CN102712596A - 新的仲8-羟基喹啉-7-羧酰胺衍生物 - Google Patents
新的仲8-羟基喹啉-7-羧酰胺衍生物 Download PDFInfo
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- CN102712596A CN102712596A CN2010800597351A CN201080059735A CN102712596A CN 102712596 A CN102712596 A CN 102712596A CN 2010800597351 A CN2010800597351 A CN 2010800597351A CN 201080059735 A CN201080059735 A CN 201080059735A CN 102712596 A CN102712596 A CN 102712596A
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- Prior art keywords
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- quinoline
- carboxylic acid
- hydroxy
- acid amides
- Prior art date
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- MMCIXNVRVDTQSG-UHFFFAOYSA-N quinoline-7-carboxamide Chemical class C1=CC=NC2=CC(C(=O)N)=CC=C21 MMCIXNVRVDTQSG-UHFFFAOYSA-N 0.000 claims description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
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Abstract
Description
本发明提供可用作抗真菌剂的新的仲8-羟基喹啉-7-羧酰胺衍生物和其药学上可接受的盐,以及用于制备它们的方法。具体地,针对红色毛癣菌(Tricophyton Rubrum)、须癣毛癣菌(Tricophyton Mentagrophytes)、黑曲霉(Aspergillus Niger)和短帚霉(Scopulariopsis Brevicaulis)检验这些化合物。这些化合物中的许多对念珠菌菌属(Candida)物种诸如白念珠菌(Candida Albicans)和光滑念珠菌(Candida Glabrata)是有效的。
发明背景
致病性真菌可分为两类:能够在正常受试者内引起疾病的真菌和只能够在严重患病的宿主内产生疾病的侵袭性较弱的真菌。在过去的二十年,侵袭性机会性真菌感染的发生率和伴随的发病率与死亡率有明显增加。这主要是因为现代医学的较大进展增加了危重患者诸如重症加强护理病房(ICU)中带有血管内导管和导尿管、总的肠胃外营养和血液透析或连接于供氧系统的那些患者的存活。
念珠菌属物种通常导致ICU中患者的医院血流感染。英国念珠菌菌血症的住院发生率是每100,000床位天数约3例,且所有病例的40%至52%发生在ICU(Schelenz S.,J.Antimicrob.Chemother.2008;61,Suppl 1,31-34)。这一类型的霉菌病经常伴随着相当大的发病率和死亡率。归因死亡率是约38%,但是可在5%与71%之间变化。在近年间,在准许进入ICU的患者中侵袭性肺部曲霉病的发生率上升。该疾病发生率从0.3%至5.8%变化,且总死亡率超过80%(Trof R.J.等,Intensive Care Med.,2007;33,1694-1703)。严重患病的患者在ICU停留期间处于发展免疫调节的扰乱的风险中,这使得他们更易遭受真菌感染。已经描述了风险因素诸如慢性阻塞性肺病、长期使用类固醇、晚期肝病、长期洗肾疗法、接近溺死和糖尿病。
免疫妥协患者的数目也有显著增加,尤其是在实体器官和骨髓移植、自身免疫综合征、获得性免疫缺陷综合症(AIDS)和肿瘤学领域。
约40%的骨髓移植人群发展侵袭性真菌感染(Khan S.A.,Wingard J.R.,Natl.Cancer Inst.Monogr.2001;29,31-36)。念珠菌菌属和曲霉属(Aspergillus)物种是在血液恶性肿瘤和骨髓移植患者造成医院浅表性和侵袭性霉菌病的最常见病原体。在这些患者中,全身性念珠菌菌病带来的死亡率非常高(50-90%)。
有关实体器官移植,在肺移植患者中感染性并发症更常见。除了免疫抑制治疗方案以外,增加的易感性主要是因为经常暴露于外部环境。平行于免疫抑制治疗强度,侵袭性真菌感染可能在手术操作后的前几天发生,其频率在前两个月最高并在6个月后降低,但还可在移植后数年发生(Hamacher J.等,Eur.Respir.J.,1999;13,180-186)。
侵袭性真菌感染在其他类型的实体器官移植诸如肾和肝脏移植中也是频繁的,报道其发生率为5%至50%(Dictar M.O.等,MedMycol.,2000;38Suppl.1,251-258)。
霉菌病是AIDS患者发病的主要原因之一,且这些感染的发生率和严重度随着疾病发展和随之发生的T-细胞介导的免疫的损伤而增加。不同霉菌病的发生率与居住地中存在的地方性机会性真菌紧密相关。一般来说,影响AIDS患者的最常见霉菌病是组织胞浆菌病、芽生菌病、球孢子菌病和南美芽生菌病(Sarosi G.A.,Davies S.F.,West J.Med.,1996;164,335-340)。
念珠菌菌的粘膜感染也是极其常见的。在正常患者中,所有这些霉菌病通常是自身限制性的,但在免疫抑制患者中变得高度侵袭性,导致渐进性和普遍的传播。
