CN104470521B - 脑啡肽酶抑制剂 - Google Patents
脑啡肽酶抑制剂 Download PDFInfo
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- CN104470521B CN104470521B CN201380030078.1A CN201380030078A CN104470521B CN 104470521 B CN104470521 B CN 104470521B CN 201380030078 A CN201380030078 A CN 201380030078A CN 104470521 B CN104470521 B CN 104470521B
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Classifications
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Abstract
在一个方面中,本发明涉及具有式X的化合物:其中Ra、Rb、R2、R7和X是如说明书中所定义,或其医药学上可接受的盐。本文所述的化合物是具有脑啡肽酶抑制活性的化合物的前药。在另一方面中,本发明涉及包含这些化合物的医药组合物;使用这些化合物的方法;以及制备这些化合物的方法和中间物。
Description
技术领域
本发明涉及新颖化合物,其在体内代谢成具有作为脑啡肽酶(neprilysin)抑制剂的活性的化合物。本发明还涉及包含这些化合物的医药组合物、制备这些化合物的方法和中间物、和使用这些化合物治疗如高血压、心脏衰竭、肺高血压和肾病的疾病的方法。
背景技术
颁予史密斯(Smith)等人的在2011年12月14日申请的共同转让的美国专利公开案第2012/0157386号描述了具有作为脑啡肽酶抑制剂的活性的新颖化合物,所述公开案的公开内容以引用的方式并入本文中。具体地说,以下种类的化合物:
经描述。取决于变量,这个种类中的化合物可被认为是处于活性形式或是前药,所述前药在体内代谢以产生化合物的活性形式。
然而,尽管有这些化合物,但仍需要这个种类中具有不同代谢和裂解性质的化合物和前药。举例来说,仍需要口服吸收经改进的活性化合物和/或前药化合物和会经历快速裂解以形成活性化合物的前药化合物。本发明是针对所述需求。
发明内容
本发明的一个方面涉及式X化合物:
其中:
(i)Ra是F;Rb是Cl;X是且
当X是:
时,
R2是H且R7是选自-CH2CH3、-CH2CH(CH3)2、-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基和
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R7是H;且
当X是:
时,
R2是H,R3是-OH,且R7是选自-CH2OC(O)CH3和-CH2OC(O)-CH[CH(CH3)2]NH2;或R2是H,R3是选自-OCH2OC(O)CH3和-OCH2OC(O)CH[CH(CH3)2]NH2,且R7是H;或
(ii)Ra是F;Rb是Cl;X是且
R2是H且R7是选自-CH2CH3、-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)-CHRd-NHC(O)O-C1-6烷基、苯甲基和
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R7是H;或
(iii)Ra是F;Rb是Cl;X是且
R2是H且R7是选自-CH2CH(CH3)2、-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基和
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R7是H;或
(iv)Ra是F;Rb是Cl;X是R是H或-CH3;且
R2是H且R7是选自-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)-COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)-O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRdNH-C(O)O-C1-6烷基、苯甲基、
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R7是H;或R2是-C(O)CH2NH2且R7是-CH2CH3;或
(v)Ra是F;Rb是Cl;X是且
R2是H且R7是选自-CH2CH3、-CH2CH(CH3)2、-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcO-C(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基和
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R7是H;或
(vi)Ra是F;Rb是Cl;X是且
R2和R4是H,且R7是选自H、-CH2CH3、-CH2CH(CH3)2、-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基、
或R2是H,R4是选自-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和-CH2OC(O)CH[CH(CH3)2]NH2,且R7是H;或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,R4是H,且R7是H;或R2是H,R4是-CH2OP(O)(ORe)2或-CH2OC(O)CH[CH(CH3)2]NH2,且R7是-CH2CH3或-CH2CH(CH3)2;或R2是-C(O)CH[CH(CH3)2]NH2,R4是H,且R7是-CH2CH3或-CH2CH(CH3)2;或
(vii)Ra是F;Rb是Cl;X是且
R2和R4是H,且R7是选自-CH2CF3、-(CH2)2CF3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)-COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基和
或R2是H,R4是选自-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和-CH2OC(O)CH[CH(CH3)2]NH2,且R7是选自H和-CH2CH3;或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R4和R7是H;或
(viii)Ra是H;Rb是Cl;X是且
R2是H,R3是-OH,且R7是选自-CH2CF3、-(CH2)2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CH[CH(CH3)2]NH2和-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3;或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,R3是-OH,且R7是H;或R2是H,R3是选自-OCHRcOC(O)-C1-4烷基、-OCH2OC(O)CH[CH(CH3)2]-NH2、-OCH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和
且R7是H;或
(ix)Ra是Cl;Rb是Cl;X是且
R2是H,R4是-OH,且R7是选自-CH2CF3、-(CH2)2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基和
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,R4是-OH,且R7是H;或R2是H,R4是选自-OCHRcOC(O)-C1-4烷基、-OCH2OC(O)CH[CH(CH3)2]NH2、-OCH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和
且R7是H;
其中每一Rc独立地是H或-C1-3烷基;每一Rd独立地是H、-CH3、-CH(CH3)2、苯基或苯甲基;且每一Re独立地是H、-C1-6烷基或苯基;
或其医药学上可接受的盐。
本发明提供化合物,其在体内代谢成已发现具有脑啡肽酶(NEP)酶抑制活性的化合物。因此,预期本发明化合物可有利地适用作治疗剂,以用于治疗罹患通过抑制NEP酶或通过增加其肽底物含量而得以治疗的疾病或病症的患者。因此,本发明的一个方面涉及一种治疗高血压、心脏衰竭或肾病的方法,其包含向患者投与治疗有效量的本发明化合物。
本发明的另一方面涉及包含医药学上可接受的载剂和本发明化合物的医药组合物。
本发明的另一方面涉及适用于制备本发明化合物的方法和中间物。本发明的另一方面涉及一种制备式I化合物的医药学上可接受的盐的方法,其包含使呈游离酸或游离碱形式的式I化合物与医药学上可接受的碱或酸接触。在其它方面中,本发明涉及通过本文所述的任何方法制备的产物以及所述方法中使用的新颖中间物。
本发明的另一方面涉及式I化合物或其医药学上可接受的盐的用途,其用于制造药剂,尤其用于制造适用于治疗高血压、心脏衰竭或肾病的药剂。本发明的另一方面涉及本发明化合物用于抑制哺乳动物中的NEP酶的用途。本发明的另一方面涉及本发明化合物作为研究工具的用途。本文中揭示本发明的其它方面和实施例。
具体实施方式
当描述本发明的化合物、组合物、方法和工艺时,除非另外指示,否则下列术语具有下列含义。另外,除非使用的上下文另外明确规定,否则如本文所用,单数形式“一”和“所述”包括相应的复数形式。术语“包含”、“包括”和“具有”打算为包括性的且意指可能存在除所列要素以外的其它要素。除非另外指示,否则本文中使用的表示成分数量、性质,如分子量、反应条件等的所有数值都应理解为在所有情况下都由术语“约”修饰。因此,本文中阐述的数值为可视本发明所设法获得的所要性质而变化的近似值。至少,且不希望等同原则(doctrine of equivalents)的应用限于权利要求书的范围,每个数值应至少根据所报导的有效数字且通过应用一般舍入技术来解释。
术语“烷基”意指可为直链或分支链的单价饱和烃基。除非另外定义,否则这些烷基通常含有1到10个碳原子,且包括例如-C1-6烷基,其意指具有1到6个碳原子的烷基,其中碳原子呈任何可接受的构型。代表性烷基包括例如甲基、乙基、正丙基、异丙基、正丁基、第二丁基、异丁基、叔丁基、正戊基、正己基等。
如本文所用,词组“具有式”或“具有结构”不打算具有限制性且以与常用术语“包含”相同的方式使用。举例来说,除非另有说明,否则如果描绘了一种结构,那么应理解所有立体异构体和互变异构体形式均涵盖在内。
术语“医药学上可接受”是指当在本发明中使用时不为生物学上不可接受或在其它方面不可接受的物质。举例来说,术语“医药学上可接受的载剂”是指可并入组合物中且向患者投与而不引起不可接受的生物效应或以不可接受的方式与组合物的其它组分相互作用的物质。这些医药学上可接受的物质通常已满足为毒理学和制造测试所需的标准且包括由美国食品和药物管理局(U.S.Food and Drug administration)鉴别为适合非活性成分的物质。
术语“医药学上可接受的盐”意指从可为向患者,如哺乳动物投与所接受的碱或酸制备的盐(例如对于既定剂量方案来说具有可接受的哺乳动物安全性的盐)。然而,应了解本发明所涵盖的盐并不需要为医药学上可接受的盐,如为不打算向患者投与的中间化合物的盐。医药学上可接受的盐可源于医药学上可接受的无机碱或有机碱,和源于医药学上可接受的无机酸或有机酸。此外,当式I化合物含有碱性部分(如胺、吡啶或咪唑)与酸性部分(如羧酸或四唑)两者时,可形成两性离子且其包括在如本文所用的术语“盐”内。源于医药学上可接受的无机碱的盐包括铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐和锌盐等。源于医药学上可接受的有机碱的盐包括以下各物的盐:伯胺、仲胺和叔胺,包括经取代胺、环胺、天然产生的胺等,如精氨酸、甜菜碱(betaine)、咖啡碱(caffeine)、胆碱(choline)、N,N'-二苯甲基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡糖胺(glucamine)、葡糖胺(glucosamine)、组氨酸、哈胺(hydrabamine)、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因(procaine)、嘌呤、可可碱(theobromine)、三乙胺、三甲胺、三丙胺、缓血酸胺(tromethamine)等。源于医药学上可接受的无机酸的盐包括以下各酸的盐:硼酸、碳酸、氢卤酸(氢溴酸、盐酸、氢氟酸或氢碘酸)、硝酸、磷酸、氨基磺酸和硫酸。源于医药学上可接受的有机酸的盐包括以下各酸的盐:脂肪族羟基酸(例如柠檬酸、葡糖酸、乙醇酸、乳酸、乳糖酸、苹果酸和酒石酸)、脂肪族单羧酸(例如乙酸、丁酸、甲酸、丙酸和三氟乙酸)、氨基酸(例如天冬氨酸和谷氨酸)、芳香族羧酸(例如苯甲酸、对氯苯甲酸、二苯基乙酸、龙胆酸(gentisic acid)、马尿酸(hippuric acid)和三苯基乙酸)、芳香族羟基酸(例如邻羟苯甲酸、对羟苯甲酸、1-羟基萘-2-甲酸和3-羟基萘-2-甲酸)、抗坏血酸、二羧酸(例如富马酸、马来酸、草酸和丁二酸)、葡萄糖醛酸、杏仁酸、粘液酸、烟酸、乳清酸、双羟萘酸、泛酸、磺酸(例如苯磺酸、樟脑磺酸、1,2-乙烷二磺酸(edisylic acid)、乙烷磺酸、羟乙磺酸、甲烷磺酸、萘磺酸、萘-1,5-二磺酸、萘-2,6-二磺酸和对甲苯磺酸)、昔萘酸(xinafoic acid)等。
如本文所用,术语“前药”打算意指在体内在生理条件下例如通过正常代谢过程转化成其活性形式的非活性(或活性显著较小)药物前体。这些化合物可能不必对NEP具有药理学活性,但可口服或肠胃外投与且此后在体内代谢,从而形成对NEP具有药理学活性的化合物。
术语“治疗有效量”意指当向有需要的患者投与时足以实现治疗的量,即为获得所要治疗效应所需的药物量。举例来说,治疗高血压的治疗有效量为例如减轻、遏制、消除或预防高血压的症状或治疗高血压的潜伏病因所需的化合物量。在一个实施例中,治疗有效量为降低血压所需的药物量或维持正常血压所需的药物量。在另一方面,术语“有效量”意指足以获得可能未必为治疗结果的所要结果的量。举例来说,当研究包含NEP酶的系统时,“有效量”可为抑制所述酶所需的量。
如本文所用的术语“治疗(treating)”或“治疗(treatment)”意指治疗患者,如哺乳动物(尤其为人类)的疾病或医学病状(如高血压),此包括以下一或多个方面:(a)预防疾病或医学病状发生,即预防疾病或医学病状复发或预防性治疗易于患有疾病或医学病状的患者;(b)改善疾病或医学病状,即消除患者的疾病或医学病状或使患者的疾病或医学病状消退;(c)遏制疾病或医学病状,即减缓或遏止患者的疾病或医学病状的发展;或(d)减轻患者的疾病或医学病状的症状。举例来说,术语“治疗高血压”将包括预防高血压发生、改善高血压、遏制高血压和减轻高血压的症状(例如降低血压)。术语“患者”打算包括需要治疗或疾病预防或目前正接受治疗以达成疾病预防或治疗特定疾病或医学病状的哺乳动物(如人类)以及在分析中评估或使用结晶化合物的测试个体,例如动物模型。
本文中使用的所有其它术语都打算具有如其所属领域的技术人员所了解的其一般含义。
本发明化合物含有一或多个手性中心且因此这些化合物可以各种立体异构形式制备和使用。在一些实施例中,为了优化本发明化合物的治疗活性,例如治疗高血压,可能希望的是碳原子具有特定(R,R)、(S,S)、(S,R)或(R,S)构型或富含具有所述构型的立体异构体。在其它实施例中,本发明化合物以外消旋化合物形式存在。因此,除非另外指示,否则本发明还涉及外消旋混合物、纯立体异构体(例如对映异构体和非对映异构体)、立体异构体富集混合物等。当在本文中描述无任何立体化学的化学结构时,应了解此结构涵盖所有可能的立体异构体。类似地,当在本文中展示或命名特定立体异构体时,所属领域的技术人员应了解除非另外指示,否则少量其它立体异构体可能存在于本发明组合物中,其限制条件为组合物的总体效用不因存在这些其它异构体而消除。个别立体异构体可通过此项技术中熟知的众多方法获得,包括使用适合手性固定相或支撑物的手性色谱获得,或通过将其以化学方式转化成非对映异构体,利用如色谱或再结晶的常规手段分离非对映异构体,接着再生原始立体异构体获得。
另外,除非另外规定,否则当适用时,本发明化合物的所有顺-反或E/Z异构体(几何异构体)、互变异构形式和拓扑异构形式都包括在本发明的范围内。
本发明化合物以及其合成中使用的化合物还可包括经同位素标记的化合物,即其中一或多个原子已用具有不同于在自然界中主要所见的原子质量的原子质量的原子富集。可并入式I化合物中的同位素的实例例如包括(但不限于)2H、3H、13C、14C、15N、18O、17O、35S、36Cl和18F。特别相关的是可用于例如组织分布研究中的富含氚或碳-14的式I化合物;尤其在产生例如具有较大代谢稳定性的化合物的代谢部位处的富含氘的本发明化合物;和可用于例如正电子发射断层成像(Positron Emission Topography,PET)研究中的富含正电子发射同位素(如11C、18F、15O和13N)的式I化合物。
本文中用于命名本发明化合物的命名法在本文的实例中加以说明。此命名法已使用市售AutoNom软件(加利福尼亚州圣莱安德罗的MDL公司(MDL,San Leandro,California))获得。
美国专利公开案第2012/0157386号特别公开了(R)-3-{N-(5′-氯-2′-氟联苯-4-基甲基)-N′-[1-(3-氯苯基)-5-氧代-4,5-二氢-1H-[1,2,4]三唑-3-羰基]肼基}-2-羟基丙酸,其由式I′表示:
在一个实施例中,这种化合物被认为是活性形式且作为前药投与,其在体内代谢以形成式I′化合物。这种化合物还可以其互变异构体形式(R)-3-{N-(5′-氯-2′-氟联苯-4-基甲基)-N′-[1-(3-氯苯基)-5-羟基-1H-[1,2,4]三唑-3-羰基]肼基}-2-羟基丙酸存在。
本发明的一个方面涉及式I'化合物的其它前药。这些前药由式X表示,其中Ra是F,Rb是Cl,且X是:
在一个实施例中,这些化合物由式Ia或Ib表示:
对于式Ia化合物,R2是H且R7是选自-CH2CH3、-CH2CH(CH3)2、-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基和
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R7是H;其中每一Rc独立地是H或-C1-3烷基;每一Rd独立地是H、-CH3、-CH(CH3)2、苯基或苯甲基;且每一Re独立地是H、-C1-6烷基或苯基;或其医药学上可接受的盐。对于式Ib化合物,R2是H,R3是-OH,且R7是选自-CH2OC(O)CH3和-CH2OC(O)CH[CH(CH3)2]NH2;或R2是H,R3是选自-OCH2OC(O)CH3和-OCH2OC(O)CH[CH(CH3)2]NH2,且R7是H;其中每一Rc独立地是H或-C1-3烷基;每一Rd独立地是H、-CH3、-CH(CH3)2、苯基或苯甲基;且每一Re独立地是H、-C1-6烷基或苯基;或其医药学上可接受的盐。
在式Ia化合物的一个具体实施例中,R2是H且R7是选自-CH2CH3和-CH2CH(CH3)2。在式Ib化合物的一个具体实施例中,R2是H,R3是-OH,且R7是选自-CH2OC(O)CH3和-CH2OC(O)CH[CH(CH3)2]NH2;或R2是H,R3是选自-OCH2OC(O)CH3和-OCH2OC(O)CH[CH(CH3)2]NH2,且R7是H。
化合物(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N′-(2-羟基噻唑-5-羰基)肼基]-2-羟基丙酸也特别公开于美国专利公开案第2012/0157386号中,且由式II′化合物表示:
在一个实施例中,这种化合物被认为是活性形式且作为前药投与,其在体内代谢以形成式II′化合物。美国专利公开案第2012/0157386号还公开了式II′化合物的异丁酯前药。
本发明的另一方面涉及式II′化合物的其它前药。这些前药由式X表示,其中Ra是F,Rb是Cl,且X是:
在一个实施例中,这些化合物由式II表示:
其中R2是H且R7是选自-CH2CH3、-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基和
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R7是H;其中每一Rc独立地是H或-C1-3烷基;每一Rd独立地是H、-CH3、-CH(CH3)2、苯基或苯甲基;且每一Re独立地是H、-C1-6烷基或苯基;或其医药学上可接受的盐。
在式II化合物的一个具体实施例中,R2是H且R7是-CH2CH3。
化合物(R)-3-{N-(5'-氯-2'-氟联苯-4-基甲基)-N'-[3-(2-氟苯基)异噁唑-5-羰基]-肼基}-2-羟基丙酸也特别公开于美国专利公开案第2012/0157386号中,且由式III′化合物表示:
在一个实施例中,这种化合物被认为是活性形式且作为前药投与,其在体内代谢以形成式III′化合物。美国专利公开案第2012/0157386号还公开了式III'化合物的乙酯和吗乙酯前药。
本发明的另一方面涉及式III'化合物的其它前药。这些前药由式X表示,其中Ra是F,Rb是Cl,且X是:
在一个实施例中,这些化合物由式III表示:
其中R2是H且R7是选自-CH2CH(CH3)2、-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基和
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R7是H;其中每一Rc独立地是H或-C1-3烷基;每一Rd独立地是H、-CH3、-CH(CH3)2、苯基或苯甲基;且每一Re独立地是H、-C1-6烷基或苯基;或其医药学上可接受的盐。
在式III化合物的一个具体实施例中,R2是H且R7是选自-CH2CH(CH3)2、-CH2CF2CF3、-(CH2)2OCH3、-CH2OC(O)CH3、-CH2OC(O)(CH2)2CH3、-CH2OC(O)OCH2CH3、-CH2OC(O)OCH(CH3)2、-CH(CH3)OC(O)O-环己基、-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和
或R2是-P(O)(OH)2且R7是H。
化合物(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)肼基]-2-羟基丙酸也特别公开于美国专利公开案第2012/0157386号中,且由式IV'化合物表示:
在一个实施例中,这种化合物被认为是活性形式且作为前药投与,其在体内代谢以形成式IV'化合物。美国专利公开案第2012/0157386号还公开了式IV'化合物的乙酯、异丙酯和异丁酯前药。
本发明的另一方面涉及式IV'化合物的其它前药。这些前药由式X表示,其中Ra是F,Rb是Cl,且X是:
其中R是H或-CH3。在一个实施例中,这些化合物由IV表示:
其中R2是H且R7是选自-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基、
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R7是H;或R2是-C(O)CH2NH2且R7是-CH2CH3;其中每一Rc独立地是H或-C1-3烷基;每一Rd独立地是H、-CH3、-CH(CH3)2、苯基或苯甲基;且每一Re独立地是H、-C1-6烷基或苯基;或其医药学上可接受的盐。
在式IV化合物的一个具体实施例中,R是-CH3,R2是H,且R7是选自-CH2CF2CF3、-(CH2)2OCH3、-CH2OC(O)CH3、-CH2OC(O)-(CH2)2CH3、-CH2OC(O)OCH2CH3、-CH2OC(O)OCH(CH3)2、-CH(CH3)OC(O)O-环己基、-CH2OC(O)CH[CH(CH3)2]NH2、-CH2OC(O)CH[CH(CH3)2]NHC(O)OCH3、
在式IV化合物的另一具体实施例中,R是-CH3;R2是选自-C(O)CH2CH3、-C(O)CH2NH2、-C(O)CH(CH3)NH2、-C(O)CH[CH(CH3)2]-NH2和-C(O)CH[CH(CH3)2]-NHC(O)OCH3;且R7是H。在式IV化合物的另一具体实施例中,R是-CH3,R2是-C(O)CH2NH2,且R7是-CH2CH3。
化合物(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(5-氧代-1-苯基-4,5-二氢-1H-[1,2,4]三唑-3-羰基)肼基]-2-羟基丙酸也特别公开于美国专利公开案第2012/0157386号中,且由式V'化合物表示:
在一个实施例中,这种化合物被认为是活性形式且作为前药投与,其在体内代谢以形成式V'化合物。
本发明的另一方面涉及式V'化合物的其它前药。这些前药由式X表示,其中Ra是F,Rb是Cl,且X是:
在一个实施例中,这些化合物由式V表示:
其中R2是H且R7是选自-CH2CH3、-CH2CH(CH3)2、-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcO-C(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基和
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R7是H;其中每一Rc独立地是H或-C1-3烷基;每一Rd独立地是H、-CH3、-CH(CH3)2、苯基或苯甲基;且每一Re独立地是H、-C1-6烷基或苯基;或其医药学上可接受的盐。
在式V化合物的一个具体实施例中,R2是H且R7是选自-CH2CH3、-CH2CH(CH3)2、-CH2CF2CF3、-CH2OC(O)CH3、-CH2OC(O)-(CH2)2CH3、-CH2OC(O)OCH2CH3、-CH2OC(O)OCH(CH3)2、-CH(CH3)OC(O)O-环己基、-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和
本发明的另一方面涉及式X化合物,其中Ra是F,Rb是Cl,且X是:
在一个实施例中,这些化合物由式VIa或VIb表示:
其中R2和R4是H,且R7是选自H、-CH2CH3、-CH2CH(CH3)2、-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)-CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)-CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基、
或R2是H,R4是选自-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和-CH2OC(O)CH[CH(CH3)2]NH2,且R7是H;或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,R4是H,且R7是H;或R2是H,R4是-CH2OP(O)(ORe)2或-CH2OC(O)CH[CH(CH3)2]NH2,且R7是-CH2CH3或-CH2CH(CH3)2;或R2是-C(O)CH[CH(CH3)2]NH2,R4是H,且R7是-CH2CH3或-CH2CH(CH3)2;其中每一Rc独立地是H或-C1-3烷基;每一Rd独立地是H、-CH3、-CH(CH3)2、苯基或苯甲基;且每一Re独立地是H、-C1-6烷基或苯基;或其医药学上可接受的盐。
在式VIa和VIb化合物的一个具体实施例中,R2是H,R4是H,且R7是选自H、-CH2CH3、-CH2CH(CH3)2、-CH2CF2CH3、-(CH2)2O-CH3、-CH2OC(O)OCH2CH3、-(CH2)2-N(CH3)2、-(CH2)3-N(CH3)2、-(CH2)4-N(CH3)2、-CH2OC(O)CH[CH(CH3)2]NH2、
在式VIa和VIb化合物的另一实施例中,R2是H,R4是选自-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和-CH2OC(O)CH[CH(CH3)2]-NH2,且R7是H。在式VIa和VIb化合物的另一具体实施例中,R2是选自-C(O)CH3、-C(O)CH(CH3)2和-C(O)CH2CH(CH3)2,R4是H,且R7是H。
在式VIa和VIb化合物的另一实施例中,R2是H,R4是-CH2-OP(O)(OH)2或-CH2OC(O)CH[CH(CH3)2]NH2,且R7是-CH2CH3或-CH2CH(CH3)2。
在式VIa和VIb化合物的另一实施例中,R2是-C(O)CH[CH(CH3)2]NH2,R4是H,且R7是-CH2CH3或-CH2CH(CH3)2。
化合物(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N′-(1H-四唑-5-羰基)肼基]-2-羟基丙酸也特别公开于美国专利公开案第2012/0157386号中,且由式VII'化合物表示:
在一个实施例中,这种化合物被认为是活性形式且作为前药投与,其在体内代谢以形成式VII'化合物。如此的化合物可以互变异构体形式存在,例如,作为(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(2H-四唑-5-羰基)肼基]-2-羟基丙酸。美国专利公开案第2012/0157386号还公开了式VII'化合物的乙酯、异丙酯和异丁酯前药。
本发明的另一方面涉及式VII'化合物的其它前药。这些前药由式X表示,其中Ra是F,Rb是Cl,且X是:
在一个实施例中,这些化合物由式VIIa或VIIb表示:
其中R2和R4是H,且R7是选自-CH2CF3、-(CH2)2CF3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基和
或R2是H,R4是选自-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和-CH2OC(O)CH[CH(CH3)2]NH2,且R7是选自H和-CH2CH3;或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R4和R7是H;其中每一Rc独立地是H或-C1-3烷基;每一Rd独立地是H、-CH3、-CH(CH3)2、苯基或苯甲基;且每一Re独立地是H、-C1-6烷基或苯基;或其医药学上可接受的盐。
在式VIIa和VIIb化合物的一个具体实施例中,R2和R4是H,且R7是选自-CH2CF2CF3、-CH2OC(O)CH3、-CH2OC(O)CH2CH3、-CH2OC(O)(CH2)2CH3、-CH2OC(O)OCH(CH3)2、-CH2OC(O)CH[CH(CH3)2]NH2、-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和
在式VIIa和VIIb化合物的另一实施例中,R2是H,R4是-CH2OC(O)CH[CH(CH3)2]NH2,且R7是-CH2CH3。在式VIIa和VIIb化合物的另一实施例中,或R2是选自-C(O)CH3、-C(O)CH2CH3、-C(O)CH[CH(CH3)2]NH2和-C(O)CH[CH(CH3)2]NHC(O)OCH3,且R4和R7是H。
化合物(R)-3-[N-(3'-氯联苯-4-基甲基)-N'-(3-羟基-异噁唑-5-羰基)肼基]-2-羟基丙酸也特别公开于美国专利公开案第2012/0157386号中,且由式VIII'化合物表示:
在一个实施例中,这种化合物被认为是活性形式且作为前药投与,其在体内代谢以形成式VIII'化合物。美国专利公开案第2012/0157386号还公开了式VIII′化合物的乙酯、异丙酯、丁酯、异丁酯、己酯、庚酯、苯甲酯、酯(medoxomil ester)、2-氟-1-氟甲基-乙酯和2,2,3,3,3-五氟丙酯前药。
本发明的另一方面涉及式VIII'化合物的其它前药。这些前药由式X表示,其中Ra是H,Rb是Cl,且X是:
在一个实施例中,这些化合物由式VIII表示:
其中R2是H,R3是-OH,且R7是选自-CH2CF3、-(CH2)2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CH[CH(CH3)2]NH2和-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3;或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,R3是-OH,且R7是H;或R2是H,R3是选自-OCHRcOC(O)-C1-4烷基、-OCH2OC(O)CH[CH(CH3)2]NH2、-OCH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和
且R7是H;其中每一Rc独立地是H或-C1-3烷基;每一Rd独立地是H、-CH3、-CH(CH3)2、苯基或苯甲基;且每一Re独立地是H、-C1-6烷基或苯基;或其医药学上可接受的盐。
在式VIII化合物的一个具体实施例中,R2是H,R3是-OH,且R7是选自-CH2OC(O)CH3、-CH2OC(O)CH[CH(CH3)2]NH2和-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3。在式VIII化合物的另一具体实施例中,R2是选自-C(O)CH2CH3、-C(O)CH2CH(CH3)2、-C(O)CH[CH(CH3)2]NH2和-C(O)CH[CH(CH3)2]-NHC(O)OCH3,R3是-OH,且R7是H。在式VIII化合物的另一具体实施例中,R2是H,R3是选自-OCH2OC(O)CH3、-OCH2OC(O)(CH2)2CH3、-OCH2OC(O)OCH2CH3、-OCH2OC(O)OCH(CH3)2、-OCH2OC(O)CH[CH(CH3)2]NH2、-OCH2OC(O)-CH[CH(CH3)2]NHC(O)OCH3和
且R7是H。
化合物(R)-3-[N-(2',5'-二氯联苯-4-基甲基)-N'-(1-羟基-1H-[1,2,3]三唑-4-羰基)肼基]-2-羟基丙酸也特别公开于美国专利公开案第2012/0157386号中,且由式IX′化合物表示:
在一个实施例中,这种化合物被认为是活性形式且作为前药投与,其在体内代谢以形成式IX′化合物。美国专利公开案第2012/0157386号还公开了式IX′化合物的异丙酯、异丁酯和庚酯前药。
本发明的另一方面涉及式IX′化合物的其它前药。这些前药由式X表示,其中Ra是Cl,Rb是Cl,且X是:
在一个实施例中,这些化合物由式IXa或IXb表示:
其中R2是H,R4是-OH,且R7是选自-CH2CF3、-(CH2)2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2-OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基和
