CN107266340A - 1,5‑二苯基‑戊‑1,4‑二烯‑3‑酮化合物 - Google Patents
1,5‑二苯基‑戊‑1,4‑二烯‑3‑酮化合物 Download PDFInfo
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- CN107266340A CN107266340A CN201710311576.3A CN201710311576A CN107266340A CN 107266340 A CN107266340 A CN 107266340A CN 201710311576 A CN201710311576 A CN 201710311576A CN 107266340 A CN107266340 A CN 107266340A
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Abstract
本发明涉及1,5‑二苯基‑戊‑1,4‑二烯‑3‑酮化合物,如在专利说明书中所显示的式(I)、(II)或(III)的化合物,其包含1,5‑二苯基‑戊‑1,4‑二烯‑3‑酮骨架。这些化合物可使用来治疗癌、炎性疾病或自体免疫性疾病。
Description
本申请是申请日为2011年08月16日、申请号为201180040406.7、发明名称为“1,5-二苯基-戊-1,4-二烯-3-酮化合物”的发明专利申请的分案申请。
技术领域
本申请涉及1,5-二苯基-戊-1,4-二烯-3-酮化合物。
相关申请的相互参照
本申请主张2010年8月20日所提出的美国临时专利申请案序号61/375,534的优先权。先述申请案的内容其全文由此以参考方式并入本文。
背景技术
信号转导及转录活化子(STAT)蛋白质是调控细胞对生长因子的反应的转录因子。这些蛋白质通过生长因子受体相关的酪氨酸激酶经由酪氨酸磷酸化而活化。经活化的STAT蛋白质促进细胞存活及增生。现在,已良好地建立出STAT3或STAT5的持续活化会促进实体及造血癌二者的细胞生长、侵袭及转移。参见例如,Expert Opin.Investig.Drugs,2009,18(1):45-56。
在正常淋巴细胞中,STAT蛋白质(例如,STAT3)也经由细胞素受体相关的Janus激酶(JAKs)调控细胞对细胞素(诸如,白细胞介素-6(IL-6))的反应。参见例如,Neoplasia2008,10:287-297。IL-6在罹患造血癌、炎性疾病、自体免疫性疾病及停经后骨质疏松症的患者中经异常地提升。IL-6的抑制细胞作用(例如,通过引发STAT3蛋白质降解)已归因于这些疾病的治疗。
就此而论,可使用去活化STAT蛋白质的化合物来治疗多种癌、炎性疾病及自体免疫性疾病。
发明内容
本发明以一群具有1,5-二苯基-戊-1,4-二烯-3-酮骨架、能去活化STAT蛋白质的化合物的发现为基础。
本发明的一个观点涉及一种式(I)的化合物:
其中X及Y各者各自独立地是H、烷基或卤基,或X与Y一起是-CH2-、-(CH2)2-、-(CH2)CRaRb(CH2)-、-(CH2)NRa(CH2)-或-(CH2)O(CH2)-,Ra及Rb各者各自独立地系H、烷基、C(O)-烷基、C(O)-环烷基、C(O)-NH-烷基或C(O)-NH-环烷基;及R1、R2、R3、R4、R5、R1’、R2’、R3’、R4’及R5’各者各自独立地是H、烷基(例如,经卤基或SO2Rd取代的烷基)、卤基、OH、Rc-O-、RdS(O)2-O-或(Rd)2P(O)-O-,Rc是未经取代的烷基或经卤基、OH、烷氧基、胺基、环烷基、杂环烷基、芳基或杂芳基取代的烷基,及RdH、OH、烷基、烷氧基、胺基或芳基;其中R1与R1’或R5’不同、R2与R2’或R4’不同、R3与R3’不同、R4与R2’或R4’不同、或R5与R1’或R5’不同。
参照式(I),该化合物的支组具有一或多个下列特征:R2是OH,或R2是RdS(O)2-O-或(Rd)2P(O)-O-(Rd是H、OH、烷基、烷氧基、胺基或芳基,例如,Rd是乙基);R2’是Rc-O-(Rc是经胺基取代的烷基);X及Y各者是H,或X与Y一起是-(CH2)NRa(CH2)-;及Ra是C(O)-R、C(O)NRR’或经环烷基取代的烷基(R及R’各者各自独立地是烷基或环烷基)。
本发明的另一个观点涉及一种式(II)的化合物:
其中X及Y各者各自独立地是H、烷基或卤基,或X与Y一起是-CH2-、-(CH2)2-、-(CH2)CRaRb(CH2)-、-(CH2)NRa(CH2)-或-(CH2)O(CH2)-,Ra及Rb各者各自独立地是H、烷基、C(O)-烷基、C(O)-环烷基、C(O)-NH-烷基或C(O)-NH-环烷基;及R1、R2、R3、R4、R5、R1’、R2’、R3’、R4’及R5’各者各自独立地是H、烷基(例如,经卤基或SO2Rd取代的烷基)、卤基、OH、Rc-O-、RdS(O)2-O-或(Rd)2P(O)-O-,Rc是未经取代的烷基或经卤基、OH、烷氧基、胺基、环烷基、杂环烷基、芳基或杂芳基取代的烷基,及Rd是H、OH、烷基、烷氧基、胺基或芳基;其中R1、R2、R3、R4、R5、R1’、R2’、R3’、R4’及R5’的至少一个是RdS(O)2-O-、(Rd)2P(O)-O-或(RdO)2P(O)-O-。
参照式(II),该化合物的支组具有一或多个下列特征:X及Y各者是H;R2是RdS(O)2-O-或(Rd)2P(O)-O-(Rd是H、OH、烷基、烷氧基、胺基或芳基;例如,Rd是乙基);R2’是R-O-(R是经胺基取代的烷基),或R2’是RdS(O)2-O-或(Rd)2P(O)-O-(Rd是H、OH、烷基、烷氧基、胺基或芳基,例如,Rd是乙基);及R1’、R3’及R4’之一是RdS(O)2-O-或(Rd)2P(O)-O-(Rd是H、OH、烷基、烷氧基、胺基或芳基,例如,Rd是乙基)。
本发明的又另一个观点是涉及一种式(III)的化合物:
其中每个X是N或CH;R1、R2、R3、R4、R5、R1’、R2’、R3’、R4’及R5’各者各自独立地是H、烷基(例如,经卤基或SO2Rd取代的烷基)、卤基、OH、Rc-O-、RdS(O)2-O-或(Rd)2P(O)-O-,Rc是未经取代的烷基或经卤基、OH、烷氧基、胺基、环烷基、杂环烷基、芳基或杂芳基取代的烷基,及Rd是H、OH、烷基、烷氧基、胺基或芳基;及R6是C(O)-Re、C(O)NReRf或烷基(例如,未经取代的烷基或经环烷基取代的烷基),Re及Rf各者各自独立地是烷基或环烷基。
参照式(III),该化合物的支组具有一或多个下列特征:X是N;R2是OH或R-O-(R是经胺基取代的烷基,例如,R是CH2H2N(C2H5)2);及R6是环丙基羰基或环丙基甲基。
用语”烷基”指为包含1-10个碳原子的饱和线性或分支烃部分,诸如-CH3或-CH(CH3)2。用语”环烷基”指为3-10员饱和环状烃部分,诸如环己基。用语”杂环烷基”指为3-10员具有至少一个环杂原子(例如,N、O或S)的饱和环状部分,诸如4-四氢哌喃基。用语”芳基”指为具有一或多个芳香环的烃部分。该芳基部分的实施例包括苯基(Ph)、苯撑基、萘基、萘撑基、芘基、蒽基及菲基。用语”杂芳基”指为具有一或多个包含至少一个杂原子(例如,N、O或S)的芳香环的一部分。该杂芳基部分的实施例包括呋喃基、伸呋喃基、茀基、吡咯基、噻吩基、噁唑基、咪唑基、噻唑基、吡啶基、嘧啶基、喹唑啉基、喹啉基、异喹啉基及吲哚基。
除非有详细指明,否则于此提到的烷基、环烷基、杂环烷基、芳基及杂芳基包括经取代及未经取代的部分二者。在环烷基、杂环烷基、芳基及杂芳基上可能的取代基包括(但不限于)C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C20环烷基、C3-C20环烯基、C1-C20杂环烷基、C1-C20杂环烯基、C1-C10烷氧基、芳基、芳氧基、杂芳基、杂芳氧基、胺基、C1-C10烷基胺基、C1-C20二烷基胺基、芳基胺基、二芳基胺基、C1-C10烷基磺胺基、芳基磺胺基、C1-C10烷基亚胺基、芳基亚胺基、C1-C10烷基磺亚胺基、芳基磺亚胺基、羟基、卤基、硫基、C1-C10烷硫基、芳硫基、C1-C10烷基砜基、芳基砜基、酰基胺基、胺酰基、胺基硫酰基、脒基、胍、脲基、氰基、硝基、亚硝基、迭氮基、酰基、硫酰基、酰氧基、羧基及羧酸酯。另一方面,在烷基上可能的取代基包括上述叙述的全部取代基,除了C1-C10烷基外。该环烷基、杂环烷基、芳基及杂芳基也可彼此并合。
若合适的话,上述化合物包括该化合物它们本身、和其盐、前药体及溶剂化物。例如,可在1,5-二苯基-戊-1,4-二烯-3-酮化合物的阴离子与正电荷基团(例如,铵离子)间形成盐。合适的阴离子包括氯化物、溴化物、碘化物、硫酸盐、硝酸盐、磷酸盐、柠檬酸盐、甲磺酸盐、三氟醋酸盐、醋酸盐、琥珀酸盐、苹果酸盐、甲苯磺酸盐、酒石酸盐、反丁烯二酸盐、麸氨酸盐、葡萄糖醛酸盐、乳酸盐、戊二酸盐及顺丁烯二酸盐。同样地,也可在1,5-二苯基-戊-1,4-二烯-3-酮化合物的阳离子与负电荷基团(例如,羧酸盐)间形成盐。合适的阳离子包括钠离子、钾离子、镁离子、钙离子及铵阳离子。该化合物也可呈前药体及溶剂化物形式。该前药体的实施例包括酯类及其它医药可接受的衍生物(其在给药至患者后能提供活性化合物)。该溶剂化物指为在活性化合物与医药可接受的溶剂间形成的复合物。该医药可接受的溶剂的实施例包括水、乙醇、异丙醇、醋酸乙酯、醋酸及乙醇胺。
该化合物包括非芳香族双键。因此,它们可发生如为顺或反异构物形式。此异构物形式是经考虑到。
本发明的又另一个观点是涉及一种用来治疗癌、炎性疾病或自体免疫性疾病的方法。该方法包括将一有效量的一或多种上述化合物给药至需要其的患者。
在本发明的范围内也包括一使用来治疗癌/炎性疾病/自体免疫性疾病的包含一或多种上述化合物与医药可接受的载剂的组合物,及一此组合物用于仅提到的治疗的药剂的制造的用途。
在下列描述中提出本发明的一或多个具体实例的细节。将从描述中及从权利要求书中明了本发明的其它特征、目标及优点。
具体实施方式
上述化合物可通过在本领域中熟知的方法制备。下列反应方案1、2及3阐明使用来各别合成式(I)、(II)及(III)的化合物的一般合成途径。
反应方案1
