CN111032040B - 组蛋白去乙酰酶的双环抑制剂 - Google Patents
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Abstract
本文提供了可用于治疗与抑制HDAC(例如HDAC2)相关的病症的化合物及其药学上可接受的盐,以及其药物组合物。
Description
相关申请
本申请要求于2017年8月7日提交的美国临时申请号62/541,807的优先权,其内容通过引用并入本文。
关于联邦政府赞助的研究与开发的声明
本发明是在美国国立卫生研究院(NIH)授予的小型企业创新研究(SBIR)基金1R43AG048651-01A1的政府支持下完成的。该政府对本发明享有一定的权利。
背景技术
组蛋白去乙酰酶(HDAC)抑制剂已显示出调节转录并诱导细胞生长停滞、分化和凋亡。HDAC抑制剂还增强了用于癌症治疗的治疗剂(包括放疗药物和化疗药物)的细胞毒性作用。Marks,P.,Rifkind,R.A.,Richon,V.M.,Breslow,R.,Miller,T.,Kelly,W.K.Histonedeacetylases and cancer:causes and therapies.Nat Rev Cancer,1,194-202,(2001);以及Marks,P.A.,Richon,V.M.,Miller,T.,Kelly,W.K.Histone deacetylaseinhibitors.Adv Cancer Res,91,137-168,(2004)。此外,最近的证据表明了转录失调可能导致某些神经退行性病症的分子发病机理,例如亨廷顿病、脊髓性肌萎缩症、肌萎缩性侧索硬化症和缺血。Langley,B.,Gensert,J.M.,Beal,M.F.,Ratan,R.R.Remodeling chromatinand stress resistance in the central nervous system:histone deacetylaseinhibitors as novel and broadly effective neuroprotective agents.Curr DrugTargets CNS Neurol Disord,4,41-50,(2005)。最近的综述已总结的证据表明了异常的组蛋白乙酰转移酶(HAT)和组蛋白去乙酰酶(HDAC)活性可能代表了导致神经变性的常见潜在机制。此外,使用小鼠的抑郁症模型,Nestler最近已经强调了组蛋白去乙酰酶抑制剂(HDAC5)在抑郁症中的治疗潜力。Tsankova,N.M.,Berton,O.,Renthal,W.,Kumar,A.,Neve,R.L.,Nestler,E.J.Sustained hippocampal chromatin regulation in a mouse modelof depression and antidepressant action.Nat Neurosci,9,519-525,(2006)。
存在18种已知的人类组蛋白去乙酰酶,基于其辅助结构域的结构将其分为四类。I类包括HDAC1、HDAC2、HDAC3和HDAC8,且与酵母RPD3具有同源性。HDAC4、HDAC5、HDAC7和HDAC9属于IIa类,且与酵母具有同源性。HDAC6和HDAC10含有两个催化位点,并被分类为IIb类。III类(去乙酰化酶)包括SIRT1、SIRT2、SIRT3、SIRT4、SIRT5、SIRT6和SIRT7。HDAC11是HDAC家族中另一个最近鉴定的成员,并在其催化中心具有保守的残基,这些残基被I类和II类去乙酰酶共享,且有时被置于IV类中。
相反,HDAC已显示出长期记忆过程的强大负调节剂。非特异性HDAC抑制剂增强了突触可塑性以及长期记忆(Levenson等人.,2004,J.Biol.Chem.279:40545-40559;Lattal等人,2007,Behav Neurosci 121:1125-1131;Vecsey等人,2007,J.Neurosci 27:6128;Bredy,2008,Learn Mem 15:460-467;Guan等人,2009,Nature 459:55-60;Malvaez等人,2010,Biol.Psychiatry 67:36-43;Roozendaal等人,2010,J.Neurosci.30:5037-5046)。例如,HDAC抑制可将不会导致长期记忆的学习事件转变为会导致大量长期记忆的学习事件(Stefanko等人,2009,Proc.Natl.Acad.Sci.USA 106:9447-9452)。此外,HDAC抑制还可产生长期记忆的形式,这种记忆会持续超出正常记忆故障的时间点。已显示HDAC抑制剂可改善阿尔茨海默氏病遗传模型中的认知缺陷(Fischer等人,2007,Nature 447:178-182;Kilgore等人,2010,Neuropsychopharmacology 35:870-880)。这些证明表明了经由HDAC抑制的调节记忆对许多记忆和认知病症具有巨大的治疗潜力。
当前,最近的两项研究已探索了单个HDAC在长期记忆中的作用。Kilgore等人2010,Neuropsychopharmacology 35:870-880揭示了非特异性HDAC抑制剂(例如丁酸钠)抑制I类HDAC(HDAC1、HDAC2,HDAC3、HDAC8),而对IIa类HDAC家族成员(HDAC4、HDAC5、HDAC7、HDAC9)影响很小。这表明了抑制I类HDAC对许多研究中观察到的认知增强可能至关重要。实际上,HDAC2而不是HDAC1的前脑和神经元特异性过表达降低了树突棘密度、突触密度、突触可塑性和记忆形成(Guan等人,2009,Nature,459:55-60)。相反,HDAC2敲除小鼠显示出神经元中增加的突触密度、增加的突触可塑性和增加的树突密度。这些HDAC2缺陷小鼠还表现出一系列学习行为范例中增强的学习和记忆。该工作证明了HDAC2是突触发生和突触可塑性的关键调节剂。另外,Guan等人表明了用SAHA(HDAC 1、2、3、6、8抑制剂)慢性治疗小鼠可再现在HDAC2缺陷小鼠中看到的效果并消除HDAC2过表达小鼠中的认知障碍。
HDAC2的抑制(选择性或与其它I类HDAC抑制组合)是一种有吸引力的治疗靶标。这种抑制具有通过增加神经元细胞群体中突触和树突密度来增强认知并促进学习过程的潜力。另外,HDAC2的抑制还可以治疗性地用于治疗多种其它疾病和病症中。
发明内容
公开了可用于治疗与HDAC(例如HDAC2)活性有关的病症的化合物及其药学上可接受的盐、以及药物组合物。参见例如表1。
本文所述某些化合物的优点之一是它们具有增强的安全性参数。例如,某些化合物的底部苯环上包括一个额外的氟原子,这提供几乎提高2倍的安全性,表明对人类红系细胞和髓系祖细胞的影响较小。参见例如表4,比较物1与化合物10;比较物2与化合物3;比较物5与化合物1;以及比较物6与化合物2。在位置异构体(将比较物4与化合物8进行比较)和用氢代替氟(将比较物3与化合物6进行比较)之间观察到类似的结果。
所公开的化合物可治疗的病症包括但不限于神经系统病症、记忆或认知功能障碍或损伤、灭绝学习障碍、真菌疾病或感染、炎性疾病、血液疾病、肿瘤性疾病、精神病和记忆减退。
具体实施方式
1.化合物
本文提供的化合物具有选自以下的式子:
或其药学上可接受的盐。
实施例部分提供了本公开中包括的化合物的其它示例。包括这些化合物的药学上可接受的盐以及中性形式。
2.定义
如本文所用的术语“受试者”和“患者”可以互换使用,并且是指需要治疗的哺乳动物,例如伴侣动物(例如狗、猫等),农场动物(例如牛、猪、马、绵羊、山羊等)和实验动物(例如大鼠、小鼠、豚鼠等)。通常,受试者是需要治疗的人。
