CN115605208A - 噁唑烷酮化合物及其作为抗菌剂的使用方法 - Google Patents
噁唑烷酮化合物及其作为抗菌剂的使用方法 Download PDFInfo
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- CN115605208A CN115605208A CN202180036146.XA CN202180036146A CN115605208A CN 115605208 A CN115605208 A CN 115605208A CN 202180036146 A CN202180036146 A CN 202180036146A CN 115605208 A CN115605208 A CN 115605208A
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- mycobacterium tuberculosis
- bacterial infection
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- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明涉及式(I)的噁唑烷酮化合物及其药学上可接受的盐。本发明也涉及含有式(I)的化合物的组合物。本发明还提供了通过施用治疗有效量的式(I)和/或其药学上可接受的盐或包含这样的化合物和/或盐的组合物来抑制分枝杆菌细胞的生长的方法以及治疗结核分枝杆菌的分枝杆菌感染的方法。
Description
发明领域
本发明涉及噁唑烷酮化合物,其可用于治疗细菌感染,特别是分枝杆菌感染。本发明还涉及使用噁唑烷酮化合物治疗分枝杆菌感染诸如由结核分枝杆菌(Mycobacteria tuberculosis)造成的感染的方法。
发明背景
分枝杆菌属(Mycobacterium)是一种细菌属,既不是真正的革兰氏阳性菌也不是真正的革兰氏阴性菌,包括导致结核病(结核分枝杆菌(M. tuberculosis))和麻风病(麻风分枝杆菌(M. leprae))的病原体。特别是,尽管可利用抗-TB药物诸如异烟肼和利福平,结核病(TB)仍被认为是世界上最致命的疾病之一。根据世界卫生组织,在2018年,有1000万新TB病例和150万例TB死亡。参见世界卫生组织公布的2019年全球结核病报告。使TB流行复杂化的是多重耐药株的不断增加,并且与HIV非常相关。HIV阳性并且感染TB的人发展活动性TB的可能性是HIV阴性的人的30倍,并且TB是造成全球每三名HIV/AIDS患者中一人死亡的原因。参见,例如,Kaufmann等人,Trends Microbiol. 1: 2-5 (1993)和Bloom等人,N. Engl. J. Med. 338: 677-678 (1998)。
除了结核分枝杆菌以外的分枝杆菌越来越多地存在于折磨AIDS患者的机会性感染中。来自鸟胞内分枝杆菌复合体(M. avium-intracellulare complex, MAC)的生物体,尤其是血清型IV和VIII,占来自AIDS患者的分枝杆菌分离株的68%。发现大量MAC (高达每克组织1010个耐酸杆菌),并且因此,受感染的AIDS患者的预后不良。
噁唑烷酮是一类含有2-噁唑烷酮(含有氮和氧的5元环)的化合物,其被用作抗微生物剂。参见,例如WO 2009157423。一般而言,已知噁唑烷酮是单胺氧化酶抑制剂并具有针对革兰氏阳性微生物的活性。WO 2006022794, Suzuki等人, Med.Chem. Lett.4:1074-1078 (2013), Yang等人, J. Med. Chem. 58:6389-6409 (2015), Shaw等人, Ann. N.Y.Acad. Sci. 1241:48-70 (2011)。另外,PCT公开号WO2017/070024公开了用于治疗结核病的噁唑烷酮抗生素。
几种噁唑烷酮抗生素已被批准或在临床试验中用于治疗革兰氏阳性细菌感染诸如耐甲氧西林金黄色葡萄球菌(Staphylococcus aureus)。噁唑烷酮抗生素的例子包括利奈唑胺(Zyvox™, Pfizer Inc., New York, NY)和特地唑胺(Sivextro™, Merck Sharp& Dohme Corp., Kenilworth, NJ)。特地唑胺用于治疗由特定易感革兰氏阳性菌引起的急性细菌性皮肤和皮肤结构感染。利奈唑胺适用于治疗由革兰氏阳性微生物易感菌株引起的几种感染,包括医院获得性肺炎、复杂的皮肤和皮肤结构感染以及社区获得性肺炎。此外,它已经在临床试验中测试用于治疗多重耐药的(MDR)和广泛耐药的(XDR)结核分枝杆菌(Mtb)。Lee等人,N. Engl. J. Med 367: 1508-18 (2012)。尽管在治疗这些疾病方面具有临床效力,但利奈唑胺的长期使用与不良事件相关联,包括骨髓抑制(包括贫血和白细胞减少症) (Hickey等人, Therapy 3(4):521-526 (2006),神经病和血清素综合征。假设这些不良事件与线粒体蛋白合成的抑制有关。Flanagan等人,Antimicrobial Agents and Chemotherapy 59(1):178-185 (2015)。
比已批准的噁唑烷酮更安全但至少同样有效的噁唑烷酮抗生素的开发将大大有利于Mtb患者。
发明概述
本发明涉及具有抗菌活性的噁唑烷酮化合物。所述化合物及其药学上可接受的盐例如可用于治疗细菌感染,例如,分枝杆菌感染。更具体地,本发明包括式I的化合物或其药学上可接受的盐:
本发明也涉及一种用于治疗对象的细菌感染、特别是结核分枝杆菌感染的药物组合物,其包含式I的噁唑烷酮化合物和/或药学上可接受的载体、稀释剂或赋形剂。
式I的化合物和/或其药学上可接受的盐例如可用于抑制结核分枝杆菌的生长,和/或用于治疗或预防患者的结核病。不受任何具体理论约束,据信,本发明的噁唑烷酮化合物用于治疗结核病的用途可能比已知的噁唑烷酮化合物诸如利奈唑胺引起更少的骨髓抑制,因为它们与线粒体蛋白合成的高度抑制不相关,和/或在抗结核分枝杆菌的效力和线粒体蛋白合成的抑制之间具有更高的分离度。此外,与已知的噁唑烷酮相比,本文所述的化合物表现出这样的药代动力学特性,其与化合物抗结核分枝杆菌的效力相结合,更可能以合理的剂量在人类中提供每天一次(QD)给药。此外,基于其药代动力学特性,与已知的噁唑烷酮相比,本文所述的化合物更可能具有在给药后24小时在体内的最大和最小浓度之间的更小差异,这使得在Mtb的治疗中可以更好地分离效力和潜在不良作用。
本发明也涉及1)在需要其治疗的对象中治疗结核病的方法,所述方法包括给所述对象施用有效量的式I的噁唑烷酮化合物;和2)式I的噁唑烷酮化合物用于治疗结核病的用途。
本发明的实施方案、子实施方案和特征进一步描述于本文中,或者从随后的说明书、实施例和所附权利要求书将是显而易见的。
发明详述