如显示在上述反应方案1中,于碱性条件下缩合苯甲醛与过量的丙酮以提供4-苯基丁-3-烯-2-酮化合物,使其与第二苯甲醛化合物缩合以获得式(I)的化合物。从而获得的产物可经进一步修改以制备其它的式(I)的化合物。
反应方案2
如显示在上述反应方案2中,使经羟基取代的1,5-二苯基戊-1,4-二烯-3-酮化合物(其可通过上述的方法制备)与磺酰氯或氯化膦/氯磷酸酯/三氯化磷酰或酰基氯缩合,以提供式(II)的化合物。类似地,3,5-二亚苄基哌啶-4-酮化合物可与砜基氯/氯化膦/酰基氯缩合以提供也由式(II)涵盖的化合物。
反应方案3
如显示在上述反应方案3中,使哌啶-4-酮与酰基氯或溴烷反应以提供N-经取代的哌啶-4-酮,其随后与2当量的苯甲醛缩合以获得由式(III)涵盖的对称的3,5-二亚苄基哌啶-4-酮化合物。该N-经取代的哌啶-4-酮可首先与1当量的苯甲醛,然后与1当量的第二苯甲醛反应,以制备不对称的3,5-二亚苄基哌啶-4-酮化合物,其也由式(III)涵盖。
下列显示依上述方法制备的典型的式(I)、(II)及(III)的化合物:
上述化合物会去活化STAT蛋白质。因此,本发明涵盖一种将一有效量的一或多种化合物给药至患有癌、炎性疾病或自体免疫性疾病的患者的方法。
用语”以…治疗”或”治疗”指为将一或多种化合物给药至具有上述症状、此症状的征兆或朝向此症状的体质的患者,其目的为提供治疗效应,例如以治愈、减轻、改变、影响、改善或防止上述病症、其征兆或朝向其的体质。”有效量”指为在经治疗的患者上提供治疗效应所需要的活性化合物的量。如由本领域技术人员了解,有效剂量将依所治疗的疾病型式、给药途径、赋形剂的使用及与其它治疗性治疗共使用的可能性而变化。
可通过本发明的方法治疗的癌包括多种器官的实体及血液肿瘤二者。该实体肿瘤的实施例包括胰癌、膀胱癌、结肠癌、结肠直肠癌、乳房癌(例如,转移性乳房癌)、前列腺癌(例如,雄性激素相依、雄性激素无关或阉割抗性前列腺癌)、肾脏癌(例如,转移性肾细胞癌)、肝细胞癌、肺癌(例如,非小细胞肺癌、细支气管肺泡癌或肺腺癌)、卵巢癌(例如,进行性上皮或原发性腹膜癌)、子宫颈癌、胃癌、食道癌、头颈癌(例如,头及颈的鳞状细胞癌)、黑肿瘤、神经内分泌癌(例如,转移性神经内分泌肿瘤)、脑肿瘤(例如,神经胶质瘤、分化不良寡树突胶质瘤、成年多形神经胶母细胞瘤或成年分化不良星细胞瘤)、骨癌及软组织肉瘤。该血液肿瘤的实施例包括多种白血病(例如,骨髓性白血病、慢性骨髓性白血病或CML[加速期CML及CML急性期]、急性淋巴胚细胞白血病或慢性淋巴球性白血病)、Hodgkin’s病、非Hodgkin’s淋巴瘤(例如,滤泡淋巴瘤或外套细胞淋巴瘤)、B细胞淋巴瘤、T细胞淋巴瘤、多发性骨髓瘤、Waldenstrom’s大球蛋白血症、骨髓造血分化不良症候群(例如,顽固性贫血、含有环状含铁胚血球的顽固性贫血、含有过量芽细胞的顽固性贫血或RAEB、或转变中RAEB)、及骨髓增生性症候群。
可通过本发明的方法治疗的炎性疾病包括(但不限于)气喘、动脉粥瘤硬化、类风湿性关节炎、发炎性肠道疾病、Crohn、溃疡性结肠炎、缺血性心脏病、心肌病、肾丝球肾炎、肾症候群、肝炎B或C感染、呼吸道融合瘤病毒感染(肺)及Guillain-Barré症候群。
可通过本发明的方法治疗的自体免疫性疾病包括(但不限于)过敏性脑病、慢性阻塞性肺疾、牛皮癣、牛皮癣性关节炎、糖尿病、全身性红斑狼疮、多发性硬化、多肌炎、皮肌炎、混合性结缔组织疾病、症候群、Wegener’s肉芽肿病、结节性多动脉炎、类风湿性关节炎及自发性血小板减少性紫瘢病。
为了实行本发明的方法,可非经肠道、口服、鼻、直肠、局部或颊地给药含有一或多种上述化合物的组合物。如于本文中所使用的用语”非经肠式”指为皮下、皮内、静脉内、肌肉内、关节内、动脉内、滑膜内、胸骨内、鞘内、病灶内或颅内注射,和任何合适的输液技术。
无菌可注射组合物可为在无毒非经肠道的可接受的稀释剂或溶剂中的溶液或悬浮液,诸如在1,3-丁二醇中的溶液。在可接受的媒剂及溶剂当中,使用的有甘露醇、水、Ringer’s溶液及等渗压氯化钠溶液。此外,习知上使用非挥发性油作为溶剂或悬浮培养基(例如,合成的单或二甘油酯类)。在注射物质的制备中,脂肪酸(诸如油酸及其甘油酯衍生物)有用作为天然医药可接受的油,诸如橄榄油或蓖麻油,特别是其聚氧乙基化的形式。这些油溶液或悬浮液也可包含长链醇稀释剂或分散剂、羧甲基纤维素或类似的分散剂。为了调配的目的,也可使用其它普通使用的界面活性剂(诸如Tweens或Spans)或其它类似的乳化剂或生物可利用率促进剂(其普通使用来制造医药可接受的固体、液体或其它剂型)。
用于口服给药的组合物可为任何口服可接受的剂形,包括胶囊、锭剂、乳液及水性悬浮液、分散液及溶液。在锭剂的情况中,普通使用的载剂包括乳糖及玉黍蜀粉。典型上,也加入润滑剂,诸如硬脂酸镁。对以胶囊形式口服给药来说,有用的稀释剂包括乳糖及干玉黍蜀粉。当口服给药水性悬浮液或乳液时,该活性成分可悬浮或溶解在与乳化或悬浮剂结合的油相中。若须要时,可加入某些变甜、风味或着色剂。
可根据在医药调配物的本领域中熟知的技术来制备鼻喷雾剂或吸入组合物。例如,此组合物可使用苄醇或其它合适的防腐剂、吸收促进剂(以提高生物可利用率)、碳氟化合物、和/或在本领域中已知的其它溶解或分散剂制备成在盐液中的溶液。
该含有一或多种活性化合物的组合物也可以栓剂形式给药而用于直肠给药。
在该医药组合物中的载剂必需”可接受”,在观念上其与该组合物的活性成分相容(及以能稳定该活性成分为较佳)且对欲治疗的患者无害。可使用一或多种增溶剂作为医药赋形剂来传递活性1,5-二苯基-戊-1,4-二烯-3-酮化合物。其它载剂的实施例包括胶态氧化硅、硬脂酸镁、纤维素、硫酸月桂酯钠及D&C黄色#10。
上述的1,5-二苯基-戊-1,4-二烯-3-酮化合物可对其在去活化STAT蛋白质及治疗上述疾病的效力来进行初步筛选,此通过试管内试验,然后通过动物实验及临床试验证实。将也由一般本领域技术人员明了其它方法。
下列特定实施例欲解释仅作为阐明用,且无论如何不以任何方式限制本揭示的剩余部分。相信本领域技术人员可没有进一步详细阐述而根据于此的描述将本发明使用至其最大程度。全部于此所引用的公告其全文由此以参考方式并入本文。
化学合成
使用未经校正的Fisher-John熔点装置来测量熔点。在Varian Gemini 300或Inova 400光谱仪上测量质子核磁共振(1H NMR)及13C NMR光谱,且使用四甲基硅烷作为内部标准。以δ(ppm)报导化学位移。在Shimadzu LCMS-2010上获得质谱(MS)。在Grace硅凝胶匣上进行CombiFlash层析系统,用于一般的分离及纯化。也使用一使用硅凝胶板(Kieselgel 60,F254,1.00毫米)的制备型薄层色层分析法来分离及纯化。使用经预涂布的硅凝胶板(Kieselgel 60,F254,0.25毫米)用于薄层色层分析法(TLC)分析。全部试剂及溶剂皆从Aldrich、Fisher、VWR或其它供货商购买。
化合物1-4及21的合成
如在下列反应方案4中所显示般制备化合物1-4及21:
反应方案4
在4℃下,于冰浴中,在羟基苯甲醛于DMF中的溶液中加入K2CO3(每个羟基2当量)及甲基氯甲基醚(氯化MOM)(每个羟基1.3当量)。在室温下搅拌该溶液并通过TLC监视3-5小时后,加入己烷类/二氯甲烷(1:1)及允许搅拌30分钟。过滤出固体及浓缩滤出液。以EtOAc稀释所产生的残余物及以H2O清洗两次。以EtOAc萃取水层。在Na2SO4上干燥结合的有机层及浓缩。通过CombiFlash色层分析系统,使用Grace硅凝胶管柱及己烷类/醋酸乙酯(作为冲提液)纯化粗产物,以提供经MOM保护的羟基苯甲醛。通过10%NaOH(1.2当量NaOH)催化,使所产生的化合物在乙醇中进一步与过量丙酮反应。在室温下搅拌且由TLC监视1-5小时后,以CH2Cl2稀释该反应混合物,以H2O清洗两次及以CH2Cl2萃取两次。在通过CombiFlash系统使用己烷类/醋酸乙酯作为冲提液纯化后,获得经MOM保护的羟基-苯基-丁-3-烯-2-酮。使所产生的化合物与适当经MOM保护的羟基苯甲醛反应以获得经MOM保护的羟基1,5-二苯基-戊-1,4-二烯-3-酮,其通过在50%醋酸水溶液中加热去保护,以获得想要的产物。
化合物1:黄色结晶固体;ESI MS m/z:251.10[M+H]+;1H NMR(300MHz,CDCl3)δ:7.75(d,1H,J=15.0赫兹,H-1),7.63(d,1H,J=15.0赫兹,H-5),7.64(m,2H,芳香环H),7.43-7.41(m,2H,芳香环H),7.72-7.27(m,2H,芳香环H),7.21-7.19(d,1H,J=6.0赫兹,芳香环H),7.13-7.12(m,1H,芳香环H),7.08(d,1H,J=15.0赫兹,H-2),7.06(d,1H,J=15.0赫兹,H-4),6.92-6.83(m,1H,芳香环H),5.38(br.1H,OH)。
化合物2:黄色结晶固体;ESI MS m/z:267.29[M+H]+;1H NMR(300MHz,CD3OD3)δ:8.10(d,1H,J=15.0赫兹,H-1),7.63(d,1H,J=15.0赫兹,H-5),7.75-7.62(m,1H,芳香环H),7.25(d,1H,J=15.0赫兹,H-4),7.22(d,1H,J=15.0赫兹,H-2),7.21-7.11(m,4H,芳香环H),6.91-6.84(m,3H,芳香环H),3.68(br.2H,OH)。
化合物3:黄色结晶固体;ESI MS m/z:281.05[M-H]-;1H NMR(300MHz,CD3OD3)δ:7.68(d,1H,J=15.9赫兹,H-5),7.66(d,1H,J=15.9赫兹,H-1),7.27-6.97(m,5H,芳香环H),6.99(d,1H,J=15.9赫兹,H-4),6.88-6.84(m,2H,芳香环H),6.80(d,1H,J=15.9赫兹,H-2),4.91(br.3H,OH)。
