胺55的相同的程序,从1-((叔丁氧基羰基)氨基)环戊烷甲酸开始,以提供产物56。1H NMR(400MHz,DMSO-d6)δppm 11.56(br.s.,1H),8.32(br.s.,3H),3.41(d,J=11.6Hz,4H),3.05(q,J=10.6Hz,2H),2.76(d,J=4.3Hz,3H),2.10-2.22(m,2H),1.81-2.02(m,8H)。MS(ES+)[M+H]+=212。
2-氨基-2-甲基-N-(1-甲基哌啶-4-基)丙酰胺(58)的制备(6.31.)
将2-(((苯甲基氧基)羰基)氨基)-2-甲基丙酸(Z-Aib-OH,57,25.0g,105mmol)、EDC·HCl(24.2g,126mmol)、HOBt(21.2g,157mmol)和DIPEA(54.9mL,315mmol)在500mL THF中搅拌,直至所有固体溶解。加入N-甲基哌啶-4-胺(15.9mL,126mmol)并将反应在室温下搅拌18小时。将混合物用600mL EtOAc稀释,并用饱和NaHCO3水溶液洗涤两次。然后将有机层用盐水洗涤,在MgSO4上干燥,过滤,并在真空中除去溶剂。将该粗材料溶解在150mL THF和150mL MeOH中。加入Pd/C(10%水分,2.92g),并将反应在大气压氢气下搅拌8小时。将反应在硅藻土上用过量MeOH过滤,在真空中除去溶剂,并将得到的浅黄色固体在高真空下干燥过夜,以提供作为游离碱的产物57(17.4g,85%得率)。1H NMR(400MHz,氯仿-d)δppm 7.54(br.s.,1H),3.62-3.77(m,1H),2.75(d,J=11.6Hz,2H),2.27(s,3H),2.11(t,J=10.9Hz,2H),1.89(dq,J=12.6,3.8Hz,2H),1.48(qd,J=11.5,3.5Hz,2H),1.30-1.39(m,6H)。[M+H]+=200。
2-氨基-N-(2-(二甲基氨基)乙基)-2-甲基丙酰胺(59)的制备(6.32.)
利用与用于酰胺57的相同的程序,使用N,N-二甲基乙-1,2-二胺,以提供产物59。1H NMR(400MHz,氯仿-d)δppm 7.78(br.s.,1H),3.31(q,J=6.1Hz,2H),2.42(t,J=6.2Hz,2H),2.25(s,6H),1.68(br.s.,2H),1.36(s,6H)。[M+H]+=174。
N-(1-((2-(二甲基氨基)乙基)氨基)-2-甲基-1-氧丙烷-2-基)-4-(4-(2-甲基-5- ((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-((S)-甲基亚磺酰基)四氢-2H-吡喃-2-基)苯甲基) 苯基)丁酰胺(61)的制备(6.33.)