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,R4是-OH,且R7是H;或R2是H,R4是选自-OCHRcOC(O)-C1-4烷基、-OCH2OC(O)CH[CH(CH3)2]NH2、-OCH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和
且R7是H;其中每一Rc独立地是H或-C1-3烷基;每一Rd独立地是H、-CH3、-CH(CH3)2、苯基或苯甲基;且每一Re独立地是H、-C1-6烷基或苯基;或其医药学上可接受的盐。
在式IXa和IXb化合物的一个具体实施例中,R2是H,R4是-OH且R7是选自-CH2OC(O)CH3、-CH2OC(O)(CH2)2CH3、-CH2OC(O)-OCH2CH3、-CH2OC(O)OCH(CH3)2、-CH(CH3)OC(O)O-环己基、-CH2OC(O)-CH[CH(CH3)2]NHC(O)OCH3和
在式IXa和IXb化合物的另一实施例中,R2是H,R4是选自-OCH2OC(O)CH3、-OCH2OC(O)(CH2)2CH3、-OCH2OC(O)CH[CH(CH3)2]-NH2、-OCH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和
且R7是H。
一般合成程序
本发明化合物可使用下列一般方法、实例中阐述的程序从易于获得的起始物质制备,或使用所属领域的技术人员已知的其它方法、试剂和起始物质加以制备。尽管下列程序可说明本发明的特定实施例,但应了解本发明的其它实施例可使用相同或类似方法或通过使用所属领域的技术人员已知的其它方法、试剂和起始物质类似地加以制备。还应了解除非另外陈述,否则在指定典型或优选加工条件(例如反应温度、时间、反应物的摩尔比、溶剂、压力等)的情况下,也可使用其它加工条件。在一些情况下,在室温下进行反应且未获取实际温度测量结果。应了解室温可用以意指通常与实验室环境中的环境温度相关的范围内的温度且通常将在约18℃到约30℃的范围内。在其它情况下,在室温下进行反应且实际测量并记录温度。尽管最佳反应条件将通常视所用的各种反应参数,如特定反应物、溶剂和数量而变化,但所属领域的技术人员可易于使用常规最佳化程序确定适合的反应条件。
另外,如将为所属领域的技术人员显而易知,常规保护基可为防止某些官能团经历不合需要的反应所必需或所需要。选择适用于特定官能团的保护基以及适用于保护这些官能团和脱除其保护基的条件和试剂在此项技术中已熟知。必要时,可使用除本文所述的程序中说明的保护基以外的保护基。举例来说,众多保护基和其引入和去除描述于T.W.格林(T.W.Greene)和G.M.瓦兹(G.M.Wuts),有机合成中的保护基(Protecting Groups inOrganic Synthesis),第四版,纽约的威利出版社(Wiley,New York),2006和其中引用的参考文献中。
羧基保护基适于防止羧基处发生不合需要的反应,且实例包括(但不限于)甲基、乙基、叔丁基、苯甲基(Bn)、对甲氧基苯甲基(PMB)、9-芴基甲基(Fm)、三甲基硅烷基(TMS)、叔丁基二甲基硅烷基(TBDMS)、二苯基甲基(二苯甲基,DPM)等。氨基保护基适于防止氨基处发生不合需要的反应,且实例包括(但不限于)叔丁氧基羰基(BOC)、三苯甲基(Tr)、苯甲氧基羰基(Cbz)、9-芴基甲氧基羰基(Fmoc)、甲酰基、三甲基硅烷基(TMS)、叔丁基二甲基硅烷基(TBDMS)等。
标准脱除保护基技术和试剂用于去除保护基,且可视所用基团而变化。举例来说,氢氧化钠或氢氧化锂通常在羧基保护基为甲基时使用,如TFA或HCl的酸(例如含4.0M HCl的1,4-二噁烷)通常在羧基保护基为乙基或叔丁基时使用,且H2/Pd/C可在羧基保护基为苯甲基时使用。BOC氨基保护基可使用酸性试剂,如含TFA的DCM或含HCl的1,4-二噁烷加以去除,而Cbz氨基保护基可通过采用催化氢化条件,如H2(1个大气压)和10%Pd/C于醇性溶剂中(“H2/Pd/C”)加以去除。
离去基团为可在取代反应(如亲核取代反应)中由另一个官能团或原子取代的官能团或原子。举例来说,代表性离去基团包括氯基、溴基和碘基;磺酸酯基,如甲磺酸酯、甲苯磺酸酯、溴苯磺酸酯、硝基苯磺酸酯等;和酰氧基,如乙酰氧基、三氟乙酰氧基等。
适用于这些流程中的碱(通过说明而非限制的方式)包括碳酸钾、碳酸钙、碳酸钠、三乙胺(Et3N)、吡啶、1,8-二氮杂二环-[5.4.0]十一-7-烯(DBU)、N,N-二异丙基乙胺(DIPEA)、4-甲基吗啉、氢氧化钠、氢氧化钾、叔丁醇钾和金属氢化物。
适用于这些流程中的惰性稀释剂或溶剂(通过说明而非限制的方式)包括四氢呋喃(THF)、乙腈(MeCN)、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、二甲亚砜(DMSO)、甲苯、二氯甲烷(DCM)、氯仿(CHCl3)、四氯化碳(CCl4)、1,4-二噁烷、甲醇、乙醇、水、乙醚、丙酮等。
适合的羧酸/胺偶合试剂包括六氟磷酸苯并三唑-1-基氧基三(二甲氨基)鏻(BOP)、六氟磷酸苯并三唑-1-基氧基三(N-吡咯烷基)鏻(PyBOP)、六氟磷酸N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)脲(HATU)、1,3-二环己基碳化二亚胺(DCC)、N-(3-二甲氨基丙基)-N'-乙基碳化二亚胺(EDC)、羰基二咪唑(CDI)、1-羟基苯并三唑(HOBt)等。偶合反应是在如DIPEA的碱存在下于惰性稀释剂中进行,且在常规酰胺键形成条件下进行。
所有反应都通常在约-78℃到100℃的范围内的温度下,例如在室温下进行。反应可通过使用薄层色谱(TLC)、高效液相色谱(HPLC)和/或LCMS来监测直到完成。反应可在数分钟内完成,或可花费数小时,通常1到2小时且长达48小时。在完成后,所得混合物或反应产物可进一步处理以获得所要产物。举例来说,可对所得混合物或反应产物执行一或多个下列程序:浓缩或分配(例如分配于EtOAc与水之间或分配于含5%THF的EtOAc与1M磷酸之间);萃取(例如用EtOAc、CHCl3、DCM、氯仿萃取);洗涤(例如用NaCl饱和水溶液、NaHCO3饱和水溶液、Na2CO3(5%)、CHCl3或1M NaOH洗涤);干燥(例如经MgSO4、Na2SO4干燥或真空干燥);过滤;结晶(例如从EtOAc和己烷结晶);浓缩(例如真空浓缩);和/或纯化(例如硅胶色谱、快速色谱、制备型HPLC、反相HPLC或结晶)。
通过说明的方式,本发明化合物以及其盐可如流程I-IV中所示加以制备。
流程I
流程I是酯交换反应。一般来说,这种反应涉及使酯在加热、所需醇(HO-R7)和适合的酸催化剂(例如盐酸)下反应。HO-R7醇是市售的或可通过此项技术中已知或本文中所述的技术制备。示例性HO-R7化合物包括HO-CH2CF3、HO-(CH2)2CF3、HO-CH2CF2CH3、HO-CH2CF2CF3、HO-C(CH3)(CF3)2、HO-CH(CH2CH3)CF3、HO-CH(CH3)CF2CF3、苯甲醇和
流程II
流程II是亲核取代反应,其中L是适合的离去基团。一般来说,这种反应在适合的碱(如三乙胺)存在下在适合的惰性稀释剂或溶剂(如丙酮)中进行。L-R7化合物是市售的或可通过此项技术中已知或本文中所述的技术制备。示例性L-R7化合物包括Br-(CH2)2OH、Br-(CH2)3OH、Br-(CH2)2OCH3、Br-CH2OC(O)CH3、Cl-CH2OC(O)(CH2)2CH3、Cl-CH2OC(O)OCH2CH3、Cl-CH2OC(O)OCH(CH3)2、Cl-CH2OC(O)O-环己基、(S)-2-苯甲氧基羰基氨基-3-甲基-丁酸氯甲酯和(S)-2-叔丁氧基羰基氨基-3-甲基-丁酸氯甲酯。
或者,在流程II中,醇已代替L-R7(例如HO-C2-4亚烷基-N(CH3)2)用于使用HOBt和EDC的偶合反应中。
流程III
流程III是亲核取代反应,其中L是适合的离去基团。一般来说,这种反应在适合的碱(如N,N-二异丙基乙胺)存在下在适合的惰性稀释剂或溶剂(如二氯甲烷)中进行。L-R2化合物是市售的或可通过此项技术中已知或本文中所述的技术制备。示例性L-R2化合物包括Cl-C(O)-CH3、Cl-C(O)-CH(CH3)2和Cl-C(O)-CH2CH(CH3)2。
流程IV
流程IV是偶合反应,其中P是H或适合的氨基保护基。当P是氨基保护基时,所述方法进一步包含在偶合步骤前面或原位将化合物脱除保护基。示例性偶合试剂包括HATU和HOBt与EDC。一般来说,这些反应在碱(如DIPEA或4-甲基吗啉)和惰性稀释剂或溶剂(如DMF或DMA)存在下进行。羧酸起始物质一般是市售的或可使用此项技术中已知的程序制备。
关于制备本发明的代表性化合物或其中间物的特定反应条件和其它程序的其它详情在下述实例中加以描述。
效用
式I'-V'和VII'-IX'化合物具有作为脑啡肽酶抑制剂的活性,且预计具有作为脑啡肽酶抑制剂的治疗效用。这些化合物的前药一旦在体内代谢预期即会具有相同效用。因此,当论述本发明化合物的活性时,应理解这些前药一旦代谢即具有预期的活性。
示例性分析(通过说明而非限制的方式)包括测量NEP抑制的分析。适用的二级分析包括测量ACE抑制和氨基肽酶P(APP)抑制(例如,如描述于苏尔皮齐奥(Sulpizio)等人(2005)药理学与实验治疗学杂志(JPET)315:1306-1313中)的分析。评估对麻醉大鼠中ACE和NEP的体内抑制效能的药效学分析描述于西摩(Seymour)等人(1985)高血压(Hypertension)7(增刊I):I-35-I-42和维格勒(Wigle)等人(1992)加拿大生理学和药理学杂志(Can.J.Physiol.Pharmacol.)70:1525-1528),其中ACE抑制被测量为血管紧张素I升压反应的抑制百分比且NEP抑制被测量为尿环鸟苷3',5'-单磷酸(cGMP)输出量的增加。
还存在可使用的许多体内分析。有知觉的自发性高血压大鼠(SHR)模型为一种肾素(renin)依赖性高血压模型。参见例如因特甘(Intengan)等人(1999)循环(Circulation)100(22):2267-2275和百德亚(Badyal)等人(2003)印度药理学杂志(Indian Journal ofPharmacology)35:349-362。有知觉的乙酸脱氧皮质酮-盐(DOCA-盐)大鼠模型为一种适用于测量NEP活性的容量依赖性高血压模型。参见例如特拉帕尼(Trapani)等人(1989)心血管药理学杂志(J.Cardiovasc.Pharmacol.)14:419-424;因特甘等人(1999)高血压34(4):907-913和百德亚等人(2003)(同上)。DOCA-盐模型特别适用于评估测试化合物降低血压的能力以及测量测试化合物预防或延迟血压上升的能力。Dahl盐敏感性(DSS)高血压大鼠模型为一种对膳食性盐(NaCl)敏感的高血压模型,且描述于例如拉普(Rapp)(1982)高血压4:753-763中。描述于例如加藤(Kato)等人(2008)心血管药理学杂志51(1):18-23中的大鼠野百合碱(monocrotaline)肺动脉高血压模型为一种治疗肺动脉高血压的临床功效的可靠预测模型。心脏衰竭动物模型包括心脏衰竭的DSS大鼠模型和主动脉-腔静脉瘘模型(动静脉短路(AV shunt)),其中后者描述于例如诺林(Norling)等人(1996)美国肾脏病学会杂志(J.Amer.Soc.Nephrol.)7:1038-1044中。其它动物模型(如热板、甩尾(tail-flick)和福尔马林(formalin)测试)以及神经病变性疼痛的脊神经结扎(SNL)模型可用于测量化合物的止痛性质。参见例如马姆伯格(Malmberg)等人(1999)神经科学实验室指南(CurrentProtocols in Neuroscience)8.9.1-8.9.15。化合物的其它性质和效用可使用所属领域的技术人员熟知的各种体外和体内分析加以证实。
预期本发明化合物适用于治疗和/或预防对NEP抑制起反应的医学病状。因此,预期罹患通过抑制NEP酶或通过增加其肽底物的含量而得以治疗的疾病或病症的患者可通过投与治疗有效量的本发明化合物加以治疗。举例来说,预期化合物通过抑制NEP可增强NEP代谢产生的内源性肽(如利钠肽、铃蟾素(bombesin)、缓激肽、降钙素(calcitonin)、内皮素(endothelin)、脑啡肽、神经降压素(neurotensin)、物质P和血管活性肠肽(vasoactiveintestinal peptide))的生物效应。因此,预期化合物例如对肾系统、中枢神经系统、生殖系统和胃肠系统具有其它生理作用。
心血管疾病
预期本发明化合物可通过增强血管活性肽,如利钠肽和缓激肽的效应而适用于治疗和/或预防如心血管疾病的医学病状。参见例如罗克斯(Roques)等人(1993)药理学评论(Pharmacol.Rev.)45:87-146和登普西(Dempsey)等人(2009)美国病理学杂志(Amer.J.ofPathology)174(3):782-796。特别相关的心血管疾病包括高血压和心脏衰竭。高血压(通过说明而非限制的方式)包括:原发性高血压,其也称为本态性高血压或特发性高血压;继发性高血压;伴有肾病的高血压;伴有或不伴有肾病的重度高血压;肺高血压,包括肺动脉高血压;和顽固性高血压。心脏衰竭(通过说明而非限制的方式)包括:充血性心脏衰竭;急性心脏衰竭;慢性心脏衰竭,例如伴有左心室射血分数降低(也称为收缩性心脏衰竭)或伴有左心室射血分数保持(也称为舒张性心脏衰竭);和急性和慢性代偿失调心脏衰竭,伴有或不伴有肾病。因此,本发明的一个实施例涉及一种治疗高血压,具体来说原发性高血压或肺动脉高血压的方法,其包含向患者投与治疗有效量的本发明化合物。
对于治疗原发性高血压,治疗有效量通常为足以降低患者的血压的量。此包括轻度到中度高血压与重度高血压两者。当用于治疗高血压时,化合物可与其它治疗剂组合投与,所述其它治疗剂如醛固酮(aldosterone)拮抗剂、血管紧张素转化酶抑制剂和双重作用性血管紧张素转化酶/脑啡肽酶抑制剂、血管紧张素转化酶2(ACE2)活化剂和刺激剂、血管紧张素II疫苗、抗糖尿病药剂、抗脂质药剂、抗血栓药剂、AT1受体拮抗剂和双重作用性AT1受体拮抗剂/脑啡肽酶抑制剂、β1-肾上腺素能受体拮抗剂、双重作用性β-肾上腺素能受体拮抗剂/α1-受体拮抗剂、钙通道阻断剂、利尿剂、内皮素受体拮抗剂、内皮素转化酶抑制剂、脑啡肽酶抑制剂、利钠肽和其类似物、利钠肽清除受体拮抗剂、一氧化氮供体、非类固醇消炎剂、磷酸二酯酶抑制剂(具体来说是PDE-V抑制剂)、前列腺素(prostaglandin)受体激动剂、肾素抑制剂、可溶性鸟苷酸环化酶(guanylate cyclase)刺激剂和活化剂、和其组合。在本发明的一个特定实施例中,本发明化合物与AT1受体拮抗剂、利尿剂、钙通道阻断剂或其组合组合且用于治疗原发性高血压。在本发明的另一特定实施例中,本发明化合物与AT1受体拮抗剂组合且用于治疗伴有肾病的高血压。
对于治疗肺动脉高血压,治疗有效量通常为足以降低肺血管阻力的量。疗法的其它目的在于改良患者的运动能力。举例来说,在一个临床配置中,治疗有效量可为改良患者舒适步行6分钟的时期(涵盖约20米到40米的距离)的能力的量。当用于治疗肺动脉高血压时,化合物可与其它治疗剂组合投与,所述其它治疗剂如α-肾上腺素能拮抗剂、β1-肾上腺素能受体拮抗剂、β2-肾上腺素能受体激动剂、血管紧张素转化酶抑制剂、抗凝剂、钙通道阻断剂、利尿剂、内皮素受体拮抗剂、PDE-V抑制剂、前列腺素类似物、选择性血清素再摄取抑制剂和其组合。在本发明的一个特定实施例中,本发明化合物与PDE-V抑制剂或选择性血清素再摄取抑制剂组合且用于治疗肺动脉高血压。
本发明的另一实施例涉及一种治疗心脏衰竭,具体来说充血性心脏衰竭(包括收缩性与舒张性充血性心脏衰竭两者)的方法,其包含向患者投与治疗有效量的本发明化合物。通常,治疗有效量为足以降低血压和/或改良肾功能的量。在一个临床配置中,治疗有效量可为足以改良心脏血液动力学,如例如降低楔压(wedge pressure)、右心房压力、填充压和血管阻力的量。在一个实施例中,化合物是以静脉内剂型投与。当用于治疗心脏衰竭时,化合物可与其它治疗剂组合投与,所述其它治疗剂如腺苷受体拮抗剂、晚期糖基化终末产物裂解剂、醛固酮拮抗剂、AT1受体拮抗剂、β1-肾上腺素能受体拮抗剂、双重作用性β-肾上腺素能受体拮抗剂/α1-受体拮抗剂、糜酶(chymase)抑制剂、地高辛(digoxin)、利尿剂、内皮素转化酶(ECE)抑制剂、内皮素受体拮抗剂、利钠肽和其类似物、利钠肽清除受体拮抗剂、一氧化氮供体、前列腺素类似物、PDE-V抑制剂、可溶性鸟苷酸环化酶活化剂和刺激剂、和血管加压素(vasopressin)受体拮抗剂。在本发明的一个特定实施例中,本发明化合物与醛固酮拮抗剂、β1-肾上腺素能受体拮抗剂、AT1受体拮抗剂或利尿剂组合,且用于治疗充血性心脏衰竭。
腹泻
预期本发明化合物可作为NEP抑制剂来抑制内源性脑啡肽的降解且因此这些化合物还可适用于治疗腹泻,包括感染性和分泌性/水性腹泻。参见例如鲍默(Baumer)等人(1992)肠道(Gut)33:753-758;法新(Farthing)(2006)消化疾病(Digestive Diseases)24:47-58;和马尔赛-科拉多(-Collado)(1987)欧洲药理学杂志(Eur.J.Pharmacol.)144(2):125-132。当用于治疗腹泻时,本发明化合物可与一或多种其它止泻疗法组合。
肾病
预期本发明化合物可通过增强血管活性肽,如利钠肽和缓激肽的效应来增强肾功能(参见陈(Chen)等人(1999)循环100:2443-2448;利普金(Lipkin)等人(1997)国际肾脏学(Kidney Int.)52:792-801;和迪索勒(Dussaule)等人(1993)临床科学(Clin.Sci.)84:31-39),且适用于治疗和/或预防肾病。特别相关的肾病包括糖尿病性肾病变、慢性肾脏疾病、蛋白尿,且尤其是急性肾损伤或急性肾衰竭(参见沙尔科夫斯基(Sharkovska)等人(2011)临床实验室(Clin.Lab.)57:507-515和纳瓦扎(Newaz)等人(2010)肾衰竭(Renal Failure)32:384-390)。当用于治疗肾病时,化合物可与其它治疗剂,如血管紧张素转化酶抑制剂、AT1受体拮抗剂和利尿剂组合投与。
预防性疗法
由于利钠肽具有抗肥大和抗纤维变性效应(参见波特(Potter)等人(2009)实验药理学手册(Handbook of Experimental Pharmacology)191:341-366),因此还预期本发明化合物可通过增强利钠肽的效应而适用于预防性疗法,例如心肌梗塞之后预防心机能不全的进展、血管成形术之后预防动脉再狭窄、血管手术之后预防血管壁变厚、预防动脉粥样硬化和预防糖尿病性血管病变。
青光眼
预期本发明化合物可通过增强利钠肽的效应而适用于治疗青光眼。参见例如迪斯特尔霍斯特(Diestelhorst)等人(1989)国际眼科学(International Ophthalmology)12:99-101。当用于治疗青光眼时,本发明化合物可与一或多种其它抗青光眼药剂组合。
减轻疼痛
预期本发明化合物可作为NEP抑制剂来抑制内源性脑啡肽的降解且因此这些化合物还可适用作止痛剂。参见例如罗克斯等人(1980)自然(Nature)288:286-288和蒂纳瓦拉(Thanawala)等人(2008)当代药靶(Current Drug Targets)9:887-894。当用于治疗疼痛时,本发明化合物可与一或多种其它镇痛药物组合,所述药物如氨基肽酶N或二肽基肽酶III抑制剂、非类固醇消炎剂、单胺再摄取抑制剂、肌肉松弛剂、NMDA受体拮抗剂、阿片样物质受体激动剂、5-HT1D血清素受体激动剂和三环抗抑郁剂。
其它效用
由于本发明化合物的NEP抑制性质,因此还预期其适用作止咳剂以及适用于治疗与以下相关的门静脉高血压:肝硬化(参见桑索(Sansoe)等人(2005)肝病学杂志(J.Hepatol.)43:791-798)、癌症(参见韦塞利(Vesely)(2005)研究医学杂志(J.Investigative Med.)53:360-365)、抑郁(参见诺布尔(Noble)等人(2007)治疗靶标专家意见(Exp.Opin.Ther.Targets)11:145-159)、月经失调、早产(preterm labor)、子痫前期(pre-eclampsia)、子宫内膜异位、生殖病症(例如男性和女性不育症、多囊性卵巢综合症、植入失败(implantation failure))和男性和女性性功能障碍,包括男性勃起功能障碍和女性性唤起病症。更具体来说,预期本发明化合物适用于治疗女性性功能障碍(参见普赖德(Pryde)等人(2006)医学化学杂志(J.Med.Chem.)49:4409-4424),其常定义为女性患者难以或不能对性表达感到满意。此涵盖多种不同的女性性功能障碍,(通过说明而非限制的方式)包括性欲减退病症(hypoactive sexual desire disorder)、性唤起病症、性高潮病症和性疼痛病症。当用于治疗这些病症,尤其女性性功能障碍时,本发明化合物可与一或多种下列第二药剂组合:PDE-V抑制剂、多巴胺(dopamine)激动剂、雌激素受体激动剂和/或拮抗剂、雄激素和雌激素。归因于本发明化合物的NEP抑制性质,还预期其具有消炎性质,且预期其具有如此效用,尤其与他汀类(statins)组合使用时。
新近研究表明在胰岛素缺乏性糖尿病和膳食诱发性肥胖症中,NEP在调节神经功能方面起作用。库佩(Coppey)等人(2011)神经药理学(Neuropharmacology)60:259-266。因此,归因于本发明化合物的NEP抑制性质,还预期其适用于提供预防由糖尿病或膳食诱发性肥胖症引起的神经损害。
本发明化合物的每剂投与量或每天总投与量可预先确定或其可基于个别患者通过考虑众多因素加以确定,所述因素包括患者病状的性质和严重性;所治疗的病状;患者的年龄、体重和一般健康状况;患者对活性药剂的耐受性;投药途径;药理学考虑,如所投与的化合物和任何第二药剂的活性、功效、药物动力学和毒理学概况;等。治疗罹患疾病或医学病状(如高血压)的患者可以预定剂量或由治疗医师确定的剂量开始,且将持续一段为预防、改善、遏制或减轻疾病或医学病状的症状所必需的时期。经受此治疗的患者通常将受常规监测以确定疗法的有效性。举例来说,在治疗高血压时,血压测量结果可用于确定治疗的有效性。本文所述的其它疾病和病状的类似指标已熟知且易由治疗医师获得。医师进行连续监测将确保将在任何既定时间投与最佳量的本发明化合物,以及有助于确定治疗的持续时间。当还投与第二药剂时,此举特别有价值,因为所述第二药剂的选择、剂量和疗法的持续时间也可能需要调整。以此方式,可在治疗过程中调整治疗方案和给药时程以便投与展现所要有效性的最低量活性药剂且另外,只要成功治疗疾病或医学病状必需,便可连续投药。
研究工具
因为本发明化合物在体内代谢成具有作为脑啡肽酶抑制剂的活性的化合物,故其还适用作探查或研究具有NEP酶的生物系统或样本的研究工具,以便例如研究NEP酶或其肽底物起作用的疾病。因此,本发明的一个方面涉及一种使用本发明化合物作为研究工具的方法,其包含使用本发明化合物进行生物分析。具有NEP酶的任何适合生物系统或样本都可用于可体外或体内进行的这些研究中。适于这些研究的代表性生物系统或样本包括(但不限于)细胞、细胞提取物、质膜、组织样本、经分离器官、哺乳动物(如小鼠、大鼠、豚鼠、兔、狗、猪、人类等)等,其中哺乳动物特别相关。在本发明的一个特定实施例中,哺乳动物中的NEP酶活性是通过投与NEP抑制量的本发明化合物而加以抑制的。这些化合物还可通过使用这些化合物进行生物分析而用作研究工具。
当用作研究工具时,通常使包含NEP酶的生物系统或样本与NEP酶抑制量的本发明化合物接触。在生物系统或样本暴露于化合物之后,使用常规程序和设备,如通过在结合分析中测量受体结合或在功能性分析中测量配体介导的变化来测定抑制NEP酶的效应。暴露涵盖使细胞或组织与化合物接触;例如通过腹膜内(i.p.)、口服(p.o)、静脉内(i.v.)、皮下(s.c.)或吸入投与等向哺乳动物投与结晶化合物。此测定步骤可涉及测量反应(定量分析)或可涉及进行观测(定性分析)。对反应进行测量涉及例如使用常规程序和设备,如酶活性分析来测定化合物对生物系统或样本的作用和在功能性分析中测量酶底物或产物介导的变化。分析结果可用于确定为实现所要结果所必需的化合物的活性程度以及量,即NEP酶抑制量。通常,测定步骤将涉及测定抑制NEP酶的效应。
另外,本发明化合物可用作评估其它化合物的研究工具,且因此还适用于筛选分析中以发现例如具有NEP抑制活性的新的化合物。因此,本发明的另一方面涉及一种在生物分析中评估测试化合物的方法,其包含:(a)用测试化合物进行生物分析以提供第一分析值;(b)用本发明化合物进行所述生物分析以提供第二分析值;其中步骤(a)是在步骤(b)之前、之后或与步骤(b)同时进行;和(c)将来自步骤(a)的所述第一分析值与来自步骤(b)的所述第二分析值进行比较。示例性生物分析包括NEP酶抑制分析。以此方式,将本发明化合物用作分析中的标准物,以允许比较用测试化合物获得的结果和用本发明化合物获得的结果,从而鉴别具有大约相等或较高活性的测试化合物(如果存在)。举例来说,对一种测试化合物或一组测试化合物的pKi数据与本发明化合物的pKi数据进行比较,从而鉴别具有所要性质的测试化合物,例如pKi值约等于或高于本发明化合物的测试化合物(如果存在)。本发明的此方面包括产生比较数据(使用适当分析)与分析测试数据两者作为各别实施例以鉴别相关测试化合物。
本发明的另一方面涉及一种研究包含NEP酶的生物系统或样本的方法,所述方法包含:(a)使所述生物系统或样本与本发明化合物接触;和(b)测定由所述化合物引起的对所述生物系统或样本的影响。
医药组合物和调配物
本发明化合物通常以医药组合物或调配物形式投与患者。这些医药组合物可通过任何可接受的投药途径投与患者,包括(但不限于)口服、经直肠、经阴道、经鼻、吸入、局部(包括经皮)、经眼和肠胃外投药模式。另外,本发明化合物可例如口服以每天多次剂量(例如每日两次、三次或四次)、单次每日剂量或单次每周剂量投与。应了解适于特定投药模式的本发明化合物的任何形式(即游离碱、游离酸、医药学上可接受的盐、溶剂合物等)都可用于本文论述的医药组合物中。
因此,在一个实施例中,本发明涉及一种包含医药学上可接受的载剂和本发明化合物的医药组合物。必要时,组合物可含有其它治疗剂和/或调配剂。当论述组合物时,“本发明化合物”在本文中也可称为“活性药剂”,从而将其与调配物的其它组分,如载剂区分。因此,应了解术语“活性药剂”包括式I化合物以及所述化合物的医药学上可接受的盐、溶剂合物和前药。
本发明的医药组合物通常含有治疗有效量的本发明化合物。然而,所属领域的技术人员应认识到医药组合物可含有大于治疗有效量(如在大批组合物中)或小于治疗有效量(即经设计用于多次投药以实现治疗有效量的个别单位剂量)。通常,组合物将含有约0.01重量%到95重量%的活性药剂,包括约0.01重量%到30重量%,如约0.01重量%到10重量%,其中实际量视调配物自身、投药途径、给药频率等而定。在一个实施例中,适于口服剂型的组合物例如可含有约5重量%到70重量%或约10重量%到60重量%的活性药剂。
任何常规载剂或赋形剂都可用于本发明的医药组合物中。选择特定载剂或赋形剂、或载剂或赋形剂的组合将视用于治疗特定患者的投药模式或医学病状或疾病状态的类型而定。就此来说,制备适于特定投药模式的组合物完全在医药领域的技术人员的技能范围内。另外,这些组合物中使用的载剂或赋形剂可购得。通过进一步说明的方式,常规调配技术描述于以下中:雷明顿:药学科学和实践(Remington:The Science and Practice ofPharmacy),第20版,马里兰州巴尔的摩的利平科特威廉斯与怀特出版社(LippincottWilliams&White,Baltimore,Maryland)(2000);和H.C.安塞尔(H.C.Ansel)等人,药物剂型和药物递送系统(Pharmaceutical Dosage Forms and Drug Delivery Systems),第7版,马里兰州巴尔的摩的利平科特威廉斯与怀特出版社(1999)。
可充当医药学上可接受的载剂的物质的代表性实例包括(但不限于)下列各物:糖,如乳糖、葡萄糖和蔗糖;淀粉,如玉米淀粉和马铃薯淀粉;纤维素,如微晶纤维素和其衍生物,如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;粉末状黄蓍胶;麦芽;明胶;滑石;赋形剂,如可可脂和栓剂蜡;油,如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇,如丙二醇;多元醇,如甘油、山梨糖醇、甘露糖醇和聚乙二醇;酯,如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,如氢氧化镁和氢氧化铝;海藻酸;无热原质水;等渗盐水;林格氏溶液(Ringer's solution);乙醇;磷酸盐缓冲溶液;压缩推进剂气体,如氯氟碳化物和氢氟碳化物;和医药组合物中采用的其它无毒相容性物质。
通常通过充分且精细混合或掺合活性药剂与医药学上可接受的载剂和一或多种任选的成分来制备医药组合物。所得均一掺合的混合物接着可使用常规程序和设备成形为或装入片剂、胶囊、丸剂、罐、药筒、分配器等中。
在一个实施例中,医药组合物适于口服投药。适于口服投药的组合物可呈以下形式:胶囊、片剂、丸剂、含片、扁囊剂、糖衣丸、粉剂、颗粒剂;于水性或非水性液体中的溶液或悬浮液;水包油型或油包水型液体乳液;酏剂或糖浆;等;各自含有预定量的活性药剂。
当打算以固体剂型(胶囊、片剂、丸剂等)口服投药时,组合物通常将包含活性药剂和一或多种医药学上可接受的载剂,如柠檬酸钠或磷酸二钙。固体剂型还可包含:填充剂或增量剂,如淀粉、微晶纤维素、乳糖、蔗糖、葡萄糖、甘露糖醇和/或硅酸;粘合剂,如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶(acacia);保湿剂,如甘油;崩解剂,如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和/或碳酸钠;溶解延迟剂,如石蜡;吸收促进剂,如季铵化合物;润湿剂,如单硬脂酸十六烷醇酯和/或单硬脂酸甘油酯;吸收剂,如高岭土(kaolin)和/或膨润土(bentonite clay);润滑剂,如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠和/或其混合物;着色剂;和缓冲剂。
释放剂、润湿剂、包衣剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂也可存在于医药组合物中。用于片剂、胶囊、丸剂等的示例性包衣剂包括用于肠溶包衣的包衣剂,如邻苯二甲酸乙酸纤维素、聚乙酸乙烯酯邻苯二甲酸酯、邻苯二甲酸羟丙基甲基纤维素、甲基丙烯酸-甲基丙烯酸酯共聚物、偏苯三酸乙酸纤维素、羧甲基乙基纤维素、丁二酸乙酸羟丙基甲基纤维素等。医药学上可接受的抗氧化剂的实例包括:水溶性抗氧化剂,如抗坏血酸、半胱氨酸盐酸盐、硫酸氢钠、偏亚硫酸钠、亚硫酸钠等;油溶性抗氧化剂,如抗坏血酸棕榈酸酯、丁基化羟基苯甲醚、丁基化羟基甲苯、卵磷脂(lecithin)、没食子酸丙酯、α-生育酚(alpha-tocopherol)等;和金属螯合剂,如柠檬酸、乙二胺四乙酸、山梨糖醇、酒石酸、磷酸等。
组合物还可使用例如不同比例的羟丙基甲基纤维素或其它聚合物基质、脂质体和/或微球体调配,从而提供活性药剂的缓慢释放或控制释放。此外,本发明的医药组合物可含有乳浊剂,且可经调配以使其任选地以延迟方式仅或优先在胃肠道的特定部分释放活性药剂。可使用的包埋组合物的实例包括聚合物质和蜡。活性药剂还可任选地与一或多种上述赋形剂一起呈微囊封形式。
适于口服投药的液体剂型包括例如医药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆和酏剂。液体剂型通常包含活性药剂和惰性稀释剂,如水或其它溶剂、增溶剂和乳化剂,如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、油(例如棉籽油、落花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃醇、聚乙二醇和脱水山梨糖醇的脂肪酸酯和其混合物。悬浮液可含有悬浮剂,如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇和脱水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土(bentonite)、琼脂和黄蓍胶和其混合物。
当打算口服投与时,本发明的医药组合物可以单位剂型包装。术语“单位剂型”是指适于对患者给药的物理个别单元,即每个单元单独或与一或多种其它单元组合时含有经计算可产生所要治疗效应的预定量的活性药剂。举例来说,这些单位剂型可为胶囊、片剂、丸剂等。
在另一实施例中,本发明组合物适于吸入投药,且通常将呈气雾剂或粉剂形式。通常使用熟知递送装置,如喷雾器、干粉或定剂量吸入器投与这些组合物。喷雾器装置产生高速气流,其使组合物喷成雾状而携带入患者的呼吸道中。一种示例性喷雾器调配物包含活性药剂溶解于载剂中以形成溶液,或活性药剂经微粒化并与载剂合并而形成具有可呼吸尺寸的微粒化粒子的悬浮液。干粉吸入器投与呈自由流动粉末形式的活性药剂,其在吸气期间分散于患者的气流中。一种示例性干粉调配物包含活性药剂与赋形剂(如乳糖、淀粉、甘露糖醇、右旋糖、聚乳酸、聚丙交酯-共-乙交酯和其组合)的干燥掺合物。定剂量吸入器使用压缩推进剂气体放出数量经测量的活性药剂。一种示例性定剂量调配物包含活性药剂于液化推进剂(如氯氟碳化物或氢氟烷烃)中的溶液或悬浮液。这些调配物的任选的组分包括共溶剂,如乙醇或戊烷;和表面活性剂,如脱水山梨糖醇三油酸酯、油酸、卵磷脂、甘油和月桂基硫酸钠。这些组合物通常通过将经冷冻或加压的氢氟烷烃加入含有活性药剂、乙醇(如果存在)和表面活性剂(如果存在)的适合容器中来制备。为制备悬浮液,使活性药剂微粒化且接着与推进剂合并。或者,悬浮液调配物可通过使活性药剂的微粒化粒子上的表面活性剂涂层喷雾干燥来加以制备。调配物接着装入形成吸入器的一部分的气雾剂罐中。
本发明化合物还可肠胃外(例如通过皮下、静脉内、肌肉内或腹膜内注射)投与。对于此类投与,活性药剂是以无菌溶液、悬浮液或乳液形式提供。制备这些调配物的示例性溶剂包括水、盐水、低分子量醇(如丙二醇)、聚乙二醇、油、明胶、脂肪酸酯(如油酸乙酯)等。肠胃外调配物还可含有一或多种抗氧化剂、增溶剂、稳定剂、防腐剂、润湿剂、乳化剂和分散剂。表面活性剂、其它稳定剂或pH值调节剂(酸、碱或缓冲剂)和抗氧化剂特别适用于对调配物提供稳定性,例如使可存在于化合物中的酯和酰胺键的水解或硫醇的二聚化降到最低或避免。可通过使用无菌可注射介质、杀菌剂、过滤、辐射或加热而使这些调配物无菌。在一个特定实施例中,肠胃外调配物包含环糊精水溶液作为医药学上可接受的载剂。适合的环糊精包括含有6个或6个以上在1,4位置经键联连接的α-D-葡萄吡喃糖单元的环状分子,在淀粉酶、β-环糊精或环庚直链淀粉中同样如此。示例性环糊精包括环糊精衍生物,如羟丙基和磺酸丁基醚环糊精,如羟丙基-β-环糊精和磺酸丁基醚β-环糊精。这些调配物的示例性缓冲液包括基于羧酸的缓冲液,如柠檬酸盐、乳酸盐和马来酸盐缓冲溶液。
本发明化合物还可使用已知经皮递送系统和赋形剂经皮投与。举例来说,化合物可与渗透增强剂(如丙二醇、聚乙二醇单月桂酸酯、氮杂环烷-2-酮等)掺合,且并入贴片或类似递送系统中。必要时,在这些经皮组合物中可使用其它赋形剂,包括胶凝剂、乳化剂和缓冲剂。
第二药剂