化合物4:黄色结晶固体;ESI MS m/z:281.05[M-H]-;1H NMR(300MHz,CD3OD3)δ:7.70(d,1H,J=15.9赫兹,H-5),7.65(d,1H,J=15.9赫兹,H-1),7.60-7.56(dd,2H,芳香环H),7.15-7.06(m,2H,芳香环H),7.12(d,1H,J=15.9赫兹,H-4),6.98(d,1H,J=15.9赫兹,H-2),6.81(t,3H,J=8.4赫兹,芳香环H)。
化合物21:黄色结晶固体;ESI MS m/z:281.09[M-H]-;1H NMR(300MHz,CD3OD3)δ:7.63(d,1H,J=15.9赫兹,H-5),7.56(d,1H,J=15.9赫兹,H-1),7.21-7.05(m,3H,芳香环H),7.12(d,1H,J=15.9赫兹,H-4),7.03(d,1H,J=15.9赫兹,H-2),6.82-6.778(m,1H,芳香环H),6.57(d,2H,J=2.1赫兹,芳香环H),6.29(t,1H,J=2.1赫兹,芳香环H)。
化合物20、30、31、38、39、41、42、44、62-64、73及75的合成
如在下列反应方案5中所显示出般制备化合物20、30、31、38、39、41、42、44、62-64、73及75:
反应方案5
使用与如上所述相同的方式使经甲氧基取代的苯甲醛与丙酮反应,接着与经第二甲氧基取代的苯甲醛缩合,以获得经甲氧基取代的1,5-二苯基-戊-1,4-二烯-3-酮化合物30及31或经甲基甲氧基取代的1,5-二苯基-戊-1,4-二烯-3-酮。在CH2Cl2中,以BBr3(每个甲氧基2当量)从-78℃至0℃至室温去甲基化(或部分去甲基化),提供想要的酚粗产物。通过TLC监视该反应。在完成后,将该反应混合物倾入酸性的冰/水中,然后通过乙基醚萃取。在CombiFlash色层分析系统上纯化后,获得想要的产物(即,化合物20、62-64)。
化合物20:红色结晶固体;ESI MS m/z:281.10[M-H]-;1H NMR(300MHz,CD3OD3)δ:8.06(d,1H,J=15.9赫兹,H-5),7.63(d,1H,J=15.9赫兹,H-1),7.26-7.05(m,5H,芳香环H及H-2,4),6.86-6.62(m,4H,芳香环H)。
化合物62:非晶相,ESI MS m/z:309.0[M+H]+;1H NMR(400MHz,丙酮-d6)δ:8.03-7.94(m,2H,H-1,5),7.15-7.00(m,3H,芳香环H),6.96-6.87(m,3H,芳香环H),6.68(d,J=16.0赫兹,1H,H-2),6.65(d,J=16.0赫兹,1H,H-4),3.85(s,3H,OCH3),2.12(s,3H,CH3),2.10(s,3H,CH3)。
化合物63:明黄色固体,ESI MS m/z:295.1[M+H]+;1H NMR(400MHz,CD3OD)δ:8.01(d,2H,J=15.6赫兹,H-1,5),7.66-7.64(m,2H,芳香环H),6.98(d,2H,J=15.6赫兹,H-2,4),6.66-6.64(m,4H,芳香环H),2.40(s,6H,CH3)。
化合物64:非晶相,ESI MS m/z:309.1[M+H]+;1H NMR(400MHz,丙酮-d6)δ:8.07-7.94(m,2H,H-1,5),7.75-7.67及7.08-7.01(m,1H,芳香环H),7.50-7.44(m,2H,芳香环H),6.83-6.73(m,1H,芳香环H),6.70-6.66(m,2H,芳香环H),6.48(d,J=16.0赫兹,1H,H-2),6.47(d,J=16.0赫兹,1H,H-4),3.81(s,3H,OCH3),1.98(s,3H,CH3),1.94(s,3H,CH3)。
如在上述反应方案5中所显示般,通过在室温下,于乙醇/20%NaOH水溶液中,使经取代的苯甲醛与(E)-4-(3-羟基苯基)丁-3-烯-2-酮反应来合成化合物38、39、41、42、44、73及75。通过TLC监视该反应。在完成后,通过醋酸中和该溶液,以醋酸乙酯萃取及浓缩,以获得想要的产物。为了供应化合物44,通过在室温下,于乙醇溶液中,以0.1当量的对-甲苯磺酸吡锭处理来移除THP保护基团(其经引进以制得3-甲氧基-4-(四氢-哌喃-2-基氧基)-苯甲醛)。
化合物38:淡黄色针;mp 159-160℃;C19H18O4,ESI-MS:m/z311.2[M+H]+;1H NMR(300MHz,DMSO-d6):7.75,7.65(1H每个,二者d,J=16.2赫兹,H-1,5),7.42(1H,d,J=2.1赫兹,H-2’),7.34(1H,dd,J=2.1,8.4赫兹,H-6’),7.25,7.23(1H每个,二者d,J=16.2赫兹,H-2,4),7.28-7.13(2H,m,H-4”,5”),7.14(1H,br.t,H-2”),7.04(1H,d,J=8.4赫兹,H-5’),6.86(1H,br.d,8.4赫兹,H-6”),3.84,3.82(二者s,3H每个,OCH3X 2)。
化合物39:黄色细结晶;mp 152-153℃;C18H16O3,ESI-MS:m/z281.2[M+H]+;1H NMR(300MHz,DMSO-d6):7.76,7.62(1H每个,二者d,J=16.2赫兹,H-1,5),7.72(2H,d,J=9.0赫兹,H-2’,6’),7.22(1H,d,8.0赫兹,H-6”),7.18,7.17(1H每个,二者d,J=16.2赫兹,H-2,4),7.17(1H,m,5”),7.09(1H,br.3,H-2”),6.98(2H,d,J=9.0赫兹,H-3’,5’),6.81(1H,br.d,8.0赫兹,H-4”),3.77(s,3H,OCH3)。
化合物41:淡黄色针;mp 138-139℃;C18H13F3O2,ESI-MS:m/z319.2[M+H]+;1H NMR(300MHz,DMSO-d6):8.14(1H,br.,H-2’),8.07(1H,br.d,J=7.8赫兹,H-6’),7.81,7.50(1H每个,二者d,J=15.9赫兹,H-1,2),7.78-7.62(2H,m,H-4’,5’),7.69,7.19(1H每个,二者d,J=16.2赫兹,H-4,5),7.22(2H,4”,5”),7.10(1H,br.s,H-2”),6.83(1H,br.d,J=8.7赫兹,H-6”)。
化合物42:淡黄色细结晶;mp 159-160℃;C17H13FO2,ESI-MS:m/z269.2[M+H]+;1HNMR(300MHz,DMSO-d6):7.92(1H,dt,J=1.8,7赫兹,H-4’),7.73,7.42(1H每个,二者d,J=16.2赫兹,H-1,2),7.69,7.16(1H每个,二者d,J=16.2赫兹,H-4,5),7.47(1H,m,H-5”),7.30-7.12(3H,m,2’,5’,6’,4”),7.10(1H,br.s,H-2”),6.82(1H,dt,J=1.8,7.2赫兹,H-6”)。
化合物44:黄色细结晶;mp 144-145℃;C23H26O10S3,ESI-MS:m/z559.1[M+H]+;1HNMR(300MHz,DMSO-d6):7.63-6.93(11H,m,芳香族H及乙烯基H),3.81(2H,s,OCH3)。
化合物73:灰白色固体,ESI MS m/z:269.5[M+H]+;1H NMR(400MHz,CDCl3)δ:7.68(d,J=16.0赫兹,1H,H-1),7.67(d,J=16.0赫兹,1H,H-5),7.37-7.35(m,2H,芳香环H),7.29-7.24(m,2H,芳香环H),7.18-7.16(m,1H,芳香环H),7.11-7.08(m,2H,芳香环H),7.04(d,J=16.0赫兹,1H,H-4),7.01(d,J=16.0赫兹,1H,H-2),6.91-6.88(m,1H,芳香环H)。
化合物75:浅黄色固体,ESI MS m/z:335.5[M+H]+;1H NMR(400MHz,CDCl3)δ:7.69(d,J=15.6赫兹,1H,H-1),7.67(d,J=15.6赫兹,1H,H-5),7.49-7.47(m,1H,芳香环H),7.42-7.39(m,2H,芳香环H),7.28-7.22(m,2H,芳香环H),7.16-7.14(m,2H,芳香环H),7.05(d,J=16.0赫兹,1H,H-4),7.02(d,J=16.0赫兹,1H,H-2),6.95-6.92(m,1H,芳香环H)。
化合物12、13及15-17的合成
如在反应方案6中所显示般,通过以在Roberta Costi等人,Bioorganic&Medicinal Chemistry 2004,12:199-215中所描述者为基准所修改的方法来合成化合物12、13及15-17。
反应方案6
在哌啶-4-酮于DMF中的溶液中,加入三乙基胺(1.5当量)及氯化N,N-二乙基乙酰胺(1.5当量)。在室温下搅拌所产生的溶液5小时或直到完成(通过TLC观察)。蒸发溶剂及将残余物分配在H2O与EtOAc中。以EtOAc萃取水层,并在Na2SO4上干燥结合的有机层及浓缩。通过CombiFlash色层分析系统,使用硅凝胶匣及CH2Cl2/MeOH梯度冲提液来纯化粗产物,以获得4-侧氧-哌啶-1-羧酸二乙基酰胺,其随后在醋酸(99.7%)中且充入HCl气体(0.5-1小时)与3-羟基苯醛(2.5当量)反应。在室温下搅拌3小时后,蒸发溶剂及通过CombiFlash色层分析系统与己烷类/EtOAc作为冲提液来纯化粗产物,接着从MeOH结晶以获得化合物12,如为黄色结晶固体。
化合物12:黄色结晶固体;ESI MS m/z:407.49[M+H]+;1H NMR(300MHz,CD3OD)δ:7.61(s.2H,亚苄基CH=),7.16(t,2H,J=7.5赫兹,芳香环H),6.82-6.79(m,2H,芳香环H),6.75-6.71(m,4H,芳香环H),4.36(s,4H,4-侧氧-哌啶-H-2,6),2.95(q,4H,-NCH2 CH3),0.71(t,6H,-NCH2CH3 )。
以与如上所述相同的方式制备化合物16,除了使用环丙羰基氯(1.5当量)取代氯化N,N-二乙基乙酰胺外。
