CN109641919A - 微生物β-葡糖苷酸酶的抑制剂及其用途 - Google Patents
微生物β-葡糖苷酸酶的抑制剂及其用途 Download PDFInfo
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- CN109641919A CN109641919A CN201780052385.8A CN201780052385A CN109641919A CN 109641919 A CN109641919 A CN 109641919A CN 201780052385 A CN201780052385 A CN 201780052385A CN 109641919 A CN109641919 A CN 109641919A
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Abstract
提供化合物和组合物,其包含选择性β‑葡糖苷酸酶抑制剂。该化合物和组合物可以改善化疗剂的副作用,并且可以改善这些药剂的功效,所述药剂包括伊立替康和非甾体抗炎药。
Description
政府支持
本发明是在国立卫生研究院授予的Grant CA098468的政府支持下完成的。政府拥有本发明的某些权利。
技术领域
本发明一般地涉及作为微生物β-葡糖苷酸酶(“GUS”)特异性抑制剂的化合物,其能够减轻某些化疗剂如抗癌药物和非甾体类抗炎药物的毒性。
背景技术
伊立替康是一种常用的化疗剂,用于治疗各种恶性肿瘤。不幸的是,用伊立替康治疗的患者经常遭受副作用,例如严重的腹泻,这增加了患者的痛苦,从而降低了剂量增加和改善功效的可行性。目前,没有有效的疗法来克服这种腹泻。它可能如此严重,以致实际上它会成为限制剂量的副作用。
伊立替康诱发腹泻的潜在机制已被广泛研究。该机制开始于肠中细菌β-葡糖苷酸酶(GUS)将伊立替康的无毒性代谢物SN-38G转化成有毒的SN-38。化合物SN-38是伊立替康的治疗活性形式,当其存在于肠中时,导致肠上皮细胞的损伤和腹泻。
哺乳动物胃肠(GI)道中的微生物β-葡糖苷酸酶(GUS)是微生物组中首先建立的药物靶标。已显示GUS酶将药物代谢物重新激活至其毒性形式,其可显著损害GI上皮并降低药物耐受性和功效。(Wallace B.D.等人,Science,330,831-835(2010))。
需要能够安全有效地防止药物代谢物重新激活的化合物和方法。本文描述的主题解决了这种需要。
发明内容
在一个实施方案中,本文描述的主题涉及式I的化合物,其是选择性微生物GUS抑制剂。
发现该化合物能够抑制β-葡糖苷酸酶水解葡糖苷酸,并由此减轻在某些药物如抗肿瘤剂中观察到的副作用。在一个实施方案中,本文所述的主题涉及通过向有需要的受试者施用式I的化合物或其药物制剂治疗诸如胃肠道不适的病症的方法,所述病症通常伴随疾病例如癌症的治疗。
另一个实施方案包括药物组合物,其包含式I的化合物或药学上可接受的盐和药学上可接受的载体。
又一实施方案包括抑制β-葡糖苷酸酶的方法,其包括用有效量的式I的化合物或药学上可接受的盐接触β-葡糖苷酸酶。
又一个实施方案包括制备式I化合物的方法。
更进一步的实施方案如本文所述。
附图说明
图1示出EcGUS的分辨率晶体结构,揭示二哌嗪化合物12在两个方向(A和B)结合在GUS活性位点。
图2示出与化合物29复合的微生物GUS以及与酶和化合物29共结晶的底物分子中的葡糖苷酸的分辨率晶体结构。
图3显示了EcGUS(蓝色)、CpGUS和SaGUS的活性位点与化合物29重叠的结构表示。
具体实施方式
本文公开的式I的选择性抑制剂及其组合物可以与治疗癌症和减少抗肿瘤剂(例如喜树碱衍生的抗肿瘤剂)的副作用的方法联合使用。通常伴随特定化疗剂治疗的胃肠道不适可以得到减弱或改善。该方法还可用于减轻或改善与葡糖苷酸酶-底物剂或化合物的施用相关的任何不良反应。本文所述的主题包括用于抑制细菌β-葡糖苷酸酶和改善喜树碱衍生的抗肿瘤剂或葡糖苷酸酶-底物剂或化合物的功效的组合物和方法,其是通过减弱由这些药剂的葡糖醛酸化代谢物的再活化引起的胃肠道不适。
已经发现,抑制微生物β-葡糖苷酸酶(GUS)可以减轻抗癌药物(例如伊立替康)以及几种非甾体抗炎药的副作用和毒性。成功的微生物GUS酶抑制剂具有以下三个特征:效力,对细菌和哺乳动物细胞的非致死性,以及微生物GUS酶相对哺乳动物GUS蛋白的选择性。(Wallace,(2010))。如本文所用,“beta-葡糖苷酸酶”、“β-葡糖苷酸酶”等是指能够水解β-葡糖苷酸但不水解α-葡糖苷酸或β-葡糖苷的酶(EC3.2.1.31)。(Basinska&Florianczyk(2003)Ann.Univ.Mariae Curie Sklodowska Med.58:386-389;Miles等人(1955)J.Biol.Chem.217:921-930)。如本文所用,“葡糖苷酸”等是指通过糖苷键将葡糖醛酸与另一种物质连接而产生的物质。本文感兴趣的葡糖苷酸的实例包括但不限于喜树碱衍生的抗肿瘤剂的葡糖苷酸,例如SN-38G(7-乙基-10-羟基喜树碱葡糖苷酸)。微生物群β-葡糖苷酸酶的进一步细节公开在美国专利号8,557,808中,其全部内容通过引用并入本文。
非活性代谢物如SN-38G重新激活为活性SN-38发生在胃肠道中,并且由细菌β-葡糖苷酸酶引起。重新激活的代谢物可导致胃肠不适,例如腹泻,这通常可能是癌症治疗或治疗任何其他病症的疗法的剂量限制性副作用。如本文所用,“剂量限制”表示施用喜树碱衍生的抗肿瘤剂或葡糖苷酸酶-底物剂或化合物的副作用阻止了需要癌症治疗或治疗任何其他病症的疗法的受试者接受推荐量。随着增加量的喜树碱衍生的抗肿瘤剂或葡糖苷酸酶-底物剂或化合物被施用于受试者,因此可以获得增加量的葡糖醛酸化代谢物作为细菌β-葡糖苷酸酶的底物。由此产生的重新激活的代谢物不仅通过引起严重的副作用,特别是胃肠道不适而对受试者的健康产生不利影响,而且还通过限制可以施用给受试者的喜树碱衍生的抗肿瘤剂或葡糖苷酸酶-底物剂或化合物的量损害治疗结果。
虽然不受理论束缚,但据信本文所述的化合物是糖基水解酶反应机理的共价糖-酶中间体的水解抑制剂。如本文所述,所述化合物和方法对重新激活肠道中药物的细菌微生物组具有选择性。因此,下面的化合物和方法可用于改善许多药物和治疗的副作用。
现在将在下文中更全面地描述本公开的主题。然而,具有前述描述中呈现的教导益处的本公开主题涉及领域的技术人员将会想到本文所述的公开主题的许多修改和其他实施方案。因此,应理解当前公开的主题不限于所公开的具体实施方案,并且旨在将修改和其他实施方案包括在所附权利要求的范围内。换言之,本文中所描述的主题涵盖所有备选方案、修改和等同项。如果所并入的文献、专利和类似材料中的一个或多个与本申请不同或相矛盾,包括但不限于定义的术语、术语用法,所描述的技术等,则以本申请为准。除非另外定义,否则本文使用的所有技术和科学术语具有与本领域普通技术人员通常所理解的相同含义。本文提及的所有出版物、专利申请、专利和其他参考文献都通过引用整体并入。
I.定义
术语“取代基”是指替换分子上的氢原子的原子或原子团。术语“取代的”表示指定的分子带有一个或多个取代基。术语“所述式的化合物”或“式的化合物”指的是选自由式I所定义的化合物的种类的任意化合物。
如本文所用,术语“烷基”是指直链或支链烃基。烷基的实例包括甲基、乙基、正丙基、异丙基、叔丁基和正戊基。烷基可任选地被一个或多个取代基取代。
术语“苄基”是指具有式C6H5CH2的烃,其中与所述基团的连接点在CH2位置。苄基可以在芳环上取代。在一个实施方案中,芳基的0、1、2、3、4或5个原子可以被取代基取代。
如本文所用,术语“卤素”、“卤代”或“卤基”是指-F、-Cl、-Br或-I。
术语“环烷基”是指具有至少一个饱和环或具有至少一个非芳族环的烃3-8元单环或7-14元双环环系统,其中非芳环可具有一定程度的不饱和度。环烷基可任选地被一个或多个取代基取代。在一个实施方案中,环烷基的每个环的0、1、2、3或4个原子可以被取代基取代。环烷基的代表性实例包括环丙基、环戊基、环己基、环丁基、环庚基、环戊烯基、环戊二烯基、环己烯基、环己二烯基等。
术语“芳基”是指烃单环、双环或三环芳环系统。芳基可任选地被一个或多个取代基取代。在一个实施方案中,芳基的每个环的0、1、2、3、4、5或6个原子可以被取代基取代。芳基的实例包括苯基、萘基、蒽基、芴基、茚基、薁基等。
术语“杂芳基”是指芳族5-8元单环、8-12元双环或11-14元三环系统,如果是单环,其具有1-4个环杂原子,如果是双环,其具有1-6个杂原子,或如果是三环的,其具有1-9杂原子,所述杂原子选自O、N或S,其余的环原子是碳(除非另有说明,否则具有适当的氢原子)。杂芳基可任选地被一个或多个取代基取代。在一个实施方案中,杂芳基的每个环的0、1、2、3或4个原子可以被取代基取代。杂芳基的实例包括吡啶基、呋喃基、噻吩基、吡咯基、噁唑基、噁二唑基、咪唑基、噻唑基、异噁唑基、喹啉基、吡唑基、异噻唑基、哒嗪基、嘧啶基、吡嗪基、三嗪基、异喹啉基、吲唑基等。
术语“含氮杂芳基”是指具有1-4个环氮杂原子(如果是单环的)、1-6个环氮杂原子(如果是双环的)、或1-9个环氮杂原子(如果是三环的)的杂芳基。
术语“杂环烷基”是指非芳族3-8元单环、7-12元双环或10-14元三环系统,如果是单环,则包含1-3个杂原子,如果是双环,则包含1-6个杂原子,或如果是三环,则包含1-9个杂原子,所述杂原子选自O、N、S、B、P或Si,其中非芳族环系统完全饱和。杂环烷基可任选地被一个或多个取代基取代。在一个实施方案中,杂环烷基的每个环的0、1、2、3或4个原子可以被取代基取代。代表性的杂环烷基包括哌啶基、哌嗪基、四氢吡喃基、吗啉基、硫代吗啉基、1,3-二氧戊环基、四氢呋喃基、四氢噻吩基、噻吩基等。
术语“互变异构体”或“互变异构形式”是指可通过低能壁垒相互转化的不同能量的结构异构体。例如,质子互变异构体(也称为质子异变互变异构体)包括通过质子迁移相互转换,例如酮-烯醇和亚胺-烯胺异构化。价互变异构体包括通过重组一些键合电子的相互转换。
术语“手性”是指具有镜像配偶体不可重叠性的分子,而术语“非手性”是指可与其镜像配偶体重叠的分子。
术语“非对映异构体”是指具有两个或多个不对称中心并且其分子不是彼此的镜像的立体异构体。
术语“对映体”是指化合物的两种立体异构体,它们是彼此不可重叠的镜像。两种对映体的等摩尔混合物称为“外消旋混合物”或“外消旋体”。
术语“异构体”或“立体异构体”是指具有相同化学组成但在空间中原子或基团排列方面不同的化合物。
此外,本文所述的化合物可包括具有任一几何形状的烯烃:“Z”表示所谓的“顺式”(同侧)构型,而“E”表示所谓的“反式”(相反侧)构型。
“溶剂化物”是指一个或多个溶剂分子和本发明的化合物的缔合或复合物。形成溶剂化物的溶剂的实例包括但不限于水,异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。术语“水合物”是指溶剂分子为水的络合物。
“代谢物”是通过喜树碱衍生的抗肿瘤剂或葡糖苷酸酶-底物剂或化合物的体内代谢产生的产物。可使用本领域已知的常规技术鉴定代谢物,并使用如本文所述的测试确定其活性。这些产物可以由例如所施用的化合物的氧化、羟化、还原、水解、酰胺化、脱酰胺、酯化、脱酯化、酶促裂解等产生。
短语“药学上可接受的”表示该物质或组合物必须在化学和/或毒理学上与构成制剂的其他成分和/或用其治疗的受试者相容。
本文所用的短语“药学上可接受的盐”是指本发明的化合物的药学上可接受的有机或无机盐。示例性盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、丹宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐“甲磺酸盐(mesylate)”、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、双羟萘酸盐(即1,1'-亚甲基双-(2-羟基-3-萘甲酸盐))、碱金属(例如钠和钾)盐、碱土金属(例如镁)盐和铵盐。药学上可接受的盐可包括包含另一种分子,例如乙酸根离子、琥珀酸根离子或其他抗衡离子。抗衡离子可以是稳定母体化合物上的电荷的任何有机或无机部分。此外,药学上可接受的盐在其结构中可具有多于一个带电原子。多个带电原子是药学上可接受的盐的一部分的实例可具有多个抗衡离子。因此,药学上可接受的盐可具有一个或多个带电原子和/或一个或多个抗衡离子。抗衡离子可具有正电荷或负电荷。正抗衡离子可以是单价(例如碱金属或铵)、二价(例如碱土金属)或三价(例如铝)。碱金属阳离子的非限制性实例是Li+、Na+和K+。负抗衡离子的非限制性实例包括氯离子、溴离子、碘离子、硫酸根、链烷磺酸根、芳基磺酸根、磷酸根、高氯酸根、四氟硼酸根和硝酸根。