本发明化合物可单独用于治疗疾病或可与一或多种其它治疗剂组合以获得所要治疗效应。因此,在一个实施例中,本发明的医药组合物含有与本发明化合物共投与的其它药物。举例来说,组合物可另外包含一或多种药物(也称为“第二药剂”)。这些治疗剂在此项技术中已熟知,且包括腺苷受体拮抗剂、α-肾上腺素能受体拮抗剂、β1-肾上腺素能受体拮抗剂、β2-肾上腺素能受体激动剂、双重作用性β-肾上腺素能受体拮抗剂/α1-受体拮抗剂、晚期糖基化终末产物裂解剂、醛固酮拮抗剂、醛固酮合成酶抑制剂、氨基肽酶N抑制剂、雄激素、血管紧张素转化酶抑制剂和双重作用性血管紧张素转化酶/脑啡肽酶抑制剂、血管紧张素转化酶2活化剂和刺激剂、血管紧张素II疫苗、抗凝剂、抗糖尿病药剂、止泻药剂、抗青光眼药剂、抗脂质药剂、镇痛药剂、抗血栓药剂、AT1受体拮抗剂和双重作用性AT1受体拮抗剂/脑啡肽酶抑制剂和多功能血管紧张素受体阻断剂、缓激肽受体拮抗剂、钙通道阻断剂、糜酶抑制剂、地高辛、利尿剂、多巴胺激动剂、内皮素转化酶抑制剂、内皮素受体拮抗剂、HMG-CoA还原酶抑制剂、雌激素、雌激素受体激动剂和/或拮抗剂、单胺再摄取抑制剂、肌肉松弛剂、利钠肽和其类似物、利钠肽清除受体拮抗剂、脑啡肽酶抑制剂、一氧化氮供体、非类固醇消炎剂、N-甲基d-天冬氨酸受体拮抗剂、阿片样物质受体激动剂、磷酸二酯酶抑制剂、前列腺素类似物、前列腺素受体激动剂、肾素抑制剂、选择性血清素再摄取抑制剂、钠通道阻断剂、可溶性鸟苷酸环化酶刺激剂和活化剂、三环抗抑郁剂、血管加压素受体拮抗剂和其组合。这些药剂的特定实例详述于本文中。
因此,在本发明的另一方面中,医药组合物包含本发明化合物、第二活性药剂和医药学上可接受的载剂。第三、第四活性药剂等也可包括在组合物中。在组合疗法中,所投与的本发明化合物的量以及第二药剂的量可小于单一疗法中通常投与的量。
本发明化合物可与第二活性药剂以物理方式混合,从而形成含有两种药剂的组合物;或每个药剂可存在于各别和不同组合物中,所述组合物同时或在不同时间投与患者。举例来说,可使用常规程序和设备将本发明化合物与第二活性药剂组合以形成包含本发明化合物和第二活性药剂的活性药剂组合。另外,活性药剂可与医药学上可接受的载剂组合,从而形成包含本发明化合物、第二活性药剂和医药学上可接受的载剂的医药组合物。在此实施例中,通常混合或掺合组合物的组分以产生物理混合物。接着使用本文所述的任何途径以治疗有效量投与物理混合物。
或者,活性药剂可在投与患者之前保持独立和不同。在此实施例中,药剂在投与之前不以物理方式混合在一起,而是以各别组合物形式同时或在不同时间投与。这些组合物可分别包装或可一起包装于试剂盒中。当在不同时间投与时,第二药剂将通常在投与本发明化合物之后不到24小时(从投与本发明化合物同时到给药后约24小时范围内的任何时间)投与。此也称为依序投药。因此,本发明化合物与另一活性药剂可使用两种片剂(每个活性药剂对应一种片剂)同时或依序口服投与,其中依序可意指在投与本发明化合物之后即刻投与或在随后某一预定时间(例如随后1小时或随后3小时)投与。还预期第二药剂可在投与本发明化合物之后超过24小时加以投与。或者,组合可通过不同投药途径投与,即一种药剂口服投与且另一药剂通过吸入投与。
在一个实施例中,试剂盒包含含量足以执行本发明方法的包含本发明化合物的第一剂型、和至少一种包含本文阐述的一或多种第二药剂的另一剂型。第一剂型和第二(或第三等)剂型合起来包含用于治疗或预防患者疾病或医学病状的治疗有效量的活性药剂。
当包括第二药剂时,其是以治疗有效量存在以便其当与本发明化合物共投与时通常以产生治疗有益效应的量投与。第二药剂可呈医药学上可接受的盐、溶剂合物、光学纯立体异构体等形式。第二药剂还可呈前药形式,例如具有已经酯化的羧酸基团的化合物。因此,本文所列的第二药剂打算包括所有这些形式,且可购得或可使用常规程序和试剂加以制备。
在一个实施例中,本发明化合物是与腺苷受体拮抗剂组合投与,所述拮抗剂的代表性实例包括(但不限于)那昔茶碱(naxifylline)、罗咯茶碱(rolofylline)、SLV-320、茶碱(theophylline)和托纳普茶碱(tonapofylline)。
在一个实施例中,本发明化合物是与α-肾上腺素能受体拮抗剂组合投与,所述拮抗剂的代表性实例包括(但不限于)多沙唑嗪(doxazosin)、哌唑嗪(prazosin)、他苏洛辛(tamsulosin)和特拉唑嗪(terazosin)。
本发明化合物还可与β1-肾上腺素能受体拮抗剂(“β1阻断剂”)组合投与。代表性β1阻断剂包括(但不限于)醋丁洛尔(acebutolol)、阿普洛尔(alprenolol)、氨磺洛尔(amosulalol)、阿罗洛尔(arotinolol)、阿替洛尔(atenolol)、苯呋洛尔(befunolol)、倍他洛尔(betaxolol)、贝凡洛尔(bevantolol)、比索洛尔(bisoprolol)、波吲洛尔(bopindolol)、布新洛尔(bucindolol)、布库洛尔(bucumolol)、布非洛尔(bufetolol)、丁呋洛尔(bufuralol)、布尼洛尔(bunitrolol)、布拉洛尔(bupranolol)、巴布里丁(bubridine)、丁非洛尔(butofilolol)、卡拉洛尔(carazolol)、卡替洛尔(carteolol)、卡维地洛(carvedilol)、塞利洛尔(celiprolol)、塞他洛尔(cetamolol)、氯拉洛尔(cloranolol)、地来洛尔(dilevalol)、依泮洛尔(epanolol)、艾司洛尔(esmolol)、茚诺洛尔(indenolol)、拉贝洛尔(labetolol)、左布诺洛尔(levobunolol)、甲吲洛尔(mepindolol)、美替洛尔(metipranolol)、美托洛尔(metoprolol)(如美托洛尔丁二酸盐和美托洛尔酒石酸盐)、莫普洛尔(moprolol)、纳多洛尔(nadolol)、萘肟洛尔(nadoxolol)、奈必洛尔(nebivalol)、尼普地洛(nipradilol)、氧烯洛尔(oxprenolol)、喷布洛尔(penbutolol)、培布洛尔(perbutolol)、品多洛尔(pindolol)、普拉洛尔(practolol)、丙萘洛尔(pronethalol)、普萘洛尔(propranolol)、索他洛尔(sotalol)、萨非洛尔(sufinalol)、塔尼多(talindol)、特他洛尔(tertatolol)、替利洛尔(tilisolol)、噻吗洛尔(timolol)、托利洛尔(toliprolol)、希苯洛尔(xibenolol)和其组合。在一个特定实施例中,β1拮抗剂是选自阿替洛尔、比索洛尔、美托洛尔、普萘洛尔、索他洛尔和其组合。通常,β1阻断剂将以足以提供每剂约2mg到900mg的量投与。
在一个实施例中,本发明化合物是与β2-肾上腺素能受体激动剂组合投与,所述激动剂的代表性实例包括(但不限于)沙丁胺醇(albuterol)、比托特罗(bitolterol)、非诺特罗(fenoterol)、福莫特罗(formoterol)、吲达卡特罗(indacaterol)、异他林(isoetharine)、左旋沙丁胺醇(levalbuterol)、间羟异丙肾上腺素(metaproterenol)、吡布特罗(pirbuterol)、沙丁胺醇(salbutamol)、沙甲胺醇(salmefamol)、沙美特罗(salmeterol)、特布他林(terbutaline)、维兰特罗(vilanterol)等。通常β2-肾上腺素受体激动剂将以足以提供每剂约0.05μg到500μg的量投与。
在一个实施例中,本发明化合物是与晚期糖基化终末产物(AGE)裂解剂组合投与,所述裂解剂的实例(通过说明而非限制的方式)包括阿拉格布(alagebrium)(或ALT-711)和TRC4149。
在另一实施例中,本发明化合物是与醛固酮拮抗剂组合投与,所述拮抗剂的代表性实例包括(但不限于)依普利酮(eplerenone)、螺内酯(spironolactone)和其组合。通常,醛固酮拮抗剂将以足以提供每天约5mg到300mg的量投与。
在一个实施例中,本发明化合物是与氨基肽酶N或二肽基肽酶III抑制剂组合投与,所述抑制剂的实例(通过说明而非限制的方式)包括苯丁抑制素(bestatin)和PC18(2-氨基-4-甲基磺酰基丁烷硫醇、蛋氨酸硫醇)。
本发明化合物还可与血管紧张素转化酶(ACE)抑制剂组合投与。代表性ACE抑制剂包括(但不限于)阿库普利(accupril)、阿拉普利(alacepril)、贝那普利(benazepril)、贝那普利拉(benazeprilat)、卡托普利(captopril)、施瑞普利(ceranapril)、西拉普利(cilazapril)、地拉普利(delapril)、依那普利(enalapril)、依那普利拉(enalaprilat)、福辛普利(fosinopril)、福辛普利拉(fosinoprilat)、咪达普利(imidapril)、赖诺普利(lisinopril)、莫西普利(moexipril)、蒙诺普利(monopril)、莫福普利(moveltipril)、喷托普利(pentopril)、培哚普利(perindopril)、喹那普利(quinapril)、喹那普利拉(quinaprilat)、雷米普利(ramipril)、雷米普利拉(ramiprilat)、色拉新乙酸盐(saralasin acetate)、螺普利(spirapril)、替莫普利(temocapril)、群多普利(trandolapril)、佐芬普利(zofenopril)和其组合。
在一个特定实施例中,ACE抑制剂是选自:贝那普利、卡托普利、依那普利、赖诺普利、雷米普利和其组合。通常,ACE抑制剂将以足以提供每天约1mg到150mg的量投与。在另一实施例中,本发明化合物是与双重作用性血管紧张素转化酶/脑啡肽酶(ACE/NEP)抑制剂组合投与,所述药剂的实例包括(但不限于):AVE-0848((4S,7S,12bR)-7-[3-甲基-2(S)-硫基丁酰氨基]-6-氧代-1,2,3,4,6,7,8,12b-八氢吡啶并[2,1-a][2]-苯并氮杂卓-4-甲酸);AVE-7688(艾尔帕曲(ilepatril))和其母体化合物;BMS-182657(2-[2-氧代-3(S)-[3-苯基-2(S)-硫基丙酰氨基]-2,3,4,5-四氢-1H-1-苯并氮杂卓-1-基]乙酸);CGS-35601(N-[1-[4-甲基-2(S)-硫基戊酰氨基]环戊基羰基]-L-色氨酸);法西多曲(fasidotril);法西多曲拉(fasidotrilate);依那普利拉;ER-32935((3R,6S,9aR)-6-[3(S)-甲基-2(S)-硫基戊酰氨基]-5-氧代全氢化噻唑并[3,2-a]氮杂卓-3-甲酸);格帕曲拉;MDL-101264((4S,7S,12bR)-7-[2(S)-(2-(N-吗啉基)乙酰硫基)-3-苯基丙酰氨基]-6-氧代-1,2,3,4,6,7,8,12b-八氢吡啶并[2,1-a][2]苯并氮杂卓-4-甲酸);MDL-101287([4S-[4α,7α(R*),12bβ]]-7-[2-(羧甲基)-3-苯基丙酰氨基]-6-氧代-1,2,3,4,6,7,8,12b-八氢吡啶并[2,1-a][2]苯并氮杂卓-4-甲酸);奥帕曲拉;RB-105(N-[2(S)-(巯基甲基)-3(R)-苯丁基]-L-丙氨酸);山帕曲拉;SA-898((2R,4R)-N-[2-(2-羟基苯基)-3-(3-巯基丙酰基)噻唑烷-4-基羰基]-L-苯基丙氨酸);Sch-50690(N-[1(S)-羧基-2-[N2-(甲烷磺酰基)-L-赖氨酰基氨基]乙基]-L-缬氨酰基-L-酪氨酸);且还可包括其组合。在一个特定实施例中,ACE/NEP抑制剂是选自:AVE-7688、依那普利拉、法西多曲、法西多曲拉、奥帕曲拉、山帕曲拉和其组合。
在一个实施例中,本发明化合物是与血管紧张素转化酶2(ACE2)活化剂或刺激剂组合投与。
在一个实施例中,本发明化合物是与血管紧张素II疫苗组合投与,所述疫苗的实例包括(但不限于)ATR12181和CYT006-AngQb。
在一个实施例中,本发明化合物是与抗凝剂组合投与,所述抗凝剂的代表性实例包括(但不限于):香豆素类(coumarins),如华法林(warfarin);肝素(heparin);和直接凝血酶抑制剂,如阿加曲班(argatroban)、比伐卢定(bivalirudin)、达比加群(dabigatran)和来匹卢定(lepirudin)。
在另一实施例中,本发明化合物是与抗糖尿病药剂组合投与。代表性抗糖尿病药剂包括可注射药物以及口服有效药物和其组合。可注射药物的实例包括(但不限于)胰岛素和胰岛素衍生物。口服有效药物的实例包括(但不限于):双胍(biguanides),如二甲双胍(metformin);升糖素(glucagon)拮抗剂;α-葡糖苷酶(α-glucosidase)抑制剂,如阿卡波糖(acarbose)和米格列醇(miglitol);二肽基肽酶IV抑制剂(DPP-IV抑制剂),如阿格列汀(alogliptin)、德纳列汀(denagliptin)、利那列汀(linagliptin)、沙克列汀(saxagliptin)、西他列汀(sitagliptin)和维格列汀(vildagliptin);美格列奈(meglitinide),如瑞格列奈(repaglinide);噁二唑烷二酮(oxadiazolidinedione);磺酰脲(sulfonylurea),如氯磺丙脲(chlorpropamide)、格列美脲(glimepiride)、格列甲嗪(glipizide)、格列本脲(glyburide)和妥拉磺脲(tolazamide);噻唑烷二酮(thiazolidinedione),如吡格列酮(pioglitazone)和罗格列酮(rosiglitazone);和其组合。
在另一实施例中,本发明化合物是与止泻治疗组合投与。代表性治疗选项包括(但不限于)口服复水溶液(oral rehydration solution;ORS)、洛哌丁胺(loperamide)、地芬诺酯(diphenoxylate)和次水杨酸铋。
在另一实施例中,本发明化合物是与抗青光眼药剂组合投与。代表性抗青光眼药剂包括(但不限于):α-肾上腺素能激动剂,如溴莫尼定(brimonidine);β1-肾上腺素能受体拮抗剂;表面β1阻断剂,如倍他洛尔、左布诺洛尔和噻吗洛尔;碳酸酐酶抑制剂,如乙酰唑胺(acetazolamide)、布尔佐胺(brinzolamide)或多佐胺(dorzolamide);胆碱能激动剂,如西维美林(cevimeline)和DMXB-假木贼碱(DMXB-anabaseine);肾上腺素化合物;缩瞳药,如毛果芸香碱(pilocarpine);和前列腺素类似物。
在另一实施例中,本发明化合物是与抗脂质药剂组合投与。代表性抗脂质药剂包括(但不限于):胆固醇酯转移蛋白质抑制剂(CETP),如安赛曲匹(anacetrapib)、达塞曲匹(dalcetrapib)和托赛曲匹(torcetrapib);他汀类,如阿托伐他汀(atorvastatin)、氟伐他汀(fluvastatin)、洛伐他汀(lovastatin)、普伐他汀(pravastatin)、罗素他汀(rosuvastatin)和辛伐他汀(simvastatin);和其组合。
在一个实施例中,本发明化合物是与抗血栓药剂组合投与。代表性抗血栓药剂包括(但不限于):阿司匹林(aspirin);抗血小板药剂,如克罗匹多(clopidogrel)、普拉格雷(prasugrel)和噻氯匹啶(ticlopidine);肝素;和其组合。
在一个实施例中,本发明化合物是与也称为血管紧张素II 1型受体阻断剂(ARB)的AT1受体拮抗剂组合投与。代表性ARB包括(但不限于)阿比沙坦(abitesartan)、阿齐沙坦(azilsartan)(例如阿齐沙坦麦多米尔(azilsartan medoxomil))、本洛沙坦(benzyllosartan)、坎地沙坦(candesartan)、坎地沙坦西来替昔(candesartancilexetil)、依利沙坦(elisartan)、恩布沙坦(embusartan)、伊洛他索沙坦(enoltasosartan)、依普罗沙坦(eprosartan)、EXP3174、范沙坦(fonsartan)、福拉沙坦(forasartan)、格洛沙坦(glycyllosartan)、伊贝沙坦(irbesartan)、伊索特林(isoteoline)、洛沙坦(losartan)、麦多西米(medoxomil)、米法沙坦(milfasartan)、奥美沙坦(olmesartan)(例如奥美沙坦麦多米尔(olmesartan medoxomil))、奥普米沙坦(opomisartan)、普拉沙坦(pratosartan)、利匹沙坦(ripisartan)、沙普立沙坦(saprisartan)、色拉新(saralasin)、萨美新(sarmesin)、TAK-591、他索沙坦(tasosartan)、替米沙坦(telmisartan)、缬沙坦(valsartan)、佐拉沙坦(zolasartan)和其组合。在一个特定实施例中,ARB是选自阿齐沙坦麦多米尔、坎地沙坦西来替昔、依普罗沙坦、伊贝沙坦、洛沙坦、奥美沙坦麦多米尔、沙普立沙坦、他索沙坦、替米沙坦、缬沙坦和其组合。示例性盐和/或前药包括坎地沙坦西来替昔、依普罗沙坦甲磺酸盐、洛沙坦钾盐和奥美沙坦麦多米尔。通常,ARB将以足以提供每剂约4mg到600mg的量投与,其中示例性每日剂量在每天20mg到320mg范围内。
本发明化合物还可与双重作用性药剂,如AT1受体拮抗剂/脑啡肽酶抑制剂(ARB/NEP)抑制剂组合投与,所述药剂的实例包括(但不限于)描述于2008年4月23日申请的均属于阿莱格雷蒂(Allegretti)等人的美国公开案第2008/0269305号和第2009/0023228号中的化合物,如化合物4′-{2-乙氧基-4-乙基-5-[((S)-2-巯基-4-甲基戊酰基氨基)-甲基]咪唑-1-基甲基}-3′-氟联苯-2-甲酸。
本发明化合物还可与如库尔茨(Kurtz)和克莱因(Klein)(2009)高血压研究(Hypertension Research)32:826-834中所述的多功能血管紧张素受体阻断剂组合投与。
在一个实施例中,本发明化合物是与缓激肽受体拮抗剂,例如艾替班特(icatibant)(HOE-140)组合投与。预期此组合疗法可呈现预防血管性水肿(angioedema)或缓激肽含量升高的其它非所要后果的优点。
在一个实施例中,本发明化合物是与钙通道阻断剂组合投与。代表性钙通道阻断剂包括(但不限于)氨氯地平(amlodipine)、阿尼帕米(anipamil)、阿拉尼平(aranipine)、巴尼地平(barnidipine)、苄环烷(bencyclane)、贝尼地平(benidipine)、苄普地尔(bepridil)、克仑硫卓(clentiazem)、西尼地平(cilnidipine)、桂利嗪(cinnarizine)、地尔硫卓(diltiazem)、依福地平(efonidipine)、依高地平(elgodipine)、依他苯酮(etafenone)、非洛地平(felodipine)、芬地林(fendiline)、氟桂利嗪(flunarizine)、加洛帕米(gallopamil)、伊拉地平(isradipine)、拉西地平(lacidipine)、乐卡地平(lercanidipine)、利多氟嗪(lidoflazine)、洛美利嗪(lomerizine)、马尼地平(manidipine)、米贝地尔(mibefradil)、尼卡地平(nicardipine)、硝苯地平(nifedipine)、尼古地平(niguldipine)、尼鲁地平(niludipine)、尼伐地平(nilvadipine)、尼莫地平(nimodipine)、尼索地平(nisoldipine)、尼群地平(nitrendipine)、尼伐地平(nivaldipine)、哌克昔林(perhexiline)、普尼拉明(prenylamine)、里奥斯汀(ryosidine)、司莫地尔(semotiadil)、特罗地林(terodiline)、替阿帕米(tiapamil)、维拉帕米(verapamil)和其组合。在一个特定实施例中,钙通道阻断剂是选自氨氯地平、苄普地尔、地尔硫卓、非洛地平、伊拉地平、拉西地平、尼卡地平、硝苯地平、尼古地平、尼鲁地平、尼莫地平、尼索地平、里奥斯汀、维拉帕米和其组合。通常,钙通道阻断剂将以足以提供每剂约2mg到500mg的量投与。
在一个实施例中,本发明化合物是与糜酶抑制剂,如TPC-806和2-(5-甲酰基氨基-6-氧代-2-苯基-1,6-二氢嘧啶-1-基)-N-[{3,4-二氧代-1-苯基-7-(2-吡啶基氧基)}-2-庚基]乙酰胺(NK3201)组合投与。
在一个实施例中,本发明化合物是与利尿剂组合投与。代表性利尿剂包括(但不限于):碳酸酐酶抑制剂,如乙酰唑胺和双氯非那胺(dichlorphenamide);髓袢利尿剂(loopdiuretics),其包括磺酰胺衍生物(如乙酰唑胺、安布赛特(ambuside)、阿佐酰胺(azosemide)、布美他尼(bumetanide)、布他唑胺(butazolamide)、氯米非那胺(chloraminophenamide)、氯非那胺(clofenamide)、氯帕胺(clopamide)、氯索隆(clorexolone)、二磺法胺(disulfamide)、依索唑胺(ethoxzolamide)、呋塞米(furosemide)、美夫西特(mefruside)、醋甲唑胺(methazolamide)、吡咯他尼(piretanide)、托拉塞米(torsemide)、曲帕胺(tripamide)和氯磺水杨胺(xipamide))以及非磺酰胺利尿剂(如依他尼酸(ethacrynic acid))和其它苯氧基乙酸化合物(如替尼酸(tienilic acid)、茚达立酮(indacrinone)和喹卡酯(quincarbate));渗透性利尿剂,如甘露糖醇;保钾利尿剂(potassium-sparing diuretics),其包括醛固酮拮抗剂(如螺内酯)和Na+通道抑制剂(如氨氯吡脒(amiloride)和氨苯喋啶(triamterene));噻嗪和类似噻嗪的利尿剂,如阿尔噻嗪(althiazide)、苄氟噻嗪(bendroflumethiazide)、苄氢氯噻嗪(benzylhydrochlorothiazide)、苄噻嗪(benzthiazide)、布噻嗪(buthiazide)、氯噻酮(chlorthalidone)、氯噻嗪(chlorothiazide)、环戊噻嗪(cyclopenthiazide)、环噻嗪(cyclothiazide)、依匹噻嗪(epithiazide)、乙噻嗪(ethiazide)、芬喹唑(fenquizone)、氟甲噻嗪(flumethiazide)、氢氯噻嗪(hydrochlorothiazide)、氢氟噻嗪(hydroflumethiazide)、吲达帕胺(indapamide)、甲氯噻嗪(methylclothiazide)、美替克仑(meticrane)、美托拉宗(metolazone)、对氟噻嗪(paraflutizide)、多噻嗪(polythiazide)、喹乙唑酮(quinethazone)、四氯噻嗪(teclothiazide)和三氯噻嗪(trichloromethiazide);和其组合。在一个特定实施例中,利尿剂是选自氨氯吡脒、布美他尼、氯噻嗪、氯噻酮、双氯非那胺、依他尼酸、呋塞米、氢氯噻嗪、氢氟噻嗪、吲达帕胺、甲氯噻嗪、美托拉宗、托拉塞米、氨苯喋啶和其组合。利尿剂将以足以提供每天约5mg到50mg、更通常每天6mg到25mg的量投与,其中常用剂量为每天6.25mg、12.5mg或25mg。
本发明化合物还可与内皮素转化酶(ECE)抑制剂组合投与,所述抑制剂的实例包括(但不限于)膦酰二肽(phosphoramidon)、CGS 26303和其组合。
在一个特定实施例中,本发明化合物是与内皮素受体拮抗剂组合投与。代表性内皮素受体拮抗剂包括(但不限于):影响内皮素A受体的选择性内皮素受体拮抗剂,如阿伏生坦(avosentan)、安贝生坦(ambrisentan)、阿曲森坦(atrasentan)、BQ-123、克拉生坦(clazosentan)、达卢生坦(darusentan)、西他塞坦(sitaxentan)和齐泊腾坦(zibotentan);和影响内皮素A与B受体两者的双重内皮素受体拮抗剂,如波生坦(bosentan)、马西替坦(macitentan)、替唑生坦(tezosentan)。
在另一实施例中,本发明化合物是与一或多种也称为他汀类的HMG-CoA还原酶抑制剂组合投与。代表性他汀类包括(但不限于)阿托伐他汀、氟伐他汀、洛伐他汀、匹伐他汀(pitavastatin)、普伐他汀、罗素他汀和辛伐他汀。
在一个实施例中,本发明化合物是与单胺再摄取抑制剂组合投与,所述抑制剂的实例(通过说明而非限制的方式)包括去甲肾上腺素再摄取抑制剂,如阿托莫西汀(atomoxetine)、丁氨苯丙酮(buproprion)和丁氨苯丙酮代谢物羟基丁氨苯丙酮、马普替林(maprotiline)、瑞波西汀(reboxetine)和维洛沙嗪(viloxazine);选择性血清素再摄取抑制剂(SSRI),如西酞普兰(citalopram)和西酞普兰代谢物去甲西酞普兰(desmethylcitalopram)、达泊西汀(dapoxetine)、依地普兰(escitalopram)(例如依地普兰草酸盐)、氟西汀(fluoxetine)和氟西汀去甲基代谢物去甲氟西汀(norfluoxetine)、氟伏沙明(fluvoxamine)(例如氟伏沙明马来酸盐)、帕罗西汀(paroxetine)、舍曲林(sertraline)和舍曲林代谢物去甲舍曲林(demethylsertraline);双重血清素-去甲肾上腺素再摄取抑制剂(SNRI),如比西发定(bicifadine)、度洛西汀(duloxetine)、米那普仑(milnacipran)、奈法唑酮(nefazodone)和文拉法辛(venlafaxine);和其组合。
在另一实施例中,本发明化合物是与肌肉松弛剂组合投与,所述肌肉松弛剂的实例包括(但不限于):肌安宁(carisoprodol)、氯唑沙宗(chlorzoxazone)、环苯扎平(cyclobenzaprine)、二氟尼柳(diflunisal)、美他沙酮(metaxalone)、美索巴莫(methocarbamol)和其组合。
在一个实施例中,本发明化合物是与利钠肽或类似物组合投与,所述利钠肽或类似物的实例包括(但不限于):卡培立肽(carperitide)、CD-NP(尼尔疗法公司(NileTherapeutics))、CU-NP、奈西立肽(nesiritide)、PL-3994(帕拉丁科技公司(PalatinTechnologies,Inc.))、乌拉立肽(ularitide)、森德立肽(cenderitide)和小川(Ogawa)等人(2004)生物化学杂志(J.Biol.Chem.)279:28625-31中描述的化合物。这些化合物也称为利钠肽受体-A(NPR-A)激动剂。在另一实施例中,本发明化合物是与利钠肽清除受体(NPR-C)拮抗剂,如SC-46542、cANF(4-23)和AP-811(维尔(Veale)(2000)生物有机化学与医药化学通讯(Bioorg Med Chem Lett)10:1949-52)组合投与。举例来说,当与NEP抑制剂塞奥芬组合时,AP-811已展示协同作用(韦格纳(Wegner)(1995)临床与实验高血压(Clin.Exper.Hypert.)17:861-876)。
在另一实施例中,本发明化合物是与脑啡肽酶(NEP)抑制剂组合投与。代表性NEP抑制剂包括(但不限于):AHU-377;坎沙曲;坎沙曲拉;右卡多曲(dexecadotril)((+)-N-[2(R)-(乙酰硫基甲基)-3-苯基丙酰基]甘氨酸苯甲酯);CGS-24128(3-[3-(联苯-4-基)-2-(膦酰基甲基氨基)丙酰氨基]丙酸);CGS-24592((S)-3-[3-(联苯-4-基)-2-(膦酰基甲基氨基)丙酰氨基]丙酸);CGS-25155(N-[9(R)-(乙酰硫基甲基)-10-氧代-1-氮杂环癸-2(S)-基羰基]-4(R)-羟基-L-脯氨酸苯甲酯);描述于赫普沃思(Hepworth)等人(辉瑞公司(PfizerInc.))的WO 2006/027680中的3-(1-氨甲酰基环己基)丙酸衍生物;JMV-390-1(2(R)-苯甲基-3-(N-羟基氨甲酰基)丙酰基-L-异亮氨酰基-L-亮氨酸);依卡曲尔(ecadotril);膦酰二肽;里曲塞奥芬(retrothiorphan);RU-42827(2-(巯基甲基)-N-(4-吡啶基)苯丙酰胺);RU-44004(N-(4-吗啉基)-3-苯基-2-(硫基甲基)丙酰胺);SCH-32615((S)-N-[N-(1-羧基-2-苯乙基)-L-苯基丙氨酰基]-β-丙氨酸)和其前药SCH-34826((S)-N-[N-[1-[[(2,2-二甲基-1,3-二氧戊环-4-基)甲氧基]羰基]-2-苯乙基]-L-苯基丙氨酰基]-β-丙氨酸);塞洛非(sialorphin);SCH-42495(N-[2(S)-(乙酰基硫基甲基)-3-(2-甲基苯基)丙酰基]-L-蛋氨酸乙酯);斯匹洛非(spinorphin);SQ-28132(N-[2-(巯基甲基)-1-氧代-3-苯基丙基]亮氨酸);SQ-28603(N-[2-(巯基甲基)-1-氧代-3-苯基丙基]-β-丙氨酸);SQ-29072(7-[[2-(巯基甲基)-1-氧代-3-苯基丙基]氨基]庚酸);塞奥芬和其前药消旋卡多曲(racecadotril);UK-69578(顺-4-[[[1-[2-羧基-3-(2-甲氧基乙氧基)丙基]环戊基]羰基]氨基]环己烷甲酸);UK-447,841(2-{1-[3-(4-氯苯基)丙基氨甲酰基]-环戊基甲基}-4-甲氧基丁酸);UK-505,749((R)-2-甲基-3-{1-[3-(2-甲基苯并噻唑-6-基)丙基氨甲酰基]环戊基}丙酸);5-联苯-4-基-4-(3-羧基丙酰基氨基)-2-甲基戊酸和5-联苯-4-基-4-(3-羧基丙酰基氨基)-2-甲基戊酸乙酯(WO 2007/056546);凯德(Khder)等人(诺华公司(Novartis AG))的WO2007/106708中描述的达格鲁曲(daglutril)[(3S,2'R)-3-{1-[2'-(乙氧基羰基)-4'-苯丁基]-环戊-1-羰基氨基}-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂卓-1-乙酸];和其组合。在一个特定实施例中,NEP抑制剂是选自AHU-377、坎沙曲、坎沙曲拉、CGS-24128、膦酰二肽、SCH-32615、SCH-34826、SQ-28603、塞奥芬和其组合。在一个特定实施例中,NEP抑制剂为具有作为内皮素转化酶(ECE)与NEP两者的抑制剂活性的化合物,如达格鲁曲或CGS-26303([N-[2-(联苯-4-基)-1(S)-(1H-四唑-5-基)乙基]氨基]甲基膦酸)。也可使用其它双重作用性ECE/NEP化合物。NEP抑制剂将以足以提供每天约20mg到800mg的量投与,其中典型每日剂量在每天50mg到700mg、更通常为每天100mg到600mg或100mg到300mg范围内。
在一个实施例中,本发明化合物是与一氧化氮供体组合投与,所述供体的实例包括(但不限于)尼可地尔(nicorandil);有机硝酸酯,如季戊四醇四硝酸酯;和斯德酮亚胺(sydnonimine),如林西多明(linsidomine)和吗多明(molsidomine)。
在另一实施例中,本发明化合物是与非类固醇消炎剂(NSAID)组合投与。代表性NSAID包括(但不限于):阿西美辛(acemetacin)、乙酰水杨酸(acetyl salicylic acid)、阿氯芬酸(alclofenac)、阿明洛芬(alminoprofen)、氨芬酸(amfenac)、氨普立糖(amiprilose)、阿洛泼林(aloxiprin)、阿尼罗酸(anirolac)、阿扎丙宗(apazone)、阿扎丙酮(azapropazone)、贝诺酯(benorilate)、苯噁洛芬(benoxaprofen)、苯哌隆(bezpiperylon)、溴哌莫(broperamole)、布氯酸(bucloxic acid)、卡洛芬(carprofen)、环氯茚酸(clidanac)、双氯芬酸(diclofenac)、二氟尼柳、地弗他酮(diftalone)、依诺利康(enolicam)、依托度酸(etodolac)、依托昔布(etoricoxib)、芬布芬(fenbufen)、芬氯酸(fenclofenac)、芬克洛酸(fenclozic acid)、非诺洛芬(fenoprofen)、芬替酸(fentiazac)、非普拉宗(feprazone)、氟芬那酸(flufenamic acid)、氟苯柳(flufenisal)、氟洛芬(fluprofen)、氟比洛芬(flurbiprofen)、呋罗芬酸(furofenac)、异丁芬酸(ibufenac)、布洛芬(ibuprofen)、吲哚美辛(indomethacin)、吲哚洛芬(indoprofen)、伊索克酸(isoxepac)、伊索昔康(isoxicam)、酮洛芬(ketoprofen)、酮洛酸(ketorolac)、洛非咪唑(lofemizole)、氯诺昔康(lornoxicam)、甲氧芬那酸盐(meclofenamate)、甲氯芬那酸(meclofenamic acid)、甲芬那酸(mefenamic acid)、美洛昔康(meloxicam)、美沙胺(mesalamine)、咪洛芬(miroprofen)、莫非布宗(mofebutazone)、萘丁美酮(nabumetone)、萘普生(naproxen)、尼氟酸(niflumic acid)、奥沙普嗪(oxaprozin)、噁平酸(oxpinac)、羟布宗(oxyphenbutazone)、苯基丁氮酮(phenylbutazone)、吡罗昔康(piroxicam)、吡洛芬(pirprofen)、普拉洛芬(pranoprofen)、双水杨酯(salsalate)、舒多昔康(sudoxicam)、柳氮磺胺吡啶(sulfasalazine)、舒林酸(sulindac)、舒洛芬(suprofen)、替诺昔康(tenoxicam)、硫平酸(tiopinac)、噻洛芬酸(tiaprofenic acid)、硫噁洛芬(tioxaprofen)、托芬那酸(tolfenamicacid)、托美丁(tolmetin)、三氟米酯(triflumidate)、齐多美辛(zidometacin)、佐美酸(zomepirac)和其组合。在一个特定实施例中,NSAID是选自依托度酸、氟比洛芬、布洛芬、吲哚美辛、酮洛芬、酮洛酸、美洛昔康、萘普生、奥沙普嗪、吡罗昔康和其组合。
在一个实施例中,本发明化合物是与N-甲基d-天冬氨酸(NMDA)受体拮抗剂组合投与,所述拮抗剂的实例(通过说明而非限制的方式)包括金刚烷胺(amantadine)、右甲吗喃(dextromethorphan)、右丙氧芬(dextropropoxyphene)、氯胺酮(ketamine)、凯托米酮(ketobemidone)、美金刚(memantine)、美沙酮(methadone)等。
在另一实施例中,本发明化合物是与阿片样物质受体激动剂(也称为阿片样物质止痛剂)组合投与。代表性阿片样物质受体激动剂包括(但不限于):丁丙诺啡(buprenorphine)、布托啡诺(butorphanol)、可待因(codeine)、二氢可待因(dihydrocodeine)、芬太尼(fentanyl)、氢可酮(hydrocodone)、氢吗啡酮(hydromorphone)、左洛啡烷(levallorphan)、左啡诺(levorphanol)、哌替啶(meperidine)、美沙酮、吗啡(morphine)、纳布啡(nalbuphine)、纳美芬(nalmefene)、烯丙吗啡(nalorphine)、纳洛酮(naloxone)、纳曲酮(naltrexone)、烯丙吗啡(nalorphine)、氧可酮(oxycodone)、氧化吗啡酮(oxymorphone)、戊唑星(pentazocine)、丙氧芬(propoxyphene)、曲马多(tramadol)和其组合。在某些实施例中,阿片样物质受体激动剂是选自可待因、二氢可待因、氢可酮、氢吗啡酮、吗啡、氧可酮、氧化吗啡酮、曲马多和其组合。