化合物16:黄色固体;ESI MS m/z:376.16[M+H]+;1H NMR(300MHz,DMSO-d6)δ:7.59(s.2H,亚苄基CH=),7.30(t,2H,J=7.5Hz,芳香环H),6.98-6.93(m,4H,芳香环H),6.87-6.85(m,2H,芳香环H),3.39(s,4H,4-侧氧-哌啶-H-2,6),1.69(m,1H,环丙羰基CH),0.62-0.58(m,4H,环丙羰基CH2 )。
通过在DMF中,于K2CO3存在下,使哌啶-4-酮与1-溴-丁烷(1.5当量)或溴甲基-环丙烷(1.5当量)反应来合成化合物15及17。在室温下搅拌24小时后或通过MS监视,通过蒸发移除该反应溶剂。将残余物分配在H2O与EtOAc中,及以H2O清洗有机层两次。然后,以EtOAc萃取水层及在Na2SO4上干燥萃取物。通过CombiFlash色层分析系统,使用硅凝胶匣及CH2Cl2/MeOH梯度冲提液来纯化粗产物。遵循上述相同的程序,使所获得的N-经取代的4-侧氧-哌啶化合物与3-羟基苯醛(2.5当量)缩合,以获得想要的产物。
化合物15:黄色固体;ESI MS m/z:364.19[M+H]+;1H NMR(300MHz,CD3OD)δ:7.64(s.2H,亚苄基CH=),7.21(t,2H,J=8.1赫兹,芳香环H),6.85(d,br,2H,J=8.1赫兹,芳香环H),6.80-6.76(m,4H,芳香环H),3.80(s,4H,4-侧氧-哌啶-H-2,6),2.50(t,2H,J=8.1赫兹,-NCH2 CH2-),1.42-1.30(m,2H,-NCH2 CH2 CH2-),1.27-1.14(m,2H,-NCH2CH2 CH2 CH3),0.81(t,3H,-NCH2CH2CH2 CH3 )。
化合物17:黄色固体;ESI MS m/z:362.18[M+H]+;1H NMR(300MHz,DMSO-d3)δ:7.66(s.2H,亚苄基CH=),7.21(t,2H,J=7.8赫兹,芳香环H),6.86(d,br,2H,J=7.2赫兹,芳香环H),6.81-6.75(m,4H,芳香环H),3.90(s,4H,4-侧氧-哌啶-H-2,6),2.40(d,2H,J=6.6赫兹,亚甲基-环丙烷-CH2 ),0.65(m,1H,环丙烷CH),0.43-0.37(m,2H,环丙烷CH2 ),0.11-0.07(m,2H,环丙烷CH2 )。
从在DMF中处理侧氧-(4-侧氧-环己基)-醋酸与1-乙基-3-(3-二甲基胺基丙基)碳二酰亚胺(2当量)及4-二甲基胺基吡啶(催化量)开始来合成化合物13。在室温下搅拌大约10分钟后,在冰浴中冷却该反应混合物及加入二乙胺(1.5当量)。在室温下搅拌所得的混合物5小时伴随着TLC监视。通过蒸发移除溶剂。以EtOAc稀释残余物及以H2O清洗两次。然后,以EtOAc萃取水层及在Na2SO4上干燥有机层。在透过CombiFlash色层分析系统使用硅凝胶匣及CH2Cl2/MeOH梯度冲提液纯化后,获得想要的中间物N,N-二乙基-2-侧氧-2-(4-侧氧-环己基)-乙酰胺,遵循上述相同的程序,使其进一步与3-羟基苯醛(2.5当量)缩合,以获得想要的产物,如为黄色固体。ESI MS m/z:406.51[M+H]+;1H NMR(300MHz,DMSO-d6)δ:7.54(s.2H,亚苄基CH=),7.25(t,2H,J=7.8赫兹,芳香环H),6.93-6.89(m,4H,芳香环H),6.81-6.78(m,2H,芳香环H),3.23(q,4H,J=7.2赫兹,-NCH2 CH3),2.95(m,4H,4-侧氧-环己基-H-2,6),2.54(m,1H,环己基-H-1),0.94(m,6H,-NCH2CH3 )。化合物5-11、14、18、22-29、32-34、37、40、43、53、65-66、69-70、74、77及78的合成
这些化合物的合成显示在反应方案7中。
反应方案7
在CH2Cl2(包含小量DMF)中的1,5-双-(3-羟基-苯基)-戊-1,4-二烯-3-酮(通过显示在反应方案4中的方法合成)溶液中,慢慢加入乙磺酰基氯(~10当量)及Et3N(~10当量)。在室温下搅拌所得的混合物4-5小时。以CH2Cl2稀释该反应混合物,以水清洗两次及以CH2Cl2萃取。在Na2SO4上干燥有机萃取物,过滤及浓缩以获得粗产物,如为黄色固体。通过快速管柱过滤来纯化粗产物,然后结晶及从EtOAc再结晶,以获得想要的产物化合物6,如为浅黄色结晶固体。产率>78%。ESI MS m/z:451.2[M+H]+;1H NMR(300MHz,CDCl3)δ:7.71(d,2H,J=15.9赫兹,H-1,5),7.57-7.53(m,4H,芳香环H),7.47(t,2H,J=7.8赫兹,芳香环H),7.34-7.31(m,2H,芳香环H),7.08(d,2H,J=15.9赫兹,H-2,4),3.34(q,4H,J=7.5赫兹,-OSO2CH2 CH3),1.58(t,6H,J=7.5赫兹,-OSO2CH2CH3 )。
以类似于上述所描述的方式合成化合物5、7-11、22、26、27、40、43、53、65-66、69-70、74及77。
化合物5:浅黄色结晶固体;ESI MS m/z:451.2[M+H]+;1H NMR(300MHz,CDCl3)δ:7.72(d,2H,J=15.9赫兹,H-1,5),7.66(d,4H,J=8.7赫兹,芳香环H),7.34(d,4H,J=8.7赫兹,芳香环H),7.04(d,2H,J=15.9赫兹,H-2,4),3.33(q,4H,J=7.5赫兹,-OSO2CH2 CH3),1.57(t,6H,J=7.5赫兹,-OSO2CH2CH3 )。
化合物7:黄色结晶固体;ESI MS m/z:343.4[M+H]+;1H NMR(300MHz,CDCl3)δ:7.76(d,1H,J=15.9赫兹,H-5),7.70(d,1H,J=15.9赫兹,H-1),7.65-7.62(m,2H,芳香环H),7.57-7.53(m,2H,芳香环H),7.49-7.42(m,4H,芳香环H),7.34-7.30(m,1H,芳香环H),7.10(d,1H,J=15.9赫兹,H-4),7.09(d,1H,J=15.9赫兹,H-2),3.33(q,2H,J=7.5赫兹,-OSO2CH2 CH3),1.58(t,3H,J=7.5赫兹,-OSO2CH2CH3 )。
化合物8:灰白色结晶固体;ESI MS m/z:423.2[M+H]+;1H NMR(300MHz,CDCl3)δ:7.70(d,2H,J=15.9赫兹,H-1,5),7.58-7.38(m,4H,芳香环H),7.48(t,2H,J=7.5Hz,芳香环H),7.36-7.33(m,2H,芳香环H),7.08(d,2H,J=15.9赫兹,H-2,4),3.21(s,6H,-OSO2CH3 )。
化合物9:黄色结晶固体;ESI MS m/z:479.2[M+H]+;1H NMR(300MHz,CDCl3)δ:7.71(d,2H,J=15.9赫兹,H-1,5),7.57-7.53(m,4H,芳香环H),7.47(t,2H,J=7.8赫兹,芳香环H),7.34-7.31(m,2H,芳香环H),7.08(d,2H,J=15.9赫兹,H-2,4),3.31-3.26(m,4H,-OSO2CH2 CH2CH3),2.12-1.99(m,4H,-OSO2CH2CH2 CH3),1.16(t,6H,J=7.5赫兹,-OSO2CH2CH2 CH3)。
化合物10:浅黄色浓油;ESI MS m/z:547.2[M+H]+;1H NMR(300MHz,CDCl3)δ:7.88-7.85(m,4H,磺酸苯酯芳香环H),7.71(t,2H,磺酸苯酯芳香环H),7.59(d,2H,J=15.9赫兹,H-1,5),7.59-7.48(m,6H,磺酸苯酯经取代的及联苯芳香环H),7.35(t,2H,J=7.8赫兹,芳香环H),7.27-7.25(m,2H,联苯芳香环H),7.03-7.00(m,2H,联苯芳香环H),6.95(d,2H,J=15.9赫兹,H-2,4)。
化合物11:浅黄色结晶固体;ESI MS m/z:559.1[M+H]+;1H NMR(300MHz,CDCl3)δ:7.73(d,1H,J=15.9赫兹,H-5),7.72-7.70(dd,1H,芳香环H),7.67(d,1H,J=15.9赫兹,H-1),7.67(d,2H,J=8.7赫兹,2”,6”芳香环H),7.55-7.50(m,2H,芳香环H),7.34(d,2H,J=8.7赫兹,3”,5”芳香环H),7.05(d,1H,J=15.9赫兹,H-4),7.03(d,1H,J=15.9赫兹,H-2),3.47(m,6H,-OSO2CH2 CH3),1.58(m,9H,-OSO2CH2CH3 )。
化合物26:非晶相;ESI MS m/z:559.1[M+H]+;1H NMR(300MHz,CDCl3)δ:8.02(d,1H,J=15.9赫兹,H-1),7.72-7.70(dd,1H,芳香环H),7.73(d,1H,J=15.9赫兹,H-5),7.59-7.33(m,6H,芳香环H),7.20(d,1H,J=15.9赫兹,H-2),7.07(d,1H,J=15.9赫兹,H-4),3.58(q,2H,J=7.5赫兹,-OSO2CH2 CH3),3.45(q,2H,J=7.5赫兹,-OSO2CH2 CH3),3.35(q,2H,J=7.5赫兹,-OSO2CH2 CH3),1.67(t,3H,J=7.5赫兹,-OSO2CH2CH3 ),1.63-1.56(m,6H,-OSO2CH2CH3 )。
化合物27:非晶相;ESI MS m/z:559.1[M+H]+;1H NMR(300MHz,CDCl3)δ:7.71(d,1H,J=15.9赫兹,H-1),7.65(d,1H,J=15.9赫兹,H-5),7.54-7.39(m,5H,芳香环H),7.34-7.25(m,2H,芳香环H),7.09(d,1H,J=15.9赫兹,H-2),7.06(d,1H,J=15.9赫兹,H-4),3.40-3.01(m,6H,-OSO2CH2 CH3),1.61-156(m,9H,-OSO2CH2CH3 )。