而且,生物体对现有疗法的耐药性导致的霉菌病增加在近年变得明显。这一现象对于由白念珠菌导致的真菌感染和氟康唑与其他唑类尤其明显(Bastert J.等,Int.J.Antimicrob.Agents,2001;17,81-91)。
由于其活性谱有限和其使用带来的严重副作用,现在可获得的抗真菌药物不是完全令人满意的。
例如,多烯药物两性霉素B是对至少曲霉属、接合菌(Zygomycete)和其他霉菌有效的,且由于其毒性,用于治疗侵袭性霉菌病的批准剂量是每天3-5mg/kg。在患有侵袭性曲霉病的高度免疫妥协患者中,以每天3mg/kg施用脂质体包封的两性霉素B在50%的患者提供有利的响应和提供72%的12周存活率(Cornely O.A.等,Clin.Infect.Dis.,2007;44,1289-1297)。该药物在14-16%的患者引起肾毒性和低钾血。
当以每天10mg/kg施用时,两性霉素B不提供任何另外的益处并导致更高比例的肾毒性(31%)。
在1970年代的后半期引入的唑类是麦角固醇合成的阻断剂。属于这一家族的药物的使用被它们窄的活性谱限制。例如,伏立康唑对于治疗侵袭性曲霉病比两性霉素B更有效,但对接合菌无活性(Johnson L.B.,Kauffman C.A.,Clin.Infect.Dis.,2003,36,630-637)。唑类的采用也被引起许多副作用而限制。唑类与哺乳动物p450酶相互作用,导致干扰其他药物的代谢,另外,一些唑类诸如酮康唑能够阻断心脏钾通道Kv1.5,导致Q-T延长和‘尖端扭转型室性心动过速’(Dumaine R.,Roy M.L.,Brown A.M.,J. Pharmacol.Exp.Ther.,1998;286,727-735)。
烯丙胺类诸如特比萘芬结合于角鲨烯环氧酶并抑制它,导致麦角固醇合成的阻断。这些药物对皮肤真菌(Dermatophytes)非常强效,但其对念珠菌菌属物种的活性非常差。在一些病例中,烯丙胺类治疗伴有严重的皮肤副反应。最近的多国病例-对照研究(euroSCAR)(Sidoroff A.等,Br.J.Dermatol.,2007;15,989-996)揭示,特比萘芬全身性治疗强烈地伴有急性泛发性发疹性脓疱病(AGEP)的发展。这一疾病的特征是迅速出现许多无菌性非毛囊性脓疱,通常伴随白细胞增多和发热。AGEP通常归因于以特定药物治疗患者,并表现为与改变的T细胞活性相关。特比萘芬治疗还可能引起皮肌炎,这是一种严重的自身免疫性结缔组织疾病,特征为红斑、肌无力和间质性肺纤维化(Magro C.M.等,J.Cutan.Pathol.,2008;35,74-81)。另外,如同多种抗真菌药物,特比萘芬可能导致严重的肝脏损伤(Perveze Z.等,Liver Transpl.,2007;13,162-164)。
灰黄霉素是在1960年代引入的一种苯并呋喃,用于治疗皮肤真菌感染。该化合物通过干扰微管产生来引起其抑制真菌活性。灰黄霉素在治疗甲癣方面展示有限的活性,并经常导致严重的副作用诸如恶心、腹泻、头痛、意识障碍和疲乏(Korting H.C.等,Antimicrob.Agents Chemother.,1993;37,2064-2068),可导致治疗停止。
两种N-羟基吡啶酮即环吡酮胺和羟甲辛吡酮,表现为主要通过螯合多价阳离子来作用,导致金属依赖性酶的抑制。采用它们来针对不同的真菌感染,但其使用限于局部治疗。
棘球白素(卡泊芬净、米卡芬净、阿尼芬净)是半合成的脂-肽类,是最近引入的抗霉菌药。它们通过非竞争性地抑制维持细胞壁必需的酶β-(1-3)-D葡聚糖合酶来作用,主要用于静脉内治疗侵袭性念珠菌菌病和曲霉病。它们对酵母是杀真菌的但对丝状真菌仅是抑制真菌的;另外,它们对双相真菌诸如芽生菌属(Blastomyces)和组织胞浆菌属(Histoplasma)相当无效。棘球白素通常是良好耐受的,但动物生殖研究显示对胎儿的副作用。为此,FDA将棘球白素列为怀孕风险C类(http://www.fda.gov/medwatch/SAFETY/2004/mar_PI/Cancidas_PI.pdf;http://www.fda.gov/medwatch/safety/2007/Aug_PI/Mycamine_PI.pdf)。
EP1375486公开具有HIV整合酶抑制活性的通用和非常广的类别的化合物。这一广的通用类别包括在7-位被宽范围的取代基取代的8-羟基-喹啉衍生物,所述取代基例如取代的羧酰胺基团。这一参考文献中公开的具体化合物与本发明的化合物在结构上都不相似。
EP1541558公开具有HIV整合酶抑制活性的通用和非常广的类别的化合物。事实上,这一参考文献中公开的具体化合物通常在吡啶环上带有取代基并优选地是3-(4-氟苄基)-8-羟基喹啉。这一参考文献中公开的具体化合物与本发明的化合物在结构上都不相似。
WO98/11073(US6310211)公开具有HIV整合酶抑制活性的通用类别的抗病毒化合物。这一参考文献中公开的具体化合物与本发明的化合物在结构上都不相似。
WO02/30426公开具有HIV整合酶抑制活性的通用类别的化合物。事实上,这一参考文献中公开的大多数具体化合物带有萘啶基残基。这一参考文献中公开的具体化合物与本发明的化合物在结构上都不相似。
WO02/30930公开具有HIV整合酶抑制活性的通用和非常广的类别的化合物。这一参考文献中公开的具体化合物与本发明的化合物在结构上都不相似。
US0326330和US0326328公开包含两种杀真菌剂的组合的杀真菌组合物,其中之一是喹啉或噌啉化合物。这一参考文献中公开的具体化合物与本发明的化合物在结构上都不相似。
WO96/32015公开由喹啉衍生物和细胞色素III复合物抑制剂制成的协同杀真菌组合物。这一参考文献中公开的具体化合物与本发明的化合物在结构上都不相似。
EP1669348公开以非常宽的式定义的抗真菌剂,包括某些仲酰胺。