包括本文所述的化合物的药学上可接受的盐以及中性形式。对于药物用途,化合物的盐是指无毒的“药学上可接受的盐”。药学上可接受的盐形式包括药学上可接受的酸性/阴离子或碱性/阳离子盐。药学上可接受的碱性/阳离子盐包括钠、钾、钙、镁、二乙醇胺、正甲基-D-葡萄糖胺、L-赖氨酸、L-精氨酸、铵、乙醇胺、哌嗪和三乙醇胺的盐。药学上可接受的酸性/阴离子盐包括例如乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、酒石酸氢盐、碳酸盐、柠檬酸盐、二盐酸盐、葡萄糖酸盐、谷氨酸盐、甘氨酰水杨酸盐、间苯二酚己酸盐、氢溴酸盐、盐酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、硝酸盐、水杨酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐和甲苯磺酸盐。
术语“药学上可接受的载体”是指不破坏与其配制的化合物的药理活性的无毒载体、佐剂或媒介物。可以用于本文所述的组合物中的药学上可接受的载体、佐剂或媒介物包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(例如人血清白蛋白)、缓冲物质(例如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质(例如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素基物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物、聚乙二醇和羊毛脂。
术语“治疗(treatment)”、“治疗(treat)”和“治疗(treating)”是指逆转、减轻、减少患病的可能性或抑制疾病或障碍或本文所述其一种或多种症状的进展。在一些实施方式中,可以在一种或多种症状发生后给予治疗,即治疗性治疗。在其它实施方式中,可以在没有症状下给予治疗。例如,可以在症状发作之前对易感个体给予治疗(例如根据症状史和/或根据遗传或其它易感因素),即预防性治疗。症状缓解后也可以继续治疗,例如预防或延迟其复发。
术语“有效量”或“治疗有效量”包括本文所述的化合物的量,该量将引起受试者的生物学或医学反应,例如在0.01-100mg/kg体重/天之间的所提供化合物,例如0.1-100mg/kg体重/天。
3.用途、制剂和施用
在一些实施方式中,本文所述的化合物和组合物可用于治疗与HDAC的活性有关的病症。这样的条件包括例如以下描述的那些。
最近报告具有详细的组蛋白乙酰化在中枢神经系统(“CNS”)功能(例如神经元分化、记忆形成、药物成瘾和抑郁症)中的重要性(Citrome,Psychopharmacol.Bull.2003,37,Suppl.2,74-88;Johannessen,CNS Drug Rev.2003,9,199-216;Tsankova等人,2006,Nat.Neurosci.9,519-525)。因此,在一方面,提供的化合物和组合物可用于治疗神经系统障碍。神经系统障碍的示例包括:(i)慢性神经退行性疾病,例如家族性和偶发性肌萎缩性侧索硬化症(分别为FALS和ALS)、家族性和偶发性帕金森氏病、亨廷顿病、家族性和偶发性阿尔茨海默病、多发性硬化症、肌肉营养不良、橄榄桥脑小脑萎缩、多系统萎缩、威尔逊氏病、进行性核上性麻痹、弥漫性路易体病、皮质十二指肠退变、进行性家族性肌阵挛性癫痫、纹状体退变、扭转肌张力障碍、家族性震颤、唐氏综合症、多发性抽动秽语综合症、哈勒沃登-施帕茨病、糖尿病周围神经病变、拳击员痴呆(dementia pugilistica)、艾滋病痴呆、年龄相关的痴呆、年龄有关的记忆受损以及淀粉样变性相关的神经退行性疾病,例如由病毒蛋白(PrP)引起的与传染性海绵状脑病有关的那些疾病(克雅氏病、杰茨曼-斯脱司勒-史茵克综合征、瘙痒病和库鲁病)以及由胱抑素C过量积累引起的那些疾病(遗传性胱抑素C血管病);(ii)急性神经退行性疾病,例如外伤性脑损伤(例如与手术相关的脑损伤)、脑水肿、周围神经损伤、脊髓损伤、利氏病、格林巴利综合征、溶酶体贮积症(例如脂褐藻病)、阿尔珀氏病、腿不安综合征、中枢神经系统退变导致的眩晕;慢性酒精或药物滥用引起的病理包括例如蓝小脑和小脑神经元的退变、药物引起的运动障碍;衰老引起的病理,包括小脑神经元和皮质神经元的退变导致认知和运动障碍;慢性苯丙胺滥用引起的病理,包括基底神经节神经元退变导致运动受损;由局灶性创伤引起的病理变化,例如中风、局灶性缺血、血管功能不全、缺氧缺血性脑病、高血糖症、低血糖症或直接创伤;治疗药物和治疗的负面副作用引起的病理(例如对NMDA类谷氨酸受体拮抗剂的抗惊厥剂量响应的扣带回和内嗅皮层神经元退变)和Wernicke-Korsakoff氏相关痴呆。影响感觉神经元的神经系统障碍包括弗里德赖希氏共济失调、糖尿病、周围神经病变和视网膜神经元退变。其它神经系统障碍包括神经损伤或与脊髓损伤相关的创伤。边缘和皮质系统的神经系统障碍包括脑淀粉样变性、皮克氏萎缩和瑞兹综合症。在另一方面,神经系统障碍包括情绪障碍,例如情感障碍和焦虑症;以及社会行为障碍,例如性格缺陷和人格障碍;学习、记忆和智力障碍,例如智力低下和痴呆。因此,在一方面,所公开的化合物和组合物可用于治疗精神分裂症、谵妄、注意力缺陷障碍(ADD)、分裂情感障碍、阿尔茨海默病、鲁宾斯坦-泰比综合征、抑郁症、躁狂症、注意力缺陷障碍、药物成瘾、痴呆、躁动、冷漠、焦虑、精神病、人格障碍、双相情感障碍、单相情感障碍、强迫症、进食障碍、创伤后应激障碍、易怒、青少年行为障碍和去抑制。
转录被认为是长期记忆过程的关键步骤(Alberini,2009,Physiol.Rev.89,121-145)。特异性染色质修饰(例如组蛋白乙酰化)可促进转录,该修饰可调节组蛋白与DNA的相互作用(Kouzarides,2007,Cell,128:693-705)。修饰酶(例如组蛋白乙酰转移酶(HAT)和组蛋白去乙酰酶(HDAC))可调节组蛋白尾巴上的乙酰化状态。通常,组蛋白乙酰化可促进基因表达,而组蛋白去乙酰化可导致基因沉默。大量研究已经表明了有效的HAT(即cAMP响应元件结合蛋白(CREB)-结合蛋白(CBP))对长效形式的突触可塑性和长期记忆是必需的,(有关综述参见Barrett,2008,Learn Mem 15:460-467)。因此,在一方面,提供的化合物和组合物可用于促进认知功能并增强学习和记忆形成。
本文所述的化合物和组合物还可用于治疗真菌疾病或感染。
在另一方面,本文所述的化合物和组合物可用于治疗炎性疾病,例如中风、类风湿性关节炎、红斑狼疮、溃疡性结肠炎和创伤性脑损伤(Leoni等人,PNAS,99(5);2995-3000(2002);Suuronen等人.J.Neurochem.87;407-416(2003)和Drug Discovery Today,10:197-204(2005))。
在另一方面,本文所述的化合物和组合物可用于治疗由肿瘤细胞的增殖引起的癌症。这样的癌症包括例如实体瘤、肿瘤、癌、肉瘤、白血病、淋巴瘤等。一方面,可以通过本文所述的化合物和组合物治疗的癌症包括但不限于:贲门癌、肺癌、胃肠道癌、泌尿生殖道癌、肝癌、神经系统癌、妇科癌、血液癌、皮肤癌和肾上腺癌。在一方面,本文所述的化合物和组合物可用于治疗选自以下的贲门癌:肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤),粘液瘤,横纹肌瘤,纤维瘤,脂肪瘤和畸胎瘤。在另一方面,本文所述的化合物和组合物可用于治疗选自以下的肺癌:支气管癌(鳞状细胞、未分化的小细胞、未分化的大细胞、腺癌),肺泡(支气管)癌,支气管腺瘤,肉瘤,淋巴瘤,软骨瘤性错构瘤和间皮瘤。在一方面,本文所述的化合物和组合物可用于治疗选自以下的胃肠道癌:食道(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤),胃(癌、淋巴瘤、平滑肌肉瘤),胰腺(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类肿瘤,血管活性肠肽瘤),小肠(腺癌、淋巴瘤、类癌、卡波济肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤,纤维瘤)和大肠(腺癌、肾小管腺瘤、绒毛腺瘤,错构瘤、平滑肌瘤)。在一方面,本文所述的化合物和组合物可用于治疗选自以下的泌尿生殖道癌:肾脏(腺癌、威尔姆氏肿瘤[肾母细胞瘤]、淋巴瘤、白血病),膀胱和尿道(鳞状细胞癌、移行细胞癌、腺癌),前列腺(腺癌、肉瘤)和睾丸(精原细胞瘤、畸胎瘤、胚胎癌、畸胎癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤、脂肪瘤)。在一方面,本文所述的化合物和组合物可用于治疗选自以下的肝癌:肝癌(肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤,肝细胞腺瘤和血管瘤。