化合物40:油状糖浆;C21H22O6S,ESI-MS:m/z 403.2[M+H]+;1H NMR(300MHz,DMSO-d6):7.77-6.99(11H,m,芳香族H及乙烯基H),3.80(3H每个,s,OCH3 ),3.77(3H每个,s,OCH3 ),3.50(2H,m,SO2CH2 CH3),1.34(3H,m,SO2CH2CH3 )。
化合物43:淡黄色针,mp 102-103℃;C23H26O10S3,ESI-MS:m/z559.1[M+H]+;1H NMR(300MHz,DMSO-d6):7.89-7.35(11H,m,芳香族H及乙烯基H),3.62(4H,m,SO2CH2 CH3X 2),3.53(2H,q,J=7.5赫兹,SO2CH2 CH3),1.37(9H,m,SO2CH2CH3 X 3)。
化合物22:黄色固体;ESI MS m/z:546.19[M+H]+;1H NMR(300MHz,CDCl3)δ:7.77(s.2H,亚苄基CH=),7.50-7.28(m,8H,芳香环H),3.92(s,4H,环己基-H-3,5),3.35-3.25(m,6H,-OSO2CH2 CH3),2.46(d,2H,J=6.6赫兹,-CH2 ),1.59-1.50(m,9H,-OSO2CH2CH3 ),0.86(m,1H,环丙烷基CH),0.50-0.44(m,2H,环丙烷基CH2 ),0.15-0.08(m,2H,环丙羰基CH2 )。
化合物53:黄色油状,ESI MS m/z:481.0[M+H]+;1H NMR(400MHz,CD3OD)δ:7.68(d,2H,J=16.2赫兹,H-1,5),7.63-7.54(m,2H,芳香环H),7.46-7.39(m,1H,芳香环H),7.33-7.01(m,4H,芳香环H;2H,H-2,4亚苄基CH=),6.84-6.81(m,1H,芳香环H),2.95(s,12H,-OSO2N(CH3 )2)。
化合物65:非晶相,ESI MS m/z:479.6[M+H]+;1H NMR(400MHz,CDCl3)δ:7.65(d,2H,J=16.0赫兹,H-1,5),7.48(br,2H,芳香环H),7.46-7.43(m,2H,芳香环H),7.31(d,2H,J=8.4赫兹,芳香环H),6.99(d,2H,J=16.0赫兹,H-2,4),3.36(q,4H,J=7.2赫兹,-OSO2CH2 CH3),2.37(s,6H,CH3),1.57(t,6H,J=7.2赫兹,-OSO2CH2CH3 )。
化合物66:橙色带黄色固体,ESI MS m/z:401.6[M+H]+;1H NMR(400MHz,CDCl3)δ:7.67(d,1H,J=16.0赫兹,H-1),7.63(d,1H,J=16.0赫兹,H-5),7.48-7.40(m,4H,芳香环H),7.30(d,1H,J=8.4赫兹,芳香环H),6.00(d,1H,J=16.0赫兹,H-2),5.91(d,1H,J=16.0赫兹,H-4),6.82(d,1H,J=8.4赫兹,芳香环H),3.86(s,3H,OCH3),3.36(q,2H,J=7.2赫兹,-OSO2CH2 CH3),2.37(s,3H,CH3),2.23(s,3H,CH3),1.57(t,3H,,J=7.2赫兹,-OSO2CH2CH3 )。
化合物69:带褐色固体,ESI MS m/z:479.6[M+H]+;1H NMR(400MHz,CDCl3)δ:7.94(d,2H,J=16.0赫兹,H-1,5),7.65(d,2H,J=8.4赫兹,芳香环H),7.14-7.12(m,4H,芳香环H),6.92(d,2H,J=16.0赫兹,H-2,4),3.28(q,4H,J=7.2赫兹,-OSO2CH2 CH3),2.46(s,6H,-CH3 ),1.53(t,6H,J=7.2赫兹,-OSO2CH2CH3 )。
化合物70:浅带褐色固体,ESI MS m/z:401.1[M+H]+;1H NMR(400MHz,CDCl3)δ:7.99(d,1H,J=15.6赫兹,H-1),7.91(d,1H,J=15.6赫兹,H-5),7.65-7.61(m,2H,芳香环H),7.14-7.12(m,3H,芳香环H),6.93(d,1H,J=15.6赫兹,H-2),6.86(d,1H,J=15.6赫兹,H-4),6.77-6.74(m,1H,芳香环H),3.82(s,3H,OCH3),3.29(q,2H,J=7.2赫兹,-OSO2CH2 CH3),2.46(s,6H,CH3),1.53(t,3H,,J=7.2赫兹,-OSO2CH2CH3 )。
化合物74:浅带黄色固体,ESI MS m/z:361.1[M+H]+;1H NMR(400MHz,CDCl3)δ:7.66(d,2H,J=16.0赫兹,H-1,5),7.52-7.50(m,2H,芳香环H),7.45-7.41(m,1H,芳香环H),7.37-7.35(m,2H,芳香环H),7.30-7.28(m,2H,芳香环H),7.11-7.08(m,1H,芳香环H),7.04(d,1H,J=16.0赫兹,H-2),7.03(d,1H,J=16.0赫兹,H-4),3.26(q,2H,J=7.6赫兹,-OSO2CH2 CH3),1.55(t,3H,,J=7.6赫兹,-OSO2CH2CH3 )。
化合物77:带黄色固体,ESI MS m/z:427.1[M+H]+;1H NMR(400MHz,CDCl3)δ:7.68(d,2H,J=16.0赫兹,H-1,5),7.53-7.51(m,3H,芳香环H),7.46-7.41(m,3H,芳香环H),7.31-7.26(m,2H,芳香环H),7.05(dd,2H,J=16.0,1.6赫兹,H-2,4),3.31(q,2H,J=7.2赫兹,-OSO2CH2 CH3),1.55(t,3H,J=7.2赫兹,-OSO2CH2CH3 )。
以类似于合成1,5-双-(3-羟基-苯基)-戊-1,4-二烯-3-酮的方式合成化合物78。使用乙酰氯(3当量)取代乙磺酰基氯。在室温下搅拌3-4小时后,将该反应混合物倾入水中及以CH2Cl2萃取。以水然后盐水清洗结合的有机层,在Na2SO4上干燥,过滤及浓缩以提供浅黄色固体粗产物。以CombiFlash色层分析计使用正己烷/EtOAc作为冲提液纯化,提供定量产率的想要的化合物。浅带黄色结晶固体,ESI MS m/z:351.1[M+H]+;1H NMR(400MHz,CDCl3)δ:7.67(d,2H,J=16.0赫兹,H-1,5),7.46-7.38(m,4H,芳香环H),7.34-7.33(m,2H,芳香环H),7.14-7.11(m,2H,芳香环H),7.02(d,2H,J=16.0,H-2,4),2.31(s,6H,-COCH3 )。
以类似于合成1,5-双-(3-羟基-苯基)-戊-1,4-二烯-3-酮的方式合成化合物14及24。使用氯磷酸二乙基酯(~10当量,对化合物14来说)或氯磷酸二甲基酯(~10当量,对化合物24来说)取代乙磺酰基氯。在室温下搅拌2小时后,将该反应混合物倾入水中及以CH2Cl2萃取。以水然后盐水清洗结合的有机层,在Na2SO4上干燥,过滤及浓缩以提供黄色固体粗产物。以CombiFlash色层分析计使用CH2Cl2/MeOH作为冲提液纯化,提供定量产率的想要的化合物。
化合物14:非晶相;ESI MS m/z:539.22[M+H]+;1H NMR(300MHz,CDCl3)δ:7.69(d,2H,J=15.9赫兹,H-1,5),7.51(br.2H,芳香环H),7.46-7.39(m,4H,芳香环H),7.32-7.28(m,2H,芳香环H),7.09(d,2H,J=15.9赫兹,H-2,4),4.32-4.22(m,8H,OCH2 CH3),1.41(t,12H,J=7.2赫兹,OCH2CH3 )。
化合物24:非晶相,ESI MS m/z:483.09[M+H]+;1H NMR(300MHz,CDCl3)δ:7.69(d,2H,J=15.9赫兹,H-1,5),7.49-7.37(m,6H,芳香环H),7.28-7.25(m,2H,芳香环H),7.06(d,2H,J=15.9赫兹,H-2,4),3.91(s,6H,OCH3 ),3.87(s,6H,OCH3 )。
以类似于上述的方式合成化合物18、23、25、32-34及37。使用二乙基氯化膦(~10-15当量)来制备化合物18、35及38,使用二苯基氯化膦(~10当量)来制得化合物23,及使用二甲基氯化膦(~10当量)来制得化合物25、32及33。在室温下搅拌2小时后,将该反应混合物倾入水中及以CH2Cl2萃取。以水及盐水清洗有机层,在Na2SO4上干燥,过滤及浓缩以提供粗产物化合物,如为黄色固体。以CombiFlash色层分析计使用CH2Cl2/MeOH作为冲提液纯化,提供定量产率的想要的化合物。
化合物18:非晶相;ESI MS m/z:475.22[M+H]+;1H NMR(300MHz,CDCl3)δ:7.70(d,2H,J=15.9赫兹,H-1,5),7.52(d,2H,J=0.9赫兹,芳香环H),7.40-7.27(m,6H,芳香环H),7.09(d,2H,J=15.9赫兹,H-2,4),1.99-1.86(m,8H,CH2 CH3),1.30-1.16(m,12H,CH2CH3 )。
化合物23:黄色结晶固体;ESI MS m/z:667.61[M+H]+;1H NMR(300MHz,CDCl3)δ:7.95-7.88(m,8H,芳香环H),7.76-7.67(m,2H,芳香环H),7.60(d,2H,J=15.9赫兹,H-1,5),7.55-7.26(m,18H,芳香环H),6.97(d,2H,J=15.9赫兹,H-2,4)。
化合物25:黄色结晶固体;ESI MS m/z:419.07[M+H]+;1H NMR(300MHz,CDCl3)δ:7.70(d,2H,J=15.9赫兹,H-1,5),7.50(d,2H,J=1.5赫兹,芳香环H),7.45-7.37(m,4H,芳香环H),7.30-7.26(m,2H,芳香环H),7.08(d,2H,J=15.9赫兹,H-2,4),1.71(s,6H,CH3),1.67(s,6H,CH3)。