从以上描述明显的是,在近几年对有效抗真菌药物的临床需求已经显著增加。遗憾地是,由于其窄的作用谱、药代动力学特性和严重的副作用,实际上可获得的药物不令人满意。
发明描述
本发明具体地提供被赋予强效抗真菌活性的通式(I)的化合物
其中R0是:
●-H、
●-F、
●-Cl、
●-Br、
●-NO2、
●-CF3、
●-C1-C6烷基、
●-(CH2)m-NR1R2、
●-(SO2)-NR1R2、
●-(C=O)-NR1R2、
●-(N-C=O)-NR1R2、
●-CN、
●-W-R3、
●-(CH2)m-芳基,任选地被一个或两个R4取代、或
●-(CH2)m-杂环,任选地被一个或两个R4取代;
其中R1和R2彼此独立地选自:
●-H、
●-C1-C6烷基、
●-(CH2)m-芳基,任选地被一个或两个R4取代、
●-(CH2)m-环烷基,任选地被一个或两个R5取代、
●-(CH2)m-杂环,任选地被一个或两个R4取代、
●-(CH2)m-W-R3、
●-(CH2)m-CN、
●与它们所连接的氮原子一起形成包含选自由氮、氧和硫组成的组的一至三个杂原子的任选地取代的5-元至8-元的杂单环、或
●与它们所连接的氮原子一起形成任选地取代的5-元至8-元的杂单环,所述杂单环与一个或两个任选地取代的饱和或不饱和的环稠合或与包含选自由氮、氧和硫组成的组的一至三个杂原子的其他任选地取代的杂环稠合;
其中W是:
●-O-、或
●-S-;
其中R3是:
●-H、
●-C1-C6烷基、
●-(CH2)m-芳基,任选地被一个或两个R4取代、
●-(CH2)m-环烷基,任选地被一个或两个R5取代、或
●-(CH2)m-杂环,任选地被一个或两个R4取代;
其中R4是:
●-F、
●-Br、
●-NO2、
●-C1-C6烷基、
●-(CH2)m-NR1R2、
●-(SO2)-NR1R2、
●-(C=O)-NR1R2、
●-(N-C=O)-NR1R2、
●-CN、
●-W-R3,条件是当W是-O-时,R3不同于氢或甲基、
●-(CH2)m-芳基,任选地被一个或两个R7取代、或
●-(CH2)m-杂环,任选地被一个或两个R7取代;
其中R5是:
●-C1-C4烷基、
●-W-H、
●-CH2-W-H、
●-(CH2)m-芳基,任选地被一个或两个R7取代、或
●-(CH2)m-杂环,任选地被一个或两个R7取代;
其中R6是:
●-H、
●-F、
●-Cl、
●-Br、
●-OH、或
●-O-C1-C3烷基;
其中R7是:
●-H、
●-F、
●-Cl、
●-Br、
●-CF3、
●-W-R3、
●-C1-C6烷基、
●-(CH2)m-芳基,任选地被一个或两个R6取代、
●-(CH2)m-杂环,任选地被一个或两个R6取代、或
●-(CH2)m-C3-C8环烷基;
其中m是0至6的整数;
其中A是:-(CH2)n-X;
其中n是0至1的整数,条件是:
当n=0时,X是:
●任选地取代的单环杂环或2,3-二氢苯并[b][1,4]二噁烯残基,条件是所述杂环不是任选地取代的吡啶、噻二唑、噻吩、呋喃或苯并[d][1,3]间二氧杂环戊烯、或
●在对位被NR1R2取代的芳基;
其中R1和R2如以上定义;
当n=1时,X是:
●任选地取代的杂环,优选地2,3-二氢苯并[b][1,4]二噁烯残基,条件是所述杂环不是任选地取代的3-吡啶、噻二唑、噻吩、呋喃或苯并噻唑、或
在对位被R4取代的芳基,条件是R4不是-NO2,
其中R4如以上定义;
或其药学上可接受的盐或衍生物。
本文所用的术语C1-C6烷基是指具有1至6个碳原子的直链或支链的烷基基团,并包括所有的己基和戊基烷基异构体以及正丁基、异丁基、仲丁基和叔丁基、正丙基和异丙基、乙基和甲基。
术语环烷基是指环状环的烷,选自环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
术语芳基是指芳香族单碳环系统和多碳环系统,其中多环系统中的单个碳环可经由单键彼此稠合或连接。适合的芳基基团包括但不限于,苯基、萘基和联苯基。
术语杂环(和其变化形式诸如“杂环的”)宽泛地是指4-元至8-元的单环、7-元至12-元的二环环系统或11-元至16-元的三环环系统,其任一个环是饱和或不饱和的,且其由碳原子和选自N、O和S的一个或多个杂原子组成,且其中氮和硫杂原子可任选地被氧化且氮杂原子可任选地被季铵化。杂环的环可在任何杂原子或碳原子处被连接,条件是连接导致产生稳定结构。当杂环的环具有取代基时,应理解取代基可连接于环中无论是杂原子或碳原子的任何原子,条件是导致稳定的化学结构。
术语杂单环(和其变化形式诸如“杂单环的”)是指饱和或不饱和的4-元至8-元的单环,且其由碳原子和选自N、O和S的一个或多个杂原子组成,且其中氮和硫杂原子可任选地被氧化且氮杂原子可任选地被季铵化。杂环的环可在任何杂原子或碳原子处被连接,条件是连接导致产生稳定结构。当杂环的环是芳香族杂环时,其可被定义为“杂芳香族环”。
除非相反地明确陈述,否则“不饱和”的环是部分或完全不饱和的环。例如,“不饱和单环C6碳环”是指环己烯、环己二烯和苯。
术语取代的包括被指定的取代基单取代和多取代到化学上允许的单取代和多取代的程度。例如,被多于一个取代基取代的碳环或杂环可在同一个环原子上具有多个取代基,到化学上允许的程度。饱和杂环中的环硫原子可例如通常被一个(-S(=O)-)或两个氧基团(-SO2-)取代。
“药学上可接受的盐”或衍生物是指具备母体化合物的生物效力和特性,且不是生物学上或以其他方式不期望的那些盐或衍生物。这样的盐包括无机酸或有机酸的那些盐,例如氢溴酸盐、盐酸盐、硫酸盐、磷酸盐、钠盐、镁盐;这样的衍生物包括酯类、醚类和N-氧化物。
本发明的化合物和其药学上可接受的盐或衍生物可具有不对称中心,除了具体指明时之外,可作为立体异构体的混合物或作为单独的非对映异构体或对映异构体存在,且所有异构体形式被包括在本发明中。
