CN102612367B - 脯氨酰羟化酶抑制剂 - Google Patents
脯氨酰羟化酶抑制剂 Download PDFInfo
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- CN102612367B CN102612367B CN201080050181.9A CN201080050181A CN102612367B CN 102612367 B CN102612367 B CN 102612367B CN 201080050181 A CN201080050181 A CN 201080050181A CN 102612367 B CN102612367 B CN 102612367B
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- methyl
- hydroxyl
- piperazine
- dihydropyridine
- oxo
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Abstract
本发明公开的是可稳定缺氧诱导因子-1α(HIF-1α)以及缺氧诱导因子-2(HIF-2)的脯氨酰羟化酶抑制剂。本发明还公开了包含一种或多种所公开化合物的药物组合物。本发明还进一步公开了用于刺激哺乳动物中细胞免疫反应例如增加吞噬作用的方法,例如延长吞噬细胞(尤其是角质化细胞和中性粒细胞)的寿命。由此,所公开的化合物提供治疗涉及身体免疫反应的疾病的方法。
Description
优先权
本申请要求均在2009年11月6日提交的序列号61/258,914的临时申请和序列号61/258,918的临时申请的优先权,两申请的全文通过引用的方式纳入本文。
技术领域
本文公开了可稳定缺氧诱导因子-1α(HIF-1α)以及缺氧诱导因子-2
α(HIF-2α)的脯氨酰羟化酶抑制剂。本文还公开了包含一种或多种所公开化合物的药物组合物。还公开了用于刺激哺乳动物中细胞免疫反应例如增加吞噬作用的方法,例如延长吞噬细胞(尤其角质化细胞和中性粒细胞)的寿命。由此,所公开的化合物提供治疗与身体免疫反应有关的疾病的方法。
发明内容
所公开的化合物可稳定HIF-1α和HIF-2α以及受损的免疫系统中存在的或因疾病状态或所述疾病状态的表现(尤其败血症)而耗尽或负担过度的其他因子。所公开的化合物可用于治疗癌症并可与其他癌症治疗药物共同给药。此外,所公开的化合物可用于当与疫苗(例如流感疫苗、疟疾疫苗、黄热病疫苗、癌症疫苗等)共同给药时促进哺乳动物的免疫反应。
附图说明
图1绘出了HIF-1α在常氧条件下的正常代谢途径。
图2绘出了50μM和200μM的表VIII中公开的化合物与对照(DMSO)相比在第60分钟和90分钟对中性粒细胞杀死金黄色葡萄球菌(S.aureus)(Newman株)的强化。
图3绘出了与未处理的样本相比,10μM的表VIII中公开的化合物对在人单核细胞细胞系(U937)抗金黄色葡萄球菌(Newman株)的强化。
图4绘出了在用10μM的表VIII中公开的化合物预处理1小时(黑色)或2小时(阴影)后,被金黄色葡萄球菌(Newman株)感染后的经处理的U937细胞中相对于未处理的U937细胞中存活细菌的平均百分比。
图5绘出了在用10μM的表VIII中公开的化合物预处理1小时后,被金黄色葡萄球菌的两种菌株——Newman(黑色)或耐甲氧苯青霉素黄色葡萄球菌(MRSA)(阴影)感染后的经处理的U937细胞中相对于未处理的U937细胞中存活细菌的平均百分比。
图6绘出了在被金黄色葡萄球菌的两种菌株——Newman(黑色)或MRSA(阴影)感染后并用10μM的表VIII中公开的化合物处理后,经处理的U937细胞中相对于未处理的U937细胞中存活细菌的平均百分比。
图7绘出了用100mM的含羞草素(A)、10μM的表VIII中公开的化合物(B)或2mg/mL的万古霉素(C)处理后,被金黄色葡萄球菌的两种菌株——Newman(阴影条)或MRSA(黑色条)感染后2小时经处理的U937细胞中相对于未处理的U937细胞中存活细菌的平均百分比。
图8绘出了不进行预处理以及在用10μM的表VIII中公开的化合物预处理1小时或2小时后,被金黄色葡萄球菌(Newman株)感染后的经处理的U937细胞中相对于未处理的U937细胞中存活细菌的平均百分比。
图9绘出了在被金黄色葡萄球菌的两种菌株——Newman(阴影条)或MRSA(黑色条)感染并用DMSO(对照)、800μM的含羞草素或10μM的表VIII中公开的化合物或1μg/mL的万古霉素预处理1小时后,经处理的HaCaT细胞中相对于未处理的HaCaT细胞中存活细菌的平均百分比。示出的数据是处理后2小时。
图10绘出了用10μM的表VIII中公开的化合物预处理后,被金黄色葡萄球菌的两种菌株——Newman(阴影条)或MRSA(黑色条)感染的经处理的HaCaT细胞中相对于未处理的HaCaT细胞中存活细菌的平均百分比。
图11绘出了相对野生型对照(H),用剂量为1μM(E)、10μM(F)和50μM(G)的表VIII中公开的化合物处理后的野生型鼠胚胎成纤维细胞中磷酸甘油酸激酶(PGK)表达的上调;以及用1μM(A)、10μM(B)和50μM(C)的表VIII中公开的化合物处理后的HIF-1敲除细胞以及HIF-1敲除对照(D)中PGK表达的上调的缺失。所述两种细胞类型均被处理7小时。
图12绘出了相对野生型对照(G),用剂量为1μM(E)和10μM(F)的化合物1-(3-氯苄基)-3-羟基吡啶-2(1H)-酮处理后的野生型鼠胚胎成纤维细胞中磷酸甘油酸激酶(PGK)表达的上调;以及用1μM(A)、10μM(B)和50μM(C)的表VIII中公开的化合物处理后的HIF-1敲除细胞以及HIF-1敲除对照(D)中PGK表达的上调的缺失。
图13绘出了相对野生型对照(H),用剂量为1μM(E)、10μM(F)和50μM(G)的表VIII中公开的化合物处理后的野生型鼠胚胎成纤维细胞中磷酸甘油酸激酶(PGK)表达的上调;以及用1μM(A)、10μM(B)和50μM(C)的表VIII中公开的化合物处理后的HIF-1敲除细胞以及HIF-1敲除对照(D)中PGK表达的上调的缺失。
图14绘出了相对对照(H),用剂量为1μM(E)、10μM(F)和50μM(G)的表VIII中公开的化合物处理后的野生型鼠胚胎成纤维细胞中血管内皮生长因子(VEGF)表达的上调;以及用1μM(A)、10μM(B)和50μM(C)的表VIII中公开的化合物处理后的HIF-1敲除细胞以及HIF-1敲除对照(D)的VEGF表达的上调的缺失。所述两种细胞类型均被处理7小时。
图15绘出了实施例11的结果,其中用抗生素敏感的金黄色葡萄球菌Newman株处理3组动物。数据示出了相对被给予单次注射DMSO的动物(实心方块(■)),用10μM的表VIII中公开的化合物处理的第1组中的动物(实心圆(●))的皮肤损伤(创伤)大小的显著减小。图15绘出了被金黄色葡萄球菌Newman株感染并在感染后2小时用10μM的表VIII中公开的化合物或DMSO(对照)处理的小鼠。数据示出了用表VIII中公开的化合物(实心圆(●))或DMSO(实心方块(■))处理的动物的皮肤损伤(创伤)大小的统计上显著的减小。
图16也绘出了实施例11的结果,显示了相对于未处理的动物(实心三角(▲)),用10μM的表VIII中公开的化合物处理的第1组中的动物(实心圆(●))的皮肤损伤(创伤)大小的减小。图16绘出了被金黄色葡萄球菌Newman株感染并在感染后2小时用10μM的表VIII中公开的化合物处理或不进行处理的小鼠。数据示出了用表VIII中公开的化合物处理(实心圆(●))或不进行处理(实心三角(▲))的动物的皮肤损伤(创伤)大小的减小。
图17的绘图绘出了实施例12的结果,其中用抗生素敏感的金黄色葡萄球菌Newman株[ATCC#25904]处理3组动物。数据示出了未处理组的结果(A)、用DMSO处理的组的结果(B)和用10μM的表VIII中公开的化合物处理的组的结果(C)。
图18也绘出了实施例12的结果,其中绘出了以下各组肾脏中菌落形成单位的数量:未处理组(A)、用DMSO处理的组(B)和用10μM的表VIII中公开的化合物处理的组(C)。
图19绘出了实施例13的结果,其中用酿脓链球菌(Streptococcuspyogenes)NZ131[M49株]处理2组动物。数据示出了相对于载体对照(环糊精)处理的动物(实心圆(●)),用0.5mg/kg的表VIII中公开的化合物处理的第1组中的动物(实心三角(▲))的皮肤损伤(创伤)大小的减小。
图20的绘图也绘出了实施例12的结果,其中绘出了在用载体对照(环糊精)处理的动物上观察到的皮肤损伤的菌落形成单位的数量(A),并且绘出了用0.5mg/kg的表VIII中公开的化合物处理的组的结果(B)。
具体实施方式
在本说明书和所附的权利要求书中,将涉及多个术语,所述术语将被定义为具有以下含义:
在整个本说明书中,除非另外声明,词“包括(包含)”和该词的其他形式,例如“comprising”和“comprises”,应理解为是指包括(包含)陈述的整数或步骤或者整数或步骤的组,但不排除任何其他整数或步骤或者整数或步骤的组。
必需说明,除非文中另有明确指出,说明书和所附权利要求书中所用单数形式“一”、“一个”和“该”包括复数个指示物。因此,例如提及“一种载体”时,包括两种或多种这类载体的混合物,等等。
“任选的”或“任选地”意指随后描述的事件或情况可能发生或可能不发生,并且该描述包括该事件或情况发生的情形和其不发生的情形。
“可药用”意指不是生物学不适或其他不适的物质,即所述物质可与相关的活性化合物一起给予个体,不造成临床上不可接受的生物效应或以有害的方式与包含其在内的药学组合物的任何其他组分相互作用。在本文中范围可表示为自“约”一个具体值,和/或至“约”另一具体值。当表示所述范围时,另一方面包括自所述一个具体值和/或至所述另一具体值。类似地,当通过使用前缀“约”将数值表示为近似值时,应理解为所述具体值形成另一方面。还应理解,每个范围的端点与另一端点相关和独立于另一端点时均是有意义的。
除非明确描述为相反,组分的重量百分数是基于包括所述组分在内的制剂或组合物的总重量计。
本文所使用的“有效量”意指“一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂在实现所需结果或治疗结果需要的剂量和时间周期下有效的量”。有效量可根据本领域中已知的因素而变化,例如待治疗的人或动物的疾病状况、年龄、性别和重量。虽然具体的剂量方案可能在本文中的实施例中描述,但本领域技术人员应了解,所述剂量方案可改变以提供最佳的治疗响应。例如,可每日给予数个分开的剂量或可就治疗情形紧迫所表示的成比例减少剂量。此外,本发明的组合物可按所需的频率给予,以实现治疗量。
本文中通常使用的“混合物”或“掺合物”意指两种或多种不同组分的物理结合物。
本文所使用的“赋形剂”包括可包含在一种或多种所公开抑制剂中或与之结合的非治疗活性化合物或非生物活性化合物的任何其他化合物。因此,赋形剂应该是药学上或生物学上可接受的或相关的(例如,赋形剂通常应该对受试者是无毒的)。“赋形剂”包括单种这类化合物,也意欲包括多种赋形剂。
本文所使用的“受试者”意指个体。因此,所述“受试者”可包括家养动物(例如,猫、狗等)、家畜(例如,牛、马、猪、绵羊、山羊等)、实验动物(例如,小鼠、兔子、大鼠、豚鼠等),和禽类。“受试者”还可包括哺乳动物,例如灵长类或人。
“防止”或该词的其他形式如“阻止”或“预防”意指停止具体事件或特征,以稳定或推迟具体事件或特征的发展或进展,或者以使具体事件或特征将发生的几率最小化。防止不要求与对照相比,因为其通常比例如减少更绝对。如本文所使用的,某些事物可减少但不防止,但减少的某些事物也可防止。同样,某些事物可防止但不减少,但防止的某些事物也可减少。应理解,当使用减少或防止时,除非另外明确指出,也明确公开了使用另一词语。
“减少(reduce)”或该词的其他形式如“减少(reducing)”或“减少(reduction)”意指事件或特征(如,血管渗漏)的降低。应理解,这通常与一些标准值或预计值相关,换句话说它是相对的,但不总是必需提及所述标准值或相对值。
本文使用的术语“治疗(treat)”或该词的其他形式如“治疗的(treated)”或“治疗(treatment)”意指给予本发明的化合物减轻宿主的疾病或病症,并且/或者减少、抑制或消除与病症相关的具体特征或事件(例如微生物引起的感染)。因此,术语“治疗”包括防止宿主发生病症,特别是当所述宿主容易患所述疾病、但尚未确诊所述疾病之时;抑制病症;以及/或者减轻或反转病症。只要本发明的方法涉及防止病症,应理解术语“防止”不需要疾病状态完全阻止。相反,本文使用的术语防止是指本领域技术人员的以下能力:鉴定易感病症的群体,使得可以在疾病发病前给予本发明的化合物。该术语并不意味着所述疾病状态被完全避免。
本文中范围可表示为从“约”一个具体值和/或至“约”另一个具体值。当表示这样的范围时,另一方面包括从一个具体值和/或至另一个具体值。类似地,当通过使用前缀“约”将数值表示为近似值时,应理解为所述具体值形成另一方面。还应理解,每个范围的端点在与另一端点相关和独立于另一端点时均是有意义的。还应理解,本文公开了很多数值,并且每个数值在本文中也公开为除了所述数值本身之外的“约”该具体数值。例如,如果公开了数值“10”,那么也就公开了“约10”。还应理解,当一个数值被公开时,也就公开了“小于或等于”该数值,“大于或等于该数值”,以及数值之间的可能范围,这是为本领域技术人员所适当理解的。例如,如果公开了数值“10”,那么也就公开了“小于或等于10”和“大于或等于10”。还应理解,在整个申请中,数据以多种不同形式提供,并且该数据代表终点和起点以及所述数据点任意结合的范围。例如,如果公开了具体的数据点“10”和具体的数据点“15”,应理解认为公开了大于、大于或等于、小于、小于或等于、等于10和15以及10和15之间的数值。还应理解,还公开了两个具体单位之间的每个单位。例如,如果公开了10和15,那么也公开了11、12、13和14。“抗微生物”是指以任何浓度治疗或控制(例如减少、防止、抑制、瓦解或消除)微生物生长或存活的能力。类似地,术语“抗细菌”、“抗病毒”和“抗真菌”分别是指以任何浓度治疗或控制(例如减少、防止、抑制、瓦解或消除)细菌、病毒和真菌生长或存活的能力。
术语“阴离子”是一种类型的离子,包括在术语“离子”的意义范围内。“阴离子”是含净负电荷或者可以使其含净负电荷的任何分子、分子部分(例如两性离子)、分子簇、分子复合体、部分或原子。本文使用的术语“阴离子前体”特别是指可以经化学反应(例如脱质子化)转化成阴离子的分子。
术语“阳离子”是一种类型的离子,包括在术语“离子”的意义范围内。“阳离子”是含净正电荷或者可以使其含净正电荷的任何分子、分子部分(例如两性离子)、分子簇、分子复合体、部分或原子。本文使用的术语“阳离子前体”特别是指可以经化学反应(例如质子化或烷基化)转化成阳离子的分子。
本文使用的“化疗剂”包括可用于与所公开的HIF-1α脯氨酰羟化酶抑制剂结合使用的任何其他药用活性化合物,例如细胞毒性药物如6-羟基甲基酰基富烯、环磷酰胺、达卡巴嗪、卡莫司汀、多柔比星和氨甲蝶呤。其他化疗剂还包括消炎药,即非类固醇类消炎化合物如阿司匹林。
除非声明为相反,具有仅显示为实线而非楔形或虚线的化学键的式考虑每种可能的同分异构体,例如每种对映异构体、非对映异构体和内消旋化合物,以及同分异构体的混合物,例如外消旋混合物或部分消旋(scalemic)混合物。
转录因子缺氧诱导因子-1(HIF-1)是氧平衡的重要调控因子之一。其调控对低氧水平(缺氧)的生理反应以及心脏病发作、癌症、中风和慢性肺病的病理生理学。HIF-1是由两个亚基——HIF-1α和HIF-1β——构成的异源二聚体蛋白。而HIF-1β是组成型表达的,HIF-1α的表达受低于6%的氧浓度的诱导。HIF-1异源二聚体可结合于缺氧反应元件(HRE),共有序列5-RCGTG-3。迄今已确定多个HIF-1-调控的基因,包括编码参与血管生成、能量代谢、红细胞生成、细胞增殖和存活、血管重塑和血管运动反应的蛋白的基因。因此,HIF在细胞中活化的调制对防止、控制、治愈或影响多种疾病、疾病状态和病况起重要作用。
缺氧诱导型转录因子1α(HIF-1α)在降低氧利用率的细胞适应中起核心作用。在缺氧压力下,活化的HIF-1α努力恢复氧平衡,不仅通过诱导血管生成和糖酵解来维持细胞内能量产生,而且通过抑制细胞增殖和DNA修复来限制能量消耗。通常,HIF-1α通过结合于基因启动子中的缺氧反应元件来活化其靶基因,例如EPO、VEGF和PGK1(Wang,G.L.et al.,J Biol Chem(1993);268:21513-21518)。
HIF-1α在细胞具有足够氧气供应的正常健康情况下,容易通过数种4-脯氨酰羟化酶之一尤其是EGLN1(以下称为HIFPH2)转化为降解形式。如上所述,当细胞经受缺氧时,这种酶促转化变慢或完全停止,并且HIF-1α开始在细胞中积聚。当这种HIF-1α的积聚发生时,此蛋白与HIF-1β结合以形成有活性的转录因子复合体HIF-1。然后这种转录因子活化数种生物途径,所述生物途径作为对身体缺氧状态的反应和缓解身体缺氧状态的手段存在。这些反应包括,尤其,血管生成、红细胞生成(EPO)、糖代谢(PGK)、基质改变和对病原体反应的吞噬细胞能力增强。
图1概括了正常健康情况下HIF-1α的代谢。HIFα亚基在常氧条件下不稳定;细胞持续合成和降解这些蛋白。短半衰期的HIF-1α是O2-和铁依赖的脯氨酰羟化酶家族(PH1-3)的副产物,其作用是在依赖与von Hippel–Lindau肿瘤抑制蛋白(vHL)的相互作用的过程中通过泛素-蛋白酶体途径指导HIFα亚基降解。在图1中,PDH’s示出了在天冬酰羟化酶的存在下羟化脯氨酸402和564以及天冬酰胺804的脯氨酰羟化酶。由此,由于被羟化的HIF-1α也因为其他因子而被阻止与p300-CPB结合,泛素连接酶经vHL途径开始代谢被羟化的HIF-1α。
在需要刺激此反应的患者(例如在因周围血管性疾病(PVD)而需要增加组织氧的患者)中,抑制HIF1酶例如Egl九联体1(HIFPH2)会刺激身体自身的血管生成反应而不造成缺氧的后果。此外,在缺血疾病(尤其是CAD和贫血症)中,刺激血管生成、红细胞生成和代谢适应可提供有益治疗。HIF-1α的上调还提供一种例如通过增加吞噬细胞的能力而增强免疫性的方法。
因此存在对控制HIF-1α的活性的方法的长期需要,所述需求可由抑制降解HIF-1α的4-脯氨酰羟化酶的化合物来有效地实现。这种对4-脯氨酰羟化酶尤其是HIFPH2(以下也称为EGLN1或PHD2)和HIFPH3(本文也称为EGLN3或PHD-3)的抑制藉此提供了一种增加细胞中HIF-1α浓度的方法并因此提供了治疗多种疾病或疾病状态的方法。
本文公开了治疗受缺氧诱导型转录因子水平影响的一种或多种疾病、病况、症状等的方法。在缺氧和常氧条件下对这些因子的调控可提供重新平衡或调控与异常条件相关的一种或多种生物途径的方法,所述异常条件尤其是病原体(尤其是细菌、真菌、病毒和寄生虫)对身体的侵入、异常细胞调控即癌症缺血症,和接种导致的副作用。
以细胞中的HIF1稳定为目标
意图通过脯氨酰羟化来破坏HIF-1α,脯氨酰羟化是一种氧依赖的修饰,其为含有von Hippel-Lindau肿瘤抑制因子(VHL)的E3泛素连接酶复合体的识别提供信号。在文献中正式称为EGLN1、EGLN2和EGLN3(还已在哺乳动物中确定,其中,EGLN1也称为HIFPH2或PHD2,EGLN3也称为HIFPH3或PHD3)的三种脯氨酰羟化酶以HIF-1α依赖的方式在其mRNA水平上可被缺氧诱导。在人中这些脯氨酰-4-羟化酶通过羟化HIF-1α脯氨酸残基Pro-402和Pro-564来控制HIF-1α水平(Ivan,M.et al.,(2001)“HIFαtargeted forVHL-mediated destruction by proline hydroxylation:implications forO2 sensing.”Science 292,464-468;Jaakkola,P.et al.,(2001)“Targeting of HIF-1α to the von Hippel-Lindau ubiquitylationcomplex by O2-regulated prolyl hydroxylation.”Science 292,468-472;and Masson,N.et al.,(2001)“Independent function of twodestruction domains in hypoxia-inducible factor-α chains activatedby prolyl hydroxylation.”EMBO J.20,5197-5206)。在缺氧条件下,EGLN1和EGLN3活性被抑制。
磷酸甘油酸激酶(PGK)和血管内皮生长因子(VEGF)的产生受到HIF-1α的细胞浓度的积聚的刺激。已经证明VEGF的刺激可诱导小鼠角膜中功能性新血管的形成并增强了冠状动脉疾病狗模型中的血流。本发明的HIF-1α脯氨酰羟化酶抑制剂增强了包括VEGF、GAPDH和红细胞生成素(EPO)的多个缺氧诱导基因的表达。此外,本发明的HIF-1α脯氨酰羟化酶抑制剂增强了细胞质和细胞核中的HIF1-α的积聚。在皮肤中表达组成型活性HIF-1Α的转基因小鼠皮肤血管增加并且具有13倍的VEGF水平。
创伤
慢性、不愈合的创伤是老年人群长时间处于病态的主要原因。对于形成严重的、不愈合的皮肤溃疡的卧床或糖尿病患者尤其如此。在许多这些病例中,愈合的延迟是由于连续压力或血管堵塞而导致的血液供给不足的结果。由于小动脉动脉粥样硬化或静脉停滞造成的毛细血管循环差导致不能修复的损坏的组织。这些组织经常受到微生物感染,所述微生物的增殖未激发身体需要良好血管化的组织来有效消除病原生物体的先天防御系统。因此,大多数治疗介入聚焦于恢复到缺血组织的血流从而使得营养素和免疫因子到达创伤位置。
本发明涉及治疗受试者创伤和促进受试者创伤愈合的方法,包括给予需要治疗的受试者有效量的一种或多种所公开的化合物。
本发明涉及一种或多种所公开的化合物用于制备治疗创伤和促进创伤愈合的药剂的用途。
抗微生物
缺氧反应转录因子HIF-1α对体内炎症的调控是必需的。因此,已经发现(Peyssonnaux C.et al.,“HIF-1α expression regulates thebactericidal capacity of phagocytes”J.Clinical Investigation 115(7),pp 1808-1815(2005))细菌感染即使在常氧条件下也可诱导骨髓细胞中HIF-1α的表达,并且HIF-1α可调控免疫防御的关键分子效应物包括颗粒蛋白酶、抗微生物肽、一氧化氮和TNF-α的生成。细菌感染可诱导与微生物杀死特异性相关的一组HIF-1α靶基因,从而表明HIF-1α在与缺氧反应截然不同的先天免疫中具有关键作用。因此,HIF-1α功能对骨髓细胞杀菌活性和宿主限制原始组织病灶的感染全身扩散的能力很重要。通过vHL删除增加HIF-1α途径的活性可支持骨髓细胞产生防卫因子并提高杀菌能力。所公开的化合物可诱导HIF-1α活性并还可以HIF-1α特异性方式促进细菌杀死和NO产生。这些发现提供了增强对微生物例如细菌的感染的先天免疫反应的方法。
不希望囿于理论,所公开的化合物可通过直接或间接作用于一种或多种细胞过程而增加HIF-1蛋白的稳定,所述细胞过程使细胞组分不稳定或对其进行代谢,所述细胞组分可稳定HIF-1蛋白的存在、保护其免受抑制或增加其活性。或者,所公开的化合物可通过抑制或阻断抑制HIF-1蛋白活性的化合物的活性而增加HIF-1蛋白的活性。因此,本文公开了一种改善对微生物感染的治疗的方法,所述方法通过给予可增加患有微生物感染或具有增加微生物感染危险的受试者中至少一种HIF-1蛋白的活性或水平的物质而实现。
在一个方面,本文公开了调制至少一种HIF-1蛋白的活性的方法。因此,所公开的方法包括将至少一种HIF-1蛋白或HIF-1相互作用蛋白与一种或多种所公开的调制HIF-1蛋白活性的化合物接触,或者导致所述蛋白与物质之间接触。在该实施方案中,所述接触是在体外进行的。在另一实施方案中,所述接触是在活体内进行的。在又一实施方案中,所述接触是在活体外进行的。
在另一方面,本文公开了一种治疗感染微生物的或具有感染微生物危险的受试者的方法,包括给予受试者治疗有效量的一种或多种所公开的化合物。在一个实施方案中,所述化合物可增加HIF-1的量或活性。在另一个实施方案中,所述微生物是病原体。涉及病原体的这一实施方案的重复包括细菌、真菌、原生动物、病毒、酵母等。此方面的另一重复涉及一种治疗感染微生物或具有感染微生物的危险的受试者的方法,包括增加所述受试者的免疫细胞的微生物病原体杀死活性。
增加HIF-1的稳定的一种方法是抑制4-脯氨酰羟化酶活性,该酶发起HIF-1α的细胞分解从而防止HIF-1α与HIF-1β结合以形成HIF-1。因此,本文公开了通过增加吞噬作用来增加对疾病状态例如感染(即存在病原体例如细菌、病毒、寄生虫、酵母、真菌等)的细胞反应的方法。本文还公开了通过增加细胞免疫反应(例如通过稳定HIF-1)来治疗癌症,从而增加身体减小肿瘤大小的能力的方法。本文还公开了治疗其中可通过接种刺激免疫反应的疾病的方法。
以下化学体系在整个说明书中用于描述和充分公开本公开的范围,并且具体地指出并清楚地要求包含本公开化合物的单元,然而,除非另外明确定义,否则本文使用的术语与本领域普通技术人员所理解的相同。术语“烃基”表示任何基于碳原子的单元(有机分子),所述单元任选包含一个或多个有机官能团,包括含有无机原子的盐,尤其是羧酸盐、季铵盐。在术语“烃基”的广义含义中有“无环烃基”和“环烃基”类,所述术语用于将烃基单元分为有环类和无环类。
当“环烃基”单元涉及以下定义时,在其环上可仅包含碳原子(碳环和芳环),或者在其环上可包含一个或多个杂原子(杂环和杂芳环基)。对于“碳环”,环中最少的碳原子数是3个碳原子;环丙基。对于“芳”环,环中最少的碳原子数是6个碳原子;苯基。对于“杂环”,环中最少的碳原子数是1个碳原子;二氮丙啶基(diazirinyl)。环氧乙烷包含2个碳原子,是C2杂环。对于“杂芳”环,环中最少的碳原子数是1个碳原子;1,2,3,4-四唑基。以下是本文所用的术语“无环烃基”和“环烃基”的非限制性描述。
A.取代的和未取代的无环烃基:
对于本发明的目的,术语“取代的和未取代的无环烃基”包括3类单元:
1)直链或支链烷基,其非限制性实例包括,甲基(C1)、乙基(C2)、正丙基(C3)、异丙基(C3)、正丁基(C4)、仲丁基(C4)、异丁基(C4)、叔丁基(C4)等;取代的直链或支链烷基,其非限制性实例包括,羟基甲基(C1)、氯甲基(C1)、三氟甲基(C1)、氨基甲基(C1)、1-氯乙基(C2)、2-羟基乙基(C2)、1,2-二氟乙基(C2)、3-羧基丙基(C3)等。
2)直链或支链烯基,其非限制性实例包括,乙烯基(C2)、3-丙烯基(C3)、1-丙烯基(也称作2-甲基乙烯基)(C3)、异丙烯基(也称作2-甲基乙烯-2-基)(C3)、丁烯-4-基(C4)等;取代的直链或支链烯基,其非限制性实例包括,2-氯乙烯基(也称作2-氯乙烯基)(C2)、4-羟基丁烯-1-基(C4)、7-羟基-7-甲基辛-4-烯-2-基(C9)、7-羟基-7-甲基辛-3,5-二烯-2-基(C9)等。
3)直链或支链炔基,其非限制性实例包括,乙炔基(C2)、丙-2-炔基(也称作炔丙基)(C3)、丙炔-1-基(C3)和2-甲基-己-4-炔-1-基(C7);取代的直链或支链炔基,其非限制性实例包括,5-羟基-5-甲基己-3-炔基(C7)、6-羟基-6-甲基庚-3-炔-2-基(C8)、5-羟基-5-乙基庚-3-炔基(C9)等。
B.取代的和未取代的环状烃基:
对于本公开的目的,术语“取代的和未取代的环烃基”包括5类单元:
1)术语“碳环的(carbocyclic)”在本文中定义为“包括含3至20个碳原子的环,其中构成所述环的原子限于碳原子,并且各个环还可独立地由能够代替一个或多个氢原子的一个或多个部分取代”。以下是“取代的和未取代的碳环”的非限制性实例,包括以下类单元:
i)具有单个取代烃环或未取代烃环的碳环,其非限制性实例包括,环丙基(C3)、2-甲基-环丙基(C3)、环丙烯基(C3)、环丁基(C4)、2,3-二羟基环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环戊二烯基(C5)、环己基(C6)、环己烯基(C6)、环庚基(C7)、环辛基(C8)、2,5-二甲基环戊基(C5)、3,5-二氯环己基(C6)、4-羟基环己基(C6)和3,3,5-三甲基环己-1-基(C6)。
ii)具有两个或多个取代稠合烃环或未取代稠合烃环的碳环,其非限制性实例包括,八氢环戊二烯基(C8)、八氢-1H-茚基(C9)、3a,4,5,6,7,7a-六氢-3H-茚-4-基(C9)、十氢萘基(C10)、十氢薁基(C10)。
iii)取代双环烃环或未取代双环烃环的碳环,其非限制性实例包括,双环-[2.1.1]己基、双环[2.2.1]庚基、双环[3.1.1]庚基、1,3-二甲基[2.2.1]庚-2-基、双环[2.2.2]辛基和双环[3.3.3]十一烷基。2)术语“芳基”在本文中定义为“包含至少一个苯环或萘环的单元,其中不存在稠合于所述苯环或萘环的杂芳环或杂环且各个环还可独立地由能够替代一个或多个氢原子的一个或多个部分取代”。以下是“取代的和未取代的芳环”的非限制性实例,包括以下类单元:
i)C6或C10取代芳环或未取代芳环;无论取代或未取代的苯环和萘环,其非限制性实例包括,苯基(C6)、萘-1-基(C10)、萘-2-基(C10)、4-氟苯基(C6)、2-羟基苯基(C6)、3-甲基苯基(C6)、2-氨基-4-氟苯基(C6)、2-(N,N-二乙基氨基)苯基(C6)、2-氰基苯基(C6)、2,6-二叔丁基苯基(C6)、3-甲氧基苯基(C6)、8-羟基萘-2-基(C10)、4,5-二甲氧基萘-1-基(C10)和6-氰基-萘-1-基(C10)。
ii)与1或2个饱和环稠合的C6或C10芳环,其非限制性实例包括,双环[4.2.0]辛-1,3,5-三烯基(C8)和二氢茚基(C9)。
3)术语“杂环的”和/或“杂环”在本文中定义为“包含一个或多个具有3至20个碳原子的环的单元,其中在至少一个环中的至少一个原子是选自氮(N)、氧(O)或硫(S)的杂原子或者N、O和S的混合物,并且其中另外包含杂原子的环也不是芳环”。以下是“取代杂环和未取代杂环”的非限制性实例,包括以下类单元:
i)具有含一个或多个杂原子的单环的杂环单元,其非限制性实例包括,二氮丙啶基(C1)、吖丙啶基(C2)、尿唑基(C2)、氮杂环丁基(C3)、吡唑烷基(C3)、咪唑烷基(C3)、噁唑烷基(C3)、异噁唑烷基(C3)、噻唑烷基(C3)、异噻唑烷基(C3)、氧杂噻唑烷酮基(C3)、噁唑烷酮基(C3)、乙内酰脲基(C3)、四氢呋喃基(C4)、吡咯烷基(C4)、吗啉基(C4)、哌嗪基(C4)、哌啶基(C4)、二氢吡喃基(C5)、四氢吡喃基(C5)、哌啶-2-酮基(戊内酰胺)(C5)、2,3,4,5-四氢-1H-氮杂基(azepinyl)(C6)、2,3-二氢-1H-吲哚(C8)、和1,2,3,4-四氢喹啉(C9)。
ii)具有其中之一为杂环的2个或多个环的杂环单元,其非限制性实例包括六氢-1H-吡咯烷基(pyrrolizinyl)(C7)、3a,4,5,6,7,7a-六氢-1H-苯并[d]咪唑基(C7)、3a,4,5,6,7,7a-六氢-1H-吲哚基(C9)、1,2,3,4-四氢喹啉基(C9)和十氢-1H-环辛[b]吡咯基(C10)。
4)术语“杂芳基”在本文中定义为“包括一个或多个含5至20个原子的环,其中在至少一个环中的至少一个原子是选自氮(N)、氧(O)或硫(S)的杂原子或者N、O和S的混合物,并且其中另外至少一个包含杂原子的环是芳环”。以下是“取代杂环和未取代杂环”的非限制性实例,其包括以下类单元:
i)含单环的杂芳环,其非限制性实例包括,1,2,3,4-四唑基(C1)、[1,2,3]三唑基(C2)、[1,2,4]三唑基(C2)、三嗪基(C3)、噻唑基(C3)、1H-咪唑基(C3)、噁唑基(C3)、异噁唑基(C3)、异噻唑基(C3)、呋喃基(C4)、苯硫基(C4)、嘧啶基(C4)、2-苯基嘧啶基(C4)、吡啶基(C5)、3-甲基吡啶基(C5)和4-二甲基氨基吡啶基(C5)。
ii)含其中之一为杂芳环的2个或多个稠合环的杂芳环,其非限制性实例包括:7H-嘌呤基(C5)、9H-嘌呤基(C5)、6-氨基-9H-嘌呤基(C5)、5H-吡咯并[3,2-d]嘧啶基(C6)、7H-吡咯并[2,3-d]嘧啶基(C6)、吡啶并[2,3-d]嘧啶基(C7)、2-苯基苯并[d]噻唑基(C7)、1H-吲哚基(C8)、4,5,6,7-四氢-1-H-吲哚基(C8)、喹喔啉基(C8)、5-甲基喹喔啉基(C8)、喹唑啉基(C8)、喹啉基(C9)、8-羟基-喹啉基(C9)和异喹啉基(C9)。
5)C1-C6连接的(tethered)环烃基单元(无论是碳环单元、C6或C10芳基单元、杂环单元或杂芳基单元),其通过C1-C6亚烷基单元连接至所述分子的其他部分、单元或核心。连接的环烃基单元的非限制性实例包括具有下式的苄基C1-(C6):
其中Ra任选是一个或多个独立选择的对氢的取代基。其他实例包括其他芳基单元,尤其是(2-羟基苯基)己基C6-(C6);萘-2-基甲基C1-(C10)、4-氟苄基C1-(C6)、2-(3-羟基苯基)乙基C2-(C6),还有取代的和未取代的C3-C10亚烷基碳环单元,例如环丙基甲基C1-(C3)、环戊基乙基C2-(C5)、环己基甲基C1-(C6)。
该类中包括取代的和未取代的C1-C10亚烷基-杂芳基单元,例如具有下式的2-吡啶甲基C1-(C6)单元:
其中Ra是与以上所定义的相同。另外,C1-C12连接的环烃基
单元包括C1-C10亚烷基杂环单元和亚烷基-杂芳基单元,其非限制
性实例包括,吖丙啶基甲基C1-(C2)和噁唑-2-基甲基C1-(C3)。
对于本发明的目的,碳环选自C3至C20;芳环选自C6或C10;杂环选自C1至C9;杂芳环选自C1至C9。
对于本发明的目的,并为提供对本公开定义中的一致性,包含单个杂原子的稠合环单元以及螺环、双环等在本文中将以与含杂原子的环对应的环家族表征并由其涵盖,但本领域技术人员可有另外的表征。例如,对于本公开的目的,具有下式的1,2,3,4-四氢喹啉:
被认为是杂环单元。对于本公开的目的,具有下式的6,7-二氢-5H-环戊嘧啶:
被认为是杂芳基单元。当稠合环单元在饱和环(杂环)和芳环(杂芳环)二者中都包含杂原子时,对于描述本公开的目的,以芳环为主并且芳环决定所述环在本文中被分配的种类类型。例如,对于本公开的目的,具有下式的1,2,3,4-四氢-[1,8]二氮杂萘:
被认为是杂芳基单元。
术语“取代的”在说明书中通篇使用。术语“取代的”适用于这样的单元,即在本文中描述为“取代的单元或部分是烃基单元或部分,无论是无环的还是有环的,其一个或多个氢原子由本文下文所定义的一个取代基或多个取代基替代”。当取代氢原子时,所述单元每次能够替代所述烃基部分的一个氢原子、两个氢原子或三个氢原子。另外,这些取代基可替代两个相邻碳上的两个氢原子从而形成所述取代基、新的部分或单元。例如,要求单一氢原子替代的取代单元包括卤素、羟基等。两个氢原子替代包括羰基、肟基等。自相邻碳原子的两个氢原子替代包括环氧基等。三个氢原子取代包括氰基等。术语取代的在本说明书通篇中使用以表明烃基部分,尤其是芳环、烷基链;其一个或多个氢原子可由取代基替代。当一个部分描述为“取代的”时,任何数目的氢原子可被替代。例如,4-羟基苯基是“取代的芳香族碳环(芳环)”,(N,N-二甲基-5-氨基)辛基是“取代的C8直链烷基单元”,3-胍基丙基是“取代的C3直链烷基单元”,2-羧基吡啶基是“取代的杂芳基单元”。
以下是可取代碳环、芳基、杂环或杂芳基单元上氢原子的单元的非限制性实例:
i)取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;例如,甲基(C1)、氯甲基(C1)、三氟甲基(C1)、氨甲基(C1)、乙基(C2)、羟甲基1-氯乙基(C2)、2-羟乙基(C2)、1,2-二氟乙基(C2)、正丙基(C3)、异丙基(C3)、3-羧丙基(C3)、环丙基(C3)、2-甲基-环丙基(C3)、正丁基(C4)、仲丁基(C4)、异丁基(C4)、叔丁基(C4)、环丁基(C4)、2,3-二羟基环丁基(C4)、戊基(C5)、环戊基(C5)、己基(C6)、环己基(C6)等;
ii)取代或未取代的C2-C12直链、C3-C12支链或C3-C12环状烯基;例如,乙烯基(C2)、2-氯乙烯基(也称为2-氯乙烯基(chlorovinyl))(C2)、3-丙烯基(C3)、1-丙烯基(也称为2-甲基乙烯基)(C3)、异丙烯基(也称为2-甲基乙烯-2-基)(C3)、丁烯-4-基(C4)、4-羟丁烯-1-基(C4)、环丁烯基(C4)、环戊烯基(C5)、环戊二烯基(C5)、环己烯基(C6)、7-羟基-7-甲基辛-4-烯-2-基(C9)、7-羟基-7-甲基辛-3,5-二烯-2-基(C9)等;
iii)取代或未取代的C2-C12直链或C3-C12支链炔基;例如,乙炔基(C2)、丙-2-炔基(也称为炔丙基)(C3)、丙炔-1-基(C3)、2-甲基-己-4-炔-1-基(C7);5-羟基-5-甲基己-3-炔基(C7)、6-羟基-6-甲基庚-3-炔-2-基(C8)、5-羟基-5-乙基庚-3-炔基(C9)等;
iv)取代或未取代的C6或C10芳基;例如,苯基、2-氯苯基、3-羟苯基、4-硝基苯基、2-氟-4-甲基苯基、3,5-二硝基苯基、8-羟基萘-1-基、6-磺酰基萘-2-基等;
v)取代或未取代的C1-C9杂环;例如,如本文进一步定义的;
vi)取代或未取代的C1-C11杂芳基;例如,如本文进一步定义的;
vii)卤素;例如,氟、氯、溴和碘;
viii)–[C(R23a)(R23b)]xOR10;
R10选自:
a)–H;
b)取代或未取代的C1-C12直链、C3-C12支链或C3-C12环烷基;
c)C6或C10取代或未取代的芳基或亚烷基芳基;
d)C1-C9取代或未取代的杂环;
e)C1-C11取代或未取代的杂芳基;
ix)–[C(R23a)(R23b)]xN(R11a)(R11b);
R11a和R11b彼此独立地选自:
a)–H;
b)–OR12;
R12为氢或C1-C4直链烷基;
c)取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
d)C6或C10取代或未取代的芳基;
e)C1-C9取代或未取代的杂环;
f)C1-C11取代或未取代的杂芳基;或
g)R11a和R11b可以一起形成取代或未取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
x)–[C(R23a)(R23b)]xC(O)R13;
R13为:
a)取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
b)–OR14;
R14为氢、取代或未取代的C1-C4直链烷基、C6或C10取代或未取代的芳基、C1-C9取代或未取代的杂环、C1-C11取代或未取代的杂芳基;
c)–N(R15a)(R15b);
R15a和R15b彼此独立地为氢、取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;C6或C10取代或未取代的芳基;C1-C9取代或未取代的杂环;C1-C11取代或未取代的杂芳基;或者R15a和R15b可以一起形成取代或未取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
xi)–[C(R23a)(R23b)]xOC(O)R16;
R16为:
a)取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
b)–N(R17a)(R17b);
R17a和R17b彼此独立地为氢、取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;C6或C10取代或未取代的芳基;C1-C9取代或未取代的杂环;C1-C11取代或未取代的杂芳基;或R17a和R17b可以一起形成取代或未取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
xii)–[C(R23a)(R23b)]xNR18C(O)R19;
R18为:
a)–H;或
b)取代或未取代的C1-C4直链、C3-C4支链或C3-C4环状烷基;
R19为:
a)取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
b)–N(R20a)(R20b);
R20a和R20b彼此独立地为氢、取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;C6或C10取代或未取代的芳基;C1-C9取代或未取代的杂环;C1-C11取代或未取代的杂芳基;或R20a和R20b可以一起形成取代或未取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
xiii)–[C(R23a)(R23b)]xCN;
xiv)–[C(R23a)(R23b)]xNO2;
xv)–[C(R23a)(R23b)]xR21;
R21为被1-21个选自–F、–Cl、–Br或–I的卤素原子取代的C1-C10直链、C3-C10支链或C3-C10环状烷基;
xvi)–[C(R23a)(R23b)]xSO2R22;
R22为氢、羟基、取代或未取代的C1-C4直链或C3-C4支链烷基;取代或未取代的C6、C10或C14芳基;C7-C15亚烷基芳基;C1-C9取代或未取代的杂环;或C1-C11取代或未取代的杂芳基;
R23a和R23b彼此独立地为氢或C1-C4烷基;并且
指数x为整数0至5。
本文公开的化合物包括所有盐形式,例如,碱性基团(尤其是胺)的盐以及酸性基团(尤其是羧酸)的盐。以下是可与碱性基团形成盐的阴离子的非限制性实例:氯离子、溴离子、碘离子、硫酸根、硫酸氢根、碳酸根、碳酸氢根、磷酸根、甲酸根、乙酸根、丙酸根、丁酸根、丙酮酸根、乳酸根、草酸根、丙二酸根、马来酸根、琥珀酸根、酒石酸根、延胡索酸根、柠檬酸根等。以下是可形成酸性基团的盐的阳离子的非限制性实例:钠离子、锂离子、钾离子、钙离子、镁离子、铋离子等。
对于本发明的目的,术语“化合物”、“类似物”和“物质的组合物”可同样地彼此代替,包括所有对映异构体形式、非对映体形式、盐等,以及术语“化合物”、“类似物”和“物质的组合物”。
HIF-1α脯氨酰羟化酶抑制剂
所公开的化合物具有下式:
其中L选自CH2或SO2,从而得到N-取代的苄基或N-取代的磺酰基芳基-3-羟基吡啶-2-(1H)-酮。Y、R1和R2在下文中进一步定义。
本文公开了N-取代的苄基和N-取代的磺酰基芳基-4-氨基亚甲基-3-羟基吡啶-2-(1N)-酮,其是具有下式的HIF-1α脯氨酰羟化酶抑制剂:
其中R1和R2在下文中进一步定义。
哌嗪(piperizine)-1-甲酸烷基酯
这些化合物的一个类别涉及具有下式的4-{[(1-N-(氯-或氟-取代的)-苄基]-3-羟基-2-氧代-1,2-二氢吡啶-4-基)甲基}哌嗪-1-甲酸C1-C4直链或支链烷基酯:
其中Z为被1-5个选自氯和氟的卤素原子取代的苯基基团,R1和R2一起形成被烷基羧基单元取代的哌嗪环,其中R4选自C1-C4直链或C3-C4支链烷基,例如,具有下式的4{[1-(4氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯:
R4单元的一方面涉及其中R4为叔丁基(C4)的化合物。R4单元的另一方面涉及其中R4为甲基(C1)的化合物。R4单元的又一方面涉及其中R4为乙基(C2)的化合物。R4单元的再一方面涉及其中R4选自正丙基(C3)、异丙基(C3)、正丁基(C4)、仲丁基(C4)和异丁基(C4)的化合物。R4不为氢,因此,具有式:–CO2H的羧化物单元明确排除该类别之外,但可以包括在下文描述的其他类别中。
Z为被1-5个选自氟和氯的卤素取代的苯基。Z单元的一个方面涉及其中Z为4-氯苯基的化合物。Z单元的另一个方面涉及其中Z选自2-氯苯基、3-氯苯基、2-氟苯基、3-氟苯基或4-氟苯基的化合物。Z单元的又一个方面涉及其中Z选自2,3-二氟苯基、2,4-二氟苯基、2,5-二氟苯基、2,6-二氟苯基、2,3-二氯苯基、2,4-二氯苯基、2,5-二氯苯基和2,6-二氯苯的化合物。
以下是该类别化合物的非限制性实例:
具有下式的4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸甲酯:
具有下式的4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸甲酯:
具有下式的4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸甲酯:
具有下式的4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸乙酯:
具有下式的4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸乙酯:
具有下式的4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸乙酯:
具有下式的4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸叔丁酯:
具有下式的4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸叔丁酯:
具有下式的4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸叔丁酯:
具有下式的4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸甲酯:
具有下式的4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸甲酯:
具有下式的4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸甲酯:
具有下式的4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸乙酯:
具有下式的4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸乙酯:
具有下式的4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸乙酯:
具有下式的4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸叔丁酯:
具有下式的4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸叔丁酯:
具有下式的4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯:
另一化合物类别涉及具有下式的N-未取代的-苄基-4-氨基甲基-3-羟基吡啶-2-(1H)-酮,其中Z为未取代的苯基基团:
其中R1和R2一块形成取代或未取代的杂环或杂芳基环。
该类别的第一方面涉及具有下式的化合物:
其中R1和R2一起形成取代或未取代的具有2-20个碳原子和1-7个杂原子的环A表示的杂环或杂芳环;R200表示0-40个氢的取代基。指数w为整数0-40。所述环的非限制性实例包括二氮丙啶基(C1)、1,2,3,4-四唑基(C1)、吖丙啶基(C2)、尿唑基(C2)、[1,2,3]三唑基(C2)、[1,2,4]三唑基(C2)、氮杂环丁基(C3)、吡唑烷基(C3)、咪唑烷基(C3)、噁唑烷基(C3)、异噁唑啉基(C3)、异噁唑基(C3)、噻唑烷基(C3)、异噻唑基(C3)、异噻唑啉基(C3)、噁噻唑烷酮基(C3)、噁唑烷酮基(C3)、乙内酰脲基(C3)、1H-咪唑基(C3)、吡咯烷基(C4)、吗啉基(C4)、哌嗪基(C4)、哌啶基(C4)、哌啶-2-酮基(戊内酰胺)(C5)、7H-嘌呤基(C5)、9H-嘌呤基(C5)、6-氨基-9H-嘌呤基(C5)、2,3,4,5-四氢-1H-氮杂基(C6)、5H-吡咯并[3,2-d]嘧啶基(C6)、7H-吡咯并[2,3-d]嘧啶基(C6)和1,2,3,4-四氢喹啉(C9)。
每个R200单元独立地选自:
i)取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;例如,甲基(C1)、(C1)、氯甲基(C1)、三氟甲基(C1)、氨甲基(C1)、乙基(C2)、羟甲基1-氯乙基(C2)、2-羟乙基(C2)、1,2-二氟乙基(C2)、正丙基(C3)、异丙基(C3)、3-羧丙基(C3)、环丙基(C3)、2-甲基-环丙基(C3)、正丁基(C4)、仲丁基(C4)、异丁基(C4)、叔丁基(C4)、环丁基(C4)、2,3-二羟基环丁基(C4)、戊基(C5)、环戊基(C5)、己基(C6)和环己基(C6)等;
ii)取代或未取代的C2-C12直链、C3-C12支链或C3-C12环状烯基;例如,乙烯基(C2)、2-氯乙烯基(也称为2-氯乙烯基)(C2)、3-丙烯基(C3)、1-丙烯基(也称为2-甲基乙烯基)(C3)、异丙烯基(也称为2-甲基乙烯-2-基)(C3)、丁烯-4-基(C4)、4-羟丁烯-1-基(C4)、环丁烯基(C4)、环戊烯基(C5)、环戊二烯基(C5)、环己烯基(C6)、7-羟基-7-甲基辛-4-烯-2-基(C9)和7-羟基-7-甲基辛-3,5-二烯-2-基(C9)等;
iii)取代或未取代的C1-C12直链或C3-C12支链炔基;例如,乙炔基(C2)、丙-2-炔基(也称为炔丙基)(C3)、丙炔-1-基(C3)、2-甲基-己-4-炔-1-基(C7);5-羟基-5-甲基己-3-炔基(C7)、6-羟基-6-甲基庚-3-炔-2-基(C8)、5-羟基-5-乙基庚-3-炔基(C9)等;
iv)取代或未取代的C6或C10芳基;例如,苯基(C6)、萘-1-基(C10)、萘-2-基(C10)、4-氟苯基(C6)、2-羟苯基(C6)、3-甲基苯基(C6)、2-氨基-4-氟苯基(C6)、2-(N,N-二乙氨基)苯基(C6)、2-氰苯基(C6)、2,6-二-叔丁基苯基(C6)、3-甲氧苯基(C6)、8-羟基萘-2-基(C10)、4,5-二甲氧萘-1-基(C10)、6-氰-萘-1-基(C10)等;
v)取代或未取代的C1-C9杂环;例如,二氮丙啶基(C1)、吖丙啶基(C2)、尿唑基(C2)、氮杂环丁基(C3)、吡唑烷基(C3)、咪唑烷基(C3)、噁唑烷基(C3)、异噁唑啉基(C3)、异噁唑基(C3)、噻唑烷基(C3)、异噻唑基(C3)、异噻唑啉基(C3)、噁噻唑烷酮基、(C3)、噁唑烷酮基(C3)、乙内酰脲基(C3)、四氢呋喃基(C4)、吡咯烷基(C4)、吗啉基(C4)、哌嗪基(C4)、哌啶基(C4)、二氢吡喃基(C5)、四氢吡喃基(C5)、哌啶-2-酮基(戊内酰胺)(C5)等;
vi)取代或未取代的C1-C11杂芳基;例如,1,2,3,4-四唑基(C1)、[1,2,3]三唑基(C2)、[1,2,4]三唑基(C2)、三嗪基(C3)、噻唑基(C3)、1H-咪唑基(C3)、噁唑基(C3)、呋喃基(C4)、噻吩基(C4)、嘧啶基(C4)、吡啶基(C5)等;
vii)卤素;例如,–F、–Cl、–Br或–I;
viii)–[C(R37a)(R37b)]yOR24;
R24选自:
a)–H;
b)取代或未取代的C2-C12直链、C3-C12支链或C3-C12环状烷基;
c)取代或未取代的C6或C10芳基或C7或C10亚烷基芳基;例如,苯基或苄基
d)取代或未取代的C1-C9杂环;
e)取代或未取代的C1-C11杂芳基;
例如,–OH、–CH2OH、–OCH3、–CH2OCH3、–OCH2CH3、–CH2OCH2CH3、–OCH2CH2CH3和–CH2OCH2CH2CH3;
ix)–[C(R37a)(R37b)]yN(R25a)(R25b);
R25a和R25b彼此独立地选自:
a)–H;
b)–OR26;
R26为氢或C1-C4直链烷基;
c)取代或未取代的C2-C12直链、C3-C12支链或C3-C12环状烷基;
d)取代或未取代的C6或C10芳基;
e)取代或未取代的C1-C9杂环;
f)取代或未取代的C1-C11杂芳基;或者
g)R25a和R25b可以一起形成取代或未取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,–NH2、-CH2NH2、-NHCH3、-N(CH3)2、-NHOH、-NHOCH3、-NH(CH2CH3)、-CH2NHCH3、-CH2N(CH3)2、–CH2NH(CH2CH3)等;
x)–[C(R37a)(R37b)]yC(O)R27;
R27为:
a)取代或未取代的C2-C12直链、C3-C12支链或C3-C12环状烷基;
b)–OR28;
R28为氢、取代或未取代的C1-C4直链烷基、取代或未取代的C6或C10芳基、取代或未取代的C1-C9杂环、取代或未取代的C1-C11杂芳基;
c)–N(R29a)(R29b);
R29a和R29b彼此独立地为氢、取代或未取代的C2-C12直链、C3-C12支链或C3-C12环状烷基;取代或未取代的C6或C10芳基、取代或未取代的C1-C9杂环、取代或未取代的C1-C11杂芳基;或R29a和R29b可以一起形成取代或未取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,–COCH3、-CH2COCH3、-OCH2CH3、-CH2COCH2CH3、-COCH2CH2CH3、-CH2COCH2CH2CH3等;
xi)–[C(R37a)(R37b)]yOC(O)R30;
R30为:
a)C1-C12取代或未取代的直链、支链或环状烷基;
b)–N(R31a)(R31b);
R31a和R31b彼此独立地为氢、取代或未取代的C2-C12直链、C3-C12支链或C3-C12环状烷基;取代或未取代的C6或C10芳基、取代或未取代的C1-C9杂环、取代或未取代的C1-C11杂芳基;或R31a和R31b可以一块形成取代或未取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,–OC(O)CH3、-CH2OC(O)CH3、-OC(O)NH2、-CH2OC(O)NH2、-OC(O)NHCH3、-CH2OC(O)NHCH3、-OC(O)N(CH3)2、-CH2OC(O)N(CH3)2等;
xii)–[C(R37a)(R37b)]yNR32C(O)R33;
R32为:
a)–H;或者
b)取代或未取代的C1-C4直链、C3-C4支链或C3-C4环状烷基;
R33为:
a)取代或未取代的C2-C12直链、C3-C12支链或C3-C12环状烷基;
b)–N(R34a)(R34b);
R34a和R34b彼此独立地为氢、取代或未取代的C2-C12直链、C3-C12支链或C3-C12环状烷基;取代或未取代的C6或C10芳基、取代或未取代的C1-C9杂环、取代或未取代的C1-C11杂芳基;C1-C11取代或未取代的杂芳基;或R34a和R34b可以一块形成取代或未取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,–NHC(O)CH3、-CH2NHC(O)CH3、-NHC(O)NH2、-CH2NHC(O)NH2、-NHC(O)NHCH3、-CH2NHC(O)NHCH3、-OC(O)N(CH3)2、-CH2NHC(O)N(CH3)2等;
xiii)–[C(R37a)(R37b)]yCN;例如,–CN、-CH2CN和-CH2CH2CN;
xiv)–[C(R37a)(R37b)]yNO2;例如,–NO2、-CH2NO2和-CH2CH2NO2;
xv)–[C(R37a)(R37b)]yR35;例如,-CH2F、-CHF2、-CF3、-CCl3或–CBr3;
R35为被1-21个选自–F、–Cl、–Br或–I的卤素原子取代的C1-C10直链、C3-C10支链或C3-C10环状烷基;
xvi)–[C(R37a)(R37b)]ySO2R36;
R36为氢、羟基、取代或未取代的C1-C4直链或C3-C4支链烷基;取代或未取代的C6、C10或C14芳基;C7-C15亚烷基芳基;取代或未取代的C1-C9杂环;或取代或未取代的C1-C11杂芳基;
例如,–SO2H、-CH2SO2H、-SO2CH3、-CH2SO2CH3、-SO2C6H5和-CH2SO2C6H5;并且
xvii)环碳原子上的两个氢原子可以被取代以形成=O、=S或=NH单元;
R37a和R37b彼此独立地为氢或C1-C4烷基;并且
指数y为整数0至5。
该方面的第一实施方案涉及其中R1和R2一起形成5元取代或未取代的C1-C4杂环或者取代或未取代的C1-C4杂芳基环的化合物,其非限制性实例包括选自如下的环:
i)
ii)
ii)
iii)
iv)
v)
vi)
vii)
viii)
该实施方案的第一重复涉及具有下式的HIF-1α脯氨酰羟化酶抑制剂:
R200代表环氢的0-2个取代基,其中所述氢的取代基独立地选自:
i)C1-C4直链或C3-C4支链烷基;
ii)C1-C4直链或C3-C4支链烷氧基;
iii)羟基;
iv)氰基;
v)硝基;
vi)氨基、甲基氨基或二甲基氨基;
vii)羧基、甲基羧基;或乙基羧基;
viii)甲酰基、乙酰基或丙酰基;
ix)酰胺基、甲基酰胺基或二甲基酰胺基;
x)卤素;
xi)杂环;或
xii)杂芳基。
该重复的非限制性实例包括具有下式的HIF-1α脯氨酰羟化酶抑制剂:
该实施方案的进一步重复涉及其中R1和R2一起形成环中具有多于一个杂原子的5元取代或未取代的杂环或杂芳环的HIF-1α脯氨酰羟化酶抑制剂非限制性实例包括:
该方面的另一实施方案涉及其中R1和R2一起形成取代或未取代的C4-C11杂环或者取代或未取代的C4-C11杂芳环的HIF-1α脯氨酰羟化酶抑制剂,其非限制性实例选自:
i)
ii)
iii)
iv)
v)
该实施方案的非限制性实例包括:
另一类别的化合物具有下式:
其中R200和指数w与上文定义相同。R代表0-5个氢的取代基,其中每个R独立地选自:
i)C1-C12取代或未取代的直链、支链或环状烷基;例如,甲基(C1)、(C1)、氯甲基(C1)、三氟甲基(C1)、氨甲基(C1)、乙基(C2)、羟甲基1-氯乙基(C2)、2-羟乙基(C2)、1,2-二氟乙基(C2)、正丙基(C3)、异丙基(C3)、3-羧丙基(C3)、环丙基(C3)、2-甲基-环丙基(C3)、正丁基(C4)、仲丁基(C4)、异丁基(C4)、叔丁基(C4)、环丁基(C4)、2,3-二羟基环丁基(C4)、戊基(C5)、环戊基(C5)、己基(C6)和环己基(C6)等;