在一个特定实施例中,本发明化合物是与磷酸二酯酶(PDE)抑制剂,具体来说PDE-V抑制剂组合投与。代表性PDE-V抑制剂包括(但不限于)阿伐那非(avanafil)、罗地那非(lodenafil)、米罗那非(mirodenafil)、西地那非(sildenafil)他达那非(tadalafil)伐地那非(vardenafil)和优地那非(udenafil)。
在另一实施例中,本发明化合物是与前列腺素类似物(也称为类前列腺素(prostanoids)或前列环素(prostacyclin)类似物)组合投与。代表性前列腺素类似物包括(但不限于)贝拉普罗钠(beraprost sodium)、比马前列素(bimatoprost)、依前列醇(epoprostenol)、伊洛前列素(iloprost)、拉坦前列素(latanoprost)、他氟前列素(tafluprost)、曲伏前列素(travoprost)和曲前列环素(treprostinil),其中比马前列素、拉坦前列素和他氟前列素特别相关。
在另一实施例中,本发明化合物是与前列腺素受体激动剂组合投与,所述激动剂的实例包括(但不限于)比马前列素、拉坦前列素、曲伏前列素等。
本发明化合物还可与肾素抑制剂组合投与,所述抑制剂的实例包括(但不限于)阿利吉仑(aliskiren)、依那吉仑(enalkiren)、瑞米吉仑(remikiren)和其组合。
在另一实施例中,本发明化合物是与选择性血清素再摄取抑制剂(SSRI)组合投与。代表性SSRI包括(但不限于):西酞普兰和西酞普兰代谢物去甲西酞普兰、达泊西汀、依地普兰(例如依地普兰草酸盐)、氟西汀和氟西汀去甲基代谢物去甲氟西汀、氟伏沙明(氟伏沙明马来酸盐)、帕罗西汀、舍曲林和舍曲林代谢物去甲舍曲林、和其组合。
在一个实施例中,本发明化合物是与5-HT1D血清素受体激动剂组合投与,所述激动剂的实例(通过说明而非限制的方式)包括普坦(triptans),如阿莫曲普坦(almotriptan)、阿维曲普坦(avitriptan)、依来曲普坦(eletriptan)、夫罗曲普坦(frovatriptan)、那拉曲普坦(naratriptan)、利扎曲普坦(rizatriptan)、舒马曲普坦(sumatriptan)和佐米曲普坦(zolmitriptan)。
在一个实施例中,本发明化合物是与钠通道阻断剂组合投与,所述阻断剂的实例(通过说明而非限制的方式)包括卡马西平(carbamazepine)、磷苯妥英(fosphenytoin)、拉莫三嗪(lamotrigine)、利多卡因(lidocaine)、美西律(mexiletine)、奥卡西平(oxcarbazepine)、苯妥英(phenytoin)和其组合。
在一个实施例中,本发明化合物是与可溶性鸟苷酸环化酶刺激剂或活化剂组合投与,所述刺激剂或活化剂的实例包括(但不限于)阿他西哌(ataciguat)、里奥西哌(riociguat)和其组合。
在一个实施例中,本发明化合物是与三环抗抑郁剂(TCA)组合投与,所述三环抗抑郁剂的实例(通过说明而非限制的方式)包括阿米替林(amitriptyline)、氧阿米替林(amitriptylinoxide)、布替林(butriptyline)、氯米帕明(clomipramine)、地美替林(demexiptiline)、地昔帕明(desipramine)、二苯西平(dibenzepin)、二甲他林(dimetacrine)、度硫平(dosulepin)、多塞平(doxepin)、丙咪嗪(imipramine)、氧米帕明(imipraminoxide)、洛夫帕明(lofepramine)、美利曲辛(melitracen)、美他帕明(metapramine)、硝沙西平(nitroxazepine)、去甲替林(nortriptyline)、诺昔替林(noxiptiline)、哌泊非嗪(pipofezine)、丙吡西平(propizepine)、普罗替林(protriptyline)、奎纽帕明(quinupramine)和其组合。
在一个实施例中,本发明化合物是与血管加压素受体拮抗剂组合投与,所述拮抗剂的实例(通过说明而非限制的方式)包括考尼伐坦(conivaptan)和托伐普坦(tolvaptan)。
组合的第二治疗剂还可在用本发明化合物进行的其它组合疗法中有益。举例来说,本发明化合物可与利尿剂和ARB、或钙通道阻断剂和ARB、或利尿剂和ACE抑制剂、或钙通道阻断剂和他汀类组合。特定实例包括ACE抑制剂依那普利(呈马来酸盐形式)与利尿剂氢氯噻嗪的组合,其在商标下销售;或钙通道阻断剂氨氯地平(呈苯磺酸盐形式)与ARB奥美沙坦(呈麦多米尔前药形式)的组合;或钙通道阻断剂与他汀类的组合,所有这些实例也都可与本发明化合物一起使用。如α2-肾上腺素能受体激动剂和血管加压素受体拮抗剂的其它治疗剂也可在组合疗法中有益。示例性α2-肾上腺素能受体激动剂包括可乐定(clonidine)、右美托咪定(dexmedetomidine)和胍法辛(guanfacine)。
下列调配物说明本发明的代表性医药组合物。
用于口服投与的示例性硬质明胶胶囊
充分掺合本发明化合物(50g)、440g喷雾干燥的乳糖和10g硬脂酸镁。接着将所得组合物装入硬质明胶胶囊中(每胶囊500mg组合物)。或者,充分掺合本发明化合物(20mg)与淀粉(89mg)、微晶纤维素(89mg)和硬脂酸镁(2mg)。接着使混合物过筛号第45号美国筛(U.S.sieve)且装入硬质明胶胶囊中(每胶囊200mg组合物)。
或者,如上所述充分掺合并加工本发明化合物(30g)、第二药剂(20g)、440g喷雾干燥的乳糖和10g硬脂酸镁。
用于口服投与的示例性明胶胶囊调配物
充分掺合本发明化合物(100mg)与聚氧乙烯脱水山梨糖醇单油酸酯(50mg)和淀粉(250mg)。接着将混合物装入明胶胶囊中(每胶囊400mg组合物)。或者,充分掺合本发明化合物(70mg)和第二药剂(30mg)与聚氧乙烯脱水山梨糖醇单油酸酯(50mg)和淀粉(250mg),且将所得混合物装入明胶胶囊中(每胶囊400mg组合物)。
或者,充分掺合本发明化合物(40mg)与微晶纤维素(Avicel PH 103;259.2mg)和硬脂酸镁(0.8mg)。接着将混合物装入明胶胶囊(1号尺寸,白色,不透明)中(每胶囊300mg组合物)。
用于口服投与的示例性片剂调配物
使本发明化合物(10mg)、淀粉(45mg)和微晶纤维素(35mg)过筛号第20号美国筛且充分混合。由此产生的颗粒在50℃到60℃下干燥且过筛号第16号美国筛。使聚乙烯吡咯烷酮的溶液(4mg于无菌水中的10%溶液)与羧甲基淀粉钠(4.5mg)、硬脂酸镁(0.5mg)和滑石(1mg)混合,且接着使此混合物过筛号第16号美国筛。接着将羧甲基淀粉钠、硬脂酸镁和滑石加入颗粒中。在混合之后,在压片机上压制混合物,得到重100mg的片剂。
或者,充分掺合本发明化合物(250mg)与微晶纤维素(400mg)、烟雾状二氧化硅(10mg)和硬脂酸(5mg)。接着压制混合物以形成片剂(每片665mg组合物)。
或者,充分掺合本发明化合物(400mg)与玉米淀粉(50mg)、交联羧甲纤维素钠(25mg)、乳糖(120mg)和硬脂酸镁(5mg)。接着压制混合物以形成单刻痕片剂(每片600mg组合物)。
或者,用明胶(20mg)水溶液充分掺合本发明化合物(100mg)与玉米淀粉(100mg)。干燥混合物且研磨成细粉。接着使微晶纤维素(50mg)和硬脂酸镁(5mg)与明胶调配物掺合,粒化且压制所得混合物以形成片剂(每片100mg本发明化合物)。
用于口服投与的示例性悬浮液调配物
混合下列成分以形成每10mL悬浮液含有100mg本发明化合物的悬浮液:
用于口服投与的示例性液体调配物
适合的液体调配物为含基于羧酸的缓冲液,如柠檬酸盐、乳酸盐和马来酸盐缓冲溶液的调配物。举例来说,使本发明化合物(其可预先与DMSO混合)与100mM柠檬酸铵缓冲液掺合且调整pH值到pH 5,或与100mM柠檬酸溶液掺合且调整pH值到pH 2。这些溶液还可包括增溶性赋形剂,如环糊精,例如溶液可包括10重量%羟丙基-β-环糊精。
其它适合的调配物包括含或不含环糊精的5%NaHCO3溶液。
用于通过注射投与的示例性可注射调配物
掺合本发明化合物(0.2g)与0.4M乙酸钠缓冲溶液(2.0mL)。必要时使用0.5N盐酸水溶液或0.5N氢氧化钠水溶液调整所得溶液的pH值到pH 4,且接着加入足够注射用水以提供20mL的总体积。混合物接着经无菌过滤器(0.22微米)过滤以提供适于通过注射投与的无菌溶液。
用于通过吸入投与的示例性组合物
本发明化合物(0.2mg)经微粒化且接着与乳糖(25mg)掺合。接着将此经掺合的混合物装入明胶吸入药筒中。使用例如干粉吸入器投与药筒的内含物。
或者,使微粒化的本发明化合物(10g)分散于通过将卵磷脂(0.2g)溶解于去矿物质水(200mL)中而制备的溶液中。喷雾干燥所得悬浮液且接着进行微粒化以形成包含平均直径小于约1.5μm的粒子的微粒化组合物。接着将微粒化组合物装入含有加压的1,1,1,2-四氟乙烷的定剂量吸入器药筒中,此装药量当通过吸入器投与时足以提供每剂约10μg到约500μg本发明化合物。
或者,将本发明化合物(25mg)溶解于经柠檬酸盐缓冲(pH 5)的等渗盐水(125mL)中。搅拌混合物且进行声波处理直到化合物溶解。检查溶液的pH值且必要时通过缓慢加入1N NaOH水溶液来调整到pH 5。使用喷雾器装置投与溶液可提供每剂约10μg到约500μg本发明化合物。
实例
提供下列制备和实例以说明本发明的特定实施例。然而,除非明确指示,否则这些特定实施例不打算以任何方式限制本发明的范围。
除非另外指示,否则下列缩写具有下列含义,且本文中使用且未加以定义的任何其它缩写都具有其标准公认含义:
AcOH 乙酸
BOC 叔丁氧基羰基(-C(O)OC(CH3)3)
DCM 二氯甲烷(dichloromethane或methylene chloride)
DIPEA N,N-二异丙基乙胺
DMA N,N-二甲基乙酰胺
DMF N,N-二甲基甲酰胺
EDC 1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺
Et3N 三乙胺
Et2O 乙醚
EtOAc 乙酸乙酯
EtOH 乙醇
Et3SiH 三乙基硅烷
HATU 六氟磷酸N,N,N',N'-四甲基-O-(7-氮杂苯并三唑-1-基)脲
HCTU (六氟磷酸2-(6-氯-1H-苯并三唑-1-基)-1,1,3,3-四甲基铵)
HEPES 4-(2-羟乙基)-1-哌嗪乙烷磺酸
HOBt 1-羟基苯并三唑
MeCN 乙腈
MeOH 甲醇
MeTHF 2-甲基四氢呋喃
Pd(dppf)2Cl2 [1,1′-双(二苯基膦基)二茂铁]二氯化钯
Pd(PPh3)4 四(三苯基膦)钯(0)
PE 石油醚
PMB 对甲氧基苯甲基
PyBOP 六氟磷酸苯并三唑-1-基氧基三(吡咯烷基)磷
DPP-Pd 基于二氧化硅的二苯基膦钯(II)催化剂
TFA 三氟乙酸
THF 四氢呋喃
除非另外指示,否则所有物质,如试剂、起始物质和溶剂都购自商业供货商(如西格玛-奥德里奇公司(Sigma-Aldrich)、福路卡里德尔-德汉公司(Fluka Riedel-de)等)且不经进一步纯化即使用。
除非另外指示,否则反应在氮气气氛下进行。反应进展是通过薄层色谱(TLC)、分析型高效液相色谱(分析型HPLC)和质谱加以监测的,其详情在特定实例中给出。分析型HPLC中使用的溶剂如下:溶剂A为98%H2O/2%MeCN/1.0mL/L TFA;溶剂B为90%MeCN/10%H2O/1.0mL/L TFA。
如例如每个制备中明确所述处理反应物;通常通过萃取和其它纯化方法,如温度依赖性和溶剂依赖性结晶和沉淀来纯化反应混合物。此外,反应混合物是通过通常使用Microsorb C18和Microsorb BDS柱填充物和常规洗脱剂进行制备型HPLC来加以常规纯化的。反应进展通常通过液相色谱质谱(LCMS)来测量。异构体的表征是通过核奥弗豪泽效应光谱分析(Nuclear Overhauser effect spectroscopy,NOE)进行。通过质谱和1H-NMR光谱按常规进行反应产物的表征。对于NMR测量,将样品溶解于氘化溶剂(CD3OD、CDCl3或DMSO-d6)中,且用Varian Gemini 2000仪器(400MHz)在标准观察条件下获得1H-NMR光谱。通常使用以Applied Biosystems(加利福尼亚州福斯特城(Foster City,CA))型号API 150EX仪器或Agilent(加利福尼亚州帕洛阿尔托(Palo Alto,CA))型号1200LC/MSD仪器进行的电喷雾电离法(ESMS)来进行化合物的质谱鉴别。
制备1:(R)-3-[N-(4-溴苯甲基)-N′-叔丁氧基羰基肼基]-2-羟基丙酸甲酯
将溴化4-溴苄(5.0g,20mmol)和DIPEA(3.5mL,20.0mmol)溶解于DMF(20mL)中。加入肼基甲酸叔丁酯(7.9g,60.0mmol),且在室温下搅拌混合物直到反应完成。将混合物部分浓缩,接着将残余物分配于EtOAc与NaHCO3饱和水溶液之间。EtOAc层接着经Na2SO4干燥并浓缩。粗产物通过快速色谱纯化,得到化合物1(3.8g)。
将化合物1(1.9g,6.3mmol)溶解于异丙醇(26.4mL)中。加入(2R)-缩水甘油酸甲酯(1.1mL,12.6mmol),且将混合物在90℃下加热直到反应完成(约4天)。将混合物冷却到室温并浓缩,得到呈白色固体状的标题化合物(2.5g)。
制备2:N′-(4-溴苯甲基)肼甲酸叔丁酯
向经搅拌的肼基甲酸叔丁酯(50g,0.4mol)于无水THF(400mL)中的溶液中逐滴加入4-溴苯甲醛(70g,0.4mol)于无水THF(200mL)中的溶液。将混合物在室温下搅拌2小时,且接着在真空中浓缩,得到呈黄色固体状的化合物1(113.8g)。LC-MS:243[M-tBu+H]+。
在0℃下向化合物1(113.8g,0.4mol)于无水THF(1L)中的溶液中分批加入NaCNBH3(36g,0.6mol)。逐滴加入AcOH(180mL),且将所得混合物在室温下搅拌过夜。加入水(2L)和EtOAc(1.5L),且用Na2CO3饱和水溶液将水相调节到pH=7。分离有机层,用NaCl饱和水溶液和水(200mL)洗涤,经无水Na2SO4干燥,且在真空中浓缩。残余物用MeOH(2L)和1N NaOH(1.5L)处理,且接着在室温下搅拌2小时。在去除MeOH溶剂之后,通过过滤收集沉淀,得到呈白色固体状的标题化合物(112g)。LC-MS:245[M-tBu+H]+。
制备3:(R)-3-[N′-叔丁氧基羰基-N-(5′-氯-2′-氟联苯-4-基甲基)肼基]-2-羟基
丙酸甲酯
向N'-(4-溴苯甲基)肼甲酸叔丁酯(60g,0.2mol)于1,4-二噁烷(1.5mL)中的溶液中加入5-氯-2-氟苯基硼酸(38g,0.2mol)和Pd(dppf)Cl2(7.3g)。将混合物在室温下在氮气下搅拌10分钟,且接着加入含K2CO3(55.2g,0.4mol)的水(240mL)。将所得混合物在60℃下搅拌3小时,且接着冷却到室温且在真空中浓缩。残余物用EtOAc(3×300mL)萃取。合并的有机层经无水Na2SO4干燥且在真空中浓缩。产物通过柱色谱(己烷/EtOAc=10:1到5:1)纯化,得到呈粉红色固体状的化合物1(56g)。LC-MS:701[2M+H]+。
在氮气下向化合物1(20g,57mmol)于异丙醇(250mL)中的溶液中加入(2R)-缩水甘油酸甲酯(8.7g,86mmol)。将混合物在85℃下搅拌3天,接着冷却到室温。通过过滤收集沉淀的固体,得到呈灰白色固体状的标题化合物(18.5g)。LC-MS:397[M-tBu+H]+。
制备4:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯
将(R)-3-[N-(4-溴苯甲基)-N′-叔丁氧基羰基肼基]-2-羟基丙酸甲酯(1.0g,2.5mmol)、5-氯-2-氟苯基硼酸(865mg,5.0mmol)和K2CO3(857mg,6.2mmol)组合在EtOH(30mL,500mmol)和水(8mL,400mmol)中,随后加入 DPP-Pd(0.28mmol/g负载;886mg,248μmol)。将混合物在90℃下加热直到反应完成(2小时)。滤出沉淀,且将滤液浓缩并通过反相色谱(30%-95%MeCN/水与0.5%TFA)纯化。收集纯净的洗脱份,冻干,并与含4MHCl的二噁烷(8mL,30mmol)和EtOH(10mL,200mmol)组合。将所得混合物在室温下搅拌直到反应完成(7小时)。浓缩混合物,得到油状物,所述油状物用几滴EtOH在醚中搅拌过夜。将沉淀滤出且用醚冲洗,得到标题化合物(140mg)。
(R)-3-[N-(5'-氯-2′-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯的替代制备
将(R)-3-[N′-叔丁氧基羰基-N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸甲酯(20g,16mmol)于HCl/EtOH(1.1M,200mL)中的溶液搅拌过夜且接着在真空中浓缩。将残余物分散在EtOAc(2×40mL)中,且通过过滤收集沉淀,得到呈灰白色固体盐酸盐形式的标题化合物(8.8g)。LC-MS:367[M+H]+。1H NMR(300MHz,DMSO-d6)δ1.05(t,J=7.2Hz,3H),3.05-3.03(q,J=7.2Hz,2H),4.06-3.95(m,4H),4.42(br,1H),6.46(br,1H),7.62-7.40(m,7H),9.42(s,3H)。
制备5:1-(3-氯苯基)-5-氧代-4,5-二氢-1H-[1,2,4]三唑-3-甲酸
将1-(3-氯苯基)-5-氧代-4,5-二氢-1H-1,2,4-三唑-3-甲酸乙酯(200.0mg,747μmol)、LiOH(71.6mg,1.5mmol)于水(2mL)和MeOH(10.0mL,247mmol)中的混合物在室温下搅拌过夜,接着浓缩。残余物用1N HCl酸化到pH 3-4,形成沉淀,过滤所述沉淀,用水(2×5mL)洗涤,且在真空中干燥,得到标题化合物(100.6mg)。
制备6:(R)-3-[N-(4-溴苯甲基)肼基]-2-羟基丙酸乙酯
将(R)-3-[N-(4-溴苯甲基)-N'-叔丁氧基羰基肼基]-2-羟基丙酸甲酯(25g,62mmol)于EtOH/HCl(1M,310mL,0.3mol)中的溶液搅拌过夜,直到反应完成。接着浓缩混合物,且残余物用EtOAc(120mL)洗涤且过滤。收集固体,得到呈白色固体盐酸盐形式的标题化合物(15g)。
制备7:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸5-甲基-2-氧
代-[1,3]间二氧杂环戊烯-4-基甲酯
将含水合LiOH(3g,73mmol)的水(60mL)加入到含(R)-3-[N'-叔丁氧基羰基-N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸甲酯(16.5g,36.5mmol)的MeOH(300mL)中。将混合物在室温下搅拌2小时,且在真空中蒸发MeOH。用1M HCl水溶液将混合物调节到pH=5,且残余物用EtOAc(2×300mL)萃取。合并的有机层经无水Na2SO4干燥,且在真空中浓缩,得到呈白色固体状的化合物1(18g)。LC-MS:383[M-tBu+H]+。
向化合物1(1.5g,3.42mmol)、K2CO3(0.95g,6.84mmol)和碘化钾(20mg)于DMF(40mL)中的溶液中加入含4-(溴甲基)-5-甲基-1,3-间二氧杂环戊烯-2-酮(0.8g,4.1mmol)的DMF(15mL)。将所得混合物在室温下搅拌4小时。加入NaCl饱和水溶液(30mL),且用EtOAc(2×50mL)萃取混合物。合并的有机层经无水Na2SO4干燥且在真空中浓缩。残余物通过柱色谱(己烷/EtOAc=1:1)纯化,得到呈黄色固体状的化合物2(930mg)。LC-MS:495[M-tBu+H]+。
将化合物2(400mg,0.73mmol)溶解于MeCN(20mL)中,且冷却到0℃。逐滴加入N-三甲基硅烷基咪唑(290mg,1.46mmol),且将所得混合物搅拌2小时。加入MeOH(50mL)以淬灭反应。混合物用NaCl饱和水溶液(2×50mL)洗涤且用DCM(2×80mL)萃取。合并的有机层经无水Na2SO4干燥且在真空中浓缩。收集产物,得到呈黄色固体状的标题化合物(200mg)。LC-MS:451[M+H]+。
制备8:5-氧代-1-苯基-4,5-二氢-1H-[1,2,4]三唑-3-甲酸
将2,5-二氢-5-氧代-1-苯基-1h-1,2,4-三唑-3-甲酸甲酯(300.0mg,1.4mmol)与MeOH(4.5mL,110mmol)和水(0.5mL,30mmol)在室温下混合,接着在室温下用一水合LiOH(0.1g,2.7mmol)处理过夜。浓缩混合物,且用1N HCl水溶液将所得残余物酸化到pH约1。将所得固体过滤且用水冲洗,接着在真空中干燥,得到呈微黄色固体状的标题化合物(185mg),其不经进一步纯化即使用。
制备9:2-三苯甲基-2H-四唑-5-甲酸锂盐
将乙基-5-四唑甲酸钠盐(2.3g,14mmol)溶解于DMF(20mL,200mmol)中。将混合物在0℃下冷却。加入三苯甲基氯(3.9g,14.1mmol),且将所得混合物在室温下搅拌过夜,得到浆料。将浆料缓慢倾入经搅拌的冷水(200mL)中。将所得浆料搅拌15分钟(加入碳酸氢盐以保持pH碱性),接着过滤且干燥,得到白色固体(5.1g)。将固体悬浮在MeOH(50mL,1.0mol)中,随后加入溶解于水(10mL)中的一水合LiOH(886mg,21.1mmol)。将所得混合物在室温下搅拌3小时。滤出任何固体,且通过旋转蒸发浓缩滤液。加入EtOAc(50mL),且将混合物干燥。将此举重复两次。接着将产物在高真空下在室温下干燥,得到标题化合物。
制备10:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(2-三苯甲基-2H-四唑-5-
羰基)肼基]-2-羟基丙酸
将含2-三苯甲基-2H-四唑-5-甲酸锂盐(385.2mg,1.1mmol)和HATU(404.3mg,1.1mmol)的DMF(5.9mL,76mmol)在室温下搅拌10分钟。依序加入(R)-3-[N-(5'-氯-2′-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯(300mg,818μmol)和DIPEA(285μL,1.6mmol)。将所得混合物在室温下搅拌过夜。将混合物分配于EtOAc(10.0mL)与水(2.0mL)之间。有机层用水(2.0mL)洗涤,经Na2SO4干燥,过滤且浓缩,得到微黄色油状物。油状残余物接着通过快速色谱(0%-50%EtOAc/己烷)纯化。将所需洗脱份合并且浓缩,得到淡微黄色油状物(与其它批次合并成总共147.2mg)。将此残余物在室温下溶解于MeOH(5.0mL,120mmol)和水(0.5mL,30mmol)中。加入一水合LiOH(17.5mg,417μmol),并使其静置30分钟。浓缩混合物,且所得残余物用EtOAc(10.0mL)处理并用1NHCl酸化直到pH约3。有机层用NaCl饱和水溶液(3×3.0mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到呈白色泡沫状的标题化合物(99.4mg)。
制备11:1-烯丙基-1H-四唑-5-甲酸锂
在0℃下向经搅拌的1H-四唑-5-甲酸乙酯(2.0g,14.1mmol)于DMF(20mL)中的溶液中加入K2CO3(2.3g,16.9mmol)和3-溴丙-1-烯(1.9g,15.4mmol)。将混合物温热到室温,搅拌过夜,接着倾入到水(200mL)中。所得溶液用EtOAc(3×100mL)萃取。合并的有机层用NaCl饱和水溶液(100mL)洗涤,经无水Na2SO4干燥,过滤并在真空中浓缩,得到呈黄色油状物的化合物1(2.3g)。LC-MS:183[M+H]+。
向化合物1(2.3g,12.6mmol)于EtOH(20mL)中的溶液中加入LiOH·H2O(636mg,15.2mmol)于水(10mL)中的溶液。将混合物在室温下搅拌3小时,滤出固体,并将滤液在真空中浓缩,得到呈黄色固体状的标题化合物(2.0g),其不经进一步纯化即使用。
制备12:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯
向经搅拌的肼基甲酸叔丁酯(50g,0.4mol)于无水THF(400mL)中的溶液中逐滴加入4-溴苯甲醛(70g,0.4mol)于无水THF(200mL)中的溶液。将混合物在室温下搅拌2小时,且接着在真空中浓缩,得到呈黄色固体状的化合物1(113.8g)。LC-MS:243[M-tBu+H]+。
在0℃下向化合物1(113.8g,0.4mol)于无水THF(1L)中的溶液中分批加入NaCNBH3(36g,0.6mol)。逐滴加入AcOH(180mL),且将所得混合物在室温下搅拌过夜。加入水(2L)和EtOAc(1.5L),且用Na2CO3饱和水溶液将水相调节到pH 7。分离有机层,用NaCl饱和水溶液和水(200mL)洗涤,经无水Na2SO4干燥,且在真空中浓缩。残余物用MeOH(2L)和1N NaOH(1.5L)处理,且接着在室温下搅拌2小时。在去除MeOH溶剂之后,通过过滤收集沉淀,得到呈白色固体状的化合物2(112g)。LC-MS:245[M-tBu+H]+。
向化合物2(60g,0.2mol)于1,4-二噁烷(1.5mL)中的溶液中加入5-氯-2-氟苯基硼酸(38g,0.2mol)和Pd(dppf)Cl2(7.3g)。将混合物在室温下在氮气下搅拌10分钟,且加入含K2CO3(55.2g,0.4mol)的水(240mL)。将所得混合物在60℃下搅拌3小时,接着冷却到室温且在真空中浓缩。残余物用EtOAc(3×300mL)萃取。合并的有机层经无水Na2SO4干燥且在真空中浓缩。产物通过柱色谱(PE:EtOAc=10:1到5:1)纯化,得到呈粉红色固体状的化合物3(56g)。LC-MS:701[2M+H]+。
在氮气下向化合物3(20g,57mmol)于异丙醇(250mL)中的溶液中加入(2R)-缩水甘油酸甲酯(8.7g,86mmol)。将混合物在85℃下搅拌3天,接着冷却到室温。通过过滤收集沉淀的固体,得到呈灰白色固体状的化合物4(18.5g)。LC-MS:397[M-tBu+H]+。
将化合物4(20g,16mmol)于HCl/EtOH(1.1M,200mL)中的溶液搅拌过夜且接着在真空中浓缩。将残余物分散在EtOAc(2×40mL)中,且通过过滤收集沉淀,得到呈灰白色固体盐酸盐形式的标题化合物(8.8g)。LC-MS:367[M+H]+。1H NMR(300MHz,DMSO-d6)δ1.05(t,J=7.2Hz,3H),3.05-3.03(q,J=7.2Hz,2H),4.06-3.95(m,4H),4.42(br,1H),6.46(br,1H),7.62-7.40(m,7H),9.42(s,3H)。
制备13:(R)-3-(2-(1-烯丙基-1H-四唑-5-羰基)-1-((5′-氯-2′-氟联苯-4-基)甲
基)肼基)-2-羟基丙酸锂
在0℃下在氮气下向(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯(3.4g,8.3mmol)和1-烯丙基-1H-四唑-5-甲酸锂(2.0g,12.50mmol)于DMF(40mL)中的溶液中逐滴加入PyBOP(8.7g,16.7mmol)和DIPEA(2.1g,16.7mmol)。将所得混合物搅拌2.5小时,接着倾入到水(400mL)中。所得溶液用EtOAc(2×200mL)萃取。合并的有机层用NaCl饱和水溶液(100mL)洗涤,经无水Na2SO4干燥,过滤,且在真空中浓缩。残余物通过柱色谱(PE:EtOAc=5:1到4:1到3:1)纯化,得到呈黄色油状物的化合物1(2.5g)。LC-MS:503[M+H]+。
向化合物1(2.5g,4.97mmol)于EtOH(25mL)中的溶液中加入LiOH·H2O(250mg,6.0mmol)于水(10mL)中的溶液。将混合物在室温下搅拌3小时,滤出固体,并将滤液在真空中浓缩,得到呈黄色固体状的标题化合物(2.2g),其不经进一步纯化即使用。
制备14:(R)-3-{N-(3′-氯联苯-4-基甲基)-N'-[3-(4-甲氧基苯甲氧基)异噁唑-
5-羰基]肼基}-2-羟基丙酸异丙酯
在氮气下将N'-(3'-氯联苯-4-基甲基)肼甲酸叔丁酯(400.0g,1.2mol)与IPA(7.0L,91mol)和(R)-环氧乙烷-2-甲酸甲酯(105.2mL,1.2mol)组合。将混合物在83℃下加热51小时。再加入(R)-环氧乙烷-2-甲酸甲酯(52.61mL,600.9mmol),且将混合物在84℃下加热48小时。加入氰基硼氢化钠(1.0g,16mmol),且将混合物在80℃下加热,并监测反应(约等于48小时)。再加入氰基硼氢化钠(1g),且将混合物在回流下加热(约等于3天)。接着将混合物在15℃下缓慢冷却;过滤,并干燥,得到化合物1(470g)。
将化合物1(880mg,1.9mmol)与含3M HCl的CPME(7mL,20mmol)组合。接着将混合物在冰浴上搅拌,并监测反应完成(约等于2.5小时)。收集固体,用CPME(0.5mL)洗涤,并干燥,得到白色粉末(0.6g;盐酸盐)。接着将粉末溶解于IPA(15mL)中并加热到回流。使所得浆料冷却到室温并搅拌1小时。收集固体,得到呈白色固体状的化合物2。
在0℃下向经搅拌的3-羟基异噁唑-5-甲酸甲酯(5.0g,35mmol)于DMF(20mL,300mmol)中的溶液中加入K2CO3(5.4g,39.4mmol)。在室温下10分钟后,一次性加入对甲氧基苯甲基氯(5.5mL,40.2mmol)。将所得混合物在60℃下加热2小时,且接着冷却到室温并搅拌过夜。加入含1.0M HCl的水(150mL)和EtOAc(150mL),并分离各相。有机层用NaCl饱和水溶液(10mL)洗涤,经Na2SO4干燥,并通过旋转蒸发去除溶剂,得到浓稠油状物。将油状物溶解于THF(35mL)和MeOH(35mL)中,随后加入溶解于水(35mL)中的一水合LiOH(2.9g,69.9mmol)。将所得混合物在室温下搅拌,并监测反应完成(约等于3小时)。溶剂在30℃下通过旋转蒸发去除,得到糊状固体。加入甲苯(100mL)并将体积减小(达到约50ml)。加入EtOAc(200mL)并将体积减小(达到约50ml)。过滤并干燥,得到固体(10g),将所述固体溶解于水(200mL)中,并用浓HCl将pH缓慢调节到约等于2。加入EtOAc(200mL),并分离各相。水层用EtOAc(200mL)反萃取。合并的有机层经Na2SO4干燥,随后去除溶剂。产物在EtOAc:己烷(1:1)中重新打浆,随后过滤,得到化合物3(纯度>99%)。
将含化合物2(18.0g,26.8mmol)的DMF(90mL)与含化合物3(7.3g,29mmol)的DIPEA(12mL,67mmol)组合。将混合物在0℃下冷却,随后分批加入PyBOP(18g,35mmol),并监测反应完成(在0℃下约等于30分钟)。加入水(540mL)和EtOAc(540mL),并分离各相。有机层用NaCl饱和水溶液(500mL)洗涤并经Na2SO4干燥,随后去除溶剂。将粗产物纯化(SiG色谱;300g柱,10%-30%-50%EtOAc/己烷),得到标题化合物(9g,纯度>98%)。
制备15:(R)-3-[N-(3'-氯联苯-4-基甲基)-N'-(3-羟基异噁唑-5-羰基)肼基]-2-
羟基丙酸2-氧代-2-苯基乙酯
将(R)-3-{N-(3'-氯联苯-4-基甲基)-N'-[3-(4-甲氧基苯甲氧基)异噁唑-5-羰基]肼基}-2-羟基丙酸异丙酯(2.0g,3.4mmol)与MeOH(40mL,1.0mol)组合。加入溶解于水(5mL,300mmol)中的一水合LiOH(170mg,4.0mmol),并将所得混合物在室温下搅拌过夜。混合物通过旋转蒸发浓缩。将残余物与MeOH混合并再通过旋转蒸发浓缩。接着将残余物在高真空下在室温下干燥,得到粗化合物1(2g)。
将2-溴苯乙酮(44.6mg,224μmol)加入到化合物1(100.0mg,179.2μmol)和K2CO3(49.5mg,358.5μmol)于DMF(2.0mL,26mmol)中的混合物中。将所得混合物在室温下搅拌30分钟,浓缩,并通过快速色谱(EtOAc-己烷=20%-80%)纯化,得到固体(107.7mg)。将固体与TFA(82.86μL,1.075mmol)和苯甲醚(194.8μL,1.8mmol)组合于DCM(5.0mL,78mmol)中,并在室温下搅拌24小时。将混合物浓缩,并将残余物溶解于AcOH(2mL)中,过滤,并通过反相制备型HPLC纯化。将所需洗脱份合并且冻干,得到标题化合物(79.4mg)。
制备16:(S)-2-叔丁氧基羰基氨基-3-甲基丁酸氯甲酯
在0℃下向(S)-2-(叔丁氧基羰基氨基)-3-甲基丁酸(28.6g,130mmol)和NaHCO3(44g,520mmol)和Bu4NHSO4(4.4g,13mmol)于DCM(200mL)和水(200mL)中的混合物中加入氯磺酸氯甲酯(26g,158mmol)。将混合物在室温下搅拌24小时,且接着用DCM(3×150mL)萃取。合并的有机层用水(2×300mL)洗涤,且DCM层通过快速柱(PE:EtOAc=15:1)纯化,得到呈黄色固体状的标题化合物(35g)。LC-MS:266[M+H]+。
制备17:(S)-2-甲氧基羰基氨基-3-甲基丁酸氯甲酯
在0℃下(S)-2-叔丁氧基羰基氨基-3-甲基丁酸氯甲酯(35g,132mmol)于DCM(200mL)中的溶液逐滴加入TFA(50mL)于DCM(100mL)中的溶液。将所得混合物在室温下搅拌过夜,且接着在真空中浓缩,得到呈黄色油状物的粗化合物1(21.8g)。LC-MS:166[M+H]+。
在0℃下向化合物1(21.8g,139mmol)和氯甲酸甲酯(12mL,157mmol)于THF(1L)中的混合物中加入TEA(38mL,278mmol)。将所得混合物在室温下搅拌12小时,接着在真空中浓缩。残余物通过快速柱(PE:EtOAc=6:1)纯化,得到呈黄色固体状的标题化合物(20.3g)。LC-MS:224[M+H]+。1H NMR(400MHz,DMSO-d6):δ0.97-1.02(m,6H),2.16-2.21(m,1H),3.68(s,1H),4.14(d,J=4Hz,1H),5.76-5.91(m,2H)。
制备18:(R)-3-[N-(4-溴苯甲基)肼基]-2-羟基丙酸甲酯
将(R)-3-[N-(4-溴苯甲基)-N'-叔丁氧基羰基肼基]-2-羟基丙酸甲酯(1.1g,2.8mmol)溶解于MeCN(10mL)和含4N HCl的二噁烷(6mL,20mmol)中。将混合物在室温下搅拌,直到脱除保护基完成(1小时)。将沉淀过滤并干燥,得到呈盐酸盐形式的标题化合物(840mg)。
制备19:1-烯丙氧基-1H-[1,2,3]三唑-4-甲酸
在室温下向1-羟基-1H-[1,2,3]三唑-4-甲酸乙酯(5g,31.8mmol)于DMF(20mL)中的溶液中加入K2CO3(5.3g,38.2mmol)。在10分钟之后,加入烯丙基溴(4g,33.4mmol)。将混合物在室温下搅拌过夜。加入水(150mL),并用EtOAc(3×50mL)萃取混合物。合并的有机层用NaCl饱和水溶液(50mL)洗涤并经无水Na2SO4干燥。将溶液蒸发,且残余物通过硅胶色谱(硅胶:200-300目,用PE:EA=10:1到5:1到1:1洗脱)纯化,得到呈黄色油状物的化合物1(4.3g)。LC-MS:198[M+H]+。