与包含本发明化合物的制剂关联使用的短语“药学上可接受的”是指这样的制剂的分子部分和其他成分是生理上可耐受的且当施用于动物诸如哺乳动物(例如人类)时通常不产生不利的反应。优选地,本文所用的术语“药学上可接受的”是指被管理机构诸如FDA或EMEA批准的,或在美国药典或欧洲药典或其他一般公认药典中列出用于哺乳动物、更尤其是用于人类的。
优选地在式(I)中:
R0是:
●-H、
●-Br、或
●-NO2。
进一步优选地在式(I)中:
R0是-H;
R1和R2彼此独立地选自:
●-C1-C6烷基、或
●与它们所连接的氮原子一起形成包含选自由氮、氧和硫组成的
组的一至三个杂原子的任选地取代的5-元至8-元的杂单环;
R3是-C1-C6烷基;
R4是:
●-Br、
●-(CH2)m-NR1R2、或
●-W-R3,条件是当W是-O-时,R3不同于氢或甲基;
W是-O-;
和/或m是0至1的整数。
本发明的优选化合物包括但不限于选自由以下组成的组的化合物:
8-羟基-N-(1,1-二氧代四氢噻吩-3-基)喹啉-7-羧酰胺(实施例3);
8-羟基-N-(四氢-2H-吡喃-4-基)喹啉-7-羧酰胺(实施例5);
8-羟基-N-(4-吗啉代苯基)喹啉-7-羧酰胺(实施例6);
8-羟基-N-(噻唑-2-基)喹啉-7-羧酰胺(实施例8);
8-羟基-N-(异噁唑-3-基)喹啉-7-羧酰胺(实施例13);
8-羟基-N-((5-甲基吡嗪-2-基)甲基)喹啉-7-羧酰胺(实施例15);
8-羟基-N-((1-甲基-1H-咪唑-2-基)甲基)喹啉-7-羧酰胺(实施例16);
8-羟基-N-((4-苯基噻唑-2-基)甲基)喹啉-7-羧酰胺(实施例17);
8-羟基-N-(吡啶-4-基甲基)喹啉-7-羧酰胺(实施例18);
8-羟基-N-(2,3-二氢苯并[b][1,4]二噁烯-6-基)喹啉-7-羧酰胺(实施例9);
8-羟基-N-(4-(二甲氨基)苄基)喹啉-7-羧酰胺(实施例4);
8-羟基-N-(4-溴苄基)喹啉-7-羧酰胺(实施例2);
8-羟基-N-(苯并[d]噻唑-2-基甲基)喹啉-7-羧酰胺(实施例14);
8-羟基-N-(4-吗啉代苄基)喹啉-7-羧酰胺(实施例10);
8-羟基-N-((4-甲基噻唑-2-基)甲基)喹啉-7-羧酰胺(实施例12);
8-羟基-N-(吡啶-2-基甲基)喹啉-7-羧酰胺(实施例1);
8-羟基-N-(4-(1H-1,2,4-三唑-1-基)苯基)喹啉-7-羧酰胺(实施例7);
8-羟基-N-((5-甲基异噁唑-3-基)甲基)喹啉-7-羧酰胺(实施例11)。
本发明的化合物可通过偶联适合的8-羟基喹啉-7-羧酸1-1(或酸衍生物诸如酰基卤或酯)与适合的胺1-2来制备,如由以下总图1表示的:
图1
可选地,可在进行与胺偶联之前保护羧酸的羟基(如Bioorg.Med.Chem.,14,2006,5742-5755或Synthesis,12,1997,1425-1428或DE540842中所述),然后在最后阶段中脱保护。
用于偶联羧酸与胺来形成羧酰胺的方法是本领域公知的。适合的方法描述在例如Jerry March,Advanced Organic Chemistry,4th edition,John Wiley&Sons,1992,pp.417-425中。
用于保护和脱保护芳香族羟基的方法是本领域公知的。按照有机合成的标准方法操纵保护基(Green T.W.和Wuts P.G.M.(1991)Protecting Groupsin Organic Synthesis,John Wiley et Sons)。
下图2说明并详述图1中描绘的化学反应。
当R1是Br时,羧酸2-1通过将可商业获得的8-羟基喹啉-7-羧酸与一当量的溴在乙酸中反应来获得(1998年3月19日公布的国际公布WO98/11073)。
当R1是F或Cl时,羧酸2-1可使用在1998年3月19日公布的国际公布WO98/11073中描述的方法从相应的可商业获得的起始材料5-卤代-8-羟基喹啉制备。
当R1是NO2时,羧酸2-1通过将相应的乙基酯与HNO3和H2SO4的混合物反应,随后碱水解来制备。可选地,R1=NO2的羧酸2-1通过将3-氨基-2-羟基-5-硝基苯甲酸与丙烯醛在6N HCl中反应来制备。
对本领域技术人员明显的是,描述的合成方案本质上仅是代表性的,且替代的合成方法是有机化学领域技术人员已知的。
以下实施例仅为了说明本发明和其实施。实施例不解释为对本发明的范围或精神的限制。
实验部分
1.化学合成
除非另外指明,否则所有起始试剂都是可商业获得的,且不经任何预先纯化来使用。使用常规合成方案可容易地制备本发明的化合物。在这些反应中,还可以使用本身是本领域技术人员已知的,但没有更详细提及的变体。而且,根据以下反应方案和实施例,用于制备本发明化合物的其他方法对于本领域技术人员将是容易明显的。除非另外指明,否则所有变量都如以上定义。
当提及使用“类似”方案时,如本领域技术人员将理解的,这样的方案可包括在例如反应温度、试剂/溶剂量、反应时间、后处理条件或色谱纯化条件方面的微小改变。
本说明书中尤其是表格和实施例中使用的缩写概述在表1。
表1
LC-MS(液相色谱质谱) | ESI(电喷雾电离) |
UPLC(超高效液相色谱) | Rt(以分钟计的保留时间) |
TFA(三氟乙酸) | min(分钟) |
μm(微米) | h(小时) |
mmol(毫摩尔) | RT(室温) |
μL(微升) | CH3CN(乙腈) |
THF(四氢呋喃) | DCM(二氯甲烷) |
DMSO(二甲基亚砜) | Na2SO4(硫酸钠) |
SPE-SI(硅胶固相萃取) | CFU(菌落形成单位) |
除非另外指明,否则所有温度都以℃(摄氏度)或K(开尔文)表示。
质子核磁共振(1H-NMR)光谱在Brucker 300MHz上记录。化学位移以百万分之几(ppm,δ单位)表示。裂分图案描述表观多重性,称为s(单峰)、d(双峰)、t(三重峰)、q(四重峰)、quint(五重峰)、sxt(六重峰)、m(多重峰)、br.s(宽单峰)。
