CN104520277A - 脑啡肽酶抑制剂 - Google Patents
脑啡肽酶抑制剂 Download PDFInfo
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- CN104520277A CN104520277A CN201380042178.6A CN201380042178A CN104520277A CN 104520277 A CN104520277 A CN 104520277A CN 201380042178 A CN201380042178 A CN 201380042178A CN 104520277 A CN104520277 A CN 104520277A
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- alkyl
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- alkylidene group
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Abstract
在一个方面中,本发明涉及具有式(I)的化合物:其中X、Ra、Rb、R2和R7如本说明书中所定义,或其医药学上可接受的盐。这些化合物为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;和用于制备这些化合物的方法和中间物。
Description
技术领域
本发明涉及具有脑啡肽酶抑制活性或体内代谢为具有所述活性的化合物的新颖化合物。本发明还涉及包含这些化合物的医药组合物、用于制备这些化合物的方法和中间物、和使用这些化合物治疗疾病(如高血压、心脏衰竭、肺高血压和肾病)的方法。
背景技术
弗洛瑞(Fleury)等人于2012年2月16日申请的共同转让的美国专利公开案第2012/0213806号描述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。具体来说,描述以下种类的化合物:
视变数而定,此种类内的化合物可视为呈活性形式或视为前药,所述前药经体内代谢以产生所述化合物的活性形式。
然而尽管存在这些化合物,但仍需要此种类内的具有不同代谢和裂解特性的化合物和前药。举例来说,仍需要口服吸收改善的活性化合物和/或前药化合物,且需要可进行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要。
发明内容
本发明的一个方面涉及式I化合物,
其中:
(i)X为且
(a)Ra和Rb为H;R2为H;且R7是选自-CH2CF2CH3、-CH2CF2CF3、-(CH2)5CH3、-(CH2)6CH3和
或R2为-C1-6烷基或-C(O)-C1-6烷基,且R7为H;或
(b)Ra是选自-CH3、-OCH3和Cl,且Rb为H;或Ra是选自H、-CH3、Cl和F,且Rb为Cl;或Ra为H,且Rb是选自-CH3和-CN;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
(c)Ra为H,且Rb为F;或Ra为F,且Rb为H;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
(ii)X为且
(a)Ra为Cl,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R4是选自-OH、-OCH3、-OCH2CH3和-C1-4烷基;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
(b)Ra为F,且Rb为H;R2为H;R4为-OH;且R7是选自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
(iii)X为且
(a)Ra为Cl,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
(b)Ra为F,且Rb为H;R2为H;且R7是选自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
(iv)X为
(a)Ra和Rb为H;R2是选自-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R3是选自-OH、-OCH3、-OCH2CH3和-C1-4烷基;且R7为H;或
(b)Ra是选自Cl和F,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R3是选自-OH、-OCH3、-OCH2CH3和-C1-4烷基;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
(v)X为
Ra是选自Cl和F,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R3是选自-OH、-OCH3、-OCH2CH3和-C1-4烷基;R4是选自H、-C1-6烷基和苯基;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
(vi)X为
Ra是选自Cl和F,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R4是选自H、-C1-6烷基和苯基;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
(vii)X为
Ra是选自Cl和F,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
(viii)X为
Ra是选自Cl和F,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
其中各Rc独立地为H或-C1-3烷基;各Rd独立地为H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re独立地为H或-CH3;或其医药学上可接受的盐。
本发明提供经体内代谢为发现具有脑啡肽酶(NEP)酶抑制活性的化合物的化合物。相应地,预期本发明化合物适用作且宜用作治疗剂,所述治疗剂用于治疗罹患可通过抑制NEP酶或通过增加其肽底物的含量来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,所述方法包含向患者投与治疗有效量的本发明化合物。
本发明的另一个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。
本发明的又一个方面涉及适用于制备本发明化合物的方法和中间物。本发明的另一个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,所述方法包含使呈游离酸或碱形式的式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中所述的任何方法制备的产物,以及在所述方法中所使用的新颖中间物。
本发明的又另一个方面涉及式I化合物或其医药学上可接受的盐用于制造药剂,尤其用于制造适用于治疗高血压、心脏衰竭或肾病的药剂的用途。本发明的另一个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。本发明的再另一个方面涉及本发明化合物作为研究工具的用途。本文中公开本发明的其它方面和实施例。
具体实施方式
当描述本发明化合物、组合物、方法和工艺时,除非另外指明,否则下列术语具有下列含义。另外,除非所使用的上下文另外明确指示,否则如本文中所用,单数形式“一(a/an)”和“所述”包括相应复数形式。术语“包含”、“包括”和“具有”打算为包含性的,且意指可能存在除所列要素之外的其它要素。除非另外指明,否则本文中所用的表示成分数量、特性(如分子量、反应条件等)的所有数量均应理解为在所有情况下均由术语“约”修饰。相应地,本文中所阐述的数值为可视本发明所设法获得的所需特性而变化的近似值。最低限度,且不试图将等效物原则的应用限制为权利要求书的范围,各数值应至少根据所报导的有效数字且通过应用普通舍入技术来解释。
术语“烷基”意指可为直链或支链的单价饱和烃基。除非另外定义,否则所述烷基通常含有1到10个碳原子,且包括例如-C1-6烷基,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。举例来说,代表性烷基包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、正己基等。
如本文中所用,短语“式”或“具有式”或“具有结构”并不打算为限制性的,且以与通常使用术语“包含”的方式相同的方式使用。举例来说,如果描绘一种结构,那么应了解除非另外说明,否则包涵所有立体异构体和互变异构体形式。
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。所述医药学上可接受的物质通常满足毒理学和制造测试的所需标准,且包括由美国食品与药物管理局(U.S.Food and Drug administration)鉴别为适合的非活性成分的那些物质。
术语“医药学上可接受的盐”意指从碱或酸制备的在向患者(如哺乳动物)投与时可接受的盐(例如对于指定剂量方案来说具有可接受的哺乳动物安全性的盐)。然而,应了解由本发明所涵盖的盐不必为医药学上可接受的盐,如不打算用于向患者投与的中间化合物的盐。医药学上可接受的盐可衍生自医药学上可接受的无机或有机碱,且衍生自医药学上可接受的无机或有机酸。另外,当式I化合物含有碱性部分(如胺、吡啶或咪唑)和酸性部分(如甲酸或四唑)时,可形成两性离子,且包括在如本文中所用的术语“盐”内。衍生自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。衍生自医药学上可接受的有机碱的盐包括伯、仲和叔胺的盐:所述胺包括经取代的胺、环状胺、天然产生的胺等,如精氨酸、甜菜碱(betaine)、咖啡因、胆碱、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、海卓胺(hydrabamine)、异丙胺、赖氨酸、甲基还原葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因(procaine)、嘌呤、可可豆碱(theobromine)、三乙胺、三甲胺、三丙胺、缓血酸胺(tromethamine)等。衍生自医药学上可接受的无机酸的盐包括以下的盐:硼酸、碳酸、氢卤酸(氢溴酸、氢氯酸、氢氟酸或氢碘酸)、硝酸、磷酸、氨基磺酸和硫酸。衍生自医药学上可接受的有机酸的盐包括以下的盐:脂肪族羟基酸(例如柠檬酸、葡萄糖酸、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、马尿酸和三苯基乙酸)、芳香族羟基酸(例如邻羟基苯甲酸、对羟基苯甲酸、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、乙二酸和丁二酸)、葡萄糖醛酸(glucoronic acid)、扁桃酸、粘液酸、烟碱酸、乳清酸、双羟萘酸(pamoic acid)、泛酸、磺酸(例如苯磺酸、樟脑磺酸、乙二磺酸(edisylic acid)、乙磺酸、羟乙基磺酸、甲磺酸、萘磺酸、萘-1,5-二磺酸、萘-2,6-二磺酸和对甲苯磺酸)、辛那酸(xinafoic acid)等。
如本文中所用,术语“前药”打算意指在体内于生理条件下(例如通过正常代谢过程)转化为其活性形式的非活性(或活性明显较小)的药物前体。所述化合物可能不必具有对NEP的药理学活性,但可口服或肠胃外投与且其后在体内代谢,以形成对NEP具有药理学活性的化合物。
术语“治疗有效量”意指在向有需要的患者投与时足以实现治疗的量,即为获得所需治疗效果所需的药物量。举例来说,用于治疗高血压的治疗有效量为例如减轻、抑制、消除或预防高血压的症状或治疗高血压的潜在原因所需的化合物量。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。另一方面,术语“有效量”意指足以获得所需结果(可能不必为治疗结果)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。
如本文中所用的术语“治疗(treating/treatment)”意指治疗患者(如哺乳动物,尤其人类)中的疾病或医学病状(如高血压),其包括下列一或多者:(a)预防疾病或医学病状出现,即预防疾病或医学病状复发或预防性治疗易患所述疾病或医学病状的患者;(b)改善疾病或医学病状,即消除患者中的疾病或医学病状或使所述疾病或医学病状消退;(c)抑制疾病或医学病状,即减缓或阻止患者中疾病或医学病状的发展;或(d)减轻患者中的疾病或医学病状的症状。举例来说,术语“治疗高血压”将包括预防高血压出现、改善高血压、抑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,或目前正为了疾病预防或治疗特定疾病或医学病状而进行治疗的那些哺乳动物(如人类),以及其中对结晶化合物进行评估或用于分析的测试个体(例如动物模型)。
本文中所用的所有其它术语均打算具有其所属领域的技术人员所理解的其普通含义。
本发明化合物含有一或多个手性中心,且因此,这些化合物可以其各种立体异构形式制备并使用。在一些实施例中,为使本发明化合物的治疗活性(例如治疗高血压)优化,可能需要碳原子具有特定(R,R)、(S,S)、(S,R)或(R,S)构型或富含所述构型的立体异构形式。在其它实施例中,本发明化合物以外消旋混合物形式存在。相应地,除非另外指明,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)、立体异构体富集的混合物等。当在本文中描绘无任何立体化学的化学结构时,应了解所述结构包涵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理解,除非另外指明,否则本发明的组合物中可能存在少量的其它立体异构体,其限制条件为组合物整体的效用不因所述其它异构体的存在而消除。个别立体异构体可通过此项技术中熟知的大量方法来获得,包括使用适合的手性固定相或载体的手性色谱;或通过将所述立体异构体化学转化为非对映异构体,通过常规手段(如色谱或再结晶)分离所述非对映异构体,随后再生初始立体异构体来获得。
另外除非另外说明,否则在适用情况下,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均包括在本发明的范围内。举例来说,尽管化学式描绘如下:
但应了解所述化合物也可以互变异构形式存在,如:
且本发明涵盖两种形式。还应理解,一种互变异构形式可能会占主导地位。
本发明化合物以及用于其合成的那些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中原子质量不同于在自然界中主要所见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。尤其受关注的为氚或碳-14富集的式I化合物,其可用于例如组织分布研究;氘富集(尤其在代谢位点处氘富集)的本发明化合物,其产生例如具有较大代谢稳定性的化合物;和正电子发射同位素(如11C、18F、15O和13N)富集的式I化合物,其可用于例如正电子发射断层成像(Positron Emission Topography,PET)研究中。
本文中用于命名本发明化合物的命名法在本文的实例中进行说明。此命名法已使用可商购的AutoNom软件(加利福尼亚州圣莱安德罗的MDL公司(MDL,San Leandro,California))得到。
美国专利公开案第2012/0213806号特定公开(2S,4R)-5-联苯-4-基-2-羟甲基-2-甲基-4-[(3H-[1,2,3]三唑-4-羰基)氨基]-戊酸,其由式I'表示(其中Ra和Rb为H):
诸如此类的化合物可以互变异构体形式存在,例如(2S,4R)-5-联苯-4-基-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]-戊酸。在一个实施例中,此化合物称为活性形式且作为前药投与,其经体内代谢以形成式I'化合物。美国专利公开案第2012/0213806号还公开式I'化合物的某些前药,如乙酯、丙酯、异丙酯、丁酯、异丁酯、3-甲基丁酯、戊酯、美度米(medoxomil)酯、2-吗啉-4-基乙酯、2-吗啉-4-基-2-氧代-乙酯、2-甲氧基乙酯、2-(2-甲氧基乙氧基)乙酯、2-甲磺酰基乙酯、2-二甲氨基乙酯、2-哌啶-1-基乙酯、茚满-5-基酯、氧杂环丁烷-3-基酯、二甲基氨甲酰基甲酯、甲氧基羰基-甲酯、乙酰氧基甲酯、丁酰氧基甲酯、苯甲氧基羰基甲酯、2-(2-氧代吡咯烷-1-基)乙酯、乙氧基羰基氧基甲酯、苯甲酯、(S)-2-氨基-3-甲基-丁酰氧基甲酯、(S)-2-甲氧基羰基氨基-3-甲基-丁酰氧基甲酯、(R)-1-环己基氧基羰基氧基乙酯、(S)-1-环己基氧基羰基氧基乙酯;和5-甲基-2-氧代-[1,3]二氧杂环戊烯-4-基甲酯前药。
本发明的一个方面涉及式I'化合物的其它前药和变化形式。这些化合物为其中X为以下的式I化合物:
这些化合物由式IIa或IIb表示:
在式IIa和IIb化合物的一个实施例中,Ra和Rb为H;R2为H;且R7是选自-CH2CF2CH3、-CH2CF2CF3、-(CH2)5CH3、-(CH2)6CH3和
或R2为-C1-6烷基或-C(O)-C1-6烷基,且R7为H。在一个特定实施例中,R2为H,且R7是选自-CH2CF2CH3、-CH2CF2CF3、-(CH2)5CH3、-(CH2)6CH3和
R2是选自-CH3、-CH2CH3、-C(O)CH3、-C(O)CH(CH3)2和-C(O)CH2CH(CH3)2;且R7为H。
在式IIa和IIb化合物的另一个实施例中,Ra是选自-CH3、-OCH3和Cl,且Rb为H;或Ra是选自H、-CH3、Cl和F,且Rb为Cl;或Ra为H,且Rb是选自-CH3和-CN;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
其中各Rc独立地为H或-C1-3烷基;各Rd独立地为H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re独立地为H或-CH3。在一个特定实施例中,Ra是选自-CH3、-OCH3和Cl,且Rb为H;或Ra是选自H、-CH3、Cl和F,且Rb为Cl;或Ra为H,且Rb是选自-CH3和-CN;R2是选自H、-C1-6烷基(例如-CH3、-CH2CH3、-CH(CH3)或-(CH2)4CH3)和其中Re为H的-(CH2)2-3ORe(例如-(CH2)2OH和-(CH2)3OH)或其中Re为-CH3的(CH2)2-3ORe(例如-(CH2)2OCH3);且R7为H。
美国专利公开案第2012/0213806号还公开其中Ra为H且Rb为F的式I'化合物,即(2S,4R)-5-(3'-氟联苯-4-基)-2-羟甲基-2-甲基-4-[(3H-[1,2,3]三唑-4-羰基)氨基]戊酸,和其中Ra为F且Rb为H的式I'化合物,即(2S,4R)-5-(2'-氟联苯-4-基)-2-羟甲基-2-甲基-4-[(3H-[1,2,3]三唑-4-羰基)氨基]戊酸。因此,本发明的另一个方面涉及所述化合物的前药。因此,在式Ia和Ib化合物的另一个实施例中,Ra为H,且Rb为F;或Ra为F,且Rb为H;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
其中各Rc独立地为H或-C1-3烷基;各Rd独立地为H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re独立地为H或-CH3。
本发明的另一个方面涉及其中X为以下的式I化合物:
这些化合物由式III表示:
在式III化合物的一个实施例中,Ra为Cl,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R4是选自-OH、-OCH3、OCH2CH3和-C1-4烷基;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
其中各Rc独立地为H或-C1-3烷基;各Rd独立地为H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re独立地为H或-CH3。在一个特定实施例中,Ra为F,Rb为Cl,R2为H,R4为-OCH3或-OCH2CH3,且R7为H。
美国专利公开案第2012/0213806号公开其中Ra为F,Rb为H,R2为H且R7为H的式III化合物,即(2S,4R)-5-(2'-氟联苯-4-基)-2-羟甲基-4-[(1-羟基-1H-[1,2,3]三唑-4-羰基)氨基]-2-甲基戊酸。因此,本发明的另一个方面涉及此化合物的前药。因此,在式III化合物的另一个实施例中,Ra为F,且Rb为H;R2为H;R4为-OH;且R7是选自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRdNH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
其中各Rc独立地为H或-C1-3烷基;且各Rd独立地为H、-CH3、-CH(CH3)2、苯基或苯甲基。
本发明的另一个方面涉及其中X为以下的式I化合物:
这些化合物由式IVa或IVb表示:
在式IVa和IVb化合物的一个实施例中,Ra为Cl,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
其中各Rc独立地为H或-C1-3烷基;各Rd独立地为H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re独立地为H或-CH3。在一个特定实施例中,Ra为F,Rb为Cl,R2为H,且R7为H。
美国专利公开案第2012/0213806号公开其中Ra为F,Rb为H,R2为H且R7为H的式IVa化合物,即(2S,4R)-5-(2'-氟联苯-4-基)-2-羟甲基-2-甲基-4-[(2-氧代-2,3-二氢噁唑-4-羰基)氨基]戊酸,和其中Ra为F,Rb为H,R2为H且R7为H的式IVb化合物,即(2S,4R)-5-(2'-氟联苯-4-基)-2-羟甲基-2-甲基-4-[(2-氧代-2,3-二氢噁唑-5-羰基)氨基]戊酸。因此,本发明的另一个方面涉及这些化合物的前药。因此,在式IVa和IVb化合物的另一个实施例中,Ra为F,且Rb为H;R2为H;且R7是选自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
其中各Rc独立地为H或-C1-3烷基;且各Rd独立地为H、-CH3、-CH(CH3)2、苯基或苯甲基。
美国专利公开案第2012/0213806号特定公开(2S,4R)-5-联苯-4-基-4-[(3-羟基异噁唑-5-羰基)氨基]-2-羟甲基-2-甲基戊酸,其由式V'(其中Ra和Rb为H且R3为-OH)表示:
美国专利公开案第2012/0213806号还公开式V'化合物的某些前药,如其乙酯。本发明的一个方面涉及式V'化合物的其它前药和变化形式。这些化合物为其中X为以下的式I化合物:
这些化合物由式V表示:
在式V化合物的一个实施例中,Ra和Rb为H;R2是选自C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R3是选自-OH、-OCH3、OCH2CH3和-C1-4烷基;且R7为H;其中各Re独立地为H或-CH3。在式V化合物的一个特定实施例中,Ra和Rb为H,R2为-CH3,R3为-OH或-OCH3,且R7为H。
在式V化合物的另一个实施例中,Ra是选自Cl和F,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R3是选自-OH、-OCH3、-OCH2CH3和-C1-4烷基;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
其中各Rc独立地为H或-C1-3烷基;各Rd独立地为H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re独立地为H或-CH3。在式V化合物的一个特定实施例中,Ra为H,Rb为Cl,R2为H、-CH3、-CH2CH3或-(CH2)2OH,R3为-OH或-OCH3,且R7为H;或Ra为F,Rb为Cl,R2为H或-C1-6烷基(例如-CH3或-CH2CH3),R3为-OH、-OCH3或-C1-4烷基(例如-CH2CH3、-(CH2)2CH3或-CH2CH(CH3)2),且R7为H。
本发明的另一个方面涉及其中X为以下的式I化合物:
这些化合物由式VIa或VIb表示:
在式VI化合物的一个实施例中,Ra是选自Cl和F,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R3是选自-OH、-OCH3、-OCH2CH3和-C1-4烷基;R4是选自H、-C1-6烷基和苯基;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
其中各Rc独立地为H或-C1-3烷基;各Rd独立地为H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re独立地为H或-CH3。在式VIa和VIb化合物的一个特定实施例中,Ra为H或F;Rb为Cl;R2为H或-C1-6烷基(例如-CH3);R3为-OCH3、-OCH2CH3或-C1-4烷基(例如-CH(CH3)2或-CH2CH(CH3)2);R4存在时为H;且R7为H。
本发明的另一个方面涉及其中X为以下的式I化合物:
这些化合物由式VIIa或VIIb表示:
在式VII化合物的一个实施例中,Ra是选自Cl和F,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R4是选自H、-C1-6烷基和苯基;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