在一些实施方式中,本文所述的化合物涉及治疗选自以下的骨癌:成骨肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤,尤因氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨软骨瘤(骨软骨性外生骨疣)、良性软骨瘤、软骨母细胞瘤、软骨粘膜纤维瘤,骨样骨瘤和巨细胞瘤。
在一方面,本文所述的化合物和组合物可用于治疗选自以下的神经系统癌症:颅骨(骨瘤、血管瘤、肉芽肿、黄瘤、畸形性骨炎),脑膜(脑膜瘤、脑膜肉瘤、胶质瘤),脑(星形细胞瘤、髓母细胞瘤、神经胶质瘤、室管膜瘤、生殖细胞瘤[松果体瘤]、多形性胶质母细胞瘤、少突胶质细胞瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤)和脊髓(神经纤维瘤、脑膜瘤、神经胶质瘤、肉瘤)。
在一方面,本文所述的化合物和组合物可用于治疗选自以下的妇科癌症:子宫(子宫内膜癌),子宫颈(宫颈癌、肿瘤前宫颈发育不良),卵巢(卵巢癌[浆液性囊腺癌、粘液性囊腺癌,未分类癌],颗粒细胞-鞘膜细胞瘤,睾丸间质细胞瘤,免疫缺陷,恶性畸胎瘤),外阴(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤),阴道(透明细胞癌、鳞状细胞癌、葡萄状肉瘤(胚胎型横纹肌肉瘤)和输卵管(癌)。
在一方面,本文所述的化合物和组合物可用于治疗选自以下的皮肤癌:恶性黑素瘤、基底细胞癌、鳞状细胞癌、卡波济肉瘤、痣性增生痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕疙瘩和牛皮癣。
在一方面,本文所述的化合物和组合物可用于治疗选自神经母细胞瘤的肾上腺癌。
在一方面,本文所述的化合物和组合物可用于治疗癌症,所述癌症包括但不限于:白血病,包括急性白血病和慢性白血病,例如急性淋巴细胞白血病(ALL)、急性髓细胞白血病(AML)、慢性淋巴细胞白血病(CLL)、慢性粒细胞白血病(CML)和毛细胞白血病;淋巴瘤,例如皮肤T细胞淋巴瘤(CTCL),非皮肤外周T细胞淋巴瘤,与人T细胞淋巴营养病毒(HTLV)相关的淋巴瘤,例如成人T细胞白血病/淋巴瘤(ATLL)、霍奇金氏病(Hodgkin's disease)和非霍奇金氏病淋巴瘤、大细胞淋巴瘤,弥漫性大B细胞淋巴瘤(DLBCL);伯基特氏淋巴瘤;间皮瘤,原发性中枢神经系统(CNS)淋巴瘤;多发性骨髓瘤;儿童期实体瘤,例如脑肿瘤,神经母细胞瘤,视网膜母细胞瘤,威尔姆氏肿瘤,骨肿瘤和软组织肉瘤,成人常见的实体瘤,例如头颈癌(例如口腔癌、喉癌和食道癌),生殖泌尿系统癌(例如前列腺癌、膀胱癌、肾癌、子宫癌、卵巢癌、睾丸癌、直肠癌和结肠癌),肺癌,乳腺癌,胰腺癌,黑色素瘤和其它皮肤癌,胃癌,脑肿瘤,肝癌和甲状腺癌。
在一方面,本公开提供了一种治疗本文所述的病症的方法,所述方法包括向受试者施用有效量的本文所述的化合物或其药学上可接受的盐或组合物。
还提供了一种或多种本文所述的化合物或其药学上可接受的盐或所提供的组合物以用于治疗本文所述的病症。
还提供了一种或多种本文所述的化合物或其药学上可接受的盐在用于制造用于治疗本文所述病症的药物中的用途。
在用一种或多种所述化合物或药学上可接受的盐或组合物治疗之前,还可以选择受试者为正患有一种或多种所述病症。
本公开还提供了包含本文所述化合物或其药学上可接受的盐;以及药学上可接受的载体的药学上可接受的组合物。这些组合物可用于治疗一种或多种上述病症。
本文所述的组合物可以口服、胃肠外、通过吸入喷雾、局部、直肠、鼻、口腔黏膜、阴道、阴道或通过植入储库施用。本文所用的术语“胃肠外”包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。本文包括用于化合物的局部或透皮施用的液体剂型、可注射制剂、固体分散体形式和剂型。
还应理解,针对任何特定患者的特定剂量和治疗方案将取决于多种因素,包括年龄、体重、总体健康、性别、饮食、施用时间、排泄率、药物组合、主治医师的判断以及所治疗特定疾病的严重程度。组合物中提供的化合物的量也将取决于组合物中的特定化合物。
实施例
一般信息
通过紫外光(254和365nm)使斑点可视化。通过柱色谱和快速色谱法使用硅胶(200-300目)进行纯化。以溶剂的比例报告溶剂体系。
将1H NMR光谱记录在Bruker Avance III 400MHz或Bruker Fourier 300MHz上。以四甲基硅烷(TMS,=0.00ppm)作为内标,以δ值(ppm)报告1H化学位移。参见例如表1中提供的数据。
在具有ESI(+)电离模式的Agilent 1200系列6110或6120质谱仪上获得LCMS光谱。(色谱柱:C18(50×4.6mm,5μm),在ES(+)或(-)电离模式下运行;T=30℃;流速=1.5mL/min;检测波长:220nm。参见例如表1中提供的数据。
实施例1.化合物1的合成
中间体101的合成。在0℃下向中间体100(350g,3.00mol)的DMF(5500mL)溶液中添加NaH(360g,9.00mol),并将混合物在该温度下搅拌30分钟。添加炔丙基溴(1.43kg,12.0mol)的DMF(1500mL)溶液,并将反应混合物温热至室温并搅拌4h。然后将反应混合物用饱和氯化铵溶液淬灭,并用EtOAc(2000mL×3)萃取。用饱和NaCl水溶液(2000mL×2)洗涤合并的有机层,用Na2SO4干燥,过滤并真空浓缩。通过使用硅胶的柱色谱法将粗产物纯化,以得到呈黄色油状的中间体101(245g,42.5%)。1H NMR(CDCl3,400MHz):δ(ppm)1.48(s,9H),2.22(t,2H,J=4.8Hz),4.17(s,4H)。
中间体102的合成。在室温Ar气氛下在15分钟内向中间体101(270g,1.40mol)和Cp*RuCl(cod)(13.5g,35.6mmol)的干燥、脱气的1,2-二氯乙烷(2200mL)溶液中添加氯乙腈(157g,2.10mol)的干燥、脱气的1,2-二氯乙烷(500mL)溶液中。然后将反应混合物温热至60℃并搅拌0.5h,然后蒸发溶剂,并通过柱色谱法使用硅胶将粗残余物纯化,以得到呈灰白色固体的中间体102(210g,56.0%)。1H NMR(CDCl3,400MHz):δ(ppm)1.52(s,9H),4.67–4.73(m,6H),7.40(d,1H,J=19.2Hz),8.50(d,1H,J=15.6Hz)。MS 269.1[M+H]+。
中间体103的合成。用Pd/C(21.0g)处理中间体102(210g,784mmol)的MeOH(4000mL)溶液,并将反应混合物在室温H2气氛下搅拌2h。然后将反应混合物过滤,并将滤液真空浓缩,以提供呈灰白色固体的中间体103(120g,65.6%)。1H NMR(CDCl3,400MHz):δ(ppm)1.53(s,9H),2.98(s,3H),4.86–4.90(m,4H),7.53–7.60(m,1H),8.62–8.67(m,1H)。MS235.1[M+H]+。