(2S,3S,4R,5S,6R)-2-(3-(4-(4-甲氧基-4-氧丁基)苯甲基)-4-甲基苯基)-6- ((S)-甲基亚磺酰基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(60)的制备。在0℃下,向(2S,3S,4R,5S,6R)-2-(3-(4-(4-甲氧基-4-氧丁基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(9,100mg,0.170mmol)在1mL HOAc和2mL CH3CN中的溶液加入过乙酸(32%,在稀HOAc中,0.12mL,0.512mmol)。将反应在0℃下搅拌20min。将反应用1N NaOH水溶液淬灭,然后用EtOAc萃取两次。将合并的有机层用盐水洗涤,在MgSO4上干燥,过滤,并在真空中除去溶剂,以提供亚砜60的2:1的非对映异构体混合物(60mg,58%得率),其不需进一步纯化用于下一步。1H NMR(400MHz,氯仿-d,在S处的非对映异构体的2:1混合物,被称为主要Ha和次要Hb)δppm 7.11-7.17(m,2H),7.05–7.09(m,2H),6.97-7.02(m,3H),5.59(t,J=9.3Hz,1Hb),5.46(t,J=9.3Hz,1Hb),5.41(t,J=9.6Hz,1Ha),5.21(t,J=9.9Hz,1Ha),5.17(t,J=9.3Hz,1Hb),5.13(t,J=9.9Hz,1Ha),4.50(t,J=10.4Hz,1Ha),4.48(d,J=9.9Hz,1Ha),4.46(d,J=10.1Hz,1Hb),4.31(d,J=10.1Hz,1Hb),3.93(m,2Hb),3.92(m,2Ha),3.66(s,3H),2.67(s,3Ha),2.64(s,3Hb),2.61(t,J=7.8Hz,2H),2.33(t,J=7.3Hz,2H),2.23(s,3H),2.09(s,3Ha),2.08(s,3Hb),2.02(s,3Hb),2.01(s,3Ha),1.93(quin,J=7.3Hz,2H),1.75(s,3Ha),1.74(s,3Hb)。MS(ES+)[M+H]+=603。
N-(1-((2-(二甲基氨基)乙基)氨基)-2-甲基-1-氧丙烷-2-基)-4-(4-(2-甲基-5- ((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-((S)-甲基亚磺酰基)-四氢-2H-吡喃-2-基)苯甲基) 苯基)丁酰胺(61)的制备。将亚砜60(60mg,0.10mmol)悬浮在2.5mL MeOH/H2O/THF的2:2:1混合物中。加入LiOH(24mg,1.0mmol)。将反应在室温搅拌4小时,在此时间内起始原料进入溶液。将反应用饱和NaHSO4水溶液淬灭。将该酸性层用EtOAc萃取三次。将合并的有机层用盐水洗涤,在MgSO4上干燥,过滤,并在真空中除去溶剂。将该粗残留物溶解在1mL CH3CN中。加入EDC·HCl(31mg,0.16mmol)、HOBt(31mg,0.16mmol)和DIPEA(50μL,0.30mmol)并搅拌10分钟。加入0.5mL CH3CN中的2-氨基-N-(2-(二甲基氨基)乙基)-2-甲基-丙酰胺(30mg,0.17mmol)。将反应在室温搅拌过夜。在反应完成后,在真空中除去溶剂。将残留物通过制备HPLC(C18 30x 100mm柱,5-95%MeOH/10mM甲酸水溶液,45mL/min)进行纯化,以提供作为甲酸盐的亚砜61(23mg,35%得率),其被提供为亚砜的2:1非对映异构体混合物。1H NMR(400MHz,MeOH-d4,在S处的非对映异构体的2:1混合物,被称为主要Ha和次要Hb)δppm 8.54(br.s,1H,甲酸盐),7.14–7.19(m,3H),7.04–7.10(m,4H),4.47(d,J=9.6Hz,1Ha),4.28(d,J=9.1Hz,1Hb),4.26(d,J=9.3Hz,1Ha),4.12(d,J=9.9Hz,1Hb),3.97(s,3Hb),3.96(s,3Ha),3.82(t,J=9.6Hz,1Hb),3.68(t,J=9.1Hz,1Ha),3.60(t,J=9.0Hz,1Hb),3.58(t,J=8.8Hz,1Ha),3.45(t,J=5.6Hz,2H),3.39–3.47(m,1Ha+1Hb),2.91(t,J=5.1Hz,2H),2.73(s,3Ha),2.64(s,6H),2.61(s,3Hb),2.60(t,J=7.6Hz,2H),2.22(s,3Ha),2.21(s,3Hb),2.21(t,J=7.6Hz,2H),1.87(quin,J=7.3Hz,2H),1.41(s,6H)。MS(ES+)[M+H]+=618。
N-(1-((2-(二甲基氨基)乙基)氨基)-2-甲基-1-氧丙烷-2-基)-4-(4-(2-甲基-5- ((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基磺酰基)四氢-2H-吡喃-2-基)苯甲基)苯基)丁 酰胺(63)的制备(6.34.)