其中各Rc独立地为H或-C1-3烷基;各Rd独立地为H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re独立地为H或-CH3。在式VIIa和VIIb化合物的一个特定实施例中,Ra为F,Rb为Cl,R2为H或-C1-6烷基(例如-CH3或-CH2CH3),R4存在时为H,且R7为H。
本发明的另一个方面涉及其中X为以下的式I化合物:
这些化合物由式VIII表示:
在式VIII化合物的一个实施例中,Ra是选自Cl和F,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
其中各Rc独立地为H或-C1-3烷基;各Rd独立地为H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re独立地为H或-CH3。
本发明的另一个方面涉及其中X为以下的式I化合物:
这些化合物由式IX表示:
在式IX化合物的一个实施例中,Ra是选自Cl和F,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
其中各Rc独立地为H或-C1-3烷基;各Rd独立地为H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re独立地为H或-CH3。
一般合成程序
本发明化合物可使用下列一般方法、在实例中所阐述的程序从易于获得的起始物质来制备,或通过使用所属领域的技术人员已知的其它方法、试剂和起始物质来制备。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的方法,或通过使用所属领域的技术人员已知的其它方法、试剂和起始物质来类似地制备。还应理解,当指定典型或优选工艺条件(例如反应温度、时间、反应物的摩尔比、溶剂、压力等)时,除非另外说明,否则也可使用其它工艺条件。在一些情况下,在室温下进行反应,且不进行实际温度测量。应了解室温可用来意指在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。虽然最佳反应条件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使用常规优化程序容易地确定适合的反应条件。
另外,如对所属领域的技术人员来说显而易知,可能必需或需要常规保护基来防止某些官能团发生非所需反应。适合于特定官能团的保护基以及适合于对所述官能团进行保护和脱去保护基的条件和试剂的选择为此项技术中所熟知。如果需要,可使用除本文所述的程序中所说明的那些保护基之外的保护基。举例来说,大量保护基和其引入和移除描述于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 in Organic Synthesis),第四版,纽约的威利出版社(Wiley,New York),2006和其中所引用的参考文献中。
羧基保护基适合于防止羧基处的非所需反应,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)、二苯甲基(diphenylmethyl/benzhydryl,DPM)等。氨基保护基适合于防止氨基处的非所需反应,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。羟基保护基适合于防止羟基处的非所需反应,且实例包括(但不限于)C1-6烷基;硅烷基,包括三C1-6烷基硅烷基,如三甲基硅烷基(TMS)、三乙基硅烷基(TES)和叔丁基二甲基硅烷基(TBDMS);酯基(酰基),包括C1-6烷酰基,如甲酰基、乙酰基和特戊酰基,和芳香族酰基,如苯甲酰基;芳基甲基,如苯甲基(Bn)、对甲氧基苯甲基(PMB)、9-芴基甲基(Fm)和二苯甲基(DPM);等。
标准脱去保护基技术和试剂用于移除保护基,且可视所用的基团而变化。举例来说,当羧基保护基为甲基时,通常使用氢氧化钠或氢氧化锂;当羧基保护基为乙基或叔丁基时,通常使用酸,如TFA或HCl(例如4.0M HCl的1,4-二噁烷溶液);而当羧基保护基为苯甲基时,可使用H2/Pd/C。BOC氨基保护基可使用酸性试剂,如TFA的DCM溶液或HCl的1,4-二噁烷溶液来移除,而Cbz氨基保护基可通过采用催化氢化条件,如H2(1标准大气压)和于醇溶剂中的10%Pd/C(“H2/Pd/C”)来移除。当羟基保护基为苯甲基时,通常使用H2/Pd/C;而当羟基保护基为酰基时,通常使用NaOH。
离去基为可在取代反应(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,代表性离去基包括氯基、溴基和碘基;磺酸酯基,如甲磺酸酯基、甲苯磺酸酯基、溴苯磺酸酯基、硝基苯磺酸酯基等;和酰氧基,如乙酰氧基、三氟乙酰氧基等。
用于这些流程的适合的碱包括(举例来说但不加以限制)碳酸钾、碳酸钙、碳酸钠、三乙胺(Et3N)、吡啶、1,8-二氮杂双环-[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。
用于这些流程的适合的惰性稀释剂或溶剂(举例来说但不加以限制)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)(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。偶合反应在碱(如DIPEA)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。
所有反应通常均在约-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监测直到完成。反应可在数分钟内完成,或可耗时数小时,通常1-2小时到长达48小时。在完成后,所得混合物或反应产物可经进一步处理以获得所需产物。举例来说,所得混合物或反应产物可经历一或多种下列程序:浓缩或分配(例如在EtOAc与水之间,或在5%THF的EtOAc溶液与1M磷酸之间);萃取(例如用EtOAc、CHCl3、DCM、氯仿);洗涤(例如用饱和NaCl水溶液、饱和NaHCO3水溶液、Na2CO3(5%)、CHCl3或1M NaOH);干燥(例如经MgSO4、经Na2SO4或在真空中);过滤;结晶(例如从EtOAc和己烷);浓缩(例如在真空中);和/或纯化(例如硅胶色谱、快速色谱、制备型HPLC、反相HPLC或结晶)。
举例来说,式I化合物以及其盐可如流程I-IV中所示来制备。
流程I
流程I为酯基转移反应。一般来说,此反应涉及使酯与热、所需醇(HO-R7)和适合的酸催化剂(例如盐酸)反应。HO-R7醇为可商购的,或可通过此项技术中已知或本文所述的技术来制备。示例性HO-R7包括HO-CH2CF2CH3、HO-CH2CF2CF3和
流程II
流程II为亲核取代反应,其中L为适合的离去基。一般来说,此反应在适合的碱(如三乙胺)存在下于适合的惰性稀释剂或溶剂(如丙酮)中进行。L-R7化合物为可商购的,或可通过此项技术中已知或本文所述的技术来制备。
流程III
流程III为亲核取代反应,其中L为适合的离去基。一般来说,此反应在适合的碱(如N,N-二异丙基乙胺)存在下于适合的惰性稀释剂或溶剂中(如二氯甲烷)进行。L-R2化合物为可商购的,或可通过此项技术中已知或本文所述的技术来制备。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为偶合反应,其中P为H或适合的氨基保护基。当P为氨基保护基为氨基保护基时,所述工艺进一步包含在偶合步骤之前或当场对化合物脱去保护基。示例性偶合试剂包括HATU和含EDC的HOBt。一般来说,此反应在碱(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。羧酸起始物质一般为可商购的,或可使用此项技术中已知的程序来制备。
举例来说,式II-式X化合物以及其盐可如流程V中所示制备。
流程V
于惰性稀释剂中,在适合的碱(如碳酸钾或碳酸钠)存在下将(R)-3-(4-溴苯基)-2-叔丁氧基羰基氨基丙酸和所需卤代苯基硼酸与钯催化剂组合。示例性卤代苯基硼酸为2-氟苯基硼酸、3-氟苯基硼酸、2-氯苯基硼酸、3-氯苯基硼酸和2-氟-5-氯苯基硼酸。示例性钯催化剂包括1,1-双(二苯基膦基)二茂铁氯化钯、二氯双(三苯基膦)钯(II)、双(三叔丁基膦)钯(0)和四(三苯膦)钯(0)。
随后通过包含若干步骤的工艺将化合物1转变为化合物5(其中P为H或适合的氨基保护基),所述工艺于实例部分中详细描述。
最后,如上文流程IV中所描述,将化合物5与所需X基团偶合。
关于用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细节描述于以下所阐述的实例中。
效用
式I'化合物具有作为脑啡肽酶抑制剂的活性,且预期其具有作为脑啡肽酶抑制剂的治疗效用。预期此化合物的前药一旦经体内代谢即具有相同效用。因此,当论述本发明化合物的活性时,应了解这些前药一旦经代谢即具有预期的活性。
示例性分析(举例来说但不加以限制)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)抑制的分析(例如在苏尔皮齐奥(Sulpizio)等人(2005)药理学与实验治疗学杂志(JPET)315:1306-1313中所描述)。用于评定ACE和NEP在麻醉的大鼠中的体内抑制效能的药力学分析描述于西摩(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)中,其中ACE抑制以对血管紧张素I(angiotensin I)升压反应的抑制的百分比来测量,而NEP抑制以泌尿系统环状鸟苷3',5'-单磷酸(cGMP)的排出增加来测量。
也可使用许多体内分析。有意识的自发性高血压大鼠(SHR)模型为肾素(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 of Pharmacology)35:349-362。有意识的乙酸去氧皮质固酮-盐(DOCA-盐)大鼠模型为适用于测量NEP活性的体积依赖性高血压模型。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)同前)。DOCA-盐模型尤其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。达尔盐敏感性(Dahl salt-sensive,DSS)高血压大鼠模型为对膳食盐(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中的肺动脉高血压的大鼠野百合碱模型为用于治疗肺动脉高血压的临床功效的可靠预测因子。心脏衰竭动物模型包括心脏衰竭的DSS大鼠模型和主动脉-下腔静脉瘘管模型(AV分流),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、闪尾(tail-flick)和福尔马林测试)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特性。参见例如马姆伯格(Malmberg)等人(1999)神经科学实验室指南(Current Protocols inNeuroscience)8.9.1-8.9.15。化合物的其它特性和效用可使用所属领域的技术人员所熟知的各种体外和体内分析进行论证。
预期本发明化合物适用于治疗和/或预防对NEP抑制有响应的医学病状。因此预期罹患可通过抑制NEP酶或通过增加其肽底物的含量而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来治疗。举例来说,预期所述化合物通过抑制NEP来增强由NEP代谢的内源性肽的生物效应,所述内源性肽如利钠肽(natriuretic peptide)、铃蟾素(bombesin)、缓激肽(bradykinin)、降钙素(calcitonin)、内皮素(endothelin)、脑啡肽(enkephalin)、神经调压素(neurotensin)、P物质和血管活性肠肽(vasoactive intestinalpeptide)。因此,预期所述化合物对例如肾系统、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/或预防医学病状(如心血管疾病)。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。尤其受关注的心血管疾病包括高血压和心脏衰竭。高血压(举例来说但不加以限制)包括:原发性高血压,也称为本态性高血压或特发性高血压;继发性高血压;伴随有肾病的高血压;伴随有或不伴随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(举例来说但不加以限制)包括:充血性心脏衰竭;急性心脏衰竭;慢性心脏衰竭,例如伴随有左心室射血分数降低的心脏衰竭(也称为收缩性心脏衰竭)或伴随有左心室射血分数保持的心脏衰竭(也称为舒张性心脏衰竭);和伴随有或不伴随有肾病的急性和慢性代偿失调心脏衰竭。因此,本发明的一个实施例涉及一种用于治疗高血压,尤其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和重度高血压。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AT1受体拮抗剂/脑啡肽酶抑制剂、β1-肾上腺素能受体(adrenergic receptor)拮抗剂、双重作用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(确切地说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。在本发明的另一个特定实施例中,本发明化合物与AT1受体拮抗剂组合,且用于治疗伴随有肾病的高血压。
对治疗肺动脉高血压,治疗有效量通常为足以降低肺血管阻力的量。疗法的其它目的为改善患者的运动能力。举例来说,在一种临床配置中,治疗有效量可为改善患者舒适步行6分钟的时间段(涵盖约20-40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(anticoagulant)、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(serotonin)再吸收抑制剂和其组合。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吸收抑制剂组合,且用于治疗肺动脉高血压。
本发明的另一个实施例涉及一种用于治疗心脏衰竭,具体来说充血性心脏衰竭(包括收缩性和舒张性充血性心脏衰竭)的方法,其包含向患者投与治疗有效量的本发明化合物。治疗有效量通常为足以降低血压和/或改善肾功能的量。在一种临床配置中,治疗有效量可为足以改善心脏血液动力学,例如降低楔压(wedge pressure)、右心房压、填充压和血管阻力的量。在一个实施例中,化合物以静脉内剂型投与。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
预期本发明化合物作为NEP抑制剂可抑制内源性脑啡肽的降解,且因此所述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(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。尤其受关注的肾病包括糖尿病性肾病、慢性肾病、蛋白尿,且尤其包括急性肾脏损伤或急性肾衰竭(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组合投与,所述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。
预防性疗法
还预期本发明化合物通过增强利钠肽的效应而适用于预防性疗法,此是由于所述利钠肽的抗肥厚性和抗纤维化性效应(参见波特(Potter)等人(2009)实验药理学手册(Handbook of Experimental Pharmacology)191:341-366),所述预防性疗法例如用于预防心肌梗塞之后心机能不全的发展、预防血管成形术之后动脉再狭窄、预防血管手术之后血管壁变厚、预防动脉粥样硬化和预防糖尿病性血管病。
青光眼
预期本发明化合物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。
疼痛缓解
预期本发明化合物作为NEP抑制剂可抑制内源性脑啡肽的降解,且因此所述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抗伤痛感受性药物组合,所述抗伤痛感受性药物如氨基肽酶N或二肽基肽酶III抑制剂、非类固醇消炎剂、单胺再吸收抑制剂、肌肉松弛剂、NMDA受体拮抗剂、类鸦片受体激动剂、5-HT1D血清素受体激动剂和三环抗抑郁剂。
其它效用
还预期本发明化合物由于其NEP抑制特性而适用作止咳剂,并且适用于治疗伴随有肝硬化的肝门性高血压(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)、抑郁症(参见诺布尔(Noble)等人(2007)治疗靶标专家意见(Exp.Opin.Ther.Targets)11:145-159)、月经异常、早产、子痫前症、子宫内膜异位症、生殖障碍(例如男性和女性不孕症、多囊性卵巢综合症、着床失败(implantation failure))和男性和女性性功能障碍,包括男性勃起困难和女性性兴奋障碍。更确切地说,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),女性性功能障碍常常被定义为女性患者难以或无法在性行为中得到满足。此涵盖各种不同女性性功能障碍,包括(举例来说但不加以限制)减退性性欲障碍(hypoactive sexual desire disorder)、性兴奋障碍、性高潮障碍和性疼痛障碍。当用于治疗所述病症,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、多巴胺激动剂、雌激素受体激动剂和/或拮抗剂、雄激素和雌激素。还预期本发明化合物由于其NEP抑制特性而具有消炎特性,且预期其尤其在与他汀类(statin)组合使用时具有如此效用。
近期研究表明,NEP在胰岛素缺乏性糖尿病和膳食诱导性肥胖症中起调控神经功能的作用。库佩(Coppey)等人(2011)神经药理学(Neuropharmacology)60:259-266。因此,由于本发明化合物的NEP抑制特性,还预期其适用于针对由糖尿病或膳食诱导性肥胖症造成的神经损伤提供保护。
本发明化合物每剂投与量或每天投与总量可预先确定,或其可针对个别患者通过考虑大量因素而确定,所述因素包括患者的病状的性质和严重性;所治疗的病状;患者的年龄、重量和一般健康状况;患者对活性剂的耐受性;投药途径;药理学考虑因素,如所投与的化合物和任何第二药剂的活性、功效、药代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)的患者可以预先确定的剂量或由治疗医师确定的剂量开始,且将持续预防、改善、抑制或缓解疾病或医学病状的症状所必需的时间段。正进行所述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,血压测量值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为人所熟知,且容易由治疗医师获得。由医师进行连续监测将保证在任何既定时间投与最佳量的本发明化合物,以及促进确定治疗的持续时间。这在也投与第二药剂时特别有价值,因为第二药剂的选择、剂量和疗法的持续时间也可能需要调节。以此方式,可在治疗过程中调节治疗方案和给药时程,以投与展现所需有效性的最低量的活性剂,且此外,投药仅持续成功治疗疾病或医学病状所必需的时间长度即可。
研究工具
因为本发明化合物经体内代谢为具有作为脑啡肽酶抑制剂的活性的化合物,所以其还适用作调查或研究具有NEP酶的生物系统或样品的研究工具,例如研究其中NEP酶或其肽底物起作用的疾病。相应地,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酶的任何适合的生物系统或样品均可用于所述研究中,所述研究可在体外或体内进行。适合于所述研究的代表性生物系统或样品包括(但不限于)细胞、细胞提取物、质膜(plasma membrane)、组织样品、分离的器官、哺乳动物(如小鼠、大鼠、天竺鼠、兔、狗、猪、人类等)等,其中哺乳动物尤其受关注。在本发明的一个特定实施例中,哺乳动物中的NEP酶活性通过投与NEP抑制量的本发明化合物而得以抑制。也可通过使用所述化合物进行生物分析来将这些化合物用作研究工具。
当用作研究工具时,通常使包含NEP酶的生物系统或样品与NEP酶抑制量的本发明化合物接触。在将生物系统或样品暴露于化合物之后,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。暴露包涵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.)或吸入投药等向哺乳动物投与结晶化合物。此测定步骤可涉及测量响应(定量分析)或可涉及进行观测(定性分析)。测量响应涉及例如,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品的影响,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达成所需结果所必需的化合物的活性程度以及量,即NEP酶抑制量。所述确定步骤通常涉及测定抑制NEP酶的效应。
另外,本发明化合物可用作用于评估其它化合物的研究工具,且因此还适用于筛检分析以发现例如具有NEP抑制活性的新颖化合物。因此,本发明的另一个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生物分析以提供第二分析值;其中步骤(a)在步骤(b)之前、之后或与步骤(b)同时进行;和(c)比较来自步骤(a)的第一分析值与来自步骤(b)的第二分析值。示例性生物分析包括NEP酶抑制分析。以此方式,本发明化合物在分析中用作标准样品,以比较用测试化合物与用本发明化合物所获得的结果,由此鉴别具有大致相等或优越活性的那些测试化合物(如果存在)。举例来说,将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数据相比,以鉴别具有所需特性的那些测试化合物,例如pKi值大致等于或优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)与分析测试数据作为独立实施例来鉴别所关注的测试化合物。
本发明的再另一个方面涉及一种研究包含NEP酶的生物系统或样品的方法,所述方法包含(a)使生物系统或样品与本发明化合物接触;和(b)测定由所述化合物对所述生物系统或样品所产生的效应。
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向患者投与。所述医药组合物可通过任何可接受的投药途径向患者投与,包括(但不限于)口服、经直肠、经阴道、经鼻、吸入、局部(包括经皮)、经眼和肠胃外的投药模式。此外,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),以单次日剂量或以单次周剂量投与。应了解,适合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)均可用于本文中所论述的医药组合物中。
相应地,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。如果需要,那么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“活性剂”,以将其与调配物的其它组分(如载剂)进行区分。因此,应了解术语“活性剂”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达成治疗有效量的个别单元剂量)。组合物通常将含有约0.01重量%-95重量%的活性剂,包括约0.01重量%-30重量%,如约0.01重量%-10重量%,其中实际量视调配物本身、投药途径、给药频率等而定。在一个实施例中,适合于口服剂型的组合物例如可含有约5重量%-70重量%或约10重量%-60重量%的活性剂。
任何常规载剂或赋形剂可用于本发明的医药组合物中。特定载剂或赋形剂,或载剂或赋形剂的组合的选择取决于用于治疗特定患者或特定类型的医学病状或疾病病况的投药模式。就此来说,制备适合特定投药模式的组合物完全处于医药领域的技术人员的范围内。另外,所述组合物中所用的载剂或赋形剂为可商购的。进一步举例来说,常规调配技术描述于雷明顿: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)中。
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;和在医药组合物中采用的其它无毒相容物质。
通常通过将活性剂与医药学上可接受的载剂和一或多种任选的成分充分且紧密地混合或掺合来制备医药组合物。所得均匀掺合的混合物可随后使用常规程序和设备来成形或装入片剂、胶囊、丸剂、罐、药筒、分配器等中。
在一个实施例中,医药组合物适合于口服投药。适合用于口服投药的组合物可呈以下形式:胶囊、片剂、丸剂、口含片、扁囊剂、糖衣药丸、散剂、颗粒剂;在水性或非水性液体中的溶液或悬浮液;水包油或油包水液体乳液;酏剂或糖浆;等;各自含有预定量的活性剂。