如本文所用“载体”包括在所采用的剂量和浓度下对暴露其中的细胞或哺乳动物无毒的药学上可接受的载体、赋形剂或稳定剂。生理学上可接受的载体通常是含水pH缓冲溶液。生理学上可接受的载体的非限制性实例包括缓冲剂,例如磷酸盐、柠檬酸盐和其他有机酸;抗氧化剂,包括抗坏血酸;低分子量(少于约10个残基)的多肽;蛋白质,如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,如聚乙烯吡咯烷酮;氨基酸,如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸;单糖、二糖和其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂如EDTA;糖醇类,如甘露醇或山梨糖醇;成盐抗衡离子如钠;和/或非离子表面活性剂如TWEENTM、聚乙二醇(PEG)和PLURONICSTM。在某些实施方案中,药学上可接受的载体是非天然存在的药学上可接受的载体。
本文中“抑制剂”一词的使用是指抑制微生物GUS酶活性的分子。本文用“抑制”意指与不存在抑制剂时酶的活性相比,降低靶酶的活性。在一些实施方案中,术语“抑制”意指GUS活性降低至少约5%、至少约10%、至少约20%、至少约25%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%或至少约95%。在其他实施方案中,抑制意指GUS活性降低约5%至约25%、约25%至约50%、约50%至约75%、或约75%至100%。在一些实施方案中,抑制意指GUS活性降低约95%至100%,例如活性降低95%、96%、97%、98%、99%或100%。可以使用本领域技术人员可识别的各种技术,包括体外测定,测量这种降低。
如本文所用,“β-葡糖苷酸酶抑制剂”、“GUS抑制剂”或“GUS的抑制剂”是降低、抑制或以其他方式减少微生物GUS酶的一种或多种生物活性的化合物。抑制不一定表明完全消除GUS活性。而是,活性可以降低统计学上显著的量,包括例如与合适的对照相比,GUS活性减少至少约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、95%或100%。在一些实施方案中,本文公开的化合物减小、抑制或以其他方式减少微生物GUS酶活性。
“特异性抑制”是指与另一种微生物GUS酶或直向同源物的活性相比,更多地减少、抑制或以其他方式降低特定微生物GUS酶或直向同源物的活性的试剂。例如,特异性抑制剂降低GUS直向同源物(例如大肠杆菌GUS(EcGUS))的至少一种生物活性,其量在统计学上大于该化合物对另一种GUS直向同源物(例如无乳链球菌(Streptococcus agalactiae))(SaGUS)或产气荚膜梭菌(Clostridium perfringens)(CpGUS)的抑制作用。在一些实施方案中,直向同源物的抑制剂的IC50为另一直向同源物的抑制剂的IC50的约90%、80%、70%、60%、50%、40%、30%、20%、10%、5%、1%、0.1%、0.01%、0.001%或更少。本公开的化合物可以是或可以不是特异性抑制剂。特异性抑制剂将特定GUS的生物活性降低了统计学上大于该抑制剂对任何其他GUS的抑制作用的量。
如本文所用,“选择性抑制”等意指β-葡糖苷酸酶抑制剂降低细菌而非哺乳动物β-葡糖苷酸酶活性。也就是说,β-葡糖苷酸酶抑制剂可以结合并且可以防止细菌而非哺乳动物β-葡糖苷酸酶水解葡糖苷酸。有用的式I化合物对细菌β-葡糖苷酸酶具有选择性。也就是说,与哺乳动物β-葡糖苷酸酶相比,化合物使细菌β-葡糖苷酸酶的活性降低了统计学上显著的量。有利地,本文所述的β-葡糖苷酸酶抑制剂对细菌β-葡糖苷酸酶具有选择性。也就是说,该化合物抑制细菌中的β-葡糖苷酸酶,但对哺乳动物β-葡糖苷酸酶(包括人β-葡糖苷酸酶)没有抑制活性。虽然不打算受任何特定作用机制的束缚,但化合物似乎与细菌β-葡糖苷酸酶中的~12残基环结合,所述细胞β-葡糖苷酸酶悬浮在活性位点开口上方。该环不存在于哺乳动物β-葡糖苷酸酶中,因此其可以容纳更大的底物并从长链糖胺聚糖切割葡糖醛酸部分。β-葡糖苷酸酶抑制剂具有其他优点。例如,化合物不会杀死肠细菌或损害人上皮细胞,但对有氧和厌氧条件下培养的细菌有效。
如本文所用,“肠细菌”等是指居住在人胃肠道中的正常细菌。肠细菌的实例包括但不限于拟杆菌属(Bacteroides sp.)(例如拟杆菌(Bacteroides vulgatus))、双歧杆菌属(Bifidobacterium sp.)(例如两岐双歧杆菌和婴儿双歧杆菌)、儿茶杆菌属(Catenabacterium sp.)、梭菌属(Clostridium sp.)、棒状杆菌属(Corynebacteriumsp.)、肠球菌属(Enterococcus sp.)(例如粪肠球菌(Enterococcus faecalis))、肠杆菌科(Enterobacteriaceae)(例如大肠杆菌)、乳酸杆菌属(Lactobacillus sp.)、消化链球菌属(Peptostreptococcus sp.)、丙酸杆菌属(Propionibacterium sp.)、变形杆菌属(Proteussp.)、分枝杆菌属(Mycobacterium sp.)、假单胞菌属(Pseudomonas sp.)(例如铜绿假单胞菌(Pseudomonas aeruginosa))、葡萄球菌属(Staphylococcus sp.)(例如表皮葡萄球菌(Staphylococcus epidermidis)和金黄色葡萄球菌(Staphylococcus aureus))和链球菌属(Streptococcus sp.)(例如链球菌(Streptococcus mitis))。由于肠道细菌共同栖息于胃肠道,它们通过防止梭状芽孢杆菌(Clostridium difficle)等机会性细菌的感染来促进胃肠健康。
术语“治疗”是指治疗性治疗和预防性或防治性措施,其中目的是预防或减缓(减轻)有害生理变化或病症。术语“减轻”和“减弱”是指与GI不适相关的客观和主观症状的程度和发生率。有益或期望的临床结果包括但不限于症状的缓解、病症程度的减少、病症的稳定(即不恶化)、副作用的延迟或减缓、相对于接受式I化合物之前遭受的GI不适的GI不适的减轻。“治疗”还意味着与如果不接受治疗预期的副作用相比改善的副作用。需要治疗的那些包括已经患有病状或病症的那些以及易于患所述病状或病症的那些或者要预防所述病状或病症的那些。
术语“施用”或“给药”包括将化合物引入受试者以实现其预期功能的途径。
术语“有效量”包括在必要的剂量和时间段内有效实现所需结果的量。有效量的化合物可根据诸如受试者的疾病状态、年龄和体重等因素以及化合物在受试者中引发所需反应的能力而变化。可以调整剂量方案以提供最佳治疗反应。有效量也是其中治疗有益效果超过抑制剂化合物的任何毒性或有害作用(例如副作用)的量。
短语“治疗有效量”是指(i)治疗或预防特定疾病、状况或病症,(ii)减弱、改善或消除特定疾病、状况或病症的一种或多种症状,或(iii)预防或延迟本文所述的特定疾病、状况或病症的一种或多种症状的发作的本发明化合物的量。
术语“受试者”是指动物,例如哺乳动物,包括但不限于灵长类动物(例如人)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠等。在某些实施方案中,受试者是人。
下面还提供了其他定义。
II.化合物
式I的化合物,其还包括药学上可接受的盐,具有以下结构:
其中,
R1选自:
i.-ORA,其中RA选自H、CF3、任选取代的直链或支链C2-6烷基、任选取代的苄基和C3-8环烷基;
ii.-NRBRC,其中RB和RC各自独立地选自H、任选被氨基取代的直链或支链C1-6烷基、任选取代的苄基、C2-5杂芳基、C2-5杂烷基和C3-8环烷基;
iii.任选被羟基、卤素或氨基取代的C2-5杂芳基;
iv.-N(CH2)p-Z,其中p为1或2;Z是任选被羟基、卤素或氨基取代的杂芳基或杂环烷基;
v.其中s为1、2或3;和RD是氨基、羟基、卤素或直链或支链C1-6烷基;和
vi.其中
R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,其中R7可以形成桥;和
R8是H,任选被卤素、羟基或氨基取代的直链或支链C1-4烷基;或R1选自:
i.-ORA,其中RA选自H、CF3、任选取代的直链或支链C2-6烷基、任选取代的苄基和C3-8环烷基;
ii.-NRBRC,其中RB和RC各自独立地选自H、任选被氨基取代的直链或支链C1-6烷基、任选取代的苄基、C2-5杂芳基、C2-5杂烷基和C3-8环烷基;
iii.任选被羟基、卤素或氨基取代的C2-5杂芳基;
iv.-N(CH2)p-Z,其中p为1或2;Z是任选被羟基、卤素或氨基取代的杂芳基或杂环烷基;
v.其中s为1、2或3;和RD是氨基、羟基、卤素或直链或支链C1-6烷基;
vi.其中
R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,其中R7可以形成桥;和
R8是H,任选被卤素、羟基或氨基取代的直链或支链C1-4烷基;和
vii.其中
R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,其中R7可以形成桥;
Y是抗衡离子;和
R9在每种情况下独立地是任选被卤素、羟基或氨基取代的直链或支链C1-4烷基;
R2为H、芳基、杂环烷基或-NRFRG,其中
RF和RG独立地选自H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基,任选取代的苄基和C3-8环烷基;
X是N或-CR3,其中
R3选自H、卤素、-ORI和-NRIRJ,其中
RI和RJ各自独立地选自H和直链或支链C1-6烷基,其中所述烷基可任选被羟基取代;和
R4和R5为H或与各自连接的碳一起形成任选取代的C5-7元环;
条件是当R4和R5一起形成6元未取代环时,X是N或CH,R2是吗啉基,R1不是哌嗪基或-NHCH2CH2NH2。
在实施方案中,R4和R5与各自连接的碳一起形成任选取代的C5-7元环。
在任何上述实施方案中,X是N。
在任何上述实施方案中,R2是杂环烷基。
在任何上述实施方案中,R2是含有1或2个氮原子的4-8元环。
在上述任何实施方案中,R2选自:
在上述任何实施方案中,R2为吗啉基。
在上述任何实施方案中,R1为
-NRBRC,其中RB和RC各自独立地选自H、任选被氨基取代的直链或支链C1-6烷基、任选取代的苄基、C2-5杂芳基、C2-5杂烷基和C3-8环烷基;
R1为任选被羟基、卤素或氨基取代的C2-5杂芳基;或,
R1是其中
R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,并且当q为2时,两个R7基团可以连接形成桥连化合物;
和
R8是H,任选被卤素、羟基或氨基取代的直链或支链C1-4烷基。
在上述任何实施方案中,R1是
其中R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,其中R7可以连接形成桥接化合物;和
R8是H,任选被卤素、羟基或氨基取代的直链或支链C1-4烷基。
在任何上述实施方案中,t和q各自为1。
在任何上述实施方案中,R8为H。
在任何上述实施方案中,R7是甲基。
在任何上述实施方案中,R1是
其中
s是1、2或3;和
RD是氨基、羟基、卤素或直链或支链C1-6烷基;或
R1为其中
R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,其中R7可以连接形成桥接化合物;和