(2S,3S,4R,5S,6R)-2-(3-(4-(4-甲氧基-4-氧丁基)苯甲基)-4-甲基苯基)-6-(甲 基磺酰基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(62)的制备。将过氧化氢脲(UHP,48mg,0.512mmol)和邻苯二甲酸酐(151mg,1.02mmol)溶解在1.5mL CH3CN和0.3mL MeOH中。加入溶解在2mL CH3CN中的(2S,3S,4R,5S,6R)-2-(3-(4-(4-甲氧基-4-氧丁基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(9,100mg,0.170mmol)。将反应在室温搅拌16小时。在反应中装入另外的UHP(12mg,0.128mmol)和邻苯二甲酸酐(38mg,0.255mmol),并搅拌1小时。在充分转化成砜后,将反应用饱和NaHCO3水溶液淬灭。将该水性层用EtOAc萃取三次。将合并的有机层用盐水洗涤,在MgSO4上干燥,过滤,在真空中除去溶剂,以提供砜62(95mg,92%得率),其不需进一步纯化用于下一步。1H NMR(400MHz,氯仿-d)δppm 7.11-7.20(m,2H),7.08(d,J=8.1Hz,2H),6.93-7.04(m,3H),5.57(t,J=9.7Hz,1H),5.41(t,J=9.3Hz,1H),5.17(t,J=9.7Hz,1H),4.49(d,J=9.7Hz,1H),4.52(d,J=9.7Hz,1H),3.93(m,2H),3.67(s,3H),2.92(s,3H),2.62(t,J=7.5Hz,2H),2.33(t,J=7.5Hz,2H),2.24(s,3H),2.09(s,3H),2.02(s,3H),1.94(quin,J=7.5Hz,2H),1.75(s,3H)。MS(ES+)[M+H]+=619。
N-(1-((2-(二甲基氨基)乙基)氨基)-2-甲基-1-氧丙烷-2-基)-4-(4-(2-甲基-5- ((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基磺酰基)四氢-2H-吡喃-2-基)苯甲基)苯基)丁 酰胺(63)的制备。将砜62(95mg,0.15mmol)悬浮在5mL MeOH/H2O/THF的2:2:1混合物。加入LiOH(37mg,1.53mmol)。将反应在室温搅拌4小时,在该时间内起始原料进入溶液。将反应用饱和NaHSO4水溶液淬灭。将该酸性层用EtOAc萃取三次。将合并的有机层用盐水洗涤,在MgSO4上干燥,过滤,并在真空中除去溶剂。将该粗残留物溶解在1.5mL CH3CN中。加入EDC·HCl(43mg,0.22mmol)、HOBt(43mg,0.22mmol)和DIPEA(75μL,0.30mmol)并搅拌10min。加入0.5mL CH3CN中的2-氨基-N-(2-(二甲基氨基)乙基)-2-甲基丙酰胺(30mg,0.45mmol)。将反应在室温搅拌过夜。在反应完成后,在真空中除去溶剂。将残留物通过制备HPLC(C1830x100mm柱,5-95%MeOH/10mM甲酸水溶液,45mL/min)进行纯化,以提供作为甲酸盐的标题化合物63(30mg,30%得率)。1H NMR(400MHz,MeOH-d4)δppm 8.54(br.s,1H,甲酸盐),7.12-7.22(m,3H),7.10(d,J=8.0Hz,2H),7.06(d,J=8.0Hz,2H),4.52(d,J=9.5Hz,1H),4.28(d,J=9.5Hz,1H),3.96(s,2H),3.88(t,J=9.2Hz,1H),3.56(t,J=8.9Hz,1H),3.45(t,J=5.3Hz,2H),3.41(t,J=9.3Hz,1H),2.93(s,3H),2.89(t,J=5.3Hz,2H),2.64(s,6H),2.61(t,J=7.8Hz,2H),2.21(t,J=8.0Hz,5H),2.14-2.29(m,3H),1.88(quin,J=7.5Hz,2H),1.41(s,6H)。MS(ES+)[M+H]+=634。
亚砜/N-氧化物(64)和砜/N-氧化物(65)的制备(6.35.)