打算以固体剂型(胶囊、片剂、丸剂等)用于口服投药时,组合物通常包含活性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、聚乙烯基吡咯烷酮、蔗糖和/或阿拉伯胶;保湿剂,如甘油;崩解剂,如琼脂-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;湿润剂,如鲸蜡醇和/或甘油单硬脂酸酯;吸附剂,如高岭土和/或膨润土;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、湿润剂、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衣的那些包衣剂,如邻苯二甲酸乙酸纤维素、聚邻苯二甲酸乙酸乙烯酯、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,如棕榈酸抗坏血酸酯、丁基化羟基大茴香醚、丁基化羟基甲苯、卵磷脂、没食子酸丙酯、α-生育酚等;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。
组合物也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/或微球体来调配,以提供活性剂的缓慢或控制释放。另外,本发明的医药组合物可含有乳浊剂,且可经调配以使得其仅在或优先在胃肠道的某一部分释放活性剂,任选地以延迟的方式释放。可使用的包埋组合物的实例包括聚合物质和蜡。活性剂也可呈微囊封形式,任选地与一或多种上述赋形剂一起。
适合用于口服投药的液体剂型(举例来说)包括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、碳酸乙盐、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、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃基醇、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、琼脂-琼脂和黄蓍胶、和其混合物。
当打算用于口服投药时,本发明的医药组合物可以单位剂型包装。术语“单位剂型”是指适合于向患者给药的物理性的分开的单元,即各单元单独含有或与一或多个其它单元组合含有经计算可产生所需治疗效果的预定量的活性剂。举例来说,所述单位剂型可为胶囊、片剂、丸剂等。
在另一个实施例中,本发明的组合物适合于吸入投与,且通常呈气雾剂或散剂形式。一般使用熟知的递送装置(如喷雾器、干粉或定剂量吸入器)投与所述组合物。喷雾器装置产生高速气流,以使组合物以薄雾形式喷出而携载入患者的呼吸道中。一种示例性喷雾器调配物包含活性剂溶解于载剂中以形成溶液,或活性剂经微米尺寸化且与载剂组合以形成含有可吸入尺寸的微米尺寸化粒子的悬浮液。干粉吸入器投与呈自由流动粉末形式的活性剂,所述活性剂在吸气期间分散在患者的气流中。一种示例性干粉调配物包含与赋形剂(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)干式掺合的活性剂。定剂量吸入器使用压缩推进剂气体排出量定量的活性剂。一种示例性定剂量调配物包含活性剂于液化推进剂(如氯氟碳化物或氢氟烷烃)中的溶液或悬浮液。所述调配物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。所述组合物通常通过向含有活性剂、乙醇(如果存在)和表面活性剂(如果存在)的适合容器中加入经冷却或经加压的氢氟烷烃来制备。为制备悬浮液,将活性剂微米尺寸化,随后与推进剂组合。或者,悬浮液调配物可通过喷雾干燥活性剂的微米尺寸化粒子上的表面活性剂涂层来制备。随后将调配物装入气雾剂罐中,所述气雾剂罐形成吸入器的一部分。
本发明化合物也可肠胃外(例如通过皮下、静脉内、肌肉内或腹膜内注射)投与。对所述投药,活性剂以无菌溶液、悬浮液或乳液形式提供。用于制备所述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。肠胃外调配物也可含有一或多种抗氧化剂、增溶剂、稳定剂、防腐剂、湿润剂、乳化剂和分散剂。表面活性剂、其它稳定剂或pH调节剂(酸、碱或缓冲剂)和抗氧化剂尤其适用于为调配物提供稳定性,例如使酯键和酰胺键的水解或可存在于化合物中的硫醇的二聚化最小或得以避免。可通过使用无菌可注射介质、灭菌剂、过滤、照射或加热来使这些调配物无菌。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在1,4位置处由如在淀粉酶、β-环糊精或环庚直链淀粉中的键连接的六个或六个以上α-D-葡萄吡喃糖单元的环状分子。示例性环糊精包括环糊精衍生物,如羟丙基环糊精和磺酸基丁醚环糊精,如羟丙基-β-环糊精和磺酸基丁醚β-环糊精。用于所述调配物的示例性缓冲剂包括基于羧酸的缓冲剂,如柠檬酸盐、乳酸盐和马来酸盐缓冲溶液。
本发明化合物也可使用已知经皮递送系统和赋形剂来经皮投与。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)混合,且并入贴片或类似递送系统中。如果需要那么可在所述经皮组合物中使用其它赋形剂,包括胶凝剂、乳化剂和缓冲剂。
第二药剂
本发明化合物可适用于单独治疗疾病,或可与一或多种其它治疗剂组合以获得所需治疗作用。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同投与的其它药物。举例来说,组合物可进一步包含一或多种药物(也称为“第二药剂”)。所述治疗剂为此项技术中所熟知的,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β-肾上腺素能受体拮抗剂/α1-受体拮抗剂、晚期糖基化终产物裂解剂、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、止泻剂、抗青光眼药剂、抗脂质药剂、抗伤痛感受性药剂、抗血栓药剂、AT1受体拮抗剂和双重作用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、单胺再吸收抑制剂、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、类鸦片受体激动剂、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、选择性血清素再吸收抑制剂、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。
相应地,在本发明的又另一个方面中,医药组合物包含本发明化合物、第二活性剂和医药学上可接受的载剂。第三、第四活性剂等也可包括在组合物中。在组合疗法中,本发明化合物的投与量以及第二药剂的量可小于单药疗法中通常投与的量。
本发明化合物可与第二活性剂以物理方式混合以形成含有两种药剂的组合物;或各药剂存在于独立且不同的组合物中,所述组合物是同时或在不同时间投与给患者。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剂组合,以形成包含本发明化合物和第二活性剂的活性剂组合。另外,所述活性剂可与医药学上可接受的载剂组合,以形成包含本发明化合物、第二活性剂和医药学上可接受的载剂的医药组合物。在此实施例中,通常是将组合物的组分加以混合或掺合以产生物理性的混合物。随后使用本文所述的任何途径以治疗有效量投与所述物理性的混合物。
或者,所述活性剂在投与给患者之前是保持独立且不同的。在此实施例中,药剂在投药之前不以物理方式混合在一起,而是以独立组合物形式同时或在不同时间投与。所述组合物可分别包装或可一起包装在试剂盒中。当在不同时间投与时,第二药剂通常是在投与本发明化合物之后24小时以内投与,即在从与投与本发明化合物同时到给药后约24小时的范围内的任何时间。此也称为依序投药。因此,本发明化合物与另一活性剂可使用两个片剂以同时方式或依序方式口服投与,各活性剂对应于一个片剂,其中依序是意指在投与本发明化合物后立即投与,或在某一预定时间后(例如一小时后或三小时后)投与。还预期第二药剂可在投与本发明化合物之后超过24小时投与。或者,可通过不同投药途径投与组合,即一种药剂口服投与而另一种药剂通过吸入投与。
在一个实施例中,试剂盒包含第一剂型和至少一种其它剂型,所述第一剂型包含本发明化合物,所述至少一种其它剂型包含本文中所阐述的一或多种第二药剂,其量均足以进行本发明的方法。第一剂型和第二(或第三等)剂型一起包含用于治疗或预防患者的疾病或医学病状的治疗有效量的活性剂。
当包括第二药剂时,其以治疗有效量存在,以使得其在与本发明化合物共同投与时,通常以可产生治疗学上有益的效应的量投与。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。第二药剂也可呈前药形式,例如具有已经酯化的羧酸基团的化合物。因此,本文中所列的第二药剂打算包括所有所述形式,且为可商购的或可使用常规程序和试剂制备。
在一个实施例中,本发明化合物与腺苷受体拮抗剂组合投与,所述腺苷受体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,本发明化合物与α-肾上腺素能受体拮抗剂组合投与,所述α-肾上腺素受体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)。
本发明化合物也可与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)(如丁二酸美托洛尔和酒石酸美托洛尔)、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。β1-阻断剂通常将以足以提供每剂约2-900mg的量投与。
在一个实施例中,本发明化合物与β2-肾上腺素能受体激动剂组合投与,所述β2-肾上腺素受体激动剂的代表性实例包括(但不限于)阿布叔醇(albuterol)、比托特罗(bitolterol)、非诺特罗(fenoterol)、福莫特罗(formoterol)、茚达特罗(indacaterol)、异他林(isoetharine)、左旋阿布叔醇(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)、维拉特罗(vilanterol)等。β2-肾上腺素能受体激动剂通常以足以提供每剂约0.05-500μg的量投与。
在一个实施例中,本发明化合物与晚期糖基化终产物(AGE)裂解剂组合,所述晚期糖基化终产物裂解剂的实例(举例来说但不加以限制)包括阿拉格布(alagebrium)(或ALT-711)和TRC4149。
在另一个实施例中,本发明化合物与醛固酮拮抗剂组合投与,所述醛固酮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。醛固酮拮抗剂通常将以足以提供每天约5-300mg的量投与。
在一个实施例中,本发明化合物与氨基肽酶N或二肽基肽酶III抑制剂组合投与,所述氨基肽酶N或二肽基肽酶III抑制剂的实例(举例来说但不加以限制)包括苯丁抑制素(bestatin)和PC18(2-氨基-4-甲磺酰基丁硫醇、蛋氨酸硫醇)。
本发明化合物也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)、莫维普利(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)、乙酸色拉新(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。ACE抑制剂通常将以足以提供每天约1-150mg的量投与。在另一个实施例中,本发明化合物与双重作用血管紧张素转化酶/脑啡肽酶(ACE/NEP)抑制剂组合投与,所述ACE/NEP抑制剂的实例包括(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);法西多利拉(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-氧代全氢噻唑并[3,2-a]氮杂卓-3-甲酸);格帕曲拉(gempatrilat);MDL-101264((4S,7S,12bR)-7-[2(S)-(2-吗啉基乙酰基硫基)-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);奥马曲拉(omapatrilat);RB-105(N-[2(S)-(巯基甲基)-3(R)-苯基丁基]-L-丙氨酸);山帕曲拉(sampatrilat);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-苯丙氨酸);Sch-50690(N-[1(S)-羧基-2-[N2-(甲磺酰基)-L-赖氨酰基氨基]乙基]-L-缬氨酰基-L-酪氨酸);和其组合也可包括在内。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、法西多利拉、奥马曲拉、山帕曲拉和其组合。
在一个实施例中,本发明化合物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,本发明化合物与血管紧张素-II疫苗组合投与,所述血管紧张素-II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(coumarin),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)。
在又另一个实施例中,本发明化合物与抗糖尿病药剂组合投与。代表性抗糖尿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(biguanide),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)、地那列汀(denagliptin)、利拉利汀(linagliptin)、沙格列汀(saxagliptin)、西他列汀(sitagliptin)和维格列汀(vildagliptin);美格替耐(meglitinide);如瑞格列奈(repaglinide);噁二唑烷二酮、磺酰脲,如氯磺丙脲(chlorpropamide)、格列美脲(glimepiride)、格列吡嗪(glipizide)、格列本脲(glyburide)和妥拉磺脲(tolazamide);噻唑烷二酮,如吡格列酮(pioglitazone)和罗格列酮(rosiglitazone);和其组合。
在另一个实施例中,本发明化合物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(ORS)、洛哌丁胺(loperamide)、苯乙哌啶(diphenoxylate)和次水杨酸铋。
在又另一个实施例中,本发明化合物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;局部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)、布林佐胺(brinzolamide)或多佐胺(dorzolamide);胆碱激导性激动剂,如西维美林(cevimeline)和DMXB-假木贼碱(DMXB-anabaseine);肾上腺素化合物;缩瞳剂(miotic),如匹鲁卡品(pilocarpine);和前列腺素类似物。
在又另一个实施例中,本发明化合物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),如安塞曲匹(anacetrapib)、达塞曲匹(dalcetrapib)和托塞曲匹(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,如氯吡格雷(clopidogrel)、普拉格雷(prasugrel)和噻氯匹定(ticlopidine);肝素和其组合。
在一个实施例中,本发明化合物与AT1受体拮抗剂(也称为血管紧张素II 1型受体阻断剂(ARB))组合。代表性ARB包括(但不限于)阿比沙坦(abitesartan)、阿齐沙坦(azilsartan)(例如阿齐沙坦美度米(azilsartan medoxomil))、本洛沙坦(benzyllosartan)、坎地沙坦(candesartan)、坎地沙坦西来替昔(candesartan cilexetil)、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)、依贝沙坦(irbesartan)、伊索特林(isoteoline)、洛沙坦(losartan)、美度米(medoxomil)、米法沙坦(milfasartan)、奥美沙坦(olmesartan)(例如奥美沙坦美度米(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)、维沙坦(valsartan)、佐拉沙坦(zolasartan)和其组合。在一个特定实施例中,ARB是选自阿齐沙坦美度米、坎地沙坦西来替昔、依普罗沙坦、依贝沙坦、洛沙坦、奥美沙坦美度米、沙普立沙坦、他索沙坦、替米沙坦、维沙坦和其组合。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美度米。ARB通常将以足以提供每剂约4-600mg的量投与,其中示例性每日剂量在每天20-320mg的范围内。
本发明化合物也可与双重作用药剂组合投与,所述双重作用药剂如AT1受体拮抗剂/脑啡肽酶抑制剂(ARB/NEP抑制剂),所述双重作用药剂的实例包括(但不限于)在均由Allegretti等人于2008年4月23日申请的美国专利公开案第2008/0269305号和第2009/0023228号中所描述的化合物,如化合物4'-{2-乙氧基-4-乙基-5-[((S)-2-巯基-4-甲基戊酰氨基)-甲基]咪唑-1-基甲基}-3'-氟联苯基-2-甲酸。
本发明化合物也可与如库尔茨(Kurtz)和克莱因(Klein)(2009)高血压研究(Hypertension Research)32:826-834中所描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,本发明化合物与缓激肽受体拮抗剂组合投与,所述缓激肽受体拮抗剂例如艾替班特(icatibant)(HOE-140)。预期此组合疗法可提供预防血管性水肿(angioedema)或缓激肽含量升高的其它非所需后果的优点。
在一个实施例中,本发明化合物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。钙通道阻断剂通常将以足以提供每剂约2-500mg的量投与。
在一个实施例中,本发明化合物与糜酶抑制剂组合投与,所述糜酶抑制剂如TPC-806和2-(5-甲酰氨基-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-吡啶氧基)}-2-庚基]乙酰胺(NK3201)。
在一个实施例中,本发明化合物与利尿剂组合投与。代表性利尿剂包括(但不限于):碳酸酐酶抑制剂,如乙酰唑胺(acetazolamide)和双氯非那胺(dichlorphenamide);环利尿剂(loop diuretics),其包括磺酰胺衍生物(如乙酰唑胺、安布赛特(ambuside)、阿佐塞米(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(ethoxolamide)、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)和希帕胺(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;留钾利尿剂(potassium-sparing diuretics),其包括醛固酮拮抗剂(如螺内酯(spironolactone))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。利尿剂以足以提供每天约5-50mg(更通常每天6-25mg)的量投与,其中常用剂量为每天6.25mg、12.5mg或25mg。
本发明化合物也可与内皮素转化酶(ECE)抑制剂组合投与,所述ECE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)、安立生坦(ambrisentan)、阿曲生坦(atrasentan)、BQ-123、克拉生坦(clazosentan)、达卢生坦(darusentan)、西他塞坦(sitaxentan)和齐泊替坦(zibotentan);和影响内皮素A与B受体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)。
在又另一个实施例中,本发明化合物与一或多种HMG-CoA还原酶抑制剂(也称为他汀类)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,本发明化合物与单胺再吸收抑制剂组合投与,所述单胺再吸收抑制剂的实例(举例来说但不加以限制)包括去甲肾上腺素再吸收抑制剂,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、麦普替林(maprotiline)、瑞波西汀(reboxetine)和维洛沙嗪(viloxazine);选择性血清素再吸收抑制剂(SSRI),如西它普兰(citalopram)和西它普兰代谢物去甲西它普兰(desmethylcitalopram)、达泊西汀(dapoxetine)、依地普兰(escitalopram)(例如乙二酸依地普兰)、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)(例如马来酸氟伏沙明)、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-去甲肾上腺素再吸收抑制剂(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。
在另一个实施例中,本发明化合物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(Nile Therapeutics))、CU-NP、奈西立肽(nesiritide)、PL-3994(帕拉丁科技公司(Palatin Technologies,Inc.))、乌拉立肽(ularitide)、森德立肽(cenderitide)和在小川(Ogawa)等人(2004)生物化学杂志(J.Biol.Chem.).279:28625-31中所描述的化合物。这些化合物也称为利钠肽受体-A(NPR-A)激动剂。在另一个实施例中,本发明化合物与利钠肽清除受体(NPR-C)拮抗剂组合投与,所述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)。举例来说,当与NEP抑制剂、塞奥芬(thiorphan)组合时,AP-811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)。
在另一个实施例中,本发明化合物与脑啡肽酶(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(candoxatril);坎沙曲拉(candoxatrilat);右卡多曲(dexecadotril)((+)-N-[2(R)-(乙酰基硫基甲基)-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)-(乙酰基硫基甲基)-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(Pfizer Inc.))的WO 2006/027680中的3-(l-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;反向塞奥芬(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-(磺酰基甲基)丙酰胺);SCH-32615((S)-N-[N-(1-羧基-2-苯乙基)-L-苯丙氨酰基]-β-丙氨酸)和其前药SCH-34826((S)-N-[N-[1-[[(2,2-二甲基-1,3-二氧杂环戊烷-4-基)甲氧基]羰基]-2-苯乙基]-L-苯丙氨酰基]-β-丙氨酸);萨洛芬(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);司皮诺芬(spinorphin);SQ-28132(N-[2-(巯基甲基)-1-氧代-3-苯丙基]亮氨酸);SQ-28603(N-[2-(巯基甲基)-1-氧代-3-苯丙基]-β-丙氨酸);SQ-29072(7-[[2-(巯基甲基)-1-氧代-3-苯丙基]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-羧基丙酰氨基)-2-甲基戊酸和5-联苯-4-基-4-(3-羧基丙酰氨基)-2-甲基戊酸乙酯(WO 2007/056546);描述于凯德(Khder)等人(诺华公司(Novartis AG))的WO2007/106708中的达鲁曲(daglutril)[(3S,2'R)-3-{1-[2'-(乙氧基羰基)-4'-苯基丁基]-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抑制剂为如达鲁曲或CGS-26303([N-[2-(联苯-4-基)-1(S)-(1H-四唑-5-基)乙基]氨基]甲基膦酸)的化合物,其具有作为内皮素转化酶(ECE)抑制剂和NEP抑制剂的活性。也可使用其它双重作用ECE/NEP化合物。NEP抑制剂将以足以提供每天约20-800mg的量投与,其中典型每日剂量在每天50-700mg,更通常每天100-600mg或100-300mg的范围内。
在一个实施例中,本发明化合物与一氧化氮供体组合投与,所述一氧化氮供体的实例包括(但不限于)尼可地尔(nicorandil);有机硝酸酯,如异戊四醇四硝酸酯;和斯德酮亚胺(sydnonimine),如林西多明(linsidomine)和吗多明(molsidomine)。