化合物32:浅橙色固体;ESI MS m/z:381.14[M+Na]+;1H NMR(400MHz,CD3OD)δ:8.09(d,1H,J=16.0赫兹,H-1),7.65(d,1H,J=16.0赫兹,H-5),7.26(d,1H,J=16.0赫兹,H-2),7.15(d,1H,J=16.0赫兹,H-4),7.23(t,1H,J=8.0赫兹,芳香环H),7.15-7.08(m,3H,芳香环H),6.85-6.81(m,2H,芳香环H),6.70(t,1H,J=8.0赫兹,芳香环H),1.26(s,6H,CH3 )。
化合物33:黄色固体;ESI MS m/z:457.14[M+Na]+;1H NMR(400MHz,CD3OD)δ:8.11(d,1H,J=16.0赫兹,H-1),7.70(d,1H,J=16.0赫兹,H-5),7.56-7.54(m,1H,芳香环H),7.44(t,1H,J=8.0赫兹,芳香环H),7.28(d,1H,J=16.0赫兹,H-2),7.15(d,1H,J=16.0赫兹,H-4),7.28-7.21(m,1H,芳香环H),7.15-7.08(m,3H,芳香环H),6.84-6.82(m,1H,芳香环H),6.70(t,1H,J=8.0赫兹,芳香环H),1.72(s,3H,CH3 ),1.68(s,3H,CH3 ),1.27-1.19(m,6H,CH3 )。
化合物34:非晶相;ESI MS m/z:489.08[M-H]-;1H NMR(400MHz,CDCl3)δ:8.14(d,1H,J=15.2赫兹,H-1),7.73(d,1H,J=15.2赫兹,H-5),7.58-7.56(m,2H,芳香环H),7.48-7.45(m,1H,芳香环H),7.33-7.28(m,3H,芳香环H),7.17-7.14(m,1H,芳香环H),6.87-6.71(m,2H,H-2,4),2.03-1.98(m,4H,CH2 CH3),1.86-1.66(m,4H,CH2 CH3),1.28-1.13(m,12H,CH2CH3 )。
化合物37:非晶相;ESI MS m/z:595.08[M-H]-;1H NMR(400MHz,CDCl3)δ:7.77(d,1H,J=15.6赫兹,H-5),7.69(d,1H,J=15.6赫兹,H-1),7.56-7.53(m,2H,芳香环H),7.44-7.40(m,2H,芳香环H),7.32-7.14(m,4H,芳香环H及H-2,4),7.02-6.93(m,1H,芳香环H),2.02-1.89(m,12H,CH2 CH3),1.26-1.06(m,18H,CH2CH3 )。
通过下列程序合成化合物28及29。将1,5-双-(3-羟基-苯基)-戊-1,4-二烯-3-酮(通过在反应方案4中所阐明的方法合成)(0.16毫摩尔)在乙腈中的溶液冷却至-78℃。在其中加入在乙腈中的Et3N(20当量)及新鲜蒸馏的POCl3(10当量)。在-78℃下搅拌所得的混合物2.5小时或通过TLC监视。在完成后,将该反应溶液升温至0℃及加入水(~1毫升)与吡啶(0.4毫升)。在0℃至室温下搅拌所产生的反应混合物1.5小时及浓缩至干燥。通过逆相管柱色层分析计,使用C18硅凝胶及MeOH/H2O纯化该粗产物(如为化合物28或29的混合物)以获得想要的产物。
化合物28:黄色固体;ESI MS m/z:377.01[M-H+MeOH]+;1H NMR(300MHz,D2O)δ:7.63(d,2H,J=15.9赫兹,H-1,5),7.45-7.38(m,6H,芳香族H),7.24-7.21(m,2H,芳香族H),7.11(d,2H,J=15.9赫兹,H-2,4)。
化合物29:黄色固体;ESI MS m/z:425.1[M-H]+;1H NMR(300MHz,D2O)δ:7.47(d,2H,J=15.9赫兹,H-1,5),7.40-7.26(m,6H,芳香族H),7.21(br,2H,芳香族H),6.95(d,2H,J=15.9赫兹,H-2,4)。
化合物19、35-36、45-46、48、52、54-59及76的合成。
反应方案8
从1,5-双-(3-羟基-苯基)-戊-1,4-二烯-3-酮或化合物20及62-64制备化合物19、35、36、67、68、71及72(反应方案8)。于K2CO3(2.5当量)存在下,使用在DMF中的(2-溴-乙基)-二乙基-胺氢溴酸(1当量)来制备化合物19。在室温下搅拌该反应混合物24小时。过滤出固体及浓缩滤出液。以CH2Cl2稀释所产生的残余物及以水清洗两次。以CH2Cl2萃取水层两次及在Na2SO4上干燥。在通过CombiFlash色层分析系统使用Grace硅凝胶匣及CH2Cl2/MeOH纯化后,获得化合物19。
化合物19:非晶相;ESI MS m/z:366.30[M+H]+;1H NMR(300MHz,CD3OD)δ:7.74(d,1H,J=15.9赫兹,H-1),7.73(d,1H,J=15.9赫兹,H-5),7.39-7.12(m,7H,芳香族H),7.22(d,1H,J=15.9赫兹,H-2),7.17(d,1H,J=15.9赫兹,H-4),7.63-7.02及6.89-6.84(m,1H,芳香族H),4.25(t,2H,J=5.4赫兹,OCH2 CH2N(CH2CH3)2),3.17(t,2H,J=5.4赫兹,OCH2CH2 N(CH2CH3)2),2.93(q,4H,J=7.2赫兹,OCH2CH2N(CH2 CH3)2),1.21(t,6H,J=7.2赫兹,OCH2CH2N(CH2CH3 )2)。
化合物35:ESI MS m/z:382.75[M+H]+;1H NMR(400MHz,CD3OD)δ:8.03(d,1H,J=16.0赫兹,H-1),7.34(d,1H,J=16.0赫兹,H-5),7.17(d,1H,J=16.0赫兹,H-4),7.10(d,1H,J=16.0赫兹,H-2),7.23-7.07(m,4H,芳香族H),6.98(t,1H,J=8.0赫兹,芳香族H),6.87(dd,1H,J=1.6,8.4赫兹,芳香族H),6.83(dd,1H,J=2.0,8.4赫兹,芳香族H),4.03(t,2H,J=4.8,9.6赫兹,OCH2 CH2N(CH2CH3)2),2.85(t,2H,J=4.8,9.6赫兹,OCH2CH2 N(CH2CH3)2),2.74(q,4H,J=7.2赫兹,OCH2CH2N(CH2 CH3)2),1.13(t,6H,J=7.2赫兹,OCH2CH2N(CH2CH3 )2)。
化合物36:ESI MS m/z:481.28[M+H]+;1H NMR(400MHz,CD3OD)δ:8.04(d,1H,J=16.0赫兹,H-1),7.74(d,1H,J=16.0赫兹,H-5),7.25-7.15(m,6H,芳香族H,及H-4,2),7.02-6.95(m,2H,芳香族H),6.89-6.85(m,1H,芳香族H),4.20(dd,2H,J=5.2,4.8赫兹,OCH2 CH2N(CH2CH3)2),4.05(dd,2H,J=5.2,4.8赫兹,OCH2 CH2N(CH2CH3)2),3.10(dd,2H,J=4.8,4.4赫兹,OCH2CH2 N(CH2CH3)2),2.92(dd,2H,J=4.8,4.4赫兹,OCH2CH2 N(CH2CH3)2),2.66(m,8H,OCH2CH2N(CH2 CH3)2),1.13(m,12H,OCH2CH2N(CH2CH3 )2)。
化合物67:非晶相,ESI MS m/z:394.2[M+H]+;1H NMR(400MHz,CD3OD)δ:7.67(d,2H,J=15.6赫兹,H-1,5),7.51-7.36(m,4H,芳香环H),7.08-6.70(m,4H,H-2,4及芳香环H),4.15(t,2H,J=5.2赫兹,OCH2 CH2N(CH2CH3)2),2.99(t,2H,J=5.2赫兹,OCH2CH2 N(CH2CH3)2),2.73-2.71(m,4H,OCH2CH2N(CH2 CH3)2),2.23(s,3H,CH3),2.23-2.17(m,3H,CH3),1.13-1.09(m,6H,OCH2CH2N(CH2CH3 )2)。
化合物68:非晶相,ESI MS m/z:408.1[M+H]+;1H NMR(400MHz,CD3OD)δ:7.68(d,2H,J=15.2赫兹,H-1,5),7.52-7.44(m,4H,芳香环H),7.07(dd,2H,J=15.2,4.8赫兹,H-2,4),6.96-6.92(m,2H,芳香环H),4.18(t,2H,J=4.8赫兹,OCH2 CH2N(CH2CH3)2),3.85(s,3H,OCH3),3.08(t,2H,J=5.2赫兹,OCH2CH2 N(CH2CH3)2),2.80(m,4H,OCH2CH2N(CH2 CH3)2),2.24(s,3H,CH3),2.20(s,3H,CH3),1.14(t,6H,J=6.8赫兹,OCH2CH2N(CH2CH3 )2)。
化合物71:浅带褐色固体,ESI MS m/z:408.1[M+H]+;1H NMR(400MHz,CD3OD)δ:8.03(d,2H,J=16.0赫兹,H-1,5),7.74(d,2H,J=9.2赫兹,芳香环H),7.07(d,2H,J=16.0,H-2,4),6.81-6.75(m,3H,芳香环H),6.64(br,1H,芳香环H),4.11(t,2H,J=5.6赫兹,OCH2 CH2N(CH2CH3)2),3.80(s,3H,OCH3),2.90(t,2H,J=5.6赫兹,OCH2CH2 N(CH2CH3)2),2.66(m,4H,OCH2CH2N(CH2 CH3)2),2.45(s,6H,CH3),1.08(t,6H,J=7.2赫兹,OCH2CH2N(CH2CH3 )2)。
化合物72:带黄色固体,ESI MS m/z:394.1[M+H]+;1H NMR(400MHz,CD3OD)δ:8.02(dd,2H,J=15.6,4.8赫兹,H-1,5),7.74-7.65(m,2H,芳香环H),7.03(d,1H,J=15.6赫兹,H-2),7.99(d,1H,J=15.6赫兹,H-4),6.81(br,2H,芳香环H),6.66-6.65(m,2H,芳香环H),4.13(t,2H,J=5.6赫兹,OCH2 CH2N(CH2CH3)2),2.94(t,2H,J=5.5赫兹,OCH2CH2 N(CH2CH3)2),2.73-2.66(m,4H,OCH2CH2N(CH2 CH3)2),2.45(s,3H,CH3),2.40(s,3H,CH3),1.11-1.04(m,6H,OCH2CH2N(CH2CH3 )2)。