R8是H,任选被卤素、羟基或氨基取代的直链或支链C1-4烷基。
在上述任何实施方案中,R1特别是
其中
R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,其中R7可以连接形成桥接化合物;和
R8是H,任选被卤素、羟基或氨基取代的直链或支链C1-4烷基。
在任何上述实施方案中,t和q各自为1。
在上述任何实施方案中,R7为H。
在上述任何实施方案中,R8是H。
在上述任何实施方案中,R2是H、杂环烷基或-NRFRG,其中
RF和RG独立地选自H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基,任选取代的苄基和C3-8环烷基。
在任何上述实施方案中,R2是杂环烷基。
在一个具体实施方案中,式I化合物是
在上述任何实施方案中,R2是-NRFRG,其中
RF和RG独立地选自H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基,任选取代的苄基和C3-8环烷基。
在任何上述实施方案中,RF和RG独立地选自H或任选被卤素、氨基或羟基取代的直链或支链C1-6烷基。
在一个具体实施方案中,式I化合物是
或,
在任何上述实施方案中,其中R4和R5是H。
在任何上述实施方案中,R1是
其中
s是1、2或3;和
RD是氨基、羟基、卤素或直链或支链C1-6烷基;或
R1为其中
R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,其中R7可以连接形成桥接化合物;和
R8是H,任选被卤素、羟基或氨基取代的直链或支链C1-4烷基。
在任何上述实施方案中,R1是
其中
R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,其中R7可以连接形成桥接化合物;和
R8是H,任选被卤素、羟基或氨基取代的直链或支链C1-4烷基。
在任何上述实施方案中,t和q各自为1。
在上述任何实施方案中,R7为H。
在上述任何实施方案中,R1为哌嗪基。
在上述任何实施方案中,R2为H、芳基、杂环烷基或-NRFRG,其中
RF和RG独立地选自H、直链或支链C1-6烷基、任选取代的苄基和C3-8环烷基。
在上述任何实施方案中,R2为芳基。
在上述任何实施方案中,R2为苯基。
在上述任何实施方案中,R2为杂环烷基。
在任何上述实施方案中,R2是含有包含在环内的1或2个氮原子的4-8元环。
在任何上述实施方案中,R2选自:
在上述任何实施方案中,R2为吗啉基。
在上述任何实施方案中,R2为-NRFRG,其中
RF和RG独立地选自H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基,任选取代的苄基和C3-8环烷基。
在任何上述实施方案中,RF和RG独立地为H或任选被卤素、氨基或羟基取代的直链或支链C1-6烷基。
在上述任何实施方案中,RF和RG独立地是H或未取代的直链C1-6烷基。
在一个具体实施方案中,式I化合物是
或,
在实施方案中,式I化合物选自:
在实施方案中,本文描述的主题涉及药物组合物,其包括式I的化合物和药学上可接受的载体或赋形剂。
在实施方案中,本文描述的主题涉及在有需要的受试者中治疗疾病的方法,其包括向所述受试者施用有效量的式I的化合物。
本文描述的主题还包括式I化合物的药学上可接受的盐。
在上述任何实施方案中,与另一种微生物GUS酶或直向同源物相比,式I化合物更大特异性抑制一种微生物GUS酶或直向同源物。在一个实施方案中,直向同源物的抑制剂的IC50为另一直向同源物的抑制剂的IC50的约90%、80%、70%、60%、50%、40%、30%、20%、10%、5%、1%、0.1%、0.01%、0.001%或更少。在一个实施方案中,与其他GUS直向同源物相比,式I化合物特异性地抑制EcGUS。在一个实施方案中,与其他GUS直向同源物相比,式I化合物特异性抑制SaGUS。在一个实施方案中,与其他GUS直向同源物相比,式I化合物特异性抑制CpGUS。
在进一步的实施方案中,式I的化合物的EcGUS IC50在任何其他GUS直向同源物的IC50的约1%至约10%范围。在进一步的实施方案中,式I的化合物的EcGUS IC50在任何其他GUS直向同源物的IC50的约10%至约25%、约25%至约50%或约50%至约90%的范围。在进一步的实施方案中,式I化合物的SaGUS IC50在任何其他GUS直向同源物的IC50的约20%至约30%范围。在进一步的实施方案中,式I的化合物的SaGUS IC50在任何其他GUS直向同源物的IC50的约30%至约50%、约50%至约75%或约75%至约90%范围。
如果式I化合物是碱,则可以通过本领域可用的任何合适方法制备所需的药学上可接受的盐,例如,用无机酸或用有机酸处理游离碱,无机酸例如盐酸、氢溴酸、硫酸、硝酸、甲磺酸、磷酸等,有机酸例如乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、吡喃糖苷酸如葡糖醛酸或半乳糖醛酸、α羟基酸如柠檬酸或酒石酸、氨基酸如天冬氨酸或谷氨酸、芳香酸如苯甲酸或肉桂酸、磺酸例如对甲苯磺酸或乙磺酸等。
其他合适的盐的说明性实例包括但不限于衍生自氨基酸例如甘氨酸和精氨酸,氨,伯、仲和叔胺,以及环胺例如哌啶、吗啉和哌嗪的有机盐,以及衍生自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂的无机盐。
III.组合物
式I化合物可根据标准药学实践配制成药物组合物。根据该方面,提供了药物组合物,其包含式I化合物和药学上可接受的赋形剂,例如载体或稀释剂。
通过混合式I化合物和一种或多种赋形剂来制备典型的制剂。合适的赋形剂是本领域技术人员公知的,包括诸如碳水化合物、蜡、水溶性和/或可溶胀聚合物、亲水或疏水性物质、明胶、油、溶剂、水等物质。所用的具体赋形剂取决于式I化合物的应用方式和目的。通常基于本领域技术人员认为对哺乳动物施用安全(GRAS)的溶剂来选择溶剂。一般而言,安全溶剂是无毒的水性溶剂,例如水和其它在水中可溶或可混溶的无毒溶剂。合适的水性溶剂包括水、乙醇、丙二醇、聚乙二醇(例如,PEG 400、PEG 300)等及其混合物。制剂还可包括一种或多种缓冲剂、稳定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、避光剂、助流剂、加工助剂、着色剂、甜味剂、芳香剂、调味剂和其它已知的添加剂以提供药物(即式I化合物或其药物组合物)的精致呈现或有助于制造药物产品(即药剂)。
可以使用常规的溶解和混合程序来制备制剂。例如,在上述一种或多种赋形剂的存在下将散装药物质(即式I化合物或稳定形式的式I化合物(例如,与环糊精衍生物或其它已知络合剂的络合物)溶解在合适的溶剂中。通常将式I化合物配制成药物剂型以提供易于控制的药物剂量并使患者能够遵守规定的方案。
用于施用的药物组合物(或制剂)可以以多种方式包装,这取决于用于施用药物的方法。通常,用于分配的制品包括其中以适当的形式沉积药物制剂的容器。合适的容器是本领域技术人员公知的,包括诸如瓶子(塑料和玻璃)、小袋、安瓿、塑料袋、金属圆筒等材料。容器还可以包括防干扰组件,以防不慎接触包装内容物。另外,容器上沉积有描述容器内容物的标签。标签还可能包含适当的警告。在一个实施方案中,容器是泡罩包装。
可以制备药物制剂用于各种途径和类型的施用。例如,具有所需纯度的式I化合物可任选地与药学上可接受的赋形剂混合(Remington’s Pharmaceutical Sciences(1980)第16版,Osol,A.Ed.,Mack Publishing Co.,Easton,PA),呈冻干制剂、研磨粉末或水溶液的形式。配制可以通过在环境温度下在适当的pH和所需的纯度下与生理学上可接受的载体混合来进行,所述载体即在所用剂量和浓度下对受者无毒的载体。制剂的pH主要取决于具体用途和化合物浓度,但范围可为约3至约8。在pH 5的乙酸盐缓冲液中配制是合适的实施方案。
式I化合物可以是无菌的。具体而言,用于体内施用的制剂必须是无菌的。通过无菌过滤膜过滤可以容易地完成这种灭菌。
化合物通常可以作为固体组合物、冻干制剂或水溶液储存。
包含式I化合物的药物组合物可以以一定的方式配制、给药和施用,即量、浓度、时间表、疗程、媒介物和施用途径,与良好的医疗实践一致。在这种情况下考虑的因素包括所治疗的特定病症、所治疗的特定哺乳动物、个体患者的临床状况、病症原因、药剂的递送部位、施用方法、施用方案以及医师所知的其他因素。待施用的化合物的“治疗有效量”将受这些考虑因素的支配。在所用的剂量和浓度下,可接受的赋形剂对受者无毒,并且可包括缓冲剂,例如磷酸盐、柠檬酸盐和其他有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(如十八烷基二甲基苄基氯化铵;六甲基氯化铵;苯扎氯铵、苄索氯铵;苯酚、丁醇或苄醇;对羟基苯甲酸烷基酯,如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;儿茶酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(少于约10个残基)的多肽;蛋白质,如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,如聚乙烯吡咯烷酮;氨基酸,如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖和其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂如EDTA;糖类,如蔗糖、甘露醇、海藻糖或山梨糖醇;成盐抗衡离子如钠;金属络合物(例如,锌-蛋白质络合物);和/或非离子表面活性剂如聚山梨醇酯(例如,TWEENTM)、泊洛沙姆(例如,PLURONICSTM)或聚乙二醇(PEG)。活性药物成分也可以包埋在例如通过凝聚技术或通过界面聚合制备的微胶囊中,例如分别在胶体药物递送系统(例如,脂质体、白蛋白微球、微乳液、纳米粒子和纳米胶囊)或在粗乳液中的羟甲基纤维素或明胶-微胶囊和聚-(甲基丙烯酸甲酯)微胶囊。在Remington’s Pharmaceutical Sciences中公开了这些技术。
可以制备式I化合物的持续释放制剂。持续释放制剂的合适实例包括含有式I化合物的固体疏水性聚合物的半透性基质,该基质是成型制品的形式,例如薄膜或微胶囊。持续释放基质的实例包括聚酯、水凝胶(例如,聚(2-羟乙基-甲基丙烯酸酯)或聚(乙烯醇))、聚交酯(US 3773919)、L-谷氨酸和γ-乙基-L-谷氨酸的共聚物、不可降解的乙烯-乙酸乙烯酯、可降解的乳酸-乙醇酸共聚物,如由乳酸-乙醇酸共聚物和醋酸亮丙瑞林(LUPRONDEPOTTM)和聚-D-(-)-3-羟基丁酸组成的可注射微球。
制剂包括适用于本文详述的施用途径的制剂。制剂可以方便地以单位剂型存在,并且可以通过药学领域熟知的任何方法制备。通常在Remington's PharmaceuticalSciences中找到技术和制剂。此类方法包括使活性成分与构成一种或多种辅助成分的载体缔合的步骤。一般而言,通过将活性成分与液体载体或细碎固体载体或两者均匀且紧密地缔合,然后,如果需要,使产品成形,制备制剂。
适于口服施用的式I化合物的制剂可以制备成离散单位,例如丸剂、胶囊剂、扁囊剂或片剂,其各自含有预定量的式I化合物。
压缩片剂可以通过在合适的机器中压制自由流动形式如粉剂或粒剂,任选地与粘合剂、润滑剂、惰性稀释剂、防腐剂、表面活性剂或分散剂混合的活性成分来制备。模制片剂可以通过在合适的机器中模制用惰性液体稀释剂润湿的粉末状活性成分的混合物来制备。片剂可任选地有包衣或刻痕,并任选地配制,以便从中提供缓释或控释活性成分。