在又另一个实施例中,本发明化合物与非类固醇消炎剂(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)、阿洛普令(aloxiprin)、阿尼罗酸(anirolac)、阿帕宗(apazone)、阿扎丙宗(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(diflunisal)、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(flufenamicacid)、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)、甲氯芬那酸盐(meclofenamate)、甲氯芬那酸(meclofenamic acid)、甲芬那酸(mefenamic acid)、美洛昔康(meloxicam)、美沙拉嗪(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)、双水杨酸酯(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、酮咯酸、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,本发明化合物与N-甲基d-天冬氨酸(NMDA)受体拮抗剂组合投与,所述NMDA受体拮抗剂的实例(举例来说但不加以限制)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。
在再另一个实施例中,本发明化合物与类鸦片受体激动剂(也称为类鸦片止痛剂)组合投与。代表性类鸦片受体激动剂包括(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(methadone)、吗啡(morphine)、纳布啡(nalbuphine)、纳美芬(nalmefene)、纳洛芬(nalorphine)、纳洛酮(naloxone)、纳曲酮(naltrexone)、纳洛芬(nalorphine)、氧可酮(oxycodone)、氧吗啡酮(oxymorphone)、戊唑星(pentazocine)、丙氧芬(propoxyphene)、曲马多(tramadol)和其组合。在某些实施例中,类鸦片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,本发明化合物与磷酸二酯酶(PDE)抑制剂(尤其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)他达拉非(tadalafil)伐地那非(vardenafil)和优地那非(udenafil)。
在另一个实施例中,本发明化合物与前列腺素类似物(也称为前列腺素(prostanoid)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)贝前列素钠(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尤其受关注。
在又另一个实施例中,本发明化合物与前列腺素受体激动剂组合投与,所述前列腺素受体激动剂的实例包括(但不限于)比马前列素、拉坦前列素、曲伏前列素等。
本发明化合物也可与肾素抑制剂组合投与,所述肾素抑制剂的实例包括(但不限于)阿利吉仑(aliskiren)、依那吉仑(enalkiren)、瑞米吉仑(remikiren)和其组合。
在另一个实施例中,本发明化合物与选择性血清素再吸收抑制剂(SSRI)组合投与。代表性SSRI包括(但不限于):西它普兰和西它普兰代谢物去甲西它普兰、达泊西汀、依地普兰(例如乙二酸依地普兰)、氟西汀和氟西汀去甲基代谢物去甲氟西汀、氟伏沙明(例如马来酸氟伏沙明)、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,本发明化合物与5-HT1D血清素受体激动剂组合投与,所述5-HT1D血清素受体激动剂的实例(举例来说但不加以限制)包括曲普坦(triptan),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,本发明化合物与钠通道阻断剂组合投与,所述钠通道阻断剂的实例(举例来说但不加以限制)包括卡马西平(carbamazepine)、磷苯妥英(fosphenytoin)、拉莫三嗪(lamotrignine)、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,本发明化合物与可溶性鸟苷酸环化酶刺激剂或活化剂组合投与,所述可溶性鸟苷酸环化酶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,本发明化合物与三环抗抑郁剂(TCA)组合投与,所述TCA的实例(举例来说但不加以限制)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,本发明化合物与血管加压素受体拮抗剂组合投与,所述血管加压素受体拮抗剂的实例(举例来说但不加以限制)包括考尼伐坦(conivaptan)和托伐普坦(tolvaptan)。
组合的第二治疗剂也可有助于使用本发明化合物的其它组合疗法。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,其以商标出售;或钙通道阻断剂氨氯地平(呈苯磺酸盐形式)与ARB奥美沙坦(呈美度米前药形式)的组合;或钙通道阻断剂与他汀的组合,所有也可与本发明化合物一起使用。其它治疗剂(如α2-肾上腺素能受体激动剂和血管加压素受体拮抗剂)也可有助于组合疗法。示例性α2-肾上腺素能受体激动剂包括可乐定(clonidine)、右美托咪啶(dexmedetomidine)和胍法新(guanfacine)。
下列调配物说明本发明的代表性医药组合物。
用于口服投药的示例性硬明胶胶囊
将本发明化合物(50g)、440g喷雾干燥的乳糖和10g硬脂酸镁充分掺合。随后将所得组合物装入硬明胶胶囊中(每粒胶囊500mg组合物)。或者,将本发明化合物(20mg)与淀粉(89mg)、微晶纤维素(89mg)和硬脂酸镁(2mg)充分掺合。随后使混合物通过45号目美国筛,且装入硬明胶胶囊中(每粒胶囊200mg组合物)。
或者,将本发明化合物(30g)、第二药剂(20g)、440g喷雾干燥的乳糖和10g硬脂酸镁充分掺合,且如上文所描述进行加工。
用于口服投药的示例性明胶胶囊调配物
将本发明化合物(100mg)与聚氧乙烯脱水山梨糖醇单油酸酯(50mg)和淀粉(250mg)充分掺合。随后将混合物装入明胶胶囊中(每粒胶囊400mg组合物)。或者,将本发明化合物(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)充分掺合,且将所得混合物装入明胶胶囊中(每粒胶囊400mg组合物)。
或者,将本发明化合物(40mg)与微晶纤维素(Avicel PH 103;259.2mg)和硬脂酸镁(0.8mg)充分掺合。随后将混合物装入明胶胶囊(1号尺寸,白色,不透明)中(每粒胶囊300mg组合物)。
用于口服投药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)通过20号目美国筛,且充分混合。由此产生的颗粒在50℃-60℃下干燥,且通过16号目美国筛。将聚乙烯吡咯烷酮溶液(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,随后使此混合物通过16号目美国筛。随后向所述颗粒中加入羧甲基淀粉钠、硬脂酸镁和滑石。在混合之后,在制片机上压缩混合物以得到重量为100mg的片剂。
或者,将本发明化合物(250mg)与微晶纤维素(400mg)、烟雾状二氧化硅(10mg)和硬脂酸(5mg)充分掺合。随后压缩混合物以形成片剂(每片665mg组合物)。
或者,将本发明化合物(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)充分掺合。随后压缩混合物以形成单刻痕片剂(每片600mg组合物)。
或者,用明胶水溶液(20mg)将本发明化合物(100mg)与玉米淀粉(100mg)充分掺合。干燥混合物,且研磨为细粉。随后将微晶纤维素(50mg)和硬脂酸镁(5mg)与明胶调配物混合,造粒,且压缩所得混合物以形成片剂(每片100mg本发明化合物)。
用于口服投药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:
用于口服投药的示例性液体调配物
适合的液体调配物为含有基于羧酸的缓冲剂(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,将本发明化合物(其可与DMSO预混)与100mM柠檬酸铵缓冲剂掺合且将pH值调节到pH 5,或与100mM柠檬酸溶液掺合且将pH值调节到pH 2。所述溶液也可包括增溶性赋形剂(如环糊精),举例来说,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有或不含有环糊精的5%NaHCO3溶液。
用于注射投药的示例性可注射调配物
将本发明化合物(0.2g)与0.4M乙酸钠缓冲溶液(2.0mL)掺合。视需要使用0.5N盐酸水溶液或0.5N氢氧化钠水溶液将所得溶液的pH值调节到pH 4,随后加入足够的注射用水以提供20mL的总体积。随后经由无菌过滤器(0.22微米)过滤混合物,以提供适合于注射投药的无菌溶液。
用于吸入投药的示例性组合物
将本发明化合物(0.2mg)微米尺寸化,随后与乳糖(25mg)掺合。随后将此掺合的混合物装入明胶吸入筒中。举例来说,使用干粉吸入器来投与所述药筒的内容物。
或者,将微米尺寸化的本发明化合物(10g)分散在通过将卵磷脂(0.2g)溶解于去矿物质水(200mL)中所制备的溶液中。喷雾干燥所得悬浮液,随后经微米尺寸化以形成包含平均直径小于约1.5μm的粒子的微米尺寸化组合物。随后将微米尺寸化的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筒中,当用所述吸入器投与时,所述1,1,1,2-四氟乙烷的量足以提供每剂约10μg到约500μg本发明化合物。
或者,将本发明化合物(25mg)溶解于柠檬酸盐缓冲(pH 5)的等渗盐水(125mL)中。搅拌混合物且进行超声波处理直到化合物溶解。检查溶液的pH值,且如果需要那么通过缓慢加入1N NaOH水溶液来将pH值调节到pH 5。使用每剂提供约10μg到约500μg本发明化合物的喷雾器装置来投与所述溶液。
实例
提供下列制备和实例以说明本发明的特定实施例。然而除非特定指明,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。
除非另外指明,否则下列缩写具有下列含义,且本文中所使用但未定义的任何其它缩写具有其一般接受的标准含义:
除非另外指示,否则所有物质(如试剂、起始物质和溶剂)均从商业供应商(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)购得,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。通过薄层色谱(TLC)、分析型高效液相色谱(分析型HPLC)和质谱来监测反应的进程,监测的细节在特定实例中给出。用于分析型HPLC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。
如例如在各制备中具体所述来处理反应,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以及沉淀)来纯化反应混合物。另外,通过制备型HPLC,通常使用Microsorb C18和Microsorb BDS柱填充物和常规洗脱剂来常规地纯化反应混合物。通常通过液相色谱质谱(LCMS)来测量反应的进程。通过核奥氏效应光谱分析(NuclearOverhauser effect spectroscopy,NOE)来进行异构体的表征。通过质谱和1H-NMR光谱分析来常规地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,且在标准观测条件下用Varian Gemini 2000仪器(400MHz)获得1H-NMR光谱。通常用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仪器使用电喷雾电离法(ESMS)来进行化合物的质谱鉴别。
制备1:1-三苯甲基-1H-1,2,3-三唑-4-甲酸
将1H-1,2,3-三唑-4-甲酸(20.0g,177mmol)与DMF(200mL,2.6mol)和吡啶(100mL,1.2mol)组合,且将所得混合物冷却到0℃。逐份加入三苯甲基氯(54g,190mmol),且在室温下搅拌混合物24小时。过滤所得浆料,且用水(2×200mL)洗涤滤饼且风干,得到灰白色固体(60g)。于室温下在THF(800mL)中将固体制成浆料且持续4小时,随后过滤。随后通过旋转蒸发浓缩滤液,得到浓稠油状物。加入EtOAc(500mL),且将体积减少到约200mL。过滤所得浓稠浆料且干燥,得到标题化合物(35.5g)。
制备2:(2S,4R)-5-联苯-4-基-4-叔丁氧基羰基氨基-2-甲基-2-(四氢吡喃-2-基氧基甲基)戊酸
在DMAP(3.2g,26.4mmol)中组合(R)-3-联苯-4-基-2-叔丁氧基羰基氨基-丙酸(5.0g,15mmol)和2,2-二甲基-1,3-二噁烷-4,6-二酮(2.3g,16.1mmol)。加入另外的DMAP(2.0g,16.1mmol)和DCM(50mL),且搅拌所得混合物且冷却到-5℃(氮气吹扫)持续30分钟。逐份加入EDCI(HCl;(3.1g,16.1mmol)),同时在搅拌下保持内部温度在0℃以下。随后将混合物冷却到-5℃,在所述温度下搅拌3小时,随后留在-20℃下持续过夜。随后用0.4M KHSO4水溶液(80mL)和饱和NaCl水溶液(20mL)洗涤混合物,随后经MgSO4干燥过夜。滤出固体,随后将滤液蒸发到干燥,得到粗化合物1(3.2g)。
于-5℃下在氮气下将AcOH(8.6mL)加入到粗化合物1(6.4g,14mmol,1.0当量)于无水MeCN(90mL)中的溶液中加入AcOH(8.6mL)。在-5℃下搅拌混合物30分钟,随后经2小时以小份加入硼氢化钠(1.3g,34.5mmol,2.5当量)。在于-5℃下再搅拌1小时之后,加入饱和NaCl水溶液和1.7M NaCl水溶液(30mL)。分离各层,且用饱和NaCl水溶液(2×30mL)和水(2×30mL)洗涤有机层,经MgSO4干燥,过滤且蒸发。通过色谱(5:1庚烷:EtOAc)来进一步纯化所得粗产物,得到呈淡黄色固体状的化合物2(1.1g,纯度98.4%)。
在搅拌下于氮气下将化合物2(5.0g,11mmol,1.0当量)和K2CO3(1.8g,13.2mmol,1.2当量)溶解于DMF(33.9mL)中,且冷却到0℃。加入碘代甲烷(892μL,1.3当量),且在0℃下搅拌所得混合物1小时。使混合物升温到室温(23℃)且保持过夜。加入饱和NaCl水溶液(35mL)和EtOAc(35mL),且搅拌所得混合物2分钟。分离各层,且蒸发有机层。用EtOAc(20mL)湿磨残余物。滤出固体,且在真空下干燥。浓缩滤液且再次用EtOAc湿磨,得到化合物3(3.9g),[(R)-2-联苯-4-基-1-(2,2,5-三甲基-4,6-二氧代-[1,3]二噁烷-5-基甲基)乙基]氨基甲酸叔丁酯。
将化合物3(400.0g,855.5mmol)与CPME(2L)组合以形成浆料。在0℃下冷却浆料,且加入3.0M HCl的CPME溶液(2.0L)。在室温下搅拌所得混合物24小时,得到自由流动的浆料。过滤且干燥,得到呈非对映异构体的93:7混合物形式的化合物4(总共206g)。于室温下在MeTHF(1L)中再制成浆料,继而加入CPME(1L;浆料在室温下过夜),得到化合物5(170g,非对映异构体过量(de)和纯度为98%)。
将化合物5(25.0g,80.8mmol)与THF(500mL)和NMM(25mL,230mmol)组合。在0℃下冷却所得混合物(夹套温度设定在-5℃),且借助加料漏斗逐滴加入氯甲酸异丁酯(21.0mL,162mmol),同时维持内部温度在5℃以下。在0℃下搅拌混合物20分钟。逐滴加入溶解于水(40mL)中的硼氢化钠(12.2g,323mmol),且在0℃下搅拌混合物20分钟(>98%转化)。用1M HCl水溶液(300mL)淬灭反应,且在室温下搅拌混合物1小时。蒸馏出大部分溶剂,留下白色浆料。搅拌浆料60分钟,随后过滤(小粒子,缓慢过滤),得到呈白色固体状的化合物6(23g,纯度>98%)。
组合化合物6(300g,1.0mol)和DCM(3.8L),且在0℃下冷却所得混合物。加入二氢吡喃(185mL,2.0mol)和对甲苯磺酸(52.5g,305mmol),且在室温下搅拌混合物2小时。加入饱和NaHCO3水溶液(10:90,NaHCO3:水,3L),且分离各相。经Na2SO4干燥有机层,继而移除溶剂到约500mL。向粗产物中加入二异丙醚(2L)和晶种。在室温下搅拌所得浆料过夜。过滤且干燥,得到结晶化合物7(320g,纯度>98%)。
将化合物7(320.0g,843.2mmol)溶解于THF(2.5L)中,得到澄清溶液,用氮气吹扫。在0℃下冷却溶液,且经30分钟逐滴加入1.0M NaHMDS的THF溶液(920mL,920mmol)。在0℃下搅拌混合物15分钟,随后经1小时逐滴加入溶解于THF(500mL)中的二碳酸二叔丁酯(202g,926mmol),同时维持内部温度在5℃以下。使混合物升温到室温(>99%转化为化合物8)。将混合物冷却到<5℃,继而加入1.0M LiOH水溶液(2.5L,2.5mol)。移除冷却浴,且在27℃下搅拌混合物过夜(剩余约4%起始物质)。在35℃下加热混合物4小时(>98%转化),随后冷却到15℃。用EtOAc(3L)和饱和NH4Cl水溶液(0.37:0.63,NH4Cl:水,3L)稀释混合物。分离各相,且用饱和NH4Cl水溶液(3L)和饱和NaCl水溶液(3L)洗涤有机层。经Na2SO4(1kg)干燥有机层,继而移除溶剂,得到呈玻璃状粘性固体状的粗标题化合物(463g)。
制备3:(2S,4R)-5-联苯-4-基-2-甲基-2-(四氢吡喃-2-基氧基甲基)-4-[(1-三苯甲基-1H-1,2,3-
三唑-4-羰基)氨基]戊酸
将(2S,4R)-5-联苯-4-基-4-叔丁氧基羰基氨基-2-甲基-2-(四氢吡喃-2-基氧基甲基)戊酸(10.0g,20.1mmol)与DMF(50mL,600mmol)组合,且搅拌。加入K2CO3(3.3g,24mmol),且将所得混合物冷却到0℃。加入溴甲苯(3.0mL,25mmol),且在0℃到室温下搅拌混合物,随后过夜。加入1.0M HCl水溶液(250mL,250mmol)和EtOAc(300mL,3.0mol)。分离各相,且用饱和NaCl水溶液(200mL)洗涤有机层,且经Na2SO4干燥,继而移除溶剂。加入DCM(50mL)和3.0M HCl的CPME溶液(100mL,300mmol),且在室温下搅拌所得混合物过夜。通过旋转蒸发将体积减少一半,得到自由流动的浆料,过滤所述浆料。用CPME(20mL)洗涤烧瓶和滤饼,且干燥。将残余物溶解于DCM(50mL,800mmol)中,且在0℃到10℃下冷却所得悬浮液。加入二氢吡喃(3.7mL,40.2mmol)和对甲苯磺酸(692mg,4.0mmol),且在0℃下搅拌所得混合物2小时,随后在较冷温度下搅拌过夜。通过旋转蒸发将体积减少到约20mL。加入MTBE(约30mL),继而加入晶种,在搅拌15分钟之后得到稀浆料。将体积减少一半,且加入另外MTBE(20mL),同时在室温下搅拌,得到浓稠浆料。加入另外MTBE(到100mL体积),且搅拌混合物1小时。过滤且干燥,得到呈盐酸盐形式的化合物1(8.9g)。
将1-三苯甲基-1H-1,2,3-三唑-4-甲酸(9.2g,26mmol)溶解于THF(200mL,2.0mol)中。加入DIPEA(9.0mL,52mmol),且将所得混合物冷却到0℃。逐份加入HCTU(11g,26mmol),且在0℃下搅拌混合物15分钟。加入化合物1(盐酸盐;9.0g,17mmol),且从0℃到室温搅拌所得混合物。监测反应,且在90分钟之后用水(200mL)淬灭。加入EtOAc(200mL)。用饱和NaCl水溶液(200mL)洗涤有机层,经Na2SO4干燥,且移除溶剂。将残余物(15g)溶解于DCM(100mL)中,滤出固体,且纯化澄清溶液(300g SiG柱;用10%-30%EtOAc/己烷洗脱),得到化合物2(7.5g)。
将化合物2(0.20g,0.24mmol)与EtOAc(3mL,30mmol)组合。加入NaHCO3(50mg,0.6mmol),且用氮气吹扫所得澄清溶液。加入10%Pd/C(0.05:0.45,钯:碳黑,50mg,0.05mmol),且用氢气吹扫所得混合物,随后在室温下氢化过夜。滤出固体,且通过旋转蒸发移除溶剂,得到标题化合物。
制备4:(2S,4R)-5-联苯-4-基-2-甲基-2-(四氢吡喃-2-基氧基甲基)-4-[(1H-1,2,3-三唑-4-羰
基)氨基]戊酸
将(2S,4R)-5-联苯-4-基-2-甲基-2-(四氢吡喃-2-基氧基甲基)-4-[(1-三苯甲基-1H-1,2,3-三唑-4-羰基)氨基]戊酸苯甲酯(7.5g,9.1mmol)与EtOAc(80mL,800mmol)组合。用氮气吹扫所得澄清溶液,且加入10%Pd/C(0.05:0.45,钯:碳黑,1.0g,0.94mmol)。用氢气吹扫所得混合物,随后在室温下氢化过夜。用氮气吹扫混合物,滤出固体,且通过旋转蒸发移除溶剂,得到标题化合物(7g)。
制备5:(R)-3-(4-溴苯基)-2-叔丁氧基羰基氨基丙酸
在-5℃下向(R)-2-氨基-3-(4-溴苯基)丙酸(50g,0.2mol)于MeCN(700mL)中的溶液中加入NaOH(16.4g,0.4mol)于水(700mL)中的溶液。在搅拌10分钟之后,加入(BOC)2O(44.7g,0.2mol)于MeCN(100mL)中的溶液。将混合物升温到室温,且搅拌过夜。在蒸发MeCN之后,用DCM(800mL)稀释残余物,且在-5℃下用1M HCl酸化到pH 2。用DCM(3×200mL)萃取水层。用饱和NaCl水溶液(500mL)洗涤经合并的有机层,经无水Na2SO4干燥且浓缩,得到呈白色固体状的标题化合物(64.2g)。LC-MS:[M+Na]:366,[2M+Na]:709。
制备6:[(R)-1-(3'-氟联苯-4-基甲基)-2-(2,2,5-三甲基-4,6-二氧代-[1,3]二噁烷-5-基)乙基]
氨基甲酸叔丁酯
在室温下在氮气下向(R)-3-(4-溴苯基)-2-叔丁氧基羰基氨基丙酸(64.2g,187mmol)于1,4-二噁烷(500mL)中的溶液中加入3-氟苯基硼酸(31.3g,224mmol)和Pd(dppf)2Cl2(13.7g,19mmol)。在搅拌10分钟之后,加入K2CO3(51.7g,374mmol)于水(250mL)中的溶液。加热混合物到100℃,且搅拌过夜。在蒸发溶剂之后,加入水(200mL)。用1M HCl将水层酸化到pH 2,且用EtOAc(3×200mL)萃取。用饱和NaCl水溶液(400mL)洗涤经合并的有机层,经无水Na2SO4干燥且浓缩,得到粗产物,通过柱色谱(己烷:EtOAc=4:1)来进一步纯化所述粗产物,得到呈淡黄色油状的化合物1(45g)。LC-MS:[M+Na]:382,[2M+Na]:741。
于-5℃下在氮气下经1小时向化合物1(45g,125mmol)、米氏酸(Meldrum's acid)(23.5g,163mmol)和DMAP(26.0g,213mmol)于无水DCM(500mL)中的溶液中加入DCC(33.3g,163mmol)于无水DCM(200mL)中的溶液。在-5℃下搅拌混合物8小时,随后冷藏过夜,在此期间微小的二环已基脲晶体发生沉淀。在过滤之后,用5%KHSO4(4×200mL)和饱和NaCl水溶液(1×200mL)洗涤混合物,随后在冷藏下经无水MgSO4干燥过夜。蒸发溶液,得到呈淡黄色油状的粗化合物2(57.7g)。LC-MS:[M+Na]:508,[2M+Na]:993。
于-5℃下在氮气下向化合物2(57.7g,119mmol)于无水DCM(1L)中的溶液中加入AcOH(78.4g,1.3mol)。在-5℃下搅拌混合物0.5小时,随后经1小时以小份加入NaBH4(11.3g,0.3mol)。在-5℃下再搅拌1小时之后,加入饱和NaCl水溶液(300mL)。用饱和NaCl水溶液(2×300mL)和水(2×300mL)洗涤有机层,经无水MgSO4干燥,过滤且浓缩,得到粗产物,通过色谱(己烷:EtOAc=6:1)来进一步纯化所述粗产物,得到呈淡黄色油状的化合物3(28g)。LC-MS:[M+Na]:494,[2M+Na]:965。
于0℃下在氮气下向化合物3(28g,60mmol)于无水DMF(250mL)中的溶液中加入K2CO3(9.9g,72mmol)和碘代甲烷(25.6g,180mmol)。在0℃下搅拌1小时之后,将混合物升温到室温,且搅拌过夜。用水(3L)稀释混合物,且用EtOAc(3×300mL)萃取。用饱和NaCl水溶液(500mL)洗涤经合并的有机层,经无水Na2SO4干燥且浓缩,得到粗产物,通过色谱(己烷:EtOAc=5:1)来进一步纯化所述粗产物,得到呈淡黄色固体状的标题化合物(11.7g)。LC-MS:[M+Na]=508,[2M+Na]=993。1H NMR(300MHz,CD3OD):δ7.52-7.49(m,2H),7.41-7.39(m,2H),7.32-7.27(m,3H),7.07-7.01(m,1H),6.21-6.18(d,1H),3.79(m,1H),2.78-2.61(m,2H),2.35-2.20(m,2H),1.76(s,6H),1.59(s,3H),2.21(s,1H),1.28(s,9H)。
制备7:(2S,4R)-4-叔丁氧基羰基氨基-5-(3'-氟联苯-4-基)-2-羟甲基-2-甲基-戊酸(化合物1)