化合物52、54及58是衍生自1,5-双-(3-羟基-苯基)-戊-1,4-二烯-3-酮(通过显示在反应方案4中的方法合成),其通过于碳酸氢钾存在下,在DMF中使该酮与1-溴丁烷(3.0当量及1.2当量,各别对化合物52及54来说)或1-溴-3-氯丙烷(1.2当量,对化合物58来说)反应。在室温下(对化合物52及58来说)或在80℃下(对化合物58来说)搅拌该反应混合物过夜,或以TLC监视。在减压下蒸发溶剂及将残余物分配在醋酸乙酯与水中。以水清洗有机层两次,及以醋酸乙酯萃取水性洗涤液两次。在Na2SO4上干燥后,过滤及浓缩,通过CombiFlash系统使用正己烷/醋酸乙酯冲提液来纯化油状粗产物,以提供想要的化合物52、54及58。
化合物52:黄色结晶固体;ESI MS m/z:379.17[M+H]+;1H NMR(400MHz,CDCl3)δ:7.61(d,2H,J=16.0赫兹,H-1,5),7.30-7.26(m,2H,芳香环H),7.16-7.15(m,2H,芳香环H),7.10(br,2H,芳香环H),7.02(dd,2H,J=16.0,2.0赫兹,H-2,4),6.93-6.91(m,2H,芳香环H),3.97(t,4H,J=6.8赫兹,-OCH2 CH2CH2CH3),1.79-1.72(m,4H,OCH2CH2 CH2CH3),1.51-1.45(m,4H,OCH2CH2CH2 CH3),0.98-0.94(m,6H,OCH2CH2CH2CH3 )。
化合物54:带黄色固体;ESI MS m/z:323.08[M+H]+;1H NMR(400MHz,CD3OD)δ:7.68(dd,2H,J=15.6,4.4赫兹,H-1,5),7.32-7.24(m,4H,芳香环H),7.18-7.16(m,2H,芳香环H),7.11(br,2H,芳香环H),7.04(dd,2H,J=15.6,4.0赫兹,H-2,4),6.95-6.88(m,2H,芳香环H),3.99(t,2H,J=12.8,6.8赫兹,OCH2 CH2CH2CH3),1.81-1.74(m,2H,OCH2CH2 CH2CH3),1.53-1.47(m,2H,OCH2CH2CH2 CH3),0.99-0.96(m,3H,OCH2CH2CH2CH3 )。
化合物58:浅黄色固体;ESI MS m/z:329.12[M+H]+;1H NMR(400MHz,CDCl3)δ:7.67(d,2H,J=16.0赫兹,H-1,5),7.34-7.23(m,2H,芳香族H),7.22(d,1H,J=8.0赫兹,芳香环H),7.16(d,1H,J=8.0赫兹,芳香环H),7.13(t,1H,J=2.4赫兹,芳香环H),7.11(t,1H,J=2.0赫兹,芳香环H),7.03(dd,2H,J=16.0,2.4赫兹,H-2,4),6.97-6.94(m,1H,芳香环H),6.91-6.88(m,1H,芳香环H),4.26(t,2H,J=6.0赫兹,-OCH2 CH2Cl),3.82(t,2H,J=6.0赫兹,-OCH2CH 2Cl)。
化合物55-57及59是衍生自化合物58(对化合物57及59来说)或化合物58的类似物,其中R1基团是以3-氯丙氧基置换(反应方案8)。在化合物58于DMF中的溶液中加入哌啶(~4当量)。将所产生的反应混合物加热至80℃及搅拌过夜。在冷却至室温后,在减压下蒸发溶剂及将残余物分配在醋酸乙酯与水中。以水清洗有机相两次及以醋酸乙酯萃取水性洗涤液两次。在Na2SO4上干燥后,过滤及浓缩,通过CombiFlash系统使用二氯甲烷/甲醇冲提液来纯化粗产物,然后从甲醇结晶以提供化合物57。非晶相,ESI MS m/z:378.25[M+H]+;1HNMR(400MHz,CD3OD)δ:7.60(d,1H,J=16.0赫兹,H-1),7.57(d,1H,J=16.0赫兹,H-5),7.27-7.22(m,2H,芳香环H),7.15-7.11(m,2H,芳香环H),7.02(t,1H,J=2.0赫兹,芳香环H),6.97(d,1H,J=16.0赫兹,H-2),6.92(d,1H,J=16.0赫兹,H-4),6.88-6.84(m,3H,芳香环H),4.13(t,2H,J=5.6赫兹,OCH2 CH2N(CH2CH2)2CH2),2.82(t,2H,J=5.6赫兹,OCH2CH2 N(CH2CH2)2CH2),2.58(br,4H,OCH2CH2N(CH2 CH2)2CH2),1.68-1.63(m,4H,OCH2CH2N(CH2CH2 )2CH2),1.48-1.45(m,2H,OCH2CH2N(CH2CH2)2CH2 )。
以与如上所述相同的方式,通过使经3-氯丙氧基取代的1,5-双-(3-经取代的-苯基)-戊-1,4-二烯-3-酮与二乙胺反应来合成化合物55。产率:40%,非晶相,ESI MS m/z:380.25[M+H]+;1H NMR(400MHz,CD3OD)δ:7.72(d,1H,J=16.0赫兹,H-1),7.71(d,1H,J=16.0赫兹,H-5),7.35-7.25(m,4H,芳香环H),7.23-7.21(m,1H,芳香环H),7.15(d,2H,J=16.0赫兹,H-2,4),7.10(t,1H,J=2.0赫兹,芳香环H),7.01-6.98(m,1H,芳香环H),6.86-6.83(m,1H,芳香环H),4.11(t,2H,J=6.4赫兹,OCH2 CH2CH2N(CH2CH3)2),2.99-2.95(m,2H,OCH2CH2CH2 N(CH2CH3)2),2.88(q,4H,J=7.2赫兹,OCH2CH2CH2N(CH2 CH3)2),2.10-2.03(m,2H,OCH2CH2 CH2N(CH2CH3)2),1.18(t,6H,J=7.2赫兹,OCH2CH2CH2N(CH2CH3 )2)。
以与如上所述相同的方式,通过使经3-氯丙氧基取代的1,5-双-(3-经取代的-苯基)-戊-1,4-二烯-3-酮与哌啶反应来合成化合物56。非晶相。ESI MS m/z:392.25[M+H]+;1HNMR(400MHz,CD3OD)δ:7.72(d,1H,J=16.0赫兹,H-1),7.70(d,1H,J=16.0赫兹,H-5),7.34-7.21(m,4H,芳香环H),7.23(d,1H,J=16.0赫兹,H-2),7.15(d,1H,J=16.0赫兹,H-4),7.16-7.15(m,1H,芳香环H),7.09(t,1H,J=2.4赫兹,芳香环H),6.99-6.96(m,1H,芳香环H),6.86-6.83(m,1H,芳香环H),4.06(t,2H,J=6.4赫兹,-OCH2 CH2CH2N(CH2CH2)2CH2),2.62-2.54(m,6H,-OCH2CH2CH2 N(CH2 CH2)2CH2),2.05-1.98(m,2H,OCH2CH2 CH2N(CH2CH2)2CH2),1.66-1.61(m,4H,OCH2CH2CH2N(CH2CH2 )2CH2),1.51-1.49(m,2H,OCH2CH2CH2N(CH2CH2 )2CH2 )。
以与如上所述相同的方式,通过使化合物58与哌啶反应来合成化合物59。产率:35%,非晶相,ESI MS m/z:380.25[M+H]+;1H NMR(400MHz,CD3OD)δ:7.72(d,1H,J=16.0赫兹,H-1),7.70(d,1H,J=16.0赫兹,H-5),7.35-7.21(m,5H,芳香环H),7.14(d,2H,J=16.0赫兹,H-2,4),7.09(t,1H,J=2.0赫兹,芳香环H),7.02-6.99(m,1H,芳香环H),6.86-6.83(m,1H,芳香环H),4.19(t,2H,J=5.6赫兹,OCH2 CH2N(CH2CH2)2O),3.71(t,4H,J=4.8赫兹,OCH2CH2N(CH2CH2 )2O),2.84-2.81(m,2H,OCH2CH2 N(CH2CH2)2O),2.61(t,4H,J=4.8赫兹,OCH2CH2N(CH2 CH2)2O)。
通过于K2CO3(2.5当量)存在下,在DMF中使化合物16与1当量的(2-溴-乙基)-二乙基-胺氢溴酸反应来合成化合物45(反应方案7)。在室温下搅拌该反应混合物过夜,或以TLC监视。在减压下蒸发溶剂及将残余物分配在二氯甲烷与水中。以水清洗有机相三次(或至pH~6-7),及以二氯甲烷萃取水性洗涤液两次。在Na2SO4上干燥后,过滤及浓缩,通过CombiFlash系统使用二氯甲烷/甲醇冲提液来纯化油状粗产物以提供想要的产物,如为黄色固体。ESI MS m/z:475.13[M+H]+;1H NMR(400MHz,CD3OD)δ:7.75(d,1H,J=11.6赫兹,亚苄基CH=),7.38(s,br,1H,亚苄基CH=),7.28(s,br,1H,芳香环H),7.11-6.84(m,7H,芳香环H),5.04(s,2H,哌啶-4-酮),4.91(s,2H,哌啶-4-酮),4.21(m,2H,OCH2 CH2N(CH2CH3)2),3.14(m,2H,OCH2CH2 N(CH2CH3)2),2.87(m,4H,OCH2CH2N(CH2 CH3)2),1.17(m,6H,OCH2CH2N(CH2CH3 )2),0.87(m,1H,环丙羰基CH),0.74(m,2H,环丙羰基CH2 ),0.62(m,2H,环丙羰基CH2 )。
以与如上所述相同的方式合成化合物46,除了使用2当量的(2-溴-乙基)-二乙基-胺氢溴酸及5当量的K2CO3外。