可以制备片剂、糖锭、锭剂、水性或油性悬浮液、可分散粉剂或粒剂、乳液、硬或软胶囊(例如明胶胶囊)、糖浆或酏剂用于口服使用。旨在用于口服使用的式I化合物的制剂可以根据本领域已知的用于制造药物组合物的任何方法制备,并且此类组合物可以含有一种或多种试剂,包括甜味剂、调味剂、着色剂和防腐剂,以便提供可口制剂。含有与适合制造片剂的无毒药学上可接受的赋形剂混合的活性成分的片剂是可接受的。这些赋形剂可以是,例如,惰性稀释剂,如碳酸钙或碳酸钠、乳糖、磷酸钙或磷酸钠;造粒和崩解剂,如玉米淀粉或海藻酸;粘合剂,如淀粉、明胶或阿拉伯胶;和润滑剂,如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的,或者可以通过已知技术包衣,包括微囊化以延迟在胃肠道中的崩解和吸附,从而提供更长时间的持续作用。例如,可以使用延时材料,例如单独的单硬脂酸甘油酯或二硬脂酸甘油酯或与蜡一起使用。
式I化合物的水性悬浮液含有与适于制造水性悬浮液的赋形剂混合的活性物质。这些赋形剂包括悬浮剂,例如羧甲基纤维素钠、交联羧甲基纤维素、聚维酮、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯树胶,以及分散剂或润湿剂,例如天然存在的磷脂(例如,卵磷脂),烯化氧与脂肪酸的缩合产物(例如,聚氧乙烯硬脂酸酯),环氧乙烷与长链脂族醇(例如,十七亚乙氧基十六烷基醇)的缩合产物,环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物(例如,聚氧乙烯脱水山梨糖醇单油酸酯)。水性悬浮液还可含有一种或多种防腐剂(例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯)、一种或多种着色剂、一种或多种调味剂和一种或多种甜味剂(例如蔗糖或糖精)。
式I化合物的药物组合物可以是无菌可注射制剂的形式,例如无菌可注射水性或油性悬浮液。这种悬浮液可以根据已知技术使用上面提到的那些合适的分散剂或润湿剂和悬浮剂配制。无菌注射制剂还可以是在无毒的肠胃外可接受的稀释剂或溶剂例如1,3-丁二醇中的无菌注射溶液或悬浮液。无菌注射制剂也可以制备成冻干粉末。可以使用的可接受的媒介物和溶剂是水、林格氏溶液(Ringer’s solution)和等渗氯化钠溶液。另外,无菌不挥发性油通常可用作溶剂或悬浮介质。为此,可以使用任何温和的不挥发性油,包括合成的甘油单酯或甘油二酯。另外,脂肪酸如油酸同样可用于制备注射剂。
可以与载体材料组合以产生单一剂型的活性成分的量将根据所治疗的宿主和特定的施用模式而变化。例如,用于人口服施用的定时释放制剂可含有约1至1000mg活性物质,其与适当且方便量的载体材料化合,其可在总组合物的约5至约95%(重量:重量)之间变化。可以制备药物组合物以提供易于测量的施用量。例如,旨在用于静脉内输注的水溶液可以含有每毫升溶液约3至500μg的活性成分,以便可以按约30mL/小时的速率输注合适的体积。
适于肠胃外施用的制剂包括水性和非水性无菌注射溶液,其可含有抗氧化剂、缓冲剂、抑菌剂和溶质,使制剂与预期受者的血液等渗;水性和非水性无菌悬浮液,其可包括悬浮剂和增稠剂。
适于局部施用于眼睛的制剂还包括滴眼剂,其中活性成分溶解或悬浮在合适的载体中,尤其是活性成分的含水溶剂中。活性成分优选以约0.5至20%w/w的浓度存在于此类制剂中,例如约0.5至10%w/w,例如约1.5%w/w。
适于在口腔中局部施用的制剂包括在调味基质,通常是蔗糖和阿拉伯胶或黄蓍胶中含有活性成分的锭剂;在惰性基质如明胶和甘油或蔗糖和阿拉伯胶中含有活性成分的锭片;和在合适的液体载体中含有活性成分的漱口水。
用于直肠给药的制剂可以作为栓剂呈现,其具有合适的基质,包括例如可可脂或水杨酸酯。
适于肺内或鼻内施用的制剂的粒度例如在0.1至500微米范围内(包括粒度在0.1至500微米范围内,微米增量为例如0.5、1、30微米、35微米等),其通过鼻腔快速吸入或通过口腔吸入以便到达肺泡囊来施用。合适的制剂包括活性成分的水性或油性溶液。适于气溶胶或干粉施用的制剂可以根据常规方法制备,并且可以与其他治疗剂一起递送,例如迄今为止用于治疗或预防下述病症的化合物。
制剂可以包装在单位剂量或多剂量容器中,例如密封的安瓿和小瓶,并且可以在冷冻干燥(冻干)条件下储存,仅需在使用前立即添加无菌液体载体(例如水)进行注射。临时注射溶液和悬浮液由前述类型的无菌粉剂、粒剂和片剂制备。优选的单位剂量制剂是含有如上所述的每日剂量或单位每日亚剂量或其适当分数的活性成分的那些。
该主题还提供了兽用组合物,其包含至少一种如上定义的活性成分以及兽用载体。兽用载体是可用于施用组合物的材料,并且可以是固体、液体或气体材料,其是惰性的或在兽医领域中可接受的并且与活性成分相容。这些兽用组合物可以经胃肠外、口服或任何其他所需途径施用。
在特定的实施方案中,包含本公开的化合物的药物组合物还包含化疗剂。
IV.方法
本文描述的方法提供了选择性抑制细菌β-葡糖苷酸酶的方法。在该方法中,可以将有效量的至少一种选择性β-葡糖苷酸酶抑制剂给予有需要的受试者。即,用化疗剂例如喜树碱衍生的抗肿瘤剂或葡糖苷酸酶-底物剂或化合物治疗的受试者。
本文还描述了通过减弱喜树碱衍生的抗肿瘤剂或葡糖苷酸酶-底物剂或化合物的葡糖醛酸化代谢物的细菌β-葡糖醛酸糖酶的再活化来改善喜树碱衍生的抗肿瘤剂或葡糖苷酸酶-底物剂或化合物的功效的方法。在该方法中,治疗有效量的至少一种选择性β-葡糖苷酸酶抑制剂可以给予受试者,所述受试者已经或即将用化疗剂,特别是喜树碱衍生的抗肿瘤剂或任何其他葡糖苷酸酶-底物剂或化合物治疗。
本文公开的化合物可用于抑制细菌β-葡糖苷酸酶和改善喜树碱衍生的抗肿瘤剂或葡糖苷酸酶-底物剂或化合物的功效的组合物和方法中,其是通过减弱由这些药剂的葡糖醛酸化代谢物的再活化引起的胃肠道不适。本公开的化合物可用于选择性抑制哺乳动物胃肠道中发现的一种或多种微生物β-葡糖苷酸酶(GUS)的活性。本公开的化合物减小、抑制或以其他方式降低一种或多种GUS酶的活性。本公开的化合物可以是或可以不是特异性GUS抑制剂。然而,与其他非微生物β-葡糖苷酸酶相比,GUS抑制剂对微生物或细菌β-葡糖苷酸酶具有选择性。该方法包括使GUS与有效量的式I化合物接触。这些方法包括以下内容。
该化合物和组合物可用于治疗癌症的方法中,以减少抗肿瘤剂如喜树碱衍生的抗肿瘤剂的副作用。因此,通常伴随抗肿瘤剂治疗的胃肠道不适可以减弱。该方法还可用于减轻或改善与葡糖苷酸酶-底物剂或化合物的施用相关的任何不良反应。本发明的方法包括向有需要的受试者施用治疗有效量的至少一种β-葡糖苷酸酶抑制剂,其选择性地抑制细菌β-葡糖苷酸酶水解葡糖苷酸。
一种改善有需要的人的副作用的方法,包括给所述人施用有效量的式I化合物。
一种抑制GUS的方法,包括使GUS与式I化合物接触。
“接触”是指使化合物足够接近目标GUS,使得化合物能够抑制GUS的活性。通过将化合物给予受试者,可以使化合物在体外或体内与GUS接触。
在实施方案中,所述方法涉及:
一种选择性抑制细菌β-葡糖苷酸酶的方法,该方法包括给有需要的受试者施用有效量的至少一种式I化合物。在实施方案中,细菌选自拟杆菌属(Bacteroides sp.)、双歧杆菌属(Bifidobacterium sp.)、儿茶杆菌属(Catenabacterium sp.)、梭菌属(Clostridiumsp.)、棒状杆菌属(Corynebacterium sp.)、肠球菌属(Enterococcus sp.)、肠杆菌科(Enterobacteriaceae)、乳酸杆菌属(Lactobacillus sp.)、消化链球菌属(Peptostreptococcus sp.)、丙酸杆菌属(Propionibacterium sp.)、变形杆菌属(Proteussp.)、分枝杆菌属(Mycobacterium sp.)、假单胞菌属(Pseudomonas sp.)、葡萄球菌属(Staphylococcus sp.)和链球菌属(Streptococcus sp.)。
一种改善喜树碱衍生的抗肿瘤剂效率的方法,该方法包括在给予喜树碱衍生的抗肿瘤剂之前、同时或之后给予受试者治疗有效量的至少一种式I化合物。
一种减轻施用喜树碱衍生的抗肿瘤剂的受试者的副作用的方法,该方法包括在施用喜树碱衍生的抗肿瘤剂之前、同时或之后给予治疗有效量的至少一种式I化合物。
在实施方案中,喜树碱衍生的抗肿瘤剂选自喜树碱、二氟替康(diflomotecan)、依沙替康(exatecan)、吉马替康(gimatecan)、伊立替康、卡瑞汀、勒托替康(lurtotecan)、鲁比替康(rubitecan)、丝拉替康(silatecan)和拓扑替康。特别地,喜树碱衍生的抗肿瘤剂是伊立替康。
一种减轻与化学疗法相关的胃肠道不适的方法,包括:a)给动物施用抗癌有效量的化疗剂,和b)给同一动物施用抑制有效量的一种式I化合物。在该实施方案的一个方面,化疗活性剂是喜树碱衍生的抗肿瘤剂。
一种提高葡糖苷酸酶-底物剂或化合物效率的方法,该方法包括在给予所述药剂或化合物之前、同时或之后给予受试者治疗有效量的至少一种式I化合物。
评估β-葡糖苷酸酶活性的方法是本领域已知的。参见,例如Farnleitner等,(2002)Water Res.36:975-981;Fior等人(2009)Plant Sci.176:130-135;和Szasz(1967)Clin.Chem.13:752-759。本领域技术人员熟悉用于测试活性化合物选择性抑制β-葡糖苷酸酶而对居住在胃肠道的细菌具有轻微或无毒性的能力的测定法。与未提供选择性β-葡糖苷酸酶抑制剂的细菌相比,选择性β-葡糖苷酸酶抑制剂提供的细菌β-葡糖苷酸酶活性可降低至少约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%。
在一个方面,本文提供了用于在有需要的受试者中减轻治疗癌症中的副作用,特别是胃肠道的副作用的方法。术语“癌症”是指或描述哺乳动物中通常以不受调节的细胞生长为特征的生理状况。癌症的实例包括但不限于癌、淋巴瘤、胚细胞瘤、肉瘤和白血病或淋巴恶性肿瘤。此类癌症的更具体的实例包括黑素瘤,鳞状细胞癌(例如上皮鳞状细胞癌),包括黑素瘤的肺癌,多发性骨髓瘤,小细胞肺癌,非小细胞肺癌(“NSCLC”),肺腺癌和肺鳞癌,腹膜癌,肝细胞癌,胃部癌或胃癌,包括胃肠癌,胰腺癌,胶质母细胞瘤,多形性胶质母细胞瘤,KRAS突变实体瘤,惰性非霍奇金淋巴瘤,慢性淋巴细胞白血病(CLL),弥漫性大B细胞淋巴瘤,甲状腺癌,非霍奇金淋巴瘤,基底细胞癌,血液肿瘤,B细胞非霍奇金淋巴瘤,急性髓性白血病(AML),宫颈癌,卵巢癌,肝癌,膀胱癌,肝癌,乳腺癌,包括三阴性乳腺癌,结肠癌,直肠癌,结肠直肠癌,子宫内膜癌或子宫癌,唾液腺癌,肾部癌或肾癌,前列腺癌,外阴癌,甲状腺癌,肝部癌,肛门癌,阴茎癌以及头颈癌。还包括“血液恶性肿瘤”或“血液癌症”,其是影响血液、骨髓和淋巴结的癌症类型。血液恶性肿瘤可能源自两种主要血细胞谱系:髓样细胞系和淋巴细胞系。髓样细胞系通常产生粒细胞,红细胞、血小板、巨噬细胞和肥大细胞;淋巴细胞系产生B、T、NK和浆细胞。淋巴瘤、淋巴细胞性白血病和骨髓瘤来自淋巴系,而急性和慢性髓性白血病、骨髓增生异常综合征和骨髓增生性疾病起源于骨髓。白血病包括急性成淋巴细胞性白血病(ALL)、急性髓细胞性白血病(AML)、慢性淋巴细胞性白血病(CLL)、慢性髓细胞性白血病(CML)、急性单核细胞白血病(AMOL)和小淋巴细胞性淋巴瘤(SLL)。淋巴瘤包括霍奇金淋巴瘤(所有四种亚型)和非霍奇金淋巴瘤(NHL,所有亚型)。
本公开的化合物可以以本领域已知的任何合适的方式施用。在一些实施方案中,式I化合物或其药学上可接受的盐通过静脉内、肌肉内、皮下、局部、口服、透皮、腹膜内、眼内、植入、吸入、鞘内、心室内、肿瘤内或鼻内施用。
在一些实施方案中,连续施用式I化合物。在其他实施方案中,间歇施用式I化合物。此外,用有效量的式I化合物治疗受试者可以包括单一治疗,或可包括一系列治疗。
应理解,活性化合物的适当剂量取决于普通技术医师或兽医知识范围内的许多因素。活性化合物的剂量可以变化,例如,取决于受试者的年龄、体重、总体健康状况、性别和饮食,施用时间、施用途径、排泄率和任何药物组合。
还将理解的是,用于治疗的式I化合物或药学上可接受的盐的有效剂量在特定治疗过程中可以增加或减少。剂量变化可能导致并且从诊断测定的结果变得明显。
在一些实施方案中,式I化合物按介于约0.001μg/kg至约1000mg/kg的剂量施用给受试者,包括但不限于约0.001μg/kg、0.01μg/kg、0.05μg/kg、0.1μg/kg、0.5μg/kg、1μg/kg、10μg/kg、25μg/kg、50μg/kg、100μg/kg、250μg/kg、500μg/kg、1mg/kg、5mg/kg、10mg/kg、25mg/kg、50mg/kg、100mg/kg和200mg/kg。