和(2S,4R)-4-氨基-5-(3'-氟联苯-4-基)-2-羟甲基-2-甲基-戊酸(化合物2)
在氮气下吹扫蒸馏水(181mL)1小时,随后借助于导管引入含有0.1M二碘化钐的THF溶液(800mL)的容器中。在维持氮气气氛的同时,借助于导管加入以类似方式脱气的[(R)-1-(3'-氟联苯-4-基甲基)-2-(2,2,5-三甲基-4,6-二氧代-[1,3]二噁烷-5-基)乙基]氨基甲酸叔丁酯(4.9g,10.0mmol,1.0当量)和THF(20mL)的溶液。搅拌所得混合物15分钟,随后暴露于空气中。蒸发溶剂,且加入EtOAc(200mL)、饱和NaCl水溶液(50mL)和10%柠檬酸(20mL)。搅拌混合物5分钟,随后萃取两层。经Na2SO4干燥有机层,且在真空下浓缩。通过色谱(330g金柱,1:1乙醚:EtOAc(含0.5%AcOH))来纯化粗产物,得到标题化合物1(1.5g)。将一部分化合物1溶解于存于二噁烷中的4M HCl(6mL)和MeCN(10mL)中。在真空下蒸发溶剂,得到标题化合物2。
制备8:[(R)-1-(4-溴苯甲基)-2-(2,2,5-三甲基-4,6-二氧代-[1,3]二噁烷-5-基)乙基]氨基甲酸
叔丁酯
在0℃下向(R)-2-氨基-3-(4-溴苯基)丙酸(100g,410μmol)于MeCN(600mL)中的混合物中逐滴加入NaOH(32.8g,820μmol)于水(800mL)中的溶液。搅拌所得溶液30分钟。加入(BOC)2O(93.8g,430μmol)于MeCN(200mL)中的溶液,且将所得混合物升温到室温且搅拌过夜。蒸发MeCN,且用DCM(1L)稀释残余物,且在-5℃下用2M HCl酸化到pH=2。萃取水层,且用饱和NaCl水溶液(500mL)洗涤经合并的有机层,经无水Na2SO4干燥且浓缩,得到呈黄色固体状的粗化合物1(141g,100%)。LC-MS:366[M+Na]+。
将化合物1(20g,58.1mmol)与2,2-二甲基-1,3-二噁烷-4,6-二酮(9.2g,63.9mmol)、DMAP(10.7g,87.2mmol)和无水DCM(400mL)组合,且冷却到0℃。在搅拌30分钟之后,于0℃下在氮气下逐滴加入DCC(13.2g,63.9mmol)于DCM(50mL)中的溶液。在加入之后,移除冰浴,且在室温下搅拌混合物过夜。在-20℃下冷却溶液1小时,随后滤出固体。用5%KHSO4溶液(4×100mL)和饱和NaCl水溶液(200mL)洗涤滤液。经无水Na2SO4干燥有机层且蒸发,得到呈灰色固体状的粗化合物2(27.5g)。LC-MS:492[M+Na]+。
于-5℃下在氮气下向化合物2(27.5g,58.1mmol)于无水DCM(400mL)中的溶液中加入AcOH(38.4g,639.1mmol)。在-5℃下搅拌混合物30分钟。经30分钟逐份加入NaBH4(5.5,145.2mmol),且在室温下搅拌所得溶液3小时。加入饱和NaCl水溶液(300mL)以淬灭反应。用饱和NaCl水溶液(2×200mL)洗涤有机层,经无水Na2SO4干燥且浓缩,得到粗化合物3(22.6g)。LC-MS:478[M+Na]+。
在0℃下向化合物3(22.6g,49.6mmol)和K2CO3(8.3g,59.5mmol)于无水DMF(160mL)中的溶液中逐滴加入碘代甲烷(14g,99.2mmol)。在加入之后,在室温下搅拌溶液过夜。蒸发混合物,且将残余物溶解于EtOAc(500mL)中,且用饱和NaCl水溶液(2×200mL)洗涤。经无水Na2SO4干燥有机溶液且浓缩,得到粗产物,用乙醚(100mL)湿磨所述粗产物,随后过滤,得到呈白色固体状的标题化合物(14.5g)。LC-MS:492[M+Na]+。
制备9:(2S,4R)-4-叔丁氧基羰基氨基-5-(3'-氯联苯-4-基)-2-羟甲基-2-甲基戊酸
将[(R)-1-(4-溴苯甲基)-2-(2,2,5-三甲基-4,6-二氧代-[1,3]二噁烷-5-基)乙基]氨基甲酸叔丁酯(8g,17mmol)、3-氯苯基硼酸(3g,18.7mmol)、Pd(dppf)2Cl2(400mg,550μmol)和氟化钾(2g,34mmol)于水(80mL)和二噁烷(80mL)中的混合物于60℃下在氩气下搅拌3小时。浓缩混合物,分散于水(150mL)中,用EtOAc(2×100mL)萃取,经无水Na2SO4干燥且蒸发,得到粗产物,通过柱色谱(PE:EtOAc=10:1)来纯化所述粗产物,得到呈白色固体状的化合物1(7g)。LC-MS:524[M+Na]+。
用氩气冲洗钐粉末(50g,330μmol)(20分钟)。加入无水THF(1.5L),且用氩气使所得悬浮液鼓泡(15分钟)。加入碘(70g,270mmol),且再次用氩气冲洗混合物(10分钟)。用铝箔覆盖混合物,且在65℃下加热过夜,随后使其冷却到室温。密封化合物1(7g,13.9mmol)于THF(200mL)和水(100mL)的溶液且用氩气冲洗(10分钟),冷却到-70℃,用氩气冲洗(10分钟),冷却到-70℃,且用氩气冲洗(30分钟)。随后借助于导管向经冷却的溶液中加入钐粉末溶液(1.5L),且在室温下搅拌2小时。蒸发溶液,将残余物溶解于EtOAc(200mL)中,用酒石酸溶液(10%,150mL)洗涤,经无水Na2SO4干燥,浓缩且通过柱色谱(PE:EtOAc=0到30%,加入有0.05%AcOH)来纯化,得到呈白色固体状的标题化合物(3g)。LC-MS:470[M+Na]+。1H NMR(300MHz,CD3OD):δ7.28~7.56(m,8H),3.94(s,1H),3.56~3.66(m,2H),2.69~2.82(m,2H),1.70~1.90(m,2H),1.17~1.31(m,12H)。
制备10:(2S,4R)-4-叔丁氧基羰基氨基-5-(2'-氯联苯-4-基)-2-羟甲基-2-甲基戊酸
将[(R)-1-(4-溴苯甲基)-2-(2,2,5-三甲基-4,6-二氧代-[1,3]二噁烷-5-基)乙基]氨基甲酸叔丁酯(4.8g,30.6mmol)、2-氯苯基硼酸、Pd(dppf)2Cl2(1.0g,1.3mmol)和氟化钾(2.9g,51mmol)于水(50mL)和二噁烷(250mL)中的混合物于60℃下在氩气下搅拌3小时。浓缩混合物,溶解于水(150mL)中,用EtOAc(2×200mL)萃取,经无水Na2SO4干燥且蒸发,得到粗产物,通过柱色谱(PE:EtOAc=3:1)来纯化所述粗产物,得到呈白色固体状的化合物1(10g)。LC-MS:402[M-Boc]+。1H NMR(300MHz,CDCl3):δ7.47(m,1H),7.38(d,J=8.0Hz,2H),7.31(m,3H),7.23(dd,J=9.9,5.7Hz,2H),4.18(d,J=10.2Hz,1H),4.01(s,1H),2.87(dd,J=13.8,5.7Hz,1H),2.71(dd,J=13.7,6.6Hz,1H),2.30(m,2H),1.75(s,6H),1.65(s,3H),1.33(d,J=11.7Hz,9H)。
用氩气冲洗钐粉末(50g,330μmol)(20分钟)。加入无水THF(1.5L),且用氩气使所得悬浮液鼓泡(15分钟)。加入碘(70g,270mmol),且再次用氩气冲洗混合物(10分钟)。用铝箔覆盖混合物,且在65℃下加热过夜,随后使其冷却到室温。密封化合物1(7g,13.9mmol)于THF(200mL)和水(100mL)中的溶液且用氩气冲洗(10分钟),冷却到-70℃,用氩气冲洗(10分钟),冷却到-70℃,且用氩气冲洗(30分钟)。随后借助于导管向经冷却的溶液中加入钐粉末溶液(1.5L),且在室温下搅拌2小时。蒸发溶液,将残余物溶解于EtOAc(200mL)中,用酒石酸溶液(10%,150mL)洗涤,经无水Na2SO4干燥,浓缩且通过柱色谱(PE:EtOAc=0到30%,加入有0.05%AcOH)来纯化,得到呈灰白色固体状的标题化合物(2.8g)。LC-MS:348[M-Boc]+。1H NMR(300MHz,CD3OD):δ7.46(m,1H),7.28(m,7H),3.97(s,1H),3.63(m,2H),2.82(m,1H),2.69(m,1H),1.89(m,1H),1.74(m,1H),1.33(m,7H),1.22(m,5H)。
制备11:(2S,4R)-4-叔丁氧基羰基氨基-5-(2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸
将[(R)-1-(4-溴苯甲基)-2-(2,2,5-三甲基-4,6-二氧代-[1,3]二噁烷-5-基)乙基]氨基甲酸叔丁酯(12g,25.6mmol)、2-氟苯基硼酸(4.3g,30.7mmol)、Pd(dppf)2Cl2(950mg,1.3mmol)和氟化钾(3.0g,51.2mmol)于水(50mL)和二噁烷(100mL)中的混合物于60℃下在氩气下搅拌2小时。浓缩混合物,用水(100mL)稀释,用EtOAc(3×100mL)萃取,经无水Na2SO4干燥且蒸发,得到粗产物,通过柱色谱(PE:EtOAc=3:1)来纯化所述粗产物,得到化合物1(10g)。LC-MS:386.1[M-Boc]+。1H NMR(300MHz,CDCl3):δ7.43(m,3H),7.21(m,6H),4.15(d,J=10.6Hz,1H),3.99(s,1H),2.83(m,,1H),2.70(dd,J=13.8,6.8Hz,1H),2.26(m,2H),1.74(s,6H),1.63(s,3H),1.27(m,9H)。
用氩气冲洗钐粉末(50g,330μmol)(20分钟)。加入无水THF(1.5L),且用氩气使所得悬浮液鼓泡(15分钟)。加入碘(70g,270mmol),且再次用氩气冲洗混合物(10分钟)。用铝箔覆盖混合物,且在65℃下加热过夜,随后使其冷却到室温。密封化合物1(7g,14.4mmol)于THF(200mL)和水(100mL)的溶液且用氩气冲洗(10分钟),冷却到-70℃,用氩气冲洗(10分钟),冷却到-70℃,且用氩气冲洗(30分钟)。随后借助于针筒向经冷却的溶液加入钐粉末溶液(1.5L),且在室温下搅拌2小时。蒸发溶液,将残余物溶解于EtOAc(200mL)中,用酒石酸溶液(10%,150mL)洗涤,经无水Na2SO4干燥,浓缩且通过柱色谱(PE:EtOAc=0到30%,加入有0.05%AcOH)来纯化,得到呈灰白色固体状的标题化合物(2.6g)。LC-MS:332.0[M-Boc]+。1H-NMR(CD3OD,300Hz):δ7.29(m,8H),3.96(s,1H),3.62(m,2H),2.81(m,1H),2.68(m,1H),1.89(m,1H),1.73(m,1H),1.31(m,7H),1.23(m,5H)。
制备12:(2S,4R)-4-氨基-5-(2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸
在DMF(0.2mL)中将(2S,4R)-4-叔丁氧基羰基氨基-5-(2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(114mg,265μmol)与DIPEA(3当量)组合,得到标题化合物。
制备13:(2S,4R)-5-(4-溴苯基)-4-叔丁氧基羰基氨基)-2-(羟甲基)-2-甲基戊酸
向烘箱干燥的烧瓶中加入钐粉末(32g,210mmol),且密封所述烧瓶且用氩气冲洗20分钟。加入无水THF(800mL),且用氩气使所得悬浮液鼓泡15分钟。加入碘(44.8g,176mmol),且再次用氩气冲洗烧瓶10分钟。覆盖烧瓶且在65℃下加热,随后使其冷却到室温。所得SmI2溶液直接用于下一步骤。
密封[(R)-1-(4-溴苯甲基)-2-(2,2,5-三甲基-4,6-二氧代-[1,3]二噁烷-5-基)乙基]氨基甲酸叔丁酯(4g,8.5mmol)于THF(200mL)和水(100mL)中的溶液且用氩气冲洗10分钟,随后冷却到-70℃,且用氩气再冲洗10分钟,随后再次冷却到-70℃,且用氩气再冲洗30分钟。随后加入SmI2溶液(800mL),且在室温下搅拌所得溶液2小时。蒸发溶液,用EtOAc(200mL)稀释,用酒石酸溶液(10%,150mL)洗涤,干燥,浓缩,且通过柱色谱(PE:EA=0到30%,加入有0.05%乙酸)来纯化,得到呈灰白色固体状的标题化合物(1.7g)。LC-MS:[M-Boc]+:316。1H NMR(300MHz,CD3OD):δ7.36(m,2H),7.12(m,2H),3.97(s,1H),3.60(m,2H),2.6~2.7(m,2H),1.69~1.81(m,2H),1.15~1.37(m,12H)。
制备14:(2S,4R)-5-(4-溴苯基)-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊酸
将(2S,4R)-5-(4-溴苯基)-4-叔丁氧基羰基氨基)-2-羟甲基)-2-甲基戊酸(1.0g,2.4mmol)与MeCN(20mL)组合。加入4N HCl的二噁烷溶液(1.8mL,7.2mmol)。搅拌所得混合物30分钟,随后在减压下浓缩。
在DMF(2mL)中组合1H-[1,2,3]三唑-4-甲酸(272mg,2.4mmol)和HATU(959mg,2.5mmol),且搅拌10分钟。加入DIPEA(1.3mL,7.2mmol)和含化合物1的DMF(2mL),且搅拌所得混合物30分钟,随后浓缩。通过反相色谱(20%-100%MeCN/水)来纯化残余物,得到标题化合物(287mg)。
制备15:(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸乙酯(化合物2)和
(2S,4R)-4-叔丁氧基羰基氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸乙酯(化合物3)
将(2S,4R)-5-(4-溴苯基)-4-((叔丁氧基羰基)氨基)-2-(羟甲基)-2-甲基戊酸(1.3mg,3.1mmol)与5-氯-2-氟苯基硼酸(708mg,4.1mmol)、碳酸钠(993mg,9.4mmol)、水(0.2mL)和二噁烷(1.5mL)组合。密封反应容器,通过真空来移除空气,且用氮气吹扫容器。快速加入四(三苯膦)钯(0)(541mg,468μmol),且通过真空来移除空气。在90℃下加热混合物持续45分钟。用1N HCl/水将混合物酸化到pH约4,随后用EtOAc萃取。移除溶剂,且将残余物溶解于AcOH中,且通过反相色谱来纯化,得到化合物1。
将化合物1(1.0g,2.1mmol)溶解于EtOH(4mL)和4N HCl的二噁烷溶液(4mL)中,且在60℃下搅拌3小时。蒸发溶剂,得到粗化合物2,所述化合物直接用于进行下一步骤。
将化合物2(800mg,2.0mmol)溶解于DCM和(BOC)2O(472μl,2.0mmol)中,继而加入Et3N(566μL,4.1mmol)和DMAP(1片)。搅拌所得混合物3小时。移除溶剂,且用DCM湿磨粗产物且过滤,得到化合物3(800g),所述化合物不经进一步纯化即使用。
制备16:(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸
通过使(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸乙酯脱去保护基来制备标题化合物。
制备17:(2S,4R)-5-联苯-4-基-4-叔丁氧基羰基氨基-2-羟甲基-2-甲基戊酸(P
2
=BOC)和
(2S,4R)-4-氨基-5-联苯-4-基-2-羟甲基-2-甲基戊酸(P
2
已移除)
在氮气下吹扫蒸馏水(140mL)30分钟,随后导入含有0.1M二碘化钐的THF溶液(800mL)的容器中,注意不允许任何空气接触溶液。在维持氮气气氛的同时,借助于导管加入[(R)-2-联苯-4-基-1-(2,2,5-三甲基-4,6-二氧代-1,3-二噁烷(dioxinan)-5-基甲基)乙基]氨基甲酸叔丁酯(3.7g,8.0mmol,1.0当量)和THF(100mL)的脱气溶液。搅拌所得混合物15分钟,随后暴露于空气中。加入饱和NaCl水溶液(12mL)、10%柠檬酸(6mL)和EtOAc(30mL)。搅拌混合物5分钟,随后萃取两层。经Na2SO4干燥有机层,且在真空下浓缩。通过色谱(330g金柱,50%EtOAc(含0.5%AcOH)/乙醚梯度)来纯化粗产物,得到经BOC保护的酸(P2=BOC)(1.4g)。将经BOC保护的酸溶解于MeCN(10mL)中,继而加入4N HCl的二噁烷溶液(10mL)。蒸发溶剂,且使产物与甲苯(2×)共沸,得到酸。(P2已移除)(1.0g)。
制备18:(2S,4R)-4-氨基-5-联苯-4-基-2-甲氧基甲基-2-甲基戊酸乙酯
将(2S,4R)-5-联苯-4-基-4-叔丁氧基羰基氨基-2-羟甲基-2-甲基戊酸乙酯(100mg,226μmol)和硫酸氢四丁基铵(15mg,45μmol)与DCM(1mL)和NaOH(159μL,1.6mmol)组合。加入硫酸二甲酯(114mg,906μmol),且密封反应容器且剧烈搅拌过夜。随后在减压下浓缩混合物,且将残余物溶解于AcOH中,且通过反相色谱(30%-100%MeCN/水)来纯化,得到化合物1(30mg)。
将化合物1(30mg,66μmol)与MeCN(1mL)和4N HCl的二噁烷溶液(0.3mL)组合,且搅拌10分钟,随后在减压下浓缩,得到标题化合物(23mg)。
制备19:(2S,4R)-4-叔丁氧基羰基氨基-5-(3'-氯联苯-4-基)-2-羟甲基-2-甲基戊酸乙酯
将(2S,4R)-4-叔丁氧基羰基氨基-5-(3'-氯联苯-4-基)-2-羟甲基-2-甲基戊酸(860mg,1.9mmol)溶解于EtOH(4mL)和4N HCl的二噁烷溶液(4mL)中,且在60℃下搅拌3小时。蒸发溶剂,且粗化合物1用于下一步骤。
将化合物1(722mg,1.9mmol)溶解于DCM和(BOC)2O(446μL,1.9mmol)中。加入Et3N(535μL,3.8mmol)和DMAP(1片),且搅拌所得混合物3小时。蒸发溶剂且纯化残余物(正相色谱0%-60%EtOAc/己烷),得到标题化合物(800mg)。
制备20:(2S,4R)-4-氨基-5-(3'-氯联苯-4-基)-2-甲氧基甲基-2-甲基戊酸乙酯
将(2S,4R)-4-叔丁氧基羰基氨基-5-(3'-氯联苯-4-基)-2-羟甲基-2-甲基戊酸乙酯(100mg,226μmol)和硫酸氢四丁基铵(15mg,45μmol)与DCM(1mL)和NaOH(159μL,1.6mmol)组合。加入硫酸二甲酯(114mg,906μmol),且密封反应容器且剧烈搅拌过夜。随后在减压下浓缩混合物,且将残余物溶解于AcOH中,且通过反相色谱(30%-100%MeCN/水)来纯化,得到化合物1(32mg)。
将化合物1(32mg,66μmol)与MeCN(1mL)和4N HCl的二噁烷溶液(0.3mL)组合,且搅拌10分钟,随后在减压下浓缩,得到标题化合物(26mg)。
制备21:(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-甲氧基甲基-2-甲基戊酸乙酯
将(2S,4R)-4-叔丁氧基羰基氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基-戊酸乙酯(415mg,840μmol)和硫酸氢四丁基铵(57mg,168μmol)与DCM(1mL)和NaOH(588μL,5.9mmol)组合。加入硫酸二甲酯(424mg,3.4mmol),且密封反应容器且剧烈搅拌过夜。用DCM和水萃取混合物,纯化(正相色谱;0-60EtOAc:己烷),且在减压下浓缩,得到化合物1(220mg)。
将化合物1(88mg,173μmol)与MeCN(1mL)和4N HCl的二噁烷溶液(0.3mL)组合,且搅拌10分钟,随后在减压下浓缩,得到标题化合物(34mg)。
制备22:(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-乙氧基甲基-2-甲基戊酸乙酯
将(2S,4R)-4-叔丁氧基羰基氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基-戊酸乙酯(415mg,840μmol)和硫酸氢四丁基铵(57mg,168μmol)与DCM(1mL)和NaOH(588μL,5.9mmol)组合。加入硫酸二乙酯(518mg,3.4mmol),且密封反应容器且剧烈搅拌过夜。用DCM和水萃取混合物,纯化(正相色谱;0-60EtOAc:己烷),且在减压下浓缩,得到化合物1(110mg)。
将化合物1(90mg,173μmol)与MeCN(1mL)和4N HCl的二噁烷溶液(0.3mL)组合,且搅拌10分钟,随后在减压下浓缩,得到标题化合物(35.2mg)。
实例1
应了解实例1的化合物可以互变异构体形式存在,且两种形式均由此实例所涵盖。举例来说,实例1A中描绘(2S,4R)-5-联苯-4-基-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)-氨基]戊酸5-叔丁基-2-氧代-[1,3]二氧杂环戊烯-4-基甲酯,但应了解此化合物可以互变异构体形式存在,例如以(2S,4R)-5-联苯-4-基-2-羟甲基-2-甲基-4-[(3H-[1,2,3]三唑-4-羰基)-氨基]-戊酸5-叔丁基-2-氧代-[1,3]二氧杂环戊烯-4-基甲酯形式。实例1B-1J中的化合物同样如此。
1A:(2S,4R)-5-联苯-4-基-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)-氨基]戊酸5- 叔丁基-2-氧代-[1,3]二氧杂环戊烯-4-基甲酯
在DCM(5mL)中将(2S,4R)-5-联苯-4-基-2-甲基-2-(四氢吡喃-2-基氧基甲基)-4-[(1-三苯甲基-1H-1,2,3-三唑-4-羰基)氨基]戊酸(57mg,77μmol)与HOBt(31mg,230μmol)和EDC(41μL,230μmol)组合,且搅拌15分钟。加入DMF(0.7mL,10mmol),且搅拌所得混合物15分钟。加入4-叔丁基-5-羟甲基-1,3-二氧杂环戊烯-2-酮(40mg,230μmol)和4-甲基吗啉(34μL,0.31mmol),且在室温下搅拌混合物过夜。加入水,且用EtOAc(20mL)萃取混合物,干燥有机层,且蒸发溶剂。监测反应,随后淬灭(含MeCN的1N HCl水溶液)。加入1.2M HCl的MeOH溶液(10-20体积),且搅拌混合物2小时,随后通过制备型HPLC来纯化,得到标题化合物(1.6mg)。MS m/z[M+H]+C30H34N4O7计算值,563.24;实验值563。
1B:(2S,4R)-5-联苯-4-基-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊酸 2,2,3,3,3-五氟丙酯
在DCM(5mL)中将(2S,4R)-5-联苯-4-基-2-甲基-2-(四氢吡喃-2-基氧基甲基)-4-[(1-三苯甲基-1H-1,2,3-三唑-4-羰基)氨基]戊酸(57mg,77μmol)与HOBt(31mg,230μmol)和EDC(41μL,230μmol)组合,且搅拌15分钟。加入DMF(0.7mL,10mmol),且搅拌所得混合物15分钟。加入2,2,3,3,3-五氟-1-丙醇(23.2μL,230μmol)和4-甲基吗啉(34μL,0.31mmol),且在室温下搅拌混合物过夜。加入水,且用EtOAc(20mL)萃取混合物,干燥有机层,且蒸发溶剂。监测反应,随后淬灭(含MeCN的1N HCl水溶液)。加入1.2MHCl的MeOH溶液(10-20体积),且搅拌混合物2小时,随后通过制备型HPLC来纯化,得到标题化合物(1.2mg)。MS m/z[M+H]+C25H25F5N4O4计算值,541.18;实验值541。
1C:(2S,4R)-5-联苯-4-基-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)-氨基]戊酸2,2- 二氟丙酯
在DCM(5mL)中将(2S,4R)-5-联苯-4-基-2-甲基-2-(四氢吡喃-2-基氧基甲基)-4-[(1-三苯甲基-1H-1,2,3-三唑-4-羰基)氨基]戊酸(57mg,77μmol)与HOBt(31mg,230μmol)和EDC(41μL,230μmol)组合,且搅拌15分钟。加入DMF(0.7mL,10mmol),且搅拌所得混合物15分钟。加入2,2-二氟丙醇(22.3mg,230μmol)和4-甲基吗啉(34μL,0.31mmol),且在室温下搅拌混合物过夜。加入水,且用EtOAc(20mL)萃取混合物,干燥有机层,且蒸发溶剂。监测反应,随后淬灭(含MeCN的1N HCl水溶液)。加入1.2M HCl的MeOH溶液(10-20体积),且搅拌混合物2小时,随后通过制备型HPLC来纯化,得到标题化合物(1.4mg)。MS m/z[M+H]+C25H28F2N4O4计算值,487.21;实验值487。
1D:(2S,4R)-2-乙酰氧基甲基-5-联苯-4-基-2-甲基-4-[(3H-[1,2,3]三唑-4-羰基)氨基]戊 酸
在MeCN(0.7mL,10mmol)中将(2S,4R)-5-联苯-4-基-2-甲基-2-(四氢吡喃-2-基氧基甲基)-4-[(1H-1,2,3-三唑-4-羰基)氨基]戊酸(126mg,255μmol)与4M HCl的二噁烷溶液(191μL,765μmol)组合。随后在减压下浓缩混合物,且通过反相色谱纯化残余物。加入DCM(1mL,20mmol)和乙酰氯(24mg,306μmol),继而加入DIPEA(133μL,765μmol)。搅拌所得混合物10分钟。蒸发溶剂,且将残余物溶解于AcOH中,且通过制备型HPLC来纯化,得到标题化合物(5mg)。MS m/z[M+H]+C24H26N4O5计算值,451.19;实验值451。
1E:(2S,4R)-5-联苯-4-基-2-异丁酰氧基甲基-2-甲基-4-[(3H-[1,2,3]三唑-4-羰基)氨基] 戊酸