噁唑烷酮最初被开发用于治疗革兰氏阳性细菌感染,特别是耐甲氧西林金黄色葡萄球菌感染。如在实施例中所示,式I的噁唑烷酮化合物的体外试验揭示,该化合物在抑制结核分枝杆菌的生长方面具有优异效力,但与线粒体蛋白合成的高度抑制无关。因此,预期式I的化合物和/或其药学上可接受的盐可用于治疗结核分枝杆菌(Mtb),但不会导致与噁唑烷酮利奈唑胺相关的副作用诸如骨髓抑制。因此,相对于利奈唑胺和类似物,式I的化合物作为Mtb治疗剂将具有显著优点。
式I的化合物
本文描述了式I的化合物:
本文还描述了式I的化合物及其药学上可接受的盐:
其中所述化合物可适用于治疗细菌感染,特别是分枝杆菌感染。
提及关于式I化合物的不同实施方案,具体包括式I的化合物和任选的式I的化合物的药学上可接受的盐。
本发明的其它实施方案包括下列:
(a) 药物组合物,其包含有效量的本文定义的式I的化合物或其药学上可接受的盐,和药学上可接受的载体。
(b) (a)的药物组合物,其进一步包含第二化合物,其中所述第二化合物是抗生素。
(c) (b)的药物组合物,其中所述第二化合物选自:乙胺丁醇、吡嗪酰胺、异烟肼、左氧氟沙星、莫西沙星、加替沙星、氧氟沙星、卡那霉素、阿米卡星、卷曲霉素、链霉素、乙硫异烟胺、丙硫异烟胺、环丝氨酸、特立齐酮(terididone)、对氨基水杨酸、氯法齐明、克拉霉素、阿莫西林-克拉维酸盐、普瑞玛尼(pretomanid)、贝达喹啉、GSK 3036656、M72/AS01E疫苗、吉珀达星(gepotidacin)、氨硫脲、美罗培南-克拉维酸盐、TBA-7371(一种癸异戊烯基磷酰基-β-D-核糖2’-氧化酶(decaprenylphosphoryl-β-D-ribose 2’-oxidase,DprE1)抑制剂)、来自Otsuka Pharmaceutical的OPC-167832、来自Qurient Co., Ltd的Telacebec(Q203)和硫利达嗪。
(d) 药物组合物,其包含(i)式I的化合物或其药学上可接受的盐,和(ii)第二化合物,其中所述第二化合物是抗生素,其中式I的化合物和第二化合物各自以使组合有效治疗或预防细菌感染的量使用。
(e) (d)的组合,其中所述第二化合物选自:乙胺丁醇、吡嗪酰胺、异烟肼、左氧氟沙星、莫西沙星、加替沙星、氧氟沙星、卡那霉素、阿米卡星、卷曲霉素、链霉素、乙硫异烟胺、丙硫异烟胺、环丝氨酸、特立齐酮(terididone)、对氨基水杨酸、氯法齐明、克拉霉素、阿莫西林-克拉维酸盐、普瑞玛尼、贝达喹啉、GSK 3036656、M72/AS01E疫苗、吉珀达星、氨硫脲、美罗培南-克拉维酸盐、TBA-7371(一种癸异戊烯基磷酰基-β-D-核糖2’-氧化酶(DprE1)抑制剂)、来自Otsuka Pharmaceutical的OPC-167832、来自Qurient Co., Ltd的Telacebec(Q203)和硫利达嗪。
(f) 一种用于治疗对象的细菌感染的方法,其包括给需要这种治疗的对象施用有效量的式I的化合物或其药学上可接受的盐。
(g) 一种用于预防和/或治疗细菌感染的方法,其包括给需要这种治疗的对象施用有效量的式I的化合物或其药学上可接受的盐。
(h) 一种用于治疗细菌感染的方法,其包括给需要这种治疗的对象施用治疗有效量的(a)、(b)、(c)、(d)或(e)的组合物。
(i) 如在(f)、(g)或(h)中所述的治疗细菌感染的方法,其中所述细菌感染是由于结核分枝杆菌。
(j) 一种用于预防和/或治疗分枝杆菌感染的方法,其包括给需要这种治疗的对象施用有效量的包含式I的化合物或其药学上可接受的盐的组合物。
(k) 如在(j)中所述的治疗分枝杆菌感染的方法,其中所述分枝杆菌感染是由于结核分枝杆菌。
(l) 如在(j)中所述的治疗分枝杆菌感染的方法,其中所述组合物是(a)、(b)、(c)、(d)或(e)的组合物。
本发明还包括式I的化合物或其药学上可接受的盐,其(i)用于药物或治疗细菌感染,特别是分枝杆菌感染,(ii)用作用于药物或治疗细菌感染特别是分枝杆菌感染的药剂,或(iii)用于制备(或生产)用于药物或治疗细菌感染特别是分枝杆菌感染的药剂。在这些用途中,本发明的化合物可以任选地与一种或多种第二治疗剂组合使用,所述第二治疗剂包括乙胺丁醇、吡嗪酰胺、异烟肼、左氧氟沙星、莫西沙星、加替沙星、氧氟沙星、卡那霉素、阿米卡星、卷曲霉素、链霉素、乙硫异烟胺、丙硫异烟胺、环丝氨酸、特立齐酮(terididone)、对氨基水杨酸、氯法齐明、克拉霉素、阿莫西林-克拉维酸盐、普瑞玛尼、贝达喹啉、GSK3036656、M72/AS01E疫苗、吉珀达星、氨硫脲、美罗培南-克拉维酸盐、TBA-7371(一种癸异戊烯基磷酰基-β-D-核糖2’-氧化酶(DprE1)抑制剂)、来自Otsuka Pharmaceutical的OPC-167832、来自Qurient Co., Ltd的Telacebec (Q203)和硫利达嗪。
本发明的另外的实施方案包括在上面(a)至(l)中列出的药物组合物、组合和方法和在前述段落中列出的用途,其中在其中使用的本发明的化合物是上述实施方案、子实施方案、类别或子类之一的化合物。所述化合物在这些实施方案中可以任选地以药学上可接受的盐的形式使用。
在上面提供的化合物和盐的实施方案中,应当理解,每个实施方案可以与一个或多个其它实施方案组合,以致于这样的组合提供稳定的化合物或盐且与实施方案的描述相一致。进一步应当理解,上面(a)至(l)提供的组合物和方法的实施方案应当理解为包括所述化合物和/或盐的所有实施方案,包括由实施方案的组合产生的这样的实施方案。
本发明的另外的实施方案包括在前述段落中所述的药物组合物、组合、方法和用途中的每一种,其中在本文中采用的本发明的化合物或其盐是基本上纯的。关于包含式I的化合物或其盐和药学上可接受的载体和任选的一种或多种赋形剂的药物组合物,应当理解,术语“基本上纯的”是指式I的化合物或其盐本身;即,所述组合物中的活性成分的纯度。
定义和缩写
本文中使用的术语具有它们的普通含义,且这类术语的含义在其各处是独立的。尽管如此和除非另行指明,否则下列定义在本说明书和权利要求通篇中适用。化学名称、常用名和化学结构可互换地用于描述相同结构。如果使用化学结构和化学名称提到化合物并在结构与名称之间存在歧义,以结构为准。除非另行指明,否则无论一术语是单独使用还是与其它术语结合使用,这些定义都适用。
“抗生素”是指降低微生物的活力或抑制微生物的生长或增殖的化合物或组合物。短语“抑制生长或增殖”意指使传代时间(即,细菌细胞分裂或群体翻倍所需的时间)增加至少约2倍。优选的抗生素是可以使传代时间增加至少约10倍或更多(例如,至少约100倍或甚至无限,如在完全细胞死亡中)的抗生素。如在本公开内容中使用的,抗生素进一步意图包括抗微生物剂、抑菌剂或杀菌剂。