在以下条件下记录LC-MS:
带有样品管理器和2996PDA检测器(Waters)的UPLC连接单四极杆质谱仪ZQ(Waters)。ZQ界面:ESI正电离模式。全扫描从102至900amu。毛细管电压3.2V,锥孔电压25V,提取锥孔电压3V,RF 0.3V,源温115℃,脱溶剂温度350℃,脱溶剂气流量800L/h,锥孔气流量100L/h。
·方法A:柱Aquity UPLC-BEH C18(50×2.1mm,1.7μm)。流速0.6mL/min,柱在40℃,注入2μL。流动相:A相=水/CH3CN 95/5+0.1%TFA,B相=水/CH3CN=5/95+0.1%TFA。梯度:0-0.25min(A:95%,B:5%),3.30min(A:0%,B:100%),3.30-4.00(A:0%,B:100%),4.10min(A:95%,B:5%),4.10-5.00min(A:95%,B:5%)。
·方法B:柱Atlantis dC18(100×2.1mm,3.0μm)。流速0.3mL/min,柱在40℃,注入2μL。流动相:A相=水/CH3CN 95/5+0.1%TFA,B相=水/CH3CN=5/95+0.1%TFA。梯度:0-0.20min(A:95%,B:5%),5.00min(A:0%,B:100%),5.00-6.00(A:0%,B:100%),6.10min(A:95%,B:5%),6.10-7.00min(A:95%,B:5%)。
实施例1:
8-羟基-N-(吡啶-2-基甲基)喹啉-7-羧酰胺
在氮气下将8-羟基喹啉-7-羧酸(100mg,0.53mmol)和二(1H-咪唑-1-基)甲酮(86mg,0.53mmol)在THF(5mL)中的混合物加热到60℃持续3小时。将反应混合物冷却到室温并加入吡啶-2-基甲胺(46mg,0.424mmol)。将所得的混合物加热到40℃持续2小时,然后在室温搅拌。以H2O和碳酸氢钠的饱和水溶液骤冷反应混合物,用DCM萃取两次。通过Na2SO4干燥分离的有机物,过滤并减压浓缩。通过SPE-SI柱(2g,DCM至DCM∶MeOH 99∶1)纯化残留物,提供标题化合物(73mg,0.26mmol)为米白色固体。
LC-MS m/z(ESI+):280.14(MH+),Rt=0.57min(方法A)。
1H-NMR(DMSO-d6)δ:9.46(t,1H);8.93(dd,1H);8.54(ddd,1H);8.37(dd,1H);8.06(d,1H);7.78(td,1H);7.66(dd,1H);7.45(d,1H);7.41(d,1H);7.29(ddd,1H);4.70(d,2H)。
按照与以上描述的方案类似的方案,制备本发明的另外的化合物(表2)。
表2
2.活性检验:方法和结果
用于检验抗真菌活性的生物体
红色毛癣菌(ATCC 28188,PBI International);须癣毛癣菌(ATCC 9533,PBI International);黑曲霉(ATCC 16404,PBI International);短帚霉(ATCC36840,DSMZ);白念珠菌(ATCC 90028,PBI International);光滑念珠菌(ATCC 90030,DSMZ)。
制备和保存
菌株从冻干的安瓿或冻干的小粒制备。
在马铃薯葡萄糖琼脂(PDA)上进行悬液的分离以检验菌株纯度。然后通过在PDA平板上将微生物悬液划线来进行菌株的大规模生长。
培养是在30℃进行48-72小时(念珠菌属酵母)和进行7-10天(丝状真菌)。
以3-5mL的RPMI 1640+50%甘油收获酵母的菌落和丝状真菌的分生孢子,将等份试样冷冻在-80℃。
抗真菌易感性检验
使用按照美国临床实验室标准委员会(National Committee for ClinicalLaboratory Standards,NCCLS)开发的方法(National Committee for ClinicalLaboratory Standards.Reference Method for Broth Dilution AntifungalSusceptibility Testing of Yeasts;Approved standard-Second Edition M27-A2.2002;第22卷,第15期)(National Committee for Clinical LaboratoryStandards.Reference Method for Broth Dilution Antifungal SusceptibilityTesting of Filamentous Fungi;Approved standard M38-A.2002;第22卷,第16期),经由肉汤微量稀释易感性检验确定化合物的最小抑制浓度(MIC)。
在带有L-谷氨酰胺、以0.165M 3-(N-吗啉代)丙磺酸(MOPS)和10MNaOH缓冲到pH 7并补充有18g葡萄糖/升的RPMI 1640培养基中进行测定。使用96孔无菌板进行检验(接种量为1×105 CFU/mL)。制备化合物母液为100%DMSO中12.8mg/mL。使用RPMI 1640在平板中制备一系列两倍稀释液。最终浓度在1%DMSO下从0.125至128μg/mL变化。
MIC定义为抗真菌剂阻止任何可见生长的最低浓度,在培养酵母(35℃)48小时后和培养丝状真菌(35℃)五天后确定。
结果
最优选的化合物的MIC值计算为两次单独实验获得的数值的几何平均值,报告于表3。
表3
而且,合成在EP1669348A1中编号为E8的化合物连同一种新化合物(编号为NiK-29298),该新化合物既不包括在EP1669348A1公开的那些中也不包括在本发明中,可用作本申请中描述的化合物类别与EP1669348A1中描述的化合物类别之间的联系(表4)。
表4