在一些实施方案中,施用式I化合物的受试者为哺乳动物,例如家养动物(例如,牛、绵羊、猫、狗和马)、灵长类动物(例如,人和非人灵长类动物,例如猴子)、兔子和啮齿动物(例如,小鼠和大鼠)。在一些实施方案中,所治疗的受试者是人。
在一些实施方案中,包括向受试者施用有效量的式I化合物或其药学上可接受的盐的用于减轻副作用或改善化疗药物的效力的方法还包括施用所述化疗药物。例如,式I化合物和化疗剂可以依次施用(在不同的时间)或同时施用(在同一时间)。式I化合物和化疗剂可以通过相同的施用途径或通过不同的施用途径施用。
化疗剂可以是喜树碱衍生的抗肿瘤剂。如本文所用,“喜树碱衍生的抗肿瘤剂”等是指抑制DNA酶拓扑异构酶I的细胞毒性喹啉生物碱。喜树碱衍生的抗肿瘤剂包括但不限于喜树碱(即(S)-4-乙基-4-羟基-1H-吡喃并[3',4':6,7]吲嗪并[1,2-b]喹啉-3,14-(4H,12H)-二酮);二氟替康(即(5R)-5-乙基-9,10-二氟-1,4,5,13-四氢-5-羟基-3H,15H-氧杂[3',4':6,7]吲嗪并[1,2-b]喹啉-3,15-二酮);依沙替康(即(1S,9S)-1-氨基-9-乙基-5-氟-1,2,3,9,12,15-六氢-9-羟基-4-甲基-10H,13H-苯并(脱)吡喃并(3',4':6,7)吲嗪并(1,2-b)喹啉-10,13-二酮);吉马替康(即(4S)-11-((E)-((1,1-二甲基乙氧基)亚氨基)甲基)-4-乙基-4-羟基-1,12-二氢-14H-吡喃并(3',4':6,7)吲嗪并(1,2-b)喹啉-3,14(4H)-二酮);伊立替康(即(S)-4,11-二乙基-3,4,12,14-四氢-4-羟基-3,14-二氧代-1H-吡喃并[3',4':6,7]-吲嗪并[1,2-b]喹啉-9-基-[1,4'联哌啶]-1'-羧基酯);卡瑞汀(即(4S)-4-乙基-4-羟基-11-(2-三甲基甲硅烷基)乙基)-1H-吡喃并[3',4':6,7]吲嗪并[1,2-b]喹啉-3,14(4H,12H)-二酮);勒托替康(即7-(4-甲基哌嗪基亚甲基)-10,11-亚乙二氧基-20(S)-喜树碱);鲁比替康(即(4S)-4-乙基-4-羟基-10-硝基-1H-吡喃并[3',4':6,7]吲嗪并[1,2-b]喹啉-3,14(4H,12H)-二酮);丝拉替康(即7-叔丁基二甲基甲硅烷基-10-羟基喜树碱);和拓扑替康(即(S)-10-[(二甲基氨基)甲基]-4-乙基-4,9-二羟基-1H-吡喃并[3',4':6,7]吲嗪并[1,2-b]喹啉-3,14(4H,12H)-二酮)。
特别感兴趣的是伊立替康(CPT-11或),它是一种有效的喜树碱衍生的抗肿瘤剂,用于治疗脑、结肠和肺的实体恶性肿瘤,以及难治性形式的白血病和淋巴瘤。伊立替康是一种必须转化为其活性形式SN-38(7-乙基-10-羟基-喜树碱)以具有抗肿瘤活性的前药。在其排泄期间,SN-38通过II期药物代谢UDP-葡糖醛酸基转移酶而被葡糖苷酸化为SN-38葡糖苷酸(SN-38G)。
术语“葡糖苷酸酶-底物试剂或化合物”是指可以是葡糖苷酸酶的底物的任何药物、试剂或化合物,或特别是其代谢物。因此,在一些情况下,本文所用的该术语包括本身不是底物但代谢成底物的药物、化合物或试剂。葡糖醛酸化的任何药物、化合物或试剂或其代谢物,也称为葡糖苷酸,可以是葡糖苷酸酶的底物,并且在本文中也描述为葡糖苷酸酶-底物剂或化合物。许多药物、试剂或化合物在其新陈代谢的某些时候经历葡糖醛酸化。或者,药物、试剂或化合物可以是葡糖苷酸前药。这些葡糖苷酸可具有与母体药物、试剂或化合物不同的性质。葡糖醛酸化可以调节某些药物的效力:吗啡的6-葡糖苷酸是比母体化合物更有效的镇痛药,而3-葡糖苷酸是吗啡拮抗剂。此外,类固醇葡萄糖醛酸化可在病理生理条件下或在类固醇治疗期间产生更多活性或毒性代谢物。
作为葡糖苷酸酶底物的药物、试剂或化合物或其代谢物可以通过葡糖苷酸酶水解改变它们各自的性质。在具体的非限制性实例中,如果药物、药剂、化合物或其代谢物已被代谢成葡糖苷酸,则葡糖苷酸的水解可以再活化药物、试剂、化合物或其代谢物。在许多情况下,这种再活化会引起不良反应。例如,如果葡糖苷酸药物、药剂或化合物或其代谢物存在于肠道中,则肠道中的葡糖苷酸酶水解可导致胃肠道不适。
本文所述的方法可用于减轻、降低或改善由葡糖苷酸酶对药物、药剂或化合物或特别是其代谢物的作用引起的不良反应,例如胃肠道不适。如本文其他地方所述,葡糖苷酸的水解可导致不良反应。本文描述的方法抑制或降低β-葡糖苷酸酶的活性。因此,该方法可用于减轻、降低或改善与施用此类药物、药剂或化合物相关的不良反应,例如胃肠不适。该方法还可以改善可以形成葡糖苷酸的任何此类药物、药剂或化合物或其代谢物的耐受性。因此,葡糖苷酸酶抑制剂的施用可以挽救或改善用任何药物、药剂或化合物的治疗,其中与药物、药剂、化合物或其代谢物相关的葡糖苷酸的葡糖苷酸酶水解引起一种或多种不良反应,特别是胃肠道不适或毒性。随着不良反应的减轻,患者的依从性和面貌也会得到改善。
如上所述,术语“葡糖苷酸酶-底物试剂或化合物”是指可以是葡糖苷酸酶的底物的任何药物、试剂或化合物,或特别是其代谢物。这些可包括用于治疗疾病例如但不限于癌症的任何化学化合物。此类化疗剂的实例包括NSAID、索拉非尼、烷化剂如塞替派(thiotepa)和环磷酰胺氨基磺酸盐,例如白消安、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);吖丙啶,例如苯并多巴(benzodopa)、卡巴醌(carboquone)、美妥替哌(meturedop)和脲多巴(uredopa);乙烯亚胺和甲基胺类(methylamelamines),包括六甲蜜胺(altretamine)、曲他胺、三亚乙基磷酰胺(trietylenephosphoramide)、三亚乙基硫代磷酰胺和三甲蜜胺(trimethylolomelamine);番荔素(acetogenins)(特别是泡番荔枝辛(bullatacin)和布拉他辛酮(bullatacinone));δ-9-四氢大麻酚(屈大麻酚(dronabinol),);β-拉帕醌;拉帕醇;秋水仙碱;桦木酸;喜树碱(包括合成类似物拓扑替康CPT-11(伊立替康,)、乙酰喜树碱、莨菪亭(scopolectin)和9-氨基喜树碱);苔藓虫素;培美曲塞;callystatin;CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);鬼臼毒素;鬼臼酸;替尼泊苷;cryptophycins(特别是cryptophycin 1和cryptophycin 8);多拉司他汀;多米卡新(duocarmycin)(包括合成类似物KW-2189和CB1-TM1);eleutherobin;pancratistatin;TLK-286;CDP323,口服α-4整联蛋白抑制剂;sarcodictyin;海绵抑制(spongistatin);氮芥,如苯丁酸氮芥、萘氮芥(chlomaphazine)、环磷酰胺(cholophosphamide)、雌氮芥、异环磷酰胺、氮芥、盐酸氮芥氧化物、美法伦、新氮芥、苯芥胆留醇、泼尼氮芥、曲磷胺、尿嘧啶氮芥;亚硝基脲类,如卡莫司汀、氯嗪菌素、福莫司汀、洛莫司汀、尼莫司汀和雷尼喹碱;抗生素如烯二炔抗生素(例如加利车霉素,尤其是加利车霉素γ1I和加利车霉素ωI1)(参见例如Nicolaou等,Angew.ChemIntl.Ed.Engl.,33:183-186(1994));dynemicin,包括dynemicin A;埃斯培拉霉素(esperamicin);以及新制癌菌素(neocarzinostatin)发色团和相关的色素蛋白烯二炔抗生素发色团)、阿克拉霉素(aclacinomysin)、放线菌素、蒽霉素(authramycin)、偶氮丝氨酸、博莱霉素、放线菌素C、卡奇霉素、卡柔比星(carabicin)、洋红霉素、嗜癌霉素、色霉素、更生霉素、柔红霉素、地托比星、6-重氮-5-氧代-L-蛋氨酸、阿霉素(包括吗啉代多柔比星、氰基吗啉代多柔比星、2-吡咯啉基阿霉素、盐酸多柔比星脂质体注射液和脱氧多柔比星)、表阿霉素、依索比星、去甲氧柔红霉素、蒽环类、丝裂霉素如丝裂霉素C、霉酚酸、诺拉霉素、橄榄霉素、培洛霉素、泊非霉素(potfiromycin)、嘌呤霉素、三铁阿霉素、罗多比星、链黑霉素、链脲菌素、杀结核菌素、乌苯美司、净司他丁、佐柔比星;抗代谢物,如甲氨蝶呤、吉西他滨替加氟卡培他滨埃坡霉素和5-氟尿嘧啶(5-FU);叶酸类似物如二甲叶酸、甲氨蝶呤、蝶罗呤、三甲曲沙;嘌呤类似物,如氟达拉滨、6-巯基嘌呤、硫胺素、硫鸟嘌呤;嘧啶类似物如安西他滨、阿扎胞苷、6-氮杂尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、多西氟尿苷、依那西班和氟尿苷;抗肾上腺素,如氨鲁米特、米托坦、曲洛司坦;叶酸补充剂如氟喹啉酸;醋葡醛内酯;醛磷酰胺糖苷;氨基乙酰丙酸;恩尿嘧啶;安吖啶;比曲比新(bestrabucil);比生群;依达曲沙(edatraxate);地佛法明(defofamine);脱羰秋水仙碱;地吖醌;依氟鸟氨酸(elfornithine);依利醋铵;依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达明;美登素类,如美登素和安沙霉素;米托胍腙;米托蒽醌;莫哌达醇;硝氨丙吖啶;喷司他丁;蛋氨氮芥(phenamet);吡喃阿霉素;洛索蒽醌;2-乙基酰胼;丙卡巴胼;多糖复合物(JHS Natural Products,Eugene,OR);雷佐生(razoxane);根霉素;西佐非兰;螺环锗;替奴佐酸;三亚胺醌;2,2',2”-三氯三乙胺;单端孢霉烯(特别是T-2毒素、verracurin A、杆孢菌素A和蛇形菌毒素);氨基甲酸乙酯;长春地辛达卡巴嗪;甘露醇氮芥;二溴甘露醇;卫矛醇;哌泊溴烷;gacytosine;阿拉伯糖苷(“Ara-C”);塞替派;紫杉醇类,例如紫杉醇紫杉醇的白蛋白工程纳米颗粒制剂(ABRAXANETM)和多西紫杉醇瘤可宁(chloranbucil);6-硫鸟嘌呤;巯基嘌呤;甲氨蝶呤;铂类似物,如顺铂和卡铂;长春碱铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱奥沙利铂;甲酰四氢叶酸(leucovovin);长春瑞滨诺消灵(novantrone);依达曲沙;柔红霉素;氨基蝶呤;伊班膦酸盐;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);维生素A类,如视黄酸;任何上述的药学上可接受的盐、酸或衍生物;以及上述两种或多种的组合,例如CHOP(环磷酰胺、多柔比星、长春新碱和泼尼松龙联合治疗的缩写)和FOLFOX(奥沙利铂(ELOXATINTM)与5-FU和甲酰四氢叶酸联合治疗方案的缩写)。
化疗剂的其他实例包括抗激素剂,其用于调节、减少、阻断或抑制可促进癌症生长的激素的作用,并且通常以全身性或全身治疗的形式。它们本身可以是激素。实例包括抗雌激素和选择性雌激素受体调节剂(SERM),包括例如他莫昔芬(包括他莫昔芬)、雷洛昔芬屈洛昔芬、4-羟基他莫昔芬、曲沃昔芬、盐酸雷洛昔芬、LY117018,奥那司酮和托瑞米芬抗孕酮;雌激素受体下调因子(ERD);雌激素受体拮抗剂如氟维司群用于抑制或关闭卵巢的药剂,例如黄体化激素释放激素(LHRH)激动剂,例如醋酸亮丙瑞林(和)、醋酸戈舍瑞林、醋酸布舍瑞林和曲普瑞林;抗雄激素如氟他胺、尼鲁米特和比卡鲁胺;抑制芳香酶的芳香酶抑制剂,其调节肾上腺中雌激素的产生,例如,4(5)-咪唑类、氨鲁米特、醋酸甲地孕酮依西美坦formestanie、法倔唑、伏氯唑(vorozole)来曲唑和阿纳托唑此外,化疗剂的这种定义包括双膦酸盐,如氯膦酸盐(例如或)、依替膦酸盐NE-58095、唑来膦酸/唑来膦酸盐阿仑膦酸盐帕米膦酸盐替鲁膦酸盐或利塞膦酸盐以及曲沙他滨(1,3-二氧戊环核苷胞嘧啶类似物);反义寡核苷酸,特别是那些抑制与异常细胞增殖有关的信传导途径中基因表达的反义寡核苷酸,例如PKC-α、Raf、H-Ras和表皮生长因子受体(EGF-R);疫苗如疫苗和基因治疗疫苗,例如疫苗;疫苗和疫苗;拓扑异构酶1抑制剂(例如);抗雌激素,如氟维司群;EGFR抑制剂如厄洛替尼或西妥昔单抗;抗VEGF抑制剂如贝伐珠单抗;阿罗替康;rmRH(例如);17AAG(格尔德霉素衍生物,即热休克蛋白(Hsp)90毒)和上述任一种的药学上可接受的盐、酸或衍生物。