向N-(1-((2-(二甲基氨基)乙基)氨基)-2-甲基-1-氧丙烷-2-基)-4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯基)丁酰胺(13,30mg,0.050mmol)在0.5mL CH2Cl2中的溶液加入间氯过苯甲酸(22mg,0.125mmol)。将反应搅拌5分钟,并在真空中除去溶剂。将残留物通过制备HPLC(C18 30x100mm柱,5-100%CH3CN/10mM甲酸铵水溶液,45mL/min)进行纯化,以提供氧化的产物64(16mg,50%得率)和65(3mg,9%得率)。
N,N-二甲基-2-(2-甲基-2-(4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-((S)-甲基亚磺酰基)四氢-2H-吡喃-2-基)苯甲基)苯基)丁氨酰基)丙氨酰基)乙胺氧化物(64,在S处的非对映异构体的2:1混合物,被称为主要Ha和次要Hb):1H NMR(400MHz,MeOH-d4)δppm 8.46(s,2H,甲酸盐),7.14–7.26(m,3H),7.04–7.10(m,4H),4.46(d,J=9.6Hz,1Ha),4.27(d,J=9.6Hz,1Hb),4.26(d,J=9.6Hz,1Ha),4.12(d,J=9.9Hz,1Hb),3.97(s,3Hb),3.96(s,3Ha),3.82(t,J=9.1Hz,1Hb),3.68(t,J=9.1Hz,1Ha),3.59(t,J=8.9Hz,1Hb),3.58(t,J=8.9Hz,1Ha),3.43(t,J=6.1Hz,2H),3.41(t,J=9.1Hz,1Ha+1Hb重叠),3.20(s,6H),2.72(s,3Ha),2.62(s,3Hb),2.60(t,J=7.6Hz,2H),2.23(s,3Ha),2.22(s,3Hb),2.20(t,J=7.6Hz,2H),1.86(quin,J=7.6Hz,2H),1.41(s,6H)。MS(ES+)[M+H]+=634。
N,N-二甲基-2-(2-甲基-2-(4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基磺酰基)四氢-2H-吡喃-2-基)苯甲基)苯基)丁氨酰基)丙氨酰基)乙胺氧化物(65):1H NMR(400MHz,MeOH-d4)δppm 8.41(s,1H,甲酸盐),7.12-7.23(m,3H),7.09(d,J=7.8Hz,2H),7.05(d,J=7.8Hz,2H),4.52(d,J=9.6Hz,1H),4.28(d,J=9.6Hz,1H),3.96(s,2H),3.88(t,J=9.2Hz,1H),3.64(t,J=5.7Hz,2H),3.56(t,J=9.0Hz,1H),3.45(t,J=5.7Hz,2H),3.41(t,J=9.1Hz,1H),3.23(s,6H),2.93(s,3H),2.60(t,J=7.6Hz,2H),2.23(s,3H),2.20(t,J=7.6Hz,2H),1.87(quin,J=7.6Hz,2H),1.41(s,6H)。MS(ES+)[M+H]+=650。
其他化合物(6.36.)