对相同生物体检验、用于评价本申请中描述的衍生物的效力的这些化合物的MIC值,报告于表5。
表5
如可理解的,表3中列出的所有化合物对检验的包括酵母、皮肤癣菌和霉菌的所有6种菌株都有效。本发明的这一广谱化合物解释对人类或动物中所有种类真菌感染的预测效力,所述真菌感染包括主要由皮肤癣菌导致的皮肤、头皮和指甲感染;主要由酵母导致的阴道、口和肠感染;主要由霉菌导致的耳、肺部、眼和其他全身性感染。
相反,EP1669348A1中公开的化合物E8和以EP1669348A1中描述的相同喹啉骨架为特征的化合物NiK-29298,仅对酵母有效,对包括皮肤癣菌和霉菌的其他菌株不展示任何可评估的活性。
作用机理
本领域中已知,最强效和广谱抗真菌剂之一的环吡酮通过螯合Fe3+,即通过从真菌细胞消减铁离子来杀伤真菌细胞,且其体外作用仅通过向培养基加入足量的Fe3+离子而被抑制。本领域中还已知由于其独特的作用机理,环吡酮是唯一不对真菌菌株产生耐药性的抗真菌剂。
用于评价作用机理的方法
为了证实化合物的作用机理是否是铁离子的螯合,通过在检验培养基中加入过量铁离子(100μM FeCl3)来进行光滑念珠菌(ATCC 90030)菌株的MIC确定。暴露于带有或不带有金属离子Fe3+的药物的细胞的活力通过在540nm测量OD来评价。
在100μM(100微摩尔)Fe3+存在和不存在时评价实施例2中描述的化合物、E8和NiK-29298。
结果报告于以下图1、2和3。
在所有图中,线和点代表通过加入不同浓度抗真菌剂(横坐标)而抑制真菌生长的百分比(纵坐标)。蓝色的线和点是无铁补充时进行的实验,而红色的线和点代表在100μM Fe3+存在时进行的实验的结果。如本领域已知的,环吡酮的作用被Fe3+的存在完全抑制,光滑念珠菌能够正常生长(图1)。相反,Fe3+对本领域已知具有不同于环吡酮的作用机理的抗真菌剂两性霉素无影响。
本发明的所有化合物具有与环吡酮相似的表现,即,其抗真菌活性被Fe3+的存在完全抑制(图2)。
相反,EP1669348A1中公开的化合物E8和具有EP1669348A1中描述的喹诺酮骨架的化合物NiK-29298,不同于环吡酮也不同于本发明的化合物,不被培养基中Fe3+离子的存在抑制。
总之,EP1669348A1中公开的化合物具有窄的作用范围,局限于酵母,而它们对皮肤癣菌或霉菌不展示抗真菌活性。而且,其作用机理不依赖于铁螯合。
相反,本发明的化合物优于EP1669348A1中公开的那些,因为本发明的化合物具有强效的抗真菌活性和宽的作用范围,扩展到酵母、皮肤癣菌和霉菌。这一特征使其效力在多种真菌感染中是可预测的,所述真菌感染包括皮肤、头皮、指甲感染,还有阴道、口和肠感染,最后耳、肺部、眼和其他全身性感染。而且,本发明的化合物优于EP1669348A1中公开的那些,因为本发明化合物的作用机理是铁螯合,这是本领域中已知避免在真菌细胞中发展耐药性的机理。
Claims (10)
1.通式(I)的化合物或其药学上可接受的盐或衍生物
其中R0是:
●-H、
●-F、
●-Cl、
●-Br、
●-NO2、
●-CF3、
●-C1-C6烷基、
●-(CH2)m-NR1R2、
●-(SO2)-NR1R2、
●-(C=O)-NR1R2、
●-(N-C=O)-NR1R2、
●-CN、
●-W-R3、
●-(CH2)m-芳基,任选地被一个或两个R4取代、或
●-(CH2)m-杂环,任选地被一个或两个R4取代;
其中R1和R2彼此独立地选自:
●-H、
●-C1-C6烷基、
●-(CH2)m-芳基,任选地被一个或两个R4取代
●-(CH2)m-环烷基,任选地被一个或两个R5取代
●-(CH2)m-杂环,任选地被一个或两个R4取代
●-(CH2)m-W-R3、
●-(CH2)m-CN、
●与它们所连接的氮原子一起形成包含一至三个选自由氮、氧和硫组成的组的杂原子的任选地取代的5-元至8-元的杂单环、或
●与它们所连接的氮原子一起形成任选地取代的5-元至8-元的杂单环,所述杂单环与一个或两个任选地取代的饱和或不饱和的环稠合或与包含一至三个选自由氮、氧和硫组成的组的杂原子的其他任选地取代的杂环稠合;
其中W是:
●-O-、或
●-S-;
其中R3是:
●-H、
●-C1-C6烷基、
●-(CH2)m-芳基,任选地被一个或两个R4取代、
●-(CH2)m-环烷基,任选地被一个或两个R5取代、或
●-(CH2)m-杂环,任选地被一个或两个R4取代;
其中R4是:
●-F、
●-Br、
●-NO2、
●-C1-C6烷基、
●-(CH2)m-NR1R2、
●-(SO2)-NR1R2、
●-(C=O)-NR1R2、
●-(N-C=O)-NR1R2、
●-CN、
●-W-R3,条件是当W是-O-时,R3不同于氢或甲基、
●-(CH2)m-芳基,任选地被一个或两个R7取代、或
●-(CH2)m-杂环,任选地被一个或两个R7取代;
其中R5是:
●-C1-C4烷基、
●-W-H、
●-CH2-W-H、
●-(CH2)m-芳基,任选地被一个或两个R7取代、或
●-(CH2)m-杂环,任选地被一个或两个R7取代;
其中R6是:
●-H、
●-F、
●-Cl、
●-Br、
●-OH、或
●-O-C1-C3烷基;
其中R7是:
●-H、
●-F、
●-Cl、
●-Br、
●-CF3、
●-W-R3、
●-C1-C6烷基、
●-(CH2)m-芳基,任选地被一个或两个R6取代、
●-(CH2)m-杂环,任选地被一个或两个R6取代、或
●-(CH2)m-C3-C8环烷基;
其中m是0至6的整数;
其中A是:-(CH2)n-X;
其中n是0至1的整数,条件是:
当n=0时,X是:
●任选地取代的单环杂环或2,3-二氢苯并[b][1,4]二噁烯残基,条件是所述杂环不是任选地取代的吡啶、噻二唑、噻吩、呋喃或苯并[d][1,3]间二氧杂环戊烯、或
●在对位被NR1R2取代的芳基;
当n=1时,X是:
●任选地取代的杂环,优选地2,3-二氢苯并[b][1,4]二噁烯残基,条件是所述杂环不是任选地取代的3-吡啶、噻二唑、噻吩、呋喃或苯并噻唑、或
●在对位被R4取代的芳基,条件是R4不是-NO2。
2.如权利要求1所述的化合物,其中R0是:
●-H、
●-Br、或
●-NO2。
3.如权利要求1所述的化合物,其中R1和R2彼此独立地选自:
●-C1-C6烷基、或
●与它们所连接的氮原子一起形成包含一至三个选自由氮、氧和硫组成的组的杂原子的任选地取代的5-元至8-元的杂单环。
4.如权利要求1所述的化合物,其中R3是-C1-C6烷基。
5.如权利要求1所述的化合物,其中R4是:
●-Br、
●-(CH2)m-NR1R2、或
●-W-R3。
6.如权利要求1所述的化合物,其中W是-O-。
7.如权利要求1所述的化合物,其中m是0至1的整数。
8.如权利要求1所述的化合物,
其中A是:-(CH2)n-X
其中n是0至1的整数,条件是:
当n=0时,X是:
●任选地取代的单环杂环或2,3-二氢苯并[b][1,4]二噁烯残基,条件是所述杂环不是任选地取代的吡啶、噻二唑、噻吩、呋喃或苯并[d][1,3]间二氧杂环戊烯、或
●在对位被NR1R2取代的芳基;
当n=1时,X是:
●任选地取代的杂环,优选地2,3-二氢苯并[b][1,4]二噁烯残基,条件是所述杂环不是任选地取代的3-吡啶、噻二唑、噻吩、呋喃或苯并噻唑、或
●在对位被R4取代的芳基,条件是R4不是-NO2
其中R4是:
●-Br、
●-(CH2)m-NR1R2
其中R1和R2与它们所连接的氮原子一起形成包含选自由氮、氧和硫组成的组的一至三个杂原子的任选地取代的5-元至8-元的杂单环,其中m是0至1的整数。
9.如权利要求1所述的化合物,选自由以下组成的组:
8-羟基-N-(1,1-二氧代四氢噻吩-3-基)喹啉-7-羧酰胺
8-羟基-N-(四氢-2H-吡喃-4-基)喹啉-7-羧酰胺;
8-羟基-N-(4-吗啉代苯基)喹啉-7-羧酰胺;
8-羟基-N-(噻唑-2-基)喹啉-7-羧酰胺;
8-羟基-N-(异噁唑-3-基)喹啉-7-羧酰胺;
8-羟基-N-((5-甲基吡嗪-2-基)甲基)喹啉-7-羧酰胺;
8-羟基-N-((1-甲基-1H-咪唑-2-基)甲基)喹啉-7-羧酰胺;
8-羟基-N-((4-苯基噻唑-2-基)甲基)喹啉-7-羧酰胺;
8-羟基-N-(吡啶-4-基甲基)喹啉-7-羧酰胺;
8-羟基-N-(2,3-二氢苯并[b][1,4]二噁烯-6-基)喹啉-7-羧酰胺;
8-羟基-N-(4-(二甲氨基)苄基)喹啉-7-羧酰胺;
8-羟基-N-(4-溴苄基)喹啉-7-羧酰胺;
8-羟基-N-(苯并[d]噻唑-2-基甲基)喹啉-7-羧酰胺;
8-羟基-N-(4-吗啉代苄基)喹啉-7-羧酰胺;
8-羟基-N-((4-甲基噻唑-2-基)甲基)喹啉-7-羧酰胺;
8-羟基-N-(吡啶-2-基甲基)喹啉-7-羧酰胺;
8-羟基-N-(4-(1H-1,2,4-三唑-1-基)苯基)喹啉-7-羧酰胺;
8-羟基-N-((5-甲基异噁唑-3-基)甲基)喹啉-7-羧酰胺。
10.一种药物制剂,包含至少一种根据以上权利要求中任一项的化合物连同至少一种药学上可接受的载体、赋形剂和/或佐剂。
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EP2345642A1 (en) * | 2009-12-29 | 2011-07-20 | Polichem S.A. | Secondary 8-hydroxyquinoline-7-carboxamide derivatives for use as antifungal agents |
EP2345643A1 (en) * | 2009-12-29 | 2011-07-20 | Polichem S.A. | New tertiary 8-hydroxyquinoline-7-carboxamide derivatives and uses thereof |
CN104805147B (zh) * | 2014-01-26 | 2018-01-05 | 上海医药工业研究院 | 一种二噁英类化合物的制备方法、纯化方法及应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998011073A1 (en) * | 1996-09-10 | 1998-03-19 | Pharmacia & Upjohn Company | 8-hydroxy-7-substituted quinolines as anti-viral agents |
EP1669348A1 (en) * | 2003-09-30 | 2006-06-14 | Eisai Co., Ltd. | Novel antifungal agent comprising heterocyclic compound |
CN101611009A (zh) * | 2006-07-25 | 2009-12-23 | 伊维沃制药股份有限公司 | 喹啉衍生物 |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US326330A (en) | 1885-09-15 | Harness-support | ||
US326328A (en) | 1885-09-15 | Broiler | ||
DE540842C (de) | 1930-08-06 | 1931-12-28 | Chinosol Fabrik Akt Ges | Verfahren zur Darstellung der 8-Acetyloxychinolin-7-carbonsaeure |
FR2160718A1 (en) * | 1971-11-23 | 1973-07-06 | Roussel Uclaf | 7-benzyl aminomethyl-8-hydroxy quinolines - bacteriostats and fungistats |