向化合物1(4.3g,22.0mmol)于EtOH(30mL)中的溶液中加入LiOH(1.2g,28.5mmol)于水(10mL)中的溶液。将所得混合物在室温下搅拌过夜。将混合物浓缩,加入水(10mL),并用EtOAc(2×20mL)萃取混合物。水层通过1N HCl酸化到pH 3,并用EtOAc(3×30mL)萃取。合并的有机层用NaCl饱和水溶液(30mL)洗涤,并经无水Na2SO4干燥。蒸发溶液,得到呈白色固体状的标题化合物(3.5g)。LC-MS:170[M+H]+。
制备20:(R)-3-[N′-(1-烯丙氧基-1H-[1,2,3]三唑-4-羰基)-N-(2′,5'-二氯联
苯-4-基甲基)-肼基]-2-羟基丙酸
在0℃下向(R)-3-[N-(2',5'-二氯联苯-4-基甲基)肼基]-2-羟基-丙酸乙酯(盐酸盐,4g,9.9mmol)和1-烯丙氧基-1H-[1,2,3]三唑-4-甲酸(1.7g,9.9mmol)于DMF(30mL)中的溶液中加入PyBOP(5.2g,9.9mmol)和DIPEA(3.2g,24.8mL)。将混合物在室温下搅拌4小时。加入水(200mL),且用EtOAc(3×100mL)萃取混合物,且合并的有机层用NaCl饱和水溶液(100mL)洗涤且经无水Na2SO4干燥。将混合物浓缩,且残余物通过硅胶色谱(硅胶:200-300目;用PE:EtOAc=10:1到5:1到1:1洗脱)纯化,得到呈淡黄色固体状的化合物1(4.2g)。LC-MS:534[M+H]+,536[(M+2)+H]+。
在室温下向化合物1(4.2g,7.9mmol)于THF(20mL)和水(5mL)中的溶液中加入LiOH(0.5g,11.8mmol)。将反应混合物在室温下搅拌过夜。将混合物浓缩,加入水(50mL),并用EtOAc(2×20mL)萃取所得混合物。水层通过1N HCl酸化到pH 3,并用EtOAc(3×50mL)萃取。合并的有机层用NaCl饱和水溶液(50mL)洗涤并经无水Na2SO4干燥。蒸发溶液,得到呈黄色固体状的标题化合物(3.5g)。LC-MS:506[M+H]+,508[(M+2)+H]+。
实例1A:(R)-3-{N-(5'-氯-2'-氟联苯-4-基甲基)-N'-[1-(3-氯苯基)-5-氧代-4,
5-二氢-1H-[1,2,4]三唑-3-羰基]肼基}-2-羟基丙酸
将1-(3-氯苯基)-5-氧代-4,5-二氢-1H-[1,2,4]三唑-3-甲酸(75.8mg,316μmol)和HCTU(131mg,316μmol)组合在DMF(1.3mL,17.2mmol)中,并在室温下搅拌15分钟。加入(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯(105mg,287μmol)和DIPEA(150μL,862μmol),并将所得混合物在室温下搅拌15分钟。在减压下蒸发混合物。将残余物溶解于EtOH(1.0mL,17.2mmol)中,并加入1M LiOH于水(1.4mL,1.4mmol)中的溶液。将所得混合物在室温下搅拌1小时,接着在减压下蒸发。残余物通过反相制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(75mg,纯度100%)。MS m/z[M+H]+C25H20Cl2FN5O5的计算值560.08;实验值559.6。
实例1B和1C:(R)-3-{N-(5'-氯-2'-氟联苯-4-基甲基)-N'-[1-(3-氯苯基)-5-氧
代-4,5-二氢-1H-[1,2,4]三唑-3-羰基]肼基}-2-羟基丙酸乙酯(化合物1)和(R)-3-{N-
(5'-氯-2'-氟联苯-4-基甲基)-N'-[1-(3-氯苯基)-5-氧代-4,5-二氢-1H-[1,2,4]三唑-3-
羰基]肼基}-2-羟基丙酸异丁酯(化合物2)
将1-(3-氯苯基)-5-氧代-4,5-二氢-1H-[1,2,4]三唑-3-甲酸(27.6mg,115μmol)和HATU(52.5mg,138μmol)在DMA(1.0mL,11mmol)中搅拌10分钟。加入(R)-3-[N-(5′-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯(42.2mg,115μmol)和DIPEA(60.1μL,345μmol),并将所得混合物在室温下搅拌2小时。将混合物在减压下浓缩,并将残余物溶解于EtOAc(20mL)中。有机层用水(2×5mL)洗涤,经MgSO4干燥,并浓缩。将一半物质溶解于50%乙酸-水(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到呈三氟乙酸盐形式的化合物1(1.3mg,纯度96%)。MS m/z[M+H]+C27H24Cl2FN5O5的计算值588.11;实验值588.4。
将剩余一半的物质与异丁醇(0.5mL,6mmol)和含4.0M HCl的1,4-二噁烷(115μL,460μmol)组合,并在室温下搅拌过夜。接着,将混合物在减压下浓缩,并将残余物溶解于50%乙酸-水(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到呈三氟乙酸盐形式的化合物2(1.8mg,纯度100%)。MS m/z[M+H]+C29H28Cl2FN5O5的计算值616.15;实验值616.4。
实例1D:(S)-2-氨基-3-甲基丁酸(R)-3-{N-(5'-氯-2'-氟联苯-4-基甲基)-N′-
[1-(3-氯苯基)-5-羟基-1H-[1,2,4]三唑-3-羰基]肼基}-2-羟基丙酰氧基甲酯
使用本文所述的程序,也可制备标题化合物。
实例1E:(R)-3-{N-(5'-氯-2'-氟联苯-4-基甲基)-N'-[1-(3-氯苯基)-5-羟基-
1H-[1,2,4]三唑-3-羰基]肼基}-2-羟基丙酸乙酰氧基甲酯
使用本文所述的程序,也可制备标题化合物。
实例1F:(S)-2-氨基-3-甲基丁酸5-[N'-((R)-2-羧基-2-羟基乙基)-N'-(5'-氯-
2'-氟联苯-4-基甲基)肼基羰基]-2-(3-氯苯基)-2H-[1,2,4]三唑-3-基氧基甲酯
使用本文所述的程序,也可制备标题化合物。
实例1G:(R)-3-[N'-[5-乙酰氧基甲氧基-1-(3-氯苯基)-1H-[1,2,4]三唑-3-羰
基]-N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸
使用本文所述的程序,也可制备标题化合物。
实例2A:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(2-羟基噻唑-5-羰基)肼
基]-2-羟基丙酸
将2-羟基-5-噻唑甲酸(43.5mg,0.3mmol)和HCTU(124mg,0.3mmol)在DMF(1.3mL,16.4mmol)中在室温下搅拌15分钟。加入(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯(100mg,0.3mmol)和DIPEA(142μL,818μmol),并将所得混合物在室温下搅拌30分钟。接着在减压下蒸发混合物。将残余物溶解于EtOH(955μL,16.4mmol)中。加入1.0MLiOH于水(1.4mL,1.4mmol)中的溶液,且将所得混合物在40℃下搅拌3小时。LC/MS展示完成。在真空中去除溶剂,且残余物通过制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(22mg)。MS m/z[M+H]+C20H17ClFN3O5S的计算值466.06;实验值466.0。
实例2B:(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N′-(2-羟基噻唑-5-羰基)肼
基]-2-羟基丙酸乙酯
将2-羟基-5-噻唑甲酸(9.0mg,62μmol)和HATU(28.3mg,74μmol)在DMA(0.5mL,5mmol)中搅拌10分钟。加入(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯(22.7mg,62μmol)和DIPEA(32.4μL,186μmol),并将所得混合物在室温下搅拌2小时。接着,将混合物在减压下浓缩,并将残余物溶解于50%AcOH-水(1.5mL)中,过滤,通过反相制备型HPLC纯化,并冻干,得到呈三氟乙酸盐形式的标题化合物(11.9mg,纯度96%)。MS m/z[M+H]+C22H21ClFN3O5S的计算值494.09;实验值494.4。
实例3A:(R)-3-{N-(5'-氯-2'-氟联苯-4-基甲基)-N'-[3-(2-氟苯基)异噁唑-5-
羰基]肼基}-2-羟基丙酸
将(R)-3-[N-(4-溴苯甲基)肼基]-2-羟基丙酸乙酯(580mg,1.8mmol)、HCTU(756mg,1.8mmol)和DMF(850mL,110mmol)组合。15分钟后,加入DIPEA(956μL,5.5mmol)和3-(2-氟苯基)异噁唑-5-甲酸(417mg,2.0mmol)。将所得混合物在室温下搅拌15分钟。在压力下去除溶剂,且将粗残余物纯化(反相色谱),得到化合物1(5695mg)。
将化合物1(700mg,1mmol)和5-氯-2-氟苯基硼酸(273mg,1.6mmol)与K2CO3(541mg,3.9mmol)、EtOH(4.6mL,78.3mmol)、甲苯(13.9mL,130mmol)和水(1.2mL,65.2mmol)组合。接着在氮气下加入Pd(PPh3)4(151mg,130μmol),且将混合物在90℃下搅拌3小时。将混合物过滤并蒸发,且通过制备型HPLC纯化,得到标题化合物(40mg)。MS m/z[M+H]+C21H19ClFN3O6的计算值464.09;实验值464.0。
实例3B:(R)-3-{N-(5'-氯-2'-氟联苯-4-基甲基)-N'-[3-(2-氟苯基)异噁唑-5-
羰基]肼基}-2-羟基丙酸异丙酯
将3-(2-氟苯基)异噁唑-5-甲酸(15.4mg,74μmol)和HATU(33.9mg,89μmol)在DMA(0.5mL,5mmol)中搅拌10分钟。加入(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯(27.3mg,74μmol)和DIPEA(38.9μL,223μmol),并将所得混合物在室温下搅拌1小时。接着将混合物在减压下浓缩,并将残余物溶解于EtOAc(20mL)中并用水(2×2mL)洗涤。有机层经MgSO4干燥,过滤且浓缩。产物接着与异丁醇(0.5mL,5mmol)和含4.0M HCl的1,4-二噁烷(93μL,372μmol)混合,并在室温下搅拌过夜。将混合物在减压下浓缩,并将残余物溶解于50%AcOH-水(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(1.7mg,纯度100%)。MS m/z[M+H]+C30H28ClF2N3O5的计算值584.17;实验值584.4。
实例3C:(R)-3-{N-(5'-氯-2'-氟联苯-4-基甲基)-N′-[3-(2-氟苯基)异噁唑-5-
羰基]肼基}-2-羟基丙酸5-甲基-2-氧代-[1,3]间二氧杂环戊烯-4-基甲酯
将EDCI(92mg,480μmol)和HOBT(65mg,480μmol)加入到(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸5-甲基-2-氧代-[1,3]间二氧杂环戊烯-4-基甲酯(108mg,240μmol)和3-(2-氟苯基)异噁唑-5-甲酸(50mg,240μmol)于DMF(20mL)中的溶液中。加入DIPEA(62mg,480μmol),且将混合物在室温下搅拌5小时。混合物用NaCl饱和水溶液(2×30mL)洗涤且用EtOAc(2×50mL)萃取。合并的有机层经无水Na2SO4干燥且在真空中浓缩。残余物通过柱色谱(己烷/EtOAc=1:1)纯化,得到呈白色固体状的标题化合物(58mg)。LC-MS:640.2[M+H]+。1H-NMR:(CDCl3)2.07(s,3H),3.43(br,2H),4.4-4.2(m,2H),4.3(br,1H),4.94-4.86(m,2H),7.24-6.85(m,5H),7.97-7.27(m,8H)。
实例3D:(R)-3-{N-(5'-氯-2′-氟联苯-4-基甲基)-N′-[3-(2-氟苯基)异噁唑-5-
羰基]肼基}-2-羟基丙酸2,2,3,3,3-五氟丙酯
将(R)-3-{N-(5'-氯-2'-氟联苯-4-基甲基)-N'-[3-(2-氟苯基)异噁唑-5-羰基]肼基}-2-羟基丙酸(30.0mg,57μmol)、EDC HCl(65.4mg,341μmol)和水合HOBt(52.2mg,341μmol)于DCM(0.5mL,8mmol)中的混合物在室温下搅拌10分钟。加入2,2,3,3,3-五氟-1-丙醇(45.3μL,455μmol),且将所得混合物在室温下搅拌1小时,接着浓缩。将残余物溶解于AcOH(2mL)中,过滤,并通过反相制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(4.8mg,纯度90.2%)。MS m/z[M+H]+C29H21ClF7N3O5的计算值660.11;实验值660.3。
实例3E:(R)-3-{N-(5'-氯-2'-氟联苯-4-基甲基)-N'-[3-(2-氟苯基)-异噁唑-5-
羰基]肼基}-2-羟基丙酸乙酰氧基甲酯
将乙酸溴甲酯(11.9μL,121μmol)加入到(R)-3-{N-(5′-氯-2′-氟联苯-4-基甲基)-N'-[3-(2-氟苯基)异噁唑-5-羰基]肼基}-2-羟基丙酸(40.0mg,76μmol)和Et3N(21.1μL,152μmol)于丙酮(1.0mL,14mmol)中的混合物中。将所得混合物在室温下搅拌1小时。接着将混合物浓缩,并将残余物溶解于AcOH(2mL)中,过滤,并通过反相制备型HPLC纯化。将所需洗脱份冷冻并冻干,得到呈三氟乙酸盐形式的标题化合物(8.5mg,纯度98.5%)。MS m/z[M+H]+C29H24ClF2N3O7的计算值600.13;实验值600.1。
实例3F:(R)-3-{N-(5'-氯-2'-氟联苯-4-基甲基)-N'-[3-(2-氟苯基)异噁唑-5-
羰基]肼基}-2-羟基丙酸2-甲氧基乙酯
将乙烷1-溴-2-甲氧基(5.7μL,0.1mmol)加入到(R)-3-{N-(5'-氯-2'-氟联苯-4-基甲基)-N'-[3-(2-氟苯基)异噁唑-5-羰基]肼基}-2-羟基丙酸(20.0mg,38μmol)和Et3N(13.2μL,0.1mmol)于丙酮(1.0mL,14mmol)中的混合物中,并将所得混合物在50℃下搅拌过夜。将混合物浓缩,并将残余物溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(10.7mg,纯度95.7%)。MS m/z[M+H]+C29H26ClF2N3O6的计算值586.15;实验值585.8。
实例3G:丁酸(R)-3-{N-(5'-氯-2'-氟联苯-4-基甲基)-N'-[3-(2-氟苯基)异噁
唑-5-羰基]肼基}-2-羟基丙酰氧基甲酯
将丁酸氯甲酯(11.4μL,0.1mmol)和NaI(13.6mg,0.1mmol)组合在丙酮(0.7mL,10mmol)中,并在65℃下加热1小时。接着,将混合物冷却到室温。加入溶解于丙酮(0.2mL)中并用Et3N(8.5μL,61μmol)处理的(R)-3-{N-(5′-氯-2′-氟联苯-4-基甲基)-N'-[3-(2-氟苯基)异噁唑-5-羰基]肼基}-2-羟基丙酸(16.0mg,30μmol),且将所得混合物在室温下搅拌25分钟。将混合物浓缩,并将残余物溶解于AcOH(2.0mL)中,过滤,并通过反相制备型HPLC纯化。将所需洗脱份合并且冻干,得到微黄色固体。将此固体溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化。将所需洗脱份合并且冻干,得到呈三氟乙酸盐白色固体状的标题化合物(5.7mg,纯度100%)。MS m/z[M+H]+C31H28ClF2N3O7的计算值628.16;实验值628。
实例3H:(R)-3-{N-(5′-氯-2′-氟联苯-4-基甲基)-N′-[3-(2-氟苯基)异噁唑-5-
羰基]肼基}-2-羟基丙酸异丙氧基羰氧基甲酯
将碳酸氯甲酯异丙酯(17.3mg,114μmol)和NaI(17.0mg,114μmol)组合在丙酮(1.0mL,14mmol)中,且在60℃下加热1小时。接着,将混合物冷却到室温。加入溶解于丙酮(1.0mL)中并用Et3N(10.6μL,76μmol)处理的(R)-3-{N-(5'-氯-2'-氟联苯-4-基甲基)-N'-[3-(2-氟苯基)异噁唑-5-羰基]肼基}-2-羟基丙酸(20.0mg,38μmol),并将所得混合物在室温下搅拌5小时。将混合物浓缩,并将残余物溶解于AcOH(2.0mL)中,过滤,并通过反相制备型HPLC纯化。将产物冻干并通过反相制备型HPLC纯化,得到标题化合物(1.8mg,纯度100%)。MS m/z[M+H]+C31H28ClF2N3O8的计算值644.15;实验值644.1。
实例3I:(R)-3-{N-(5'-氯-2'-氟联苯-4-基甲基)-N'-[3-(2-氟苯基)异噁唑-5-
羰基]肼基}-2-膦酰基氧基丙酸
将含(R)-3-{N-(5'-氯-2'-氟联苯-4-基甲基)-N'-[3-(2-氟苯基)异噁唑-5-羰基]肼基}-2-羟基-丙酸(12.0mg,22.7μmol)的EtOH(80μL,1.4mmol)与4.0M HCl于1,4-二噁烷(227μL,909μmol)中的溶液组合,并将所得混合物在室温下搅拌1小时。在真空中去除溶剂,并将残余物溶解于吡啶(20μL,250μmol)中。将所得溶液加入到磷酰氯(19μL,0.2mmol)于丙酮(67μL,0.9mmol)中的溶液中,并在室温下搅拌10分钟。在真空中去除溶剂,并将残余物溶解于EtOH(80μL,1.4mmol)中。接着加入1.0M LiOH于水(1.4mL,1.4mmol)中的溶液,直到pH达到约12。将混合物搅拌1小时,且在真空中去除溶剂。残余物通过制备型HPLC纯化,得到标题化合物(5mg)。MS m/z[M+H]+C26H21ClF2N3O8P的计算值608.07;实验值608.0。
实例3J:(S)-2-甲氧基羰基氨基-3-甲基丁酸(R)-3-{N-(5'-氯-2'-氟联苯-4-基
甲基)-N'-[3-(2-氟苯基)异噁唑-5-羰基]肼基}-2-羟基丙酰氧基甲酯
向(R)-3-{N-(5′-氯-2'-氟联苯-4-基甲基)-N'-[3-(2-氟苯基)异噁唑-5-羰基]肼基}-2-羟基丙酸(200mg,380μmol)于DMF(10mL)中的溶液中加入2,6-二甲基吡啶(407mg,3.8mmol)、(S)-2-甲氧基羰基氨基-3-甲基丁酸氯甲酯(170mg,760μmol)和NaI(114mg,760μmol)。将所得混合物在室温下搅拌过夜。溶液用NaCl饱和水溶液(2×20mL)洗涤且用EtOAc(2×30mL)萃取。合并的有机层经无水Na2SO4干燥且在真空中浓缩。残余物通过柱色谱(PE/EA=4/1到1/2)纯化,得到呈白色固体状的标题化合物(90mg)。LC-MS:714.8[M+H]+。1H-NMR(CD3OD-d4):δ0.91(d,J=9.6Hz,6H),2.05-2.13(m,1H),3.39-3.45(m,2H),3.66(s,3H),4.06-4.08(m,1H),4.23-4.25(m,2H),4.66-4.48(m,1H),5.79-5.86(m,2H),7.15-7.26(m,1H),7.24-7.55(m,10H),7.97-7.95(m,1H)。
实例3K:(R)-3-{N-(5'-氯-2′-氟联苯-4-基甲基)-N'-[3-(2-氟苯基)异噁唑-5-
羰基]肼基}-2-羟基丙酸乙氧基羰氧基甲酯
将2,6-二甲基吡啶(407mg,3.8mmol)加入到(R)-3-{N-(5'-氯-2′-氟联苯-4-基甲基)-N′-[3-(2-氟苯基)异噁唑-5-羰基]肼基}-2-羟基丙酸(200mg,380μmol)、碳酸氯甲酯乙酯(105mg,760μmol)和NaI(114mg,760μmol)于DMF(10mL)中的溶液中。将混合物在室温下搅拌过夜。加入水(30mL),且用EtOAc(3×40mL)萃取混合物。合并的有机层经无水Na2SO4干燥且在真空中浓缩。残余物通过制备型HPLC(MeCN-H2O(0.1%TFA);梯度60-70)纯化,得到呈白色固体状的标题化合物(56mg)。LC-MS:630.1[M+H]+。1H-NMR:(CD3OD-d4,400MHz)δ1.24(t,J=5.9Hz,3H),3.30-3.33(m,2H),4.17-4.32(m,4H),4.45(t,J=4.2Hz,1H),5.78(br,2H),7.20-7.28(m,1H),7.57-7.29(m,10H),7.92-7.95(m,1H)。
实例3L:(R)-3-{N-(5′-氯-2'-氟联苯-4-基甲基)-N′-[3-(2-氟苯基)异噁唑-5-
羰基]肼基}-2-羟基丙酸1-环己基氧基羰氧基乙酯
在氮气下向(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯(1.5g,3.7mmol)、EDC(928mg,4.8mmol)、HOBt(653mg,4.8mmol)和3-(2-氟苯基)异噁唑-5-甲酸(848mg,4.1mmol)于DCM(20mL)中的溶液中加入DIPEA(1.9mL,11.2mmol)。将所得混合物在室温下搅拌过夜,接着浓缩到干燥。将残余物溶解于EtOAc(20mL)中,用0.5N HCl水溶液(10mL)、NaHCO3饱和水溶液(10mL)和NaCl饱和水溶液(10mL)洗涤,经无水Na2SO4干燥,过滤,且在真空中浓缩。残余物通过柱色谱(PE:EtOAc,10:1到3:1)纯化,得到呈固体状的化合物1(1.4g)。LC-MS:556[M+H]+。
向化合物1(1.4g,2.5mmol)于MeOH(15mL)中的溶液中加入LiOH·H2O(317mg,7.6mmol)于水(3mL)中的溶液。将混合物在室温下搅拌1小时,且滤出不溶性固体,且将滤液在真空中浓缩,得到黄色固体(1.2g)。LC-MS:528[M+H]+。将黄色固体(400mg,760μmol)溶解于2,6-二甲基吡啶(814mg,7.6mmol)中,且加入碳酸1-氯-乙酯环己酯(1.6g,7.6mmol)。将小瓶密封,且所得混合物接着在90℃下在微波辐射下辐射30分钟。加入水(10mL),且用EtOAc(3×10mL)萃取混合物。合并的有机层用0.5N HCl水溶液(5×5mL)和NaCl饱和水溶液(10mL)洗涤,经无水Na2SO4干燥,过滤且在真空中浓缩。粗产物通过柱色谱(PE:EtOAc,10:1到2:1)纯化,得到呈白色固体状的标题化合物(60mg)。LC-MS:698[M+H]+。1H NMR:(CDCl3,400MHz)δ1.28-1.37(m,6H),1.54(d,3H),1.72-1.75(m,2H),1.90-1.95(m,2H),3.33-3.38(m,2H),4.24-4.30(m,2H),4.38-4.40(m,1H),4.61-4.66(m,1H),6.60(t,0.5H),6.80(t,0.5H),7.00-7.10(m,1H),7.20-7.26(m,3H)7.36-7.41(m,2H),7.48-7.52(m,5H),7.85(s,0.5H),8.00-8.04(m,1H),8.15(s,0.5H)。
实例4A:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)
肼基]-2-羟基丙酸
向3-甲氧基-异噁唑-5-甲酸(140mg,1.0mmol)和HATU(373mg,1.0mmol)于DMF(5.0mL,64mmol)中的混合物中加入(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯(300.0mg,1.0mmol)和DIPEA(0.3mL,1.6mmol)。将所得混合物在室温下搅拌过夜,直到反应完成。将混合物分配于EtOAc(10.0mL)与水(3.0mL)之间。有机层用水(2×3.0mL)、NaCl饱和水溶液(3.0mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到微黄色油状物。油状物通过快速色谱(2×4g堆叠柱,0-100%EtOAc/己烷)纯化。将所需洗脱份合并且浓缩,得到淡微黄色油状物。油状残余物接着用MeOH(5.0mL,120mmol)和水(1.0mL,56mmol)的混合物处理。加入一水合LiOH(68.6mg,1.6mmol)。在室温下搅拌30分钟后,浓缩混合物。残余物用EtOAc(10.0mL)处理并用1N HCl酸化直到pH约3。有机层用NaCl饱和水溶液(2×3.0mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到呈白色泡沫状的标题化合物(289.7mg)。MS m/z[M+H]+C21H19ClFN3O6的计算值464.09;实验值464.0。
实例4B:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)
肼基]-2-羟基丙酸5-甲基-2-氧代-[1,3]间二氧杂环戊烯-4-基甲酯
将EDCI(169mg,880μmol)和HOBT(119mg,880μmol)加入到(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸5-甲基-2-氧代-[1,3]间二氧杂环戊烯-4-基甲酯(200mg,440μmol)和3-甲氧基异噁唑-5-甲酸(63mg,440μmol)于DMF(10mL)中的溶液中。加入DIPEA(114mg,880μmol),且将混合物在室温下搅拌5小时。混合物用NaCl饱和水溶液(2×30mL)洗涤且用EtOAc(2×50mL)萃取。合并的有机层经无水Na2SO4干燥且在真空中浓缩。残余物通过柱色谱(己烷/EtOAc=1:1)纯化,得到呈白色固体状的标题化合物(60mg)。LC-MS:576.1[M+H]+。1H-NMR:(DMSO-d6)2.14(s,3H),3.21-3.19(m,2H),3.91(s,3H),4.17-4.11(m,2H),4.31(br,1H),4.98(s,2H),5.57(br,1H),6.73(s,1H),7.57-7.34(m,7H),10.07(s,1H)。
实例4C:(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N′-(3-甲氧基异噁唑-5-羰基)
肼基]-2-羟基丙酸2,2,3,3,3-五氟丙酯
将(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)肼基]-2-羟基丙酸(20mg,43μmol)、EDC(40.16mg,0.2587mmol)和水合HOBt(39.62mg,0.2587mmol)组合在DCM(0.5mL,8mmol)中且在室温下搅拌。10分钟后,加入2,2,3,3,3-五氟-1-丙醇(51.8mg,345μmol)。将所得混合物在室温下搅拌过夜,得到呈三氟乙酸盐形式的标题化合物(5.9mg,纯度100%)。MS m/z[M+H]+C24H20ClF6N3O6的计算值596.09;实验值596。
实例4D:(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)
肼基]-2-羟基丙酸乙酰氧基甲酯
向(R)-3-[N-(5′-氯-2'-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)肼基]-2-羟基丙酸(40.0mg,0.1mmol)于丙酮(1.0mL,14mmol)中的溶液中依序加入乙酸溴甲酯(16.9μL,172μmol)和Et3N(24.0μL,172μmol),且将所得混合物搅拌90分钟。反应用AcOH(19.6μL,345μmol)淬灭,且将混合物浓缩。将残余物溶解于AcOH(3mL)中,过滤,并通过反相制备型HPLC纯化。将所需洗脱份合并且冻干。将固体溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(14.3mg,纯度97.8%)。MS m/z[M+H]+C24H23ClFN3O8的计算值536.12;实验值536.2。
实例4E:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N′-(3-甲氧基异噁唑-5-羰基)
肼基]-2-羟基丙酸2-甲氧基-乙酯
将1-溴-2-甲氧基乙烷(12.2μL,129μmol)加入到(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)肼基]-2-羟基丙酸(20.0mg,43μmol)和DIPEA(45.1μL,259μmol)于丙酮(1.0mL,14mmol)中的混合物中。将所得混合物在60℃下加热4小时。加入NaI(19.4mg,129μmol),且监测反应2小时。再加入1-溴-2-甲氧基乙烷(3当量)、DIEA(4当量)和NaI(3当量),且继续加热过夜。再加入1-溴-2-甲氧基乙烷(3当量)、NaI(3当量)和DIEA(3当量),且继续加热过夜。接着将混合物浓缩,并将残余物溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到标题化合物(2.6mg,纯度99%)。MS m/z[M+H]+C24H25ClFN3O7的计算值522.14;实验值522.4。
实例4F:丁酸(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-
羰基)肼基]-2-羟基丙酰氧基甲酯
将丁酸氯甲酯(16.2μL,129μmol)和NaI(19.4mg,129μmol)于丙酮(0.7mL,10mmol)中的混合物在65℃下加热1小时。接着,将混合物冷却到室温,并加入(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)肼基]-2-羟基丙酸(20.0mg)和DIPEA(15.0μL,0.1mmol)于丙酮(0.3mL)中的混合物。将所得混合物在室温下搅拌1小时,接着浓缩。将残余物溶解于AcOH(2.0mL)中,过滤,并通过反相制备型HPLC纯化。将所需洗脱份合并且冻干,得到白色固体。将固体溶解于乙酸(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到标题化合物(6.5mg,纯度100%)。MS m/z[M+H]+C26H27ClFN3O8的计算值564.15;实验值564。
实例4G:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)
肼基]-2-羟基丙酸乙氧基羰氧基甲酯
将碳酸氯甲酯乙酯(17.9mg,129μmol)和NaI(19.4mg,129μmol)于丙酮(0.7mL,10mmol)中的混合物在65℃下加热1小时。接着,将混合物冷却到室温,并加入(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)肼基]-2-羟基丙酸(20.0mg)和DIPEA(15.0μL,0.1mmol)于丙酮(0.3mL)中的混合物。将所得混合物在室温下搅拌1小时,接着浓缩。将残余物溶解于AcOH(2.0mL)中,过滤,并通过反相制备型HPLC纯化。将所需洗脱份合并且冻干,得到白色固体。将固体溶解于乙酸(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到标题化合物(5.8mg,纯度94%)。MS m/z[M+H]+C25H25ClFN3O9的计算值566.13;实验值566。
实例4H:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)
肼基]-2-羟基丙酸2-吗啉-4-基乙酯
将(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)肼基]-2-羟基丙酸(20.0mg,43μmol)、EDC(45.8μL,259μmol)和水合HOBt(39.6mg,259μmol)于DCM(0.5mL,8mmol)中的混合物在室温下搅拌10分钟。加入4-吗啉乙醇(41.8μL,345μmol),且将所得混合物在室温下搅拌过夜。将混合物浓缩,并将残余物溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(14.1mg)。MS m/z[M+H]+C27H30ClFN4O7的计算值577.18;实验值577。
实例4I:(S)-2-甲氧基羰基氨基-3-甲基丁酸(R)-3-[N-(5'-氯-2'-氟联苯-4-基
甲基)-N'-(3-甲氧基异噁唑-5-羰基)肼基]-2-羟基丙酰氧基甲酯
将(R)-3-[N-(5'-氯-2′-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)肼基]-2-羟基丙酸(200mg,430μmol)、(S)-2-甲氧基羰基氨基-3-甲基丁酸氯甲酯(193mg,860μmol)、NaI(129mg,860μmol)和吡啶(136mg,1.7mmol)于DMF(5.0mL)中的混合物在25℃下搅拌过夜。接着将混合物倾入到水(30mL)中并用EtOAc(3×20mL)萃取。合并的有机层用NaCl饱和水溶液(30mL)洗涤,经无水Na2SO4干燥,且在真空中浓缩。残余物通过柱色谱(PE:EtOAc=1:1)纯化,得到呈无色液体状的标题化合物(7mg)。LC-MS:651.1[M+H]+。1H NMR(CD3OD,400MHz):δ0.95-0.97(m,6H),2.06-2.14(m,1H),3.34-3.39(m,2H),3.69(s,3H),3.98(s,3H),4.08-4.11(m,1H),4.22-4.24(m,2H),4.38-4.40(m,1H),5.78-5.91(m,2H),6.54(s,1H),7.18-7.22(m,1H),7.34-7.36(m,1H),7.46-7.55(m,5H)。
实例4J:(R)-3-[N-(5′-氯-2'-氟联苯-4-基甲基)-N′-(3-甲氧基异噁唑-5-羰基)
肼基]-2-羟基丙酸异丙氧基羰氧基甲酯
将(R)-3-[N-(5'-氯-2′-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)肼基]-2-羟基丙酸(200mg,430μmol)、碳酸氯甲酯异丙酯(132mg,860μmol)、NaI(129mg,860μmol)和吡啶(136mg,1.7mmol)于DMF(5.0mL)中的混合物在25℃下搅拌过夜。接着将混合物倾入到水(30mL)中并用EtOAc(3×20mL)萃取。合并的有机层用NaCl饱和水溶液(30mL)洗涤,经无水Na2SO4干燥,且在真空中浓缩。残余物通过柱色谱(PE:EtOAc=1:1)纯化,得到呈无色液体状的标题化合物(10mg)。LC-MS:580[M+H]+。1H NMR(400MHz,CD3OD):δ1.28(d,J=6Hz,6H),3.37-3.39(m,2H),3.98(s,3H),4.22-4.24(m,2H),4.38-4.40(m,1H),5.78-5.91(m,2H),6.54(s,1H),7.22-7.18(t,J=9Hz,1H),7.34-7.36(m,1H),7.46-7.55(m,5H)。