ii)C2-C12取代或未取代的直链、支链或环状烯基;例如,乙烯基(C2)、2-氯乙烯基(也称为2-氯乙烯基)(C2)、3-丙烯基(C3)、1-丙烯基(也称为2-甲基乙烯基)(C3)、异丙烯基(也称为2-甲基乙烯-2-基)(C3)、丁烯-4-基(C4)、4-羟丁烯-1-基(C4)、环丁烯基(C4)、环戊烯基(C5)、环戊二烯基(C5)、环己烯基(C6)、7-羟基-7-甲基辛-4-烯-2-基(C9)、7-羟基-7-甲基辛-3,5-二烯-2-基(C9)等;
iii)C2-C12取代或未取代的直链或支链炔基;例如,乙炔基(C2)、丙-2-炔基(也称为炔丙基)(C3)、丙炔-1-基(C3)、2-甲基-己-4-炔-1-基(C7);5-羟基-5-甲基己-3-炔基(C7)、6-羟基-6-甲基庚-3-炔-2-基(C8)、5-羟基-5-乙基庚-3-炔基(C9)等;
iv)C6或C10取代或未取代的芳基;例如,苯基(C6)、萘-1-基(C10)、萘-2-基(C10)、4-氟苯基(C6)、2-羟苯基(C6)、3-甲基苯基(C6)、2-氨基-4-氟苯基(C6)、2-(N,N-二乙氨基)苯基(C6)、2-氰苯基(C6)、2,6-二-叔丁基苯基(C6)、3-甲氧苯基(C6)、8-羟基萘-2-基(C10)、4,5-二甲氧萘-1-基(C10)、6-氰-萘-1-基(C10)等;
v)C1-C9取代或未取代的杂环;例如,二氮丙啶基(C1)、吖丙啶基(C2)、尿唑基(C2)、氮杂环丁基(C3)、吡唑烷基(C3)、咪唑烷基(C3)、噁唑烷基(C3)、异噁唑啉基(C3)、异噁唑基(C3)、噻唑烷基(C3)、异噻唑基(C3)、异噻唑啉基(C3)、噁噻唑烷酮基(C3)、噁唑烷酮基(C3)、乙内酰脲基(C3)、四氢呋喃基(C4)、吡咯烷基(C4)、吗啉基(C4)、哌嗪基(C4)、哌啶基(C4)、二氢吡喃基(C5)、四氢吡喃基(C5)、哌啶-2-酮基(戊内酰胺)(C5)等;
vi)C1-C11取代或未取代的杂芳基;例如,1,2,3,4-四唑基(C1)、[1,2,3]三唑基(C2)、[1,2,4]三唑基(C2)、三嗪基(C3)、噻唑基(C3)、1H-咪唑基(C3)、噁唑基(C3)、呋喃基(C4)、噻吩基(C4)、嘧啶基(C4)、吡啶基(C5)等;
vii)卤素;例如、-F、–Cl、–Br或–I;
viii)–[C(R23a)(R23b)]xOR10;
R10选自:
a)–H;
b)C1-C12取代或未取代的直链、支链或环状烷基;
c)C6或C10取代或未取代的芳基或亚烷基芳基;
d)C1-C9取代或未取代的杂环;
e)C1-C11取代或未取代的杂芳基;
例如,–OH、-CH2OH、-OCH3、-CH2OCH3、-OCH2CH3、-CH2OCH2CH3、-OCH2CH2CH3和–CH2OCH2CH2CH3;
ix)–[C(R23a)(R23b)]xN(R11a)(R11b);
R11a和R11b彼此独立地选自:
a)–H;
b)–OR12;
R12为氢或C1-C4直链烷基;
c)C1-C12取代或未取代的直链、支链或环状烷基;
d)C6或C10取代或未取代的芳基;
e)C1-C9取代或未取代的杂环;
f)C1-C11取代或未取代的杂芳基;或者
g)R11a和R11b可以一起形成取代或未取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,–NH2、-CH2NH2、-NHCH3、-N(CH3)2、-NHOH、-NHOCH3、-NH(CH2CH3)、-CH2NHCH3、-CH2N(CH3)2、-CH2NH(CH2CH3)等;
x)–[C(R23a)(R23b)]xC(O)R13;
R13为:
a)C1-C12取代或未取代的直链、支链或环状烷基;
b)–OR14;
R14为氢、取代或未取代的C1-C4直链烷基、C6或C10取代或未取代的芳基、C1-C9取代或未取代的杂环、C1-C11取代或未取代的杂芳基;
c)–N(R15a)(R15b);
R15a和R15b彼此独立地为氢、C1-C12取代或未取代的直链、支链或环状烷基;C6或C10取代或未取代的芳基;C1-C9取代或未取代的杂环;C1-C11取代或未取代的杂芳基;或者R15a和R15b可以一块形成取代或未取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,–COCH3、-CH2COCH3、-OCH2CH3、-CH2COCH2CH3、-COCH2CH2CH3、-CH2COCH2CH2CH3等;
xi)–[C(R23a)(R23b)]xOC(O)R16;
R16为:
a)C1-C12取代或未取代的直链、支链或环状烷基;
b)–N(R17a)(R17b);
R17a和R17b彼此独立地为氢、C1-C12取代或未取代的直链、支链或环状烷基;C6或C10取代或未取代的芳基;C1-C9取代或未取代的杂环;C1-C11取代或未取代的杂芳基;或者R17a和R17b可以一起形成取代或未取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
xii)–[C(R23a)(R23b)]xNR18C(O)R19;
R18为:
a)–H;或者
b)C1-C4取代或未取代的直链、支链或环状烷基;
R19为:
a)C1-C12取代或未取代的直链、支链或环状烷基;
b)–N(R20a)(R20b);
R20a和R20b彼此独立地为氢、C1-C12取代或未取代的直链、支链或环状烷基;C6或C10取代或未取代的芳基;C1-C9取代或未取代的杂环;C1-C11取代或未取代的杂芳基;或者R20a和R20b可以一起形成取代或未取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,–NHC(O)CH3、-CH2NHC(O)CH3、-NHC(O)NH2、-CH2NHC(O)NH2、-NHC(O)NHCH3、-CH2NHC(O)NHCH3、-OC(O)N(CH3)2、-CH2NHC(O)N(CH3)2等;
xiii)–[C(R23a)(R23b)]xCN;例如,–CN、-CH2CN和-CH2CH2CN;
xiv)–[C(R23a)(R23b)]xNO2;例如,–NO2、-CH2NO2和-CH2CH2NO2;
xv)–[C(R23a)(R23b)]xR21;例如,-CH2F、-CHF2、-CF3、-CCl3或–CBr3;
R21为被1-21个选自–F、–Cl、–Br或–I的卤素原子取代的C1-C10直链、支链或环状烷基;
xvi)–[C(R23a)(R23b)]xSO2R22;
R22为氢、羟基、取代或未取代的C1-C4直链或支链烷基;取代或未取代的C6、C10或C14芳基;C7-C15亚烷基芳基;C1-C9取代或未取代的杂环;或C1-C11取代或未取代的杂芳基;例如,-SO2H、-CH2SO2H、-SO2CH3、-CH2SO2CH3、-SO2C6H5和–CH2SO2C6H5;
R23a和R23b彼此独立地为氢或C1-C4烷基;并且
指数x为整数0至5。
该类别的非限制性实例包括具有下式的化合物:
另一类别的化合物涉及具有下式的未取代的N-苄基-4-氨基甲基-3-羟基吡啶-2-(1H)-酮:
其中R1和R2彼此独立地选自:
i)氢;
ii)取代或未取代的C1-C10直链、支链或环状烷基;
iii)取代或未取代的C2-C10直链、支链或环状烯基;
iv)取代或未取代的C2-C10直链或支链炔基;
v)取代或未取代的C6或C10芳基;
vi)取代或未取代的C1-C9杂环;或
vii)取代或未取代的C1-C9杂芳基。
该类别的第一方面涉及其中R2为氢且R1为取代或未取代的C1-C9杂环或C1-C9杂芳基的HIF-1α脯氨酰羟化酶抑制剂。在第一实施方案中,R1为取代的杂环基团,其非限制性实例包括吖丙啶基(C2)、氮杂环丁基(C3)、吡咯烷基(C4)、吗啉基(C4)、哌嗪基(C4)、哌啶基(C4)、哌啶-2-酮基(戊内酰胺)(C5)和氮杂环庚-2-酮基(己内酰胺)(C6),其中所述R1单元可以结合于所述环中任意位置处的氮原子。另外,所述C1-C9杂环或C1-C9杂芳基环可以在无论环碳或环杂原子例如环氮的任意位置被取代。该实施方案的非限制性实例包括:
在另一个实施方案中,R2为氢且R1为取代或未取代的C3-C12环烷基,其中所述环烷基环可以在任意环位置处被取代。该实施方案的非限制性实例包括:
又一化合物类别涉及具有下式的未取代的N-苄基-4-氨基甲基-3-羟基吡啶-2-(1H)-酮:
R1和R2彼此独立地为氢或者取代或未取代的C1-C10直链或支链烷基,其中所述烷基单元可以被独立选自如下的一个或多个单元取代:
i)C1-C8直链、支链或环状烷氧基;
ii)羟基;
iii)卤素;
iv)氰基;
v)氨基、C1-C8单-烷基氨基、C1-C8二-烷基氨基;
vi)–SR40;R40为氢或C1-C4直链或支链烷基;
vii)取代或未取代的C6或C10芳基;
viii)取代或未取代的C1-C9杂环;或
ix)取代或未取代的C1-C9杂芳基。
该类别的非限制性实例包括:
再一类别的所公开化合物具有下式:
其中R200和指数w与上文定义相同。R代表0-5个氢的取代基、其中每个R独立地选自:
i)取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;例如,甲基(C1)、(C1)、氯甲基(C1)、三氟甲基(C1)、氨甲基(C1)、乙基(C2)、羟甲基1-氯乙基(C2)、2-羟乙基(C2)、1,2-二氟乙基(C2)、正丙基(C3)、异丙基(C3)、3-羧丙基(C3)、环丙基(C3)、2-甲基-环丙基(C3)、正丁基(C4)、仲丁基(C4)、异丁基(C4)、叔丁基(C4)、环丁基(C4)、2,3-二羟基环丁基(C4)、戊基(C5)、环戊基(C5)、己基(C6)和环己基(C6)等;
ii)取代或未取代的C2-C12直链、C3-C12支链或C3-C12环状烯基;例如,乙烯基(C2)、2-氯乙烯基(也称为2-氯乙烯基)(C2)、3-丙烯基(C3)、1-丙烯基(也称为2-甲基乙烯基)(C3)、异丙烯基(也称为2-甲基乙烯-2-基)(C3)、丁烯-4-基(C4)、4-羟丁烯-1-基(C4)、环丁烯基(C4)、环戊烯基(C5)、环戊二烯基(C5)、环己烯基(C6)、7-羟基-7-甲基辛-4-烯-2-基(C9)、7-羟基-7-甲基辛-3,5-二烯-2-基(C9)等;
iii)取代或未取代的C2-C12直链或C3-C12支链炔基;例如,乙炔基(C2)、丙-2-炔基(也称为炔丙基)(C3)、丙炔-1-基(C3)、2-甲基-己-4-炔-1-基(C7);5-羟基-5-甲基己-3-炔基(C7)、6-羟基-6-甲基庚-3-炔-2-基(C8)、5-羟基-5-乙基庚-3-炔基(C9)等;
iv)取代或未取代的C6或C10芳基;例如,苯基(C6)、萘-1-基(C10)、萘-2-基(C10)、4-氟苯基(C6)、2-羟苯基(C6)、3-甲基苯基(C6)、2-氨基-4-氟苯基(C6)、2-(N,N-二乙氨基)苯基(C6)、2-氰苯基(C6)、2,6-二-叔丁基苯基(C6)、3-甲氧苯基(C6)、8-羟基萘-2-基(C10)、4,5-二甲氧萘-1-基(C10)、6-氰-萘-1-基(C10)等;
v)取代或未取代的C1-C9杂环;例如,二氮丙啶基(C1)、吖丙啶基(C2)、尿唑基(C2)、氮杂环丁基(C3)、吡唑烷基(C3)、咪唑烷基(C3)、噁唑烷基(C3)、异噁唑啉基(C3)、异噁唑基(C3)、噻唑烷基(C3)、异噻唑基(C3)、异噻唑啉基(C3)、噁噻唑烷酮基(C3)、噁唑烷酮基(C3)、乙内酰脲基(C3)、四氢呋喃基(C4)、吡咯烷基(C4)、吗啉基(C4)、哌嗪基(C4)、哌啶基(C4)、二氢吡喃基(C5)、四氢吡喃基(C5)、哌啶-2-酮基(戊内酰胺)(C5)等;
vi)取代或未取代的C1-C11杂芳基;例如,1,2,3,4-四唑基(C1)、[1,2,3]三唑基(C2)、[1,2,4]三唑基(C2)、三嗪基(C3)、噻唑基(C3)、1H-咪唑基(C3)、噁唑基(C3)、呋喃基(C4)、噻吩基(C4)、嘧啶基(C4)、吡啶基(C5)等;
vii)卤素;例如、-F、–Cl、–Br或–I;
viii)–[C(R23a)(R23b)]xOR10;
R10选自:
a)–H;
b)取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
c)取代或未取代的C6或C10芳基或C7或C10亚烷基芳基;
d)取代或未取代的C1-C9杂环;
e)取代或未取代的C1-C11杂芳基;
例如,–OH、-CH2OH、-OCH3、-CH2OCH3、-OCH2CH3、–CH2OCH2CH3、-OCH2CH2CH3和–CH2OCH2CH2CH3;
ix)–[C(R23a)(R23b)]xN(R11a)(R11b);
R11a和R11b彼此独立地选自:
a)–H;
b)–OR12;
R12为氢或C1-C4直链烷基;
c)取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
d)取代或未取代的C6或C10芳基;
e)取代或未取代的C1-C9杂环;
f)取代或未取代的C1-C11杂芳基;或
g)R11a和R11b可以一起形成取代或未取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,–NH2、-CH2NH2、-NHCH3、-N(CH3)2、-NHOH、-NHOCH3、-NH(CH2CH3)、-CH2NHCH3、-CH2N(CH3)2、-CH2NH(CH2CH3)等;
x)–[C(R23a)(R23b)]xC(O)R13;
R13为:
a)取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
b)–OR14;
R14为氢、取代或未取代的C1-C4直链烷基、取代或未取代的C6或C10芳基、取代或未取代的C1-C9杂环、取代或未取代的C1-C11杂芳基;
c)–N(R15a)(R15b);
R15a和R15b彼此独立地为氢、取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;取代或未取代的C6或C10芳基;取代或未取代的C1-C9杂环;取代或未取代的C1-C11杂芳基;或R15a和R15b可以一起形成取代或未取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,–COCH3、-CH2COCH3、-OCH2CH3、-CH2COCH2CH3、-COCH2CH2CH3、-CH2COCH2CH2CH3等;
xi)–[C(R23a)(R23b)]xOC(O)R16;
R16为:
a)取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
b)–N(R17a)(R17b);
R17a和R17b彼此独立地为氢、取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;取代或未取代的C6或C10芳基;取代或未取代的C1-C9杂环;取代或未取代的C1-C11杂芳基;或者R17a和R17b可以一起形成取代或未取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
xii)–[C(R23a)(R23b)]xNR18C(O)R19;
R18为:
a)–H;或
b)取代或未取代的C1-C4直链、C3-C4支链或C3-C4环状烷基;
R19为:
a)取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
b)–N(R20a)(R20b);
R20a和R20b彼此独立地为氢、取代或未取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;取代或未取代的C6或C10芳基;取代或未取代的C1-C9杂环;取代或未取代的C1-C11杂芳基;或者R20a和R20b可以一起形成取代或未取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,–NHC(O)CH3、-CH2NHC(O)CH3、-NHC(O)NH2、-CH2NHC(O)NH2、-NHC(O)NHCH3、-CH2NHC(O)NHCH3、-OC(O)N(CH3)2、-CH2NHC(O)N(CH3)2等;
xiii)–[C(R23a)(R23b)]xCN;例如,–CN、-CH2CN和-CH2CH2CN;
xiv)–[C(R23a)(R23b)]xNO2;例如,–NO2、-CH2NO2和-CH2CH2NO2;
xv)–[C(R23a)(R23b)]xR21;例如,-CH2F、-CHF2、-CF3、-CCl3或–CBr3;
R21为被1-21个选自–F、–Cl、–Br或–I的卤素原子取代的C1-C10直链、支链或环状烷基;
xvi)–[C(R23a)(R23b)]xSO2R22;
R22为氢、羟基、取代或未取代的C1-C4直链或C3-C4支链烷基;取代或未取代的C6、C10或C14芳基;C7-C15亚烷基芳基;取代或未取代的C1-C9杂环;或取代或未取代的C1-C11杂芳基;例如,-SO2H、-CH2SO2H、-SO2CH3、-CH2SO2CH3、-SO2C6H5和–CH2SO2C6H5;
R23a和R23b彼此独立地为氢或C1-C4烷基;并且
指数x为整数0至5。
该类别的一方面实施方案涉及其中R1和R2一起形成5元取代或未取代的C1-C4杂环或者取代或未取代的C1-C4杂芳基环的HIF-1α脯氨酰羟化酶抑制剂,其非限制性实例包括选自如下的环:
i)
ii)
ii)
iii)
iv)
v)
vi)
vii)
viii)
该类别的另一方面涉及其中R1和R2一起形成取代或未取代的C4-C11杂环或者取代或未取代的C4-C11杂芳基环的HIF-1α脯氨酰羟化酶抑制剂,其非限制性实例选自:
i)
ii)
iii)
iv)
v)
该类别的非限制性实例包括具有下式的化合物:
又一类的所公开的化合物具有下式:
其中R代表1至5个苯环氢原子的可选取代基,R1和R2彼此独立地为氢或者取代或未取代的C1-C10直链或支链烷基,其中所述烷基单元可以被独立选自如下的一个或多个单元取代:
i)C1-C8直链、C3-C8支链或C3-C8环状烷氧基;
ii)羟基;
iii)卤素;
iv)氰基;
v)氨基、C1-C8单-烷基氨基、C1-C8二-烷基氨基;
vi)–SR40;R40为氢或C1-C4直链或支链烷基;
vii)取代或未取代的C6或C10芳基;
viii)取代或未取代的C1-C9杂环;或
ix)取代或未取代的C1-C9杂芳基。
该类别的非限制性实例包括:
再一所公开的HIF-1α脯氨酰羟化酶抑制剂类别涉及具有下式的化合物:
其中R1和R2一起形成取代或未取代的哌嗪环,所述环上的取代基如上文对R200所定义。
再一类所公开的HIF-1α脯氨酰羟化酶抑制剂具有下式:
本文还公开了具有下式的N-取代的苄基或N-取代的磺酰基芳基-3-羟基吡啶-2-(1H)-酮:
其可用于刺激受试者中的细胞免疫应答。对于这些化合物,Z和L与上文公开相同。这些化合物的非限制性实例包括:
具有下式的1-(4-氯苄基)-3-羟基吡啶-2(1H)-酮:
具有下式的1-(3-氯苄基)-3-羟基吡啶-2(1H)-酮:
具有下式的1-(2-氯苄基)-3-羟基吡啶-2(1H)-酮:
本文还公开了具有下式的N-取代的苄基或N-取代的磺酰基芳基-5-取代的-3-羟基吡啶-2-(1H)-酮:
其中Y为取代或未取代的苯基,Z和L与上文的定义相同。
Y的一个方面涉及被1-5个卤素原子取代的苯基基团,例如,Y选自2-氯苯基、3-氯苯基、2-氟苯基、3-氟苯基或4-氟苯基。Y单元的又一方面涉及其中Y选自2,3-二氟苯基、2,4-二氟苯基、2,5-二氟苯基、2,6-二氟苯基、2,3-二氯苯基、2,4-二氯苯基、2,5-二氯苯基和2,6-二氯苯基的化合物。
该类别化合物的非限制性实例包括具有下式的1-(4-氯苄基)-5-(4-氯苯基)-3-羟基吡啶-2(1H)酮:
另外的非限制性实例包括:
1-(2-氯苄基)-5-(2-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氯苄基)-5-(3-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氯苄基)-5-(4-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氯苄基)-5-(2-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氯苄基)-5-(3-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氯苄基)-5-(4-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氯苄基)-5-(2-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氯苄基)-5-(3-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氟苄基)-5-(2-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氟苄基)-5-(3-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氟苄基)-5-(4-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氟苄基)-5-(2-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氟苄基)-5-(3-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氟苄基)-5-(4-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氟苄基)-5-(2-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氟苄基)-5-(3-氯苯基)-3-羟基吡啶-2(1H)-酮
1-(4-氟苄基)-5-(4-氯苯基)-3-羟基吡啶-2(1H)-酮
1-(2-氯苄基)-5-(2-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氯苄基)-5-(3-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氯苄基)-5-(4-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氯苄基)-5-(2-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氯苄基)-5-(3-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氯苄基)-5-(4-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氯苄基)-5-(2-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氯苄基)-5-(3-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氯苄基)-5-(3-氟苯基)-3-羟基吡啶-2(1H)-酮
1-(2-氟苄基)-5-(2-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氟苄基)-5-(3-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氟苄基)-5-(4-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氟苄基)-5-(2-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氟苄基)-5-(3-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氟苄基)-5-(4-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氟苄基)-5-(2-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氟苄基)-5-(3-氟苯基)-3-羟基吡啶-2(1H)-酮;和
1-(4-氟苄基)-5-(3-氟苯基)-3-羟基吡啶-2(1H)-酮。
为严格地以非限制性方式描述制备本文未进行明确示例的化合物范围内亚属化合物的合成策略的供选方案之目的,可将所公开的化合物分成几种类别。这种主观分类不意味着本文所述物质的任何化合物或组分的生物效能的任何增加或降低。
所公开的HIF-1α脯氨酰羟化酶抑制剂的类别I涉及具有下式的化合物:
其中A为具有2-20个碳原子和1-7个杂原子的取代或未取代的杂环或杂芳基环,R200表示0-40个氢的取代基,R代表上文定义的1-5个氢的取代基,指数n为1-5。表I提供了该类别化合物的代表性实例。
表I
编号 | R | A环 |
A1 | 3-甲氧基 | 吡咯烷-1-基 |
A2 | 3-甲氧基 | 3-羟基吡咯烷-1-基 |
A3 | 3-甲氧基 | 2-(吡啶-2-基)吡咯烷-1-基 |
A4 | 3-甲氧基 | 2-甲基羧基吡咯烷-1-基 |
A5 | 3-甲氧基 | 2-(甲氧甲基)吡咯烷-1-基 |
A6 | 3-甲氧基 | 噻唑烷-3-基 |
A7 | 3-甲氧基 | 1H-咪唑-1-基 |
A8 | 3-甲氧基 | 哌啶-1-基 |
A9 | 3-甲氧基 | 4-苄基哌啶-1-基 |
A10 | 3-甲氧基 | 1,4’-联哌啶基-1’-基 |
A11 | 3-甲氧基 | 哌嗪-1-基 |
A12 | 3-甲氧基 | 4-苄基哌嗪-1-基 |
A13 | 3-甲氧基 | 4-(2-甲氧苯基)哌嗪-1-基甲基 |
A14 | 3-甲氧基 | 4-(6-氯哒嗪-3-基)哌嗪-1-基 |
A15 | 3-甲氧基 | 1,4-二氧杂-8-氮杂螺[4,5]癸-8-基 |
A16 | 3-甲氧基 | 吗啉-4-基 |
A17 | 3-甲氧基 | 硫代吗啉-4-基 |
A18 | 3-甲氧基 | 氮杂环庚-1-基 |
A19 | 3-甲氧基 | 氮杂环辛-1-基 |
A20 | 3-甲氧基 | 3,4-二氢喹啉-1(2H)-基 |
编号 | R | A环 |
A21 | 4-氯 | 吡咯烷-1-基 |
A22 | 4-氯 | 3-羟基吡咯烷-1-基 |
A23 | 4-氯 | 2-(吡啶-2-基)吡咯烷-1-基 |
A24 | 4-氯 | 2-甲基羧基吡咯烷-1-基 |
A25 | 4-氯 | 2-(甲氧甲基)吡咯烷-1-基 |
A26 | 4-氯 | 噻唑烷-3-基 |
A27 | 4-氯 | 1H-咪唑-1-基 |
A28 | 4-氯 | 哌啶-1-基 |
A29 | 4-氯 | 4-苄基哌啶-1-基 |
A30 | 4-氯 | 1,4’-联哌啶基-1’-基 |
A31 | 4-氯 | 哌嗪-1-基 |
A32 | 4-氯 | 4-苄基哌嗪-1-基 |
A33 | 4-氯 | 4-(2-甲氧苯基)哌嗪-1-基甲基 |
A34 | 4-氯 | 4-(6-氯哒嗪-3-基)哌嗪-1-基 |
A35 | 4-氯 | 1,4-二氧杂-8-氮杂螺[4,5]癸-8-基 |
A36 | 4-氯 | 吗啉-4-基 |
A37 | 4-氯 | 硫代吗啉-4-基 |
A38 | 4-氯 | 氮杂环庚-1-基 |
A39 | 4-氯 | 氮杂环辛-1-基 |
A40 | 4-氯 | 3,4-二氢喹啉-1(2H)-基 |
A41 | 4-氯 | 4-叔丁氧羰基哌嗪-1-基 |
所公开的该类别的化合物可以通过下文路线I中列出且在实施例1中描述的步骤制备。
路线I
试剂和条件:(a)TBDMSCl,咪唑,DMF:室温,30分钟。
试剂和条件:(b)(4-氯)苄基氯,Cs2CO3,THF;室温。
试剂和条件:(c)5M HCl,EtOH;30分钟。
试剂和条件:(d)(i)H2CHO,AcOH,t-Boc-哌嗪,EtOH;3天。
实施例1
{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯(4)
制备3-(叔丁基二甲基硅氧基)-1H-吡啶-2-酮(1):将3-羟基吡啶-2(1H)-酮(15g,135mmol)和咪唑(23g,338mmol)在惰性气氛下悬浮于二甲基甲酰胺(200mL)中。在室温下,经30分钟的时间将叔丁基二甲基氯硅烷(20.5g,136mmol)在二甲基甲酰胺(200mL)中的溶液逐滴加入。然后使所述反应物搅拌过夜。然后将所得到的溶液倒入水(300mL)中,以叔丁基甲基醚(3×500mL)萃取所述混合物。将合并的有机相用水(300mL)、盐水(300mL)洗涤并经Na2SO4干燥。在减压下除去溶剂,从庚烷结晶粗产物,得到16.3g(53%产率)所需产品。
1H NMR(250MHz,CDCl3)δppm 12.98(1H,m);6.91(1H,dd,J=1.Hz,J=6.8Hz);6.81(1H,dd,J=1.8Hz,J=7.2Hz);6.02-6.007(1H,m);0.90(9H,s),和0.17(6H,s).