当修饰物质或组合物的量(例如,kg、L或当量)、或物理性质的值、或表征工艺步骤的参数的值(例如,实施工艺步骤的温度)等时,“约”是指数字量的变化,其可例如经由以下产生:在物质或组合物的制备、表征和/或使用中涉及的典型测量、处理和取样程序;这些程序中的无意失误;用于制备或使用组合物或实施操作的成分的制备、来源或纯度的差异;等。在某些实施方案中,“约”可以是指适当单位的±0.1、0.2、0.3、0.4、0.5、1.0、2.0、3.0、4.0或5.0的变化。在某些实施方案中,“约”可以是指±1%、2%、3%、4%、5%、10%或20%的变化。
与分枝杆菌属有关的“耐药”是指,不再对至少一种以前有效的药物敏感的分枝杆菌属;其已经发展了耐受至少一种以前有效的药物的抗生素攻击的能力。耐药株可以将该耐受能力传给它的后代。所述耐药性可能是由于细菌细胞中改变其对单一药物或不同药物的敏感性的随机基因突变。
“结核病”包括通常与分枝杆菌物种(包括结核分枝杆菌复合体)导致的感染有关的疾病状态。术语“结核病”还与结核分枝杆菌以外的分枝杆菌(MOTT)导致的分枝杆菌感染有关。其它分枝杆菌物种包括鸟胞内分枝杆菌(M. avium-intracellulare)、堪萨斯分枝杆菌(M. kansarii)、偶发分枝杆菌(M. fortuitum)、龟分枝杆菌(M. chelonae)、麻风分枝杆菌(M. leprae)、非洲分枝杆菌(M. africanum)和田鼠分枝杆菌(M. microti)、鸟副结核分枝杆菌(M. avium paratuberculosis)、细胞内分枝杆菌(M. intracellulare)、瘰疬分枝杆菌(M. scrofulaceum)、蟾蜍分枝杆菌(M. xenopi)、海分枝杆菌(M. marinum)和溃疡分枝杆菌(M. ulcerans)。
本发明的另一个实施方案是如最初定义的或如在前述实施方案、子实施方案、方面、类别或子类中的任一个中定义的式I的化合物或其药学上可接受的盐,其中所述化合物或其盐呈基本上纯的形式。本文中使用的“基本上纯的”是指,含有式I的化合物或式I的盐的产物(例如,从提供所述化合物或盐的反应混合物中分离的产物)的适当地至少约60重量%、典型地至少约70重量%、优选地至少约80重量%、更优选地至少约90重量%(例如,约90重量%至约99重量%)、甚至更优选地至少约95重量%(例如,约95重量%至约99重量%或约98重量%至100重量%)和最优选地至少约99重量%(例如,100重量%)由所述化合物或盐组成。使用标准分析方法诸如薄层色谱法、凝胶电泳、高效液相色谱法和/或质谱法,可以确定所述化合物和盐的纯度水平。如果采用超过一种分析方法且所述方法提供确定的纯度水平的实验上显著的差异,那么以提供最高纯度水平的方法为准。100%纯度的化合物或盐是不含有可检测的杂质的化合物或盐,如通过标准分析方法所确定的。关于具有一个或多个不对称中心且可以作为立体异构体的混合物存在的本发明的化合物,基本上纯的化合物可以是基本上纯的立体异构体的混合物或基本上纯的各个非对映异构体或对映异构体。
在式I的化合物中,所述原子可以表现出它们的天然同位素丰度,或者所述原子中的一个或多个可以被人工地富集特定同位素,所述同位素具有相同原子序数,但是其原子质量或质量数不同于在自然界中占优势地存在的原子质量或质量数。本发明意在包括式I的化合物的所有合适的同位素变体。例如,氢(H)的不同同位素形式包括氕(1H)和氘(2H或D)。氕是在自然界中存在的占优势的氢同位素。氘富集可以提供某些治疗优点,诸如增加体内半衰期或减少剂量需求,或者可以提供可用作生物样品的表征的标准品的化合物。通过本领域技术人员众所周知的常规技术,或通过类似于本文实施例中描述的那些的方法,使用适当的同位素富集的试剂和/或中间体,可以制备在式I内的同位素富集的化合物,而无需过度实验。
术语“化合物”是指游离化合物,和在它们稳定的程度下,其任意水合物或溶剂化物。水合物是与水形成复合物的化合物,且溶剂化物是与有机溶剂形成复合物的化合物。
如上面指出的,本发明的化合物可以以药学上可接受的盐的形式使用。应该理解,如本文中使用的,本发明的化合物还可以包括药学上可接受的盐,以及当它们用作游离化合物或它们的药学上可接受的盐的前体时或在其它合成操作中并非药学上可接受的盐。
术语“药学上可接受的盐”是指具有母体化合物的有效性并且在生物学上或其它方面不是不合意(例如,对其接受者既无毒也在其它方面无害)的盐。术语“药学上可接受的盐”是指从药学上可接受的无毒碱或酸(包括无机或有机碱和无机或有机酸)制备的盐。被包括在术语“药学上可接受的盐”中的碱性化合物的盐是指本发明的化合物的无毒盐,其通常通过使游离碱与合适的有机酸或无机酸反应来制备。本发明的碱性化合物的代表性盐包括、但不限于以下:乙酸盐、抗坏血酸盐、己二酸盐、海藻酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、丁酸盐、樟脑酸盐、樟脑磺酸盐(camphorsulfonate)、右旋樟脑磺酸盐(camsylate)、碳酸盐、氯化物、克拉维酸盐、柠檬酸盐、环戊烷丙酸盐、二乙基乙酸盐、二葡萄糖酸盐、二盐酸盐、十二烷基磺酸盐(dodecylsulfanate)、依地酸盐、乙二磺酸盐、依托酸盐、乙磺酸盐(esylate)、乙磺酸盐(ethanesulfonate)、甲酸盐、富马酸盐、葡庚糖酸盐(gluceptate)、葡萄糖庚酸盐(glucoheptanoate)、葡萄糖酸盐、谷氨酸盐、甘油磷酸盐、对羟乙酰胺基苯胂酸盐(glycollylarsanilate)、半硫酸盐、庚酸盐、己酸盐、己基间苯二酚盐、哈胺(hydrabamine)、氢溴酸盐、盐酸盐、2-羟基乙磺酸盐、羟基萘甲酸盐、碘化物、异烟酸盐、异硫代硫酸盐(isethionate)、乳酸盐、乳糖酸盐、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲基硫酸盐、甲磺酸盐、粘酸盐、2-萘磺酸盐、萘磺酸盐、烟酸盐、硝酸盐、N-甲基葡糖胺铵盐、油酸盐、草酸盐、扑酸盐(双羟萘酸盐)、棕榈酸盐、泛酸盐、果胶酸盐、过硫酸盐、磷酸盐/二磷酸盐、庚二酸盐、苯基丙酸盐、聚半乳糖醛酸盐、丙酸盐、水杨酸盐、硬脂酸盐、硫酸盐、碱式醋酸盐、琥珀酸盐、鞣酸盐、酒石酸盐、8-氯茶碱盐(teoclate)、硫氰酸盐、甲苯磺酸盐、三乙基碘化物、三氟乙酸盐、十一酸盐(undeconate)、戊酸盐等。此外,在本发明的化合物携带酸性部分的情况下,其合适的药学上可接受的盐包括、但不限于源自无机碱的盐,包括铝、铵、钙、铜、三价铁、二价铁、锂、镁、三价锰、二价锰、钾、钠、锌等。特别优选的是铵盐、钙盐、镁盐、钾盐和钠盐。源自药学上可接受的有机无毒碱的盐包括以下物质的盐:伯胺、仲胺和叔胺,环胺,二环己胺和碱性离子交换树脂,诸如精氨酸、甜菜碱、咖啡因、胆碱、N,N-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、葡萄糖胺、组氨酸、哈胺(hydrabamine)、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。此外,所包括的碱性含氮基团可以被诸如以下试剂季铵化:低级烷基卤化物,诸如甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物;硫酸二烷基酯如硫酸二甲酯、硫酸二乙酯、硫酸二丁酯和硫酸二戊酯;长链卤化物,诸如癸基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物;芳烷基卤化物如苄基和苯乙基的溴化物等。