实例4K:(R)-2-(2-氨基乙酰氧基)-3-[N-(5'-氯-2′-氟联苯-4-基甲基)-N′-(3-
甲氧基异噁唑-5-羰基)肼基]丙酸乙酯
在室温下向(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯(300.0mg,818mmol)和3-甲氧基-异噁唑-5-甲酸(140.4mg,981μmol)于DMF(4.0mL,52mmol)中的混合物中加入HATU(373.2mg,981μmol)和DIPEA(427μL,2.4mmol)。将所得混合物在室温下搅拌1小时。将混合物分配于EtOAc(10.0mL)与水(2.0mL)之间。有机层用水(2×2.0mL)洗涤,经Na2SO4干燥,过滤且浓缩,得到微黄色油状物。油状物通过快速色谱(2×4g堆叠柱,0-100%EtOAc/己烷)纯化。将所需洗脱份合并且浓缩,得到无色油状物。
将油状物(28.8mg,58.5μmol)与DIPEA(30.6μL,176μmol)组合,并在室温下加入到N-α-(叔丁氧基羰基)甘氨酸(12.3mg,70.2μmol)和HATU(26.7mg,70.2μmol)于DMF(0.5mL,6mmol)中的混合物中。在室温下搅拌过夜后,将混合物分配于EtOAc(10.0mL)与水(2.0mL)之间。有机层经Na2SO4干燥,过滤并浓缩,得到淡微黄色油状物。接着,在室温下将油状残余物溶解于DCM(0.2mL)中并用含4.0M HCl的1,4-二噁烷(0.2mL,0.8mmol)处理30分钟。浓缩混合物,并将所得残余物与EtOAc(3×2.0mL)共蒸发,得到白色固体。将固体溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化。将所需洗脱份合并且冻干,得到呈白色固体三氟乙酸盐形式的标题化合物(8mg)。MS m/z[M+H]+C25H26ClFN4O7的计算值549.15;实验值549。
实例4L:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)
肼基]-2-丙酰氧基丙酸
将丙酰氯(7.3μL,84μmol)加入到(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)肼基]-2-羟基丙酸(17.0mg,36.7μmol)和DIPEA(12.8μL,73μmol)于DCM(0.5mL,8mmol)中的混合物中。将混合物在室温下搅拌30分钟,接着浓缩。将残余物溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化。将所需洗脱份合并且冻干,得到呈白色固体状的标题化合物(1.2mg)。MS m/z[M+H]+C24H23ClFN3O7的计算值520.12;实验值520.1。
实例4M:(S)-2-氨基-3-甲基丁酸(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-
(3-甲氧基异噁唑-5-羰基)-肼基]-2-羟基丙酰氧基甲酯
将NaI(19.4mg,129μmol)和(S)-2-叔丁氧基羰基氨基-3-甲基-丁酸氯甲酯(34.4mg,129μmol)于丙酮(0.5mL,7mmol)中的混合物在65℃下加热1小时。接着,将混合物冷却到室温,并用(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)肼基]-2-羟基丙酸(20.0mg,43.1μmol)和DIPEA(15.0μL,86.2μmol)于丙酮(0.3mL,4mmol)中的溶液处理。将混合物在室温下搅拌2小时,接着浓缩。将残余物分配于EtOAc(5.0mL)与水(2.0mL)之间。有机层用水(2.0mL)、NaCl饱和水溶液(2.0mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到无色油状物。将油状物在真空中进一步干燥30分钟,且接着在冰箱中储存过夜。油状物接着在室温下用DCM/TFA(0.3mL)的1:1混合物处理30分钟,并浓缩。将残余物溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化。将所需洗脱份合并且冻干,得到呈白色固体三氟乙酸盐形式的标题化合物(7.3mg)。MS m/z[M+H]+C27H30ClFN4O8的计算值593.17;实验值593.1。
实例4N:(S)-2-甲氧基羰基氨基-3-甲基丁酸(R)-1-羧基-2-[N-(5′-氯-2'-氟联
苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)肼基]乙酯
将(S)-2-甲氧基羰基氨基-3-甲基丁酸(5.7mg,32.3μmol)和HATU(12.3mg,32.3μmol)在DMA(1.0mL,11mmol)中搅拌15分钟。加入(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)肼基]-2-羟基丙酸(10.0mg,21.6μmol)和DIPEA(11.3μL,64.7μmol),且将所得混合物在室温下搅拌过夜。将混合物浓缩,并将残余物溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到标题化合物(2.7mg)。MSm/z[M+H]+C28H30ClFN4O9的计算值621.17;实验值621.3。
实例4O:(S)-2-氨基丙酸(R)-1-羧基-2-[N-(5′-氯-2'-氟联苯-4-基甲基)-N'-
(3-甲氧基异噁唑-5-羰基)肼基]乙酯
将(S)-2-叔丁氧基羰基氨基丙酸(12.2mg,64.7μmol)和HATU(24.6mg,64.7μmol)在DMA(1.0mL,11mmol)中搅拌10分钟。加入(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N′-(3-甲氧基异噁唑-5-羰基)肼基]-2-羟基丙酸(20.0mg,43.1μmol)和DIPEA(22.5μL,129μmol),且将所得混合物在室温下搅拌过夜,接着浓缩。加入含4.0M HCl的1,4-二噁烷(0.2mL,0.8mmol),且使所得混合物静置1小时,接着在减压下浓缩。将残余物溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(3.9mg)。MS m/z[M+H]+C24H24ClFN4O7的计算值535.13;实验值535.4。
实例4P:(S)-2-氨基-3-甲基丁酸(R)-1-羧基-2-[N-(5'-氯-2'-氟联苯-4-基甲
基)-N'-(3-甲氧基异噁唑-5-羰基)肼基]乙酯
将N-(叔丁氧基羰基)-L-缬氨酸(14.0mg,64.7μmol)和HATU(24.6mg,64.7μmol)在DMA(1.0mL,11mmol)中搅拌10分钟。加入(R)-3-[N-(5'-氯-2′-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)肼基]-2-羟基丙酸(20.0mg,43.1μmol)和DIPEA(22.5μL,129μmol),且将所得混合物在室温下搅拌过夜,接着浓缩。加入含4.0M HCl的1,4-二噁烷(0.2mL,0.8mmol),且使所得混合物静置1小时,接着在减压下浓缩。将残余物溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(3.5mg)。MSm/z[M+H]+C26H28ClFN4O7的计算值563.16;实验值563.4。
实例4Q:(R)-2-(2-氨基乙酰氧基)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N′-(3-
甲氧基异噁唑-5-羰基)肼基]丙酸
将N-α-(叔丁氧基羰基)甘氨酸(11.3mg,64.7μmol)和HATU(24.6mg,64.7μmol)在DMA(1.0mL,11mmol)中搅拌10分钟。加入(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N′-(3-甲氧基异噁唑-5-羰基)肼基]-2-羟基丙酸(20.0mg,43.1μmol)和DIPEA(22.5μL,129μmol),且将所得混合物在室温下搅拌过夜,接着浓缩。加入含4.0M HCl的1,4-二噁烷(0.2mL,0.8mmol),且使所得混合物静置1小时,接着在减压下浓缩。将残余物溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(5.8mg)。MSm/z[M+H]+C23H22ClFN4O7的计算值521.12;实验值521.6。
实例4R:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(3-甲氧基异噁唑-5-羰基)
肼基]-2-羟基丙酸1-环己基氧基羰氧基乙酯
在氮气下向化合物(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯(1.2g,3.0mmol)、EDC(742mg,3.9mmol)、HOBt(523mg,3.9mmol)和3-甲氧基异噁唑-5-甲酸(468mg,3.3mmol)于DCM(20mL)中的溶液中加入DIPEA(1.48mL,8.9mmol)。将所得混合物在室温下搅拌过夜,接着浓缩到干燥。将残余物溶解于EtOAc(20mL)中,用0.5N HCl水溶液(10mL)、NaHCO3饱和水溶液(10mL)和NaCl饱和水溶液(10mL)洗涤,经无水Na2SO4干燥,过滤,且在真空中浓缩。残余物通过柱色谱(PE:EtOAc,10:1到3:1)纯化,得到呈固体状的化合物1(970mg)。LC-MS:[M+H]+:492。
向化合物1(970mg,2.0mmol)于MeOH(15mL)中的溶液中加入LiOH·H2O(248mg,5.9mmol)于水(3mL)中的溶液。将混合物在室温下搅拌1小时,且滤出不溶性固体,且将滤液在真空中浓缩,得到黄色固体(780mg)。LC-MS:464[M+H]+。将黄色固体(200mg,430μmol)溶解于2,6-二甲基吡啶(460mg,4.3mmol)中,并加入碳酸1-氯-乙酯环己酯(888mg,4.3mmol)。将小瓶密封,且所得混合物接着在90℃下在微波辐射下辐射30分钟。加入水(10mL),且用EtOAc(3×10mL)萃取混合物。合并的有机层用0.5NHCl水溶液(4×5mL)和NaCl饱和水溶液(10mL)洗涤,经无水Na2SO4干燥,过滤且在真空中浓缩。残余物通过制备型HPLC(Gemini-C18,150×21.2mm,5μ,MeCN-H2O(0.1%TFA);从43%到43%)纯化,得到呈白色固体状的标题化合物(7mg)。LC-MS:634[M+H]+。1H NMR:(CDCl3,400MHz)δ1.28-1.37(m,6H),1.54(d,3H),1.70-1.73(m,2H),1.84-1.87(m,2H),3.26-3.29(m,2H),3.38-3.43(m,1H),3.97(s,3H),4.19-4.20(m,2H),4.38-4.50(m,1H),4.50-4.57(m,1H),6.50(m,1H),6.75(t,1H),7.18-7.20(m,1H),7.35-7.37(m,1H),7.48-7.52(m,4H)。
实例5A:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N′-(5-氧代-1-苯基-4,5-二
氢-1H-[1,2,4]三唑-3-羰基)肼基]-2-羟基丙酸
将5-氧代-1-苯基-4,5-二氢-1H-[1,2,4]三唑-3-甲酸(56.4mg,275μmol)与HCTU(154mg,371μmol)组合在DMF(852μL,11mmol)中,并在室温下搅拌15分钟。加入DIPEA(72μL,413μmol)和(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯(50mg,0.1mmol),并将所得混合物在室温下搅拌过夜。加入EtOH(402μL,6.9mmol)和含1M LiOH的水(1.1mL,1.1mmol),且将所得混合物在室温下搅拌1小时。将混合物在减压下蒸发,且残余物通过制备型HPLC纯化,得到标题化合物(39.8mg,纯度100%)。MS m/z[M+H]+C25H21ClFN5O5的计算值526.12;实验值526.0。
实例5B:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N′-(5-氧代-1-苯基-4,5-二
氢-1H-[1,2,4]三唑-3-羰基)肼基]-2-羟基丙酸5-甲基-2-氧代-[1,3]间二氧杂环戊烯-4-
基甲酯
将EDC(127mg,660μmol)和HOBt(89mg,660μmol)加入到5-氧代-1-苯基-4,5-二氢-1H-[1,2,4]三唑-3-甲酸(150mg,330μmol)和(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸5-甲基-2-氧代-[1,3]间二氧杂环戊烯-4-基甲酯(68mg,330μmol)于DMF(10mL)中的溶液中。加入DIPEA(86mg,660μmol),且将所得混合物在室温下搅拌5小时。混合物接着用NaCl饱和水溶液(2×30mL)洗涤且用EtOAc(2×50mL)萃取。合并的有机层经无水Na2SO4干燥且在真空中浓缩。残余物通过柱色谱(PE:EtOAc=1:1)纯化,得到呈白色固体状的标题化合物(67mg)。LC-MS:638.2[M+H]+。1H-NMR(400MHz,DMSO-d6):δ2.13(s,3H),3.31-3.16(m,2H),4.18-4.21(q,2H),4.35(br,1H),4.98-5.01(m,2H),5.54(br,1H),7.26-7.90(m,12H),9.98(s,1H),12.74(s,1H)。
实例5C:(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N'-(5-氧代-1-苯基-4,5-二
氢-1H-[1,2,4]三唑-3-羰基)-肼基]-2-羟基丙酸乙酯
将5-氧代-1-苯基-4,5-二氢-1H-[1,2,4]三唑-3-甲酸(89.5mg,436μmol)与HCTU(244mg,589μmol)组合在DMF(1.0mL,13mmol)中,且搅拌10分钟。加入(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯(80.0mg,0.2mmol)和DIPEA(0.1mL,0.7mmol),且将所得混合物搅拌过夜。混合物用EtOAc(10.0mL)稀释并用水(3.0mL)、NaHCO3饱和水溶液(2×3.0mL)和NaCl饱和水溶液(3.0mL)洗涤,接着经Na2SO4干燥,过滤且浓缩,得到微黄色固体。将一份(20mg)固体溶解于AcOH(1.5mL)中,过滤且通过反相制备型HPLC纯化,得到标题化合物(1.6mg,纯度100%)。MS m/z[M+H]+C27H25ClFN5O5的计算值554.15;实验值554.4。
实例5D:(R)-3-[N-(5′-氯-2'-氟联苯-4-基甲基)-N'-(5-氧代-1-苯基-4,5-二
氢-1H-[1,2,4]三唑-3-羰基)肼基]-2-羟基丙酸异丙酯
将5-氧代-1-苯基-4,5-二氢-1H-[1,2,4]三唑-3-甲酸(89.5mg,436μmol)与HCTU(244mg,589μmol)组合在DMF(1.0mL,13mmol)中,且搅拌10分钟。加入(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯(80.0mg,0.2mmol)和DIPEA(0.1mL,0.7mmol),且将所得混合物搅拌过夜。混合物用EtOAc(10.0mL)稀释并用水(3.0mL)、NaHCO3饱和水溶液(2×3.0mL)和NaCl饱和水溶液(3.0mL)洗涤,接着经Na2SO4干燥,过滤且浓缩,得到微黄色固体。一份(20mg)固体在室温下用异丁醇(170μL,1.8mmol)和含4.0M HCl的1,4-二噁烷(36.0μL,144μmol)处理过夜。将混合物浓缩,并将残余物溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到标题化合物(1.6mg,纯度100%)。MS m/z[M+H]+C29H29ClFN5O5的计算值582.18;实验值582.4。
实例5E:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(5-氧代-1-苯基-4,5-二
氢-1H-[1,2,4]三唑-3-羰基)肼基]-2-羟基丙酸2,2,3,3,3-五氟丙酯
将(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(5-氧代-1-苯基-4,5-二氢-1H-[1,2,4]三唑-3-羰基)肼基]-2-羟基丙酸(200mg,380μmol)、2,2,3,3,3-五氟丙-1-醇(114mg,760μmol)、HOBT(103mg,760μmol)、EDC(145mg,760μmol)和DIPEA(200mg,1.5mmol)于DMF(5.0mL)中的混合物在室温下搅拌过夜。接着将混合物倾入到水(30mL)中并用EtOAc(3×20mL)萃取。合并的有机层用NaCl饱和水溶液(30mL)洗涤,经无水Na2SO4干燥,且在真空中浓缩。残余物通过柱色谱(PE:EtOAc=2:1)纯化,得到呈白色固体状的标题化合物(20mg)。LC-MS:658[M+H]+。1H NMR(400MHz,CDCl3)δ3.44-3.40(m,2H),4.25(br,2H),4.58-4.61(m,3H),7.14-7.08(m,1H),7.41-7.55(m,8H),7.84-7.92(m,3H)。
实例5F:(R)-3-[N-(5′-氯-2'-氟联苯-4-基甲基)-N'-(5-氧代-1-苯基-4,5-二
氢-1H-[1,2,4]三唑-3-羰基)肼基]-2-羟基丙酸乙酰氧基甲酯
在室温下向(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N′-(5-氧代-1-苯基-4,5-二氢-1H-[1,2,4]三唑-3-羰基)肼基]-2-羟基丙酸(200mg,335μmol)于无水DMF(6mL)中的溶液中分批加入乙酸溴甲酯(76mg,503μmol)、NaI(101mg,670μmol)和2,6-二甲基吡啶(143mg,1.3mmol)。将所得混合物在室温下搅拌8小时。加入水(12mL),且用EtOAc(3×10mL)萃取混合物。合并的有机层经无水Na2SO4干燥且在真空中浓缩。残余物通过柱色谱(PE:EtOAc=3:1)纯化,得到呈白色固体状的标题化合物(15mg)。LC-MS:597.7[M+H]+。1H NMR(CDCl3,400MHz,)δ2.02(s,3H),3.37(br,2H),4.22(br,2H),4.38(br,1H),5.78-6.02(m,2H),7.15-7.20(m,1H),7.40-7.45(m,2H),7.50-7.91(m,7H),8.15-8.17(m,2H)。
实例5G:丁酸(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(5-氧代-1-苯基-4,5-
二氢-1H-[1,2,4]三唑-3-羰基)-肼基]-2-羟基丙酰氧基甲酯
在室温下向(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(5-氧代-1-苯基-4,5-二氢-1H-[1,2,4]三唑-3-羰基)肼基]-2-羟基丙酸(200mg,335μmol)于无水DMF(6mL)中的溶液中分批加入丁酸氯甲酯(68mg,503μmol)、NaI(101mg,670μmol)和2,6-二甲基吡啶(143mg,1.3mmol)。将所得混合物在室温下搅拌8小时。加入水(12mL),且用EtOAc(3×20mL)萃取混合物。合并的有机层经无水Na2SO4干燥且在真空中浓缩。残余物通过柱色谱(PE:EtOAc=3:1)纯化,得到呈白色固体状的标题化合物(21mg)。LC-MS:625.9[M+H]+。1H NMR(DMSO-d6,400MHz)δ0.84(t,J=7.4Hz,3H),1.45-1.56(m,2H),2.29(t,J=7.3Hz,2H),3.31-3.17(m,2H),4.18-4.35(m,2H),4.35(t,J=5.3Hz,1H),5.68-5.79(m,2H),7.28(t,J=7.4Hz,1H),7.34-7.40(m,1H),7.43-7.55(m,7H),7.58(dd,J=6.8,2.6Hz,1H),7.90(d,J=7.6Hz,2H),9.98(s,1H),12.76(s,1H)。
实例5H:(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N'-(5-氧代-1-苯基-4,5-二
氢-1H-[1,2,4]三唑-3-羰基)肼基]-2-羟基丙酸乙氧基羰氧基甲酯
在室温下向(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(5-氧代-1-苯基-4,5-二氢-1H-[1,2,4]三唑-3-羰基)肼基]-2-羟基丙酸(200mg,335μmol)于无水DMF(10mL)中的溶液中分批加入碳酸氯甲酯乙酯(69mg,503μmol)、NaI(101mg,670μmol)和2,6-二甲基吡啶(143mg,1.3mmol)。将所得混合物在室温下搅拌8小时。加入水(15mL),且用EtOAc(3×20mL)萃取混合物。合并的有机层经无水Na2SO4干燥且在真空中浓缩。残余物通过柱色谱(PE:EtOAc=3:1到1:100)纯化,得到呈白色固体状的标题化合物(9.5mg)。LC-MS:627.9[M+H]+。1H NMR:(CDCl3,400MHz)δ1.25(t,J=7.1Hz,3H),3.44(br,2H),4.17-4.35(m,4H),4.50(s,1H),5.75-5.78(m,2H),7.10(t,J=9.3Hz,1H),7.28-7.40(m,1H),7.42-7.52(m,7H),7.87(s,2H),8.37(s,1H)。
实例5I:(R)-3-[N-(5'-氯-2′-氟联苯-4-基甲基)-N′-(5-氧代-1-苯基-4,5-二
氢-1H-[1,2,4]三唑-3-羰基)肼基]-2-羟基丙酸异丙氧基羰氧基甲酯
在室温下向(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(5-氧代-1-苯基-4,5-二氢-1H-[1,2,4]三唑-3-羰基)肼基]-2-羟基丙酸(200mg,335μmol)于无水DMF(6mL)中的溶液中分批加入碳酸氯甲酯异丙酯(76mg,503μmol)、NaI(101mg,670μmol)和2,6-二甲基吡啶(143mg,1.3mmol)。将所得混合物在室温下搅拌8小时。加入水(12mL),且用EtOAc(3×10mL)萃取混合物。合并的有机层经无水Na2SO4干燥且在真空中浓缩。残余物通过柱色谱(PE:EtOAc=1:1)纯化,得到呈白色固体状的标题化合物(12.8mg)。LC-MS:641.9[M+H]+。1HNMR(DMSO-d6,400MHz)δ1.21(d,J=6.2Hz,6H),3.21-3.28(m,2H),4.12-4.30(m,2H),4.40-4.52(m,1H),4.77-4.79(m,1H),5.68-5.76(m,2H),7.41-7.45(m,1H),7.50-7.87(m,9H),7.90(d,J=7.7Hz,2H),9.98(s,1H),12.76(s,1H)。
实例5J:(S)-2-甲氧基羰基氨基-3-甲基丁酸(R)-3-[N-(5'-氯-2'-氟联苯-4-基
甲基)-N'-(5-氧代-1-苯基-4,5-二氢-1H-[1,2,4]三唑-3-羰基)肼基]-2-羟基丙酰氧基甲
酯
在室温下向(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N′-(5-氧代-1-苯基-4,5-二氢-1H-[1,2,4]三唑-3-羰基)肼基]-2-羟基丙酸(200mg,335μmol)于无水DMF(6mL)中的溶液中分批加入(S)-2-甲氧基羰基氨基-3-甲基丁酸氯甲酯(112mg,503μmol)、NaI(101mg,670μmol)和2,6-二甲基吡啶(143mg,1.3mmol)。将所得混合物在室温下搅拌8小时。加入水(12mL),且用EtOAc(3×20mL)萃取混合物。合并的有机层经无水Na2SO4干燥且在真空中浓缩。残余物通过柱色谱(PE:EtOAc=3:1)纯化,得到呈白色固体状的标题化合物(8.4mg)。LC-MS:712.9[M+H]+。1H NMR:(MeOD,400MHz)δ0.85(dd,J=14.1,6.8Hz,6H),2.01-2.17(m,1H),3.42-3.51(m,2H),3.69(s,3H),4.00(d,J=5.9Hz,1H),4.23(br,2H),4.42(t,J=4.7Hz,1H),5.83(dd,J=31.5,5.6Hz,2H),7.19(t,J=9.4Hz,1H),7.32-7.39(m,3H),7.47-7.51(m,4H),7.56-7.58(m,2H),7.91(d,J=8.0Hz,2H)。
实例5K:(R)-3-[N-(5'-氯-2′-氟联苯-4-基甲基)-N′-(5-氧代-1-苯基-4,5-二
氢-1H-[1,2,4]三唑-3-羰基)肼基]-2-羟基丙酸1-环己基氧基羰氧基乙酯
使用本文所述的程序,也可制备标题化合物。
实例6A:(R)-3-[N′-(5-乙酰基-2H-吡唑-3-羰基)-N-(5′-氯-2'-氟联苯-4-基甲
基)肼基]-2-羟基丙酸
将3-乙酰基-1H-吡唑-5-甲酸(69.3mg,450μmol)和HCTU(186mg,450μmol)组合在DMF(1.9mL,24.5mmol)中,且在室温下搅拌。15分钟后,加入DIPEA(214μL,1.2mmol)和(R)-3-[N-(5′-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯(150mg,0.4mmol)。将混合物在室温下搅拌30分钟,接着在减压下蒸发。将残余物溶解于EtOH(1.4mL,24.5mmol)中。加入1.0M LiOH于水(2.0mL,2.0mmol)中的溶液,且将所得混合物在40℃下搅拌3小时。在压力下去除溶剂,且残余物通过制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(110mg,纯度100%)。MS m/z[M+H]+C22H20ClFN4O5的计算值475.11;实验值475.1。
实例6B:(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟联苯-4-基甲
基)肼基]-2-羟基丙酸乙酯
将3-乙酰基-1H-吡唑-5-甲酸(168mg,1.1mmol)和HCTU(451mg,1.1mmol)组合在DMF(6.8mL,87.2mmol)中,且在室温下搅拌。15分钟后,加入DIPEA(570μL,3.3mmol)和(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)肼基]-2-羟基丙酸乙酯(400mg,1.1mmol)。将混合物在室温下搅拌20分钟,接着在减压下蒸发,得到标题化合物。MS m/z[M+H]+C24H24ClFN4O5的计算值503.14;实验值503.2。
实例6C:(R)-3-[N′-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟联苯-4-基甲
基)肼基]-2-羟基丙酸2-吗啉-4-基乙酯
将(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5′-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基-丙酸(41.0mg,86μmol)、HOBt(70.0mg,518μmol)和EDC(92μL,520μmol)组合在DCM(0.7mL,10mmol)中。将所得溶液搅拌10分钟。加入4-吗啉乙醇(84μL,691μmol),且将混合物在室温下搅拌,直到反应完成(约等于2小时)。混合物通过旋转蒸发浓缩并纯化(反相柱),得到呈三氟乙酸盐形式的标题化合物(7.5mg,纯度98%)。MS m/z[M+H]+C28H31ClFN5O6的计算值588.19;实验值588.1。
实例6D:(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5′-氯-2'-氟联苯-4-基甲
基)肼基]-2-羟基丙酸异丙酯
将(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸(15.0mg,32μmol)与异丁醇(876μL,9.5mmol)组合。加入4M HCl于二噁烷(282μL,1.1mmol)中的溶液,并将所得混合物在室温下搅拌15分钟。混合物通过旋转蒸发浓缩,并将产物冻干,得到呈白色粉末三氟乙酸盐形式的标题化合物(19mg,纯度99%)。MS m/z[M+H]+C26H28ClFN4O5的计算值531.17;实验值531.1。
实例6E:(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟联苯-4-基甲
基)肼基]-2-羟基丙酸5-甲基-2-氧代-[1,3]间二氧杂环戊烯-4-基甲酯
将(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2′-氟联苯-4-基甲基)肼基]-2-羟基丙酸(30.0mg,63μmol)、HOBt(26mg,190μmol)和EDC(34μL,190μmol)组合在DCM(243μL,3.8mmol)中并搅拌10分钟。加入4-羟甲基-5-甲基-[1,3]间二氧杂环戊烯-2-酮(66mg,0.5mmol)和4-甲基吗啉(28μL,250μmol),且将所得混合物在室温下搅拌3小时。将混合物在减压下蒸发,得到棕色油状物,所述棕色油状物通过制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(4.6mg,纯度97%)。MS m/z[M+H]+C27H24ClFN4O8的计算值587.13;实验值587.1。
实例6F:(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟联苯-4-基甲
基)肼基]-2-羟基丙酸2,2-二氟丙酯
将(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5′-氯-2′-氟联苯-4-基甲基)肼基]-2-羟基丙酸(15.0mg,32μmol)、HOBt(12.8mg,95μmol)和EDC(16.8μL,95μmol)组合在DCM(121μL,1.9mmol)中并搅拌10分钟。加入2,2-二氟丙醇(24.3mg,253μmol),并将所得混合物在室温下搅拌直到反应完成(约等于48小时)。将混合物在减压下蒸发,且将产物纯化(反相柱),得到呈三氟乙酸盐形式的标题化合物(13.8mg,纯度96%)。MS m/z[M+H]+C25H24ClF3N4O5的计算值553.14;实验值553.1。
实例6G:(R)-3-[N′-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟联苯-4-基甲
基)肼基]-2-羟基丙酸2-甲氧基乙酯
将(R)-3-[N′-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸(10.0mg,21μmol)与2-甲氧基乙醇(0.1mL,1.3mmol)组合。加入4M HCl于二噁烷(53μL,0.2mmol)中的溶液,并将所得混合物在室温下搅拌1小时。LC/MS展示所需产物的质量。混合物通过旋转蒸发浓缩并纯化(反相柱),得到呈白色固体三氟乙酸盐形式的标题化合物(2.7mg,纯度95%)。MS m/z[M+H]+C25H26ClFN4O6的计算值533.15;实验值533.1。
实例6H:(S)-2-氨基-3-甲基丁酸3-乙酰基-5-[N'-((R)-2-羧基-2-羟基乙基)-
N′-(5′-氯-2′-氟联苯-4-基甲基)肼基羰基]吡唑-1-基甲酯
将(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸(95.5mg,0.2mmol)溶解于丙酮(886μL,12.1mmol)中。加入Et3N(70μL,503μmol)和(S)-2-叔丁氧基羰基氨基-3-甲基-丁酸氯甲酯(56.1mg,211μmol),且将所得混合物在60℃下搅拌6小时。在真空中去除溶剂,且残余物使用快速色谱(正相;MeOH:EtOAc=0:50)纯化。收集纯的洗脱份,浓缩,接着将其溶解于MeCN(630μL,12.1mmol)中。加入4.0M HCl于1,4-二噁烷(503μL,2.0mmol)中的溶液,且将所得混合物在室温下搅拌2小时。在真空中去除溶剂,得到标题化合物(90mg)。
实例6I:(S)-2-甲氧基羰基氨基-3-甲基丁酸3-乙酰基-5-[N′-((R)-2-羧基-2-羟
基乙基)-N′-(5′-氯-2′-氟联苯-4-基甲基)肼基羰基]吡唑-1-基甲酯
将(S)-2-氨基-3-甲基丁酸3-乙酰基-5-[N′-((R)-2-羧基-2-羟基乙基)-N′-(5′-氯-2′-氟联苯-4-基甲基)肼基羰基]吡唑-1-基甲酯(21.0mg,35μmol)与DCM(134μL,2.1mmol)和Et3N(15μL,0.1mmol)组合。加入氯甲酸甲酯(2.7μL,35μmol),且将混合物在室温下搅拌20分钟。在真空中去除溶剂,且残余物通过制备型HPLC纯化,得到标题化合物(0.7mg)。MS m/z[M+H]+C30H33ClFN5O9的计算值662.20;实验值662.1。
实例6J:异丁酸(R)-2-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟联苯-
4-基甲基)肼基]-1-羧基乙酯
将异丁酰氯(23.4μL,221.1μmol)和(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟联苯-4-基甲基)肼基]-2-羟基丙酸(10.5mg,22.1μmol)组合在THF(108μL,1.3mmol)中,且在室温下搅拌过夜。蒸发溶剂,且残余物通过制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(4.9mg)。MS m/z[M+H]+C26H26ClFN4O6的计算值545.15;实验值545.1。
实例6K:3-甲基丁酸(R)-2-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟联