制备3-(叔丁基二甲基硅氧基)-1-(3-氯苄基)-1H-吡啶-2-酮(2):在0℃下,在惰性气氛下将4-氯苄基氯(4.44mmol)在THF(10mL)中的溶液逐滴加入3-(叔丁基二甲基硅氧基)-1H-吡啶-2-酮,1,(1g,4,44mmol)和CsCO3(2.17g,6.66mmol)在THF(10mL)的溶液中。使所述反应溶液升至室温,并继续搅拌过夜。将所得到的溶液用水(40mL)稀释,然后以EtOAc(3×30mL)萃取。将合并的有机相用盐水(30mL)洗涤然后经Na2SO4干燥。在减压下除去溶剂,经二氧化硅(EtOAc:庚烷4:1)纯化粗产物,得到白色固体的所需产品。
制备1-(4-氯苄基)-3-羟基吡啶-2(1H)-酮(3):在室温下,向3-(叔丁基二甲基硅氧基)-1-(3-氯苄基)-1H-吡啶-2-酮,2,(2.36g,10mmol)在EtOAc(25mL)中的溶液中在剧烈搅拌下加入5M HCl(25mL)。对所述反应通过TLC监测原料的消失,并在30分钟内完成反应。将有机层倒出,以二氯甲烷(2×50mL)萃取水相。将合并的有机相经Na2SO4干燥并在减压下除去溶剂。从二氯甲烷重结晶粗产物。产率几乎是定量的。
1H NMR(360MHz,DMSO-d6)δppm 5.12(2H,s);6.13(1H,t,J=7.04);6.71(1H,dd,J=7.04,1.59);7.23-7.28(2H,m);7.36-7.43(2H,m);9.10(1H,br.s).
制备{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯(4):将哌嗪-1-甲酸叔丁酯(97.6mmol)、甲醛(8mL 37%溶液(soln.),97.6mmol)和乙酸(8mL)溶解于乙醇(350mL)中并在室温下将所述溶液搅拌1小时。经30分钟将1-(4-氯苄基)-3-羟基吡啶-2(1H)-酮,3,(48.8mmol)在乙醇(350mL)中的溶液逐滴加入。在搅拌3天后,加入甲醛(3mL)并将所述反应物加热至50℃,然后在减压下浓缩所述反应溶液至大约500mL。通过从乙醇中结晶得到所需的产物。
1H NMR(250MHz,CDCl3)d ppm 1.46(s,9H);
2.38-2.57(m,4H);3.40-3.49(m,4H);3.51(s,2H);5.13(s,2H);6.13(d,J=7.16Hz),1H);
6.79(d,J=7.16Hz,1H);7.20-7.41(m,4H);8.33-8.85(m,1H).
所公开的生物学数据涉及A41。
所公开的脯氨酰羟化酶抑制剂的类别II涉及具有下式的化合物:
其中A为具有2-20个碳原子和1-7个杂原子的取代或未取代的杂环或杂芳基环,R200表示0-40个氢的取代基。表II提供了该类别化合物的代表性实例。
表II
编号 | A环 |
B1 | 吡咯烷-1-基 |
B2 | 3-羟基吡咯烷-1-基 |
B3 | 2-(吡啶-2-基)吡咯烷-1-基 |
B4 | 2-甲基羧基吡咯烷-1-基 |
B5 | 2-(甲氧甲基)吡咯烷-1-基 |
B6 | 噻唑烷-3-基 |
B7 | 1H-咪唑-1-基 |
B8 | 哌啶-1-基 |
B9 | 4-苄基哌啶-1-基 |
B10 | 1,4’-联哌啶基-1’-基 |
B11 | 哌嗪-1-基 |
B12 | 4-苄基哌嗪-1-基 |
B13 | 4-(2-甲氧苯基)哌嗪-1-基甲基 |
B14 | 4-(6-氯哒嗪-3-基)哌嗪-1-基 |
B15 | 1,4-二氧杂-8-氮杂螺[4,5]癸-8-基 |
编号 | A环 |
B16 | 吗啉-4-基 |
B17 | 硫代吗啉-4-基 |
B18 | 氮杂环庚-1-基 |
B19 | 氮杂环辛-1-基 |
B20 | 3,4-二氢喹啉-1(2H)-基 |
类别II的化合物可以依照路线I中列出且在实施例1中公开的步骤制备。以下是类别II的抑制剂的另外的实例。
1-苄基-3-羟基-4-(哌啶-1-基甲基)吡啶-2(1H)-酮:
1H NMR (300MHz,CD3OD)δ1.81(m,6H),3.07(m,2H),3.51(m,2H),4.23(s,2H),5.24(s,2H),6.31(d,J=6.9Hz,1H),7.35(m,6H);19F NMR(252MHz,CD3OD)δ85.5;13C NMR(75MHz,DMSO)δ21.3,22.7,51.8,52.5,53.1,106.4,117.4,127.7,128.0,128.2,128.9,137.3,147.4,158.0;ES MS(M+1)299.12;HRMS Calcd.For C18H22N2O2,298.38.Found(M+1)299.17.
1-苄基-3-羟基-4-(吗啉-4-基甲基)吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ3.25(m,4H),3.81(m,4H),4.18(s,2H),5.17(s,2H),6.31(d,J=6.9Hz,1H),7.35(m,6H);19FNMR(300MHz,DMSO)δ88.5;13C NMR(300MHz,DMSO)δ51.6,51.8,53.4,63.5,107.9,119.1,127.8,128.0,128.2,128.9,137.3,147.5,158.3;ESMS(M+1)301.12;HRMS Calcd.For C17H20N2O3,300.35.
1-苄基-3-羟基-4-(硫代吗啉-4-基甲基)吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ2.92(m,4H),3.38(m,4H),4.17(s,2H),5.16(s,2H),6.29(d,J=7.5Hz,1H),7.34(m,6H),9.97(s,1H);19F NMR(300MHz,DMSO)δ88.4;13CNMR(75MHz,DMSO)δ24.3,51.9,53.4,53.7,107.9,110.9,127.8,128.0,128.2,128.8,137.2,147.6,157.6;ES MS(M+1)317.14;HRMS Calcd.For C17H20N2O2S,316.42.Found:(M+1)317.13.
1-苄基-3-羟基-4-(噻唑烷-3-基甲基)吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ3.09(t,J=6.3Hz,2H),3.42(t,J=6.3Hz,2H),4.03(s,2H),4.29(s,2H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H),10.48(broad s,1H);19FNMR(300MHz,DMSO)δ87.9;13CNMR(75MHz,DMSO)δ28.3,48.3,50.1,56.3,57.0,107.4,122.1,127.8,128.2,128.8,137.4,146.3,157.6;ES MS(M+1)303.08;Anal.Calcd forC18H19N2O4SF,C,51.92;H,4.60;N,6.73;S,7.70.Found:C,51.67;H,4.48;N,6.69;S,7.65.
1-苄基-3-羟基-4-(吡咯烷-1-基甲基)吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.96(s,4H),3.16(s,2H),3.43(s,2H),4.23(s,4H),5.17(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H);19F NMR(252MHz,DMSO)δ88.7;13C NMR(75MHz,DMSO)δ22.8,50.9,51.8,53.7,107.3,118.0,128.0,128.2,128.9,137.3,146.7,157.6;ESMS(M+1)285.13;Anal.Calcd.For C19H21F3N2O4,C,57.28;H,5.31;N,7.03.Found:C,57.10;H,5.11,N,7.02.
1-苄基-3-羟基-4-(4-苄基哌啶-1-基甲基)吡啶-2(1H)-酮:
1HNMR(DMSO)δ1.43(m,2H),1.72(m,4H),2.96(m,2H),3.41(m,3H),4.09(s,2H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.35(m,11H);19F NMR(252MHz,DMSO)δ88.8;13CNMR(75MHz,DMSO)δ;ES MS(M+1)389.21;HRMS Calcd.For C25H28N2O2,388.50.Found(M+1)389.22.
1-苄基-3-羟基-4-(4-苄基哌嗪-1-基甲基)吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ3.11(broad s,4H),3.81(s,2H),4.18(s,2H),5.15(s,2H),6.24(d,J=7.2Hz,1H),7.34(m,6H),7.46(m,5H);19F NMR(252MHz,DMSO)δ88.2;13C(75MHz,DMSO)δ;ES MS(M+1)390.21;HRMS Calcd.For C24H27N3O2,389.49.Found(M+1)390.21.
1-苄基-3-羟基-4-[(3-羟基吡咯烷-1-基)甲基]吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ1.90(m,1H),3.18(m,2H),3.47(m,3H),4.24(s,2H),4.43(s,1H),5.17(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H);19F NMR(252MHz,DMSO)δ89.0;13C NMR(75MHz,DMSO)δ51.8,52.6,61.3,68.6,107.4,117.9,128.0,128.2,128.9,137.3,146.7,157.6;ES MS(M+1)301.13;HRMS Calcd.For C17H20N2O3,300.35.Found:(M+1)301.15.
1-苄基-3-羟基-4-(1,4-二氧杂-8-氮杂螺[4,5]癸-8-基甲基)吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.90(m,4H),3.11(m,2H),3.43(m,2H),3.93(s,4H),4.19(s,2H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H),10.01(broad s,1H);19FNMR(252MHz,DMSO)δ88.3;13C NMR(75MHz,DMSO)δ31.7,50.7,51.9,52.5,64.5,101.1,108.0,116.5,127.8,128.0,128.3,128.9,137.3,147.5 157.6;ES MS(M+1)357.19;HRMS Calcd.For C20H24N4O2,356.42.Found(M+1)357.18.
1-苄基-3-羟基-4-氮杂环庚-1-基甲基吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.61(m,4H),1.80(m,4H),3.20(m,4H),4.17(s,2H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H);19F NMR(252MHz,DMSO)δ88.9;13C NMR(75MHz,DMSO)δ22.8,26.4,51.8,53.4,54.4,107.6,117.2,127.9,128.0,18.2,128.9,137.3,147.2,157.6;ES MS(M+1)313.18;HRMS Calcd.For C19H24N2O4,312.41.Found(M+1)313.19.
1-苄基-3-羟基-4-(氮杂环辛-1-基甲基)吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.59(m,10H),3.18(m,2H),3.38(m,2H),4.17(s,2H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H);19F NMR(252MHz,DMSO)δ88.9;13C NMR(75MHz,DMSO)δ;ES MS(M+1)327.2;HRMS Calcd.For C20H26N2O2,326.43.Found(M+1)327.20.
1-苄基-3-羟基-(1,4’-联哌啶基-1’-基甲基)吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ1.43-1.98(m,10H),2.21(m,2H),3.01(m,4H),3.43(m,3H),4.12(s,2H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H),9.85(broad s,1H);19FNMR(252MHz,DMSO)δ88.7;13C NMR(75MHz,DMSO)δ21.6,22.9,23.8,49.6,50.5,51.8,53.0,59.5,108.0,127.8,128.0,128.2,128.9,137.3,147.5,157.6;ES MS(M+1)382.4;HRMS Calcd.For C23H31N3O2,383.51.Found(M+1)382.25.
1-苄基-3-羟基-4-[(3,4-二氢喹啉-1(2H)-基)甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ3.13(t,J=6.3Hz,2H),3.52(m,2H),4.28(s,2H),4.41(s,2H),5.18(s,2H),6.34(d,J=7.2Hz,1H),7.23-7.41(m,10H),10.15(broad s,1H);19F NMR(252MHz,DMSO)δ88.9;13C NMR(75MHz,DMSO)δ25.4;49.3,51.8,52.7,52.9,107.6,11.6,116.8,126.9,127.0,127.9,128.0,128.1,128.2,128.8,128.9,131.7,137.3,147.3,157.6;ES MS(M+1)347.40;HRMS Calcd.For C22H22N2O2,346.42.Found(M+1)347.17.
1-[(1-苄基-3-羟基-2-氧代-1,2-二氢吡啶-4-基)甲基]吡咯烷-2-甲酸甲酯:
1H NMR(300MHz,DMSO)δ2.01(m,3H),2.45(m,1H),3.26(m,1H),3.53(m,1H),3.69(s,3H),4.30(m,3H),5.17(s,2H),6.27(d,6.9Hz,1H),7.35(m,6H),19F NMR(252MHz,DMSO)δ88.3;13C NMR(75MHz,DMSO)δ;ES MS(M+1)343.20;HRMS Calcd.For C19H22N2O4,342.39.Found(M+1)
1-苄基-3-羟基-4-{[2-(甲氧甲基)吡咯烷-1-基]甲基}吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.71(m,1H),1.84(m,1H),1.99(m,1H),2.15(m,1H),3.19(m,1H),3.30(s,3H),3.41(m,1H),3.62(m,2H),3.77(m,1H),4.15(m,1H),4.39(m,1H),5.17(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H);9.60(broad s,1H);19F NMR (252MHz,DMSO)δ88.3;13C NMR (75MHz,DMSO)δ;ES MS(M+1)329.2;HRMS Calcd.For C19H24N2O3,328.41.Found (M+1)
1-苄基-3-羟基-4-{[2-(吡啶-2-基)吡咯烷-1-基]甲基}吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ2.12(m,4H),3.39(m,1H),3.63(m,1H),4.07(m,2H),4.60(m,.1H),5.10(m,2H),6.15(d,J=6.9Hz,1H),7.33(m,6H),7.44(m,1H),8.05(d,J=8.1Hz,1H),8.59(d,J=4.8Hz,1H),8.74(s,1H);19F NMR(252MHz,DMSO)δ88.0;ES MS(M+1)362.22;HRMS Calcd.For C22H23N3O2,361.44.Found(M+1).
1-苄基-3-羟基-4-[4-(6-氯哒嗪-3-基)哌嗪-1-基甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ3.18(m,2H),3.48(m,4H),4.19(s,2H),4.4(m,2H),5.16(s,2H),6.62(d,J=7.2Hz,1H),7.35(m,6H),7.48(m,1H),7.68(m,1H)11.5(broad s,1H);13C NMR(75MHz,DMSO)δ42.1,50.3,51.9,52.5,108.2,116.2;118.0,128.0,128.2,128.9,129.8,137.3,147.4,.157.6,158.8;ES MS(M+1)476.09.HRMS Calcd.For C21H22ClN5N3O2,411.88.Found(M+1)412.76.
1-苄基-3-羟基-4-[4-(2-甲氧苯基)哌嗪-1-基甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ2.95(m,2H),3.30(m,2H),3.48(m,4H),3.80(s,3H),4.25(s,2H),5.18(s,2H),6.34(d,J=7.2Hz,1H),6.93(m,2H),7.01(m,2H),7.34(m,6H);19F NMR(252MHz,DMSO)δ88.5;13C NMR(75MHz,DMSO)δ47.2,51.8,53.0,55.3,108.1,112.2,114.8,116.2,118.6,121.2,123.8,127.8,128.0,128.9,137.3,139.6,147.5,152.2,157.6;ES MS(M+1)405.82;HRMS Calcd.For C24H27N3O3,405.49.Found (M+1)406.21.
注:在上述化合物图谱数据中,Calcd.For指计算值,Found指观察到的值,即实测值,broad指宽峰。
所公开的脯氨酰羟化酶抑制剂的类别III涉及具有下式的化合物:
R1和R2彼此独立地为氢或者取代或未取代的C1-C10直链或支链烷基,其中所述烷基单元可以被独立选自如下的一个或多个单元取代:
i)C1-C8直链、C3-C8支链或C3-C8环状烷氧基;
ii)羟基;
iii)卤素;
iv)氰基;
v)氨基、C1-C8单-烷基氨基、C1-C8二-烷基氨基;
vi)–SR40;R40为氢或C1-C4直链或C3-C4支链烷基;
vii)取代或未取代的C6或C10芳基;
viii)取代或未取代的C1-C9杂环;或
ix)取代或未取代的C1-C9杂芳基。
如下表III提供了该类别包含的化合物的非限制性实例。
表III
编号 | R1 | R2 |
C1 | 苄基 | 氢 |
C2 | 4-甲氧苄基 | 氢 |
C3 | 4-氟苄基 | 氢 |
C4 | 4-氯苄基 | 氢 |
C5 | 4-甲基苄基 | 氢 |
C6 | 2-(吡啶-2-基)乙基 | 氢 |
C7 | [1,3]二氧戊环-2-基甲基 | 氢 |
C8 | 四氢呋喃-2-基甲基 | 氢 |
C9 | 2-甲氧乙基 | 氢 |
C10 | 1-羟基-2-甲基丙-2-基 | 氢 |
C11 | 吡啶-4-基甲基 | 氢 |
编号 | R1 | R2 |
C12 | 呋喃-2-基甲基 | 氢 |
C13 | 2-(甲基硫)乙基 | 氢 |
C14 | 1-苯乙基 | 氢 |
C15 | 3-咪唑-1-基丙基 | 氢 |
C16 | 环庚基 | 氢 |
C17 | 4-甲基环己基 | 氢 |
C18 | 1-苄基哌啶-4-基 | 氢 |
C19 | 氮杂环庚-2-酮-3-基 | 氢 |
C20 | 1-苄基吡咯烷-3-基 | 氢 |
C21 | 苄基 | 甲基 |
C22 | 4-甲氧苄基 | 甲基 |
C23 | 4-氟苄基 | 甲基 |
C24 | 4-氯苄基 | 甲基 |
C25 | 4-甲基苄基 | 甲基 |
C26 | 2-(吡啶-2-基)乙基 | 甲基 |
C27 | [1,3]二氧戊环-2-基甲基 | 甲基 |
C28 | 四氢呋喃-2-基甲基 | 甲基 |
C29 | 2-甲氧乙基 | 甲基 |
C30 | 1-羟基-2-甲基丙-2-基 | 甲基 |
C31 | 吡啶-4-基甲基 | 甲基 |
C32 | 呋喃-2-基甲基 | 甲基 |
C33 | 2-(甲基硫)乙基 | 甲基 |
C34 | 1-苯乙基 | 甲基 |
C35 | 3-(1H-咪唑-1-基)丙基 | 甲基 |
C36 | 环庚基 | 甲基 |
C37 | 4-甲基环己基 | 甲基 |
C38 | 1-苄基哌啶-4-基 | 甲基 |
C39 | 氮杂环庚-2-酮-3-基 | 甲基 |
C40 | 1-苄基吡咯烷-3-基 | 甲基 |
所公开的该类别的化合物可以通过下文路线II中列出且在实施例2中描述的步骤制备。
路线II
试剂和条件:(a)(i)HCHO,EtOH;0.5小时(ii)3-(1-H-咪唑-1-基)丙-1-胺;2小时。
实施例2
1-苄基-3-羟基-4-{[3-(1-H-咪唑-1-基)丙基氨基]甲基}吡啶-2(1H)-酮(6)
N-苄基-3-羟基吡啶-2(1H)-酮(5)可以依照实施例1通过将苄基溴或苄基氯替代步骤(b)中的(4-氯)苄基氯而制备。
1-苄基-3-羟基-4-{[3-(1-H-咪唑-1-基)丙基氨基]甲基}吡啶-2(1H)-酮(6):将N-苄基-3-羟基吡啶-2(1H)-酮(5)(250mg,1.23mmol)和甲醛(200mg,273eq.)在乙醇水溶液(10mL)中合并搅拌30分钟。然后加入3-(1-H-咪唑-1-基)丙-1-胺(340mg,2.7mmol)并搅拌所述反应物持续12小时。通过蒸发除去溶剂,将残留物溶解于甲醇(2mL)中并经制备型HPLC以水/乙腈洗脱进行纯化,得到三氟乙酸盐形式的所需产物。
1H NMR(300MHz,DMSO)δ2.19(m,2H),2.97(m,2H),4.02(s,2H),4.30(t,J=6.6Hz,2H);5.17(s,2H),6.30(d,J=6.9Hz,1H),7.36(m,6H),7.26(s,1H),7.76(s,1H),9.03(s,1H),9.11(s,1H);19F NMR(252MHz,DMSO)δ88.5;13C NMR(75MHz,DMSO)δ26.5,44.0,46.0,51.8,106.8,118.7,120.5,122.2,127.9,128.2,128.9,135.8,137.4,146.0,158.2;ES MS(M+1)339.05;HRMSCalcd.For C19H22N4O2,338.44.Found(M+1)339.18.
以下是该方面所公开HIF-1α脯氨酰羟化酶抑制剂的另外的非限制性实例。
1-苄基-3-羟基-4-(苄基氨基甲基)吡啶-2(1H)-酮:
1HNMR (300MHz,DMSO)δ4.01(s,2H),4.20(s,2H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.36(m,11H),9.16(broad s,1H);19FNMR(252MHz,DMSO)δ88.6;13C NMR(75MHz,DMSO)δ;ES MS(M+1)321.16;Anal.Calcd.For C22H21F3N2O4,C,60.83;H,4.87;N,6.45.Found:C,60.75;H,4.56;N,6.34.
1-苄基-3-羟基-4-{[(2-(吡啶-2-基)乙氨基]甲基}吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ3.26(m,2H),3.37(m,2H),4.08(s,2H),5.17(s,2H);6.34(d,J=7.2Hz,1H),7.38(m,6H),7.86(d,J=5.7Hz,2H),8.84(m,2H),9.32(broad s,1H);19FNMR(252MHz,DMSO)δ88.6;13C NMR(75MHz,DMSO)δ31.5,44.1,46.3,51.8,106.9,114.8,127.1,128.1,128.8,137.4,143.8,146.1,155.3,157.5,158.4;ES MS(M+1)336.18;HRMS Calcd For C20H21N3O2,335.40.Found:336.16.
1-苄基-3-羟基-4-{[(四氢呋喃-2-基甲基)氨基]甲基}吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.56(m,1H),1.86(m,2H),1.99(m,1H),2.92(m,1H),3.05(m,1H),3.80(m,2H),4.09(m,3H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H);8.91(broad s,1H);19F NMR(252MHz,DMSO)δ88.5;13C NMR(75MHz,DMSO)δ;ES MS(M+1)315.16;HRMS.Calcd.For C18H22N2O3,314.38.Found(M+1)315.16.
1-苄基-3-羟基-4-[(2-甲氧乙氨基)甲基]吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ3.13(broad s,2H),3.30(s,3H),3.59(t,J=5.4Hz,2H),4.02(s,2H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H),8.91(broad s,1H);19F NMR(252MHz,DMSO)δ88.4;13C NMR(252MHz,DMSO)δ;ES MS(M+1)289.13;HRMSCalcd.For C16H20N2O3,288.34.Found(M+1)289.15.
1-苄基-3-羟基-4-[(1-羟基-2-甲基丙-2-基氨基)甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.27(s,6H),3.49(s,2H),3.95(s,2H),5.17(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H),8.47(broad s,2H),9.94(broad s,1H);19FNMR(252MHz,DMSO)δ88.7;13C NMR(75MHz,DMSO)δ;ES MS(M+1)303.19;HRMS Calcd.For C17H22N2O3,302.37.Found(M+1)303.17.
1-苄基-3-羟基-4-[(吡啶-4-基甲基氨基)甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ4.07(s,2H),4.32(s,2H),5,16(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H);7.62(d,J=5.7Hz,2H),8.71(d,J=4.5Hz,2H);19F NMR(252MHz,DMSO)δ88.0;13C NMR(75MHz,DMSO)δ;ES MS(M+1)322.17;HRMS Calcd.ForC19H19N3O2,321.37.Found(M+1)322.15.
1-苄基-3-羟基4-{[(呋喃-2-基甲基)氨基]甲基}吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ4.00(s,2H),4.28(s,2H),5.16(s,2H),6.27(d,J=6.9Hz,1H),6.54(m,1H),6.65(m,1H),7.34(m,6H),7.80(m,1H),9.27(broad s,1H);19F NMR(252MHz,DMSO)δ88.3;13C NMR(75MHz,DMSO)δ;ES MS(M+1)323.15;HRMSCalcd.For C18H18N2O3,310.35.Found(M+1)
1-苄基-3-羟基-4-{[2-(甲基硫)乙氨基]甲基}吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ2.10(s,3H),2.74(t,J=6.9Hz,2H),3.16(t,J=8.1Hz,2H),4.05(s,2H),5.17(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H),19F NMR(252MHz,DMSO)δ89.0;ES MS(M+1)305.14,HRMS Calcd.For C16H20N2O2S,304.41.Found(M+1)
1-苄基-3-羟基-4-[(4-甲氧苄基氨基)甲基]吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ3.70(s,3H),3.98(s,2H),4.13(s,2H),5.16(s,2H),6.28(d,J=7.5Hz,1H),7.00(d,J=9.0Hz,4H),7.34(m,6H);9.07(broad s,1H);19F NMR(252MHz,DMSO)δ89.0;ES MS(M+1)351.10;HRMS Calcd.For C21H22N2O3,350.41.Found(M+1)351.17.
1-苄基-3-羟基-4-[(1-苯乙氨基)甲基]吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ1.59(d,J=7.2Hz,3H),3.71-3.93(m,2H),4.45(m,1H),5.15(s,2H),6.28(d,J=7.5Hz,1H),7.34(m,11H);19F NMR(252MHz,DMSO)δ88.9;13CNMR(75MHz,DMSO)δ19.6,42.5,51.7,58.0,106.8,119.3,128.0,128.1,128.2,128.9,129.3,129.4,137.3,145.9,158.3;ES MS(M+1)335.13;HRMS Calcd.For C21H22N2O2,334.41.Found(M+1)335.17.
1-苄基-3-羟基-4-(环庚基氨基甲基)吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ1.55(m,10H),2.03(m,2H),3.18(s,1H),3.99(m,2H),5.17(s,2H),6.32(d,J=6.9Hz,1H),7.35(m,6H),8.65(broad s,2H),9.98(broad s,1H);19F NMR(252MHz,DMSO)δ88.6;13C NMR(75MHz,DMSO)δ23.0,27.2,30.4,41.6,51.7,58.9,107.0,111.7,127.9,128.0,128.2,128.8,137.4,146.0,157.5;ES MS(M+1)327.13;HRMSCalcd.For C20H26N2O2,326.43.Found(M+1)327.20.
1-苄基-3-羟基-4-[(4-甲基环己基氨基)甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ0.93(d,J=6.9Hz,3H),1.38(m,4H),1.74(m,4H),2.05(m,1H),3.10(m,1H),4.01(s,2H),5.17(s,2H),6.31(m,1H),7.34(m,6H),8.05(broad s,2H),9.98(broad s,1H);19F NMR(252MHz,DMSO)δ88.9;ES MS(M+1)327.14;HRMSCalcd.For C20H26N2O2,326.43;Found(M+1)372.20.
1-苄基-3-羟基-4-[(1-苄基哌啶-4-基氨基)甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.77(m,2H),2.31(m,2H),2.98(m,2H),3.30(m,3H),3.46(m,2H),4.03(s,2H),.29(s,2H),5.16(s,2H),6.30(d,J=7.5Hz,1H),7.34(m,6H),7.49(s,5H),9.12(broad s,1H),10.05(broad s,1H);19F NMR(252MHz,DMSO)δ88.8;13C NMR(75MHz,DMSO)δ27.1,43.4,51.8,52.1,54.2,54.7,57.6,106.9,118.5,128.0,128.1,128.8,129.3,129.8,130.7,131.3,137.3,146.2,157.4;ES MS(M+1)404.56;HRMS Calcd.For C25H28N3O2,403.52.Found (M+1)404.23.
3-[(1-苄基-3-羟基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基]氮杂环庚-2-酮:
1H NMR(300MHz,DMSO)δ1.25(m,1H),1.59(m,2H),1.74(m,1H),1.92(m,1H),2.10(m,1H),3.18(m,3H),4.03(s,2H),4.2(m,1H),5.17(s,2H),6.33(d,J=7.5Hz,1H),7.34(m,6H),8.31(t,J=5.4Hz,1H),9.07(broad s,2H),9.90(broad s,1H);19F NMR(252MHz,DMSO)δ88.4;13C NMR(75MHz,DMSO)δ27.0,27.2,28.4,43.4,51.7,59.3,107.1,118.9,127.8,127.9,128.1,128.9,137.4,146.0,157.5,166.3;ES MS(M+1)342.01;HRMS Calcd.For C19H23N3O3,341.40.Found(M+1)342.18.