这些盐可以通过已知的方法获得,例如通过将本发明的化合物与等量和含有所需酸、碱等的溶液混合,然后通过过滤盐或蒸馏出溶剂来收集所需盐。本发明的化合物及其盐可以与溶剂(诸如水、乙醇或甘油)形成溶剂化物。根据侧链取代基的类型,本发明的化合物可以同时形成酸加成盐和与碱的盐。
如上所述,本发明包括药物组合物,其包含本发明的式I的化合物,任选的一种或多种其它活性组分,和药学上可接受的载体。载体的特征将取决于施用途径。“药学上可接受的”是指,所述药物组合物的成分必须彼此相容,不会干扰活性成分的有效性,且对其接受者不是有害的(例如,有毒的)。因而,除了所述抑制剂以外,根据本发明的组合物还可以含有稀释剂、填充剂、盐、缓冲剂、稳定剂、增溶剂和本领域众所周知的其它物质。
并且,如上所述,本发明包括一种用于治疗细菌感染的方法,其包括给需要这种治疗的对象施用治疗有效量的式I的化合物或其药学上可接受的盐。本文中使用的术语“对象”(或可替换地,“患者”)是指动物,优选哺乳动物,最优选人,其已是治疗、观察或实验的对象。关于式I的化合物的术语“施用”及其变体(例如,“施用”化合物)是指将所述化合物或其药学上可接受的盐提供给需要治疗的个体。当与一种或多种其它活性剂组合提供化合物或其盐时,“施用”及其变体各自理解为包括同时或不同时提供所述化合物或其盐和其它药剂。当同时施用组合的药剂时,它们可以在单一组合物中一起施用,或它们可以分别施用。应当理解,活性剂的“组合”可以是含有所有活性剂的单一组合物或各自含有一种或多种活性剂的多种组合物。在两种活性剂的情况下,组合可以是包含两种药剂的单一组合物或各自包含药剂之一的两种单独组合物;在三种活性剂的情况下,组合可以是包含所有三种药剂的单一组合物,各自包含药剂之一的三种单独组合物,或者其中一种组合物包含所述药剂中的两种且另一种组合物包含第三种药剂的两种组合物;等等。
适当地以有效量施用本发明的组合物和组合。本文中关于式I的化合物使用的术语“有效量”是指足以造成杀细菌或抑制细菌作用的活性化合物的量。在一个实施方案中,有效量是“治疗有效量”,其指可以克服细菌耐药性并且足以抑制细菌复制和/或导致细菌杀死的活性化合物的量。当活性化合物(即,活性成分)作为盐施用时,对活性成分的量的提及是针对所述化合物的游离酸或游离碱形式。
本发明的组合物的施用适当地是胃肠外、口服、舌下、透皮、局部、鼻内、气管内、眼内或直肠内施用,其中使用本领域众所周知的配制方法将所述组合物适当地配制用于通过选定的途径施用,所述配制方法包括,例如,描述于Remington -The Science andPractice of Pharmacy, 2006年第21版的第39、41、42、44和45章中的制备和施用制剂的方法。在一个实施方案中,在医院场合静脉内施用本发明的化合物。在另一个实施方案中,施用是以片剂或胶囊等形式口服。本发明的化合物及其药学上可接受的盐的剂量可以在宽限度内改变,并且在每个特定情况下应该根据个体状况和待控制的病原体自然调节。一般而言,对于治疗细菌感染的用途,日剂量可以为0.005 mg/kg至100 mg/kg、0.01 mg/kg至10mg/kg、0.05 mg/kg至5 mg/kg、0.05 mg/kg至1 mg/kg。
在某些实施方案中,本发明的化合物的日剂量可以是0.005 mg/kg至100 mg/kg、0.01 mg/kg至10 mg/kg、0.05 mg/kg至5 mg/kg、0.05 mg/kg至1 mg/kg。在某些实施方案中,本发明的化合物的日剂量可以是1 mg/kg至5 mg/kg。在某些实施方案中,本发明的化合物的日剂量可以是2 mg/kg至5 mg/kg。在某些实施方案中,本发明的化合物的日剂量可以是大约2.1-4.3 mg/kg。
在某些实施方案中,在用于口服、静脉内、肌内、鼻或局部施用的药物制剂中提供本发明的化合物。因此,在某些实施方案中,可以将制剂制备成剂型,诸如但不限于,片剂、胶囊剂、液体(溶液或混悬液)、栓剂、软膏剂、乳膏剂或气雾剂。在某些实施方案中,本文公开的主题提供了这样的化合物和/或制剂,其已被冻干并且可以被重构以形成药学上可接受的制剂用于施用,例如通过静脉内或肌内注射。
通过用可接受的溶剂重构所述化合物的粉末形式,可以进行本发明的化合物的静脉内施用。合适的溶剂包括,例如,盐水溶液(例如,0.9%氯化钠注射液)和无菌水(例如,无菌注射用水、含有对羟基苯甲酸甲酯和对羟基苯甲酸丙酯的抑菌注射用水、或含有0.9%苯甲醇的抑菌注射用水)。可以如下得到所述化合物的粉末形式:将所述化合物γ-辐照,或将所述化合物的溶液冻干,此后可以将粉末在室温或低于室温下储存(例如,在密封瓶中)直到将它重构。在重构的静脉内溶液中的化合物的浓度可以是,例如,在约0.1 mg/mL至约20mg/mL的范围内。
在某些实施方案中,在用于每天1次(QD)给药的药物制剂中提供本发明的化合物。在其它实施方案中,在用于每天1次(QD)或更低频率给药的药物制剂中提供本发明的化合物。在某些实施方案中,在用于每天1次(QD)口服给药的药物制剂中提供本发明的化合物。在其它实施方案中,在用于每天1次(QD)或更低频率口服给药的药物制剂中提供本发明的化合物。
本文公开的主题的方法可用于治疗这些病症,因为它们抑制病症的发作、发展或传播,造成病症的消退,治愈病症,或者以其它方式改善感染病症或处于感染病症的风险中的对象的一般健康状况。因而,根据本文公开的主题,术语“治疗”及其语法变体以及短语“治疗……的方法”意在涵盖任何期望的治疗干预,包括、但不限于用于治疗对象的现有感染的方法,和用于预防(即防止)感染的方法,诸如在已经暴露于本文公开的微生物的对象中,或者在预期暴露于本文公开的微生物的对象中。
可通过本发明的化合物治疗的感染可以由多种微生物造成,包括真菌、藻类、原生动物、细菌和病毒。在某些实施方案中,所述感染是细菌感染。可以通过本发明的方法治疗的示例性微生物感染包括、但不限于,由以下的一种或多种造成的感染:金黄色葡萄球菌(Staphylococcus aureaus)、粪肠球菌(Enterococcus faecalis)、炭疽芽孢杆菌(Bacillus anthracis)、链球菌属(Streptococcus species)(例如,酿脓链球菌(Streptococcus pyogenes)和肺炎链球菌(Streptococcus pneumoniae))、大肠杆菌(Escherichia coli)、铜绿假单胞菌(Pseudomonas aeruginosa)、洋葱伯克霍尔德氏菌(Burkholderia cepacia)、变形杆菌属(Proteus species)(例如,奇异变形杆菌(Proteus mirabilis)和普通变形杆菌(Proteus vulgaris))、肺炎克雷伯氏菌(Klebsiella pneumoniae)、鲍氏不动杆菌(Acinetobacter baumannii)、嗜麦芽窄食假单胞菌(Strenotrophomonas maltophillia)、结核分枝杆菌(Mycobacterium tuberculosis)、牛分枝杆菌(Mycobacterium bovis),结核病复合群的其它分枝杆菌,和非结核性的分枝杆菌(NTM),包括溃疡分枝杆菌(Mycobacterium ulcerans)。