在MeCN(0.7mL,10mmol)中将(2S,4R)-5-联苯-4-基-2-甲基-2-(四氢吡喃-2-基氧基甲基)-4-[(1H-1,2,3-三唑-4-羰基)氨基]戊酸(126mg,255μmol)与4M HCl的二噁烷溶液(191μL,765μmol)组合。随后在减压下浓缩混合物,且通过反相色谱纯化残余物。加入DCM(1mL,20mmol)和异丁酰氯(32.6mg,306μmol),继而加入DIPEA(133μL,765μmol)。搅拌所得混合物10分钟。蒸发溶剂,且将残余物溶解于AcOH中,且通过制备型HPLC来纯化,得到标题化合物(5mg)。MS m/z[M+H]+C26H30N4O5计算值,479.22;实验值479。
1F:(2S,4R)-5-联苯-4-基-2-甲基-2-(3-甲基丁酰氧基甲基)-4-[(3H-[1,2,3]三唑-4-羰基) 氨基]戊酸
在MeCN(0.7mL,10mmol)中将(2S,4R)-5-联苯-4-基-2-甲基-2-(四氢吡喃-2-基氧基甲基)-4-[(1H-1,2,3-三唑-4-羰基)氨基]戊酸(126mg,255μmol)与4M HCl的二噁烷溶液(191μL,765μmol)组合。随后在减压下浓缩混合物,且通过反相色谱纯化残余物。加入DCM(1mL,20mmol)和异戊酰氯(39.9mg,306μmol),继而加入DIPEA(133μL,765μmol)。搅拌所得混合物10分钟。蒸发溶剂,且将残余物溶解于AcOH中,且通过制备型HPLC来纯化,得到标题化合物(3mg)。MS m/z[M+H]+C27H32N4O5计算值,493.24;实验值493。
1G:(2S,4R)-5-联苯-4-基-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊酸己酯
将(2S,4R)-5-联苯-4-基-2-甲基-2-(四氢吡喃-2-基氧基甲基)-4-[(1H-1,2,3-三唑-4-羰基)氨基]戊酸(100mg,0.2mmol)与1-己醇(0.3mL,2mmol)和4M HCl的1,4-二噁烷溶液(0.3mL,1mmol)组合。在60℃下搅拌混合物2小时。在减压下浓缩混合物,且通过反相色谱纯化残余物,得到标题化合物(51mg)。MS m/z[M+H]+C28H36N4O4计算值,493.27;实验值493。
1H:(2S,4R)-5-联苯-4-基-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊酸庚酯
将(2S,4R)-5-联苯-4-基-2-甲基-2-(四氢吡喃-2-基氧基甲基)-4-[(1H-1,2,3-三唑-4-羰基)氨基]戊酸(100mg,0.2mmol)与1-庚醇(0.3mL,2mmol)和4M HCl的1,4-二噁烷溶液(0.3mL,1mmol)组合。在60℃下搅拌混合物2小时。在减压下浓缩混合物,且通过反相色谱纯化残余物,得到标题化合物(60mg)。MS m/z[M+H]+C29H38N4O4计算值,507.29;实验值507。
1I:(2S,4R)-5-联苯-4-基-2-乙氧基甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊酸
如本文所述使1H-[1,2,3]三唑-4-甲酸与(2S,4R)-4-氨基-5-联苯-4-基-2-乙氧基甲基-2-甲基戊酸反应,得到标题化合物(0.8mg)。MS m/z[M+H]+C24H28N4O4计算值,437.21;实验值437.2。
1J:(2S,4R)-5-联苯-4-基-2-甲氧基甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊酸
在DMF(0.5mL)中组合3H-[1,2,3]三唑-4-甲酸(3.5mg,31μmol)和HATU(12mg,31μmol),且搅拌5分钟。加入(2S,4R)-4-氨基-5-联苯-4-基-2-甲氧基甲基-2-甲基戊酸乙酯(11mg,31μmol)和DIPEA(16μL,93μmol)于DMF(0.5mL)中的溶液,且搅拌所得混合物20分钟,随后在减压下浓缩。
将残余物与THF(0.6mL)和NaOH(124μL,124μmol)组合,且在60℃下搅拌2小时,随后在减压下浓缩。将残余物溶解于AcOH中,且通过制备型HPLC来纯化化合物,得到标题化合物(1mg)。MS m/z[M+H]+C23H26N4O4计算值,423.20;实验值423.2。
实例2
应了解实例2的化合物可以互变异构体形式存在,且两种形式均由此实例所涵盖。举例来说,实例2A中描绘(2S,4R)-2-羟甲基-5-(2'-甲氧基联苯-4-基)-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊酸,但应了解此化合物可以互变异构体形式存在,例如以(2S,4R)-2-羟甲基-5-(2'-甲氧基联苯-4-基)-2-甲基-4-[(3H-[1,2,3]三唑-4-羰基)氨基]戊酸形式。实例2B-2S中的化合物也如此。
2A:(2S,4R)-2-羟甲基-5-(2'-甲氧基联苯-4-基)-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨 基]戊酸
将(2S,4R)-5-(4-溴苯基)-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊酸(38mg,92μmol)与2-甲氧苯基硼酸(28.1mg,185μmol)、碳酸钠(29.4mg,277μmol)、水(0.2mL)和二噁烷(1.5mL)组合。密封反应容器,通过真空来移除空气,且用氮气吹扫容器。快速加入四(三苯膦)钯(0)(21.4mg,18μmol),且通过真空来移除空气。在90℃下加热混合物持续45分钟。将混合物酸化到pH约3且过滤,且浓缩溶剂合物。将残余物溶解于AcOH(0.7mL)中,且通过制备型HPLC来纯化,得到标题化合物(12.5mg)。MSm/z[M+H]+C23H26N4O5计算值,439.19;实验值439.2。
2B:(2S,4R)-5-(2'-氯联苯-4-基)-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊 酸
将(2S,4R)-5-(4-溴苯基)-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊酸(38mg,92μmol)与2-氯苯基硼酸(28.9mg,185μmol)、碳酸钠(29.4mg,277μmol)、水(0.2mL)和二噁烷(1.5mL)组合。密封反应容器,通过真空来移除空气,且用氮气吹扫容器。快速加入四(三苯膦)钯(0)(21.4mg,18μmol),且通过真空来移除空气。在90℃下加热混合物持续45分钟。将混合物酸化到pH约3且过滤,且浓缩溶剂合物。将残余物溶解于AcOH(0.7mL)中,且通过制备型HPLC来纯化,得到标题化合物(18.2mg)。MS m/z[M+H]+C22H23ClN4O4计算值,443.14;实验值443.2。
2C:(2S,4R)-2-羟甲基-2-甲基-5-(2'-甲基联苯-4-基)-4-[(1H-[1,2,3]三唑-4-羰基)氨基] 戊酸
将(2S,4R)-5-(4-溴苯基)-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊酸(38mg,92μmol)与2-甲基苯基硼酸(25.1mg,185μmol)、碳酸钠(29.4mg,277μmol)、水(0.2mL)和二噁烷(1.5mL)组合。密封反应容器,通过真空来移除空气,且用氮气吹扫容器。快速加入四(三苯膦)钯(0)(21.4mg,18μmol),且通过真空来移除空气。在90℃下加热混合物持续45分钟。将混合物酸化到pH约3且过滤,且浓缩溶剂合物。将残余物溶解于AcOH(0.7mL)中,且通过制备型HPLC来纯化,得到标题化合物(13.3mg)。MS m/z[M+H]+C23H26N4O4计算值,423.20;实验值423.2。
2D:(2S,4R)-5-(3'-氯联苯-4-基)-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊 酸
将(2S,4R)-5-(4-溴苯基)-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊酸(38mg,92μmol)与3-氯苯基硼酸(28.9mg,185μmol)、碳酸钠(29.4mg,277μmol)、水(0.2mL)和二噁烷(1.5mL)组合。密封反应容器,通过真空来移除空气,且用氮气吹扫容器。快速加入四(三苯膦)钯(0)(21.4mg,18μmol),且通过真空来移除空气。在90℃下加热混合物持续45分钟。将混合物酸化到pH约3且过滤,且浓缩溶剂合物。将残余物溶解于AcOH(0.7mL)中,且通过制备型HPLC来纯化,得到标题化合物(8.1mg)。MS m/z[M+H]+C22H23ClN4O4计算值,443.14;实验值443.2。
2E:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨 基]戊酸
(2S,4R)-5-(4-溴苯基)-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊酸(38mg,92μmol)与5-氯-2-氟苯基硼酸(32.2mg,185μmol)、碳酸钠(29.4mg,277μmol)、水(0.2mL)和二噁烷(1.5mL)组合。密封反应容器,通过真空来移除空气,且用氮气吹扫容器。快速加入四(三苯膦)钯(0)(21.4mg,18μmol),且通过真空来移除空气。在90℃下加热混合物持续45分钟。将混合物酸化到pH约3且过滤,且浓缩溶剂合物。将残余物溶解于AcOH(0.7mL)中,且通过制备型HPLC来纯化,得到标题化合物(2mg)。MS m/z[M+H]+C22H22ClFN4O4计算值,461.13;实验值461.2。
2F:(2S,4R)-5-(2',5'-二氯联苯-4-基)-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨 基]戊酸
将(2S,4R)-5-(4-溴苯基)-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊酸(38mg,92μmol)与2,5-二氯苯基硼酸(35.3mg,185μmol)、碳酸钠(29.4mg,277μmol)、水(0.2mL)和二噁烷(1.5mL)组合。密封反应容器,通过真空来移除空气,且用氮气吹扫容器。快速加入四(三苯膦)钯(0)(21.4mg,18μmol),且通过真空来移除空气。在90℃下加热混合物持续45分钟。将混合物酸化到pH约3且过滤,且浓缩溶剂合物。将残余物溶解于AcOH(0.7mL)中,且通过制备型HPLC来纯化,得到标题化合物(4.6mg)。MS m/z[M+H]+C22H22Cl2N4O4计算值,477.10;实验值478.2。
2G:(2S,4R)-5-(5'-氯-2'-甲基联苯-4-基)-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基) 氨基]戊酸
将(2S,4R)-5-(4-溴苯基)-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊酸(38mg,92μmol)与5-氯-2-甲基苯基硼酸(31.4mg,185μmol)、碳酸钠(29.4mg,277μmol)、水(0.2mL)和二噁烷(1.5mL)组合。密封反应容器,通过真空来移除空气,且用氮气吹扫容器。快速加入四(三苯膦)钯(0)(21.4mg,18μmol),且通过真空来移除空气。在90℃下加热混合物持续45分钟。将混合物酸化到pH约3且过滤,且浓缩溶剂合物。将残余物溶解于AcOH(0.7mL)中,且通过制备型HPLC来纯化,得到标题化合物(12.1mg)。MS m/z[M+H]+C23H25ClN4O4计算值,457.16;实验值457.2。
2H:(2S,4R)-5-(3'-氰基联苯-4-基)-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基] 戊酸
将(2S,4R)-5-(4-溴苯基)-4-叔丁氧基羰基氨基-2-羟甲基-2-甲基戊酸(40mg,96μmol)与3-氰基苯基硼酸(14mg,96μmol)、碳酸钠(10.2mg,96μmol)、水(0.5mL)和二噁烷(2mL)组合。密封反应容器,通过真空来移除空气,且用氮气吹扫容器。快速加入四(三苯膦)钯(0)(11mg,9.6μmol),通过真空来移除空气,且用氮气吹扫容器。在90℃下加热混合物持续45分钟。过滤混合物,且浓缩溶剂合物。将残余物溶解于AcOH中,且通过反相色谱来纯化,得到化合物1(30mg)。
将化合物1(30mg,68μmol)与MeCN(1mL)和4M HCl的1,4-二噁烷溶液(103μL,410μmol)组合,且搅拌10分钟。随后在减压下浓缩混合物,得到化合物2(27mg)。
在DMF(0.5mL)中将3H-[1,2,3]三唑-4-甲酸(9.1mg,80μmol)与HATU(30mg,80μmol)组合,且搅拌5分钟。加入化合物2(27mg,80μmol),继而加入DIPEA(42μL,240μmol),且搅拌所得混合物30分钟。蒸发溶剂,且将残余物溶解于AcOH中,且通过反相色谱来纯化,得到标题化合物(3mg)。MS m/z[M+H]+C23H23N5O4计算值,434.18;实验值434。
2I:(2S,4R)-2-羟甲基-2-甲基-5-(3'-甲基联苯-4-基)-4-[(1H-[1,2,3]三唑-4-羰基)氨基] 戊酸
将(2S,4R)-5-(4-溴苯基)-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊酸(38mg,92μmol)与3-甲基苯基硼酸(25.1mg,185μmol)、碳酸钠(29.4mg,277μmol)、水(0.2mL)和二噁烷(1.5mL)组合。密封反应容器,通过真空来移除空气,且用氮气吹扫容器。快速加入四(三苯膦)钯(0)(21.4mg,18μmol),且通过真空来移除空气。在90℃下加热混合物持续45分钟。将混合物酸化到pH约3且过滤,且浓缩溶剂合物。将残余物溶解于AcOH(0.7mL)中,且通过制备型HPLC来纯化,得到标题化合物(10mg)。
2J:(2S,4R)-5-(3'-氯联苯-4-基)-2-甲氧基甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基] 戊酸
在DMF(0.5mL)中组合3H-[1,2,3]三唑-4-甲酸(3.5mg,31μmol)和HATU(12mg,31μmol),且搅拌5分钟。加入(2S,4R)-4-氨基-5-(3'-氯联苯-4-基)-2-甲氧基甲基-2-甲基戊酸乙酯(12mg,31μmol)和DIPEA(16μL,93μmol)于DMF(0.5mL)中的溶液,且搅拌所得混合物20分钟,随后在减压下浓缩。
将残余物与THF(0.6mL)和NaOH(124μL,124μmol)组合,且在60℃下搅拌2小时,随后在减压下浓缩。将残余物溶解于AcOH中,且通过反相色谱来纯化,得到标题化合物(4.0mg)。MS m/z[M+H]+C23H25ClN4O4计算值,457.16;实验值457.2。
2K:(2S,4R)-5-(3'-氯联苯-4-基)-2-乙氧基甲基-2-甲基-4-[(3H-[1,2,3]三唑-4-羰基)氨 基]戊酸
向瓶中加入(2S,4R)-4-叔丁氧基羰基氨基-5-(3'-氯联苯-4-基)-2-羟甲基-2-甲基戊酸乙酯(400mg,840μmol)、硫酸氢四丁基铵(57mg,168μmol)、DCM(1mL)和NaOH(588μL,5.9mmol),继而加入硫酸二乙酯(518mg,3.4mmol)。将反应容器加盖,且剧烈搅拌过夜。用DCM和水萃取混合物,纯化(正相色谱0%-60%EtOAc:己烷),随后在减压下浓缩,得到化合物1(180mg)。
将含化合物1(87mg,173μmol)的MeCN(1mL)与4N HCl的二噁烷溶液(0.3mL)中组合。搅拌混合物10分钟,随后在减压下浓缩,得到化合物2。
在DMF(0.5mL)中将化合物2(33.7mg,83μmol)与HATU(38.0mg,100μmol)、3H-[1,2,3]三唑-4-甲酸(12.3mg,108μmol)组合。加入DIPEA(43.7μL,250μmol),且搅拌混合物2小时。加入EtOAc,继而加入饱和NH4Cl水溶液。搅拌混合物10分钟,随后在减压下浓缩,得到化合物3。
将化合物3(40.7mg,82μmol)与THF(0.6mL)和NaOH(326μL,326μmol)和几滴MeOH组合。在60℃下搅拌所得混合物2小时,随后在减压下浓缩。将残余物溶解于AcOH中,且通过反相色谱来纯化,得到标题化合物(12mg)。MS m/z[M+H]+C24H27ClN4O4计算值,471.17;实验值471.2。
2L:(2S,4R)-5-(3'-氯联苯-4-基)-2-(2-羟基乙氧基甲基)-2-甲基-4-[(1H-[1,2,3]三唑-4- 羰基)氨基]戊酸
向瓶中加入(2S,4R)-4-叔丁氧基羰基氨基-5-(3'-氯联苯-4-基)-2-羟甲基-2-甲基戊酸乙酯(400mg,840μmol)、硫酸氢四丁基铵(57mg,168μmol)、DCM(1mL)和NaOH(588μL,5.9mmol),继而加入[1,3,2]二氧硫杂环戊烷2,2-二氧化物(417mg,3.4mmol)。将反应容器加盖,且剧烈搅拌过夜。用DCM和水萃取混合物,纯化(正相色谱0%-60%EtOAc:己烷),随后在减压下浓缩,得到化合物1(90mg)。
将含化合物1(90mg,173μmol)的MeCN(1mL)与4N HCl的二噁烷溶液(0.3mL)组合。搅拌混合物10分钟,随后在减压下浓缩,得到化合物2。
在DMF(0.5mL)中将化合物2(35mg,83μmol)与HATU(38mg,100μmol)、1H-[1,2,3]三唑-4-甲酸(12.3mg,108μmol)组合。加入DIPEA(43.7μL,250μmol),且搅拌混合物2小时。加入EtOAc,继而加入饱和NH4Cl水溶液。搅拌混合物10分钟,随后在减压下浓缩,得到化合物3。
将化合物3(42mg,82μmol)与THF(0.6mL)和NaOH(326μL,326μmol)和几滴MeOH组合。在60℃下搅拌所得混合物2小时,随后在减压下浓缩。将残余物溶解于AcOH中,且通过反相色谱来纯化,得到标题化合物(11mg)。MS m/z[M+H]+C24H27ClN4O5计算值,487.17;实验值487.2。
2M:(2S,4R)-5-(3'-氯联苯-4-基)-2-(3-羟基丙氧基甲基)-2-甲基-4-[(1H-[1,2,3]三唑-4- 羰基)氨基]戊酸
向瓶中加入(2S,4R)-4-叔丁氧基羰基氨基-5-(3'-氯联苯-4-基)-2-羟甲基-2-甲基戊酸乙酯(67mg,140μmol)、硫酸氢四丁基铵(9.5mg,28μmol)、DCM(1mL)和NaOH(98μL,982μmol),继而加入1,3-丙二醇环状硫酸酯(78mg,561μmol)。搅拌混合物过夜,随后用DCM萃取,且纯化(正相色谱0-100%EtOAc:己烷),得到化合物1(7mg)。
将含化合物1(26.3mg,49μmol)的MeCN(0.3mL)与4N HCl的二噁烷溶液(0.3mL)组合。搅拌混合物10分钟,随后在减压下浓缩,得到化合物2。
将化合物2(18mg,47μmol)溶解于DMF(0.3mL)和1H-1,2,3-三唑-4-甲酸(5.3mg,47μmol)中。加入HATU(18mg,47μmol),继而加入DIPEA(25μL,141μmol)。搅拌混合物30分钟,随后在减压下浓缩,得到化合物3,所述化合物不经进一步纯化即使用。
将化合物3(23mg,47μmol)溶解于THF中,且加入NaOH(188μL,188μmol),且在60℃下搅拌混合物过夜。将残余物溶解于AcOH中,且通过制备型HPLC来纯化,得到标题化合物(1.2mg)。MS m/z[M+H]+C25H29ClN4O5计算值,501.18;实验值502.2。
2N:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-甲氧基甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰 基)氨基]戊酸
向瓶中加入(2S,4R)-4-叔丁氧基羰基氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸乙酯(82mg,166μmol)、硫酸氢四丁基铵(11mg,33μmol)、DCM(1mL)和NaOH(116μL,1.2mmol),继而加入硫酸二甲酯(84mg,664mmol)。将反应容器加盖,且剧烈搅拌过夜。用DCM萃取混合物,且在减压下浓缩。将残余物溶解于AcOH中,且通过反相色谱(30%-100%MeCN/水)来纯化,得到化合物1(30mg)。
将含化合物1(84mg,166μmol)的MeCN(1mL)与4N HCl的二噁烷溶液(0.3mL)组合。搅拌混合物10分钟,随后在减压下浓缩,得到化合物2。
将3H-[1,2,3]三唑-4-甲酸(21mg,183μmol)与HATU(69mg,183μmol)(在DMF(0.5mL)中)、化合物2(68mg,166μmol)和DIPEA(87μL,498μmol)组合。搅拌所得混合物20分钟,随后在减压下浓缩。纯化(正相色谱0%-80%EtOAc:己烷)残余物,得到化合物3。
将化合物3(65mg,129μmol)与THF(0.6mL)和NaOH(516μL,516μmol)组合。在60℃下搅拌所得混合物2小时。加入少量NaOH和MeOH,且搅拌混合物过夜。用浓HCl将混合物酸化到pH约4,随后在减压下浓缩。将残余物溶解于AcOH中,且通过制备型HPLC来纯化,得到标题化合物(35mg)。MS m/z[M+H]+C23H24ClFN4O4计算值,475.15;实验值475.2。
2O:(2S,4R)-5-(5'-氯-2'-氟-联苯-4-基)-2-乙氧基甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰 基)氨基]戊酸
向瓶中加入(2S,4R)-4-叔丁氧基羰基氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸乙酯(415mg,840μmol)、硫酸氢四丁基铵(57mg,168μmol)、DCM(1mL)和NaOH(588μL,5.9mmol),继而加入硫酸二乙酯(518mg,3.4mmol)。将反应容器加盖,且剧烈搅拌过夜。用DCM和水萃取混合物,纯化(正相色谱0%-60%EtOAc:己烷),随后在减压下浓缩,得到化合物1(110mg)。
将含化合物1(90mg,173μmol)的MeCN(1mL)与4N HCl的二噁烷溶液(0.3mL)组合。搅拌混合物10分钟,随后在减压下浓缩,得到化合物2。
在DMF(0.5mL)中将化合物2(35.2mg,83μmol)与HATU(38.0mg,100μmol)、3H-[1,2,3]三唑-4-甲酸(12.3mg,108μmol)组合。加入DIPEA(43.7μL,250μmol),且搅拌混合物2小时。加入EtOAc,继而加入饱和NH4Cl水溶液。搅拌混合物10分钟,随后在减压下浓缩,得到化合物3。
将化合物3(42.2mg,82μmol)与THF(0.6mL)和NaOH(326μL,326μmol)和几滴MeOH组合。在60℃下搅拌所得混合物2小时,随后在减压下浓缩。将残余物溶解于AcOH中,且通过反相色谱来纯化,得到标题化合物(23mg)。MS m/z[M+H]+C24H26ClFN4O4计算值,489.16;实验值489.2。
2P:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-(3-羟基丙氧基甲基)-2-甲基-4-[(3H-[1,2,3]三 唑-4-羰基)氨基]戊酸
也制备标题化合物(4mg)。MS m/z[M+H]+C25H28ClFN4O5计算值,519.17;实验值519。
2Q:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-甲基-2-戊氧基甲基-4-[(3H-[1,2,3]三唑-4-羰 基)氨基]戊酸
也制备标题化合物(6mg)。MS m/z[M+H]+C27H32ClFN4O4计算值,531.21;实验值531。
2R:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-异丙氧基甲基-2-甲基-4-[(3H-[1,2,3]三唑-4- 羰基)氨基]戊酸
也制备标题化合物(7mg)。MS m/z[M+H]+C25H28ClFN4O4计算值,503.18;实验值503。
2S:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-(2-羟基乙氧基甲基)-2-甲基-4-[(3H-[1,2,3]三 唑-4-羰基)氨基]戊酸
也制备标题化合物(4mg)。MS m/z[M+H]+C24H24FN7O2计算值,462.20;实验值462.2。
实例3
应了解实例3的化合物可以互变异构体形式存在,且两种形式均由此实例所涵盖。举例来说,实例3A中描绘(2S,4R)-5-(3'-氟联苯-4-基)-2-羟甲基-2-甲基-4-[(3H-[1,2,3]三唑-4-羰基)氨基]戊酸,但应了解此化合物可以互变异构体形式存在,例如以(2S,4R)-5-(3'-氟联苯-4-基)-2-羟甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)氨基]戊酸形式。实例3B中的化合物也如此。
3A:(2S,4R)-5-(3'-氟联苯-4-基)-2-羟甲基-2-甲基-4-[(3H-[1,2,3]三唑-4-羰基)氨基]戊 酸