“化疗剂”的定义还包括:(i)用于调节或抑制激素对肿瘤的作用的抗激素剂,例如抗雌激素和选择性雌激素受体调节剂(SERM),包括例如他莫昔芬(包括柠檬酸他莫昔芬),雷洛昔芬,屈洛昔芬,4-羟基他莫昔芬,曲沃昔芬、盐酸雷洛昔芬、LY117018,奥那司酮和和(柠檬酸托瑞米芬);(ii)芳香酶抑制剂,其抑制芳香酶,其调节肾上腺中的雌激素产生,例如,4(5)-咪唑类、氨鲁米特、(醋酸甲地孕酮)、(依西美坦;辉瑞公司)、formestanie、法倔唑、(伏氯唑)、(来曲唑;诺华公司)和(阿纳托唑;阿斯利康公司);(iii)抗雄激素如氟他胺、尼鲁米特、比卡鲁胺、亮丙瑞林和戈舍瑞林;以及曲沙他滨(1,3-二氧戊环核苷胞嘧啶类似物);(iv)蛋白激酶抑制剂;(v)脂质激酶抑制剂;(vi)反义寡核苷酸,特别是抑制与异常细胞增殖有关的信号传导途径中基因表达的反义寡核苷酸,例如PKC-α、Ralf和H-Ras;(vii)核酶如VEGF表达抑制剂(如)和HER2表达抑制剂;(viii)基因治疗疫苗等疫苗,例如和 rIL-2、拓扑异构酶1抑制剂,如 (ix)抗血管生成剂,例如贝伐单抗(基因泰克公司);(x)上述任何一种的药学上可接受的盐、酸和衍生物。
V.式I化合物的制备
式I化合物可以通过合成路线合成,所述合成路线包括与化学领域中公知的那些类似的方法,特别是根据本文所包含的描述,以及在以下描述的其他杂环的方法:Comprehensive Heterocyclic Chemistry II,Katritzky和Rees编著,Elsevier,1997,例如第3卷;Liebigs Annalen der Chemie,(9):1910-16,(1985);Helvetica Chimica Acta,41:1052-60,(1958);Arzneimittel-Forschung,40(12):1328-31,(1990),其中的每一个都通过引用明确地并入本文。原料通常可从商业来源获得,例如Aldrich Chemicals(Milwaukee,WI),或者使用本领域技术人员熟知的方法容易地制备(例如通过LouisF.Fieser和Mary Fieser,Reagents for Organic Synthesis,v.1-23,Wiley,N.Y.(1967-2006ed.)或Beilsteins Handbuch der organischen Chemie,4,Aufl.ed.Springer-Verlag,Berlin,,包括补充部分中一般描述的方法制备)(也可通过Beilstein在线数据库获得)。
可用于合成式I化合物和必需的试剂和中间体的合成化学转化和保护基团方法(保护和去保护)是本领域已知的,包括例如以下文献中描述的那些:R.Larock,Comprehensive Organic Transformations,VCH Publishers(1989);T.W.Greene和P.G.M.Wuts,Protective Groups in Organic Synthesis,3rd Ed.,John Wiley and Sons(1999);及L.Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis,JohnWiley and Sons(1995)及其后续版本。
式I化合物可以单独制备或作为包含至少2种,例如5至1,000种化合物或10至100种化合物的化合物库制备。式I化合物的库可以通过组合“分裂和混合”方法或通过使用溶液相或固相化学的多个平行合成,通过本领域技术人员已知的方法制备。因此,根据另一方面,提供了包含至少2种化合物或其药学上可接受的盐的化合物库。
一般程序和实施例提供了制备式I化合物的示例性方法。本领域技术人员将理解,可以使用其他合成途径来合成式I化合物。尽管在方案、一般程序和实施例中描述和讨论了特定的起始原料和试剂,但是可以容易地替换其他原料和试剂以提供各种衍生物和/或反应条件。此外,根据本公开内容,使用本领域技术人员熟知的常规化学方法,可以进一步改性通过所述方法制备的许多示例性化合物。
在制备式I化合物时,可能需要保护中间体的远处官能团(例如伯胺或仲胺)。对这种保护的需求将取决于远处官能团的性质和制备方法的条件而变化。合适的氨基保护基包括乙酰基、三氟乙酰基、叔丁氧基羰基(BOC)、苄氧基羰基(CBz或CBZ)和9-芴基亚甲氧基羰基(Fmoc)。本领域技术人员容易确定对这种保护的需要。有关保护基团及其用途的一般说明,请参阅T.W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991。
提供以下实施例是为了说明而不是为了限制。
实施例
实施例1.Inh9和化合物2-8的合成
方案1.Inh9的合成。
表1中的化合物2-8通过与从中间体4合成Inh9类似的方法制备。
中间体1的合成
向环己酮(5.0g,5.3mL,51mmol,1.0当量)在16mL甲醇中的溶液中缓慢加入二硫化碳(7.8g,6.1mL,102mmol,2.0当量)和丙二腈(3.4g,51mmol,1.0eq.),搅拌混合物5分钟,同时保持温度低于20℃。加入三乙胺(2.5mL),并将反应混合物在室温下搅拌过夜。过滤沉淀的产物,用甲醇洗涤并真空干燥,得到中间体1,为橙色固体(4.3g,40%)。
1H NMR(400MHz,DMSO-d6)δ8.69(s,2H),2.68(m,2H),2.59(m,2H),1.68(m,4H)
LC-MS(λ=254nm):99%,tR=5.9min.MS(ESI+):223[M+H]+
中间体2的合成
向中间体1(4.0g,18mmol,1.0当量)在乙醇(15mL)中的悬浮液中加入吗啉(8mL,90mmol,5当量),并将混合物在回流下加热过夜。将沉淀的产物冷却至室温,用氮气脱气,过滤,用乙醇洗涤并真空干燥,得到中间体2,为橙色固体(3.8g,76%)。
1H NMR(400MHz,DMSO-d6)δ4.33–4.27(m,1H),3.74(m,4H),3.67(m,4H),3.55–3.50(m,1H),2.61(t,J=5.8Hz,2H),2.41(t,J=5.8Hz,2H),1.77–1.65(m,2H),1.62–1.52(m,2H)
LC-MS(λ=254nm):99%,tR=4.9min.MS(ESI+):276[M+H]+
中间体3的合成
向中间体2(3.0g,11mmol,1.0当量)在22mL DMF中的溶液中加入2-氯乙腈(0.8mL,11.99mmol,1.1当量)并在室温下搅拌1小时。然后将KOH(10%w/v,5.5mL)水溶液的第一部分加入到反应混合物中并将其在室温下搅拌过夜,之后将KOH(10%w/v,5.5mL)水溶液的第二部分加入到反应混合物中并在室温下再搅拌4小时。将水(50mL)加入到沉淀的固体产物中,然后将其过滤并真空干燥,得到中间体3,为粉黄色固体(2.36g,69%)。
1H NMR(400MHz,DMSO-d6)δ6.35(s,2H),3.84–3.70(m,4H),3.27(t,J=6.5Hz,2H),3.19–3.10(m,4H),2.64(t,J=5.7Hz,2H),1.88–1.75(m,2H),1.70–1.58(m,2H)
LC-MS(λ=254nm):99%,tR=5.9min.MS(ESI+):315[M+H]+
中间体4的合成
在30分钟内,在0-5℃下,将亚硝酸钠(1.5g,22mmol,3.0当量)在水(7.3mL)中的溶液滴加到中间体3(2.3g,7.3mmol,1.0当量)的浓盐酸(15mL)悬浮液中。将混合物在0-5℃下搅拌一小时,然后在室温下搅拌过夜。将水(100mL)加入到沉淀的产物中,然后将其过滤,用水洗涤,并真空干燥,得到中间体4,为黄色固体(2.4g,92%)。
1H NMR(400MHz,氯仿-d)δ3.93–3.85(m,2H),3.75(t,J=6.6Hz,1H),3.48–3.41(m,2H),2.74(t,J=5.9Hz,1H),2.08–1.97(m,1H),1.88–1.77(m,1H)
LC-MS(λ=254nm):99%,tR=6.4min.MS(ESI+):362[M+H]+
中间体5的合成
向中间体4(85mg,0.23mmol,1.0当量)的CH3CN(2mL)溶液中加入K2CO3(300mg)和1-Boc-哌嗪(110mg,0.59mmol,2.5当量),将反应混合物加热回流过夜。完成后,通过加入20mL饱和NaHCO3猝灭反应。将水相用CH2Cl2(3×20mL)萃取,合并有机层,用盐水洗涤,经无水Na2SO4干燥,并过滤。通过旋转蒸发除去溶剂,得到深棕色原料。将粗制物质吸附在硅胶上,并使用CH2Cl2/MeOH/NH3溶剂系统通过正相自动Teledyne Isco色谱法纯化。得到中间体5,为浅黄色固体(50mg,43%)。
1H NMR(400MHz,氯仿-d)δ4.08–4.02(m,4H),3.92–3.83(m,4H),3.77(t,J=6.7Hz,2H),3.68–3.60(m,4H),3.38–3.30(m,4H),2.73(t,J=5.8Hz,2H),2.03–1.94(m,2H),1.85–1.76(m,2H),1.49(s,9H)
LC-MS(λ=254nm):99%,tR=6.5min.MS(ESI+):512[M+H]+
Inh9的合成
在0℃下,向中间体5(50mg,0.098mmol)的CH2Cl2(1mL)溶液中加入三氟乙酸(1mL),将反应混合物在室温下搅拌至完全。将溶液用饱和NaHCO3溶液洗涤,经无水Na2SO4干燥,过滤,真空浓缩,得到Inh9,为黄色固体(40mg,99%)。
1H NMR(400MHz,氯仿-d)δ9.91(s,1H),4.36(s,4H),3.92–3.79(m,4H),3.68(t,J=6.2Hz,2H),3.48(s,3H),3.40–3.31(m,4H),2.71(t,J=5.6Hz,2H),1.97(m,2H),1.79(m,2H)
LC-MS(λ=254nm):99%,tR=5.0min.MS(ESI+):412[M+H]+
实施例2.化合物12-17的合成
方案2.化合物15的合成。
中间体6和7根据文献合成(J.C.A.Hunt等人Bioorg.Med.Chem.Lett.17(2007)5222-5226)。
表1中的化合物12-14和16-17通过与从中间体7合成化合物15类似的方法制备。
中间体8的合成
在0℃下将中间体7(500mg,2.04mmol,1.0eq.)分批加入到在DMF(10.3mL)中的氢化钠(在矿物油中的60%分散体,85mg,2.12mmol,1.1eq.)的搅拌悬浮液中。将反应混合物在室温下搅拌35-40分钟。向所得溶液中一次性加入N-苯基-三氟甲磺酰亚胺(729mg,2.04mmol,1.0当量)。20分钟后,将二甲胺(1.06mL,2.12mmol,1.1当量)加入到反应混合物中并搅拌过夜。用水(5mL)缓慢淬灭反应,并用乙酸乙酯(3×20mL)萃取。将合并的有机部分用饱和NaHCO3溶液洗涤,经无水Na2SO4干燥,过滤,在减压下浓缩,并使用MeOH/H2O/0.1%乙酸溶剂系统通过反相自动化Teledyne Isco色谱法纯化。获得中间体8,为浅黄色固体(255mg,46%)。
1H NMR(400MHz,DMSO-d6)δ3.22(t,J=6.5Hz,2H),2.85(s,6H),2.59(t,J=5.8Hz,2H),1.84–1.72(m,2H),1.60(m,2H)
LC-MS(λ=254nm):99%,tR=6.1min.MS(ESI+):273[M+H]+
中间体9的合成
在30分钟内,在0-5℃下,将亚硝酸钠(266mg,3.9mmol,3.0当量)在水(2mL)中的溶液滴加到中间体8(350mg,1.3mmol,1.0当量)的浓盐酸(10mL)悬浮液中。将混合物在0-5℃下搅拌一小时,然后在室温下搅拌过夜。将水(100mL)加入到沉淀的产物中,然后将其过滤,用水洗涤,并真空干燥,得到中间体9,为浅黄色固体(291g,71%)。