1-苄基-3-羟基-4-[(1-苄基吡咯烷-3-基氨基)甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ2.22(m,2H),2.42(m,1H),3.39(m,3H),3.68(m,1H),4.06(s,2H),4.39(s,2H),5.17(s,2H),6.33(d,J=7.5Hz,1H),7.30-7.52(m,11H);19F NMR (252MHz,DMSO)δ88.5;13C NMR (75MHz,DMSO)δ27.1,43.4,51.8,52.1,54.2,54.7,57.5,106.9,118.5,128.0,128.8,129.3,129.8,130.7,131.3,137.3,146.2,157.5;ES MS(M+1)390.14;HRMS Calcd.For C24H27N3O2,389.49.Found(M+1)390.21.
(R)-1-苄基-3-羟基-4-[(1-苯乙氨基)甲基]吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ1.58(d,J=6.9Hz,3H),3.74(m,2H),4.44(m,1H),5.14(s,2H),6.23(d,J=7.2Hz,1H),7.35(m,6H);19F NMR(252MHz,DMSO)δ89.4;13C NMR(75MHz,DMSO)δ19.6,42.6,51.7,58.0,106.9,18.7,128.0,128.1,128.8,129.3,129.4,137.2,137.4,145.9,157.5;ES MS(M+1)335.13;Anal.Calcd.For C21H22N2O2,334.41.Found(M+1)335.31.
1-苄基-3-羟基-4-[([1,3]二氧戊环-2-基甲基甲基氨基)甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ2.81(s,3H),3.35(d,J=3.9Hz,2H),3.89(m,2H),4.01(m,2H),4.21(m,2H),5.17(s,2H);5.27(t,J=3.9Hz,1H),6.34(d,J=7.2Hz,1H),7.35(m,6H);19F NMR(252MHz,DMSO)δ88.5;13C NMR(75MHz,DMSO)δ;ES MS(M+1)331.18;HRMS Calcd.For C18H22N2O4,330.38.Found(M+1)331.16.
注:在上述化合物图谱数据中,Calcd.For指计算值,Anal.Calcd.For指分析计算值,Found指观察到的值,即实测值,broad指宽峰。
所公开的脯氨酰羟化酶抑制剂的类别IV涉及具有下式的化合物:
其中A代表任选被一个或多个R200单元取代的环。表IV提供了该类别的非限制性实例。
表IV
编号 | A环 |
D1 | 吡咯烷-1-基 |
D2 | 3-羟基吡咯烷-1-基 |
D3 | 2-(吡啶-2-基)吡咯烷-1-基 |
D4 | 2-甲基羧基吡咯烷-1-基 |
D5 | 2-(甲氧甲基)吡咯烷-1-基 |
D6 | 噻唑烷-3-基 |
D7 | 1H-咪唑-1-基 |
D8 | 哌啶-1-基 |
D9 | 4-苄基哌啶-1-基 |
D10 | 1,4’-联哌啶基-1’-基 |
D11 | 哌嗪-1-基 |
D12 | 4-苄基哌嗪-1-基 |
D13 | 4-(2-甲氧苯基)哌嗪-1-基甲基 |
D14 | 4-(6-氯哒嗪-3-基)哌嗪-1-基 |
D15 | 1,4-二氧杂-8-氮杂螺[4,5]癸-8-基 |
D16 | 吗啉-4-基 |
D17 | 硫代吗啉-4-基 |
D18 | 氮杂环庚-1-基 |
D19 | 氮杂环辛-1-基 |
D20 | 3,4-二氢喹啉-1(2H)-基 |
所公开的该类别的化合物可以通过下文路线III中列出且在实施例3中描述的步骤制备。
路线III
试剂和条件:(a)(i)n-BuLi,TsCl,THF;-78℃至室温,1小时;
(ii)HCl,MeOH;室温,1小时。
试剂和条件:(b)吡咯烷,HCHO,H2O/EtOH;室温,12小时。
实施例3
1-(4’-甲基苯磺酰基)-3-羟基-4-(吡咯烷-1-基甲基)吡啶-2(1H)-酮(8)
1-(4’-甲基苯磺酰基)-3-羟基吡啶-2(1H)-酮(7):向在干燥氮气气氛下保持于-78℃下的3-[(叔丁基二甲基硅基)氧基]吡啶-2(1H)-酮(1)(4.66g,20.7mmol)在干燥THF(150mL)中的搅拌溶液中加入正丁基锂(1.6M的己烷溶液,21.0mmol)。在20分钟后,4-甲基-苯磺酰氯(3.95g,20.7mmol)作为THF溶液加入。使所述溶液经一小时升温至室温,加入水(10mL),将所述反应容器的内含物以EtOAc(3x)萃取,用盐水(1x)洗涤,经Na2SO4干燥并浓缩。将合并的有机相经Na2SO4干燥并浓缩。将残留物溶解在在乙醇(10mL)中,并以浓HCl(2mL)处理。将所述混合物搅拌1小时,在减压下除去溶剂,得到白色固体形式的所需化合物。
1H NMR(300MHz,DMSO)δ2.43(s,3H),6.14(t,J=6.9Hz,1H),6.76(dd,J=7.65Hz,1.5Hz,1H),7.18(dd,J=6.6Hz,1.8Hz,1H),7.32(d,J=7.3Hz,2H),7.98(d,J=7.9Hz,2H).
1-(4’-甲基苯磺酰基)-3-羟基-4-(吡咯烷-1-基甲基)吡啶-2(1H)-酮(8):将1-(4’-甲基苯磺酰基)-3-羟基吡啶-2(1H)-酮(7)(250mg,0.94mmol)和甲醛(200mg,2.07mmol)在乙醇水溶液(10mL)中合并,并搅拌30分钟。然后加入吡咯烷(149mg,2.07mmol)并将所述反应物搅拌12小时。通过蒸发除去溶剂,将残留物溶解于甲醇(5mL)中,经制备型HPLC以水/乙腈洗脱进行纯化,得到所需产物。
1H NMR(300MHz,DMSO)δ1.87(m,2H),1.99(m,2H),2.44(s,3H),3.09(m,2H),3.40(m,2H),4.19(s,2H),6.51(d,J=7.5Hz,1H),7.51(d,J=8.4Hz,1H),7.76(d,J=7.5Hz,1H),7.98(d,J=8.1Hz,1H),9.93(broad s,1H);19F NMR(252MHz,DMSO)δ88.4;13C NMR(75MHz,DMSO)δ21.5,22.7,50.5,53.7,108.7,118.6,119.4,128.4,129.7,130.1,133.1,146.8,147.7,156.2;ES MS(M+1)349.25;HRMSCalcd.For C17H20N2O4S,348.42.Found(M+1)349.42.
以下是该类别脯氨酰羟化酶抑制剂的另外的非限制性实例。
1-(4’-甲基苯磺酰基)-3-羟基-4-噻唑烷-3-基甲基吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ2.43(s,3H),2.94(t,J=6.6MHz,2H),3.18(t,J=6.0Hz,2H),3.66(s,2H),4.12(s,2H),6.51(d,J=7.5Hz,1H),7.51(d,J=8.4Hz,1H),7.76(d,J=7.5Hz,1H),7.98(d,J=8.1Hz,1H),19F NMR(252MHz,DMSO)δ87.9;13C NMR(75MHz,DMSO)δ21.5,21.9,24.6,25.8,50.3,51.6,108.7,118.6,120.8,129.7,130.1,133.1,146.9,148.1,156.1,158.4,158.8;ES MS(M+1)367.18;HRMS Calcd.For C16H18N2O4S2,366.46.Found(M+1)367.43.
1-(4’-甲基苯磺酰基)-3-羟基-4-氮杂环辛-1-基甲基吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.59(m,10H),2.44(s,3H),3.17(m,2H),3.32(m,2H),4.15(s,2H),6.51(d,J=7.5Hz,1H),7.51(d,J=8.4Hz,1H),7.76(d,J=7.5Hz,1H),7.98(d,J=8.1Hz);19F NMR(252MHz,DMSO)δ88.7;13C NMR(75MHz,DMSO)δ21.5,21.9,23.7,24.6,25.8,50.3,51.6,108.7,118.9,120.8,129.8,130.1,133.1,146.9,148.2,156.1;ES MS(M+1)391.18;HRMS Calcd.For C20H26N2O4S,390.18.Found(M+1)391.23.
1-(4’-甲基苯磺酰基)-3-羟基-4-(4-苯基哌嗪-1-基甲基)吡啶-2(1H)-酮:
1H NMR(300MHz,.DMSO)δ2.43(s,3H),3.13(m,8H),3.43(s,2H),6.47(d,J=7.5Hz,1H),6.78(t,J=7.2Hz,1H),7.219m,2H),7.50(d,J=8.1Hz,2H),7.67(d,J=7.8Hz,1H),7.97(d,J=8.4Hz,2H);13C NMR(75MHz,DMSO)δ21.5,42.6,45.6,46.2,50.8,51.9,109.6,116.4,116.8,117.7,120.6,121.1,129.5,129.6,129.8,130.1,133.2,146.8,149.5,156.1;ES MS(M+1)440.15;HRMS Calcd.For C23H25N3O5S,439.53.Found (M+1)440.16.
1-(4’-甲基苯磺酰基)-3-羟基-4-[1,4’]联哌啶基-1’-基甲基吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.43(m,1h),1.67(m,2H),1.82(m,4H),2.19(m,2H),2.44(s,3H),2.94(m,4H),3.39(m,2H),3.54(m,3H),4.06(s,2H),6.47(d,J=8.1Hz,1H),7.51(d,J=8.1Hz,2H),7.73(d,7.8Hz,1H),7.99(d,J=8.4Hz,2H);19F NMR(252MHz,DMSO)δ88.7;13C NMR(75MHz,DMSO)δ21.4,22.9,23.6,48.4,49.5,59.4,109.3,114.8,117.6,120.5,122.7,129.7,130.1,133.1,146.9,148.6,156.2;ES MS(M+1)446.19;HRMS Calcd.For C23H31N3O4S,445.58.Found(M+1)446.21.
1-(4’-甲基苯磺酰基)-3-羟基-4-[4-(6-氯哒嗪-3-基)哌嗪-1-基甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ2.44(s,3H),3.17(m,2H),3.46(m,4H),4.17(s,2H),4.45(m,2H),6.77(d,J=7.8Hz,1H),7.04(m,1H),7.53(m 2H),7.68(m,2H),7.98(m,2H),11.3(broad s,1H),ES MS(M+1)476.92.HRMS Calcd.For C21H25ClN5O4S,475.95.Found(M+1)476.11.
注:在上述化合物图谱数据中,Calcd.For指计算值,Found指观察到的值,即实测值,broad指宽峰。
HIF-1α脯氨酰羟化酶抑制剂的类别V涉及具有下式的化合物:
R代表1-5个对苯环氢原子的任选取代基,R1和R2彼此独立地为氢或者取代或未取代的C1-C10直链或支链烷基,其中所述烷基单元可以被独立选自如下的一个或多个单元取代:
i)C1-C8直链、C3-C8支链或C3-C8环状烷氧基;
ii)羟基;
iii)卤素;
iv)氰基;
v)氨基、C1-C8单-烷基氨基、C1-C8二-烷基氨基;
vi)–SR40;R40为氢或C1-C4直链或C3-C4支链烷基;
vii)取代或未取代的C6或C10芳基;
viii)取代或未取代的C1-C9杂环;或
ix)取代或未取代的C1-C9杂芳基。
表V提供了该类别HIF-1α脯氨酰羟化酶抑制剂的非限制性实例。
表V
编号 | R | R1 | R2 |
E1 | 4-甲基 | 苄基 | 氢 |
E2 | 4-甲基 | 4-甲氧苄基 | 氢 |
E3 | 4-甲基 | 4-氟苄基 | 氢 |
E4 | 4-甲基 | 4-氯苄基 | 氢 |
编号 | R | R1 | R2 |
E5 | 4-甲基 | 4-甲基苄基 | 氢 |
E6 | 4-甲基 | 2-(吡啶-2-基)乙基 | 氢 |
E7 | 4-甲基 | [1,3]二氧戊环-2-基甲基 | 氢 |
E8 | 4-甲基 | 四氢呋喃-2-基甲基 | 氢 |
E9 | 4-甲基 | 2-甲氧乙基 | 氢 |
E10 | 4-甲基 | 1-羟基-2-甲基丙-2-基 | 氢 |
E11 | 4-甲基 | 吡啶-4-基甲基 | 氢 |
E12 | 4-甲基 | 呋喃-2-基甲基 | 氢 |
E13 | 4-甲基 | 2-(甲基硫)乙基 | 氢 |
E14 | 4-甲基 | 1-苯乙基 | 氢 |
E15 | 4-甲基 | 3-咪唑-1-基丙基 | 氢 |
E16 | 4-甲基 | 环庚基 | 氢 |
E17 | 4-甲基 | 4-甲基环己基 | 氢 |
E18 | 4-甲基 | 1-苄基哌啶-4-基 | 氢 |
E19 | 4-甲基 | 氮杂环庚-2-酮-3-基 | 氢 |
E20 | 4-甲基 | 1-苄基吡咯烷-3-基 | 氢 |
E21 | 4-甲基 | 苄基 | 甲基 |
E22 | 4-甲基 | 4-甲氧基苄基 | 甲基 |
E23 | 4-甲基 | 4-氟苄基 | 甲基 |
E24 | 4-甲基 | 4-氯苄基 | 甲基 |
E25 | 4-甲基 | 4-甲基苄基 | 甲基 |
E26 | 4-甲基 | 2-(吡啶-2-基)乙基 | 甲基 |
E27 | 4-甲基 | [1,3]二氧戊环-2-基甲基 | 甲基 |
E28 | 4-甲基 | 四氢呋喃-2-基甲基 | 甲基 |
E29 | 4-甲基 | 2-甲氧乙基 | 甲基 |
E30 | 4-甲基 | 1-羟基-2-甲基丙-2-基 | 甲基 |
E31 | 4-甲基 | 吡啶-4-基甲基 | 甲基 |
E32 | 4-甲基 | 呋喃-2-基甲基 | 甲基 |
E33 | 4-甲基 | 羧基甲基 | 甲基 |
E34 | 4-甲基 | 2-(甲基硫)乙基 | 甲基 |
编号 | R | R1 | R2 |
E35 | 4-甲基 | 1-苯乙基 | 甲基 |
E36 | 4-甲基 | 3-咪唑-1-基丙基 | 甲基 |
E37 | 4-甲基 | 环庚基 | 甲基 |
E38 | 4-甲基 | 4-甲基环己基 | 甲基 |
E39 | 4-甲基 | 1-苄基哌啶-4-基 | 甲基 |
E40 | 4-甲基 | 氮杂环庚-2-酮-3-基 | 甲基 |
E41 | 4-甲基 | 1-苄基吡咯烷-3-基 | 甲基 |
所公开的该类别的化合物可以通过下文路线IV中列出且在实施例4中描述的步骤制备。
路线IV
试剂和条件:(a)苄基溴,HCHO,H2O/EtOH;室温,12小时。
实施例4
1-(4’-甲基苯磺酰基)-3-羟基-4-[(苄基氨基)甲基]吡啶-2(1H)-酮(9)
1-(4’-甲基苯磺酰基)-3-羟基-4-(苄基氨基甲基)吡啶-2(1H)-酮(9):将1-(4’-甲基苯磺酰基)-3-羟基吡啶-2(1H)-酮(7)(250mg,0.94mmol)和甲醛(200mg,2.07mmol)在乙醇水溶液(10mL)中合并并搅拌30分钟。然后加入苄基胺(229mg,2.07mmol),并将所述反应物搅拌12小时。通过蒸发除去溶剂,将残留物溶解于甲醇(5mL)中,经制备型HPLC以水/乙腈洗脱进行纯化,得到三氟乙酸盐形式的所需产物。
1H NMR(300MHz,DMSO)d 2.44(s,3H),3.96(s,2H),4.16(s,2H),6.69(d,J=8.1Hz),7.40(m,7H),7.52(m,1H),7.73(d,J=8.1Hz,1H),7.97(d,J=8.1Hz,1H),9.71(broad s,2H),10.44(broad s,1H);ES MS(M+1)396.67;HRMS Calcd.For C20H20N2O4S,384.45.Found(M+1)385.12.
以下是该类别HIF-1α脯氨酰羟化酶抑制剂的另外的非限制性实例。
1-(4’-甲基苯磺酰基)-3-羟基-4-[(2-甲氧基乙氨基)甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ2.43(s,3H),3.12(m,2H),3.29(s,3H),3.56(t,J=5.1Hz,2H),3.99(s,2H),6.51(d,J=7.5Hz,1H),7.51(d,J=8.4Hz,1H),7.76(d,J=7.5Hz,1H),7.98(d,J=8.1Hz);19F NMR(252MHz,DMSO)δ88.6;13CNMR(75MHz,DMSO)δ21.5,43.8,46.2,46.5,58.5,67.2,106.7,119.2,120.2,123.9,128.4,129.7,130.1,133.1,146.8,147.0,156.0;ES MS(M+1)353.12.HRMS Calcd.ForC16H20N2O5S,352.41.Found(M+1)353.11.
注:在上述化合物图谱数据中,Calcd.For指计算值,Found指观察到的值,即实测值,broad指宽峰。
HIF-1α脯氨酰羟化酶抑制剂的类别VI涉及具有下式的化合物:
其中L选自CH2或SO2,Z为取代或未取代的苯基。该类别抑制剂的非限制性实例公开于下表VI。
表VI
编号 | L | Z |
F1 | CH2 | 2-氯苯基 |
F2 | CH2 | 3-氯苯基 |
F3 | CH2 | 4-氯苯基 |
F4 | CH2 | 2-氟苯基 |
F5 | CH2 | 3-氟苯基 |
F6 | CH2 | 4-氟苯基 |
F7 | CH2 | 2,3-二氯苯基 |
F8 | CH2 | 2,4-二氯苯基 |
F9 | CH2 | 2,5-二氯苯基 |
F10 | CH2 | 2,6-二氯苯基 |
F11 | CH2 | 3,4-二氯苯基 |
编号 | L | Z |
F12 | CH2 | 3,5-二氯苯基 |
F13 | CH2 | 2,3-二氟苯基 |
F14 | CH2 | 2,4-二氟苯基 |
F15 | CH2 | 2,5-二氟苯基 |
F16 | CH2 | 2,6-二氟苯基 |
F17 | CH2 | 3,4-二氟苯基 |
F18 | CH2 | 3,5-二氟苯基 |
F19 | CH2 | 2-氰基苯基 |
F20 | CH2 | 3-氰基苯基 |
F21 | CH2 | 4-氰基苯基 |
F22 | SO2 | 2-氯苯基 |
F23 | SO2 | 3-氯苯基 |
F24 | SO2 | 4-氯苯基 |
F25 | SO2 | 2-氟苯基 |
F26 | SO2 | 3-氟苯基 |
F27 | SO2 | 4-氟苯基 |
F28 | SO2 | 2,3-二氯苯基 |
F29 | SO2 | 2,4-二氯苯基 |
F30 | SO2 | 2,5-二氯苯基 |
F31 | SO2 | 2,6-二氯苯基 |
F32 | SO2 | 3,4-二氯苯基 |
F33 | SO2 | 3,5-二氯苯基 |
F34 | SO2 | 2,3-二氟苯基 |
F35 | SO2 | 2,4-二氟苯基 |
F36 | SO2 | 2,5-二氟苯基 |
F37 | SO2 | 2,6-二氟苯基 |
F38 | SO2 | 3,4-二氟苯基 |
F39 | SO2 | 3,5-二氟苯基 |
F40 | SO2 | 2-氰基苯基 |
F41 | SO2 | 3-氰基苯基 |
编号 | L | Z |
F42 | SO2 | 4-氰基苯基 |
该类别包括的化合物对于Z等于CH2时可以依照路线I制备,对于Z等于SO2时可以依照路线III制备。
可药用盐
所公开的HIF-1α脯氨酰羟化酶抑制剂可以为可药用盐的形式。可药用盐可以由配方者使用以提供所公开抑制剂的形式,所述形式与抑制剂至受试者的预定递送更相容或者为了所述制剂的相容性。
以下是用于制备所公开抑制剂的可药用盐——{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯——的步骤的实例。
将{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯(242mg,0.56mmol)在MeOH(15mL)中的悬浮液加热回流直至得到均质溶液。停止加热,在仍然热时加入0.1N HCl(6.7mL,1.2当量),将所述溶液冷却至室温。在减压下蒸发挥发物,在丙酮(5mL)中结晶无定形残留物。通过过滤收集所述固体物。
将{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯(217mg,0.5mmol)在MeOH(15mL)中的悬浮液加热回流直至得到均质溶液。停止加热,在仍然热时加入甲磺酸(115.2mg,1.2当量),将所述溶液冷却至室温。在减压下蒸发挥发物,在丙酮(5mL)中结晶无定形残留物。通过过滤收集所述固体物。
下文表VII提供了从有机酸和无机酸形成的{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯的可药用盐的实例。
表VII
酸 | 产率 | 纯度* | M.P.(℃) | 颜色 |
游离碱 | 99.3% | 183-184 | 粉红 | |
HCl | 90% | 99.7% | 185-186 | 白色 |
H2SO4 | 93% | 99.7% | 175(dec.) | 浅粉红 |
对甲苯磺酰基 | 74% | 99.8% | 185-186 | 白色 |
甲磺酰基 | 79% | 99.9% | 155-157 | 白色 |
*HPLC分析
1H NMR分析用于确定盐形式,例如,上文形成的甲磺酸盐具有下式:
1H NMR分析用于确定盐形成发生在所述分子的哪个位置。桥接哌嗪和吡啶酮环的亚甲基基团上的质子的化学位移从游离碱中的3.59ppm移至盐中的4.31ppm。另外,邻接叔胺的哌嗪亚甲基基团从2.50ppm移至大约3.60ppm。剩余质子的化学位移大多数未变。这些数据表明,哌嗪环的叔胺氮被质子化成盐形式。另外,相对于核心化合物整合甲磺酰基单元的甲基质子表明存在一个当量酸。
配方者可以通过任何所需的方法确定所公开抑制剂的可药用盐的溶解度。如下是用于评估所公开抑制剂的盐的溶解度的步骤的非限制性实例。在低于25℃的水浴温度下,将{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯甲磺酸盐(26.6mg)在去离子蒸馏水(3.0mL)中的悬浮物以声波处理20分钟。将所述悬浮物过滤以除去任何不溶性盐。将所述澄清滤液(200μL)以去离子蒸馏水(800μL)稀释,并进行HPLC分析。如下是上文表VII中列出的可药用盐的结果。
盐 | 溶解度(mg/mL) | 纯度* |
游离碱 | 0.001 | 99.3% |
盐酸盐 | 5.9 | 99.7% |
磺酸氢盐 | 13.2 | 99.7% |
对甲苯磺酸盐 | 2.3 | 99.8% |
甲磺酸盐 | 16.6 | 99% |
*HPLC分析
如下是可用于形成所公开抑制剂的可药用盐的其他酸的非限制性实例:乙酸、柠檬酸、马来酸、琥珀酸、乳酸、甘醇酸和酒石酸。
本文还公开了制备所公开的HIF-1α脯氨酰羟化酶抑制剂的方法,包括:
a)保护羟基吡啶-2(1H)-酮的羟基部分以制备具有下式的被保护的吡啶酮:
其中W代表保护基团;
b)使所述被保护的吡啶酮与具有下式的化合物反应:
其中R代表1-5个如本文所定义的对氢的取代基,指数n是0-5的整数,Q是离去基团,以形成具有下式的O-保护的N-苄基吡啶酮或N-磺酰基苯基吡啶酮:
c)从所述O-保护的N-苄基吡啶酮或N-磺酰基苯基吡啶酮上除去保护基团,以形成具有下式的N-苄基吡啶酮或N-磺酰基苯基吡啶酮:
d)使具有下式的的胺:
其中R1和R2与本文所定义的相同,
与甲醛反应以形成具有下式的N-甲酰胺:
e)使在步骤(d)中形成的N-甲酰胺与在步骤(c)中形成的N-苄基吡啶酮或N-磺酰基苯基吡啶酮反应,以形成具有下式的化合物:
步骤(a)O-保护的羟基吡啶-2(1H)-酮的制备
步骤(a)涉及具有下式的O-保护的羟基吡啶-2(1H)-酮的形成:
W可为任意保护基团。保护基团的非限制性实例包括氨基甲酸基,例如叔丁氧基羰基、甲氧基羰基、烷基硅烷(如三甲基甲硅烷基和叔丁基二甲基甲硅烷基)等。
步骤(b)O-保护的N-苄基羟基吡啶-2(1H)-酮或O-保护的N-磺酰基苯基羟基吡啶-2(1H)-酮的制备
步骤(b)涉及具有下式的O-保护的N-苄基羟基吡啶-2(1H)-酮或O-保护的N-磺酰基苯基羟基吡啶-2(1H)-酮的形成:
使在步骤(a)中形成的被保护的羟基吡啶-2(1H)-酮与具有下式的化合物反应:
其中Q是能够被所述被保护的羟基吡啶-2(1H)-酮环的氮消除的离去基团。
步骤(c)N-苄基-3-羟基吡啶-2(1H)-酮或N-磺酰基苯基-3-羟基吡啶-2(1H)-酮的制备
步骤(c)涉及具有下式的N-苄基-3-羟基吡啶-2(1H)-酮或N-磺酰基苯基-3-羟基吡啶-2(1H)-酮的形成:
其中所述在步骤(b)中形成的O-保护的N-苄基羟基吡啶-2(1H)-酮或O-保护的N-磺酰基苯基羟基吡啶-2(1H)-酮与适合用于除去保护基团W的一种或多种试剂反应,所述反应以与苯环上对氢的任意R取代基相容的方式进行。
步骤(d)N-甲酰胺合成子(synthon)的制备
步骤(d)涉及具有下式的N-甲酰胺合成子的形成:
所述N-甲酰胺通过使具有下式的胺:
与甲醛或能够原位生成甲醛的试剂反应而形成。
步骤(e)所公开的HIF-1α脯氨酰羟化酶抑制剂的制备
步骤(e)涉及具有下式的最终公开的化合物的形成:
其形成是通过使步骤(d)中形成的N-甲酰胺与步骤(c)中形成的N-苄基-3-羟基吡啶-2(1H)-酮或N-磺酰基苯基-3-羟基吡啶-2(1H)-酮反应实现的。
制剂
药剂和药物组合物
本发明还涉及可用于制备药剂和药物组合物的组合物或制剂。所公开的包含所公开的人蛋白HIF-1α脯氨酰羟化酶抑制剂的药剂和药物组合物可包含:
a)有效量的一种或多种本发明的HIF-1α脯氨酰羟化酶抑制剂;和
b)一种或多种赋形剂。
受通过抑制HIF-1α脯氨酰羟化酶引起的HIF-1的稳定性增加的影响的疾病或病况包括PVD、CAD、心脏衰竭、局部缺血、贫血、创伤愈合、抗微生物活性、吞噬增加、抗癌活性和疫苗有效性增加。
对于本发明的目的,术语“赋形剂”和“载体”在整个本发明的说明书中互换使用,所述术语在本文中被定义为“在配制安全和有效的药物组合物的实践中使用的成分”。
配方者会理解,赋形剂主要用于递送安全、稳定和有功能的药物,不仅用作整个递送载体的一部分,而且用作实现所述活性成分的接受者有效吸收的手段。赋形剂可作为惰性填料满足简单和直接的作用,或者本文使用的赋形剂可以是确保将所述成分安全递送到胃中的pH稳定系统或涂层的一部分。配方者还可利用以下事实:本发明的化合物具有改善的细胞潜能、药物代谢动力学性能以及改善的口服生物利用率。
本发明的组合物的非限制性实例包含:
a)约0.001mg到约1000mg的一种或多种本发明的人蛋白HIF-1α脯氨酰羟化酶抑制剂;和
b)一种或多种赋形剂。
本发明的另一实例涉及以下组合物:
a)约0.01mg到约100mg的一种或多种本发明的人蛋白HIF-1α脯氨酰羟化酶抑制剂;和
b)一种或多种赋形剂。
本发明的另一实例涉及以下组合物:
a)约0.1mg到约10mg的一种或多种本发明的人蛋白HIF-1α脯氨酰羟化酶抑制剂;和
b)一种或多种赋形剂。
本发明的组合物的又一实例包含:
a)有效量的一种或多种本发明的人蛋白HIF-1α脯氨酰羟化酶抑制剂;和
b)一种或多种如本文进一步描述的化疗剂或化疗化合物。
本发明的组合物的又一实例包含:
a)有效量的一种或多种本发明的人蛋白HIF-1α脯氨酰羟化酶抑制剂;和
b)一种或多种治疗传染性疾病的疫苗。
本发明还涉及一种或多种本文公开的HIF-1α脯氨酰羟化酶抑制剂用于制备治疗贫血症的药剂的用途。
本发明还涉及一种或多种本文公开的HIF-1α脯氨酰羟化酶抑制剂用于制备治疗细胞免疫力增加的药剂的用途。
本发明还涉及一种或多种本文公开的HIF-1α脯氨酰羟化酶抑制剂用于制备治疗癌症的药剂的用途。
本发明还涉及一种或多种本文公开的HIF-1α脯氨酰羟化酶抑制剂用于制备增加HIF-1稳定的药剂的用途。
本发明还涉及一种或多种本文公开的HIF-1α脯氨酰羟化酶抑制剂用于制备治疗贫血症的药剂的用途。
本发明还涉及一种或多种本文公开的HIF-1α脯氨酰羟化酶抑制剂用于制备治疗周围脉管疾病的药剂的用途。
本发明还涉及一种或多种本文公开的HIF-1α脯氨酰羟化酶抑制剂用于制备治疗创伤的药剂的用途。
本发明还涉及一种或多种本文公开的HIF-1α脯氨酰羟化酶抑制剂用于制备抗微生物剂的药剂的用途。
本发明还涉及一种或多种本文公开的HIF-1α脯氨酰羟化酶抑制剂用于制备治疗动脉粥样硬化病变的药剂的用途。
本发明还涉及一种或多种本文公开的HIF-1α脯氨酰羟化酶抑制剂用于制备治疗糖尿病的药剂的用途。
本发明还涉及一种或多种本文公开的HIF-1α脯氨酰羟化酶抑制剂用于制备治疗高血压的药剂的用途。
本发明还涉及一种或多种本文公开的HIF-1α脯氨酰羟化酶抑制剂用于制备治疗受脉管内皮生长因子(VEGF)、3-磷酸甘油醛脱氢酶(GAPDH)和促红细胞生成素(EPO)的水平影响的疾病的药剂的用途。
本发明还涉及一种或多种本文公开的HIF-1α脯氨酰羟化酶抑制剂用于制备治疗选自以下的疾病的药剂的用途:克罗恩病和溃疡性结肠炎、银屑病、结节病、类风湿关节炎、血管瘤、奥斯勒-韦伯-朗迪病(Osler-Weber-Rendu disease)或遗传性出血性毛细血管扩张症、实体或血源性肿瘤以及获得性免疫缺陷综合症。