在某些实施方案中,可通过本发明的化合物治疗的感染可以由多种非结核性的分枝杆菌造成。这样的非结核性的分枝杆菌包括超过150种不同的(包括临床上最相关的)NTM物种:脓肿分枝杆菌(Mycobacterium abscessus)、鸟分枝杆菌复合群(MAC)(Mycobacterium avium complex)和堪萨斯分枝杆菌(Mycobacterium kansasii)。
在某些实施方案中,所述感染是革兰氏阳性细菌的感染。在某些实施方案中,所述感染选自分枝杆菌感染、炭疽芽孢杆菌感染、粪肠球菌感染和肺炎链球菌感染。
在某些实施方案中,预防性地施用式I的化合物以防止或降低下列之一的发生率:(a)处于感染风险中的对象的结核分枝杆菌感染;(b)结核分枝杆菌感染的复发;和(c)其组合。在某些实施方案中,施用式I的化合物以治疗现有结核分枝杆菌感染。在某些实施方案中,施用式I的化合物以治疗结核分枝杆菌的多重耐药株(即,耐两种或更多种以前已知的抗结核药物诸如异烟肼、乙胺丁醇、利福平、卡那霉素、卷曲霉素、利奈唑胺和链霉素的菌株)的感染。在某些实施方案中,式I的化合物对结核分枝杆菌的最小抑制浓度(MIC)为25 μg/mL或更低。在某些实施方案中,施用式I的化合物以治疗结核分枝杆菌的多重耐药株的感染。
因此,本文公开的主题的方法可用于治疗结核病,因为它们抑制TB感染的发作、发展或传播,造成TB感染的消退,治愈TB感染,或者以其它方式改善感染结核病或处于感染结核病的风险中的对象的一般健康状况。
通过许多技术,例如痰涂片、胸部X-射线、结核菌素皮肤试验(即,Mantoux试验或PPD试验),和/或其它临床症状(例如,胸痛、咯血、发热、盗汗、食欲降低、疲劳等)的存在,可以确定患有结核分枝杆菌或其它结核病相关感染的对象。如果需要,可以从认为患有TB的对象分离细菌RNA、DNA或蛋白,通过本领域已知的方法分析,并与细菌RNA、DNA或蛋白的已知核酸或氨基酸序列对比。
在某些实施方案中,式I的化合物对结核分枝杆菌的最小抑制浓度(MIC)为25 μg/mL或更低。可以通过本领域已知的方法确定MIC,例如,在Hurdle等人, 2008, J. Antimicrob. Chemother. 62:1037-1045中描述的方法。
在某些实施方案中,本发明的方法进一步包括给所述对象施用另外的治疗性化合物。在某些实施方案中,在一种或多种另外的治疗性化合物之前、之后或同时给对象施用本发明的化合物。在某些实施方案中,所述另外的治疗性化合物是抗生素。在某些实施方案中,所述另外的治疗性化合物是抗结核治疗剂。在某些实施方案中,所述另外的治疗性化合物选自异烟肼、乙胺丁醇、利福平、卡那霉素、卷曲霉素、利奈唑胺和链霉素。
本发明因此在另一个方面提供了组合,其包含式I的化合物或其药学上可接受的盐以及一种或多种另外的治疗剂。这样的一种或多种另外的治疗剂的例子是抗结核药剂,其包括、但不限于阿米卡星、氨基水杨酸、卷曲霉素、环丝氨酸、乙胺丁醇、乙硫异烟胺、异烟肼、卡那霉素、吡嗪酰胺、利福霉素类(诸如利福平、利福喷汀和利福布汀)、链霉素、克拉霉素、阿奇霉素、噁唑烷酮类和氟喹诺酮类(诸如氧氟沙星、环丙沙星、莫西沙星和加替沙星)。这样的化学疗法通过治疗医师的判断使用优选的药物组合来确定。用于治疗非耐药性的结核分枝杆菌感染的“一线”化疗剂包括异烟肼、利福平、乙胺丁醇、链霉素和吡嗪酰胺。用于治疗已证明对一种或多种“一线”药物具有耐药性的结核分枝杆菌感染的“二线”化疗剂包括氧氟沙星、环丙沙星、乙硫异烟胺、氨基水杨酸、环丝氨酸、阿米卡星、卡那霉素和卷曲霉素。除了上述那些,还有许多新的产生于临床研究的抗结核治疗剂,其也可以用作与式I的化合物组合的一种或多种另外的治疗剂,包括、但不限于TMC-207、OPC-67683、PA-824、LL-3858和SQ-109。
因此,可与式I的化合物组合的其它抗生素是例如利福平(rifampicin或rifampin);异烟肼;吡嗪酰胺;阿米卡星;乙硫异烟胺;莫西沙星;乙胺丁醇;链霉素;对氨基水杨酸、氯法齐明、克拉霉素、阿莫西林-克拉维酸盐、普瑞玛尼、贝达喹啉、GSK 3036656、M72/AS01E疫苗、吉珀达星、氨硫脲、美罗培南-克拉维酸盐、TBA-7371(一种癸异戊烯基磷酰基-β-D-核糖2’-氧化酶(DprE1)抑制剂)、来自Otsuka Pharmaceutical的OPC-167832、来自Qurient Co.、Ltd的Telacebec (Q203)和硫利达嗪;喹诺酮类/氟喹诺酮类例如氧氟沙星、环丙沙星、司帕沙星;大环内酯类例如克拉霉素、氯法齐明、阿莫西林-克拉维酸;利福霉素;利福布汀;利福喷汀。
在另一个方面,一种或多种另外的治疗剂是例如可用于治疗哺乳动物的结核病的药剂,治疗性疫苗,抗菌剂,抗病毒剂;抗生素和/或用于治疗HIV/AIDS的药剂。这样的治疗剂的例子包括异烟肼(INH)、乙胺丁醇、利福平、吡嗪酰胺、链霉素、卷曲霉素、环丙沙星和氯法齐明。
在一个方面,一种或多种另外的治疗剂是治疗性疫苗。式I的化合物或其药学上可接受的盐因此可以与对抗分枝杆菌感染的疫苗接种、特别是对抗结核分枝杆菌感染的疫苗接种结合施用。现有的对抗分枝杆菌感染的疫苗包括卡介苗(BCG)。目前在开发中的用于治疗、预防或改善分枝杆菌感染的疫苗包括:改良的BCG菌株,其重组表达另外的抗原、细胞因子和其它旨在改善效力或安全性的药剂;减弱的分枝杆菌,其表达比BCG更类似于结核分枝杆菌的抗原组合;和亚单位疫苗。亚单位疫苗可以以一种或多种单个蛋白抗原或多个蛋白抗原的一种或多种融合体的形式施用,其中任一种可以任选地佐剂化,或以编码一种或多种单个蛋白抗原或者编码多个蛋白抗原的一种或多种融合体的多核苷酸形式施用,例如,其中在表达载体中施用所述多核苷酸。亚单位疫苗的例子包括、但不限于:M72,即一种衍生自抗原Mtb32a和Mtb39的融合蛋白;HyVac-1,即一种衍生自抗原85b和ESAT-6的融合蛋白;HyVac-4,即一种衍生自抗原85b和Tb10.4的融合蛋白;MVA85a,即一种表达抗原85a的改良痘苗病毒Ankara;和Aeras-402,即一种表达衍生自抗原85a、抗原85b和Tb10.4的融合蛋白的腺病毒35。
本文采用的缩写包括下列:
ACN = 乙腈;CBZ-Cl=氯甲酸苄酯;CDCl3 = 氘代氯仿;DCM = 二氯甲烷;DIAD= 偶氮二甲酸二异丙酯, DIEA=N,N-二异丙基乙胺;DMF = N,N-二甲基甲酰胺;DMSO = 二甲亚砜;Et = 乙基;EtOAc =乙酸乙酯;EtOH= 乙醇;GFP= 绿色荧光蛋白;HATU= (1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐), HET= 杂环;H2 =氢气, HPLC = 高效液相色谱法;LC-MS = 液相色谱法/质谱法;Me = 甲基;MeOH = 甲醇;MIC = 最小抑制浓度;MW = 分子量;MS = 质谱法;Mtb= 结核分枝杆菌;Pd-C = 炭载钯;RT= 室温;TB= 结核病;TEA = 三乙胺;TFA = 三氟乙酸;THF = 四氢呋喃;和TBDMS= 叔丁基二甲基甲硅烷基。
用于制备式I的化合物的方法:
根据下述反应方案或其修改,使用容易得到的起始材料、试剂和常规合成程序,可以制备式I的化合物。在这些反应中,也可能利用本身对于本领域普通技术人员而言已知、但未更详细提及的变化。考虑到以下反应方案,替代性合成途径和类似结构将是有机合成领域的技术人员显而易见的。
实施例
实施例1
({(5S)-3-[4-(1,1-二氧代-1λ 6 -硫代吗啉-4-基)-3,5-二氟苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)氨基甲酸甲酯的合成
步骤A:4-(2,6-二氟-4-硝基苯基)硫代吗啉的合成
将N,N-二异丙基乙胺(8.81 mL, 50.8 mmol)和硫代吗啉(1.75 g, 16.9 mmol)加入1,2,3-三氟-5-硝基苯(3.0 g, 16.9 mmol)在DMF (30 mL)中的溶液中。将反应混合物温热至80℃并将其搅拌2小时。将反应混合物冷却,加入水(20 mL),并将得到的混合物用乙酸乙酯(3 x 30 mL)萃取。将合并的有机层用饱和氯化钠水溶液洗涤并经硫酸钠干燥,过滤,并将滤液在减压下浓缩,以足够纯度提供标题化合物用于下一步。1H NMR (400 MHz,CD3Cl) δ 7.82-7.74 (m, 2 H), 3.59-3.57 (m, 4 H), 2.78-2.75 (m, 4 H)。
步骤B:3,5-二氟-4-(硫代吗啉-4-基)苯胺的合成
将铁(2.64 g, 47.3 mmol)、氯化铵(2.53 g, 47.3 mmol)和水(10 mL)加入4-(2,6-二氟-4-硝基苯基)硫代吗啉(4.1 g, 15.8 mmol)在乙醇(30 mL)中的溶液中。将反应混合物温热至70℃并将其搅拌3小时。将反应混合物冷却并在减压下浓缩。将残余物溶解在乙酸乙酯(50 mL)中并经硫酸钠干燥,过滤,并将滤液在减压下浓缩,以足够纯度提供标题化合物用于下一步。MS (ESI) m/z: 230.8 [M+H+]。
步骤C:[3,5-二氟-4-(硫代吗啉-4-基)苯基]氨基甲酸苄酯的合成
将碳酸氢钠(2.48 g, 29.5 mmol)在水(20 mL)中的溶液加入3,5-二氟-4-(硫代吗啉-4-基)苯胺(3.4 g, 14.8 mmol)在丙酮(20 mL)中的溶液中,并将反应混合物冷却至0℃。加入氯甲酸苄酯(3.02 g, 17.7 mmol),并将反应混合物温热至环境温度和搅拌3小时。将反应混合物在减压下浓缩,将残余物溶解在乙酸乙酯中,并用水洗涤。将有机层经硫酸钠干燥,过滤,并将滤液在减压下浓缩,以足够纯度提供标题化合物用于下一步。MS (ESI) m/ z: 365.3 [M+H+]。
步骤D:N-({(5S)-3-[3,5-二氟-4-(硫代吗啉-4-基)苯基]-2-氧代-1,3-噁唑烷-
5-基}甲基)乙酰胺的合成
在0℃将甲醇(0.89 mL, 22 mmol)和叔丁醇锂(5.27 g, 65.9 mmol)加入[3,5-二氟-4-(硫代吗啉-4-基)苯基]氨基甲酸苄酯(8.0 g, 22 mmol)在四氢呋喃(80 mL)中的溶液中,并将反应混合物搅拌1小时。加入乙酸(2S)-1-乙酰胺基-3-氯丙烷-2-基酯(8.50 g,43.9 mmol)并将反应混合物温热至环境温度和搅拌16小时。通过加入HCl水溶液(1 M)将反应混合物调至大约pH 6并在减压下浓缩。将残余物用二氯甲烷(3 x 30 mL)萃取,并将合并的有机层经硫酸钠干燥,过滤,并将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用乙酸乙酯: 石油醚- 1:50至100:0的梯度洗脱,以提供标题化合物。MS (ESI) m/z:371.9 [M+H+]。
步骤E:N-({(5S)-3-[4-(1,1-二氧代-1λ6-硫代吗啉-4-基)-3,5-二氟苯基]-2-氧
代-1,3-噁唑烷-5-基}甲基)乙酰胺的合成
在0℃将过硫酸氢钾制剂(3.10 g, 5.05 mmol)在水(15 mL)中的溶液加入N-({(5S)-3-[3,5-二氟-4-(硫代吗啉-4-基)苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)乙酰胺(1.5 g, 4.04 mmol)在甲醇(25 mL)中的溶液中,并将反应混合物温热至环境温度和搅拌4小时。加入亚硫酸钠饱和水溶液(20 mL)并将混合物在减压下浓缩。将残余物用二氯甲烷(3x 30 mL)萃取并将合并的有机层经硫酸钠干燥,过滤,并将滤液在减压下浓缩,以足够纯度提供标题化合物用于下一步。MS (ESI) m/z: 404.1 [M+H+]。
步骤F:4-{4-[(5S)-5-(氨基甲基)-2-氧代-1,3-噁唑烷-3-基]-2,6-二氟苯基}-1
λ6-硫代吗啉-1,1-二酮的合成
将水(3 mL)和浓HCl水溶液(12 N, 3 mL)加入N-({(5S)-3-[4-(1,1-二氧代-1λ6-硫代吗啉-4-基)-3,5-二氟苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)乙酰胺(1.6 g, 3.97mmol)在甲醇(12 mL)中的溶液中。将反应混合物温热至70℃并将其搅拌1.5天。将反应混合物冷却并在减压下浓缩,以足够纯度提供标题化合物用于下一步。MS (ESI) m/z: 361.8[M+H+]。
步骤G:({(5S)-3-[4-(1,1-二氧代-1λ6-硫代吗啉-4-基)-3,5-二氟苯基]-2-氧
代-1,3-噁唑烷-5-基}甲基)氨基甲酸甲酯的合成
在0℃将N,N-二异丙基乙胺(0.196 ml, 1.13 mmol)和氯甲酸甲酯(0.032 mL,0.415 mmol)加入4-{4-[(5S)-5-(氨基甲基)-2-氧代-1,3-噁唑烷-3-基]-2,6-二氟苯基}-1λ6-硫代吗啉-1,1-二酮(150 mg, 0.377 mmol)在二氯甲烷(2 mL)中的溶液中。将反应混合物温热至环境温度并将其搅拌1小时。将反应混合物在减压下浓缩,并将残余物通过制备型HPLC纯化,用乙腈: 水(含有0.1% 三氟乙酸)- 15:85至45:55的梯度洗脱,以提供标题化合物。MS (ESI) m/z: 419.9 [M+H+]。1H NMR (DMSO-d6, 400 MHz): δ 7.52-7.50 (m, 1H), 7.34-7.27 (m, 2 H), 4.74-4.71 (m, 1 H), 4.11-4.07 (m, 1 H), 3.75-3.71 (m,1 H), 3.54 (s, 3 H), 3.48-3.40 (m, 4 H), 3.35-3.34 (m, 2 H), 3.23-3.22 (m, 4H)。