苯-4-基甲基)肼基]-1-羧基乙酯
将异戊酰氯(51.4μL,421.2μmol)和(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5′-氯-2′-氟联苯-4-基甲基)肼基]-2-羟基丙酸(20.0mg,42.1μmol)组合在THF(205μL,2.5mmol)中,且在室温下搅拌过夜。将溶剂蒸发,且将残余物纯化(反相HPLC柱),得到呈三氟乙酸盐形式的标题化合物(11.8mg)。MS m/z[M+H]+C27H28ClFN4O6的计算值559.17;实验值559.1。
实例6L:(R)-2-乙酰氧基-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟
联苯-4-基甲基)肼基]丙酸
将乙酰氯(30μL,421.2μmol)和(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5′-氯-2′-氟联苯-4-基甲基)肼基]-2-羟基丙酸(20.0mg,42.1μmol)组合在THF(205μL,2.5mmol)中,且在室温下搅拌过夜。将溶剂蒸发,且将残余物纯化(反相HPLC柱),得到呈三氟乙酸盐形式的标题化合物(12.2mg)。MS m/z[M+H]+C24H22ClFN4O6的计算值517.12;实验值517.2。
实例6M:(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟联苯-4-基甲
基)-肼基]-2-羟基丙酸3-二甲基氨基丙酯
将(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟联苯-4-基甲基)-肼基]-2-羟基丙酸(10.0mg,21μmol)与HOBt(17.1mg,126μmol)和EDC(22μL,130μmol)组合于DCM(0.2mL,3mmol)中,并搅拌10分钟。加入3-二甲基氨基-1-丙醇(19.9μL,168μmol),且将所得混合物在室温下搅拌并监测完成(约等于4小时)。混合物通过旋转蒸发浓缩,且残余物通过制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(6.4mg)。MS m/z[M+H]+C27H31ClFN5O5的计算值560.20;实验值560.1。
实例6N:(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟联苯-4-基甲
基)-肼基]-2-羟基丙酸4-二甲基氨基丁酯
将(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5′-氯-2′-氟联苯-4-基甲基)-肼基]-2-羟基丙酸(10.0mg,21μmol)与HOBt(17.1mg,126μmol)和EDC(22μL,130μmol)组合于DCM(0.2mL,3mmol)中,并搅拌10分钟。加入4-二甲基氨基-1-丁醇(22.4μL,168μmol),且将所得混合物在室温下搅拌并监测完成(约等于4小时)。混合物通过旋转蒸发浓缩,且残余物通过制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(4.2mg)。MS m/z[M+H]+C28H33ClFN5O5的计算值574.22;实验值574.1。
实例6O:(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2′-氟联苯-4-基甲
基)-肼基]-2-羟基丙酸3-吗啉-4-基-丙酯
将(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟联苯-4-基甲基)-肼基]-2-羟基丙酸(10.0mg,21μmol)与HOBt(17.1mg,126μmol)和EDC(22μL,130μmol)组合于DCM(0.2mL,3mmol)中,并搅拌10分钟。加入3-吗啉基丙醇(24.5mg,168μmol),且将所得混合物在室温下搅拌并监测完成(约等于4小时)。混合物通过旋转蒸发浓缩,且残余物通过制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(4.9mg)。MS m/z[M+H]+C29H33ClFN5O6的计算值602.21;实验值602.1。
实例6P:(R)-3-[N′-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2′-氟联苯-4-基甲
基)-肼基]-2-羟基丙酸2-二甲基氨基乙酯
可如下制备标题化合物:将(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5′-氯-2'-氟联苯-4-基甲基)-肼基]-2-羟基丙酸(10.0mg,21μmol)与HOBt(17.1mg,126μmol)和EDC(22μL,130μmol)组合于DCM(0.2mL,3mmol)中,并搅拌10分钟。加入N,N-二甲基氨基乙醇(16.9μL,168μmol),且将所得混合物在室温下搅拌并监测完成。混合物通过旋转蒸发浓缩,且残余物通过制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物。
实例6Q:(R)-3-[N′-(5-乙酰基-2H-吡唑-3-羰基)-N-(5'-氯-2'-氟联苯-4-基甲
基)-肼基]-2-羟基丙酸4-吗啉-4-基-丁酯
使用本文所述的程序,也可制备标题化合物。
实例6R:(S)-2-氨基-3-甲基丁酸(R)-2-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-联
苯-4-基甲基肼基]-1-异丁氧基羰基乙酯
使用本文所述的程序,也可制备标题化合物。
实例6S:(S)-2-氨基-3-甲基丁酸3-乙酰基-5-[N'-联苯-4-基甲基-N'-((R)-2-羟
基-2-异丁氧基羰基乙基)肼基羰基]吡唑-1-基甲酯
使用本文所述的程序,也可制备标题化合物。
实例6T:(S)-2-氨基-3-甲基丁酸(R)-2-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-联
苯-4-基甲基肼基]-1-乙氧基羰基乙酯
使用本文所述的程序,也可制备标题化合物。
实例6U:(S)-2-氨基-3-甲基丁酸3-乙酰基-5-[N'-联苯-4-基甲基-N'-((R)-2-乙
氧基羰基-2-羟基乙基)肼基羰基]吡唑-1-基甲酯
使用本文所述的程序,也可制备标题化合物。
实例6V:(S)-2-氨基-3-甲基丁酸(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-
(5'-氯-2'-氟联苯-4-基甲基)-肼基]-2-羟基丙酰氧基甲酯
使用本文所述的程序,也可制备标题化合物。
实例6W:(R)-3-[N'-(5-乙酰基-2H-吡唑-3-羰基)-N-(5′-氯-2′-氟联苯-4-基甲
基)肼基]-2-羟基丙酸乙氧基羰氧基甲酯
使用本文所述的程序,也可制备标题化合物。
实例6X:(R)-3-[N′-(5-乙酰基-2-膦酰基氧基甲基-2H-吡唑-3-羰基)-N-(5′-氯-
2′-氟联苯-4-基甲基)-肼基]-2-羟基丙酸异丙酯
使用本文所述的程序,也可制备标题化合物。
实例7A:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(2H-四唑-5-羰基)肼基]-
2-羟基丙酸5-甲基-2-氧代-[1,3]间二氧杂环戊烯-4-基甲酯
将(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N′-(2-三苯甲基-2H-四唑-5-羰基)肼基]-2-羟基丙酸(30.0mg,44μmol)与4-氯甲基-5-甲基-1,3-间二氧杂环戊烯-2-酮(9.9mg,66μmol)和DIPEA(15.4μL,89μmol)组合在丙酮(0.4mL,5mmol)中。将混合物维持在56℃下过夜。将混合物浓缩,且将残余物与DCM(0.2mL)和2M HCl在室温下在二噁烷和DCM(0.2mL)的混合物中组合1小时。将混合物浓缩,并将残余物溶解于50%水/AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到呈白色固体三氟乙酸盐形式的标题化合物(3.3mg)。MS m/z[M+H]+C23H20ClFN6O7的计算值547.11;实验值547。
应注意,如本文中所阐明,如此的化合物可以互变异构体形成存在,例如,作为(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(1H-四唑-5-羰基)肼基]-2-羟基丙酸5-甲基-2-氧代-[1,3]间二氧杂环戊烯-4-基甲酯。
实例7B:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(2H-四唑-5-羰基)肼基]-
2-羟基丙酸2,2,3,3,3-五氟丙酯
将(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(2-三苯甲基-2H-四唑-5-羰基)肼基]-2-羟基丙酸(42.4mg,63μmol)与EDC(66.5μL,376μmol)和水合HOBt(57.5mg,376μmol)组合在DCM(0.7mL,10mmol)中,且在室温下搅拌10分钟。加入2,2,3,3,3-五氟-1-丙醇(75.2mg,501μmol),且将所得混合物在室温下搅拌过夜。将混合物浓缩,且将残余物在室温下溶解于DCM(0.4mL,6mmol)中且用含4.0M HCl的1,4-二噁烷(0.2mL,0.8mmol)处理2小时。将混合物浓缩,且将残余物溶解于AcOH(1.5mL)中,过滤,且通过反相制备型HPLC纯化。将所需洗脱份合并且冻干,得到呈白色固体三氟乙酸盐形式的标题化合物(8.3mg)。MS m/z[M+H]+C21H17ClF6N6O4的计算值567.09;实验值567。
应注意,如本文中所阐明,如此的化合物可以互变异构体形成存在,例如,作为(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N'-(1H-四唑-5-羰基)肼基]-2-羟基丙酸2,2,3,3,3-五氟丙酯
实例7C:(S)-2-氨基-3-甲基丁酸5-[N′-(5′-氯-2′-氟联苯-4-基甲基)-N′-((R)-
2-乙氧基羰基-2-羟基乙基)-肼基羰基]四唑-2-基甲酯
将(R)-3-[N-(5'-氯-2′-氟联苯-4-基甲基)-N′-(2-三苯甲基-2H-四唑-5-羰基)肼基]-2-羟基丙酸乙酯(15.1mg,21.4μmol)在室温下在DCM(0.2mL,3mmol)和含4.0M HCl的1,4-二噁烷(0.1mL,0.4mmol)的混合物中搅拌1小时,接着浓缩。向此中加入含Cs2CO3(14.0mg,42.8μmol)的丙酮(0.5mL)和已在60℃下在丙酮(0.5μL,7μmol)中搅拌1小时的(S)-2-叔丁氧基羰基氨基-3-甲基丁酸氯甲酯(17.1mg,64.2μmol)和NaI(9.6mg,64.2μmol)。将所得混合物在60℃下搅拌4小时,接着浓缩。将TFA(0.1mL,1mmol)和DCM(0.1mL,2mmol)加入到残余物中,并在室温下搅拌1小时。接着将混合物浓缩,并将残余物溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到呈白色固体三氟乙酸盐形式的标题化合物(4.3mg)。MS m/z[M+H]+C26H31ClFN7O6的计算值592.20;实验值592.4。
另外,已发现也产生了标题化合物的区域异构体,呈白色固体三氟乙酸盐形式的(S)-2-氨基-3-甲基丁酸5-[N′-(5'-氯-2'-氟联苯-4-基甲基)-N'-((R)-2-乙氧基羰基-2-羟基乙基)肼基羰基]四唑-1-基甲酯(2.7mg):
将两种区域异构体分离并通过NMR、HPLC和LCMS表征。
实例7D:丁酸(R)-3-[N-(5'-氯-2′-氟联苯-4-基甲基)-N′-(2H-四唑-5-羰基)肼
基]-2-羟基丙酰氧基甲酯
将丁酸氯甲酯(6.8μL,54.5μmol)和NaI(8.2mg,54.5μmol)于丙酮(0.5mL,7mmol)中的混合物在60℃下搅拌1小时,接着将其加入到(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N′-(2-三苯甲基-2H-四唑-5-羰基)肼基]-2-羟基丙酸(12.3mg,18.2μmol)和DIPEA(4.8μL,27.2μmol)于丙酮(0.5mL)中的混合物中。将所得混合物在40℃下搅拌2小时,浓缩且分配于EtOAc(10mL)与水(2mL)之间。有机层经MgSO4干燥,过滤且浓缩。加入4.0M HCl于1,4-二噁烷(40.0μL,160μmol)中于MeCN(0.2mL,4mmol)中,且将所得混合物在室温下搅拌20分钟。将混合物浓缩,并将残余物溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到标题化合物(1.3mg)。MS m/z[M+H]+C23H24ClFN6O6的计算值535.14;实验值535.1。
应注意,如本文中所阐明,如此的化合物可以互变异构体形成存在,例如,作为丁酸(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N′-(1H-四唑-5-羰基)肼基]-2-羟基丙酰氧基甲酯。
实例7E:(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(1H-四唑-5-羰基)肼基]-
2-羟基丙酸乙酰氧基甲酯
在0℃下在氮气下向(R)-3-(2-(1-烯丙基-1H-四唑-5-羰基)-1-((5'-氯-2'-氟联苯-4-基)甲基)肼基)-2-羟基丙酸锂(300mg,624μmol)于DMF(3mL)中的溶液中逐滴加入乙酸溴甲酯(144mg,936μmol)、NaI(140mg,936μmol)和2,6-二甲基吡啶(134mg,1.2mmol)。将所得混合物搅拌3.5小时,接着倾入到水(30mL)中。所得溶液用EtOAc(2×15mL)萃取。合并的有机层用NaCl饱和水溶液(15mL)洗涤,经无水Na2SO4干燥,过滤,且在真空中浓缩。残余物通过制备型TLC(PE:EtOAc约1:2)纯化,得到呈黄色油状物的化合物1(170mg)。LC-MS:547[M+H]+。
向化合物1(80mg,146μmol)于无水DCM(3mL)中的溶液中加入Pd(PPh3)4(50mg,43.9μmol)、三乙基硅烷(51mg,439μmol)和AcOH(26mg,439μmol)。将所得混合物在室温下在氮气下搅拌30小时。将固体滤出,且在真空中浓缩滤液。残余物通过制备型HPLC[Gemini-C18,150×21.2mm,5μ;MeCN-H2O(0.1%TFA)从43%到43%]纯化,得到呈白色固体状的标题化合物(10mg)。LC-MS:507[M+H]+。1H NMR(CDCl3):δ1.27(s,3H),3.41-3.53(m,2H),4.21-4.24(dd,2H),4.51-4.53(t,1H),5.68-5.75(dd,2H),7.05-7.09(t,1H),7.25-7.26(m,1H),7.36-7.38(dd,1H),7.48(s,4H),8.84(s,1H)。
应注意,如本文中所阐明,如此的化合物可以互变异构体形成存在,例如,作为(R)-3-[N-(5'-氯-2′-氟联苯-4-基甲基)-N′-(2H-四唑-5-羰基)肼基]-2-羟基丙酸乙酰氧基甲酯。
实例7F:(S)-2-氨基-3-甲基丁酸(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-
(1H-四唑-5-羰基)肼基]-2-羟基丙酰氧基甲酯
使用本文所述的程序,也可制备标题化合物。
应注意,如本文中所阐明,如此的化合物可以互变异构体形成存在,例如,作为(S)-2-氨基-3-甲基丁酸(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(2H-四唑-5-羰基)肼基]-2-羟基丙酰氧基甲酯。
实例7G:(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N′-(1H-四唑-5-羰基)肼基]-
2-羟基丙酸异丙氧基羰氧基甲酯
向(R)-3-(2-(1-烯丙基-1H-四唑-5-羰基)-1-((5'-氯-2'-氟联苯-4-基)甲基)肼基)-2-羟基丙酸锂(250mg,526μmol)于碳酸氯甲酯异丙酯(2mL)中的溶液中加入NaI(113mg,1.1mmol)和2,6-二甲基吡啶(158mg,1.1mmol)。将所得混合物在80℃下搅拌3小时,冷却到室温,接着倾入到水(10mL)中。所得溶液用EtOAc(2×10mL)萃取。合并的有机层经无水Na2SO4干燥,过滤并在真空中浓缩。残余物通过柱色谱(PE:EtOAc=5:1到4:1到3:1)纯化,得到呈无色油状物的化合物1(165mg)。LC-MS:591[M+H]+。
向化合物1(150mg,254μmol)于无水DCM(5mL)中的溶液中加入Pd(PPh3)4(88mg,76μmol)、三乙基硅烷(148mg,1.3mmol)和AcOH(76mg,1.3mmol)。将所得混合物在室温下在氮气下搅拌2天,接着在真空中浓缩。残余物通过制备型HPLC[Gemini-C18,150×21.2mm,5μ;MeCN-H2O(0.1%TFA)从50%到80%]纯化,得到呈白色固体状的标题化合物(15mg)。LC-MS:551[M+H]+。1H NMR(CDCl3)δ1.25-1.29(d,6H),3.44-3.56(m,2H),4.23-4.31(dd,2H),4.54-4.56(t,1H),4.85-4.91(m,1H),5.74(s,2H),7.04-7.08(t,1H),7.23-7.25(m,1H),7.35-7.36(m,1H),7.46(s,4H),9.06(s,1H)。
应注意,如本文中所阐明,如此的化合物可以互变异构体形成存在,例如,作为(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(2H-四唑-5-羰基)肼基]-2-羟基丙酸异丙氧基羰氧基甲酯。
实例7H:(S)-2-氨基-3-甲基丁酸(R)-1-羧基-2-[N-(5′-氯-2′-氟联苯-4-基甲
基)-N'-(1H-四唑-5-羰基)肼基]乙酯
使用本文所述的程序,也可制备标题化合物。应注意,如本文中所阐明,如此的化合物可以互变异构体形成存在,例如,作为(S)-2-氨基-3-甲基丁酸(R)-1-羧基-2-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(2H-四唑-5-羰基)肼基]乙酯。
实例7I:(R)-2-乙酰氧基-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N′-(1H-四唑-5-
羰基)肼基]丙酸
使用本文所述的程序,也可制备标题化合物。应注意,如本文中所阐明,如此的化合物可以互变异构体形成存在,例如,作为(R)-2-乙酰氧基-3-[N-(5'-氯-2′-氟联苯-4-基甲基)-N'-(2H-四唑-5-羰基)肼基]丙酸。
实例7J:(R)-3-[N-(5′-氯-2′-氟联苯-4-基甲基)-N′-(1H-四唑-5-羰基)-肼基]-
2-羟基丙酸乙氧基羰氧基甲酯
向(R)-3-(2-(1-烯丙基-1H-四唑-5-羰基)-1-((5′-氯-2′-氟联苯-4-基)甲基)肼基)-2-羟基丙酸锂(250mg,526μmol)于碳酸氯甲酯乙酯(2mL)中的悬浮液中加入NaI(158mg,1.1mmol)和2,6-二甲基吡啶(113mg,1.1mmol)。将所得混合物在50℃下搅拌4小时,冷却到室温,接着倾入到水(10mL)中。所得溶液用EtOAc(2×10mL)萃取。合并的有机层经无水Na2SO4干燥,过滤并在真空中浓缩。残余物通过柱色谱(PE:EtOAc=4:1到3:1到2:1)纯化,得到呈黄色固体状的化合物1(170mg)。LC-MS:577[M+H]+。
向化合物1(160mg,277μmol)于无水DCM(5mL)中的溶液中加入Pd(PPh3)4(96mg,83μmol)、三乙基硅烷(161mg,1.4mmol)和AcOH(83mg,1.4mmol)。将所得混合物在室温下在氮气下搅拌2天,接着在真空中浓缩。残余物通过制备型HPLC[Gemini-C18,150×21.2mm,5μ;MeCN-H2O(0.1%TFA)从50%到60%]纯化,得到呈白色固体状的标题化合物(7mg)。LC-MS:537[M+H]+。1H NMR(CDCl3)δ1.28-1.33(t,3H),3.47-3.50(t,2H),4.21-4.24(m,4H),4.50-4.52(t,1H),5.72-5.77(dd,2H),7.06-7.11(t,1H),7.25-7.27(m,1H),7.28-7.38(m,1H),7.49(s,4H),8.69(s,1H)。
应注意,如本文中所阐明,如此的化合物可以互变异构体形成存在,例如,作为(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(2H-四唑-5-羰基)肼基]-2-羟基丙酸乙氧基羰氧基甲酯。
实例7K:(S)-2-甲氧基羰基氨基-3-甲基丁酸(R)-3-[N-(5'-氯-2'-氟联苯-4-基
甲基)-N'-(1H-四唑-5-羰基)-肼基]-2-羟基丙酰氧基甲酯
向(R)-3-[N′-(1-烯丙基-1H-四唑-5-羰基)-N-(5′-氯-2′-氟联苯-4-基甲基)肼基]-2-羟基丙酸和甲烷(200mg,421μmol)于THF(5mL)中的悬浮液中加入(S)-2-甲氧基羰基氨基-3-甲基丁酸氯甲酯(1.88g,8.42mmol)、NaI(126mg,842μmol)和2,6-二甲基吡啶(90mg,842μmol)。将混合物在氮气下回流30小时,接着冷却到室温且倾入到水(20mL)中。混合物用EtOAc(2×10mL)萃取。合并的有机层经无水Na2SO4干燥,过滤并在真空中浓缩。残余物接着通过柱色谱(PE:EtOAc,5:1到4:1到3:1)纯化,得到呈黄色油状物的化合物1(110mg)。LC-MS:662[M+H]+。
向化合物1(110mg,166μmol)于无水DCM(3mL)中的溶液中加入Pd(PPh3)4(57mg,50μmol)、Et3SiH(97mg、831μmol)和AcOH(50mg,831μmol)。将混合物在室温下在氮气下搅拌2天,接着在真空中浓缩。残余物通过制备型HPLC(Gemini-C18,150×21.2mm,5μ,MeCN-H2O(0.1%TFA);从50%到60%)纯化,得到呈白色固体状的标题化合物(20mg)。LC-MS:622[M+H]+。1H NMR(CDCl3,400MHz):δ1.02-1.05(d,6H),2.06-2.09(m,1H),3.47(s,2H),3.85(s,3H),4.23-4.37(dd,2H),4.42(s,1H),4.70(t,1H),5.27-5.28(d,1H),5.69-5.74(dd,2H),7.06-7.08(m,1H)。7.24-7.26(m,1H),7.34-7.34(d,1H),7.42-7.44(dd,2H),7.50-7.52(dd,2H)。
应注意,如本文中所阐明,如此的化合物可以互变异构体形成存在,例如,作为(S)-2-甲氧基羰基氨基-3-甲基丁酸(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N′-(2H-四唑-5-羰基)肼基]-2-羟基丙酰氧基甲酯。
实例7L:(R)-3-[N-(5'-氯-2′-氟联苯-4-基甲基)-N'-(2H-四唑-5-羰基)肼基]-
2-丙酰氧基丙酸
将丙酰氯(24mg,55μmol)加入到(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N′-(2H-四唑-5-羰基)肼基]-2-羟基丙酸(6.1mg,66μmol)和DCM(2mL)的混合物中,且将所得混合物在室温下搅拌1小时。接着将混合物加热到60℃后持续1小时。接着停止反应,且将混合物浓缩且通过制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(1mg)。MS m/z[M+H]+C21H20ClFN6O5的计算值491.12;实验值491.2。
应注意,如本文中所阐明,如此的化合物可以互变异构体形成存在,例如,作为(R)-3-[N-(5'-氯-2′-氟联苯-4-基甲基)-N'-(1H-四唑-5-羰基)肼基]-2-丙酰氧基丙酸。
实例7M:(S)-2-甲氧基羰基氨基-3-甲基丁酸(R)-1-羧基-2-[N-(5'-氯-2'-氟联
苯-4-基甲基)-N'-(2H-四唑-5-羰基)肼基]乙酯
将(S)-2-((甲氧基羰基)氨基)-3-甲基丁酸(12.9mg,73μmol)与HOBt(12.4mg,92μmol)和EDC(11.4mg,73μmol)组合于DCM(2mL)中且搅拌15分钟。加入(R)-3-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(2H-四唑-5-羰基)肼基]-2-羟基丙酸(26.6mg,61μmol)和4-甲基吗啉(7.4mg,73μmol),且将所得混合物在室温下搅拌过夜。蒸发溶剂,且残余物通过制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(6mg)。MS m/z[M+H]+C25H27ClFN7O7的计算值592.16;实验值592.2。
应注意,如本文中所阐明,如此的化合物可以互变异构体形成存在,例如,作为(S)-2-甲氧基羰基氨基-3-甲基丁酸(R)-1-羧基-2-[N-(5'-氯-2'-氟联苯-4-基甲基)-N'-(1H-四唑-5-羰基)肼基]乙酯。
实例8A:(R)-3-[N-(3'-氯联苯-4-基甲基)-N'-(3-羟基异噁唑-5-羰基)肼基]-2-
丙酰氧基丙酸
将丙酰氯(3.5μL,40μmol)加入到(R)-3-[N-(3'-氯联苯-4-基甲基)-N′-(3-羟基异噁唑-5-羰基)肼基]-2-羟基丙酸2-氧代-2-苯基乙酯(20.0mg,36.4μmol)和Et3N(12.7μL,90.9μmol)于DCM(0.5mL,8mmol)中的混合物中。将所得混合物在室温下搅拌1小时,浓缩,并通过快速色谱(EtOAc-己烷=0-100%)纯化,得到固体(15.5mg)。将固体溶解于AcOH(1.5mL,26mmol)中。加入锌(119mg,1.8mmol),且将所得混合物在室温下搅拌2小时。过滤混合物,且用AcOH(0.5mL)洗涤锌粉。合并的洗液通过反相制备型HPLC纯化,得到标题化合物(3.9mg)。MS m/z[M+H]+C23H22ClN3O7的计算值488.11;实验值488.3。
实例8B:3-甲基丁酸(R)-1-羧基-2-[N-(3′-氯联苯-4-基甲基)-N′-(3-羟基异噁
唑-5-羰基)肼基]乙酯
将异戊酰氯(15.5μL,127μmol)加入到(R)-3-[N-(3'-氯联苯-4-基甲基)-N'-(3-羟基异噁唑-5-羰基)肼基]-2-羟基丙酸(25.0mg,58μmol)和Et3N(40.3μL,289μmol)于DCM(0.5mL,8mmol)中的混合物中。将所得混合物在室温下搅拌1小时,并浓缩。将残余物与NaHCO3饱和水溶液(10:90,NaHCO3:水,0.1mL,0.1mmol)组合在MeOH(1.0mL)中,搅拌15分钟,且接着浓缩。将残余物溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到标题化合物(2.4mg)。MS m/z[M+H]+C25H26ClN3O7的计算值516.15;实验值516.5。
实例8C:(R)-3-[N'-(3-乙酰氧基甲氧基异噁唑-5-羰基)-N-(3'-氯联苯-4-基甲
基)肼基]-2-羟基丙酸
将乙酸溴甲酯(16.0μL,164μmol)和NaI(24.5mg,164μmol)于丙酮(2.0mL,27mmol)中的混合物在60℃下搅拌1小时,接着冷却到室温。接着加入(R)-3-[N-(3'-氯联苯-4-基甲基)-N'-(3-羟基异噁唑-5-羰基)肼基]-2-羟基丙酸2-氧代-2-苯基乙酯(30.0mg,54.5μmol)和Et3N(38.0μL,273μmol)于丙酮(1mL)中的混合物。将所得混合物在室温下搅拌2小时,浓缩,溶解于AcOH(2mL)中,过滤,并通过反相制备型HPLC纯化。将所需洗脱份合并且冻干,得到固体(19.2mg)。将固体与锌(178mg,2.7mmol)组合于AcOH(1.0mL,18mmol)中并在室温下搅拌2小时。将混合物过滤并通过反相制备型HPLC纯化。将所需洗脱份合并,冻干,溶解于AcOH(1.5mL)中,并通过反相制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(3.8mg)。MS m/z[M+H]+C23H22ClN3O8的计算值504.11;实验值504.0。
实例8D:丁酸5-[N'-((R)-2-羧基-2-羟基乙基)-N′-(3′-氯联苯-4-基甲基)肼基
羰基]异噁唑-3-基氧基甲酯
将丁酸氯甲酯(20.5μL,164μmol)和NaI(24.5mg,164μmol)于丙酮(2.0mL,27mmol)中的混合物在60℃下搅拌1小时,接着冷却到室温,并加入到(R)-3-[N-(3'-氯联苯-4-基甲基)-N'-(3-羟基异噁唑-5-羰基)肼基]-2-羟基丙酸2-氧代-2-苯基乙酯(30.0mg,54.5μmol)和Et3N(38.0μL,273μmol)于丙酮(1mL)中的混合物中。将所得混合物在室温下搅拌2小时,浓缩,溶解于AcOH(2mL)中,过滤,并通过反相制备型HPLC纯化。将所需洗脱份合并且冻干。加入锌(178mg,2.7mmol)和AcOH(1.0mL,18mmol),且将所得混合物在室温下搅拌2小时。将混合物过滤并通过反相制备型HPLC纯化,得到标题化合物(2.5mg)。MS m/z[M+H]+C25H26ClN3O8的计算值532.14;实验值532.2。
实例8E:(R)-3-[N-(3'-氯联苯-4-基甲基)-N′-(3-乙氧基羰氧基甲氧基异噁唑-
5-羰基)肼基]-2-羟基丙酸
将碳酸氯甲酯乙酯(22.7μL,164μmol)和NaI(24.5mg,164μmol)于丙酮(2.0mL,27mmol)中的混合物在60℃下搅拌1小时,接着冷却到室温,并加入到(R)-3-[N-(3'-氯联苯-4-基甲基)-N'-(3-羟基异噁唑-5-羰基)肼基]-2-羟基丙酸2-氧代-2-苯基乙酯(30.0mg,54.5μmol)和碳酸铯(17.8mg,0.054.5μmol)于丙酮(1mL)中的混合物中。将所得混合物在室温下搅拌2小时,浓缩,溶解于AcOH(2mL)中,过滤,并通过反相制备型HPLC纯化。将所需洗脱份合并且浓缩。加入锌(178mg,2.7mmol)和AcOH(1.0mL,18mmol),且将所得混合物在室温下搅拌2小时。将混合物过滤并通过反相制备型HPLC纯化,得到标题化合物(2.2mg)。MS m/z[M+H]+C24H24ClN3O9的计算值534.12;实验值534.3。
实例8F:(R)-3-[N-(3′-氯联苯-4-基甲基)-N′-(3-异丙氧基羰氧基甲氧基异噁
唑-5-羰基)肼基]-2-羟基丙酸
将碳酸氯甲酯异丙酯(15.6mg,102μmol)和NaI(15.3mg,102μmol)于丙酮(0.7mL,10mmol)中的混合物在65℃下搅拌1小时,接着加入已在室温下溶解于丙酮(0.4mL,5mmol)中并用碳酸铯(13.0mg,40μmol)处理的(R)-3-[N-(3'-氯联苯-4-基甲基)-N′-(3-羟基异噁唑-5-羰基)肼基]-2-羟基丙酸2-氧代-2-苯基乙酯(20.0mg,36.4μmol)。接着将所得混合物在40℃下加热1小时。加入DIPEA(0.2mL,1mmol)并继续加热1小时。将混合物冷却到室温并浓缩。将残余物分配于EtOAc(10.0mL)与水(2.0mL)之间。有机层用NaHCO3饱和水溶液(3.0mL)、NaCl饱和水溶液(3.0mL)洗涤,经Na2SO4干燥,过滤并浓缩。加入锌(90.8mg,1.4mmol)和AcOH(0.5mL,9mmol),且将所得混合物在室温下搅拌1小时。固体用AcOH(1.0mL)洗涤,接着过滤。将滤液合并且通过反相制备型HPLC纯化,得到标题化合物(3.8mg)。MS m/z[M+H]+C25H26ClN3O9的计算值548.14;实验值548.5。
实例8G:(R)-3-{N-(3′-氯联苯-4-基甲基)-N′-[3-(5-甲基-2-氧代-[1,3]间二氧
杂环戊烯-4-基甲氧基)-异噁唑-5-羰基]肼基}-2-羟基丙酸
将4-氯甲基-5-甲基-1,3-间二氧杂环戊烯-2-酮(11.9μL,109μmol)和NaI(16.4mg,109μmol)于丙酮(2.0mL,27mmol)中的混合物在60℃下搅拌1小时,接着冷却到室温,并加入到(R)-3-[N-(3′-氯联苯-4-基甲基)-N′-(3-羟基异噁唑-5-羰基)肼基]-2-羟基丙酸2-氧代-2-苯基乙酯(20.0mg,36.4μmol)和碳酸铯(14.2mg,43.6μmol)于丙酮(1mL)中的混合物中。将所得混合物在60℃下搅拌2小时,浓缩,通过快速色谱(EtOAc/己烷=0-100%)纯化。将所需洗脱份合并且浓缩。加入锌(178mg,2.7mmol)和AcOH(1.0mL,18mmol),且将所得混合物在室温下搅拌2小时。固体用AcOH(0.5mL)洗涤,接着过滤。将滤液合并且通过反相制备型HPLC纯化,得到标题化合物(2.8mg)。MS m/z[M+H]+C25H22ClN3O9的计算值544.10;实验值544.5。
实例8H:(S)-2-氨基-3-甲基丁酸5-[N′-((R)-2-羧基-2-羟基乙基)-N'-(3'-氯-
联苯-4-基甲基)肼基羰基]异噁唑-3-基氧基甲酯
将(S)-2-叔丁氧基羰基氨基-3-甲基丁酸氯甲酯(52.8mg,198μmol)和NaI(29.8mg,198μmol)于丙酮(1.0mL,14mmol)中的混合物在65℃下加热1小时,接着加入(R)-3-[N-(3'-氯联苯-4-基甲基)-N'-(3-羟基异噁唑-5-羰基)肼基]-2-羟基丙酸2-氧代-2-苯基乙酯(36.4mg,66.2μmol)和碳酸铯(25.9mg,79.4μmol)。将所得混合物在65℃下搅拌3小时,浓缩,通过快速色谱(EtOAc/己烷=0-100%)纯化。加入锌(216mg,3.3mmol)和AcOH(1.0mL,18mmol),且将所得混合物在室温下搅拌1小时,接着通过旋转蒸发浓缩。加入TFA(0.1mL,1mmol)和DCM(0.1mL,2mmol),且将混合物搅拌30分钟,接着浓缩。将残余物溶解于AcOH(1.5mL)中,过滤,并通过反相制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(3.0mg)。MS m/z[M+H]+C26H29ClN4O8的计算值561.17;实验值561.2。
实例8I:(S)-2-甲氧基羰基氨基-3-甲基丁酸(R)-1-羧基-2-[N-(3'-氯-联苯-4-
基甲基)-N'-(3-羟基异噁唑-5-羰基)肼基]乙酯