使用与上面描述的类似的程序,制备了大量本发明的其他化合物。那些化合物包含在表1中。标题为“SLGT1”和“SGLT2”的列提供了如下所述获得的人类SGLT1IC50和SGLT1IC50测量值,其中:***是指小于0.01μM的值;**是指小于0.1μM的值;*是指小于1μM的值;并且--是指未被测量或超出μM的值。
表1
6.37.体外人类SGLT1抑制测定
将1型人类钠/葡萄糖协同转运蛋白(SGLT1;登记号NP_000334;GI:4507031)克隆在用于哺乳动物表达的pIRESpuro2载体中(构建物:HA-SGLT1-pIRESpuro2)。
用人类HA-SGLT1-pIRESpuro2载体转染HEK293细胞,并在0.5μg/ml嘌呤霉素存在下对大量稳定细胞系进行选择。人类HA-SGLT1细胞被维持在含有10%FBS、1%GPS和0.5μg/ml嘌呤霉素的DMEM培养基中。
将表达人类HA-SGLT1的HEK293细胞接种在384孔板(30,000个细胞/孔)中的含有10%FBS、1%GPS和0.5μg/ml嘌呤霉素的DMEM培养基中,然后在37℃、5%CO2下温育过夜。然后将细胞用摄取缓冲液(140mM NaCl,2mM KCl,1mM CaCl2,1mM MgCl2,10mM HEPES,5mMTris,1mg/ml牛血清白蛋白(BSA),pH 7.3)清洗。向细胞加入含有或不含测试化合物的20微升摄取缓冲液。然后向细胞加入含有14C-AMG(100nCi)的20微升摄取缓冲液。将细胞板在37℃、5%CO2下温育1-2小时。在用摄取缓冲液清洗细胞后,加入闪烁液(40微升/孔),并使用闪烁计数器(TopCoulter NXT;Packard Instruments)通过对放射活性进行计数来测量14C-AMG摄取。
体外人类SGLT2抑制测定(6.38.)
将2型人类钠/葡萄糖协同转运蛋白(SGLT2;登记号P31639;GI:400337)克隆在用于哺乳动物表达的pIRESpuro2载体中(构建物:HA-SGLT2-pIRESpuro2)。
用人类HA-SGLT2-pIRESpuro2载体转染HEK293细胞,并在0.5μg/ml嘌呤霉素存在下对大量稳定细胞系进行选择。人类HA-SGLT2细胞被维持在含有10%FBS、1%GPS和0.5μg/ml嘌呤霉素的DMEM培养基中。
将表达人类HA-SGLT2的HEK293细胞接种在384孔板(30,000个细胞/孔)中的含有10%FBS、1%GPS和0.5μg/ml嘌呤霉素的DMEM培养基中,然后在37℃、5%CO2下温育过夜。然后将细胞用摄取缓冲液(140mM NaCl,2mM KCl,1mM CaCl2,1mM MgCl2,10mM HEPES,5mMTris,1mg/ml牛血清白蛋白(BSA),pH 7.3)清洗。向细胞加入含有或不含测试化合物的20微升摄取缓冲液。然后向细胞加入含有14C-AMG(100nCi)的20微升摄取缓冲液。将细胞板在37℃、5%CO2下温育1-2小时。在用摄取缓冲液清洗细胞后,加入闪烁液(40微升/孔),并使用闪烁计数器(TopCoulter NXT;Packard Instruments)通过对放射活性进行计数来测量14C-AMG摄取。
耐受性和药理学(6.39.)
使用18周龄雄性C57/Blk6小鼠确定本发明的化合物的体内耐受性和药理学。在研究之前,将小鼠从常规食物切换到10%低脂肪饮食(LFD,D12450Bi)并单独饲养一周。然后将小鼠按照体重随机分配到下面的组中:
小鼠通过口饲管以1mg/kg的剂量并在10mL/kg体积中每日一次接受介质或化合物共4日。每日监测体重、食物消耗量和腹泻。在最后一次给药后6小时,通过球后取血从小鼠收集血液用于基线葡萄糖测定。然后向小鼠提供含葡萄糖餐食,其通过将50g低脂肪饮食(LFD)粉(10%kcal作为脂肪;饮食D12450B,Research Diets,New Brunswick,NJ)悬浮在60mL水中来制备。神志清醒的小鼠通过口饲管接受20mL/kg这种悬液以及5mL/kg 50%右旋糖,这为它们提供9.2g/kg葡萄糖、2.5g/kg蛋白质和0.6g/kg脂肪。
在餐后10、30和60分钟收集血液,以估算餐后血糖漂移。血糖使用Accu-ChekAviva葡萄糖测定仪(Roche Diagnostics,Indianapolis,IN),按照制造商推荐的流程来测量。图1A示出了1.0mg/kg(“mpk”)化合物A-E与介质相比对小鼠血糖水平的影响随它们的餐后激惹后的时间的变化。实验中每只动物的曲线下面积被示出在图1B中。
在餐食激惹后60分钟,收集另外的血液用于总胰高血糖素样肽-1(tGLP-1)分析。为了进行这种测量,通过将血样在4℃下以1000rpm离心10分钟来制备血浆。tGPL-1通过ELISA(胰高血糖素样肽-1总ELISA试剂盒,目录号EZGLP1T-36K,Millipore,St.Charles,MO),按照制造商推荐的流程来分析。图2示出了对于每只小鼠来说,与介质相比,化合物对血浆tGLP-1的影响。
在收集最后血样后,立即收集盲肠内含物用于葡萄糖分析。这种分析通过向1克盲肠内含物加入5mL冷MilliQ水来进行。然后使用Mini Beadbeater(Biospec Products,Bartlesville,OK)将混合物匀浆1分钟。将匀浆液在4℃下以3750rpm的速度离心25分钟。收集上清液。盲肠葡萄糖通过Cobas Integra 400Autoanalyzer(Roche Diagnostics)来分析。图3示出了每只小鼠的这种分析的结果。
对KKAy糖尿病小鼠的影响(6.40.)