1H NMR(400MHz,氯仿-d)δ3.68(t,J=6.6Hz,2H),3.09(s,4H),2.72(t,J=5.9Hz,2H),2.04–1.93(m,2H),1.81–1.72(m,2H)
LC-MS(λ=254nm):99%,tR=6.8min.MS(ESI+):320[M+H]+
中间体10的合成
向中间体4(150mg,0.47mmol,1.0当量)的CH3CN(4mL)溶液中加入K2CO3(300mg)和1-Boc-哌嗪(219mg,1.17mmol,2.5当量),将反应混合物加热回流过夜。完成后,通过加入20mL饱和NaHCO3猝灭反应。将水相用CH2Cl2(3×20mL)萃取,合并有机层,用盐水洗涤,经无水Na2SO4干燥,过滤,并在减压下浓缩,得到深棕色粗制物质。将粗制物质吸附在硅胶上,并使用CH2Cl2/MeOH/NH3溶剂系统通过正相自动Teledyne Isco色谱法纯化。获得中间体10,为白色固体(50mg,23%)。
1H NMR(400MHz,氯仿-d)δ4.07–3.98(m,4H),3.72(t,J=6.6Hz,2H),3.62(dd,J=6.1,4.3Hz,4H),3.01(s,6H),2.71(t,J=5.9Hz,2H),2.01–1.89(m,2H),1.76(m,2H),1.48(s,9H)
LC-MS(λ=254nm):99%,tR=6.9min.MS(ESI+):470[M+H]+
化合物15的合成
在0℃下,向中间体10(50mg,0.106mmol)的CH2Cl2(1mL)溶液中加入三氟乙酸(1mL),将反应混合物在室温下搅拌至完全。将溶液用饱和NaHCO3溶液洗涤,经无水Na2SO4干燥,过滤,真空浓缩,得到化合物15,为白色固体(35mg,90%)。
1H NMR(400MHz,DMSO-d6)δ4.15–4.06(m,4H),3.59(t,J=6.5Hz,2H),3.29–3.21(m,4H),3.00(s,6H),2.73(t,J=5.8Hz,2H),1.98–1.87(m,2H),1.77–1.64(m,2H)
LC-MS(λ=254nm):99%,tR=5.6min.MS(ESI+):370[M+H]+
实施例3.化合物18的合成
方案3.化合物18的合成。
实施例4.化合物21、28和29的合成
方案4.化合物21的合成。
表1中化合物28和29通过与化合物21类似的方法制备。
中间体11的合成
在氮气氛下,将2,6-二氯吡啶-3-甲腈(300mg,1.73mmol,1.0当量)溶解在火焰干燥的圆底烧瓶中的DMF(2mL)中。向所得溶液中加入吗啉(0.15mL,1.73mmol,1.0当量)和三乙胺(0.5mL,3.46mmol,2.0当量)。将反应在室温下在氮气下搅拌过夜。用饱和NH4Cl水溶液(10mL)淬灭反应。分离水相,用EtOAc(5×10mL)萃取。将所有合并的有机层用无水Na2SO4干燥,过滤,并在减压下浓缩,得到白色粗制物质。粗制物质的1H NMR和LC-MS显示存在单-和二-胺化产物(6:1,相同的tR)。粗制物质无需进一步纯化即可用于下一反应(350mg)。
中间体12的合成
在氮气氛下,将粗制中间体11(350mg)溶于火焰干燥的圆底烧瓶中的乙醇(9mL)中。向所得溶液中加入2-巯基乙酰胺(在甲醇氨溶液中100mg/1mL,1.71mL,1.88mmol)和无水K2CO3(521mg,3.8mmol)。将反应物在氮气下于100℃下回流过夜。用水(50mL)淬灭反应,沉淀出所需产物。过滤沉淀的产物,用水(50mL)洗涤,并在减压下浓缩,得到中间体12,为浅黄色固体(299mg,两步68%)。
1H NMR(400MHz,DMSO-d6)δ8.11(d,J=9.1Hz,1H),7.03(brs,2H),6.93(d,J=9.1Hz,1H),6.82(brs,2H),3.73–3.67(m,4H),3.59–3.53(m,4H)
LC-MS(λ=254nm):99%,tR=4.6min.MS(ESI+):279[M+H]+
中间体13的合成
在氮气氛下,将中间体12(150mg,1.56mmol,1.0当量)溶于火焰干燥的圆底烧瓶中的二噁烷(2mL)中。向所得的溶液中加入氯甲酸三氯甲酯(0.07毫升,0.61毫摩尔,1.1当量),并将反应物在氮气下在102℃回流3小时。用水(10mL)缓慢淬灭反应。过滤沉淀的产物,用水(50mL)洗涤,并在减压下浓缩,得到黄色固体(118mg,69%)。
1H NMR(400MHz,DMSO-d6)δ12.03(brs,1H),11.29(brs,1H),8.33(d,J=9.3Hz,1H),7.10(d,J=9.3Hz,1H),3.70(m,4H),3.68–3.60(m,4H)
LC-MS(λ=254nm):99%,tR=5.0min.MS(ESI+):305[M+H]+
在氮气氛下,将上述黄色固体(110mg,0.36mmol,1.0当量)加入到火焰干燥的圆底烧瓶中的苯基膦酰二氯(4mL)中。将反应混合物在氮气下170℃回流2小时。用水(10mL)缓慢淬灭反应,沉淀出所需产物。过滤沉淀的产物,用更多的水(30mL)洗涤,并在减压下浓缩,得到中间体13,为黄色固体(>30mg,>25%)。
1H NMR(400MHz,氯仿-d)δ8.34(d,J=9.1Hz,1H),6.80(d,J=9.1Hz,1H),3.85–3.75(m,8H)
LC-MS(λ=254nm):99%,tR=5.6min.MS(ESI+):342[M+H]+
中间体14的合成
向中间体13(90mg,0.088mmol,1.0当量)的CH3CN(2mL)溶液中加入K2CO3(300mg)和1-Boc-哌嗪(82mg,0.43mmol,5.0当量),将反应混合物加热回流过夜。完成后,通过加入20mL饱和NaHCO3猝灭反应。将水相用CH2Cl2(3×20mL)萃取,合并有机层,用盐水洗涤,经无水Na2SO4干燥,过滤,并在减压下浓缩,得到深棕色粗制物质。将粗制物质吸附在硅胶上,并使用CH2Cl2/MeOH/NH3溶剂系统通过正相自动Teledyne Isco色谱法纯化。得到中间体14,为浅黄色固体(40mg,93%)。
1H NMR(400MHz,氯仿-d)δ8.31(d,J=9.0Hz,1H),6.76(d,J=9.1Hz,1H),3.97–3.90(m,4H),3.85–3.77(m,4H),3.73–3.65(m,4H),3.58(m,4H),1.47(s,9H)
LC-MS(λ=254nm):99%,tR=6.6min.MS(ESI+):492[M+H]+
中间体15的合成
在氮气氛下,在火焰干燥的密封管中,将中间体14(110mg,0.36mmol,1.0当量)加入到甲胺(2M的THF溶液,5mL)中。将反应物在100℃下加热5天。然后用水(15mL)淬灭反应,并用乙酸乙酯(3×20mL)萃取。将合并的有机部分用饱和NaHCO3溶液洗涤,经无水Na2SO4干燥,过滤,在减压下浓缩,并使用MeOH/H2O/0.1%乙酸溶剂系统通过反相自动化TeledyneIsco色谱法纯化。得到中间体15,为橙色固体(74mg,54%)。
1H NMR(400MHz,氯仿-d)δ9.50(brs,1H),8.61(d,J=8.4Hz,1H),6.82(d,J=9.3Hz,1H),4.05(dd,J=6.1,4.3Hz,4H),3.83–3.78(m,4H),3.73–3.69(m,4H),3.65–3.60(m,4H),2.99(d,J=3.5Hz,3H),1.23(s,9H)
LC-MS(λ=254nm):99%,tR=5.6min.MS(ESI+):487[M+H]+
化合物21的合成
在0℃下,向中间体15(30mg,0.06mmol)的CH2Cl2(2mL)溶液中加入三氟乙酸(2mL),将反应混合物在室温下搅拌至完全。将溶液用饱和NaHCO3溶液洗涤,经无水Na2SO4干燥,过滤,真空浓缩,得到化合物21,为白色固体(10mg,10%)。
1H NMR(400MHz,DMSO-d6)δ8.93(brs,1H),8.23(d,J=9.1Hz,1H),7.08(d,J=9.1Hz,1H),4.02(s,4H),3.68(m,8H),3.29(s,4H),2.89(s,3H)
LC-MS(λ=254nm):99%,tR=4.2min.MS(ESI+):387[M+H]+
实施例5.化合物20的合成
方案5.化合物20的合成。
实施例6.化合物19的合成
方案6.化合物19的合成。
表1中化合物27通过与化合物19类似的方法制备。
中间体16的合成
在氮气氛下,在火焰干燥的圆底烧瓶中将中间体12(150mg,0.54mmol,1.0当量)加入原甲酸三乙酯(5mL,过量)中,然后加入对甲苯磺酸一水合物(10.2mg,0.05mmol,0.1当量)。将反应物在氮气下于148℃下回流过夜。用水(15mL)淬灭反应,并用乙酸乙酯(3×20mL)萃取。将合并的有机部分用饱和NaHCO3溶液洗涤,经无水Na2SO4干燥,过滤,减压浓缩,得到黄色产物,无需进一步纯化即可用于下一步反应(155mg,定量)。
1H NMR(400MHz,DMSO-d6)δ8.25(s,1H),8.22(d,J=9.1Hz,1H),7.12(d,J=9.1Hz,1H),3.69(m,8H)
LC-MS(λ=254nm):99%,tR=5.1min.MS(ESI+):289[M+H]+
中间体17的合成
在氮气氛下,在火焰干燥的圆底烧瓶中将中间体16(150mg,0.52mmol,1.0当量)加入到磷酰氯(3mL,过量)中。将反应物在106℃下回流90分钟。将反应冷却并减压浓缩,得到深黑色粗制物质。该粗产物无需进一步纯化即可用于下一反应(158mg,定量)。
1H NMR(400MHz,氯仿-d)δ8.95(s,1H),8.47(d,J=9.1Hz,1H),6.85(d,J=9.1Hz,1H),3.88–3.79(m,8H)
LC-MS(λ=254nm):99%,tR=6.1min.MS(ESI+):308[M+H]+
中间体18的合成
向中间体17(150mg,0.5mmol,1.0当量)的CH3CN(7mL)溶液中加入K2CO3(300mg)和1-Boc-哌嗪(455mg,2.4mmol,5.0当量),将反应混合物加热回流过夜。完成后,通过加入20mL饱和NaHCO3猝灭反应。将水相用CH2Cl2(3×20mL)萃取,合并有机层,用盐水洗涤,经无水Na2SO4干燥,过滤,并在减压下浓缩,得到深棕色粗制物质。将粗制物质吸附在硅胶上,并使用CH2Cl2/MeOH/NH3溶剂系统通过正相自动Teledyne Isco色谱法纯化。得到中间体18,为黄色固体(39mg,17%)。
1H NMR(400MHz,氯仿-d)δ8.61(s,1H),8.32(d,J=9.0Hz,1H),6.77(d,J=9.0Hz,1H),3.95–3.88(m,4H),3.84–3.66(m,8H),3.61–3.54(m,4H),1.47(s,9H)
LC-MS(λ=254nm):99%,tR=6.3min.MS(ESI+):457[M+H]+
化合物20的合成
在0℃下,向中间体18(39mg,0.08mmol)的CH2Cl2(2mL)溶液中加入三氟乙酸(2mL),将反应混合物在室温下搅拌至完全。将溶液用饱和NaHCO3溶液洗涤,经无水Na2SO4干燥,过滤,真空浓缩,得到化合物20,为浅黄色固体(29mg,99%)。
1H NMR(400MHz,DMSO-d6)δ8.92(brs,1H),8.67(s,1H),8.34(d,J=9.1Hz,1H),7.14(d,J=9.1Hz,1H),4.11–4.05(m,4H),3.75–3.67(m,8H),3.30(s,4H)
LC-MS(λ=254nm):99%,tR=6.6min.MS(ESI+):357[M+H]+
实施例7.化合物22的合成
方案7.化合物22的合成。
实施例8.化合物24-26的合成
方案8.化合物25的合成。
表1中的化合物24和26通过与化合物25类似的方法制备。
实施例9.化合物23的合成