本发明还涉及一种或多种本文公开的HIF-1α脯氨酰羟化酶抑制剂用于制备治疗选自以下的疾病的药剂的用途:糖尿病视网膜病变、黄斑变性、癌症、镰状细胞贫血、结节病、梅毒、弹性假黄色瘤、佩吉特氏病(Paget's disease)、静脉阻塞、动脉阻塞、颈动脉阻塞性疾病、慢性葡萄膜炎/玻璃体炎、分支杆菌感染、莱姆病(Lyme's disease)、系统性红斑狼疮、早产儿视网膜病变、伊尔斯氏病(Eales'disease)、白塞氏病(Behcet's disease)、视网膜炎或脉络膜炎引起的感染、眼假组织胞浆菌病、贝斯特氏病(Best's disease)、近视、视盘先天性小凹(optic pits)、斯塔加特氏病(Stargardt's disease)、扁平部睫状体炎、慢性视网膜脱离、高粘滞综合征、弓形虫病、外伤及激光后并发征、虹膜红变(rubeosis)相关疾病和增生性玻璃体视网膜病变。
所公开组合物和包含所述HIF-1α脯氨酰羟化酶抑制剂自身或者与另一种药物或其他治疗剂(尤其是化疗剂或化疗化合物)结合的药物制剂形式可根据预定给药途径变化。
口服给药的制剂可以为固体剂、液体剂、乳剂、悬浮剂或凝胶剂的形式,或者为剂量单位形式,例如片剂或胶囊。片剂可与其他常用组分(例如滑石、植物油、多元醇、树胶、明胶、淀粉和其他载体)结合而复合。所述HIF-1α脯氨酰羟化酶抑制剂可在溶液、悬浮液或乳液中分散在合适的液体载体中或与合适的液体载体结合。
预期用于注射(皮下注射、肌内注射或静脉注射)的肠胃外组合物可制备为液体或用于注射前配成液体溶液的固体形式,或者为乳液。所述制剂是无菌的,并且待静脉注射的液体应为等渗的。合适的赋形剂为例如水、右旋糖、盐水和甘油。
本文所述物质的可药用盐的给药包括在本发明的范围内。所述盐可由可药用的无毒碱(包括有机碱和无机碱)制备。来自无机碱的盐包括钠盐、钾盐、锂盐、铵盐、钙盐、镁盐等。来自可药用有机无毒碱的盐包括伯、仲和叔胺以及碱性氨基酸等的盐。对于药用盐的有益讨论,参见S.M.Berge et al.,Journal of Pharmaceutical Sciences66:1-19(1977),其公开内容以引用的方式纳入本文。
用于注射的物质可被制备为安瓿中的单位剂量形式,或者在多剂量容器中。待递送的HIF-1α脯氨酰羟化酶抑制剂或含有一种或多种HIF-1α脯氨酰羟化酶抑制剂的组合物可以以例如在油性或优选水性载体中的悬浮液、溶液或乳液的形式存在。或者,HIF-1α脯氨酰羟化酶抑制剂的盐可以以在递送时用合适的载体(例如无菌无致热原的水)进行再配制的冻干形式存在。液体以及待再配制的冻干形式均包含对合适调节注射溶液pH必需量的试剂(优选缓冲剂)。对于任何肠胃外使用,特别是如果所述制剂待静脉内给药,则应控制溶质的总浓度以使所述制剂等渗、低渗或弱高渗。非离子物质例如糖优选用于调节张度,特别优选蔗糖。这些形式的任一种还可包含合适的配制试剂,例如淀粉或蔗糖、甘油或盐水。每单位剂量的所述组合物(不管是液体还是固体)可含有0.1-99%的多核苷酸物质。
方法
与稳定HIF-1有关的方法
消灭入侵的微生物首先依赖在所有个体中预先存在并在感染几分钟内起作用的先天免疫机制。吞噬细胞类型(包括巨噬细胞和中性粒细胞)在先天免疫中起关键作用,因为其不需借助于适应性免疫反应即可识别、摄取并破坏许多病原体。骨髓细胞在固有防卫中的效力反映了其在低氧环境中起作用的能力。而在健康组织中氧张力通常为20-70mm HG(即2.5-9%氧),而已经报道在创伤和坏死组织病灶中的水平要低很多(<1%氧)(Arnold et al.,Br J Exp Pathol 68,569(1987);Vogelberg & Konig,Clin Investig 71,466(1993);Negus et al.,Am JPathol 150,1723(1997))。还已证明(Zinkernagel A.S.et al.,“Pharmacologic Augmentation of Hypoxia-Inducible Factor-1αwith Mimosine Boosts the Bactericidal Capacity of Phagocytes”J.Infectious Diseases(2008):197:214-217),HIF-1α激动剂含羞草素可以以剂量依赖的方式激发人吞噬细胞和全血以杀死主要病原体菌金黄色葡萄球菌的能力并在金黄色葡萄球菌皮肤感染的鼠模型中减小损伤大小。
巨噬细胞是一群参与免疫反应的效应细胞。其在天然免疫中的作用包括介导吞噬作用,以及释放细胞因子和细胞毒素介质。其还通过抗原呈递促进获得性免疫的形成并且促进免疫调制细胞因子的释放。尽管巨噬细胞是免疫效应物,然而其也容易被病原体例如细菌、原生动物、寄生虫和病毒感染(The Macrophage,C.E.Lewis & J.O'D.McGee.eds.,IRL Press at Oxford University Press,New York,N.Y.,1992)。能够感染巨噬细胞的病毒包括几种RNA病毒例如麻疹病毒(MV)(例如Joseph et al.,J.Virol.16,1638-1649,1975),respiratorysyncytial virus(RSV)(Midulla et al.,Am.Rev.Respir.Dis.140,771-777,1989)和1型人免疫缺陷病毒(HIV-1)(Meltzer and Gendelman,in Macrophage Biology and Activation,S.W.Russell and S.Gordon,eds.,Springer-Verlag,New York,N.Y.,pp.239-263(1992:Potts et al.,Virology 175,465-476,1990)。
本文公开了增加细胞中HIF-1稳定的方法,包括使体内、体外或离体的细胞与有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂接触。
本文还公开了增加需要增加细胞免疫的人或哺乳动物的细胞免疫反应的方法,包括给予有需要的人或哺乳动物有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂。
本文还公开了增加被诊断为由细胞免疫反应降低引起的医学病况的人或哺乳动物的细胞免疫反应的方法,包括给予有需要的人或哺乳动物有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂。
本文还公开了增加被诊断为由细胞免疫反应降低引起的医学病况的人或哺乳动物的细胞免疫反应的方法,包括给予有需要的人或哺乳动物有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂。
本文还公开了增加具有由细胞免疫反应降低引起的医学病况的人或哺乳动物的细胞免疫反应的方法,包括给予有需要的人或哺乳动物有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂。
因此,所述一种或多种HIF-1α脯氨酰羟化酶抑制剂和任何共给药的化合物可以通过局部、口腔内、口服、皮内、皮下、眼中的黏膜、阴道、直肠、鼻、静脉内以及肌肉内给药或与细胞接触。
与癌症治疗有关的方法
本文使用的癌症在本文中被定义为“趋于以不受控制的方式增殖并在某些情况下转移的细胞的异常生长”。因此,转移和非转移的癌症均可通过所公开的方法治疗。
本文公开了治疗人或哺乳动物的癌症的方法,包括给予患有癌症的人或哺乳动物有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂。
本文还公开了治疗被诊断患有癌症的人或哺乳动物的方法,包括共同给予人或哺乳动物一种或多种化疗剂或化疗化合物与一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂。
以下是恶性和非恶性癌症的非限制性实例:急性成淋巴细胞白血病(Acute Lymphoblastic);急性髓性白血病(Acute Myeloid Leukemia);肾上腺皮质癌(Adrenocortical Carcinoma);儿童肾上腺皮质癌(Adrenocortical Carcinoma.Childhood);阑尾癌(Appendix Cancer);基底细胞癌(Basal Cell Carcinoma);肝外胆管癌(Bile Duct Cancer,Extrahepatic);膀胱癌(Bladder Cancer);骨癌(Bone Cancer);骨肉瘤和恶性纤维组织细胞瘤(Osteosarcoma and Malignant FibrousHistiocytoma);儿童脑干胶质瘤(Brain Stemglioma,Childhood);成人脑瘤(Brain Tumor,Adult);儿童脑干胶质瘤脑瘤(Brain Tumor.BrainStemglioma,Childhood);非典型畸胎样中枢神经系统脑瘤/儿童横纹肌样瘤(Brain Tumor,Central Nervous System Atypical Teratoid/RhabdoidTumor,Childhood);中枢神经系统胚瘤(Central Nervous SystemEmbryonal Tumors);小脑星形细胞瘤(Cerebellar Astrocytoma);大脑星形细胞瘤/恶性神经胶质瘤(Cerebral Astrocytoma/MalignantGlioma);颅咽管瘤(Craniopharyngioma);成室管膜细胞瘤(Ependymoblastoma);室管膜细胞瘤(Ependymoma);成神经管细胞瘤(Medulloblastoma);髓上皮瘤(Medulloepithclioma);中度分化的松果体实质瘤(Pineal Parenchymal Tumors of Intermediate Differentiation);幕上原始神经外胚层肿瘤和成松果体细胞瘤(Supratentorial PrimitiveNeuroectodermal Tumors and Pineoblastoma);视通路和下丘脑神经胶质瘤(Visual Pathway and Hypothalamic Glioma);大脑和脊髓瘤(Brainand Spinal Cord Tumors);乳癌(Breast Cancer);支气管瘤(BronchialTumors);伯基特淋巴瘤(Burkitt Lymphoma);良性肿瘤(CarcinoidTumor);胃肠良性肿瘤(Carcinoid Tumor,Gastrointestinal);中枢神经系统非典型畸胎瘤样/横纹肌样瘤(Central Nervous System AtypicalTeratoid/Rhabdoid Tumor);中枢神经细胞胚胎性瘤(Central NervousSystem Embryonal Tumors);中枢神经系统淋巴瘤(Central NervousSystem Lymphoma);小脑星形细胞瘤(Cerebellar Astrocytoma);儿童大脑星形细胞瘤/恶性神经胶质瘤(Cerebral Astrocytoma/MalignantGlioma,Childhood);宫颈癌(Cervical Cancer);儿童脊索瘤(Chordoma,Childhood);慢性淋巴细胞性白血病(Chronic Lymphocytic Leukemia);慢性髓细胞性白血病(Chronic Myelogenous Leukemia);慢性骨髓增生病(Chronic Myeloproliferative Disorders);结肠癌(Colon Cancer);结肠直肠癌(Colorectal Cancer);颅咽管瘤(Craniopharyngioma);皮肤T细胞淋巴瘤(Cutaneous T-CeIl Lymphoma);食管癌(EsophagealCancer);尤因瘤(Ewing Family of Tumors);性腺外恶性生殖细胞肿瘤(Extragonadal Germ Cell Tumor);肝外胆管癌(Extrahepatic Bile DuctCancer);眼癌,眼内黑素瘤(Eye Cancer,Intraocular Melanoma);眼癌,视网膜母细胞瘤(Eye Cancer,Retinoblastoma);胆囊癌(GallbladderCancer);胃癌(Gastric(Stomach)Cancer);胃肠良性肿瘤(Gastrointestinal Carcinoid Tumor);胃肠间质瘤(GastrointestinalStromal Tumor)(GIST);颅外生殖细胞瘤(Germ Cell Tumor,Extracranial)、性腺外生殖细胞瘤(Germ Cell Tumor.Extragonadal);卵巢生殖细胞瘤(Germ Cell Tumor,Ovarian);妊娠滋养层瘤(GestationalTrophoblastic Tumor);神经胶质瘤(Glioma);儿童脑干神经胶质瘤(Glioma,Childhood Brain Stem);儿童大脑星形细胞神经胶质瘤(Glioma,Childhood Cerebral Astrocytoma);儿童视通路和下丘脑神经胶质瘤(Glioma.Childhood Visual Pathway and Hypothalamic);毛细胞白血病(Hairy Cell Leukemia);头颈癌(Head and Neck Cancer);肝细胞(肝)癌(Hepatocellular(Liver)Cancer);朗格汉斯细胞组织细胞增多病(Histiocytosis,Langerhans Cell);何杰金淋巴瘤(Hodgkin Lymphoma);下咽癌(Hypopharyngeal Cancer)、下丘脑和视通路神经胶质瘤(Hypothalamic and Visual Pathway Glioma);眼内黑素瘤(IntraocularMelanoma);胰岛细胞瘤(Islet Cell Tumor);肾癌(肾细胞癌)(Kidney(Renal Cell)Cancer);朗格汉斯细胞组织细胞增多病(Langerhans CellHistiocytosis);喉癌(Laryngeal Cancer);急性成淋巴细胞性白血病(Leukemia,Acute Lymphoblastic);急性髓性白血病(Leukemia,AcuteMyeloid);慢性淋巴细胞性白血病(Leukemia,Chronic Lymphocytic);慢性髓细胞性白血病(Leukemia,Chronic Myelogenous);毛细胞性白血病(Leukemia,Hairy Cell);唇和口腔癌(Lip and Oral Cavity Cancer);肝癌;非小细胞肺癌(Lung cancer,Non-Small Cell);小细胞肺癌(LungCancer,Small Cell);艾滋病相关的淋巴瘤(Lymphoma,AIDS-Related);伯基特淋巴瘤(Lymphoma,Burkitt);皮肤T细胞淋巴瘤(Lymphoma,Cutaneous T-CeIl);何杰金淋巴瘤(Lymphoma,Hodgkin);非何杰金淋巴瘤(Lymphoma,Non-Hodgkin);原发性中枢神经系统淋巴瘤(Lymphoma,Primary Central Nervous System);瓦尔登斯特伦巨球蛋白血症(Macroglobulinemia.);骨恶性纤维组织细胞瘤和骨肉瘤(Malignant Fibrous Histiocytoma of Bone and Osteosarcoma);成神经管细胞瘤(Medulloblastoma);黑素瘤(Melanoma);眼内黑素瘤(眼黑素瘤)(Melanoma,Intraocular(Eye));梅克尔(Merkel)细胞癌(MerkelCell Carcinoma);间皮瘤(Mesothelioma);潜伏的原发性转移性鳞片状颈癌(Metastatic Squamous Neck Cancer with Occult Primary);口腔癌(Mouth Cancer);(儿童)多发性内分泌肿瘤综合征(Multiple EndocrineNeoplasia Syndrome,(Childhood));多发性骨髓瘤/浆细胞瘤(MultipleMyeloma/Plasma cell Neoplasm);蕈样真菌病(Mycosis Fungoides);骨髓异常增生综合征(Myelodysplastic Syndromes);骨髓异常增生/骨髓增生病(Myelodysplastic/Myeloproliferative Diseases);慢性髓细胞性白血病(Myelogenous Leukemia,Chronic);成人急性髓性白血病(MyeloidLeukemia,Adult Acute);儿童急性髓性白血病(Myeloid Leukemia,Childhood Acute);多发性骨髓瘤(Myeloma,Multiple);慢性骨髓增生病(Myeloproliferative Disorders,Chronic);鼻腔和鼻旁窦癌(NasalCavity and Paranasal Sinus Cancer);鼻咽癌(Nasopharyngeal Cancer);神经母细胞瘤(Neuroblastoma);非小细胞肺癌(Non-Small Cell LungCancer);口癌(Oral Cancer);口腔癌(Oral Cavity Cancer);口咽癌(Oropharyngeal Cancer);骨肉瘤和骨的恶性纤维组织细胞瘤(Osteosarcoma and Malignant Fibrous Histiocytoma of Bone);卵巢癌(Ovarian Cancer);卵巢上皮癌(Ovarian Epithelial Cancer);卵巢生殖细胞瘤(Ovarian germ Cell Tumor);卵巢低度恶性肿瘤(Ovarian LowMalignant Potential Tumor);胰腺癌(Pancreatic Cancer);胰岛细胞癌(Pancreatic Cancer,Islet Cell Tumors);乳头状瘤病(Papillomatosis);甲状旁腺癌(Parathyroid Cancer);阴茎癌(Penile Cancer);咽癌(PharyngealCancer);嗜铬细胞瘤(Pheochromocytoma);中度分化的松果体实质瘤(Pineal Parenchymal Tumors of Intermediate Differentiation);成松果体细胞瘤和幕上原始神经外胚层肿瘤(Pineoblastoma and SupratentorialPrimitive Neuroectodermal Tumors);垂体瘤(Pituitary Tumor);浆细胞瘤/多发性骨髓瘤(Plasma Cell Neoplasm/Multiple Myeloma);胸膜肺母细胞瘤(Pleuropulmonary Blastoma);原发性中枢神经系统淋巴瘤(Primary Central Nervous System Lymphoma);前列腺癌(ProstateCancer);直肠癌(Rectal Cancer);肾细胞癌(肾脏癌)(Renal Cell(Kidney)Cancer);肾盂和输尿管移行细胞癌(Renal Pelvis and Ureter,Transitional Cell Cancer);涉及15号染色体上的NUT基因的呼吸道癌(Respiratory Tract Carcinoma Involving the NUT gene on Chromosome15);视网膜母细胞瘤(Retinoblastoma);横纹肌肉瘤(Rhabdomyosarcoma);唾腺癌(Salivary gland Cancer);尤因肉瘤(Sarcoma,Ewing Family of Tumors);卡波西肉瘤(Sarcoma,Kaposi);软组织肉瘤(Sarcoma,Soft Tissue);子宫肉瘤(Sarcoma,Uterine);塞扎里综合征(Sézary Syndrome);皮肤癌(非黑素瘤)(Skin Cancer(Nonmelanoma));皮肤癌(黑素瘤)(Skin Cancer(Melanoma));梅克尔细胞皮肤癌(Skin Carcinoma.Merkel Cell);小细胞肺癌(Small CellLung Cancer);小肠癌(Small Intestine Cancer);软组织肉瘤(Soft TissueSarcoma);鳞状细胞癌,潜伏的原发性转移性鳞片状颈癌(SquamousCell Carcinoma,Squamous Neck Cancer with Occult Primary,Metastatic);胃癌(Stomach(Gastric)Cancer);幕上原始神经外胚层瘤(Supratentorial Primitive Neuroectodermal Tumors);皮肤T细胞淋巴瘤(T-CeIl Lymphoma.Cutaneous);睾丸癌(Testicular Cancer);喉癌(Throat Cancer);胸腺瘤和胸腺癌(Thymoma and Thymic Carcinoma);甲状腺癌(Thyroid Cancer);肾盂和尿管的移行细胞癌(Transitional CellCancer of the Renal Pelvis and Ureter);妊娠滋养层癌(TrophoblasticTumor,gestational);尿道癌(Urethral Cancer);子宫内膜子宫癌(UterineCancer,Endometrial);子宫肉瘤(Uterine Sarcoma);阴道癌(VaginalCancer);外阴癌(Vulvar Cancer);瓦尔登斯特伦巨球蛋白血症(Macroglobulinemia)和肾母细胞瘤(Wilms Tumor)。
本文还公开了治疗人或哺乳动物癌症的方法,包括共同给予人或哺乳动物一种或多种化疗剂或化疗化合物与一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂。
本文还公开了治疗被诊断患有癌症的人或哺乳动物的方法,包括共同给予人或哺乳动物一种或多种化疗剂或化疗化合物与一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂。
“化疗剂”或“化疗化合物”是可用于治疗癌症的化学化合物。可与所公开的HIF-1α抑制剂结合使用的癌症化疗剂包括但不限于有丝分裂抑制剂(长春花生物碱)。这些化疗剂包括长春新碱、长春碱(vinblastine)、脱乙酰长春地辛(vindesine)和NavelbineTM(脱水长春花碱-5′-noranhydroblastine)。在其他实施方案中,癌症化疗剂包括拓扑异构酶I抑制剂,例如喜树碱化合物。本文使用的“喜树碱化合物”包括CamptosarTM(盐酸伊立替康)、HycamtinTM(盐酸拓扑替康(topotecan HCL))和从喜树碱及其类似物衍生的其他化合物。可用于本文公开的方法和组合物中的另一类癌症化疗剂是鬼臼毒素(podophyllotoxin)衍生物,例如依托泊苷(etoposide)、替尼泊苷(teniposide)和米托鬼臼肼(mitopodozide)。本发明的公开内容还包括其他已知为烷化剂的癌症化疗剂,其将肿瘤细胞中的遗传物质烷基化。这些癌症化疗剂包括但不局限于顺铂(cisplatin)、环磷酰胺(cyclophosphamide)、氮芥(nitrogen mustard)、三亚甲基硫磷酰胺(trimethylene thiophosphoramide)、卡莫司汀(carmustine)、白消安(busulfan)、苯丁酸氮芥(chlorambucil)、belustine、尿嘧啶氮芥(uracil mustard)、chlomaphazin和达卡巴嗪(dacarbazine)。本发明包括作为化疗剂的抗代谢物。这些类型治疗剂的实例包括胞嘧啶阿拉伯糖苷(cytosine arabinoside)、氟尿嘧啶(fluorouracil)、氨甲喋呤(methotrexate)、巯嘌呤(mercaptopurine)、硫唑嘌呤(azathioprime)和丙卡巴肼(procarbazine)。可用于本文公开的方法和组合物的另一类癌症化疗剂包括抗生素。非限制性实例包括多柔比星(doxorubicin)、博来霉素(bleomycin)、放线菌素D(dactinomycin)、红比霉素(daunorubicin)、光神霉素(mithramycin)、丝裂霉素(mitomycin)、丝裂霉素C和道诺霉素(daunomycin)。这些化合物有市售的各种脂质体制剂。本发明的公开内容还包括其他癌症化疗剂,其包括但不局限于抗肿瘤抗体、达卡巴嗪(dacarbazine)、5-氮杂胞苷(azacytidine)、安吖啶(amsacrine)、美法仑(melphalan)、异环磷酰胺(ifosfamide)和米托蒽醌(mitoxantrone)。
本文所公开的HIF-1α脯氨酰羟化酶抑制剂可与其他抗肿瘤剂结合给予,所述其他抗肿瘤剂包括细胞毒性剂/抗肿瘤剂和抗血管生成剂。细胞毒性剂/抗肿瘤剂被定义为攻击并杀死癌细胞的药剂。一些细胞毒性剂/抗肿瘤剂是烷化剂,其使肿瘤细胞中的遗传物质烷基化,例如顺铂、环磷酰胺、氮芥、三亚甲基硫磷酰胺、亚硝基脲氮芥、白消安、苯丁酸氮芥、belustine、乌拉莫司汀、chlomaphazin和达卡巴嗪。其他细胞毒性剂/抗肿瘤试剂是肿瘤细胞的抗代谢物,例如胞嘧啶阿拉伯糖苷、氟尿嘧啶、氨甲喋呤、巯嘌呤、硫唑嘌呤和丙卡巴肼。其他细胞毒性剂/抗肿瘤剂是抗生素,例如多柔比星、博来霉素、放线菌素D、红比霉素、光神霉素、丝裂霉素、丝裂霉素C和道诺霉素。这些化合物有多种市售脂质体制剂。其他细胞毒性剂/抗肿瘤剂是有丝分裂抑制剂(长春花生物碱)。这些包括长春新碱、长春碱和依托泊苷。多种细胞毒性剂/抗肿瘤剂包括紫杉醇及其衍生物、L-天冬酰胺酶、抗肿瘤抗体、达卡巴嗪、5-氮杂胞苷、安吖啶、美法仑、VM-26、异环磷酰胺、米托蒽醌和长春地辛。
抗血管生成剂为本领域技术人员所熟知。用于所公开方法和组合物中的合适的抗血管生成剂包括VEGF抗体(包括人源和嵌合抗体)、抗VEGF适体和反义寡核苷酸。其他已知的血管生成抑制剂包括血管抑素、血管内皮抑制素、干扰素、白细胞介素1(包括α和β)、白细胞介素12、维甲酸和金属蛋白酶1和-2的组织抑制剂(TIMP-1和TIMP-2)。还可使用小分子,包括拓扑异构酶例如雷佐生(razoxane),一种具有抗血管生成活性的拓扑异构酶II抑制剂。