将(S)-2-甲氧基羰基氨基-3-甲基丁酸(9.6mg,54.5μmol)和HATU(23.5mg,62μmol)在DCM(1.0mL,16mmol)中搅拌10分钟。加入(R)-3-[N-(3'-氯联苯-4-基甲基)-N'-(3-羟基异噁唑-5-羰基)肼基]-2-羟基丙酸2-氧代-2-苯基乙酯(20.0mg,36.4μmol)和DIPEA(31.7μL,182μmol),且将所得混合物在室温下搅拌过夜。接着,将混合物浓缩并通过快速色谱(EtOAc/己烷=0-100%)纯化。加入锌(119mg,1.8mmol)和AcOH(0.5mL,9mmol)。将混合物搅拌2小时且过滤。固体用AcOH(1mL)洗涤且过滤。合并的滤液通过反相制备型HPLC纯化,得到标题化合物(0.8mg)。MS m/z[M+H]+C27H29ClN4O9的计算值589.16;实验值589.3。
实例8J:(S)-2-叔丁氧基羰基氨基-3-甲基丁酸5-[N'-((R)-2-羧基-2-羟基乙
基)-N'-(3'-氯联苯-4-基甲基)肼基羰基]异噁唑-3-基氧基甲酯
将(R)-3-[N'-叔丁氧基羰基-N-(3'-氯联苯-4-基甲基)肼基]-2-羟基-丙酸(406mg,965μmol)溶解于DMF(5mL)中。依序加入碳酸钾(333mg,2.4mmol)和2-溴-1-苯基乙酮(230mg,1.2mmol)。将所得混合物在室温下搅拌过夜。在真空中去除溶剂,且将残余物纯化(CombiFlash正相柱)。收集纯净的洗脱份且合并,得到化合物1(280mg)。
将化合物1(200mg,371μmol)溶解于MeCN(3mL)中。加入4.0M HCl于二噁烷(928μL,3.7mmol)中的溶液,且将所得混合物在室温下搅拌1小时。在真空中去除溶剂,且残余物化合物2不经任何进一步纯化即用于下一步骤。
将3-((S)-2-叔丁氧基羰基氨基-3-甲基丁酰氧基甲氧基)异噁唑-5-甲酸(44.1mg,123μmol)和HATU(78mg,205μmol)组合在DMF(1mL)中且在室温下搅拌15分钟。加入化合物2(45mg,103μmol)和DIPEA(54μL,307μmol),且将所得混合物在室温下搅拌15分钟。在真空中去除溶剂,且将残余物纯化(CombiFlash正相柱)。收集纯净的洗脱份且合并,得到化合物3(41mg)。
将化合物3(41mg,53μmol)溶解于AcOH(1mL)中,且加入锌(172mg,2.6mmol)。将混合物在室温下搅拌45分钟到1小时,直到反应完成。滤出锌,且将溶液纯化(反相柱),得到标题化合物(7mg)。MS m/z[M+H]+C31H37ClN4O10的计算值661.22;实验值661.2。
实例8K:(R)-3-[N-(3′-氯联苯-4-基甲基)-N'-(3-羟基异噁唑-5-羰基)肼基]-2-
羟基丙酸乙酰氧基甲酯
使用本文所述的程序,也可制备标题化合物。
实例8L:(S)-2-氨基-3-甲基丁酸(R)-3-[N-(3'-氯联苯-4-基甲基)-N'-(3-羟基
异噁唑-5-羰基)-肼基]-2-羟基丙酰氧基甲酯
使用本文所述的程序,也可制备标题化合物。
实例8M:(S)-2-甲氧基羰基氨基-3-甲基丁酸(R)-3-[N-(3'-氯联苯-4-基甲基)-
N'-(3-羟基异噁唑-5-羰基)肼基]-2-羟基丙酰氧基甲酯
使用本文所述的程序,也可制备标题化合物。
实例8N:(S)-2-氨基-3-甲基丁酸(R)-1-羧基-2-[N-(3'-氯联苯-4-基甲基)-N'-
(3-羟基异噁唑-5-羰基)肼基]乙酯
使用本文所述的程序,也可制备标题化合物。
实例9A:(R)-3-[N-(2',5'-二氯联苯-4-基甲基)-N′-(1-羟基-1H-[1,2,3]三唑-
4-羰基)肼基]-2-羟基丙酸
将1-羟基-1H-1,2,3-三唑-4-甲酸(42.6mg,330μmol)和HATU(125mg,330μmol)组合在DMF(2mL)中,且在室温下搅拌5分钟。加入DIPEA(86μL,495μmol)和(R)-3-[N-(4-溴苯甲基)肼基]-2-羟基丙酸甲酯(50mg,0.2mmol),且将所得混合物搅拌30分钟。在减压下蒸发混合物,且将产物溶解于EtOH(0.8mL,10mmol)和水(0.2mL,10mmol)中。加入2,5-二氯苯基硼酸(57mg,297μmol)、K2CO3(68mg,495μmol)和 DPP-Pd(0.28mmol/g负载;58.9mg,16.5μmol),且将所得混合物在120℃下加热10分钟。过滤混合物,且将1M LiOH水溶液(1.2mL,1.2mmol)加入到经过滤物中。搅拌混合物直到反应完成(1小时),接着真空处理到干燥且通过制备型HPLC纯化,得到呈三氟乙酸盐形式的标题化合物(14mg,纯度95%)。MSm/z[M+H]+C19H17Cl2N5O5的计算值466.06;实验值466.2。
实例9B:(R)-3-[N'-(1-乙酰氧基甲氧基-1H-[1,2,3]三唑-4-羰基)-N-(2',5'-二
氯联苯-4-基甲基)肼基]-2-羟基丙酸
将乙酸溴甲酯(15.3mg,100μmol)加入到(R)-3-[N-(2',5'-二氯联苯-4-基甲基)-N'-(1-羟基-1H-1,2,3-三唑-4-羰基)肼基]-2-羟基丙酸(31.2mg,66.8μmol)于丙酮(0.5mL,6.8mmol)中的溶液,随后加入Et3N(18.6μL,134μmol)。将所得混合物在55℃下搅拌1小时。接着在真空中浓缩混合物,得到黄色液体。将粗液体纯化(制备型规模C18柱色谱,小柱,使用30%-90%MeCN/水与0.05%TFA),得到呈白色固体状的标题化合物(5.2mg,纯度96%)。MS m/z[M+H]+C22H21Cl2N5O7的计算值538.08;实验值538.1。
实例9C:丁酸4-[N'-((R)-2-羧基-2-羟基乙基)-N'-(2',5'-二氯联苯-4-基甲基)
肼基羰基]-[1,2,3]三唑-1-基氧基甲酯
将丁酸氯甲酯(13.7mg,100μmol)加入到(R)-3-[N-(2',5'-二氯联苯-4-基甲基)-N'-(1-羟基-1H-1,2,3-三唑-4-羰基)肼基]-2-羟基丙酸(31.2mg,66.8μmol)于丙酮(0.5mL,6.8mmol)中的溶液,随后加入Et3N(18.6μL,134μmol)。将所得混合物在65℃下搅拌2小时。接着在真空中浓缩混合物,得到黄色液体。将粗液体纯化(制备型规模C18柱色谱,小柱,使用30%-90%MeCN/水与0.05%TFA),得到呈白色固体状的标题化合物(6.1mg,纯度99%)。MS m/z[M+H]+C24H25Cl2N5O7的计算值566.11;实验值566.1。
实例9D:(R)-3-{N-(2',5'-二氯联苯-4-基甲基)-N'-[1-(5-甲基-2-氧代-[1,3]
间二氧杂环戊烯-4-基甲氧基)-1H-[1,2,3]三唑-4-羰基]肼基}-2-羟基丙酸
将4-氯甲基-5-甲基-1,3-间二氧杂环戊烯-2-酮(14.9mg,100μmol)加入到(R)-3-[N-(2′,5′-二氯联苯-4-基甲基)-N′-(1-羟基-1H-1,2,3-三唑-4-羰基)肼基]-2-羟基丙酸(31.2mg,66.8μmol)于丙酮(0.5mL,6.8mmol)中的溶液,随后加入Et3N(18.6μL,134μmol)。将所得混合物在65℃下搅拌2小时。接着在真空中浓缩混合物,得到黄色液体。将粗液体纯化(制备型规模C18柱色谱,小柱,使用30%-90%MeCN/水与0.05%TFA),得到呈白色固体状的标题化合物(10.0mg,纯度99%)。MS m/z[M+H]+C24H21Cl2N5O8的计算值578.08;实验值578.1。
实例9E:(S)-2-甲氧基羰基氨基-3-甲基丁酸(R)-3-[N-(2′,5′-二氯联苯-4-基甲
基)-N′-(1-羟基-1H-[1,2,3]-三唑-4-羰基)肼基]-2-羟基丙酰氧基甲酯
使用本文所述的程序,也可制备标题化合物。
实例9F:(R)-3-[N-(2′,5′-二氯联苯-4-基甲基)-N'-(1-羟基-1H-[1,2,3]三唑-
4-羰基)肼基]-2-羟基丙酸异丙氧基羰氧基甲酯
向(R)-3-[N'-(1-烯丙氧基-1H-[1,2,3]三唑-4-羰基)-N-(2′,5′-二氯联苯-4-基甲基)-肼基]-2-羟基丙酸(400mg,790μmol)和碳酸氯甲酯异丙酯(1.5mL)的混合物中加入NaI(237mg,1.6mmol)和二甲基吡啶(166mg,1.6mmol)。将混合物在50℃下搅拌3小时。在冷却到室温之后,混合物用水(15mL)稀释且用EtOAc(2×15mL)萃取。合并的有机层用NaCl饱和水溶液(20mL)洗涤,经无水Na2SO4干燥,浓缩,且通过柱色谱(PE:EtOAc=5:1到2:1)纯化,得到呈淡黄色固体状的化合物1(230mg)。LC-MS:622[M+H]+。
向化合物1(230mg,370μmol)于THF(5mL)中的溶液中加入Pd(PPh3)4(64mg,56μmol)和1,3-二甲基巴比妥酸(577mg,3.7mmol)。将混合物在室温下搅拌2小时,且接着浓缩。残余物通过制备型HPLC[Daisogel-C18,250×50mm,10μ;MeCN-H2O(0.1%TFA)从50%到90%]纯化,得到呈白色固体状的标题化合物(120mg)。LC-MS:582[M+H]+。1H-NMR(MeOD,400Hz):δ1.13-1.24(d,6H),3.33-3.36(m,2H),4.08-4.11(m,2H),4.34-4.35(m,1H),5.66(s,2H),7.15-7.38(m,4H),7.39-7.44(m,3H),8.11(s,1H)。
实例9G:(R)-3-[N-(2',5'-二氯联苯-4-基甲基)-N'-(1-羟基-1H-[1,2,3]三唑-
4-羰基)肼基]-2-羟基丙酸乙酰氧基甲酯
使用本文所述的程序,也可制备标题化合物。
实例9H:(R)-3-[N-(2',5'-二氯联苯-4-基甲基)-N'-(1-羟基-1H-[1,2,3]三唑-
4-羰基)肼基]-2-羟基丙酸5-甲基-2-氧代-[1,3]间二氧杂环戊烯-4-基甲酯
使用本文所述的程序,也可制备标题化合物。
实例9I:(R)-3-[N-(2',5'-二氯联苯-4-基甲基)-N'-(1-羟基-1H-[1,2,3]三唑-
4-羰基)肼基]-2-羟基丙酸乙氧基羰氧基甲酯
使用本文所述的程序,也可制备标题化合物。
实例9J:丁酸(R)-3-[N-(2′,5'-二氯联苯-4-基甲基)-N′-(1-羟基-1H-[1,2,3]三
唑-4-羰基)肼基]-2-羟基丙酰氧基甲酯
向(R)-3-[N′-(1-烯丙氧基-1H-[1,2,3]三唑-4-羰基)-N-(2',5'-二氯联苯-4-基甲基)-肼基]-2-羟基丙酸(300mg,590μmol)和丁酸氯甲酯(1.5mL)的混合物中加入NaI(178mg,1.2mmol)和二甲基吡啶(124mg,1.2mmol)。将混合物在50℃下搅拌5小时。在冷却到室温之后,混合物用水(15mL)稀释且用EtOAc(2×15mL)萃取。合并的有机层用NaCl饱和水溶液(20mL)洗涤,经无水Na2SO4干燥,浓缩,且通过硅胶色谱(硅胶:200-300目;用PE:EtOAc=5:1到2:1洗脱)纯化,得到呈淡黄色固体状的化合物1(220mg)。LC-MS:606[M+H]+,608[(M+2)+H]+。
向化合物1(220mg,360μmol)于THF(5mL)中的溶液中加入Pd(PPh3)4(22mg,20μmol)和1,3-二甲基巴比妥酸(525mg,3.6mmol)。将混合物在室温下搅拌2小时,且接着浓缩。残余物通过制备型HPLC[Daisogel-C18,250×50mm,10μ;MeCN-H2O(0.1%TFA)从60%到90%]纯化,得到呈白色固体状的标题化合物(80mg)。LC-MS:566[M+H]+,568[(M+2)+H]+。1H-NMR(CD3OD,400Hz):δ0.93(t,3H),1.62(q,2H),2.31(t,2H),3.32-3.37(m,2H),4.20(m,2H),4.41(m,1H),5.75(dd,2H),7.35(m,4H),7.47-7.54(m,3H),8.20(s,1H)。
实例9K:(R)-3-[N-(2',5'-二氯联苯-4-基甲基)-N'-(1-羟基-1H-[1,2,3]三唑-
4-羰基)肼基]-2-羟基丙酸1-环己基氧基羰氧基乙酯
向(R)-3-[N'-(1-烯丙氧基-1H-[1,2,3]三唑-4-羰基)-N-(2',5'-二氯联苯-4-基甲基)-肼基]-2-羟基丙酸(300mg,590μmol)和碳酸1-氯-乙酯环己酯(1.5mL)的混合物中加入NaI(178mg,1.2mmol)和二甲基吡啶(124mg,1.2mmol)。将混合物在50℃下搅拌5小时。在冷却到室温之后,混合物用水(15mL)稀释且用EtOAc(2×15mL)萃取。合并的有机层用NaCl饱和水溶液(20mL)洗涤,经无水Na2SO4干燥,浓缩,且通过硅胶色谱(PE:EtOAc=5:1到2:1)纯化,得到呈淡黄色固体状的化合物1(200mg)。LC-MS:676[M+H]+。
向化合物1(200mg,296μmol)于THF(5mL)中的溶液中加入Pd(PPh3)4(46mg,40μmol)和1,3-二甲基巴比妥酸(461mg,3.0mmol)。将混合物在室温下搅拌2小时,且接着浓缩。残余物通过制备型HPLC[Daisogel-C18,250×50mm,10μ;MeCN-H2O(0.1%TFA)从60%到90%]纯化,得到呈白色固体状的标题化合物(60mg)。LC-MS:636[M+H]+。1H-NMR(MeOD,400Hz):δ1.29-1.55(m,9H),1.70-1.74(m,2H),1.85-1.89(m,2H),3.33-3.40(m,2H),4.19-4.22(m,2H),4.37-4.40(m,1H),4.57-4.60(m,1H),6.67-6.74(q,1H),7.33-7.36(m,4H),7.46-7.53(m,3H),8.19(s,1H)。
实例9L:(S)-2-氨基-3-甲基丁酸4-[N'-((R)-2-羧基-2-羟基乙基)-N'-(2',5'-
二氯联苯-4-基甲基)肼基羰基]-[1,2,3]三唑-1-基氧基甲酯
使用本文所述的程序,也可制备标题化合物。
实例9M:(S)-2-甲氧基羰基氨基-3-甲基丁酸4-[N'-((R)-2-羧基-2-羟基-乙基)-
N'-(2',5'-二氯联苯-4-基甲基)肼基羰基]-[1,2,3]三唑-1-基氧基甲酯
使用本文所述的程序,也可制备标题化合物。
分析
定量抑制剂对人类和大鼠NEP和人类ACE的效能(IC
50
)的体外分析
使用如下所述的体外分析测定化合物对人类和大鼠脑啡肽酶(EC 3.4.24.11;NEP)和人类血管紧张素转化酶(ACE)的抑制活性。
从大鼠肾脏提取NEP活性
大鼠NEP是从成年斯普拉道来(Sprague Dawley)大鼠的肾脏制备的。完整肾脏于冷磷酸盐缓冲盐水(PBS)中洗涤,且以每克肾脏5毫升缓冲液的比率于冰冷溶解缓冲液(1%Triton X-114、150mM NaCl、50mM三(羟甲基)氨基甲烷(Tris),pH 7.5;博尔迪耶(Bordier)(1981)生物化学杂志256:1604-1607)中处理。使用polytron手持式组织研磨器在冰上使样本均质化。组织匀浆在3℃下于浮桶式转头中以1000×g离心5分钟。离心块再悬浮于20mL冰冷溶解缓冲液中且在冰上孵育30分钟。样本(15mL到20mL)接着层铺于25mL冰冷垫层缓冲液(cushion buffer)(6%w/v蔗糖、50mM pH 7.5Tris、150mM NaCl、0.06%Triton X-114)上,加热到37℃后持续3到5分钟,且在室温下于浮桶式转头中以1000×g离心3分钟。吸出上两层,留下含有增浓膜部分的粘稠油状沉淀物。加入甘油到50%的浓度且样本储存在-20℃下。使用BCA检测系统,以牛血清白蛋白(BSA)作为标准物定量蛋白质浓度。
酶抑制分析
重组人类NEP和重组人类ACE是购得的(明尼苏达州明尼阿波利斯的R&D系统公司(R&D Systems,Minneapolis,MN),目录号分别为1182-ZN和929-ZN)。荧光肽底物Mca-D-Arg-Arg-Leu-Dap-(Dnp)-OH(梅代罗斯(Medeiros)等人(1997)巴西医学和生物学研究杂志(Braz.J.Med.Biol.Res.)30:1157-62;加利福尼亚州圣何塞的安斯派克公司(Anaspec,SanJose,CA))和Abz-Phe-Arg-Lys(Dnp)-Pro-OH(阿劳约(Araujo)等人(2000)生物化学(Biochemistry)39:8519-8525;加利福尼亚州托兰斯的巴亨公司(Bachem,Torrance,CA))分别用于NEP和ACE分析中。
分析是使用荧光肽底物在10μM的浓度下于分析缓冲液(NEP:50mM HEPES(pH7.5)、100mM NaCl、0.01%聚乙二醇脱水山梨糖醇单月桂酸酯(Tween-20)、10μM ZnSO4;ACE:50mMHEPES(pH 7.5)、100mM NaCl、0.01%Tween-20、1μM ZnSO4)中在37℃下在384孔白色不透明板中进行。各别酶的使用浓度应使得1μM底物在37℃下20分钟之后发生定量蛋白水解。
在10μM到20pM的浓度范围内对测试化合物进行分析。将测试化合物加入酶中且在37℃下孵育30分钟,随后通过加入底物来使反应开始。在37℃下孵育20分钟之后通过加入冰乙酸到最终浓度为3.6%(v/v)来终止反应。
在激发和发射波长分别设定为320nm和405nm的荧光计上读取板。抑制常数是通过使用以下方程式对数据进行非线性回归(加利福尼亚州圣迭戈图板软件公司(GraphPadSoftware,Inc.,San Diego,CA))而获得的:
v=v0/[1+(I/K')]
其中v为反应速率,v0为未抑制的反应速率,I为抑制剂浓度且K'为表观抑制常数。
在这一分析中测试式I'化合物(实例1A)且发现其具有对人类NEP≥9.0的pKi值。实例1B和1C的前药化合物并不在这一体外分析中抑制酶,或因在这一分析中预期将无活性而不经测试;然而,基于活性形式的活性,预期这些前药具有体内NEP活性。
在这一分析中测试式II'化合物(实例2A)且发现其具有对人类NEP≥9.0的pKi值。实例2B的前药化合物并不在这一体外分析中抑制酶,或因在这一分析中预期将无活性而不经测试;然而,基于活性形式的活性,预期这种前药具有体内NEP活性。
在这一分析中测试式III'化合物(实例3A)且发现其具有对人类NEP≥9.0的pKi值。实例3B-L的前药化合物并不在这一体外分析中抑制酶,或因在这一分析中预期将无活性而不经测试;然而,基于活性形式的活性,预期这种前药具有体内NEP活性。
在这一分析中测试式IV'化合物(实例4A)且发现其具有对人类NEP≥9.0的pKi值。实例4B-Q的前药化合物并不在这一体外分析中抑制酶,或因在这一分析中预期将无活性而不经测试;然而,基于活性形式的活性,预期这些前药具有体内NEP活性。
在这一分析中测试式V'化合物(实例5A)且发现其具有对人类NEP≥9.0的pKi值。实例5B-K的前药化合物并不在这一体外分析中抑制酶,或因在这一分析中预期将无活性而不经测试;然而,基于活性形式的活性,预期这种前药具有体内NEP活性。
在这一分析中测试实例6A的化合物且发现其具有对人类NEP≥9.0的pKi值。实例6B-P的前药化合物并不在这一体外分析中抑制酶,或因在这一分析中预期将无活性而不经测试;然而,基于活性形式的活性,预期这些前药具有体内NEP活性。
在这一分析中测试式VII'化合物且发现其具有对人类NEP≥9.0的pKi值。实例7A-E和7J的前药化合物并不在这一体外分析中抑制酶,或因在这一分析中预期将无活性而不经测试;然而,基于活性形式的活性,预期这种前药具有体内NEP活性。
在这一分析中测试式VIII'化合物且发现其具有对人类NEP≥9.0的pKi值。实例8A-I的前药化合物并不在这一体外分析中抑制酶,或因在这一分析中预期将无活性而不经测试;然而,基于活性形式的活性,预期这种前药具有体内NEP活性。
在这一分析中测试实例9A的化合物且发现其具有对人类NEP≥9.0的pKi值。实例9B-K的前药化合物并不在这一体外分析中抑制酶,或因在这一分析中预期将无活性而不经测试;然而,基于活性形式的活性,预期这种前药具有体内NEP活性。
尽管本发明已参考其特定方面或实施例加以描述,但所属领域的技术人员应了解在不脱离本发明的真实精神和范围的情况下可作各种变化或可替换等效物。另外,在适用专利法令和法规允许的范围内,本文引用的所有公开案、专利和专利申请案都以全文引用的方式并入本文中,所述引用的程度就如同每个文献已个别地以引用的方式并入本文中一般。
Claims (26)
1.一种式X化合物,
(i)Ra是F;Rb是Cl;X是且
当X是:
时,
R2是H且R7是选自-CH2CH3、-CH2CH(CH3)2、-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基和
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R7是H;且
当X是:
R2是H,R3是-OH,且R7是选自-CH2OC(O)CH3和-CH2OC(O)-CH[CH(CH3)2]NH2;或R2是H,R3是选自-OCH2OC(O)CH3和-OCH2OC(O)-CH[CH(CH3)2]NH2,且R7是H;或
(ii)Ra是F;Rb是Cl;X是且
R2是H且R7是选自-CH2CH3、-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)-CHRd-NHC(O)O-C1-6烷基、苯甲基和
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R7是H;或
(iii)Ra是F;Rb是Cl;X是且
R2是H且R7是选自-CH2CH(CH3)2、-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基和
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R7是H;或
(iv)Ra是F;Rb是Cl;X是R是H或-CH3;且
R2是H且R7是选自-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)-COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)-O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基、
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R7是H;或R2是-C(O)CH2NH2且R7是-CH2CH3;或
(v)Ra是F;Rb是Cl;X是且
R2是H且R7是选自-CH2CH3、-CH2CH(CH3)2、-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基和
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R7是H;或
(vi)Ra是F;Rb是Cl;X是且
R2和R4是H,且R7是选自H、-CH2CH3、-CH2CH(CH3)2、-CH2CF3、-(CH2)2CF3、-CH2CF2CH3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基、
或R2是H,R4是选自-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和-CH2OC(O)CH[CH(CH3)2]NH2,且R7是H;或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,R4是H,且R7是H;或R2是H,R4是-CH2-OP(O)(ORe)2或-CH2OC(O)CH[CH(CH3)2]NH2,且R7是-CH2CH3或-CH2CH(CH3)2;或R2是-C(O)CH[CH(CH3)2]NH2,R4是H,且R7是-CH2CH3或-CH2CH(CH3)2;或
(vii)Ra是F;Rb是Cl;X是且
R2和R4是H,且R7是选自-CH2CF3、-(CH2)2CF3、-CH2CF2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)-COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、苯甲基和
或R2是H,R4是选自-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和-CH2OC(O)CH[CH(CH3)2]NH2,且R7是选自H和-CH2CH3;或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,且R4和R7是H;或
(viii)Ra是H;Rb是Cl;X是且
R2是H,R3是-OH,且R7是选自-CH2CF3、-(CH2)2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CH[CH(CH3)2]NH2和-CH2OC(O)-CH[CH(CH3)2]-NHC(O)OCH3;或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,R3是-OH,且R7是H;或R2是H,R3是选自-OCHRcOC(O)-C1-4烷基、-OCH2OC(O)CH[CH(CH3)2]NH2、-OCH2OC(O)-CH[CH(CH3)2]-NHC(O)OC(CH3)3和
且R7是H;或
(ix)Ra是Cl;Rb是Cl;X是且
R2是H,R4是-OH,且R7是选自-CH2CF3、-(CH2)2CF3、-C(CH3)(CF3)2、-CH(CH2CH3)CF3、-CH(CH3)CF2CF3、-(CH2)2-3OH、-CH2CH(NH2)COOCH3、-(CH2)2OCH3、-CHRcOC(O)-C1-4烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-C2-4亚烷基-N(CH3)2、-CH2OC(O)CH[CH(CH3)2]NH2、-CH2OC(O)-CH[CH(CH3)2]-NHC(O)OCH3;和
或R2是选自-C(O)-C1-6烷基、-C(O)CHRd-NH2、-C(O)CHRd-NHC(O)O-C1-6烷基和-P(O)(ORe)2,R4是-OH,且R7是H;或R2是H,R4是选自-OCHRcOC(O)-C1-4烷基、-OCH2OC(O)CH[CH(CH3)2]NH2、-OCH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和
且R7是H;
其中每一Rc独立地是H或-C1-3烷基;每一Rd独立地是H、-CH3、-CH(CH3)2、苯基或苯甲基;且每一Re独立地是H、-C1-6烷基或苯基;
或其医药学上可接受的盐。
2.根据权利要求1所述的化合物,其具有式VIa或VIb:
3.根据权利要求2所述的化合物,其中:
R2是H,R4是H,且R7是选自H、-CH2CH3、-CH2CH(CH3)2、-CH2CF2CH3、-(CH2)2OCH3、-CH2OC(O)OCH2CH3、-(CH2)2-N(CH3)2、-(CH2)3-N(CH3)2、-(CH2)4-N(CH3)2、-CH2OC(O)CH[CH(CH3)2]NH2、
或
R2是H,R4是选自-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和-CH2OC(O)CH[CH(CH3)2]NH2,且R7是H;或
R2是选自-C(O)CH3、-C(O)CH(CH3)2和-C(O)CH2CH(CH3)2,R4是H,且R7是H;或
R2是H,R4是-CH2-OP(O)(OH)2或-CH2OC(O)CH[CH(CH3)2]NH2,且R7是-CH2CH3或-CH2CH(CH3)2;或
R2是-C(O)CH[CH(CH3)2]NH2,R4是H,且R7是-CH2CH3或-CH2CH(CH3)2。
4.根据权利要求1所述的化合物,其具有式Ia或Ib:
5.根据权利要求1所述的化合物,其中Ra是F;Rb是Cl;X是:
R2是H且R7是选自-CH2CH3和-CH2CH(CH3)2;或X是:
R2是H,R3是-OH,且R7是选自-CH2OC(O)CH3和-CH2OC(O)CH[CH(CH3)2]NH2;或R2是H,R3是选自-OCH2OC(O)CH3和-OCH2OC(O)CH[CH(CH3)2]NH2,且R7是H。
6.根据权利要求1所述的化合物,其具有式II:
7.根据权利要求6所述的化合物,其中R2是H且R7是-CH2CH3。
8.根据权利要求1所述的化合物,其具有式III:
9.根据权利要求8所述的化合物,其中R2是H且R7是选自-CH2CH(CH3)2、-CH2CF2CF3、-(CH2)2OCH3、-CH2OC(O)CH3、-CH2OC(O)(CH2)2CH3、-CH2OC(O)OCH2CH3、-CH2OC(O)OCH(CH3)2、-CH(CH3)OC(O)O-环己基、-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和
或R2是-P(O)(OH)2且R7是H。
10.根据权利要求1所述的化合物,其具有式IV:
11.根据权利要求10所述的化合物,其中R是-CH3,R2是H,且R7是选自-CH2CF2CF3、-(CH2)2OCH3、-CH2OC(O)CH3、-CH2OC(O)(CH2)2CH3、-CH2OC(O)OCH2CH3、-CH2OC(O)OCH(CH3)2、-CH(CH3)OC(O)O-环己基、-CH2OC(O)CH[CH(CH3)2]NH2、-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3、
或R是-CH3;R2是选自-C(O)CH2CH3、-C(O)CH2NH2、-C(O)CH(CH3)NH2、-C(O)CH[CH(CH3)2]NH2和-C(O)CH[CH(CH3)2]-NHC(O)OCH3;且R7是H;或R是-CH3,R2是-C(O)CH2NH2,且R7是-CH2CH3。
12.根据权利要求1所述的化合物,其具有式V:
13.根据权利要求12所述的化合物,其中R2是H且R7是选自-CH2CH3、-CH2CH(CH3)2、-CH2CF2CF3、-CH2OC(O)CH3、-CH2OC(O)(CH2)2CH3、-CH2OC(O)OCH2CH3、-CH2OC(O)OCH(CH3)2、-CH(CH3)OC(O)O-环己基、-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和
14.根据权利要求1所述的化合物,其具有式VIIa或VIIb:
15.根据权利要求14所述的化合物,其中R2和R4是H,且R7是选自-CH2CF2CF3、-CH2OC(O)CH3、-CH2OC(O)CH2CH3、-CH2OC(O)(CH2)2CH3、-CH2OC(O)OCH(CH3)2、-CH2OC(O)CH[CH(CH3)2]NH2、-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和
或R2是H,R4是-CH2OC(O)CH[CH(CH3)2]NH2,且R7是选自H和-CH2CH3;或R2是选自-C(O)CH3、-C(O)CH2CH3、-C(O)CH[CH(CH3)2]NH2和-C(O)CH[CH(CH3)2]NHC(O)OCH3,且R4和R7是H。
16.根据权利要求1所述的化合物,其具有式VIII:
17.根据权利要求16所述的化合物,其中R2是H,R3是-OH,且R7是选自-CH2OC(O)CH3、-CH2OC(O)CH[CH(CH3)2]NH2和-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3;或R2是选自-C(O)CH2CH3、-C(O)CH2CH(CH3)2、-C(O)CH[CH(CH3)2]NH2和-C(O)CH[CH(CH3)2]-NHC(O)OCH3,R3是-OH,且R7是H;或R2是H,R3是选自-OCH2OC(O)CH3、-OCH2OC(O)(CH2)2CH3、-OCH2OC(O)CH2CH3、-OCH2OC(O)CH(CH3)2、-OCH2OC(O)CH[CH(CH3)2]NH2、-OCH2OC(O)CH[CH(CH3)2]NHC(O)OC(CH3)3和
且R7是H。
18.根据权利要求1所述的化合物,其具有式IXa或IXb:
19.根据权利要求18所述的化合物,其中R2是H,R4是-OH且R7是选自-CH2OC(O)CH3、-CH2OC(O)(CH2)2CH3、-CH2OC(O)OCH2CH3、-CH2OC(O)OCH(CH3)2、-CH(CH3)OC(O)O-环己基、-CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和
或R2是H,R4是选自-OCH2OC(O)CH3、-OCH2OC(O)(CH2)2CH3、-OCH2OC(O)CH[CH(CH3)2]NH2、-OCH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3和
且R7是H。
20.一种制备根据权利要求1到19中任一权利要求所述的化合物的方法,其包含以下步骤:
(a)使下式化合物
与式HO-R7化合物在酯交换反应中反应;或
(b)使下式化合物
与式L-R7化合物在亲核取代反应中反应,其中L是离去基团;或
(c)使下式化合物
与式L-R2化合物在亲核取代反应中反应,其中L是离去基团;或
(d)使下式化合物
与式HOOC-X化合物在偶合反应中反应,其中P是H或氨基保护基;
以产生式X化合物。
21.一种医药组合物,其包含医药学上可接受的载剂和根据权利要求1到19中任一权利要求所述的化合物。
22.根据权利要求21所述的医药组合物,其另外包含选自以下的治疗剂:腺苷受体拮抗剂、α-肾上腺素能受体拮抗剂、β1-肾上腺素能受体拮抗剂、β2-肾上腺素能受体激动剂、双重作用性β-肾上腺素能受体拮抗剂/α1-受体拮抗剂、晚期糖基化终末产物裂解剂、醛固酮拮抗剂、醛固酮合成酶抑制剂、氨基肽酶N抑制剂、雄激素、血管紧张素转化酶抑制剂和双重作用性血管紧张素转化酶/脑啡肽酶抑制剂、血管紧张素转化酶2活化剂和刺激剂、血管紧张素II疫苗、抗凝剂、抗糖尿病药剂、止泻药剂、抗青光眼药剂、抗脂质药剂、镇痛药剂、抗血栓药剂、AT1受体拮抗剂和双重作用性AT1受体拮抗剂/脑啡肽酶抑制剂和多功能血管紧张素受体阻断剂、缓激肽受体拮抗剂、钙通道阻断剂、糜酶抑制剂、地高辛、利尿剂、多巴胺激动剂、内皮素转化酶抑制剂、内皮素受体拮抗剂、HMG-CoA还原酶抑制剂、雌激素、雌激素受体激动剂和/或拮抗剂、单胺再摄取抑制剂、肌肉松弛剂、利钠肽、利钠肽清除受体拮抗剂、脑啡肽酶抑制剂、一氧化氮供体、非类固醇消炎剂、N-甲基d-天冬氨酸受体拮抗剂、阿片样物质受体激动剂、磷酸二酯酶抑制剂、前列腺素、前列腺素受体激动剂、肾素抑制剂、选择性血清素再摄取抑制剂、钠通道阻断剂、可溶性鸟苷酸环化酶刺激剂和活化剂、三环抗抑郁剂、血管加压素受体拮抗剂和其组合。
23.根据权利要求22所述的医药组合物,其中所述治疗剂为AT1受体拮抗剂。
24.根据权利要求1到19中任一权利要求所述的化合物,其是用于疗法中。
25.根据权利要求24所述的化合物,其是用于治疗高血压、心脏衰竭或肾病。
26.一种根据权利要求1到19中任一权利要求所述的化合物的用途,其是用于制造供治疗高血压、心脏衰竭或肾病用的药剂。
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