12周龄的雄性KKay小鼠购自Jackson Laboratory(Bar Harbor,ME)。在研究前,将它们切换至45%高脂肪饮食(HFD;饮食D12451i,Research Diets)并单独饲养一周。将小鼠根据它们的HbA1c水平和体重随机分配到下面的组中:
化合物 | 剂量 | 小鼠数目(N) |
介质(0.1%Tween 80在水中) | -- | 9 |
化合物C | 1.5mg/kg | 10 |
化合物C | 4.5mg/kg | 10 |
其中化合物C是(2S,3R,4R,5S,6R)-2-(3-(4-(3-((1-羟基-2-甲基丙-2-基)氨基)丙氧基)苯甲基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三醇。
小鼠每日一次在5:00pm接受介质或化合物C共36日。每日监测体重和食物消耗量。在第22日,在葡萄糖激惹前收集血液用于基线葡萄糖测定。然后向小鼠提供一剂快速浓注葡萄糖(2g/kg,10mL/kg)。在葡萄糖激惹后30、60和120分钟收集血液,以估算血糖漂移。血糖通过Cobas Integra 400Autoanalyzer(Roche Diagnostics)来分析。图4示出了在给药化合物C后15小时血糖漂移的剂量依赖性的降低,其中时间t=0是给药葡萄糖快速浓注的时间。
在给药后第26日,收集血液用于HbA1c。HbA1c使用由Bayer制造的测定仪,按照由Bayer推荐的流程来测量。如图5A中所示,用化合物C处理的小鼠表现出HbA1c的显著的剂量依赖性的降低。图5B示出了在第0日至第27日之间小鼠HbA1c的变化。
在第29日,小鼠再次接受葡萄糖快速浓注(2g/kg,10mL/kg)。在葡萄糖激惹后60分钟收集血液,并分析tGLP-1。通过将血样在4℃下以1000rpm离心10分钟来制备血浆。tGPL-1通过ELISA(胰高血糖素样肽-1总ELISA试剂盒,目录号EZGLP1T-36K,Millipore,St.Charles,MO),按照由Millipore推荐的流程来分析。如图6中所示,在4.5mpk组中观察到了餐后tGLP-1的显著提高(p<0.5)。
上面引用的所有出版物(例如专利和专利申请)以其整体通过参考并入本文。
Claims (4)
1.化合物,其是N-(1-((2-(二甲基氨基)乙基)氨基)-2-甲基-1-氧丙烷-2-基)-4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯基)丁酰胺:
或其可药用盐。
2.一种药物组合物,其包含权利要求1的化合物和可药用赋形剂。
3.权利要求2的药物组合物,其中可药用赋形剂是稀释剂。
4.治疗有效量的权利要求1的化合物或权利要求2或3的组合物在制备用于在需要的患者中治疗或管理心血管疾病、障碍或代谢疾病、障碍的药物中的应用。
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