在DMF(0.2mL)中将1,2,3-三唑-4-甲酸(27.3mg,241μmol)与EDC(42.7μL,241μmol)、4-甲基吗啉(1当量)和HOBt(32.6mg,241μmol)组合。在室温下搅拌所得混合物5分钟。加入(2S,4R)-4-氨基-5-(3'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(80mg,240μmol)和4-甲基吗啉(53.1μL,483μmol)于DMF(0.3mL)中的溶液,且搅拌所得混合物15分钟。用ACOH淬灭反应,且通过制备型HPLC来纯化产物,且经冻干,得到标题化合物(30mg)。MS m/z[M+H]+C22H23FN4O4计算值,427.17;实验值427.2。
3B:(2S,4R)-5-(2'-氟联苯-4-基)-2-羟甲基-2-甲基-4-[(3H-[1,2,3]三唑-4-羰基)氨基]戊 酸
在DMF(0.2mL)中将1,2,3-三唑-4-甲酸(30mg,260μmol)与DIPEA(92.4μL,531μmol)和HATU(101mg,265μmol)组合。在室温下搅拌所得混合物5分钟。加入(2S,4R)-4-叔丁氧基羰基氨基-5-(2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(114mg,265μmol)和DIPEA(3当量)于DMF(0.2mL)中的溶液,且搅拌所得混合物15分钟。用ACOH淬灭反应,且通过制备型HPLC来纯化产物,且经冻干,得到标题化合物(16mg)。MS m/z[M+H]+C22H23FN4O4计算值,427.17;实验值427.2。
实例4
4A:(2S,4R)-5-(2'-氟联苯-4-基)-2-羟甲基-4-[(1-羟基-1H-[1,2,3]三唑-4-羰基)氨基]-2- 甲基戊酸
在DMF(0.2mL)中将1-羟基-1H-1,2,3-三唑-4-甲酸(15mg,116μmol)与DIPEA(40.5μL,232μmol)和HATU(44.2mg,116μmol)组合。在室温下搅拌所得混合物5分钟。加入(2S,4R)-4-氨基-5-(2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(38.5mg,166μmol)和DIPEA(3当量)于DMF(0.2mL)中的溶液,且搅拌所得混合物15分钟。用AcOH淬灭反应,且通过制备型HPLC来纯化产物,且经冻干,得到标题化合物(8mg)。MS m/z[M+H]+C22H23FN4O5计算值,443.17;实验值443.2。
4B:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-4-[(1-甲氧基-1H-[1,2,3]三唑-4-羰基) 氨基]-2-甲基戊酸
在DMF(1mL)中组合1-甲氧基-1H-[1,2,3]三唑-4-甲酸(4.3mg,30μmol)和HATU(11.4mg,30μmol),且在室温下搅拌15分钟。加入(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(10mg,27μmol)和DIPEA(14μL,82μmol),且在室温下搅拌所得混合物15分钟。在真空中移除溶剂,且通过制备型HPLC纯化残余物,得到标题化合物(1.1mg)。MS m/z[M+H]+C23H24ClFN4O5计算值,491.14;实验值491.2。
4C:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-4-[(1-乙氧基-1H-[1,2,3]三唑-4-羰基)-氨基]-2- 羟甲基-2-甲基戊酸
在DMF(1mL)中组合1-乙氧基-1H-[1,2,3]三唑-4-甲酸(4.7mg,30μmol)和HATU(11.4mg,30μmol),且在室温下搅拌15分钟。加入(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(10mg,27μmol)和DIPEA(14μL,82μmol),且在室温下搅拌所得混合物15分钟。在真空中移除溶剂,且通过制备型HPLC纯化残余物,得到标题化合物(2mg)。MS m/z[M+H]+C24H26ClFN4O5计算值,505.16;实验值505.1。
实例5
5A:(2S,4R)-5-(2'-氟联苯-4-基)-2-羟甲基-2-甲基-4-[(2-氧代-2,3-二氢噁唑-4-羰基)氨 基]戊酸
组合THF(1mL,10mmol)、2-氧代-2,3-二氢噁唑-4-甲酸乙酯(12mg,76.4μmol)和1M NaOH水溶液(229μL,229μmol),且搅拌直到完成。用1N HCl将混合物酸化到pH约5,在真空中蒸发溶剂,且将产物在甲苯中共沸,且在真空中干燥。向其中加入DIPEA(26.6μL,153μmol)和HATU(29.0mg,76.4μmol)于DMF(0.2mL)中的溶液,且在室温下搅拌所得混合物5分钟。加入(2S,4R)-4-氨基-5-(2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(25.3mg,76.4μmol),且搅拌所得混合物15分钟。用EtOAc和饱和NH4Cl淬灭反应。萃取产物且干燥。加入AcOH,且通过制备型HPLC来纯化产物,得到标题化合物(2.5mg)。MS m/z[M+H]+C23H23FN2O6计算值,443.15;实验值443.2。
5B:(2S,4R)-5-(2'-氟联苯-4-基)-2-羟甲基-2-甲基-4-[(2-氧代-2,3-二氢噁唑-5-羰基)氨 基]戊酸
组合THF(1mL,10mmol)、2-氧代-2,3-二氢噁唑-5-甲酸乙酯(12mg,76.4μmol)和1M NaOH水溶液(229μL,229μmol),且搅拌直到完成。用1N HCl将混合物酸化到pH约5,在真空中蒸发溶剂,且将产物在甲苯中共沸,且在真空中干燥。向其中加入DIPEA(26.6μL,153μmol)和HATU(29.0mg,76.4μmol)于DMF(0.2mL)中的溶液,且在室温下搅拌所得混合物5分钟。加入(2S,4R)-4-氨基-5-(2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(25.3mg,76.4μmol),且搅拌所得混合物15分钟。用EtOAc和饱和NH4Cl淬灭反应。萃取产物且干燥。加入AcOH,且通过制备型HPLC来纯化产物,得到标题化合物(5mg)。MS m/z[M+H]+C23H23FN2O6计算值,443.15;实验值443.2。
5C:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基-4-[(2-氧代-2,3-二氢-噁唑-4- 羰基)氨基]戊酸
在DMF(0.2mL)中组合2-氧代-2,3-二氢噁唑-4-甲酸(7mg,55μmol)和HATU(20.8mg,55μmol),且使其在室温下静置10分钟。加入含(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(20mg,55μmol)的DMF和DIPEA(28.6μL,164μmol),且在室温下搅拌所得混合物20分钟。在减压下浓缩混合物,且将残余物溶解于AcOH中,通过制备型HPLC来纯化,得到标题化合物(0.6mg)。MS m/z[M+H]+C23H22ClFN2O6计算值,477.12;实验值477.2。
5D:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基-4-[(2-氧代-2,3-二氢-噁唑-5- 羰基)氨基]戊酸
在DMF(0.3mL)中组合2-氧代-2,3-二氢噁唑-5-甲酸(7.1mg,55μmol)和HATU(21mg,55μmol),且在室温下搅拌5分钟。加入含(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(20mg,55μmol)的DMF(0.5mL)和DIPEA(29μL,164μmol),且在室温下搅拌所得混合物10分钟。在减压下浓缩混合物,且将残余物溶解于AcOH中,通过制备型HPLC来纯化,得到标题化合物(3mg)。MS m/z[M+H]+C23H22ClFN2O6计算值,477.12;实验值477。
实例6
6A:(2S,4R)-5-(3'-氯联苯-4-基)-2-羟甲基-4-[(3-甲氧基异噁唑-5-羰基)氨基]-2-甲基戊 酸
将3-甲氧基异噁唑-5-甲酸(9mg,32μmol)与HATU(12mg,32μmol)和DMF(0.2mL)组合,且搅拌所得混合物5分钟。加入DIPEA(17μL,96μmol)和预先溶解于DMF中的(2S,4R)-4-氨基-5-(3'-氯联苯-4-基)-2-羟甲基-2-甲基戊酸(79mg,38μmol)和DIPEA(17μL,96μmol),且搅拌所得混合物15分钟,随后浓缩。将残余物溶解于AcOH中,且通过制备型HPLC来纯化,得到标题化合物(2.2mg)。MS m/z[M+H]+C24H25ClN2O6计算值,473.14;实验值473.2。
6B:(2S,4R)-5-(3'-氯联苯-4-基)-4-[(3-甲氧基异噁唑-5-羰基)氨基]-2-甲氧基甲基-2- 甲基戊酸
在DMF(0.5mL)中将3-甲氧基异噁唑-5-甲酸(4.4mg,31μmol)和HATU(12mg,31μmol)组合,且搅拌5分钟。加入(2S,4R)-4-氨基-5-(3'-氯联苯-4-基)-2-甲氧基甲基-2-甲基戊酸乙酯(12mg,31μmol)和DIPEA(16μL,93μmol)于DMF(0.5mL)中的溶液,且搅拌所得混合物20分钟,随后在减压下浓缩。
将残余物与THF(0.6mL)和NaOH(124μL,124μmol)组合,且在60℃下搅拌2小时,随后在减压下浓缩。将残余物溶解于AcOH中,且通过制备型HPLC来纯化化合物,得到标题化合物(1mg)。MS m/z[M+H]+C25H27ClN2O6计算值,487.16;实验值487.2。
6C:(2S,4R)-5-(3'-氯联苯-4-基)-2-乙氧基甲基-4-[(3-甲氧基异噁唑-5-羰基)氨基]-2- 甲基戊酸
如本文所述使3-甲氧基异噁唑-5-甲酸与(2S,4R)-4-氨基-5-(3'-氯联苯-4-基)-2-乙氧基甲基-2-甲基戊酸反应,得到标题化合物(2mg)。MS m/z[M+H]+C26H29ClN2O6计算值,501.17;实验值501.2。
6D:(2S,4R)-5-联苯-4-基-4-[(3-羟基异噁唑-5-羰基)氨基]-2-羟甲基-2-甲基戊酸
在DMF(0.2mL)中组合3-羟基-异噁唑-5-甲酸(10.6mg,82μmol)、EDC(14.5μL,82μmol)和HOBt(11.1mg,82μmol),且搅拌5分钟。加入(2S,4R)-4-氨基-5-联苯-4-基-2-羟甲基-2-甲基戊酸(26mg,82μmol),且搅拌所得混合物18小时。用AcOH淬灭反应,且通过制备型HPLC来纯化产物,随后冻干,得到呈TFA盐形式的标题化合物(7mg)。MS m/z[M+H]+C23H24N2O6计算值,425.16;实验值425.4。
6E:(2S,4R)-5-联苯-4-基-4-[(3-羟基异噁唑-5-羰基)氨基]-2-甲氧基甲基-2-甲基戊酸
如本文所述使3-羟基-异噁唑-5-甲酸与(2S,4R)-4-氨基-5-联苯-4-基-2-甲氧基甲基-2-甲基戊酸乙酯反应,得到标题化合物(2.4mg)。MS m/z[M+H]+C24H26N2O6计算值,439.18;实验值439.2。
6F:(2S,4R)-5-联苯-4-基-4-[(3-甲氧基异噁唑-5-羰基)氨基]-2-甲氧基甲基-2-甲基戊 酸
在DMF(0.5mL)中将3-甲氧基异噁唑-5-甲酸(4.4mg,31μmol)和HATU(12mg,31μmol)组合,且搅拌5分钟。加入(2S,4R)-4-氨基-5-联苯-4-基-2-甲氧基甲基-2-甲基戊酸乙酯(11mg,31μmol)和DIPEA(16μL,93μmol)于DMF(0.5mL)中的溶液,且搅拌所得混合物20分钟,随后在减压下浓缩。
将残余物与THF(0.6mL)和NaOH(124μL,124μmol)组合,且在60℃下搅拌2小时,随后在减压下浓缩。将残余物溶解于AcOH中,且通过制备型HPLC来纯化化合物,得到标题化合物(1mg)。MS m/z[M+H]+C25H28N2O6计算值,453.19;实验值453。
6G:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-4-[(3-甲氧基异噁唑-5-羰基)氨基]-2- 甲基戊酸
在DMF(0.2mL)中组合3-甲氧基异噁唑-5-甲酸(8mg,55μmol)和HATU(20.8mg,55μmol),且使其在室温下静置10分钟。加入含(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(20mg,55μmol)的DMF和DIPEA(28.6μL,164μmol),且在室温下搅拌所得混合物20分钟。在减压下浓缩混合物,且将残余物溶解于AcOH中,通过制备型HPLC来纯化,得到标题化合物(5.4mg)。MS m/z[M+H]+C24H24ClFN2O6计算值,491.13;实验值491.2。
6H:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-4-[(3-乙基异噁唑-5-羰基)氨基]-2-羟甲基-2-甲 基戊酸
在DMF(0.2mL)中组合3-乙基异噁唑-5-甲酸(8mg,55μmol)和HATU(20.8mg,55μmol),且使其在室温下静置10分钟。加入含(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(20mg,55μmol)的DMF和DIPEA(28.6μL,164μmol),且在室温下搅拌所得混合物20分钟。在减压下浓缩混合物,且将残余物溶解于AcOH中,通过制备型HPLC来纯化,得到标题化合物(3.6mg)。MS m/z[M+H]+C25H26ClFN2O5计算值,489.15;实验值490.2。
6I:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-4-[(3-异丁基异噁唑-5-羰基)氨基]-2- 甲基戊酸
在DMF(0.2mL)中组合3-异丁基异噁唑-5-甲酸(9mg,55μmol)和HATU(20.8mg,55μmol),且使其在室温下静置10分钟。加入含(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(20mg,55μmol)的DMF和DIPEA(28.6μL,164μmol),且在室温下搅拌所得混合物20分钟。在减压下浓缩混合物,且将残余物溶解于AcOH中,通过制备型HPLC来纯化,得到标题化合物(0.3mg)。MS m/z[M+H]+C27H30ClFN2O5计算值,517.18;实验值517.2。
6J:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基-4-[(3-丙基异噁唑-5-羰基)氨基] 戊酸
在DMF(0.2mL)中组合3-丙基异噁唑-5-甲酸(9mg,55μmol)和HATU(20.8mg,55μmol),且使其在室温下静置10分钟。加入含(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(20mg,55μmol)的DMF和DIPEA(28.6μL,164μmol),且在室温下搅拌所得混合物20分钟。在减压下浓缩混合物,且将残余物溶解于AcOH中,通过制备型HPLC来纯化,得到标题化合物(0.5mg)。MS m/z[M+H]+C26H28ClFN2O5计算值,503.17;实验值504.2。
6K:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-4-[(3-羟基异噁唑-5-羰基)氨基]-2-甲氧基甲基 -2-甲基戊酸
在DMF(0.5mL)中将3-羟基-异噁唑-5-甲酸(4μg,0.03μmol)和HATU(11μg,0.03μmol)与(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-甲氧基甲基-2-甲基戊酸乙酯(10μg,0.03μmol)组合,且搅拌5分钟。加入DIPEA(0.01μL,0.07μmol),且搅拌所得混合物20分钟,且蒸发,得到粗化合物1,所述化合物直接用于下一步骤。
将含化合物1(10mg)的THF(1mL)与1N NaOH(0.3mL)组合,且在60℃下搅拌所得混合物3小时。加入AcOH,且纯化(反相)产物,得到标题化合物(1mg)。MS m/z[M+H]+C24H24ClFN2O6计算值,491.13;实验值491。
6L:(2S,4R)-5-(3'-氯联苯-4-基)-2-(2-羟基乙氧基甲基)-4-[(3-羟基异噁唑-5-羰基)氨 基]-2-甲基戊酸
将(2S,4R)-4-叔丁氧基羰基氨基-5-(3'-氯联苯-4-基)-2-羟甲基-2-甲基戊酸乙酯(415mg,840μmol)和硫酸氢四丁基铵(57mg,168μmol)与DCM(1mL)和NaOH(588μL,5.9mmol)组合。加入[1,3,2]二氧硫杂环戊烷2,2-二氧化物(424mg,3.4mmol),且密封反应容器且剧烈搅拌过夜。用DCM和水萃取混合物,随后纯化(正相色谱0%-60%EtOAc/己烷),得到化合物1(90mg)。
将化合物1(90mg,173μmol)与MeCN(1mL)和4N HCl的二噁烷溶液(0.3mL)组合,且搅拌10分钟,随后在减压下浓缩,得到化合物(2)。
组合化合物2(35mg,83μmol)、HATU(38.0mg,100μmol)、3-羟基-异噁唑-5-甲酸(12.3mg,108μmol)和DMF(0.5mL),继而组合DIPEA(43.7μL,250μmol)。搅拌所得混合物2小时。加入EtOAc,随后加入饱和NH4Cl水溶液。随后在减压下浓缩混合物。将残余物与THF(0.6mL)和NaOH(326μL,326μmol)连同几滴MeOH组合,且在60℃下搅拌2小时。随后在减压下浓缩混合物。将残余物溶解于AcOH中,且通过制备型HPLC来纯化,得到标题化合物(8mg)。MS m/z[M+H]+C25H27ClN2O7计算值,503.15;实验值503。
6M:(2S,4R)-5-(3'-氯联苯-4-基)-2-乙氧基甲基-4-[(3-羟基异噁唑-5-羰基)氨基]-2-甲 基戊酸
将(2S,4R)-4-叔丁氧基羰基氨基-5-(3'-氯联苯-4-基)-2-羟甲基-2-甲基戊酸乙酯(415mg,840μmol)和硫酸氢四丁基铵(57mg,168μmol)与DCM(1mL)和NaOH(588μL,5.9mmol)组合。加入硫酸二乙酯(518mg,3.4mmol),且密封反应容器且剧烈搅拌过夜。用DCM和水萃取混合物,随后纯化(正相色谱0%-60%EtOAc/己烷),得到化合物1(180mg)。
将化合物1(87mg,73μmol)与MeCN(1mL)和4N HCl的二噁烷溶液(0.3mL)组合,且搅拌10分钟,随后在减压下浓缩,得到化合物(2)。
组合化合物2(33.7mg,83μmol)、HATU(38.0mg,100μmol)、3-羟基-异噁唑-5-甲酸(12.3mg,108μmol)和DMF(0.5mL),继而组合DIPEA(43.7μL,250μmol)。搅拌所得混合物2小时。加入EtOAc,随后加入饱和NH4Cl水溶液。随后在减压下浓缩混合物。将残余物与THF(0.6mL)和NaOH(326μL,326μmol)连同几滴MeOH组合,且在60℃下搅拌2小时。随后在减压下浓缩混合物。将残余物溶解于AcOH中,且通过制备型HPLC来纯化,得到标题化合物(8mg)。MS m/z[M+H]+C25H27ClN2O6计算值,487.16;实验值486.9。
6N:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-乙氧基甲基-4-[(3-羟基异噁唑-5-羰基)氨 基]-2-甲基戊酸
将(2S,4R)-4-叔丁氧基羰基氨基-5-(5'-氯-2'-氟联苯-4-基)-2-乙氧基甲基-2-甲基戊酸苯甲酯(720mg,1.2mmol)与MeCN(6mL)组合,继而加入4N HCl的二噁烷溶液(5mL)。搅拌混合物10分钟,随后在减压下浓缩,得到化合物1。
将3-羟基异噁唑-5-甲酸(53.3mg,413μmol)与HATU(157mg,413μmol)和DMF(0.5mL)组合,且搅拌所得混合物20分钟。加入N-乙基-N-异丙基丙-2-胺(1当量),且搅拌所得混合物1分钟。随后加入预先溶解于DMF(2mL)中的化合物1(100mg,207μmol)和DIPEA(108μl,620μmol),且搅拌所得混合物过夜,随后在减压下浓缩。随后通过正相色谱来纯化(40%EtOAc/己烷)所述物质,得到化合物2(90mg)。
将化合物2(90mg,151μmol)与溶解于EtOAc(1mL)和AcOH(1mL)中的钯/碳(16.1mg,30μmol)组合。将所得溶液在真空中脱气,且用氢气吹扫。搅拌溶液2小时。移除氢气,且用氮气吹扫溶液。过滤溶液,从滤液移除过量溶剂,且通过反相色谱来纯化残余物,得到标题化合物(60mg)。MS m/z[M+H]+C25H26ClFN2O6计算值,505.15;实验值505。
6O:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-乙氧基甲基-4-[(3-乙基异噁唑-5-羰基)氨 基]-2-甲基戊酸
将(2S,4R)-4-叔丁氧基羰基氨基-5-(5'-氯-2'-氟联苯-4-基)-2-乙氧基甲基-2-甲基戊酸(220mg,445μmol)与MeCN(5mL)组合,接着加入4N HCl的二噁烷溶液(4mL)。将所得混合物搅拌10分钟,接着在减压下浓缩,得到化合物1。
将3-乙基异噁唑-5-甲酸(6.0mg,42μmol)与HATU(16.1mg,42μmol)和DMF(0.5mL)DMF组合,且将所得混合物搅拌10分钟。加入N-乙基-N-异丙基丙-2-胺(1当量),且将所得混合物搅拌1分钟。接着加入预先溶解于DMF(0.5mL)中的化合物1(20mg,51μmol)以及DIPEA(22.2μL,127μmol),将所得混合物搅拌30分钟。接着在减压下浓缩混合物,移除约一半的溶剂。将AcOH加入残余物中,且物质通过制备型HPLC纯化,得到标题化合物(2.5mg)。MS m/z[M+H]+C27H30ClFN2O5计算值,517.18;实验值518.2。
按照前述实例中所述的程序,且代入适当的起始物质和试剂,也可制备下列化合物。
6P:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-4-[(3-羟基异噁唑-5-羰基)氨基]-2-羟甲基-2-甲 基戊酸
6Q:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-4-[(3-乙基异噁唑-5-羰基)氨基]-2-甲氧基甲基 -2-甲基戊酸
实例7
7A:(2S,4R)-5-(3'-氯联苯-4-基)-4-[(5-乙氧基-1H-吡唑-3-羰基)氨基]-2-羟甲基-2-甲基 戊酸
在DMF(0.2mL)中将5-乙氧基-1H-吡唑-3-甲酸(10mg,32μmol)与HATU(12mg,32μmol)组合,且搅拌所得混合物5分钟。加入DIPEA(17μL,96μmol)和预先溶解于DMF中的(2S,4R)-4-氨基-5-(3'-氯联苯-4-基)-2-羟甲基-2-甲基戊酸(79mg,38μmol)和DIPEA(17μL,96μmol),且搅拌所得混合物15分钟,随后浓缩。将残余物溶解于AcOH中,且通过制备型HPLC来纯化,得到呈TFA盐形式的标题化合物(1mg)。MS m/z[M+H]+C25H28ClN3O5计算值,486.17;实验值486.2。
7B:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-4-[(5-乙氧基-1H-吡唑-3-羰基)-氨基]-2-羟甲基 -2-甲基戊酸
在DMF(0.3mL)中将5-乙氧基-1H-吡唑-3-甲酸(8.5mg,55μmol)与HATU(21mg,55μmol)组合,且搅拌所得混合物5分钟。加入DIPEA(29μL,164μmol)和预先溶解于DMF(0.5mL)中的(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(20mg,55μmol)和DIPEA(29μL,164μmol),且搅拌所得混合物10分钟,随后浓缩。将残余物溶解于AcOH中,且通过制备型HPLC来纯化,得到呈TFA盐形式的标题化合物(2mg)。MS m/z[M+H]+C25H27ClFN3O5计算值,504.16;实验值503.9。
7C:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-4-[(5-异丙基-2H-吡唑-3-羰基)氨 基]-2-甲基戊酸
在DMF(0.2mL)中组合5-异丙基-2H-吡唑-3-甲酸(8mg,55μmol)和HATU(20.8mg,55μmol),且使其在室温下静置10分钟。加入含(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(20mg,55μmol)的DMF和DIPEA(28.6μL,164μmol),且在室温下搅拌所得混合物20分钟。在减压下浓缩混合物,且将残余物溶解于AcOH中,通过制备型HPLC来纯化,得到呈TFA盐形式的标题化合物(2mg)。MS m/z[M+H]+C26H29ClFN3O4计算值,502.18;实验值503.2。
7D:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-4-[(5-乙氧基-2H-吡唑-3-羰基)-氨基]-2-甲氧基 甲基-2-甲基戊酸
将含(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-4-[(5-乙氧基-2H-吡唑-3-羰基)氨基]-2-甲氧基甲基-2-甲基戊酸乙酯(11mg)的THF(1mL)与1N NaOH(0.3mL)组合,且在60℃下搅拌所得混合物3小时。加入AcOH,且纯化(反相)产物,得到呈TFA盐形式的标题化合物(4mg)。MS m/z[M+H]+C26H29ClFN3O5计算值,518.18;实验值518。