生物学测定
结核分枝杆菌(Mtb)生长测定
在两种体内相关的碳源(葡萄糖和胆固醇)上在pH 6.8评估结核分枝杆菌(Mtb)生长的抑制。对于作为碳源的葡萄糖,培养基由补充有4g/L葡萄糖、0.08g/L NaCl、5g/L BSA级分V和0.05%泰洛沙泊的Middlebrook 7H9液体培养基组成。对于作为碳源的胆固醇,培养基由补充有97mg/L胆固醇、0.08g/L NaCl、5g/L BSA级分V和0.05%泰洛沙泊的Middlebrook7H9液体培养基组成。在筛选之前,使表达绿色荧光蛋白的Mtb (Mtb-GFP;H37Rv pMSP12::GFP)预适应在补充有牛血清白蛋白和泰洛沙泊的Middlebrook 7H9-液体培养基基质中的相关碳源上的生长。以每孔24µL体积的大约2 X 104个活跃生长细胞,将细菌分配到384-孔微量滴定板中。用0.2µL化合物、二甲亚砜(阴性对照)或利福平(25µM;阳性对照)预分配微量滴定板。将细胞暴露于50 μM至0.049 μM的化合物的2倍连续稀释液。在一些实验中,在较低浓度下测试化合物。通过使用分光光度计测量荧光,在7天生长期后评估生长抑制。在阴性对照孔中,在读出时细胞仍在活跃生长。将抑制95%的细菌生长所需的受试化合物的最低浓度定义为MITC95。在BSL3设备中完成所有研究。
线粒体蛋白合成测定
通过对比氧化磷酸化酶复合物的两个亚基(复合物IV的亚基I (COX-I)和复合物II的70 kDa亚基(SDH-A))的水平,在HepG2细胞中评估线粒体蛋白合成的抑制。COX-I是线粒体DNA编码的,且SDH-A是核DNA编码的。将HepG2细胞以每孔8,000个细胞接种在96孔胶原包被的平板中,并暴露于100 μM至6.25 μM的化合物的2倍连续稀释液。在如制造商所述使用试剂盒(ab110217 MitoBiogenesis In Cell ELISA Kit, Abcam, Cambridge, MA)评估在蛋白水平之前,将微量滴定板温育约5个复制周期(4天)。将线粒体蛋白合成的抑制表示为COX-1水平与SDH-A水平之比和COX-1与总活细胞量(通过Janus Green (JG)染色确定)之比。
实施例 | Mtb Cho MITC95_µM | Mtb Glu MITC95_µM | MPS IC<sub>50</sub>_µM |
1 | 1.16 | 0.71 | 98 |
利奈唑胺 | 3.14 | 4.58 | 8 |
药代动力学实验
大鼠静脉内和口服单次实验
在来自口服施用和静脉内施用研究的大鼠中测定了清除率、分布容积、半衰期和口服生物利用度的血浆药代动力学参数。在给药前将4只通常体重为225 - 260克的雄性大鼠禁食过夜。根据使用的剂量,通过加入到媒介物中来制备用于口服和静脉内给药的化合物。对于典型的制品,将1 mg/mL (静脉内)或1.5 mg/mL (口服)的受试化合物加入到由20%二甲亚砜(DMSO)、60% 聚乙二醇400 (PEG400)和20%水组成的媒介物中。通过预先插管的颈静脉将静脉内(IV)制剂施用给两只大鼠,并且通过经口管饲法将口服剂量施用给两只大鼠。通过预插管的动脉收集血液,通常对于静脉内而言在给药前、给药后2、8、15、30分钟、1、2、4、6和8小时,以及对于口服给药而言在给药前、给药后15、30分钟、1、2、4、6、8小时。将样品收集在K2EDTA管中,储存在冰上并离心。将血浆转移到微量滴定板并储存在-70℃直至分析。使用蛋白沉淀法提取血浆样品,并使用每种化合物的标准曲线通过液相色谱法分离和随后的质谱检测(LC-MS/MS)进行分析。通过非房室法计算静脉内和口服给药数据的血浆药代动力学参数。将口服生物利用度确定为口服给药后剂量归一化的血浆曲线下面积(AUC)与静脉内给药后剂量归一化的血浆曲线下面积(AUC)之比。
大鼠静脉内盒实验
在来自静脉内盒施用研究的大鼠中确定了清除率、分布容积、半衰期和平均滞留时间(MRT)的血浆药代动力学参数。在给药前将2只通常体重为225 - 260克的雄性大鼠禁食过夜。根据使用的剂量,通过加入到媒介物中来制备用于静脉内给药的化合物。对于典型的制品,将1 mg/mL (静脉内)的至多5种受试化合物加入到由20% 二甲亚砜(DMSO)、60% 聚乙二醇400 (PEG400)和20% 水组成的媒介物中。通过预先插管的颈静脉将静脉内制剂施用给两只大鼠。通过预插管的动脉收集血液,通常在给药前、给药后2、8、15、30分钟、1、2、4、6和8小时。将样品收集在K2EDTA管中,储存在冰上并离心。将血浆转移到微量滴定板并储存在-70℃直至分析。使用蛋白沉淀法提取血浆样品,并使用每种化合物的标准曲线通过液相色谱法分离和随后的质谱检测(LC-MS/MS)进行分析。通过非房室法计算血浆药代动力学参数。
狗静脉内和口服单次实验
在来自口服施用和静脉内施用研究的狗中确定了清除率、分布容积、半衰期、平均滞留时间(MRT)和口服生物利用度的血浆药代动力学参数。在给药前将4只通常体重为8-12千克的雄性狗禁食过夜。根据使用的剂量,通过加入到媒介物中来制备用于口服和静脉内给药的化合物。对于典型的制品,将1 mg/mL (静脉内)或1.5 mg/mL (口服)的受试化合物加入由20% 二甲亚砜(DMSO)、60% 聚乙二醇400 (PEG400)和20% 水组成的媒介物中。通过隐静脉或头静脉将静脉内制剂施用给2只狗,并通过经口管饲法将口服剂量施用给2只狗。通过头或颈静脉收集血液,通常对于静脉内而言在给药前、给药后2、8、15、30分钟、1、2、4、6、8和24小时,以及对于口服给药而言在给药前、给药后15、30分钟、1、2、4、6、8和24小时。将样品收集在K2EDTA管中,储存在冰上并离心。将血浆转移到微量滴定板并储存在-70℃直至分析。使用蛋白沉淀法提取血浆样品,并使用每种化合物的标准曲线通过液相色谱法分离和随后的质谱检测(LC-MS/MS)进行分析。通过非房室法计算静脉内和口服给药数据的血浆药代动力学参数。将口服生物利用度确定为口服给药后剂量归一化的血浆曲线下面积(AUC)与静脉内给药后剂量归一化的血浆曲线下面积(AUC)之比。
狗静脉内盒实验