中间体104的合成。将4N HCl(600mL,HCl在EtOAc中)溶液逐滴添加到中间体103(120g,513mmol)的EtOAc(600mL)0℃溶液中。然后将反应混合物温热至室温并搅拌1h。通过过滤将溶剂除去,以得到呈白色固体的中间体104。1H NMR(DMSO_d6,400MHz):δ(ppm)2.75(s,3H),4.73–4.80(m,4H),7.97(s,1H),8.20(s,1H)。MS 135.1[M+H]+。
中间体105的合成。在室温下将中间体104(513mmol)、中间体A3(151g,308mmol)和Na2CO3(272g,2.57mol)的DMSO混合物搅拌3h。根据LCMS使反应完成后,将反应混合物倒入到冷水中,用EtOAc萃取,并将层分离。然后将有机层在真空中浓缩,并将残余物用EtOAc研磨,然后过滤,以提供呈黄色固体的中间体105(80.0g,38%,来自化合物5)。1H NMR(DMSO_d6,400MHz):δ(ppm)2.49(s,3H),4.70–4.96(m,4H),7.29–7.35(m,2H),7.45–7.49(m,1H),7.50–7.51(m,1H),8.08–8.14(m,1H),8.46(d,2H,J=8.4Hz),10.11(brs,1H)。MS 412.1[M+H]+。
化合物1的合成。在室温H2气氛下将中间体105(80.0g,195mmol)和Pd/C(8.00g)在甲醇(2500mL)中的混合物搅拌1h。1h后,通过硅藻土过滤除去Pd/C。将滤液浓缩并通过硅胶柱色谱法将残余物纯化,以提供呈灰色固体的化合物1(52.0g,70.3%)。1H NMR(DMSO_d6,400MHz):δ(ppm)2.48(s,3H),4.77(s,4H),5.28(s,2H),7.16-7.18(m,2H),7.28-7.31(m,2H),7.40–7.42(m,1H),7.92–7.94(m,1H),8.45(s,1H),8.56(s,1H)。MS 382.1[M+H]+。
中间体A2的合成。在N2气氛下用Pd(PPh3)4(72.6g,86.3mmol)处理中间体A1(300g,1.73mol)、4-氟苯基硼酸(265g,1.91mmol)和Cs2CO3(1.13kg,3.46mol)的二恶烷/H2O(6000mL/600mL)的混合物。将混合物在95℃下搅拌2h,然后真空浓缩。将残余物溶于EtOAc(4000mL)中,并将所得溶液用盐水(1000mL×3)洗涤。将合并的有机层用无水Na2SO4干燥,过滤,然后真空浓缩。通过硅胶柱色谱法将粗残余物纯化,以提供呈黄色固体的中间体A2(240g,粗品)。1H NMR(CDCl3,400MHz):δ(ppm)6.90–6.96(m,1H),6.99–7.04(m,1H),7.23–7.26(m,1H),8.02–8.08(m,1H),8.47(d,1H,J=8.4Hz)。MS 252.0[M+H]+。
中间体A3的合成。在室温下将氯代碳酸苯酯(354g,2.27mol)逐滴添加至中间体A2(240g,粗品)的吡啶(4800mL)搅拌溶液中。添加完成后,将反应混合物加热至50℃并搅拌过夜。然后将混合物真空浓缩,并通过用MTBE重结晶将粗残余物纯化,以提供呈黄色固体的中间体A3(240g,28.2%,来自化合物A1)。1H NMR(CDCl3,400MHz):δ(ppm)6.97–7.02(m,1H),7.08–7.39(m,11H),8.13(d,1H,J=8.4Hz),8.24-8.30(m,1H),8.67(d,1H,J=8.8Hz)。MS492.1[M+H]+。
实施例2.化合物2的合成
107的合成。在室温下将2-氯-6,7-二氢-5H-吡咯并[3,4-b]吡啶盐酸盐(11g,57.9mmol)、TEA(17.5g,173.7mmol)和(Boc)2O(13.9g,63.7mmol)在THF(250mL)中的混合物搅拌3h。然后将反应混合物倒入到DCM(500mL)中,用盐水(100mL×3)洗涤,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将残余物纯化(DCM:EtOAc=100:1~10:1),以得到呈白色固体的107(13.5g,92%)。MS 255.2[M+H]+。
108的合成。在100℃1.5MPa的CO气氛下将107(13.5g,53.1mmol)、乙酸钾(10.4g,106.2mmol)、dppf(883mg,1.59mmol)和乙酸钯(677mg,2.66mmol)在乙醇(20mL)中的混合物搅拌16h。然后将反应混合物冷却至室温,并通过硅藻土过滤。将滤液真空浓缩,并将残余物溶于DCM(500mL)中,用盐水(10mL×3)洗涤,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将残余物纯化(PE:EtOAc=8:1~3:1),以得到呈白色固体的108(13.4g,86%)。MS292.1[M+H]+。
109的合成。在室温下将108(13.4g,45.9mmol)和NaBH4(10.4g,275.3mmol)在乙醇(260mL)中的混合物搅拌16h。将反应混合物真空浓缩,并将残余物用DCM(500mL)溶解,用盐水(100mL×3)洗涤,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将残余物纯化(DCM:MeOH=100:1~20:1),以得到呈白色固体的109(8.6g,75%)。MS 251.4[M+H]+。
110的合成。在室温下向109(8.6g,34.4mmol)在DMF(200mL)中的混合物中添加NaH(60%在矿物油中)(4.1g,103.2mmol)。在室温下将所得混合物搅拌30分钟,随后逐滴添加MeI(14.6g,103.2mmol)。在室温下将所得反应混合物搅拌1h,然后将溶液用水(300mL)稀释,并用EtOAc(200mL×3)萃取。用盐水(100mL×3)洗涤合并的有机层,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将残余物纯化(PE:EtOAc=8:1~3:1),以得到呈灰白色固体的110(8.0g,88%)。MS 265.3[M+H]+。
111的合成。在冰浴中向110(7.6g,28.8mmol)的DCM(70mL)溶液中逐滴添加TFA(38mL)。在室温下将所得溶液搅拌1h,随后真空除去溶剂以得到粗产物111。MS 165.2[M+H]+。
112的合成。在室温下将111(28.8mmol,来自最后一步的粗产物)、A3(11.8g,24mmol)和Na2CO3(25.4g,240mmol)的DMSO(200mL)的混合物搅拌16h。通过LCMS所示,当反应完成时,将溶液用水(300mL)稀释,然后用EtOAc(200mL×3)萃取。用盐水(100mL×3)洗涤合并的有机层,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱将残余物纯化(PE:EtOAc=1:1与EtOAc),以得到呈黄色固体的112(7.0g,66%)。MS 442.2[M+H]+。
化合物2的合成。在室温H2气氛下将112(7.0g,15.9mmol)和Pd/C(2.3g)在DCM/MeOH(140mL/140mL)中的混合物搅拌2h。然后通过硅藻土过滤除去Pd/C。将滤液浓缩,并用MTBE将残余物重结晶,以得到呈浅黄色固体的化合物2(4.5g,69%)。MS 412.1[M+H]+。
实施例3.化合物3的合成