方案9.化合物23的合成。
实施例10.化合物30的合成
方案10.化合物30的合成。
实施例11.化合物31的合成
方案11.化合物31的合成。
实施例12.体外结合测定
为了评估GUS抑制,测量在抑制剂存在下通过纯化的大肠杆菌GUS切割对硝基苯基-β-D-葡糖苷酸(PNPG)。反应在96孔透明底板中以50μL的体积进行。每个反应含有5μL的100nM大肠杆菌GUS、5μL不同浓度的抑制剂、10μL的250mM HEPES和250mM的NaCl测定缓冲液和30μL的1.5mM PNPG。通过加入PNPG引发反应,并在37℃下孵育2小时。使用PHERAstarPlus酶标仪测量410nm处的终点吸光度值。将得到的数据与SigmaPlot 13.0中的四参数逻辑对数函数拟合以确定IC50值。IC50定义为在平衡时产物形成减少50%的抑制剂浓度。
表1.体外对抗大肠杆菌(EcGUS)、无乳链球菌(SaGUS)和产气荚膜梭菌(CpGUS)β-葡糖苷酸酶的效力数据。
NI=无抑制;NA=不可用;参比化合物Inh9=IC50为380±50(EcGUS);
117±6(SaGUS);154±6(CpGUS)。
令人惊讶的是,已经观察到去除环己基环通常会降低对SaGUS和CpGUS的效力。这可以在例如化合物19-31中看到。不受理论束缚,据信这是由于每个GUS直向同源物中环部分内的结构差异。例如,如图3所示,来自相邻单体的环形成抑制剂结合位点的“后端”,根据结构分析,其是环己基存在的位置。不被理论所束缚,认为不同的GUS直向同源物的环之间的显著序列差异可能解释对SaGUS和CpGUS的效力差异。相应的环序列是:EcGUS:NLSLGIG-FEAGNKPKE;
CpGUS:HLNFMATGFGGDAPKRD;
SaGUS:FQNFNAS-LDLSPKDNG。
另外,还发现R2位的取代基在一种GUS直向同源物的特异性抑制中起重要作用。例如,在化合物22-26中,苯基取代的类似物可以更有利地与EcGUS相互作用,但显示出对SaGUS和CpGUS的效力降低。不受理论束缚,这种特异性抑制可能是活性位点序列差异的结果。例如,F448是EcGUS独有的活性位点内的残基,并且可以允许其以SaGUS和CpGUS都不能的方式与平面芳香族部分相互作用,因为这两种直向同源物在相同位置具有甲硫氨酸。这种相互作用可以来自有利的π-π堆叠相互作用。
本文使用的所有技术和科学术语具有相同的含义。已经努力确保关于所用数字(例如,量、温度等)的准确性,但是应该考虑一些实验误差和偏差。
本领域技术人员将认识到与本文所述的那些类似或等同的许多方法和材料,其可用于实践本文所述的主题。本公开绝不仅限于所描述的方法和材料。
除非另外定义,否则本文使用的技术和科学术语具有与本主题所属领域的普通技术人员通常理解的含义相同的含义,并且与以下文献一致:Singleton等(1994)Dictionaryof Microbiology and Molecular Biology,第二版,J.Wiley&Sons,New York,NY;和Janeway,C.,Travers,P.,Walport,M.,Shlomchik(2001)Immunobiology,第五版,GarlandPublishing,New York。
在本说明书和权利要求书全篇,除非上下文另有要求,否则词语“包含”以非排他性的意义使用。应理解,本文描述的实施方案包括“由......组成”和/或“基本上由......组成”的实施方案。
如本文所用,术语“约”在提及值时意在涵盖与指定量的在一些实施方案中±50%,在一些实施方案中±20%,在一些实施方案中±10%,在一些实施方案中±5%,在一些实施方案中±1%,在一些实施方案中±0.5%,及在一些实施方案中±0.1%的差异,因为此类差异适合于执行所公开的方法或使用所公开的组合物。
在提供一系列值的情况下,应理解,除非上下文另有明确规定,否则涵盖介于该范围上限和下限之间的每个中间值,至下限单位的十分之一,以及该规定值范围内的任何其他规定值或中间值。这些小范围的上限和下限,可以独立地包括在更小的范围中,也被涵盖在内,以规定范围内任何特别排除的限值为条件。如果规定范围包括一个或两个限值,则还包括排除这些限值中的一个或两个的范围。
该主题所属领域的技术人员将会想到本文阐述的许多修改和其他实施方案,其具有前面的描述和附图中呈现的教导的益处。因此,应理解该主题不限于所公开的具体实施方案,并且旨在将修改和其他实施方案包括在所附权利要求的范围内。尽管本文采用了特定术语,但它们仅用于一般性和描述性意义,而不是用于限制的目的。
Claims (45)
1.式I的化合物:
其中,
R1选自:
i.-ORA,其中RA选自H、CF3、任选取代的直链或支链C2-6烷基、任选取代的苄基和C3-8环烷基;
ii.-NRBRC,其中RB和RC各自独立地选自H、任选被氨基取代的直链或支链C1-6烷基、任选取代的苄基、C2-5杂芳基、C2-5杂烷基和C3-8环烷基;
iii.任选被羟基、卤素或氨基取代的C2-5杂芳基;
iv.-N(CH2)p-Z,其中p为1或2;Z是任选被羟基、卤素或氨基取代的杂芳基或杂环烷基;
v.其中s为1、2或3;和RD是氨基、羟基、卤素或直链或支链C1-6烷基;
vi.其中
R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,其中R7可以形成桥;和
R8是H,任选被卤素、羟基或氨基取代的直链或支链C1-4烷基;和
vii.其中
R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,其中R7可以连接形成桥接化合物;
Y是抗衡离子;和
R9在每种情况下独立地是任选被卤素、羟基或氨基取代的直链或支链C1-4烷基;
R2为H、芳基、杂环烷基或-NRFRG,其中
RF和RG独立地选自H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基,任选取代的苄基和C3-8环烷基;
X是N或-CR3,其中
R3选自H、卤素、-ORI和-NRIRJ,其中
RI和RJ各自独立地选自H和直链或支链C1-6烷基,其中所述烷基可任选被羟基取代;和
R4和R5为H或与各自连接的碳一起形成任选取代的C5-7元环;
条件是当R4和R5一起形成6元未取代环时,X是N或CH,R2是吗啉基,R1不是哌嗪基或-NHCH2CH2NH2。
2.根据权利要求1所述的化合物,其中R4和R5与各自连接的碳一起形成任选取代的C5-7元环。
3.根据权利要求2所述的化合物,其中X是N。
4.根据权利要求3所述的化合物,其中R2是杂环烷基。
5.根据权利要求4所述的化合物,其中R2是含有1或2个氮原子的4-8元环。
6.根据权利要求5所述的化合物,其中R2选自:
7.根据权利要求6所述的化合物,其中R2是吗啉基。
8.根据权利要求7所述的化合物,其中R1是
-NRBRC,其中RB和RC各自独立地选自H、任选被氨基取代的直链或支链C1-6烷基、任选取代的苄基、C2-5杂芳基、C2-5杂烷基和C3-8环烷基;
R1为任选被羟基、卤素或氨基取代的C2-5杂芳基;或,
R1是其中
R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,并且当q为2时,两个R7基团可以连接形成桥连化合物;和
R8是H,任选被卤素、羟基或氨基取代的直链或支链C1-4烷基。
9.根据权利要求8所述的化合物,其中R1是
其中R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,其中R7可以连接形成桥接化合物;和
R8是H,任选被卤素、羟基或氨基取代的直链或支链C1-4烷基。
10.根据权利要求9所述的化合物,其中t和q各自为1。
11.根据权利要求10所述的化合物,其中R8是H。
12.根据权利要求11所述的化合物,其中R7是甲基。
13.根据权利要求3所述的化合物,其中R1是
其中
s是1、2或3;和
RD是氨基、羟基、卤素或直链或支链C1-6烷基;或
R1为其中
R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,其中R7可以连接形成桥接化合物;和
R8是H,任选被卤素、羟基或氨基取代的直链或支链C1-4烷基。
14.根据权利要求13所述的化合物,其中R1是
其中
R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,其中R7可以连接形成桥接化合物;和
R8是H,任选被卤素、羟基或氨基取代的直链或支链C1-4烷基。
15.根据权利要求14所述的化合物,其中t和q各自为1。
16.根据权利要求15所述的化合物,其中R7是H。
17.根据权利要求16所述的化合物,其中R8是H。
18.根据权利要求17所述的化合物,其中R2是H、杂环烷基或-NRFRG,其中
RF和RG独立地选自H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基,任选取代的苄基和C3-8环烷基。
19.根据权利要求18所述的化合物,其中R2是杂环烷基。
20.根据权利要求19所述的化合物,其是
21.根据权利要求18所述的化合物,其中R2为-NRFRG,其中
RF和RG独立地选自H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基,任选取代的苄基和C3-8环烷基。
22.根据权利要求21所述的化合物,其中RF和RG独立地选自H或任选被卤素、氨基或羟基取代的直链或支链C1-6烷基。
23.根据权利要求22所述的化合物,其是
24.根据权利要求22所述的化合物,其是
25.根据权利要求1所述的化合物,其中R4和R5是H。
26.根据权利要求25所述的化合物,其中R1是
其中
s是1、2或3;和
RD是氨基、羟基、卤素或直链或支链C1-6烷基;或
R1为其中
R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,其中R7可以连接形成桥接化合物;和
R8是H,任选被卤素、羟基或氨基取代的直链或支链C1-4烷基。
27.根据权利要求26所述的化合物,其中R1是
其中
R7是H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基;
t为1或2;
q为1或2,其中R7可以连接形成桥接化合物;和
R8是H,任选被卤素、羟基或氨基取代的直链或支链C1-4烷基。
28.根据权利要求27所述的化合物,其中t和q各自为1。
29.根据权利要求28所述的化合物,其中R7是H。
30.根据权利要求29所述的化合物,其中R1是哌嗪基。
31.根据权利要求30所述的化合物,其中R2是H、芳基、杂环烷基或-NRFRG,其中
RF和RG独立地选自H、直链或支链C1-6烷基、任选取代的苄基和C3-8环烷基。
32.根据权利要求31所述的化合物,其中R2为芳基。
33.根据权利要求32所述的化合物,其中R2是苯基。
34.根据权利要求31所述的化合物,其中R2是杂环烷基。
35.根据权利要求34所述的化合物,其中R2是含有在环内包含的1或2个氮原子的4-8元环。
36.根据权利要求35所述的化合物,其中R2选自:
37.根据权利要求36所述的化合物,其中R2是吗啉基。
38.根据权利要求31所述的化合物,其中R2为-NRFRG,其中
RF和RG独立地选自H,任选被卤素、氨基或羟基取代的直链或支链C1-6烷基,任选取代的苄基和C3-8环烷基。
39.根据权利要求38所述的化合物,其中RF和RG独立地是H或任选被卤素、氨基或羟基取代的直链或支链C1-6烷基。
40.根据权利要求39所述的化合物,其中RF和RG独立地是H或未取代的直链C1-6烷基。
41.根据权利要求40所述的化合物,其是
42.根据权利要求40所述的化合物,其是
43.根据权利要求1所述的化合物,其具有以下结构之一:
44.一种药物组合物,其包括权利要求1的化合物和药学上可接受的载体或赋形剂。
45.一种改善有需要的人的副作用的方法,包括给所述人施用有效量的权利要求1所述的化合物。
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