在来自静脉内盒施用研究的狗中确定了清除率、分布容积、半衰期和平均滞留时间(MRT)的血浆药代动力学参数。在给药前将2只通常体重为8-12千克的雄性狗禁食过夜。根据使用的剂量,通过加入到媒介物中来制备用于静脉内给药的化合物。对于典型的制品,将1 mg/mL (静脉内)的至多5种受试化合物加入到由20% 二甲亚砜(DMSO)、60% 聚乙二醇400 (PEG400)和20% 水组成的媒介物中。通过隐静脉或头静脉将静脉内制剂施用给2只狗。通过头或颈静脉收集血液,通常在给药前、给药后2、8、15、30分钟、1、2、4、6、8和24小时。将样品收集在K2EDTA管中,储存在冰上并离心。将血浆转移到微量滴定板并储存在-70℃直至分析。使用蛋白沉淀法提取血浆样品,并使用每种化合物的标准曲线通过液相色谱法分离和随后的质谱检测(LC-MS/MS)进行分析。通过非房室法计算血浆药代动力学参数。
血浆蛋白结合实验
通过在2.5µM的受试化合物存在下将适当物种血浆在37℃平衡透析4小时,确定化合物与来自大鼠和狗的血浆蛋白的结合。通过离心来沉淀和分离血浆样品。使用每种化合物的标准曲线,通过质谱检测(LC-MS/MS)分析上清液。根据以下公式计算未结合的化合物的分数:
未结合的分数(fu) = 峰面积比缓冲液/峰面积比血浆
其中
峰面积比缓冲液=缓冲液中分析物/内标的峰面积比
峰面积比血浆=血浆中分析物/内标的峰面积比
实施例 | 大鼠Cl (mL/min/kg) | 大鼠V<sub>d,ss </sub>(L/kg) | 大鼠MRT(h) | 大鼠f<sub>u</sub> | 狗Cl (mL/min/kg) | 狗V<sub>d,ss </sub>(L/kg) | 狗MRT (h) | 狗f<sub>u</sub> |
1 | 8.5 | 0.9 | 1.7 | 0.42 | 1.9 | 1.4 | 12.6 | 0.69 |
PCT公开号WO2017/070024公开了用于治疗结核病的噁唑烷酮抗生素。与早先公开的类似物、包含它们的药物组合物以及它们在治疗中的用途相比,本文所述的化合物具有非常有利的药代动力学性质。在PCT公开号WO2017/070024中公开的噁唑烷酮抗生素的药代动力学性质如下表所示:
来自WO2017/070024的实施例编号 | 结构 | 大鼠Cl (mL/min/kg) | 大鼠V<sub>d,ss </sub>(L/kg) | 大鼠MRT (h) | 大鼠f<sub>u</sub> |
48 | 85 | 2.5 | 0.5 | 0.83 | |
59 | 43 | 2.0 | 0.8 | 0.57 |
来自WO2017/070024的实施例编号 | 结构 | 狗Cl (mL/min/kg) | 狗V<sub>d,ss </sub>(L/kg) | 狗MRT (h) | 狗f<sub>u</sub> |
48 | 18 | 1.5 | 1.3 | 0.87 | |
59 | 53 | 4.2 | 1.3 | 0.81 |
如上表所示,式I的化合物具有与在合理剂量下每天1次给药的可能性更好地关联的药代动力学特性。
Claims (26)
2.药物组合物,其包含治疗有效量的权利要求1所述的化合物或其药学上可接受的盐和药学上可接受的载体。
3.用于治疗细菌感染的方法,所述方法包括给需要这种治疗的对象施用治疗有效量的权利要求1所述的化合物或其药学上可接受的盐。
4.用于治疗细菌感染的方法,所述方法包括给需要这种治疗的对象施用根据权利要求2所述的药物组合物。
5.权利要求3所述的方法,其中所述细菌感染是由于结核分枝杆菌。
6.权利要求4所述的方法,其中所述细菌感染是由于结核分枝杆菌。
7.权利要求3所述的方法,其中口服、胃肠外或局部施用所述化合物或其药学上可接受的盐。
8.权利要求4所述的方法,其中口服、胃肠外或局部施用所述药物组合物。
9.权利要求5所述的方法,其中所述结核分枝杆菌是耐药分枝杆菌菌株。
10.权利要求6所述的方法,其中所述结核分枝杆菌是耐药分枝杆菌菌株。
11.权利要求3所述的方法,所述方法进一步包括施用用于治疗结核分枝杆菌的第二治疗剂的步骤。
12.权利要求11所述的方法,其中所述第二治疗剂选自:乙胺丁醇、吡嗪酰胺、异烟肼、左氧氟沙星、莫西沙星、加替沙星、氧氟沙星、卡那霉素、阿米卡星、卷曲霉素、链霉素、乙硫异烟胺、丙硫异烟胺、环丝氨酸、特立齐酮、对氨基水杨酸、氯法齐明、克拉霉素、阿莫西林-克拉维酸盐、普瑞玛尼、贝达喹啉、GSK 3036656、吉珀达星、氨硫脲、美罗培南-克拉维酸盐、TBA-7371,一种癸异戊烯基磷酰基-β-D-核糖2’-氧化酶(DprE1)抑制剂、来自OtsukaPharmaceutical的OPC-167832、来自Qurient Co., Ltd的Telacebec (Q203)和硫利达嗪。
13.权利要求1所述的化合物或其药学上可接受的盐用于治疗对象的细菌感染的用途或在制备用于治疗对象的细菌感染的药物中的用途。
15.药物组合物,其包含治疗有效量的权利要求14所述的化合物和药学上可接受的载体。
16.用于治疗细菌感染的方法,所述方法包括给需要这种治疗的对象施用治疗有效量的权利要求14所述的化合物。
17.用于治疗细菌感染的方法,所述方法包括给需要这种治疗的对象施用根据权利要求15所述的药物组合物。
18.权利要求16所述的方法,其中所述细菌感染是由于结核分枝杆菌。
19.权利要求17所述的方法,其中所述细菌感染是由于结核分枝杆菌。
20.权利要求16所述的方法,其中口服、胃肠外或局部施用所述化合物或其药学上可接受的盐。
21.权利要求17所述的方法,其中口服、胃肠外或局部施用所述化合物或其药学上可接受的盐。
22.权利要求18所述的方法,其中所述结核分枝杆菌是耐药分枝杆菌菌株。
23.权利要求19所述的方法,其中所述结核分枝杆菌是耐药分枝杆菌菌株。
24.权利要求16所述的方法,所述方法进一步包括施用用于治疗结核分枝杆菌的第二治疗剂的步骤。
25.权利要求24所述的方法,其中所述第二治疗剂选自:乙胺丁醇、吡嗪酰胺、异烟肼、左氧氟沙星、莫西沙星、加替沙星、氧氟沙星、卡那霉素、阿米卡星、卷曲霉素、链霉素、乙硫异烟胺、丙硫异烟胺、环丝氨酸、特立齐酮、对氨基水杨酸、氯法齐明、克拉霉素、阿莫西林-克拉维酸盐、普瑞玛尼、贝达喹啉、GSK 3036656、吉珀达星、氨硫脲、美罗培南-克拉维酸盐、TBA-7371,一种癸异戊烯基磷酰基-β-D-核糖2’-氧化酶(DprE1)抑制剂、来自OtsukaPharmaceutical的OPC-167832、来自Qurient Co., Ltd的Telacebec (Q203)和硫利达嗪。
26.权利要求14所述的化合物或其药学上可接受的盐用于治疗对象的细菌感染的用途或在制备用于治疗对象的细菌感染的药物中的用途。
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AU2022399569A1 (en) * | 2021-11-30 | 2024-06-06 | Mannkind Corporation | Formulation and method for topical treatment of mycobacterium ulcerans in buruli ulcers |
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