化合物3的合成。以类似于1的方式合成化合物3,以提供呈灰白色固体的3(28mg,22%)。MS 388[M+H]+。
实施例4.化合物4的合成
114的合成。向用冰浴冷却的丙-2-炔-1-胺(5.0g,90.9mmol)和Et3N(18.4g,181.8mmol)的DCM(100mL)溶液中逐滴添加(Boc)2O(23.8g,109.1mmol)。添加(Boc)2O完成后,使所得混合物温热至室温,并在室温下搅拌16h。当反应完成时,将混合物用DCM(200mL)稀释,然后用盐水(100mL×3)洗涤。将有机层用Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将残余物纯化(PE:EtOAc=100:1~10:1),以得到呈无色油状的114(10g,71%)。MS178.3[M+23]+,100.3[M-56]+。
101的合成。用冰浴将反应混合物冷却的同时,向114(10g,64.5mmol)的DMF(200mL)溶液中缓慢添加NaH(60%在矿物油中)(2.84g,71mmol)。在室温下将所得反应混合物搅拌1h,然后将3-溴丙-1-炔(9.2g,77.4mmol)添加到上述混合物中,并在室温下搅拌2h。然后将反应用水(500mL)淬灭,并用t-BuOMe(250mL×3)萃取。用盐水(200mL×3)洗涤合并的有机层,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将残余物纯化(PE:EtOAc=100:1~10:1),以得到呈黄色油状的101(12g,96%)。MS 138.1[M-56]+。
102的合成。在N2气氛下在30分钟内向2-氯乙腈(3.13g,41.4mmol)和[Cp*RuCl(cod)](394mg,1.0mmol)的DCE(40mL)溶液中逐滴添加101(4.0g,20.7mmol)的DCE(80mL)溶液。在40℃下将所得到反应混合物搅拌16h。然后真空除去溶剂,并通过硅胶柱色谱法将粗残余物纯化(PE:EtOAc=10:1~2:1),以得到呈棕褐色固体的102(2.1g,22%)。MS 269.3[M+H]+。
115的合成。在50℃下将102(1.50g,5.6mmol)、3-氟氮杂环丁烷盐酸盐(932mg,8.4mmol)和K2CO3(2.32g,16.8mmol)在DMF(30mL)中的混合物搅拌3h。然后将混合物用水(60mL)稀释,并用EtOAc(30mL×4)萃取。用盐水(30mL×3)洗涤合并的有机层,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将残余物纯化(DCM:MeOH=100:1~30:1),以得到呈白色固体的115(1.4g,81%)。MS 308.2[M+H]+。
116的合成。向115(200mg,0.65mmol)的DCM(4mL)溶液中添加TFA(2mL),并在室温下将所得反应混合物搅拌1h。当LCMS指示反应完成时,真空除去溶剂以得到粗产物116,其无需进一步纯化即可用于下一步。MS 208.2[M+H]+。
117的合成。在室温下将A3(265mg,0.54mmol)和116(0.65mmol,来自最后一步的粗产物)在DMSO(40mL)中的混合物搅拌10分钟,然后添加Na2CO3(458mg,4.32mmol)。在室温下将所得反应混合物搅拌2h,然后用水(80mL)稀释,并用EtOAc(40mL×4)萃取。用盐水(40mL×3)洗涤合并的有机层,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将残余物纯化(DCM:MeOH=100:1~50:1),以得到呈黄色固体的117(200mg,76%)。MS 485.2[M+H]+。
化合物4的合成。在室温H2气氛下将117(200mg,0.41mmol)和Pd/C(200mg)在甲醇(8mL)中的混合物搅拌1h。通过硅藻土过滤除去Pd/C,并将滤液浓缩以提供粗残余物,通过Prep-TLC(DCM:MeOH=10:1)将其纯化三次,以得到呈黄色固体的化合物4(26mg,14%)。
实施例5.化合物5的合成
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A2的合成。在N2气氛下用Pd(PPh3)4(1.10g,0.95mmol)处理6-氯-3-硝基吡啶-2-胺(4.58g,26.4mmol)、2,4-二氟苯基硼酸(5.00g,31.7mmol)和Cs2CO3(25.73g,79.2mmol)的二恶烷/H2O(100mL/10mL)的混合物。将混合物在100℃下搅拌2h,然后真空浓缩。将残余物溶于EtOAc(200mL)中,并将溶液用盐水(100mL×3)洗涤。将有机层用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将残余物纯化(PE:EtOAc=7:1~5:1),以得到呈黄色固体的A2(4.0g,61%)。MS 252.1[M+H]+。
A3的合成。在0℃下用氯代碳酸苯酯(7.50g,47.81mmol)逐滴处理A2(4.0g,15.94mmol)吡啶(60mL)的搅拌溶液添加完成后,在50℃下将反应混合物搅拌4h。然后将混合物真空浓缩,并通过硅胶柱色谱法将粗残余物纯化(PE:DCM=3:2~1:1),以得到呈黄色固体的A3(7.1g,91%)。MS 492.1[M+H]+。
118的合成。在70℃下将3-氧吡咯烷-1-羧酸叔丁酯(15.0g,81.1mmol)和DMF-DMA(29.0g,243.3mmol)的THF(150mL)溶液搅拌16h。将溶液真空浓缩以得到粗产物118,将其直接用于下一步。MS 241.1[M+H]+。
119的合成。向118(81.1mmol,来自最后一步的粗产物)的EtOH(100mL)溶液中添加Et3N(40.4g,0.4mol)和乙酰胺盐酸盐(30.1g,0.32mol)。在80℃下将所得溶液搅拌24h。真空除去溶剂后,将残留物用水(100mL)稀释,并用DCM(50mL×3)萃取。用盐水(50mL×3)洗涤合并的有机层,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将残余物纯化(DCM:DCM=10:1~1:2),以得到呈褐色固体的119(10.5g,55%)。MS 236.2[M+H]+。
120的合成。在室温下将119(600mg,2.55mmol)的二恶烷/HCl(4N,10mL)溶液搅拌1h。将溶液真空浓缩,以得到呈白色固体的120(340mg,77%),其无需进一步纯化即可使用。MS 136.2[M+H]+。
121的合成。在室温下将A3(231mg,0.47mmol)和120(160mg,0.94mmol)在DMSO(5mL)中的混合物搅拌10分钟。然后将Na2CO3(399mg,3.76mmol)添加到上述混合物中,并在室温下将所得混合物搅拌2h。如LCMS所示,反应完成后,将反应混合物用水(30mL)稀释,并用EtOAc(10mL×3)萃取。用盐水(10mL×3)洗涤合并的有机层,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将残余物纯化(DCM:MeOH=100:1~50:1),以提供呈黄色固体的121(120mg,62%)。MS 413.2[M+H]+。
化合物5的合成。在室温H2气氛下将121(120mg,0.29mmol)和Pd/C(120mg)在甲醇(5mL)中的混合物搅拌30min。然后通过硅藻土过滤除去Pd/C,并将滤液浓缩,通过Prep-TLC(DCM:MeOH=10:1)将所得粗残余物纯化,以得到呈白色固体的化合物5(52mg,47%)。MS383.2[M+H]+,405.0[M+Na]+。
实施例6.化合物6的合成