可与所公开的HIF-1α抑制剂结合使用的其他抗癌剂包括但不限于:阿西维辛(acivicin);阿柔比星(aclarubicin);盐酸阿考达唑(acodazole hydrochloride);阿克罗宁(acronine);阿多来新(adozelesin);阿地白介素(aldesleukin);六甲蜜胺(altretamine);安波霉素(ambomycin);乙酸阿美蒽醌(ametantrone acetate);氨鲁米特(aminoglutethimide);氨吖啶(amsacrine);阿那曲唑(anastrozole);安曲霉素(anthramycin);天冬酰胺酶(asparaginase);曲林菌素(asperlin);阿扎胞苷(azacitidine);阿扎替派(azetepa);阿佐霉素(azotomycin);巴马司他(batimastat);苯佐替派(benzodepa);比卡鲁胺(bicalutamide);盐酸比生群(bisantrene hydrochloride);甲磺酸双奈法德(bisnafde dimesylate);比折来新(bizelesin);硫酸博来霉素(bleomycin sulfate);布喹那钠(brequinar sodium);溴匹立明(bropirimine);白消安(busulfan);放线菌素C(cactinomycin);卡普睾酮(calusterone);卡醋胺(caracemide);卡贝替姆(carbetimer);卡铂(carboplatin);卡莫司汀(carmustine);盐酸卡柔比星(carubicinhydrochloride);卡折来新(carzelesin);西地芬戈(cedefingol);苯丁酸氮芥(chlorambucil);西罗霉素(cirolemycin);顺铂(cisplatin);克拉屈滨(cladribine);甲磺酸克立那托(crisnatol mesylate);环磷酰胺;阿糖胞苷;达卡巴嗪;放线菌素D(dactinomycin);盐酸柔红霉素(daunorubicin hydrochloride);地西他滨(decitabine);右奥马铂(dexormaplatin);地扎胍宁(dezaguanine);甲磺酸地扎胍宁(dezaguanine mesylate);地吖醌(diaziquone);多西他赛(docetaxel);多柔比星;盐酸多柔比星;屈洛昔芬(droloxifene);柠檬酸屈洛昔芬柠(droloxifene citrate);丙酸屈他雄酮(dromostanolone propionate);达佐霉素(duazomycin);依达曲沙(edatrexate);盐酸依氟鸟氨酸(eflornithine hydrochloride);依沙芦星(elsamitrucin);恩洛铂(enloplatin);恩普氨酯(enpromate);依匹哌啶(epipropidine);盐酸表柔比星(epirubicin hydrochloride);厄布洛唑(erbulozole);盐酸依索比星(esorubicin hydrochloride);雌莫司汀(estramustine);雌莫司汀磷酸酯钠(estramustine phosphate sodium);依他硝唑(etanidazole);依托泊苷(etoposide);依托泊苷(etoposide phosphate);氯苯乙嘧胺(etoprine);盐酸法倔唑(fadrozole hydrochloride);法扎拉宾(fazarabine);芬维A胺(fenretinide);氟尿苷(fkoxuridine);磷酸氟达拉滨(fludarabine phosphate);氟尿嘧啶(fluorouracil);氟西他滨(flurocitabine);磷喹酮(fosquidone);福司曲星钠(fostriecin sodium);吉西他滨(gemcitabine);盐酸吉西他滨(gemcitabine hydrochloride);羟基脲(hydroxyurea);盐酸伊达比星(idarubicin hydrochloride);异环磷酰胺(ifosfamide);伊莫福新(ilmofosine);白细胞介素II(包括重组白细胞介素II或rIL2);干扰素α-2a;干扰素α-2b;干扰素α-n1;干扰素α-n3;干扰素β-Ia;干扰素γ-Ib;异丙铂(iproplatin);盐酸伊立替康(irinotecan hydrochloride);醋酸兰瑞肽(lanreotide acetate);来曲唑(letrozole);醋酸亮丙立德(leuprolide acetate);盐酸利阿唑(liarozole hydrochloride);洛美曲索钠(lometrexol sodium);洛莫司汀(lomustine);盐酸洛索蒽醌(losoxantrone hydrochloride);马索罗酚(masoprocol);美登素(maytansine);盐酸氮芥(mechlorethaminehydrochloride);醋酸甲地孕酮(megestrol acetate);醋酸美仑孕酮(melengestrol acetate);美法仑(melphalan);美诺立尔(menogaril);巯嘌呤(mercaptopurine);氨甲喋呤(methotrexate);氨甲喋呤钠;氯苯氨啶(metoprine);美妥替哌(meturedepa);米丁度胺(mitindomide);米托卡星(mitocarcin);丝裂红素(mitocromin);米托洁林(mitogillin);米托马星(mitomalcin);丝裂霉素(mitomycin);米托司培(mitosper);米托坦(mitotane);盐酸米托蒽醌(mitoxantronehydrochloride);麦考酚酸(mycophenolic acid);诺考达唑(nocodazole);诺拉霉素(nogalamycin);奥马铂(ormaplatin);奥昔舒仑(oxisuran);紫杉醇(paclitaxel);培门冬酶(pegaspargase);培利霉素(peliomycin);萘莫司汀(pentamustine);硫酸培洛霉素(peplomycinsulfate);培磷酰胺(perfosfamide);哌泊溴烷(pipobroman);哌泊舒凡(piposulfan);盐酸吡罗蒽醌(piroxantrone hydrochloride);普卡霉素(plicamycin);普洛美坦(plomestane);卟吩姆钠(porfimer sodium);泊非霉素(porfiromycin);泼尼莫司汀(prednimustine);盐酸丙卡巴肼(procarbazine hydrochloride);嘌呤霉素(puromycin);盐酸嘌呤霉素;吡唑呋林(pyrazofurin);利波腺苷(riboprine);罗谷亚胺(rogletimide);沙芬戈(safingol);盐酸沙芬戈(safingol hydrochloride);司莫司汀(semustine);辛曲秦(simtrazene);磷乙酰天冬氨酸钠(sparfosatesodium);司帕霉素(sparsomycin);盐酸锗螺胺(spirogermaniumhydrochloride);螺莫司汀(spiromustine);螺铂(spiroplatin);链黑霉素(streptonigrin);链佐星(streptozocin);磺氯苯脲(sulofenur);他利霉素(talisomycin);替可加兰钠(tecogalan sodium);替加氟(tegafur);盐酸替洛蒽醌(teloxantrone hydrochloride);替莫泊芬(temoporfin);替尼泊苷(teniposide);替罗昔隆(teroxirone);睾内酯(testolactone);硫咪嘌呤(thiamiprine);硫鸟嘌呤(thioguanine);塞替派(thiotepa);噻唑呋林(tiazofurin);替拉扎明(tirapazamine);柠檬酸托瑞米芬(toremifene citrate);醋酸曲托龙(trestolone acetate);磷酸曲西立滨(triciribine phosphate);三甲曲沙(trimetrexate);三甲曲沙葡糖醛酸(trimetrexate glucuronate);曲普瑞林(triptorelin);盐酸妥布氯唑(tubulozole hydrochloride);乌拉莫司汀(uracil mustard);乌瑞替派(uredepa);伐普肽(vapreotide);维替泊芬(verteporfin);硫酸长春碱;硫酸长春新碱;长春地辛;硫酸长春地辛;硫酸长春匹定(vinepidinesulfate);硫酸长春甘酯(vinglycinate sulfate);硫酸长春罗辛(vinleurosine sulfate);酒石酸长春瑞滨(vinorelbine tartrate);硫酸长春罗定(vinrosidine sulfate);硫酸长春利定(vinzolidine sulfate);伏氯唑(vorozole);折尼泊(zeniplatin);净司他丁(zinostatin);盐酸佐柔比星(zorubicin hydrochloride)。其他抗癌药物包括但不局限于:20-表-1,25二羟基维生素D3;5-乙炔尿嘧啶;阿比特龙(abiraterone);阿柔比星;酰基富烯(acylfulvene);腺环戊醇(adecypenol);阿多来新(adozelesin);阿地白介素(aldesleukin);ALL-TK拮抗剂;六甲蜜胺(altretamine);氨莫司汀(ambamustine);2,4-二氯苯氧乙酸(amidox);氨磷汀(amifostine);5-氨基酮戊酸(aminolevulinic acid);氨柔比星(amrubicin);安吖啶(amsacrine);阿那格雷(anagrelide);阿那曲唑(anastrozole);穿心莲内酯(andrographolide);血管生成抑制剂;拮抗剂D;拮抗剂G;安雷利克斯(antarelix);抗背侧形态发生蛋白1(anti-dorsalizing morphogenetic protein-1);抗雄激素(antiandrogen)、前列腺癌物质(prostatic carcinoma)、抗雌激素物质(antiestrogen);抗瘤酮(antineoplaston);反义寡核苷酸;蚜肠菌素甘氨酸(aphidicolinglycinate);细胞凋亡基因调节物质(apoptosis gene modulators);细胞凋亡调节物(apoptosis regulators);脱嘌呤核酸;ara-CDP-DL-PTBA;精氨酸脱氨基酶;asulacrine;阿他美坦(atamestane);阿莫司汀(atrimustine);海洋环肽1(axinastatin 1);海洋环肽2(axinastatin2);海洋环肽3(axinastatin 3);偶氮丝氨酸(azasetron);阿扎毒素(azatoxin);重氮酪氨酸(azatyrosine);浆果赤霉素III(baccatin III)衍生物;balanol;巴马司他(batimastat);BCR/ABL拮抗剂;苯并二氢卟吩(benzochlorin);苯酰星孢素(benzoylstaurosporine);β-内酰胺衍生物(beta lactam derivatives);beta-alethine;betaclamycin B;桦木酸(betulinic acid);bFGF抑制剂;比卡鲁胺(bicalutamide);比生群(bisantrene);双氮丙啶基精胺(bisaziridinylspermine);双奈法德(bisnafide);bistratene A;比折来新(bizelesin);breflate;溴匹立明(bropirimine);布度钛(budotitane);丁胱亚磺酰亚胺(buthioninesulfoximine);卡泊三醇(calcipotriol);calphostin C;喜树碱衍生物;canarypox IL-2;卡培他滨(capecitabine);酰胺-氨基-三唑(carboxamide-amino-triazole);羧基酰胺三唑(carboxyamidotriazole);CaRest M3;CARN 700;软骨衍生的抑制剂(cartilage derivedinhibitor);卡折来新(carzelesin);酪蛋白激酶抑制剂(casein kinaseinhibitors(ICOS));粟精胺(castanospermine);杀菌肽B(cecropin B);西曲瑞克(cetrorelix);chlorlns;磺胺氯喹(chloroquinoxalinesulfonamide);西卡前列素(cicaprost);顺式-卟啉(cis-porphyrin);克拉屈滨(cladribine);氯米芬类似物(clomifene analogues);克霉唑(clotrimazole);collismycin A;collismycin B;考布他汀A4(combretastatin A4);考布他汀类似物;conagenin;crambescidin816;克立那托(crisnatol);cryptophycin 8;cryptophycin A衍生物;curacin A;cyclopentanthraquinones;cycloplatam;cypemycin;阿糖胞苷十八烷基磷酸盐(cytarabine ocfosfate);溶细胞因子(cytolyticfactor);cytostatin;达昔单抗(dacliximab);地西他滨(decitabine);dehydrodidemnin B;地洛瑞林(deslorelin);地塞米松(dexamethasone);右异环磷酰胺(dexifosfamide);右雷佐生(dexrazoxane);右维拉帕米(dexverapamil);地吖醌(diaziquone);didemnin B;didox;diethylnorspermine;二氢-5-氮胞苷;9-二氢紫杉醇(dihydrotaxol,9-);dioxamycin;联苯螺莫司汀(diphenyl spiromustine);多西他赛(docetaxel);二十二醇(docosanol);多拉司琼(dolasetron);去氧氟尿苷(doxifluridine);屈洛昔芬(droloxifene);屈大麻酚(dronabinol);duocarmycin SA;依布硒(ebselen);依考莫司汀(ecomustine);依地福新(edelfosine);依决可单抗(edrecolomab);依氟鸟氨酸(eflornithine);榄香烯(elemene);乙嘧替氟(emitefur);表柔比星;依立雄胺(epristeride);雌氮芥类似物;雌激素激动剂(estrogen agonists);雌激素拮抗剂(estrogen antagonists);依他硝唑(etanidazole);磷酸依托泊苷;依西美坦(exemestane);法倔唑(fadrozole);法扎拉宾(fazarabine);芬维A胺(fenretinide);非格司亭(filgrastim);非那雄胺(finasteride);flavopiridol;氟卓司汀(flezelastine);fluasterone;氟达拉滨(fludarabine);fluorodaunorunicinhydrochloride;福酚美克(forfenimex);福美坦(formestane);福司曲星(fostriecin);福莫司汀(fotemustine);钆替沙林(gadoliniumtexaphyrin);硝酸镓;加洛他滨(galocitabine);加尼瑞克(ganirelix);明胶酶抑制剂;吉西他滨;谷胱甘肽抑制剂;hepsulfam;调蛋白(heregulin);六亚甲基二乙酰胺(hexamethylene bisacetamide);金丝桃素(hypericin);依班膦酸盐(ibandronic acid);伊达比星(idarubicin);艾多昔芬(idoxifene);伊决孟酮(idramantone);伊莫福新(ilmofosine);伊洛马司他(ilomastat);咪唑并吖啶酮(imidazoacridone);咪喹莫特(imiquimod);免疫刺激肽;胰岛素样生长因子-1受体抑制剂;干扰素激动剂;干扰素;白细胞介素;碘苄胍(iobenguane);碘阿霉素(iododoxorubicin);依波米醇、4-(ipomeanol,4-);伊罗普拉(iroplact);伊索拉定(irsogladine);isobengazole;isohomohalicondrin B;依他司琼(itasetron);促微丝聚合剂(jasplakinolide);kahalalide F;片螺素(lamellarin)-N triacetate;兰瑞肽(lanreotide);leinamycin;来格斯汀(lenograstim);硫酸香菇多糖(lentinan sulfate);leptolstatin;来曲唑(letrozole);白血病抑制因子;白细胞α干扰素;亮丙立德+雌激素+孕酮;亮丙瑞林(leuprorelin);左旋咪唑(levamisole);利阿唑(liarozole);直链多胺类似物(linearpolyamine analogue);亲脂二糖肽;亲脂铂化合物;lissoclinamide 7;洛铂(lobaplatin);蚯蚓磷脂(lombricine);洛美曲索(lometrexol);氯尼达明(lonidamine);洛索蒽醌(losoxantrone);洛伐他汀(lovastatin);洛索立滨(loxoribine);勒托替康(lurtotecan);lutetium texaphyrin;lysofylline;裂解肽(lytic peptide);美坦辛(maitansine);抑甘露糖苷酶素A(mannostatin A);马立马司他(marimastat);马索罗芬(masoprocol);乳腺丝抑蛋白(maspin);溶基质蛋白抑制剂(matrilysininhibitor);基质金属蛋白酶抑制剂(matrix metalloproteinaseinhibitor);美诺立尔(menogaril);merbarone;美替瑞林(meterelin);蛋氨酸酶(methioninase);甲氧氯普胺(metoclopramide);MIF抑制剂;米非司酮(mifepristone);米替福新(miltefosine);米立司亭(mirimostim);错配双链RNA;米托胍腙(mitoguazone);二溴卫矛醇(mitolactol);丝裂霉素类似物;米托萘胺(mitonafide);mitotoxinfibroblastgrowth factor-saporin;米托蒽醌;莫法罗汀(mofarotene);莫拉司亭(molgramostim);人绒毛膜促性腺激素单克隆抗体;单磷酰脂质A+分枝杆菌细胞壁sk;莫哌达醇(mopidamol);多抗药基因抑制剂;基于多肿瘤抑制剂-1的疗法(multiple tumor suppressor 1-basedtherapy);芥抗癌试剂(mustard anticancer agent);印度洋海绵B(mycaperoxide B);分枝杆菌细胞壁提取物(mycobacterial cell wallextract);myriaporone;N-乙酰地那林(N-acetyldinaline);N-取代苯酰胺;那法瑞林(nafarelin);nagrestip;纳洛酮+喷他佐新(naloxone+pentazocine);napavin;naphterpin;那托司亭(nartograstim);奈达铂(nedaplatin);奈莫柔比星(nemorubicin);奈立膦酸(neridronic acid);中性内肽酶(neutral endopeptidase);尼鲁米特(nilutamide);nisamycin;一氧化氮调节剂;一氧化二氮抗氧化剂(nitroxide antioxidant);nitrullyn;O6-苄基鸟嘌呤;奥曲肽(octreotide);okicenone;寡核苷酸;奥那司酮(onapristone);昂丹司琼(ondansetron);昂丹司琼;oracin;口服细胞因子诱导剂(oral cytokineinducer);奥马铂;奥沙特隆(osaterone);奥沙利铂(oxaliplatin);oxaunomycin;紫杉醇(paclitaxel);紫杉醇类似物;紫杉醇衍生物;六环二胍抗生素(palauamine);棕榈酰根霉素(palmitoyl rhizoxin);帕米膦酸(pamidronic acid);人参三醇(panaxytriol);帕诺米芬(panomifene);副球菌素(parabactin);帕折普汀(pazelliptine);培门冬酶(pegaspargase);培得星(peldesine);戊聚硫钠(pentosan polysulfatesodium);喷司他丁(pentostatin);pentrozole;全氟溴烷(perflubron);培磷酰胺(perfosfamide);紫苏子醇(perillyl alcohol);phenazinomycin;苯乙酸;磷酸酶抑制剂;溶血性链球菌制剂(picibanil);盐酸毛果芸香碱(pilocarpine hydrochloride);吡柔比星(pirarubicin);吡曲克辛(piritrexim);placetin A;placetin B;血纤蛋白溶酶原激活物抑制剂;铂复合物;铂化合物;铂-三胺复合物;卟吩姆钠(porfimer sodium);泊非霉素(porfiromycin);泼尼松(prednisone);丙基双吖啶酮(propylbis-acridone);前列腺素J2(prostaglandin J2);蛋白酶体抑制剂(proteasome inhibitor);基于蛋白A的免疫调节剂(protein A-basedimmune modulator);蛋白激酶C抑制剂(protein kinase C inhibitor);微藻蛋白激酶C抑制剂(protein kinase C inhibitors,microalgal);蛋白酪氨酸磷酸酶抑制剂(protein tyrosine phosphatase inhibitors);嘌呤核苷磷酸化酶抑制剂(purine nucleoside phosphorylase inhibitors);羟基茜草素(purpurins);吡唑啉吖啶(pyrazoloacridine);pyridoxylatedhemoglobin polyoxyethylene conjugate;raf拮抗剂;雷替曲塞(raltitrexed);雷莫司琼(ramosetron);ras法尼基转移酶抑制剂(rasfarnesyl protein transferase inhibitor);ras抑制剂(ras inhibitor);ras-GAP抑制剂;脱甲基瑞提普汀(retelliptine demethylated);铼Re186依替膦酸(rhenium Re 186 etidronate);根霉素(rhizoxin);核酶(ribozyme);RII异维A酰胺(RII retinamide);罗谷亚胺(rogletimide);罗希吐碱(rohitukine);罗莫肽(romurtide);罗喹美克(roquinimex);rubiginone B 1;ruboxyl;沙芬戈(safmgol);saintopin;SarCNU;sarcophytol A;沙格司亭(sargramostim);Sdi 1模拟物(Sdi 1 mimetic);司莫司汀(semustine);衰老衍生抑制剂1(senescence derived inhibitor1);有义寡核苷酸;信号转导抑制剂;信号传导调节剂;单链抗原结合蛋白;西佐喃();索布佐生(sobuzoxane);硼卡钠(sodiumboroeaptate);苯乙酸钠;solverol;生长调节素结合蛋白;索钠明(sonermin);膦门冬酸(sparfosic acid);spicamycin D;螺莫司汀(spiromustine);splenopentin;海绵抑制素1(spongistatin 1);角鲨胺(squalamine);干细胞抑制剂;干细胞分裂抑制剂;stipiamide;溶基质素抑制剂(stromelysin inhibitor);sulfmosine;超活性血管活性肠肽拮抗剂(superaetive vasoaetive intestinal peptide antagonist);suradista;苏拉明(suramin);八氢吲嗪三醇(swainsonine);合成糖胺聚糖;他莫司汀(tallimustine);甲碘他莫昔芬(tamoxifen methiodide);牛磺莫司汀(tauromustine);他扎罗汀(tazarotene);替可加兰钠(teeogalan sodium);替加氟(tegafur);tellurapyrylium;端粒酶抑制剂;替莫泊芬(temoporfin);替莫唑胺(temozolomide);替尼泊苷;tetraehlorodeeaoxide;tetrazomine;thaiiblastine;噻可拉林(thiocoraline);血小板生成素(thrombopoietin);血小板生成素模拟物(thrombopoietin mimetic);胸腺法新(thymalfasin);胸腺生成素受体激动剂(thymopoietin receptor agonist);胸腺曲南(thymotrinan);促甲状腺素;tin ethyl etiopurpurin;替拉扎明(tirapazamine);二氯化二茂钛(titanocene bichloride);topsentin;托瑞米芬(toremifene);全能干细胞因子;转录抑制剂;维生素A酸(tretinoin);三乙酰胆碱(triacetyluridine);曲西立滨(triciribine);三甲曲沙(trimetrexate);曲普瑞林(triptorelin);托烷司琼(tropisetron);妥罗雄脲(turosteride);酪氨酸激酶抑制剂;酪氨酸磷酸化抑制剂(tyrphostin);UBC抑制剂;乌苯美司(ubenimex);源自泌尿生殖窦的生长抑制因子(urogenitalsinus-derived growth inhibitory factor);尿激酶受体拮抗剂(urokinasereceptor antagonist);伐普肽(vapreotide);variolin B;载体系统,红细胞基因治疗(vector system,erythrocyte gene therapy);维拉雷琐(velaresol);藜芦明(veramine);verdin;维替泊芬(verteporfin);长春瑞滨(vinorelbine);vinxaltine;vitaxin;伏氯唑(vorozole);扎诺特隆(zanoterone);折尼铂(zeniplatin);亚苄维C(zilascorb)和净司他丁斯酯(zinostatin stimalamer)。在一个实施方案中,所述抗癌药是5-氟尿嘧啶、紫杉醇或甲酰四氢叶酸(leucovorin)。
与治疗涉及微生物的病况有关的方法
本文公开了治疗人或哺乳动物抵抗微生物感染的方法,包括给予人或哺乳动物有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂。
还公开了当人或哺乳动物被微生物感染时降低微生物毒力的方法,包括给予人或哺乳动物有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂。
还公开了治疗人或哺乳动物中由微生物引起的感染的方法,包括给予人或哺乳动物有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂。
还公开了治疗被诊断患有由微生物引起的感染的人或哺乳动物的方法,包括给予人或哺乳动物有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂。
还公开了防止由微生物引起的疾病从人或哺乳动物向人或哺乳动物传播的方法,包括给予人或哺乳动物有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂。
还公开了防止在手术过程中人或哺乳动物中感染的方法,包括给予人或哺乳动物有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂。
所述微生物可为任意有益或有毒的微生物,例如细菌、病毒、酵母、真菌或寄生虫。以下是可被所公开的HIF-1α脯氨酰羟化酶抑制剂影响的微生物的非限制性实例。术语“影响”是指微生物的毒力降低、减弱或消除。毒力降低、减弱或消除的原因可以是由于给予一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂导致的HIF-1的稳定和/或吞噬作用水平增加。
乙酸钙不动杆菌(Acinetobacter calcoaceticus)、溶血不动杆菌(Acinetobacter haemolyticus)、嗜水气单胞菌(Aeromonas hydrophilia)、根癌土壤杆菌(Agrobacterium tumefaciens)、炭疽杆菌(Bacillusanthracis)、碱性芽孢杆菌(Bacillus halodurans)、枯草芽孢杆菌(Bacillussubtilis)、吉氏拟杆菌(Bacteroides distasonis)、埃氏拟杆菌(Bacteroideseggerthii)、脆弱拟杆菌(Bacteroides fragilis)、卵形拟杆菌(Bacteroidesovalus)、3452A拟杆菌同源组(Bacteroides 3452A homology group)、内脏拟杆菌(Bacteroides splanchnicus)、多形拟杆菌(Bacteroidesthetaiotaomicron)、单形拟杆菌(Bacteroides uniformis)、普通拟杆菌(Bacteroides vulgatus)、支气管炎博得特氏菌(Bordetellabronchiseptica)、副百日咳博德特氏菌(Bordetella parapertussis)、百日咳博德特氏菌(Bordetella pertussis)、布氏疏螺旋体(Borreliaburgdorferi)、粘膜炎布兰汉球菌(Branhamella catarrhalis)、马尔他布鲁氏菌(Brucella melitensis)、洋葱伯克霍尔德菌(Burkholderia cepacia)、类鼻疽伯克霍尔德氏菌(Burkholderia pseudomallei)、结肠弯曲杆菌(Campylobacter coli)、胎儿弯曲杆菌(Campylobacter fetus)、空肠弯曲杆菌(Campylobacter jejuni)、新月柄杆菌(Caulobacter crescentus)、弗氏柠檬酸杆菌(Citrobacter freundii)、艰难梭菌(Clostridium difficile)、产气荚膜梭菌(Clostridium peftingens)、白喉棒状杆菌(Corynebacterium diphtheriae)、谷氨酸棒状杆菌(Corynebacteriumglutamicum)、溃疡棒状杆菌(Corynebacterium ulcerans)、迟钝爱德华氏菌(Edwardsiella tarda)、产气肠杆菌(Enterobacter aerogenes)、菊欧文氏菌(Erwinia chrysanthemi)、阴沟肠杆菌(Enterobacter cloacae)、粪肠球菌(Enterococcus faecalis)、屎肠球菌(Enterococcus faecium)、大肠杆菌(Escherichia coli)、土拉热弗朗西丝氏菌(Francisella tularensis)、阴道加德纳菌(Gardnerella vaginalis)、杜氏嗜血菌(Haemophilusducreyi)、溶血嗜血杆菌(Haemophilus haemolyticus)、流感嗜血杆菌(Haemophilus influenzae)、副溶血性嗜血杆菌(Haemophilusparahaemolyticus)、副流感嗜血杆菌(Haemophilus parainfluenzae)、幽门螺旋杆菌(Helicobacter pylori)、产酸克雷伯菌(Klebsiella oxytoca)、肺炎克雷伯菌(Klebsiella pneumoniae)、栖冷克吕沃尔菌(Kluyveracryocrescens)、侵肺军团菌(Legionella pneumophila)、无害李斯特菌(Listeria innocua)、单核细胞增生利斯特菌(Listeria monocytogenes)、威氏利斯特氏菌(Listeria welshimeri)、噬乙酸甲烷八叠球菌(Methanosarcina acetivorans)、梅氏甲烷八叠球菌(Methanosarcinamazei)、摩氏摩根菌(Morganella morganii)、鸟分枝杆菌(Mycobacteriumavium)、胞内分枝杆菌(Mycobacterium intracellulare)、麻风分枝杆菌(Mycobacterium leprae)、结核分枝杆菌(Mycobacterium tuberculosis)、百脉根根瘤菌(Mesorhizobium loti)、淋病奈瑟球菌(Neisseriagonorrhoeae)、脑膜炎奈瑟球菌(Neisseria meningitidis)、溶血性巴斯德氏杆菌(Pasteurella haemolytica)、多杀性巴斯德氏菌(Pasteurellamultocida)、产碱普罗威登斯菌(Providencia alcalifaciens)、雷氏普罗威登斯菌(Providencia rettgeri)、斯氏普罗威登斯菌(Providencia stuartii)、奇异变形杆菌(Proteus mirabilis)、普通变形杆菌(Proteus vulgaris)、食酸假单胞菌(Pseudomonas acidovorans)、绿脓假单胞菌(Pseudomonasaeruginosa)、产碱假单胞菌(Pseudomonas alcaligenes)、荧光假单胞菌(Pseudomonas fluorescens)、恶臭假单胞菌(Pseudomonas putida)、青枯菌(Ralstonia solanacearum)、肠霍乱沙门氏菌猪霍乱亚种(Salmonellaenterica subsp.enteridtidis)、肠道沙门氏菌亚种副伤寒沙门氏菌(Salmonella enterica subsp.paratyphi)、肠道沙门氏菌亚种鼠伤寒肠炎沙门氏菌(Salmonella enterica subsp.typhimurium)、肠道沙门氏菌亚种伤寒沙门氏菌(Salmonella enterica,subsp.typhi)、粘质沙雷氏菌(Serratia marcescens)、痢疾志贺菌(Shigella dysenteriae)、弗氏志贺菌(Shigella flexneri)、索氏志贺氏菌(Shigella sonnei)、苜蓿中华根瘤菌(Sinorhizobium meliloti)、金黄色葡萄球菌(Stahylococcus aureus)、大鼠链球菌(Streptococcus criceti)、表皮葡萄球菌(Staphylococcusepidemmidis)、溶血葡萄球菌(Stahylococcus haemolyticus)、人葡萄球菌(Stahylococcus hominis)、猪葡萄球菌(Staphylococcus hyicus)、中间葡萄球菌(Stahylococcus intermedius)、嗜麦芽糖寡养单胞菌(Stenotrophomonas maltophilia)、解糖葡萄球菌(Stahylococcussaccharolyticus)、腐生葡萄球菌(Staphylococcus sarophyticus)、松鼠葡萄球菌(Stahylococcus sciuri)、除虫链霉菌(Streptomycesavermitilis)、天蓝色链球菌(Streptomyces coelicolor)、无乳链球菌(Streptococcus agalactiae)、肺炎链球菌(Streptococcus pneumoniae)、酿脓链球菌(Streptococcus pyogenes)、硫磺矿硫化叶菌(Sulfobalblobussoffiataricus)、海栖热袍菌(Thermotoga maritima)、霍乱弧菌(Vibriocholerae)、副溶血性弧菌(Vibrio parahaemolyticus)、Vogeselaindigofera、地毯草黄单胞菌(Xanthomonas axonopodis)、野油菜黄单胞菌(Xanthomonas campestris)、小肠结肠炎耶尔森氏菌(Yersiniaenterocolitica)、中间耶尔森氏菌(Yersinia intermedia)、鼠疫耶尔森氏菌(Yersinia pestis)和假结核耶尔森氏菌(Yersinia pseudotuberculosis)。