DE3426995A1 (de) | 1984-07-21 | 1986-01-30 | Dr.Ing.H.C. F. Porsche Ag, 7000 Stuttgart | Halterung einer scheibe, vorzugsweise einer windschutzscheibe |
AU5148696A (en) | 1995-04-08 | 1996-10-30 | Basf Aktiengesellschaft | Synergistic fungicide compositions made of quinoline derivat ives and cytochrom b/c inhibitors |
US6919351B2 (en) | 2000-10-12 | 2005-07-19 | Merck & Co., Inc. | Aza-and polyaza-naphthalenyl-carboxamides useful as HIV integrase inhibitors |
NZ525088A (en) | 2000-10-12 | 2004-11-26 | Merck & Co Inc | Aza- and polyaza-naphthalenyl carboxamides useful as HIV integrase inhibitors |
EP1375486B1 (en) | 2001-03-01 | 2008-10-15 | Shionogi & Co., Ltd. | Nitrogen-containing heteroaryl compounds having hiv integrase inhibitory activity |
EP2045242A1 (en) | 2002-08-13 | 2009-04-08 | Shionogi&Co., Ltd. | Heterocyclic compounds having inhibitory activity against HIV integrase |
FR2889192A1 (fr) * | 2005-07-27 | 2007-02-02 | Cytomics Systems Sa | Composes antifongiques, compositions contenant ces composes et leurs utilisations |
EP2345643A1 (en) * | 2009-12-29 | 2011-07-20 | Polichem S.A. | New tertiary 8-hydroxyquinoline-7-carboxamide derivatives and uses thereof |
EP2345642A1 (en) * | 2009-12-29 | 2011-07-20 | Polichem S.A. | Secondary 8-hydroxyquinoline-7-carboxamide derivatives for use as antifungal agents |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998011073A1 (en) * | 1996-09-10 | 1998-03-19 | Pharmacia & Upjohn Company | 8-hydroxy-7-substituted quinolines as anti-viral agents |
US6500842B1 (en) * | 1996-09-10 | 2002-12-31 | Pharmacia & Upjohn Company | 8-hydroxy-7-substituted quinolines as anti-viral agents |
EP1669348A1 (en) * | 2003-09-30 | 2006-06-14 | Eisai Co., Ltd. | Novel antifungal agent comprising heterocyclic compound |
CN101611009A (zh) * | 2006-07-25 | 2009-12-23 | 伊维沃制药股份有限公司 | 喹啉衍生物 |
Non-Patent Citations (2)
Title |
---|
NAMAL C. WARSHAKOON ET AL: "Structure-based design, synthesis, and SAR evaluation of a new series of 8-hydroxyquinolines as HIF-1α prolyl hydroxylase inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 16, no. 21, 22 August 2006 (2006-08-22), pages 5517 - 5522 * |
XINGNAN LI ET AL: "Synthesis and biological evaluation of purine derivatives incorporating metal chelating ligands as HIV integrase inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》, vol. 14, no. 16, 5 June 2006 (2006-06-05), pages 5742 - 5755 * |
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