A4的合成。在0℃下用氯代碳酸苯酯(10.8g,69.0mmol)逐滴处理6-溴-3-硝基吡啶-2-胺(5.0g,23.0mmol)和Et3N(6.9g,69.0mmol)THF(60mL)搅拌溶液。添加完成后,在室温下将混合物搅拌1h。然后将反应混合物过滤并真空浓缩。将所得粗残余物从石油醚中重结晶以得到呈浅黄色固体的A4(10.2g,97%)。MS 458.0,460.0[M+H]+。
122和122-A的合成。向4,6-二氢吡咯并[3,4-c]吡唑-5(2H)-羧酸叔丁酯(15.0g,71.8mmol)DMF(150mL)溶液中添加NaH(60%在矿物油中)(8.6g,215.4mmol),同时用冰浴将反应混合物冷却。添加完成后,使所得混合物温热至室温,并在室温下搅拌30分钟。此时,将1-溴-2-甲氧基乙烷(19.8g,143.6mmol)添加到反应混合物中,并在室温下继续搅拌2h。然后将反应混合物用水(300mL)淬灭,并用EtOAc(150mL×3)萃取。用盐水(100mL×3)洗涤合并的有机层,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将残余物纯化(DCM:MeOH=100:1~30:1),以得到呈无色油状的122和122-A混合物(19.0g,99%)。MS 268.2[M+H]+。
123和123-A的合成。向用冰浴冷却的122和122-A(6.5g,24.3mmol)的DCM(60mL)溶液中添加TFA(30mL)。在室温下将反应混合物搅拌1h,然后真空除去溶剂以得到粗产物混合物123和123-A,其无需进一步纯化即可直接用于下一步。MS 168.1[M+H]+。
124和124-A的合成。向123和123-A(24.3mmol,来自最后一步的粗产物)和A4(9.3g,20.3mmol)DMSO(200mL)溶液中添加Na2CO3(21.5g,203mmol),并在室温下将反应混合物搅拌4h。然后将混合物用水(400mL)稀释,并用EtOAc(200mL×3)萃取。用盐水(100mL×3)洗涤合并的有机层,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将残余物纯化(DCM:MeOH=100:1~30:1),以得到呈黄色固体的124和124-A混合物(4.5g,50%)。MS411.0,413.1[M+H]+。
125和125-A的合成。在N2气氛下用Pd(PPh3)4(45mg,0.06mmol)处理124和124-A(500mg,1.22mmol)、5-氯噻吩-2-基硼酸(237mg,1.46mmol)和K2CO3(169mg,1.23mmol)在二恶烷/H2O(10mL/2mL)中的混合物。将反应混合物在50℃下搅拌3h,然后真空浓缩。将残余物溶于EtOAc(30mL)中,并将所得溶液用盐水(10mL×3)洗涤。然后将有机层用无水Na2SO4干燥,并真空浓缩。通过Prep-TLC(DCM:MeOH=20:1)将粗残余物纯化,以得到呈黄色固体的125和125-A混合物(450mg,82%)。MS 449.2[M+H]+。
化合物6和化合物6A的合成。在室温H2气氛下将125和125-A(450mg,1.0mmol)和阮内镍(100mg)在DCM/MeOH(6mL/6mL)中的混合物搅拌1h。然后通过硅藻土过滤除去阮内镍,将滤液真空浓缩,并将残余物通过Prep-TLC(DCM:MeOH=10:1)纯化。然后使用手性HPLC(柱:Chiralcel OD-3;溶剂:MeOH;流速:2mL/min;RT1843=3.477min,RT1843A=4.142min)分离位置异构体的混合物,以得到呈白色固体的化合物6(99mg,24%)(MS 419.2[M+H]+)和呈白色固体的化合物6A(50mg,12%)。MS 419.2[M+H]+。
实施例7.化合物7的合成
118的合成。在70℃下将3-氧吡咯烷-1-羧酸叔丁酯(600mg,3.24mmol)和DMF-DMA(1.2g,9.72mmol)的THF(10mL)溶液搅拌16h。将溶液真空浓缩以得到粗产物118,将其直接用于下一步。MS 241.1[M+H]+。
126的合成。向118(3.24mmol,来自最后一步的粗产物)EtOH(10mL)溶液中添加Et3N(1.6g,16.2mol)和丙亚酰胺盐酸盐(1.4g,13.0mmol)。在80℃下将所得溶液搅拌20h。真空除去溶剂后,将残留物用水(10mL)稀释,然后将混合物用DCM(10mL×3)萃取。用盐水(10mL×3)洗涤合并的有机层,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将残余物纯化(PE:DCM=10:1~1:2),以得到呈褐色固体的126(450mg,56%)。MS 250.2[M+H]+。
127的合成。用TFA(3mL)处理126(300mg,1.2mmol)DCM(6mL)溶液,并在室温下将反应混合物搅拌1h。1小时后,如LCMS所示,反应完成,并将反应混合物真空浓缩以得到粗产物127,其无需进一步纯化即可直接用于下一步。MS 150.2[M+H]+。
128的合成。在室温下将A3(294mg,0.6mmol)和127(1.2mmol,来自最后一步的粗产物)在DMSO(10mL)中的混合物搅拌10分钟。然后添加Na2CO3(636mg,6.0mmol),并在室温下将所得混合物搅拌2h。如LCMS所示,反应完成后,将反应混合物用水(30mL)稀释,并用EtOAc(10mL×3)萃取。用盐水(10mL×3)洗涤合并的有机层,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将残余物纯化(DCM:MeOH=100:1~50:1),以提供呈黄色固体的128(136mg,53%)。MS 427.2[M+H]+。
化合物7的合成。在室温H2气氛下将128(120mg,0.28mmol)和阮内镍(120mg)在甲醇(5mL)中的混合物搅拌1h。然后通过硅藻土过滤除去阮内镍,并将滤液浓缩,通过Prep-TLC(DCM:MeOH=10:1)将所得粗残余物纯化以得到呈黄色固体的化合物7(80mg,72%)。MS397.1[M+H]+。
实施例8.化合物8的合成
129和129-A的合成。在N2气氛下用Pd(PPh3)4(49mg,0.04mmol)处理124和124-A(350mg,0.85mmol)、2-氟苯基硼酸(143mg,1.02mmol)和K2CO3(352mg,2.55mmol)在二恶烷/H2O(10mL/2mL)中的混合物。将反应混合物在90℃下搅拌3h,然后真空浓缩。将粗残余物溶于EtOAc(30mL)中,并将所得溶液用盐水(10mL×3)洗涤。将有机层用无水Na2SO4干燥,然后真空浓缩。通过Prep-TLC(PE:EA=5:1)将残余物纯化,以得到呈黄色固体的129和129-A混合物(300mg,83%)。MS 427.2[M+H]+。
化合物8和化合物8A的合成。在室温H2气氛下将129和129-A(300mg,0.70mmol)和Pd/C(80mg)在DCM/MeOH(5mL/5mL)中的混合物搅拌1h。然后通过硅藻土过滤除去Pd/C,将滤液浓缩,并通过Prep-TLC(DCM:MeOH=10:1)将粗残余物纯化。然后使用手性HPLC(柱:Chiralcel OJ-3;溶剂:MeOH;流速:2mL/min;RT1849=1.201min,RT1849A=2.244min)分离位置异构体的混合物,以得到呈黄色固体的化合物8(105mg,37%)(MS397.2[M+H]+)和呈黄色固体的8A(98mg,35%)。MS 397.2[M+H]+。
实施例9.化合物9的合成