与种痘或接种有关的方法
本文公开了增强疫苗效力的方法,包括共同给予人或哺乳动物疫苗和一种或多种HIF-1α脯氨酰羟化酶抑制剂。
疫苗的非限制性实例是用于激发抗肝炎、流感、麻疹、风疹、破伤风、脊髓灰质炎、狂犬病等的抗体的疫苗。
因此,所公开的方法包括通过局部、口腔内、口服、皮内、皮下、眼中的黏膜、阴道、直肠、鼻、静脉内以及肌肉内途径,给予一种或多种HIF-1α脯氨酰羟化酶抑制剂和任何共给药的化合物,或者使体外、体内或离体细胞与一种或多种HIF-1α脯氨酰羟化酶抑制剂和任何共给药的化合物相接触。
步骤
EGLN-1活性测定
EGLN-1(或EGLN-3)酶活性使用质谱(基质辅助的激光解吸/电离飞行时间MS,MALDI-TOF MS)进行确定。重组人EGLN-1-179/426如上文和补充数据中所述进行制备。全长重组人EGLN-3以类似方式进行制备,但由于切割的蛋白的不稳定性需要使用His-MBP-TVMV-EGLN-3融合物进行所述测定。对于两种酶,与残基556-574对应的HIF-1α肽被用作底物。所述反应在包含TrisCl(5mM,pH 7.5)、抗坏血酸(120μM)、2-酮戊二酸(oxoglutarate)(3.2μM)、HIF-1α(8.6μM)和牛血清白蛋白(0.01%)的总体积50μL中进行。加入预先确定在20分钟中羟基化20%底物的的用量的酶以起始所述反应。如果使用抑制剂,则将化合物在二甲基亚砜中以终测定浓度的10倍进行制备。在室温下20分钟后,通过将10μL反应混合物转移至50μL质谱基质溶液(50%乙腈/0.1%TFA,5mM NH4PO4中5mg/mL的α-氰基-4-羟基肉桂酸)中终止所述反应。将两微升所述混合物点到MALDI-TOF MS靶板上,以装配有Nd:YAG激光器(355nm,3ns脉冲宽度,200Hz重现率)的Applied Biosystems(Foster City,CA)4700 Proteomics Analyzer MALDI-TOF MS进行分析。通过16Da的增益从底物中鉴定羟基化的肽产物。在GraphPad Prism 4中分析定义为底物向产物转化百分数的数据,以计算IC50值。
VEGF ELISA测定
将HEK293细胞以每孔20,000个细胞在DMEM(10%FBS,1%NEAA,0.1%谷氨酰胺)中接种在多赖氨酸涂敷的96孔板。孵育过夜后,将所述细胞以100μL的Opti-MEM(Gibco,Carlsbad,CA)洗涤以除去血清。将DMSO中的化合物系列稀释(起始为100μM)在Opti-MEM中,并加入细胞。以Quantikine人VEGF免疫测定试剂盒(R&D Systems,Minneapolis,MN)分析所述条件化培养基的VEGF。使用Spectra Max 250(Molecular Devices,Sunnyvale,CA)记录450nm下的光密度测量值。定义为DFO刺激%的数据被用于以GraphPadPrism 4软件(San Diego,CA)计算EC50值。
小鼠缺血性后肢研究
所有动物研究依照Guide for the Care and Use of LaboratoryAnimals(National Academy of Sciences;Copyright1996)进行。这些实验使用了来自Charles River Laboratory(Portage,MI)的9-10周龄雄性C57Bl/6小鼠。所述小鼠以载体(碳酸盐水缓冲液,50mM;pH 9.0)或50mg/kg或100mg/kg在载体中的待测试化合物口服给药。对小鼠给药三次:在第1天8AM和5PM,在第2天8AM。在第一次给药后1小时,在使用异氟烷麻醉下进行单侧动脉结扎。在接近腘动脉起源处结扎股动脉。对对侧肢进行假手术操作。结扎以左右后肢之间交替的方式进行。在第2天8AM给药后两小时,在小鼠以异氟烷麻醉下通过心室穿刺获得血。使用凝胶块血清分离管获得血清样品用于EPO分析。将心脏、肝和腓肠肌收集、快速冷冻在液氮中,并在-80C下保存至使用。
小鼠血清EPO测定
使用来自R&D Systems的Mouse Quantikine Erythropoietin ELISA试剂盒依照制造商的说明书检测小鼠血清EPO。
小鼠组织HIF蛋白质印迹分析
将在-80℃下保存的小鼠组织以液氮冷却的研钵和研棒弄成粉。使用NE-PER试剂盒(Pierce Biotechnology)制备核提取物。为进行免疫沉淀,以200:1的组织与抗体比将核提取物加入针对HIF-1α的单克隆抗体(Novus,Littleton,CO)中。在4℃下,将所述悬浮物在锥形微量离心管中孵育4小时。然后将蛋白A/G-偶联的琼脂糖珠(40μL的50%悬浮物)加入所述管中。在4℃下翻转过夜后,将所述珠以冰冷的磷酸盐缓冲盐水洗涤3次。然后用40μL的Laemmli样品缓冲液对所述珠制备用于SDS-PAGE。将在SDS-PAGE上分离的蛋白质用XCell-II Blot Module系统(Invitrogen,Carlsbad,CA)转移至硝酸纤维素膜上。以5%BSA封闭所述印迹物,然后与以1:100稀释的针对HIF-1α的兔抗体(Novus)孵育。然后,将所述印迹物以Tris-缓冲盐水/Tween-20缓冲物洗涤,并与辣根过氧化物酶缀合的山羊抗兔二抗(Pierce,Rockford,IL)孵育。将印迹物以ECL试剂(Amersham,Piscataway,NJ)显色。以EpsonExpression 1600扫描仪捕获印迹物图像。
下表VIII提供了对本发明化合物体内反应的非限制性实例,例如HIFPH2(EGLN1)抑制和VEGF刺激。
表VIII
将化合物F2在上文描述的小鼠血清EPO测定中进一步进行测试,发现具有EPO EC50=14μM。
增强中性粒细胞活性
本发明的一个方面涉及所公开的化合物可提供的中性粒细胞活性增加和中性粒细胞寿命增加。以下提供由所公开的化合物增加吞噬作用的方法和实例。在下面的实例中,金黄色葡萄球菌Newman细胞株是ATCC#25904,耐甲氧苯青霉素金黄色葡萄球菌株是ATCC#33591,U937细胞株系是ATCC#CRL-1593.2。HaCaT细胞通过Boukamp P et al.,“Normal keratinization in a spontaneouslyimmortalized aneuploid human keratinocyte cell line.”J Cell Biol.(1988)Mar:106(3):761-71的方法产生。
对于细菌测定,可将金黄色葡萄球菌(ATCC 33591)在Todd-Hewitt培养液(THB)中培养至对数期(0.4的OD600或约5x 107cfu/mL),然后沉淀、洗涤并重悬浮于PBS或RPMI 1640组织培养培养基至所需的浓度。来自健康志愿者的静脉血可用于全血和中性粒细胞分离。中性粒细胞可使用PolyMorphPrep Kit(Axis Shield)根据制造商说明书进行纯化。人单核细胞株系U937可在加有10%胎牛血清、1mmol/L NaPyr、10mmol/L HEPES和葡萄糖的RPMI 1640中增殖。全血或吞噬细胞可用含羞草素(Sigma-Aldrich)(0-500μmol/L)预孵育2-4小时,然后用金黄色葡萄球菌(100μL中105cfu加至300μL全血中,或者以对于分离的吞噬细胞的1细菌/细胞的MOI)激发。然后在30分钟(全血和中性粒细胞)或60分钟(U937单核细胞)后将小份铺板在THB琼脂糖上以计算存活的金黄色葡萄球菌的菌落形成单位。
实施例5
将分离的人中性粒细胞于37oC用对照(二甲亚砜(DMSO))以及50μM和200μM的表VIII中公开的化合物预孵育1小时。然后将金黄色葡萄球菌(Newman株)以约0.1的MOI(每10个中性粒细胞1个细菌)加入中性粒细胞中。在60和90分钟采样,其中将中性粒细胞用水溶解,并且对Todd-Hewitt培养基(THB)琼脂糖平板上的剩余总细菌计数。
图2绘出了表VIII中公开的化合物在50μM和200μM的浓度下相对对照在增强杀死金黄色葡萄球菌(Newman株)中的效力。如可在图2中可以看出的,在感染后90分钟,在200μM的浓度下约一半的菌落形成单位不存在。
实施例6
将来自人单核细胞株系U937的细胞于37oC在5%CO2的气氛下用对照(DMSO)和10μM的表VIII中公开的化合物预孵育2小时。然后将金黄色葡萄球菌(有毒Newman株)以约1的MOI(每1个中性粒细胞1个细菌)加入中性粒细胞中。在感染后30、60、90和120分钟采样。将U937细胞用TritonTM溶解并对THB琼脂糖平板上剩余的细菌量计数。
如图3所绘,表VIII中公开的化合物4-脯氨酰羟化酶抑制剂在杀死金黄色葡萄球菌方面与对照(DMSO)相比有效。在第120分钟,当用10μM的表VIII中公开的化合物处理单核细胞时,所述表VIII中公开的化合物杀死84%的Newman株金黄色葡萄球菌,藉此表明因中性粒细胞寿命延长引起了吞噬作用增加。
实施例7
将来自人单核细胞株系U937的两个细胞样品用10μM的表VIII中公开的化合物预处理。一个样品预孵育1小时,另一个样品预孵育2小时,均于37oC在5%CO2的气氛下预孵育。然后以约1-2的MOI(每1个细胞1-2个细菌)加入金黄色葡萄球菌(有毒Newman株)。在感染后30、60、90和120分钟从每个样品中取出细胞小份,将所述U937细胞立即用TritonTM溶解,并对THB琼脂糖平板上剩余总细菌计数。
如图4所绘,用10μM的表VIII公开的化合物预处理1小时的U937单核细胞(黑色条)在感染后120分钟几乎不呈现菌落形成单位,而在感染前2小时预处理的细胞与未处理的细胞相比呈现约15%的菌落形成单位。此外,图4表明在U937单核细胞暴露于金黄色葡萄球菌(Newman株)后的1小时之内,呈现的菌落形成单位数量相对于未接受HIF-1α抑制剂的细胞显著降低。
实施例8
将来自人单核细胞株系U937的两个细胞样品于37°C在5%CO2的气氛下用10μM的表VIII中公开的化合物预处理。将金黄色葡萄球菌(Newman株)加入一个样品,并将耐甲氧苯青霉素金黄色葡萄球菌(MRSA)加入另一个样品。所述两种细菌均以约2-3的MOI(每个细胞2-3个细菌)加入。在感染后30、60、90和120分钟从每个样品中取出细胞小份。将U937细胞立即用TritonTM溶解并对THB琼脂糖平板上剩余总细菌计数。
如图5所绘,在感染后120分钟MRSA感染的细胞仅呈现25%的菌落形成单位的平均百分比,如黑色条所示。图5还绘出,在感染后60分钟,金黄色葡萄球菌的Newman株与对照相比仅呈现约12%的菌落形成单位的平均百分比,而在感染后120分钟几乎不呈现菌落形成单位,如阴影条表示。
实施例9
将用10μM的表VIII中公开的化合物处理的来自人单核细胞株系U937的两个细胞样品用金黄色葡萄球菌(Newman株)或耐甲氧苯青霉素金黄色葡萄球菌(MRSA)感染。所述两种细菌均以约2-3的MOI(每个细胞2-3个细菌)加入。在感染后30、60、90和120分钟从每个样品中取出细胞小份。将U937细胞立即用TritonTM溶解并对THB琼脂糖平板上剩余总细菌计数。
如图6所绘,即使没有用表VIII中公开的化合物预处理,在感染后60分钟金黄色葡萄球菌Newman株仅呈现25%的菌落形成单位的平均百分比,如黑色条所示。MRSA菌株降低至低于约40%的菌落形成单位的平均百分比,如阴影条所示。
实施例10
将来自人单核细胞株系U937的三个细胞样品用100μM的含羞草素、2μg/mL的万古霉素或10μM的表VIII中公开的化合物处理。将每个样品均用金黄色葡萄球菌(Newman株)或耐甲氧苯青霉素金黄色葡萄球菌(MRSA)感染。所述两种细菌均以约2-3的MOI(每个细胞2-3个细菌)加入。在感染后120分钟,从全部6个样品中取出小份,将U937细胞立即用TritonTM溶解并对THB琼脂糖平板上剩余总细菌计数。
如图7所绘,与含羞草素处理的细胞相比,10μM的表VIII中公开的化合物增强了对全部两种细菌菌株即金黄色葡萄球菌Newman(阴影条)或MRSA(黑色条)的杀死。如图7还绘出的,参照代表Newman株的阴影条,用10μM的表VIII中公开的化合物处理的样品具有比用含羞草素处理的细胞更低的菌落形成单位的平均百分比。被MRSA感染的U937细胞(黑色条)相对未处理的细胞呈现约40%的菌落形成单位,小于用含羞草素处理的细胞的一半。
图8绘出了当用10μM的表VIII中公开的化合物处理时,在感染后30、60、90和120分钟,人单核细胞(U937)相对对照的菌落形成单位(Newman株)的平均百分比。其中黑色条代表在金黄色葡萄球菌感染开始时用表VIII中公开的化合物处理,阴影条代表用表VIII中公开的化合预处理,白色线代表在金黄色葡萄球菌感染前2小时预处理的细胞。
图9绘出了当将HaCaT细胞以800μM的含羞草素、10μM的表VIII中公开的化合物或1μg/mL的万古霉素根据上面的实施例预处理1小时再用金黄色葡萄球菌(Newman株,阴影条)和耐甲氧苯青霉素金黄色葡萄球菌(MRSA,黑色条)接种时,感染后120分钟相对DMSO(对照)的菌落形成单位的平均百分比。图10绘出了当将HaCaT细胞以10μM的表VIII中公开的化合物根据上面的实施例预处理1小时时,被金黄色葡萄球菌的Newman株(阴影条)和MRSA(黑色条)感染后30、60、90和120分钟的菌落形成单位的平均百分比。
图11绘出了相对野生型对照(H),用剂量为1μM(E)、10μM(F)和50μM(G)的表VIII中公开的化合物处理后野生型鼠胚胎成纤维细胞中磷酸甘油酸激酶(PGK)表达的上调;以及用剂量为1μM(A)、10μM(B)和50μM(C)的表VIII中公开的化合物处理后HIF-1敲除细胞和HIF-1敲除对照(D)中PGK表达上调的缺失。所述两种细胞类型均被处理7小时。
图12绘出了相对野生型对照(G),用剂量为1μM(E)和10μM(F)的表VIII中公开的化合物处理后野生型鼠胚胎成纤维细胞中磷酸甘油酸激酶(PGK)表达的上调;以及用剂量为1μM(A)、10μM(B)和50μM(C)的表VIII中公开的化合物处理后HIF-1敲除细胞和HIF-1敲除对照(D)中PGK表达上调的缺失。
图13绘出了相对野生型对照(H),用剂量为1μM(E)、10μM(F)和50μM(G)的表VIII中公开的化合物处理后野生型鼠胚胎成纤维细胞中磷酸甘油酸激酶(PGK)表达的上调;以及用剂量为1μM(A)、10μM(B)和50μM(C)的表VIII中公开的化合物处理后HIF-1敲除细胞和HIF-1敲除对照(D)中PGK表达上调的缺失。
血管内皮生长因子(VEGF)依赖于细胞中HIF-1的存在。图14绘出了相对对照(H),用剂量为1μM(E)、10μM(F)和50μM(G)的表VIII中公开的化合物处理后野生型鼠胚胎成纤维细胞中血管内皮生长因子表达的上调;以及用剂量为1μM(A)、10μM(B)和50μM(C)的表VIII中公开的化合物处理后HIF-1敲除细胞和HIF-1敲除对照(D)中VEGF表达上调的缺失。所述两种细胞类型均被处理7小时。如在图14中可看出的,VEGF在剂量为10μM(F)和50μM(G)时增加。在HIF-1敲除细胞中,当HIF-1敲除细胞被给予1μM(A)、10μM(B)和50μM(C)的剂量时,与野生型对照(H)和HIF-1敲除对照(D)相比PGK上调未增加。
创伤愈合
实施例11
将24只小鼠分成3组。通过于第0天皮下注射对第2组动物进行细菌接种(金黄色葡萄球菌抗生素敏感Newman株[ATCC#25904]),并从感染后2小时开始给予10μM的表VIII中公开的化合物,共给予6天(第0-5天)。第1组接受DMSO的皮下注射。第3组作为对照组,不接受处理。在所述研究过程中每日监测损伤大小。仅将开放性创伤看作损伤;不对非开放性创伤的肿块和白痕测量损伤大小。在第7天,测量最终损伤大小并杀死小鼠以确定皮肤和肾脏的细菌载量。感染后第7天,最后损伤大小测量后杀死小鼠并收集损伤的皮肤组织和两个肾脏。将皮肤和肾脏在磷酸盐缓冲液中均化后,连续稀释并铺板于Todd-Hewitt琼脂糖平板上以对细菌的菌落形成单位进行计数。
图15示出了相对用DMSO处理的动物(实心方块(■)),用10μM的表VIII中公开的化合物处理的第1组中的动物(实心圆(●))的皮肤损伤(创伤)大小的显著减小。如图15所绘,小鼠被金黄色葡萄球菌Newman株感染并在感染后2小时用10μM的表VIII中公开的化合物或DMSO(对照)处理。所述数据示出了用表VIII中公开的化合物(实心圆(●))或DMSO (实心方块(■))处理的动物的皮肤损伤(创伤)的大小的统计上显著的减小。
图16示出了相对未处理的动物(实心三角(▲)),用10μM的表VIII中公开的化合物处理的第1组中的动物(实心圆(●))的皮肤损伤(创伤)的大小的显著减小。如图16所绘,小鼠被金黄色葡萄球菌Newman株感染并在感染后2小时用10μM的表VIII中公开的化合物处理或不进行处理。所述数据示出了用表VIII中公开的化合物处理(实心圆(●))或不进行处理(实心三角(▲))的动物的皮肤损伤(创伤)大小的减小。
实施例12
将24只小鼠分成3组。通过于第0天皮下注射对第1组动物进行细菌接种(金黄色葡萄球菌抗生素敏感Newman株[ATCC#25904]),并从感染后2小时开始给予10μM的表VIII中公开的化合物,共给予6天(第0-5天)。第2组接受DMSO的皮下注射。第3组作为对照组,不接受处理。在所述研究过程中每日监测损伤大小。仅将开放性创伤看作损伤;不对非开放性创伤的肿块和白痕测量损伤大小。感染后第7天,最后损伤大小测量后杀死小鼠并收集损伤的皮肤组织和两个肾脏。将皮肤和肾脏在磷酸盐缓冲液中均化后,连续稀释并铺板于Todd-Hewitt琼脂糖平板上以对细菌的菌落形成单位进行计数。
图17是直方图,其中绘出了每克皮肤组织所观察到的菌落形成单位的数量。直线表示每组的平均值。绘出了未处理组的结果(A)、用DMSO处理的组的结果(B)和用10μM的表VIII中公开的化合物处理的组的结果(C)。
图18是对在所述动物的肾脏中所发现细菌观察到的菌落形成单位。绘出了未处理组的结果(A)、用DMSO处理的组的结果(B)和用10
μM的表VIII中公开的化合物处理的组的结果(C)。如可从这些数据看出的,一半用表VIII中公开的HIF-1α脯氨酰羟化酶抑制剂处理的动物在肾脏中无细菌,表明表VIII中公开的化合物能够系统性地防止感染从伤口到肾脏的扩散。
实施例13
将20只小鼠分成2组。通过于第0天皮下注射对第1组动物进行细菌接种(酿脓链球菌NZ131[M49株]),并从感染前2小时开始每天一次用表VIII中公开的化合物进行预处理,共持续4天(第0-3天)。将表VIII中公开的化合物在环糊精中制剂,并在蒸馏水中稀释,然后以0.5mg/kg的剂量进行皮下注射。在所述研究过程中每日监测损伤大小。仅将开放性创伤看作损伤;不对非开放性创伤的肿块和白痕测量损伤大小。感染后第4天,最后损伤大小测量后杀死小鼠并收集损伤的皮肤组织和两个肾脏。将皮肤和肾脏在磷酸盐缓冲液中均化后,连续稀释并铺板于Todd-Hewitt琼脂糖平板上以对细菌的菌落形成单位进行计数。
图19绘出了实施例13的结果,其中用酿脓链球菌NZ131[M49株]处理2组动物。数据示出了相对于用载体对照(环糊精)处理的动物(实心圆(●)),用0.5mg/kg的表VIII中公开的化合物处理的第1组中的动物(实心三角(▲))的皮肤损伤(伤口)大小的减小。图20的绘图也绘出了实施例12的结果,其中绘出了在用载体对照(环糊精)处理的动物上观察到的皮肤损伤的菌落形成单位的数量(A)和用0.5mg/kg的表VIII中公开的化合物处理的组的结果(B)。
试剂盒
还公开了包含所述HIF-1α脯氨酰羟化酶抑制剂的试剂盒,所述HIF-1α脯氨酰羟化酶抑制剂将被送递至人或哺乳动物中。所述试剂盒可以包含:一个或多个包装单位剂量的包含一种或多种将被送递至人、哺乳动物或细胞中的HIF-1α脯氨酰羟化酶抑制剂的组合物。所述单位剂量安瓿或多剂量容器,待送递的HIF-1α脯氨酰羟化酶抑制剂在使用之前包装于其中,可以包含熔封容器,所述熔封容器封装一份多核苷酸或者包含适合其药物有效剂量或多个有效剂量的物质的溶液。所述HIF-1α脯氨酰羟化酶抑制剂可以包装为无菌制剂,所述熔封容器可设计成保持所述制剂无菌至使用。
所公开的HIF-1α脯氨酰羟化酶抑制剂还可以为用于将气溶剂形式的活性治疗剂送递至体腔例如鼻、喉或支气管道的液体剂、乳剂或悬浮剂。在这些制品中,所述HIF-1α脯氨酰羟化酶抑制剂与其他复合剂的比例将随剂型的要求变化。
取决于预计的给药方式,药学组合物可以固体、半固体或液体剂型,例如片剂、栓剂、丸剂、胶囊剂、粉剂、液体剂、悬浮剂、洗剂、霜剂、凝胶剂等,优选适合用于单次精确剂量给药的单位剂型。如上所述,所述组合物将包括与可药用载体结合的有效量的所述HIF-1α脯氨酰羟化酶抑制剂,并且另外可包括其他医学剂、药物剂、载体、助剂、稀释剂等。
对于固体组合物,常规无毒固体载体包括,例如,医药级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石、纤维素、葡萄糖、蔗糖、碳酸镁等。液体药物给药的组合物可通过例如如以下方式制备:将本文所述的活性化合物和任选的药学助剂在赋形剂(例如水、右旋糖盐水、甘油、乙醇等)中溶解、分散等,从而形成溶液或悬浮液。如果需要,待给药的药物组合物还可包含微量的无毒辅助物质例如润湿剂或乳化剂、pH缓冲剂等,例如乙酸钠、脱水山梨醇单月桂酸酯、三乙醇胺乙酸钠、三乙醇胺油酸酯等。制备所述剂型的实际方法是已知的,或者对本领域技术人员是显而易见的;例如参见以上参考的Remington′s PharmaceuticalSciences。
如果使用肠胃外给药,其特征通常是注射。注射剂可以制备为常规形式,为液体溶液剂或悬浮剂、为适合用于在注射之前溶于或悬浮于液体的固体形式,或为乳剂。肠胃外给药的最近修改的方法包括使用缓释或持续释放体系,使得保持不变的剂量水平。参见,例如美国专利3,710,795,其通过引用的方式纳入本文。
当HIF-1α脯氨酰羟化酶抑制剂被送递至人之外的哺乳动物中时,所述哺乳动物可为非人类灵长类、马、猪、兔、狗、绵羊、山羊、牛、猫、豚鼠或啮齿目动物。术语人和哺乳动物不表示特定年龄或性别。因此,成年和新生受试者,以及胎儿,无论是雄性或雌性,均意欲被涵盖在内。患者、受试者、人或哺乳动物指患有疾病或病症的受试者。术语“患者”包括人和兽医受试者。
尽管已举例说明并描述了本发明公开的具体实施方案,但是对于本领域技术人员来说明显的是,可在不脱离本发明的主旨和范围的情况下做出多种其他变化和修改。因此,所附的权利要求书意欲包括本发明范围内的所有这些变化和修改。
Claims (34)
2.权利要求1的化合物,其中R4是甲基。
3.权利要求1的化合物,其中R4是乙基。
4.权利要求1的化合物,其中R4是叔丁基。
5.权利要求1-4任一项的化合物,其中Z是4-氯苯基。
6.权利要求1-4任一项的化合物,其中Z选自2-氯苯基、3-氯苯基、2-氟苯基、3-氟苯基或4-氟苯基。
7.权利要求1-4任一项的化合物,其中Z选自2,3-二氟苯基、2,4-二氟苯基、2,5-二氟苯基、2,6-二氟苯基、2,3-二氯苯基、2,4-二氯苯基、2,5-二氯苯基和2,6-二氯苯基。
8.化合物4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯。
9.选自以下的化合物:
4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯;
4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯;
4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯;
4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯;和
4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯。
10.权利要求1-9任一项的化合物,其中所述化合物是选自以下的阴离子的可药用盐:氯离子、溴离子、碘离子、硫酸根、硫酸氢根、碳酸根、碳酸氢根、磷酸根、磺酸氢根、对甲苯磺酸根、甲磺酸根、甲酸根、乙酸根、丙酸根、丁酸根、丙酮酸根、乳酸根、草酸根、丙二酸根、马来酸根、琥珀酸根、酒石酸根、延胡索酸根、甘醇酸根或柠檬酸根。
12.权利要求11的组合物,其中R4是甲基。
13.权利要求11的组合物,其中R4是乙基。
14.权利要求11的组合物,其中R4是叔丁基。
15.权利要求11-14任一项的组合物,其中Z是4-氯苯基。
16.权利要求11-14任一项的组合物,其中Z选自2-氯苯基、3-氯苯基、2-氟苯基、3-氟苯基或4-氟苯基。
17.权利要求11-14任一项的组合物,其中Z选自2,3-二氟苯基、2,4-二氟苯基、2,5-二氟苯基、2,6-二氟苯基、2,3-二氯苯基、2,4-二氯苯基、2,5-二氯苯基和2,6-二氯苯基。
18.权利要求11的组合物,包含4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯。
19.权利要求11的组合物,包含一种或多种选自以下的化合物:
4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯;
4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯;
4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯;
4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯;和
4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯。
20.权利要求11-19任一项的组合物,其中所述化合物是选自以下的阴离子的可药用盐:氯离子、溴离子、碘离子、硫酸根、硫酸氢根、碳酸根、碳酸氢根、磷酸根、磺酸氢根、对甲苯磺酸根、甲磺酸根、甲酸根、乙酸根、丙酸根、丁酸根、丙酮酸根、乳酸根、草酸根、丙二酸根、马来酸根、琥珀酸根、酒石酸根、延胡索酸根、甘醇酸根或柠檬酸根。
21.权利要求11-20任一项的组合物,还包含一种或多种化疗剂。
22.权利要求21的组合物,其中所述化疗剂选自5-氟尿嘧啶、紫杉醇或甲酰四氢叶酸。
23.权利要求11-20任一项的组合物,还包含一种或多种疫苗。
24.权利要求23的组合物,其中所述疫苗激发抗肝炎、流感、麻疹、风疹、破伤风、脊髓灰质炎或狂犬病的抗体。
26.权利要求25的用途,其中R4是甲基。
27.权利要求25的用途,其中R4是乙基。
28.权利要求25的用途,其中R4是叔丁基。
29.权利要求25的用途,其中Z是4-氯苯基。
30.权利要求25的用途,其中Z选自2-氯苯基、3-氯苯基、2-氟苯基、3-氟苯基或4-氟苯基。
31.权利要求25的用途,其中Z选自2,3-二氟苯基、2,4-二氟苯基、2,5-二氟苯基、2,6-二氟苯基、2,3-二氯苯基、2,4-二氯苯基、2,5-二氯苯基和2,6-二氯苯基。
32.权利要求25的用途,其中包含4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯。
33.权利要求25的用途,其中所述化合物选自:
4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯;
4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯;
4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯;
4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯;和
4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯。
34.权利要求25的用途,其中所述化合物是选自以下的阴离子的可药用盐:氯离子、溴离子、碘离子、硫酸根、硫酸氢根、碳酸根、碳酸氢根、磷酸根、磺酸氢根、对甲苯磺酸根、甲磺酸根、甲酸根、乙酸根、丙酸根、丁酸根、丙酮酸根、乳酸根、草酸根、丙二酸根、马来酸根、琥珀酸根、酒石酸根、延胡索酸根、甘醇酸根或柠檬酸根。
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