7E:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-4-[(5-甲氧基-1H-吡唑-3-羰基)氨 基]-2-甲基戊酸
将(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸乙酯(30mg,76μmol)、HATU(29.0mg,0.076mmol)和DIPEA(39.9μl,0.228mmol)与含1H-[1,2,4]三唑-3-甲酸(8.61mg,0.076mmol)的DMF(0.5mL)组合。搅拌所得混合物2小时,随后在减压下浓缩。将残余物与THF(1mL)和NaOH(456μL,456μmol)组合,且在40℃下搅拌2天。用AcOH淬灭反应,且通过制备型HPLC来纯化物质,得到呈TFA盐形式的标题化合物(16.4mg)。MS m/z[M+H]+C24H25ClFN3O5计算值,490.15;实验值490.2。
7F:(2S,4R)-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-4-[(5-异丁基-2H-吡唑-3-羰基)氨基]-2- 甲基戊酸
组合5-异丁基-2H-吡唑-3-甲酸(10.1mg,60μmol)和HATU(22.9mg,60μmol),随后在室温下于DMF(1mL)搅拌15分钟。将(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(20mg,55μmol)和Et3N(38μL,273μmol)预混合在一起,随后加入到反应溶液中。在室温下搅拌所得混合物1小时。在真空中移除溶剂,且通过制备型HPLC纯化残余物,得到呈TFA盐形式的标题化合物(13.3mg)。MS m/z[M+H]+C27H31ClFN3O4计算值,516.20;实验值516.2。
实例8
8A:(2S,4R)-4-[(5-乙酰基-2H-吡唑-3-羰基)氨基]-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基 -2-甲基戊酸
在DMF(0.2mL)中组合5-乙酰基-2H-吡唑-3-甲酸(8mg,55μmol)和HATU(20.8mg,55μmol),且使其在室温下静置10分钟。加入含(2S,4R)-4-氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸(20mg,55μmol)的DMF和DIPEA(28.6μL,164μmol),且在室温下搅拌所得混合物20分钟。在减压下浓缩混合物,且将残余物溶解于AcOH中,通过制备型HPLC来纯化,得到呈TFA盐形式的标题化合物(2.1mg)。MS m/z[M+H]+C25H25ClFN3O5计算值,502.15;实验值503.2。
8B:(2S,4R)-4-[(5-乙酰基-2H-吡唑-3-羰基)氨基]-5-(5'-氯-2'-氟联苯-4-基)-2-甲氧基甲 基-2-甲基戊酸
向瓶中加入(2S,4R)-4-叔丁氧基羰基氨基-5-(5'-氯-2'-氟联苯-4-基)-2-羟甲基-2-甲基戊酸乙酯(415mg,840μmol)、硫酸氢四丁基铵(57mg,168μmol)、DCM(1mL)和NaOH(588μL,5.9mmol),继而加入硫酸二乙酯(518mg,3.4mmol)。将反应容器加盖,且剧烈搅拌过夜。用DCM和水萃取混合物,纯化(正相色谱0%-60%EtOAc:己烷),随后在减压下浓缩,得到化合物1(220mg)。
将含化合物1(88mg,173μmol)的MeCN(1mL)与4N HCl的二噁烷溶液(0.3mL)组合。搅拌混合物10分钟,随后在减压下浓缩,得到化合物2。
将含化合物2(10μg,0.03μmol)的DMF(0.5mL)与HATU(11μg,0.03μmol)和5-乙酰基-2H-吡唑-3-甲酸(4μg,0.03μmol)组合,且搅拌所得混合物5分钟。加入DIPEA(0.01μl,0.07μmol),且搅拌混合物20分钟。蒸发溶剂,得到化合物3,所述化合物不经进一步纯化即使用。
将化合物3(11mg,20μmol)与THF(1mL)和1N NaOH(0.3mL)组合。在60℃下搅拌所得混合物3小时。加入AcOH,且通过反相HPLC来纯化产物,得到呈TFA盐形式的标题化合物(2mg)。MS m/z[M+H]+C26H27ClFN3O5计算值,516.16;实验值516。
8C:(2S,4R)-4-[(5-乙酰基-1H-吡唑-3-羰基)氨基]-5-(5'-氯-2'-氟联苯-4-基)-2-乙氧基甲 基-2-甲基戊酸
将(2S,4R)-4-叔丁氧基羰基氨基-5-(5'-氯-2'-氟联苯-4-基)-2-乙氧基甲基-2-甲基戊酸(220mg,445μmol)与MeCN(5mL)组合,接着加入4N HCl的二噁烷溶液(4mL)。将所得混合物搅拌10分钟,接着在减压下浓缩,得到化合物1。
将5-乙酰基-1H-吡唑-3-甲酸(6.5mg,42μmol)与HATU(16.1mg,42μmol)和DMF(0.5mL)DMF合并,且将所得混合物搅拌10分钟。加入N-乙基-N-异丙基丙-2-胺(1当量),且将所得混合物搅拌1分钟。接着加入预先溶解于DMF(0.5mL)中的化合物1(20mg,51μmol)以及DIPEA(22.2μL,127μmol),将所得混合物搅拌30分钟。接着在减压下浓缩混合物,移除约一半的溶剂。将AcOH加入残余物中,且物质通过制备型HPLC纯化,得到呈TFA盐形式的标题化合物(3.1mg)。MS m/z[M+H]+C27H29ClFN3O5计算值,530.18;实验值531.2。
分析
用于定量抑制剂对人类和大鼠NEP以及人类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。
从大鼠肾提取NEP活性
从成年史泊格多利(Sprague Dawley)大鼠的肾制备大鼠NEP。在冷磷酸盐缓冲盐水(PBS)中洗涤整个肾,且以每一克肾脏5mL缓冲剂的比率在冰冷溶解缓冲液(1%TritonX-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)中培养。使用polytron手持式组织研磨器在冰上使样品均匀化。在3℃下于旋桶式转筒(swinging bucket rotor)中以1000×g将匀浆离心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。随后使样品(15-20mL)于25mL冰冷缓冲液(6%w/v蔗糖,50mM pH 7.5Tris,150mM NaCl,0.06%,TritonX-114)上分层,加热到37℃且持续3-5分钟,且在室温下于旋桶式转筒中以1000×g离心3分钟。吸出上两层,留下含有富集的膜部分的粘稠油状沉淀。加入甘油到50%的浓度,且将样品储存在-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
NEP和重组人类ACE为市售获得的(密西西比州明尼阿波利斯伯乐系统公司(R&DSystems,Minneapolis,MN),,目录号分别为1182-ZN和929-ZN)。NEP和ACE分析中分别使用荧光肽底物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,San Jose,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))。
在384孔白色不透明培养板中,于37℃下,使用在分析缓冲液(NEP:50mM HEPES,pH 7.5,100mM NaCl,0.01%聚乙二醇脱水山梨糖醇单月桂酸酯(Tween-20),10μMZnSO4;ACE:50mM HEPES,pH 7.5,100mM NaCl,0.01%Tween-20,1μM ZnSO4)中浓度为10μM的荧光肽底物进行分析。各别酶以使1μM底物在37℃下20分钟之后发生定量蛋白分解的浓度使用。
在10μM到20pM的浓度范围内分析测试化合物。将测试化合物加入到酶中,且在37℃下孵育30分钟,随后通过加入底物开始反应。在37℃下孵育20分钟之后,通过加入冰乙酸到3.6%(v/v)的最终浓度来终止反应。
在荧光计上用分别设定为320nm和405nm的激发和发射波长读取培养板。通过使用以下方程式(加利福尼亚州圣迭戈图板软件公司(GraphPad Software,Inc.,San Diego,CA))对数据进行非线性回归来获得抑制常数:
v=v0/[1+(I/K')]
其中v为反应速率,v0为不受抑制的反应速率,I为抑制剂浓度,且K'为表观抑制常数。
在此分析中测试其中Ra和Rb为H的式I'化合物,且发现其对人类NEP的pKi值≥9.0。发现下列化合物对人类NEP的pKi值如下:
实例 | pKi |
1A | n.d. |
1B | n.d. |
1C | n.d. |
1D | ≥9.0 |
1E | ≥9.0 |
1F | ≥9.0 |
1G | n.d. |
1H | n.d. |
1I | 8.5-9.0 |
1J | 8.5-9.0 |
2A | 8.5-9.0 |
2B | ≥9.0 |
实例 | pKi |
2C | ≥9.0 |
2D | ≥9.0 |
2E | 8.5-9.0 |
2F | ≥9.0 |
2G | ≥9.0 |
2H | 8.0-8.5 |
2I | n.d. |
2J | 8.5-9.0 |
2K | ≥9.0 |
2L | ≥9.0 |
2M | ≥9.0 |
2N | ≥9.0 |
2O | ≥9.0 |
2P | ≥9.0 |
2Q | 8.5-9.0 |
2R | ≥9.0 |
2S | 8.0-8.5 |
其余化合物未测试(n.d.),这是因为预期其在此体外分析中不具有活性;然而,基于其活性形式的活性,预期相应前药具有体内NEP活性。
在此分析中测试其中Ra为H且Rb为F的式I'化合物(实例3A)和其中Ra为F且Rb为H的式I'化合物(实例3B),且发现其对人类NEP的pKi值≥9.0。基于这些活性形式的活性,预期相应前药化合物具有体内NEP活性。
在此分析中测试Ra为F、Rb为H、R2为H且R7为H的式II化合物(实例4A),且发现其对人类NEP的pKi值≥9.0。基于此活性形式的活性,预期相应前药化合物具有体内NEP活性。还发现下列化合物对人类NEP具有如下pKi值:
实例 | pKi |
4B | ≥9.0 |
4C | ≥9.0 |
在此分析中测试其中Ra为F、Rb为H、R2为H且R7为H的式IIIa化合物(实例5A)和其中Ra为F、Rb为H、R2为H且R7为H的式IIIb化合物(实例5B),且发现其对人类NEP的pKi值≥9.0。基于这些活性形式的活性,预期相应前药化合物具有体内NEP活性。另外,还发现下列化合物对人类NEP具有如下pKi值:
实例 | pKi |
5C | ≥9.0 |
5D | ≥9.0 |
在此分析中测试其中Ra为H、Rb为Cl、R2为H、R3为-OCH3且R7为H的式V化合物(实例6A)和式V'化合物(其中Ra和Rb为H且R3为-OH;实例6D),且发现其对人类NEP的pKi值≥9.0。基于这些活性形式的活性,预期相应前药化合物具有体内NEP活性。另外,还发现下列化合物对人类NEP具有如下pKi值:
实例 | pKi |
6B | 7.0-8.0 |
6C | n.d. |
6E | n.d. |
6F | n.d. |
6G | ≥9.0 |
6H | ≥9.0 |
6I | ≥9.0 |
6J | ≥9.0 |
6K | 8.5-9.0 |
6L | ≥9.0 |
6M | ≥9.0 |
6N | ≥9.0 |
6O | ≥9.0 |
其余化合物在此体外分析中未加以测试,或不展示活性(n.d.),这是因为预期其不具有活性;然而,基于活性形式的活性,预期这些相应前药具有体内NEP活性。
在此分析中测试式VI化合物,且发现其对人类NEP具有如下pKi值:
实例 | pKi |
7A | ≥9.0 |
7B | ≥9.0 |
7C | ≥9.0 |
7D | 8.5-9.0 |
7E | ≥9.0 |
7F | ≥9.0 |
基于这些活性形式的活性,预期相应前药化合物具有体内NEP活性。
在此分析中测试式VII化合物,且发现其对人类NEP具有如下pKi值:
基于此活性形式的活性,预期相应前药化合物具有体内NEP活性。
虽然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,在不偏离本发明的真实精神和范围的情况下,可作出各种变化或可代入等效物。另外,在由适用的专利状况和规定允许的程度上,本文中所引用的所有公开案、专利和专利申请案均以全文引用的方式并入本文中,所述引用的程度如同将各文件个别地以引用的方式并入本文中一般。
Claims (32)
1.一种式I化合物,
其中:
(i)X为且
(a)Ra和Rb为H;R2为H;且R7是选自-CH2CF2CH3、-CH2CF2CF3、-(CH2)5CH3、-(CH2)6CH3和
或R2为-C1-6烷基或-C(O)-C1-6烷基,且R7为H;或
(b)Ra是选自-CH3、-OCH3和Cl,且Rb为H;或Ra是选自H、-CH3、Cl和F,且Rb为Cl;或Ra为H,且Rb是选自-CH3和-CN;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
或
(c)Ra为H,且Rb为F;或Ra为F,且Rb为H;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
或
(ii)X为且
(a)Ra为Cl,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R4是选自-OH、-OCH3、-OCH2CH3和-C1-4烷基;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
或
(b)Ra为F,且Rb为H;R2为H;R4为-OH;且R7是选自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
或
(iii)X为且
(a)Ra为Cl,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
或
(b)Ra为F,且Rb为H;R2为H;且R7是选自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
或
(iv)X为
(a)Ra和Rb为H;R2是选自-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R3是选自-OH、-OCH3、-OCH2CH3和-C1-4烷基;且R7为H;或
(b)Ra是选自Cl和F,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R3是选自-OH、-OCH3、-OCH2CH3和-C1-4烷基;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
或
(v)X为
Ra是选自Cl和F,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R3是选自-OH、-OCH3、-OCH2CH3和-C1-4烷基;R4是选自H、-C1-6烷基和苯基;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
或
(vi)X为
Ra是选自Cl和F,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R4是选自H、-C1-6烷基和苯基;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
或
(vii)X为
Ra是选自Cl和F,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
或
(viii)X为
Ra是选自Cl和F,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
其中各Rc独立地为H或-C1-3烷基;各Rd独立地为H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re独立地为H或-CH3;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IIa或IIb:
3.根据权利要求2所述的化合物,其中Ra和Rb为H;且R2为H;且R7是选自-CH2CF2CH3、-CH2CF2CF3、-(CH2)5CH3、-(CH2)6CH3和
或R2为-C1-6烷基或-C(O)-C1-6烷基,且R7为H。
4.根据权利要求3所述的化合物,其中R2为H,且R7是选自-CH2CF2CH3、-CH2CF2CF3、-(CH2)5CH3、-(CH2)6CH3和
R2是选自-CH3、-CH2CH3、-C(O)CH3、-C(O)CH(CH3)2和-C(O)CH2CH(CH3)2;且R7为H。
5.根据权利要求2所述的化合物,其中Ra是选自-CH3、-OCH3和Cl,且Rb为H;或Ra是选自H、-CH3、Cl和F,且Rb为Cl;或Ra为H,且Rb是选自-CH3和-CN;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
6.根据权利要求5所述的化合物,其中Ra是选自-CH3、-OCH3和Cl,且Rb为H;或Ra是选自H、-CH3、Cl和F,且Rb为Cl;或Ra为H,且Rb是选自-CH3和-CN;R2是选自H、-C1-6烷基和其中Re为H或-CH3的-(CH2)2-3ORe;且R7为H。
7.根据权利要求2所述的化合物,其中Ra为H,且Rb为F;或Ra为F,且Rb为H;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
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Ra为Cl,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R4是选自-OH、-OCH3、OCH2CH3和-C1-4烷基;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
10.根据权利要求9所述的化合物,其中Ra为F,Rb为Cl,R2为H,R4为-OCH3或-OCH2CH3,且R7为H。
11.根据权利要求8所述的化合物,其中Ra为F,且Rb为H;R2为H;R4为-OH;且R7是选自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRdNH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
12.根据权利要求1所述的化合物,其具有式IVa或IVb:
13.根据权利要求12所述的化合物,其中Ra为Cl,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
14.根据权利要求13所述的化合物,其中Ra为F,Rb为Cl,R2为H,且R7为H。
15.根据权利要求12所述的化合物,其中Ra为F,且Rb为H;R2为H;且R7是选自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
16.根据权利要求1所述的化合物,其具有式V:
17.根据权利要求16所述的化合物,其中Ra和Rb为H;R2是选自-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R3是选自-OH、-OCH3、-OCH2CH3和-C1-4烷基;且R7为H。
18.根据权利要求17所述的化合物,其中Ra和Rb为H,R2为-CH3,R3为-OH或-OCH3,且R7为H。
19.根据权利要求16所述的化合物,其中Ra是选自Cl和F,且Rb为H;或Ra为H,且Rb是选自Cl、F、-CH3和-CN;或Ra为F,且Rb为Cl;R2是选自H、-C1-6烷基、-(CH2)2-3ORe和-(CH2)2-3NReRe;R3是选自-OH、-OCH3、-OCH2CH3和-C1-4烷基;且R7是选自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-环己基、-CH2CH(NH2)C(O)OCH3、-C2-4亚烷基-N(CH3)2、-C0-6亚烷基吗啉基和
20.根据权利要求19所述的化合物,其中Ra为H,Rb为Cl,R2为H、-CH3、-CH2CH3或-(CH2)2OH,R3为-OH或-OCH3,且R7为H;或Ra为F,Rb为Cl,R2为H或-C1-6烷基,R3为-OH、-OCH3或-C1-4烷基,且R7为H。
21.根据权利要求1所述的化合物,其具有式VIa或VIb:
22.根据权利要求21所述的化合物,其中Ra为H或F;Rb为Cl;R2为H或-C1-6烷基;R3为-OCH3、-OCH2CH3或-C1-4烷基;R4存在时为H;且R7为H。
23.根据权利要求1所述的化合物,其具有式VIIa或VIIb:
24.根据权利要求23所述的化合物,其中Ra为F,Rb为Cl,R2为H或-C1-6烷基,R4存在时为H,且R7为H。
25.根据权利要求1所述的化合物,其具有式VIII:
26.根据权利要求1所述的化合物,其具有式IX:
27.一种医药组合物,其包含医药学上可接受的载剂和根据权利要求1到26中任一权利要求所述的化合物。
28.根据权利要求27所述的医药组合物,其进一步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β-肾上腺素能受体拮抗剂/α1-受体拮抗剂、晚期糖基化终产物裂解剂、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、止泻剂、抗青光眼药剂、抗脂质药剂、抗伤痛感受性药剂、抗血栓药剂、AT1受体拮抗剂和双重作用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、单胺再吸收抑制剂、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、类鸦片受体激动剂、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、选择性血清素再吸收抑制剂、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。
29.根据权利要求28所述的医药组合物,其中所述治疗剂为AT1受体拮抗剂。
30.根据权利要求1到26中任一权利要求所述的化合物,其用于疗法中。
31.根据权利要求30所述的化合物,其用于治疗高血压、心脏衰竭或肾病。
32.一种根据权利要求1到26中任一权利要求所述的化合物的用途,其用于制造用于治疗高血压、心脏衰竭或肾病的药剂。
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CN108779084A (zh) * | 2016-03-08 | 2018-11-09 | 施万生物制药研发Ip有限责任公司 | 结晶型(2s,4r)-5-(5′-氯-2′-氟-[1,1′-联苯]-4-基)-2-(乙氧基甲基)-4-(3-羟基异恶唑-5-甲酰氨基)-2-甲基戊酸和其用途 |
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PT2651896E (pt) | 2010-12-15 | 2015-11-03 | Theravance Biopharma R&D Ip Llc | Inibidores de neprilisina |
CN103380119B (zh) | 2011-02-17 | 2016-02-17 | 施万生物制药研发Ip有限责任公司 | 作为脑啡肽酶抑制剂的经取代的氨基丁酸衍生物 |
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EP2714662B1 (en) | 2011-05-31 | 2017-10-11 | Theravance Biopharma R&D IP, LLC | Neprilysin inhibitors |
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ES2710932T3 (es) | 2012-06-08 | 2019-04-29 | Theravance Biopharma R&D Ip Llc | Inhibidores de neprilisina |
ME02626B (me) | 2012-08-08 | 2017-06-20 | Theravance Biopharma R&D Ip Llc | Inhibitori neprilisina |
PL2964616T3 (pl) | 2013-03-05 | 2017-10-31 | Theravance Biopharma R&D Ip Llc | Inhibitory neprylizyny |
MX2016009760A (es) | 2014-01-30 | 2016-11-08 | Theravance Biopharma R&D Ip Llc | Inhibidores de neprilisina. |
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WO2016086798A1 (zh) * | 2014-12-03 | 2016-06-09 | 上海翰森生物医药科技有限公司 | Nep抑制剂结晶型游离酸、钙盐多晶型及其制备方法和应用 |
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