130的合成。在N2气氛下用Pd(PPh3)4(17mg,0.01mmol)处理6-氯-3-硝基吡啶-2-胺(0.5g,2.9mmol)、2-氟苯基硼酸(487mg,3.48mmol)和K2CO3(1.20g,8.7mmol)的二恶烷/H2O(10mL/1mL)的混合物。将反应混合物在90℃下搅拌2h,然后真空浓缩。将粗残余物溶于EtOAc(200mL)中,并将所得溶液用盐水(100mL×3)洗涤。然后将有机层用无水Na2SO4干燥,并真空浓缩。通过硅胶柱色谱法将残余物纯化(PE:EtOAc=10:1~3:1),以得到呈黄色固体的130(301mg,45%)。MS 234.2[M+H]+。
131的合成。用冰浴将反应混合物冷却的同时,向130(301mg,1.3mmol)的吡啶(10mL)搅拌溶液中逐滴添加氯代碳酸苯酯(608mg,3.9mmol)。将所得反应混合物在55℃下搅拌4h,随后将反应混合物真空浓缩。通过硅胶柱色谱法将所得粗残余物纯化(PE:EtOAc=8:1~3:1),以得到呈黄色固体的131(500mg,82%)。MS 474.2[M+H]+。
132的合成。用NaH(60%在矿物油中)(940mg,23.5mmol)处理冰浴冷却的MeOH烧瓶(30mL),并将反应混合物在0℃下搅拌30分钟。然后添加化合物102(2.1g,7.8mmol),并将反应混合物在35℃下搅拌16小时。此时,将反应混合物用水(30mL)淬灭,并用DCM(10mL×3)萃取,将合并的有机层用盐水(10mL×3)洗涤,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将所得粗残余物纯化(PE:EtOAc=100:1~10:1),以得到呈米色固体的132(1.8g,94%)。MS 265.1[M+H]+。
133的合成。将反应混合物在冰浴中冷却,向132(301mg,1.3mmol)的DCM(6mL)溶液中逐滴添加TFA(2mL)。在室温下将反应物搅拌1h,随后真空除去溶剂以得到粗产物133,其可直接用于下一步。MS 165.1[M+H]+。
134的合成。用Na2CO3(678mg,6.4mmol)处理131(313mg,0.64mmol)和133(0.83mmol,来自最后一步的粗产物)在DMSO(10mL)中的混合物,然后将反应混合物在室温下搅拌2h。此时,将反应混合物用水(20mL)稀释,并用EtOAc(20mL×3)萃取。用盐水(20mL×3)洗涤合并的有机层,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱法将残余物纯化(EA与EA:MeOH=50:1),以得到呈黄色固体的134(200mg,74%)。MS 424.0[M+H]+。
化合物9的合成。在室温H2气氛下将134(200mg,0.47mmol)和Pd/C(200mg)在DCM/MeOH(4mL/4mL)中的混合物搅拌1h。然后通过硅藻土过滤除去Pd/C,并将滤液浓缩,通过Prep-TLC(DCM:MeOH=10:1)将所得粗残余物纯化,以得到呈黄色固体的化合物9(105mg,57%)。MS 394.2[M+H]+。
实施例10.化合物10的合成
135和135-A的合成。向4,6-二氢吡咯并[3,4-c]吡唑-5(2H)-羧酸叔丁酯(250mg,1.2mmol)DMF(5mL)溶液中添加NaH(96mg,2.4mmol(60%在矿物油中)),同时用冰浴将反应混合物冷却。在室温下将所得反应混合物搅拌1h,随后添加碘乙烷(374mg,2.4mmol),并在室温下将所得反应混合物搅拌2h。然后将反应混合物用水(10mL)稀释,并用EtOAc(10mL×3)萃取。用盐水(10mL×3)洗涤合并的有机层,用无水Na2SO4干燥,然后真空浓缩以得到粗产物135和135-A。MS 238.2[M+H]+。
136和136-A的合成。在用冰浴将反应混合物冷却的同时,向135和135-A(1.2mmol,来自最后一步的粗产物)DCM(6mL)溶液中逐滴添加TFA(2mL)。在室温下将反应混合物搅拌1h,然后真空除去溶剂以得到粗产物136和136-A,其无需进一步纯化即可用于下一步。MS138.2[M+H]+。
137的合成。在室温下将136和136-A(1.2mmol,来自最后一步的粗产物)和A3(491mg,1.0mmol)在DMSO(10mL)中的混合物搅拌10分钟,然后添加Na2CO3(848mg,8.0mol)并在室温下将反应混合物搅拌2h。然后将反应混合物用水(20mL)稀释,并用EtOAc(20mL×3)萃取。用盐水(20mL×3)洗涤合并的有机层,用无水Na2SO4干燥,然后真空浓缩。通过硅胶柱色谱将粗残留物纯化(DCM:MeOH=100:1~50:1)以得到粗产物,该粗产物为位置异构体137和137-A的混合物。通过Prep-TLC(DCM:MeOH=30:1)将粗残余物进一步纯化,以得到呈黄色固体的137(150mg,36%)。MS 415.1[M+H]+。
化合物10的合成。在室温H2气氛下将137(150mg,0.36mmol)和Pd/C(150mg)在MeOH(5mL)中的混合物搅拌1h。然后通过硅藻土过滤除去Pd/C,并将滤液浓缩,通过Prep-TLC(DCM:MeOH=15:1)将残余物纯化,以得到呈黄色固体的化合物10(85mg,61%)。MS 385.1[M+H]+。
表1化合物的光谱数据
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HDAC2和HDAC1酶法测定(HDAC2 IC50数据)
以下描述了一种用于测定酶HDAC2或HDAC1对肽底物脱乙酰化的测定方案。将酶、底物和辅因子在微量滴定板的孔中合并,并在25℃下温育3h。温育结束时,通过添加含SDS的缓冲液淬灭反应物。使用来自Caliper Life Sciences的基于微流体的LabChip 3000药物发现系统将底物和产物通过电泳分离和定量。用于该测定的肽底物是FAM-TSRHK(AC)KL-CONH2(FAM是羧基荧光素)。通过毛细管电泳,肽的纯度应该>98%。
1、向384孔板的一个孔中添加5μL 2X酶缓冲液。使用Labcyte Echo 550添加100nl化合物。如果需要,可以在此时将酶和化合物进行预温育。
2、添加5μL 2X底物缓冲液。
3、在25℃下将板温育17h。
4、通过添加40μL 1.55X终止缓冲液将反应终止。
5、在Caliper Lab3000药物发现系统上创建作业。
6、上样板并使用蓝色激光(480nm)进行激发和绿色CCD(520nm)进行检测(CCD2)以开始电泳。
反应时间=17h;反应温度=25℃。
最终测定反应混合物
100mM HEPES,pH 7.5 0.1%BSA 0.01%Triton X-100 25mM KCl
1%DMSO(来自化合物)1μM FAM-TSRHK(AC)KL-CONH2 5nM HDAC酶(批次之间的比活可能不同,可能需要调整酶浓度以得到约10-20%的底物转化为产物)。
使用LabChip 3000毛细管电泳仪对每个样品中存在的底物和产物肽进行电泳分离。当将底物和产物肽分离时,观察到两个荧光峰。底物和产物峰的相对荧光强度的变化是所测量的参数,其反映了酶活性。使用HTS孔分析仪软件(Caliper Life Sciences)分析毛细管电泳图(RDA采集文件)。将每个样品中的酶活性确定为产物总和比(PSR):P/(S+P),其中,P是产物肽的峰高,S是底物肽的峰高。对于每种化合物,在各种浓度(以3倍的稀释间隔将12种浓度的化合物隔开)下测量酶活性。一式四份将阴性对照样品(0%-在不存在抑制剂下的抑制)和阳性对照样品(100%-在存在20mM EDTA下的抑制)组装,并用于计算在每个浓度下每种化合物的抑制%。使用以下公式确定抑制百分比(Pinh):Pinh=(PSR0%-PSRinh)/(PSR0%-PSR100%)*100,其中,PSRinh是存在抑制剂下的产物总和比,PSR0%是不存在抑制剂下的平均产物总和比,PSR100%是100%抑制对照样品的平均产物总和比。
使用XLfit 4软件(IBDS)通过4个参数S形剂量响应模型拟合抑制曲线(Pinh与抑制剂浓度)来确定抑制剂的IC50值。
某些化合物的该测定结果报告在下表2中。在表中,A表示Kd值小于0.1μM;B表示Kd值在0.1μM和0.5μM之间;C表示Kd值大于0.5μM且小于或等于5.0μM;并且D表示Kd值大于5.0μM。
表2
SH-SY5Y细胞裂解物中的HDAC2酶抑制测定
细胞培养和抑制剂治疗
在补充有10%胎牛血清的青霉素/链霉素Eagle改良基本培养基中培养SH-SY5Y细胞(Sigma)。化合物给药前二十四小时,将20uL细胞以1500个细胞/孔的密度平铺在白色384孔板中。将化合物在纯DMSO中连续稀释,然后以1:100v/v稀释到不含FBS的培养基中并混合。从平铺细胞中除去培养基,然后添加稀释化合物的无血清培养基(1%v/v最终DMSO),并在37℃下温育5h。然后添加10uL含0.1%Triton X-100的HDAC-Glo 2试剂,将板混合并使其在室温下显影100分钟。然后用Spectramax LMax发光计利用0.4s积分时间读取板。用归一化数据构建剂量响应曲线,其中,将100uM处的CI-994定义为100%抑制,并将DMSO单独定义为0%抑制。
某些化合物的该测定结果报告在下表3中。在表中,“A”表示IC50值在0.1μM至1μM之间;“B”表示IC50值在1.0μM至1.5μM之间;“C”表示IC50值大于1.5μM。
表3
红系细胞和骨髓CFU检测
在含rhIL-3(10ng/mL)、rhGM-SCF(10ng/mL)、rhSCF(50ng/mL)和Epo(3U/mL)半固体甲基纤维素类培养基配方中评估了人类红系细胞(CFU-E、BFU-E)、粒细胞-单核细胞(CFU-GM)和多潜能(CFU-GEMM)谱系的克隆祖细胞。
细胞
将源自正常骨髓(NorCal Biologics,加利福尼亚州)并在ReachBio被鉴定的正常人累骨髓光密度细胞储存在液氮的气相中(-152℃),直到测定所需。实验当天,将细胞快速融化,将每个小瓶中的内容物稀释在10mL含10%胎牛血清(IMDM+10%FBS)的Iscove改良Dulbecco培养基中,并通过离心(室温,约1200r.p.m.,持续10分钟)洗涤。丢弃上清液,并将细胞沉淀重悬于已知体积的IMDM+10%FBS中。对骨髓样品进行细胞计数(3%冰醋酸)和生存力评估(锥虫蓝排斥试验)。
化合物
实验当天,将化合物溶解在DMSO中至储备浓度为10mM。从原液浓度制备系列稀释液以达到2和0.4mM的浓度。当以1:1000(v/v)添加到甲基纤维素类培养基时,最终测试浓度达到10、2和0.4μM。另外,以1.0、0.1和0.01μg/mL评价5-FU。
方法总结
在上述甲基纤维素类培养基配方中建立了人类红系细胞(CFU-E和BFU-E)和髓性(CFU-GM)谱系的克隆祖细胞。将所有化合物添加到培养基中以达到最终所需浓度(10、2和0.4μM)。将5-氟尿嘧啶(Sigma Aldrich)用作祖细胞增殖的阳性对照(抑制菌落生长),并以1.0、0.1和0.01μg/mL引入到人类骨髓培养物中。还启动了溶剂对照培养物(不含化合物,但含0.1%DMSO)以及标准对照(不含化合物,不含DMSO)。
每种培养物以2.0×104个细胞启动了人类髓系和红系细胞祖细胞测定。培养14天后,对显微镜下的髓系和红系细胞菌落进行显微镜评估,并由受过培训的人员进行评分。根据大小和形态将菌落分为以下几类:CFU-E、BFU-E、CFU-GM和CFU-GEMM。
CFC数量的统计分析
对于每种类别的祖细胞(CFU-E、BFU-E等)计算了三个重复培养物的平均值±1个标准差。进行了双尾t检验以评估溶剂对照和处理的培养物之间产生的菌落数量是否存在差异。由于菌落计数的潜在主观性,p值小于0.01被认为是显著的。为了计算每种化合物的菌落生长抑制50%(IC50)浓度,使用XLfit软件(IDBS)绘制化合物浓度对数与对照菌落生长百分比而产生了剂量响应曲线。基于S形曲线拟合,使用剂量响应一站式模型公式计算出50%的菌落生长抑制浓度(IC50):y=A+[(B–A)/(1+((C/x)^D))],其中A=初始值(基线响应),B=最大响应,C=中心(在A和B中间引起响应的药物浓度),D=曲线在中点处的斜率。此外,使用GraphPad Prism 7.0产生图和其它剂量响应曲线。
菌落形态学评估
拍摄了来自各种谱系的代表性源自造血祖细胞菌落的照片,示出了在溶剂对照存在下的菌落以及在测试化合物存在下的菌落。
由受过培训的人员进行红系细胞(CFU-E和BFU-E)、髓系细胞(CFU-GM)和多潜能(CFU-GEMM)菌落计数。分析菌落类型的分布以及一般菌落和细胞形态。为了统计分析,将化合物处理的培养物中的菌落数量与溶剂对照培养物进行比较。在这些测定中,将5-FU用作毒性的阳性对照,并且该化合物获得的抑制作用完全符合预期。该实验用于评价在甲基纤维素类培养基中测试化合物对人类红系和髓系祖细胞增殖的潜在影响。IC50值由XLfit计算出。XLfit产生的红系细胞和髓系细胞毒性的剂量响应曲线。最后,通过Prism 7.0.-GEMM计算非线性回归曲线拟合和IC50±95%CI。
结果显示在表4中。
表4
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贯穿本申请引用的所有参考文献(包括文学参考文献、已发布的专利、已公开的专利申请和共同待决的专利申请)的内容在此通过引用明确地并入本文。除非另有定义,否则本文中所用的所有技术和科学术语均与本领域普通技术人员通常已知的含义相同。
Claims (14)
1.一种下式的化合物或其药学上可接受的盐:
2.根据权利要求1所述的化合物,其中所述化合物是下式的化合物或其药学上可接受的盐:
3.根据权利要求1所述的化合物,其中所述化合物是下式的化合物或其药学上可接受的盐:
4.根据权利要求1所述的化合物,其中所述化合物是下式的化合物或其药学上可接受的盐:
5.根据权利要求1所述的化合物,其中所述化合物是下式的化合物或其药学上可接受的盐:
6.根据权利要求1所述的化合物,其中所述化合物是下式的化合物或其药学上可接受的盐:
7.根据权利要求1所述的化合物,其中所述化合物是下式的化合物或其药学上可接受的盐:
8.根据权利要求1所述的化合物,其中所述化合物是下式的化合物或其药学上可接受的盐:
9.根据权利要求1所述的化合物,其中所述化合物是下式的化合物或其药学上可接受的盐:
10.根据权利要求1所述的化合物,其中所述化合物是下式的化合物或其药学上可接受的盐:
11.根据权利要求1所述的化合物,其中所述化合物是下式的化合物或其药学上可接受的盐:
12.一种组合物,其包含:根据权利要求1至11中任一项所述的化合物或其药学上可接受的盐;和药学上可接受的载体。
13.根据权利要求1至11中任一项所述的化合物或其药学上可接受的盐用于制备治疗选自以下病症的药物中的用途:阿尔茨海默病、亨廷顿病、弗里德赖希氏共济失调、创伤后应激障碍、帕金森氏病、物质依赖恢复、记忆或认知功能障碍或受损、灭绝学习障碍、与阿尔茨海默病相关的认知功能障碍或受损、路易体痴呆、精神分裂症、鲁宾斯坦-泰比综合征、瑞兹综合症、脆性X、多发性硬化症、年龄相关记忆受损、年龄相关认知衰退、以及与自闭症相关的社交、认知和学习障碍。
14.根据权利要求1至11中任一项所述的化合物或其药学上可接受的盐用于制备治疗精神病的药物中的用途。
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EA202090424A1 (ru) | 2020-05-26 |
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