化合物46:黄色固体;ESI MS m/z:574.21[M+H]+;1H NMR(400MHz,CD3OD)δ:7.75(d,1H,J=11.6赫兹,亚苄基CH=),7.38(s,br,1H,亚苄基CH=),7.28(s,br,1H,芳香环H),7.11-6.84(m,7H,芳香环H),5.05(s,2H,哌啶-4-酮),4.91(s,2H,哌啶-4-酮),4.49(m,2H,OCH2 CH2N(CH2CH3)2),3.86(m,2H,OCH2 CH2N(CH2CH3)2),3.55(q,4H,J=7.6赫兹,OCH2CH2N(CH2 CH3)2),3.49(t,2H,J=6.4赫兹,OCH2CH2 N(CH2CH3)2),2.87(t,2H,J=6.4赫兹,OCH2CH2 N(CH2CH3)2),2.62(q,4H,J=7.6赫兹,OCH2CH2N(CH2 CH3)2),1.38(t,6H,J=7.6赫兹,OCH2CH2N(CH2CH3 )2),1.05(t,J=7.6赫兹,6H,OCH2CH2N(CH2CH3 )2),0.87(m,1H,环丙羰基CH),0.74(m,2H,环丙羰基CH2 ),0.64(m,2H,环丙羰基CH2 )。
通过在CH2Cl2中各别使化合物19及59与乙磺酰基氯(~1.3当量)及Et3N(~1.5当量)反应来合成化合物48及76(反应方案8)。在室温下进行反应伴随着搅拌4-5小时。在完成后,将该反应混合物倾入水中及以水清洗两次。以CH2Cl2萃取水层两次。在以CombiFlash系统使用CH2Cl2/MeOH冲提液纯化后,获得定量的化合物48,如为浅棕色固体。ESI MS m/z:458.21[M+H]+;1H NMR(400MHz,CD3OD)δ:7.72(d,1H,J=16.0赫兹,H-1),7.71(d,1H,J=16.0赫兹,H-5),7.64(d,1H,J=7.6赫兹,芳香环H),7.61(t,1H,J=2.0赫兹,芳香环H),7.46(t,1H,J=8.0赫兹,芳香环H),7.34-7.29(m,2H,芳香环H),7.24-7.23(m,2H,芳香环H),7.24(d,1H,J=16.0赫兹,H-2),7.19(d,1H,J=16.0赫兹,H-4),6.99-6.97(m,1H,芳香环H),4.11(t,2H,J=5.6赫兹,OCH2 CH2N(CH2CH3)2),3.40(q,2H,J=7.6赫兹,SO2CH2 CH3),2.91(t,2H,J=5.6赫兹,OCH2CH2 N(CH2CH3)2),2.67(q,4H,J=7.2赫兹,OCH2CH2N(CH2 CH3)2),1.47(t,3H,J=7.6赫兹,SO2CH2CH3 ),1.08(t,J=7.2赫兹,6H,OCH2CH2N(CH2CH3 )2)。
化合物76:非晶相。ESI MS m/z:470.1[M+H]+;1H NMR(400MHz,CDCl3)δ:7.67(dd,2H,J=16.0,4.4赫兹,H-1,5),7.54-7.50(m,2H,芳香环H),7.43(t,1H,J=7.6赫兹,芳香环H),7.32(m,2H,芳香环H),7.20-7.15(m,2H,芳香环H),7.05(dd,2H,J=16.0,4.4赫兹,H-2,4),6.95-6.92(m,1H,芳香环H),4.30(t,2H,J=4.8赫兹,OCH2 CH2N(CH2CH2)2CH2),3.30(q,2H,J=7.6赫兹,SO2CH2 CH3),3.01(t,2H,J=4.8赫兹,OCH2CH2 N(CH2CH2)2CH2),2.78(br,4H,OCH2CH2N(CH2 CH2)2CH2),1.76(br,4H,OCH2CH2N(CH2CH2 )2CH2),1.56-1.52(m,5H,SO2CH2CH3 ,及OCH2CH2N(CH2CH2)2CH2 )。
反应方案9
通过在丙酮中使化合物19与琥珀酸反应来制备化合物47。参见上述反应方案9。
在琥珀酸(0.397克,3.36毫摩尔)于丙酮(9.5毫升)中的溶液中,慢慢加入在3-4毫升丙酮中的化合物19(1.23克,3.36毫摩尔)伴随着搅拌。在加入期间,形成及析出浅黄色结晶固体。在室温下搅拌2小时后,将该反应混合物贮存在冰箱中过夜。通过过滤收集固体及以丙酮清洗以提供化合物47,如为浅黄色结晶固体,产率85%。
化合物47:mp.104-106℃;ESI MS m/z:366.30[M-C4H6O4+1]+;1H NMR(400MHz,CD3OD)δ:7.72(d,1H,J=16.0赫兹,H-1),7.70(d,1H,J=16.0赫兹,H-5),7.39-7.32(m,3H,芳香族H),7.26(d,1H,J=16.0赫兹,H-2),7.23(t,1H,J=8.0赫兹,芳香族H),7.14(d,1H,J=16.0赫兹,H-4),7.13-7.09(m,2H,芳香族H),7.07-7.04(m,1H,芳香族H),6.86-6.84(m,1H,芳香族H),4.37(t,2H,J=5.2赫兹,OCH2 CH2N(CH2CH3)2),3.50(t,2H,J=5.2赫兹,OCH2CH2 N(CH2CH3)2),3.23(q,4H,J=7.2赫兹,OCH2CH2N(CH2 CH3)2),2.49(s,4H,琥珀酸-CH2 CH2 COOH),1.32(t,6H,J=7.2赫兹,OCH2CH2N(CH2CH3 )2)。
以类似的方式从化合物48制备化合物49。参见上述反应方案9。
化合物49:棕色黏油。ESI MS m/z:458.21[M-C4H6O4+1]+;1H NMR(400MHz,CD3OD)δ:7.77(d,2H,J=16.0赫兹,H-1,5),7.67(d,1H,J=8.0赫兹,芳香环H),7.65(t,1H,J=2.0赫兹,芳香环H),7.51(t,1H,J=8.0赫兹,芳香环H),7.38-7.33(m,4H,芳香环H),7.30(d,1H,J=16.0赫兹,H-2),7.26(d,1H,J=16.0赫兹,H-4),7.08-7.05(m,1H,芳香环H),4.34(t,2H,J=5.2赫兹,OCH2 CH2N(CH2CH3)2),3.44(t,2H,J=5.2赫兹,OCH2CH2 N(CH2CH3)2),3.42(q,2H,J=7.2赫兹,SO2CH2 CH3),3.18(q,4H,J=7.2赫兹,OCH2CH2N(CH2 CH3)2),2.49(s,4H,琥珀酸-CH2 CH2 COOH),1.49(t,3H,J=7.2赫兹,SO2CH2CH3 ),1.30(t,6H,J=7.2赫兹,OCH2CH2N(CH2CH3 )2)。
通过在丙酮中使化合物48与磷酸(85%水溶液)反应来制备化合物50。参见上述反应方案9。
在化合物48(0.28克,3.36毫摩尔)于丙酮(0.5毫升)中的溶液中,在0℃下慢慢加入85%H3PO4水溶液(1当量的H3PO4,0.6毫摩尔)伴随着搅拌。在室温下搅拌后1小时,将该反应混合物贮存在冰箱中过夜。在蒸发溶剂后,将残余物溶解在7毫升H2O中,然后冷冻。冷冻干燥法提供化合物50,如为黄色结晶固体,产率95%。
化合物50:ESI MS m/z:458.21[M-H3PO4+1]+;1H NMR(400MHz,CD3OD)δ:7.78(d,2H,J=16.0赫兹,H-1,5),7.69(d,1H,J=7.6赫兹,芳香环H),7.65(t,1H,J=1.6赫兹,芳香环H),7.51(t,1H,J=8.0赫兹,芳香环H),7.39-7.35(m,4H,芳香环H),7.30(d,1H,J=16.0赫兹,H-2),7.27(d,1H,J=16.0赫兹,H-4),7.11-7.06(m,1H,芳香环H),4.43(t,2H,J=4.8赫兹,OCH2 CH2N(CH2CH3)2),3.60(t,2H,J=4.8赫兹,OCH2CH2 N(CH2CH3)2),3.42(q,2H,J=7.2赫兹,SO2CH2 CH3),3.33(q,4H,J=7.2赫兹,OCH2CH2N(CH2 CH3)2),1.49(t,3H,J=7.2赫兹,SO2CH2CH3 ),1.37(t,6H,J=7.2赫兹,OCH2CH2N(CH2CH3 )2)。
从化合物19,以类似的方式制备化合物51,如为明黄色结晶固体。参见上述反应方案9。
化合物51:ESI MS m/z:366.30[M-H3PO4+1]+;1H NMR(400MHz,CD3OD)δ:7.74(d,1H,J=16.0赫兹,H-1),7.72(d,1H,J=16.0赫兹,H-5),7.39-7.35(m,3H,芳香族H),7.28(d,1H,J=16.0赫兹,H-2),7.24(t,1H,J=7.6赫兹,芳香族H),7.16(d,1H,J=16.0赫兹,H-4),7.17-7.15(m,1H,芳香族H),7.11-7.06(m,2H,芳香族H),6.87-6.84(m,1H,芳香族H),4.42(t,2H,J=4.8赫兹,OCH2 CH2N(CH2CH3)2),3.61(t,2H,J=4.8赫兹,OCH2CH2 N(CH2CH3)2),3.33(q,4H,J=7.2赫兹,OCH2CH2N(CH2 CH3)2),1.37(t,6H,J=7.2赫兹,OCH2CH2N(CH2CH3 )2)。
通过使化合物48与2.0M氯化氢乙基醚溶液反应来制备化合物79,如为黄色结晶固体。
在化合物48于甲醇中的溶液中,在0℃下慢慢加入2.0M氯化氢乙基醚溶液伴随着搅拌。在室温下搅拌1小时后,将该反应混合物贮存在冰箱中过夜。蒸发溶剂及以三级丁基甲基醚清洗残余物三次。冷冻干燥法提供定量产率的化合物79,如为黄色结晶固体。
在化合物48于甲醇中的溶液中,在0℃下慢慢加入2.0M氯化氢乙基醚溶液伴随着搅拌。在室温下搅拌1小时后,将该反应混合物贮存在冰箱中过夜。蒸发溶剂及以三级丁基甲基醚清洗残余物三次。冷冻干燥法提供定量产率的化合物79,如为黄色结晶固体。ESI MSm/z:458.21[M-HCl+1]+;1H NMR(400MHz,CD3OD)δ:7.80(d,2H,J=16.0赫兹,H-1,5),7.71(d,1H,J=8.0赫兹,芳香环H),7.67(t,1H,J=2.4赫兹,芳香环H),7.53(t,1H,J=8.0赫兹,芳香环H),7.42-7.41(m,2H,芳香环H),7.39-7.37(m,2H,芳香环H),7.32(d,1H,J=16.0赫兹,H-2),7.29(d,1H,J=16.0赫兹,H-4),7.13-7.10(m,1H,芳香环H),4.44(t,2H,J=4.8赫兹,OCH2 CH2N(CH2CH3)2),3.65(t,2H,J=4.8赫兹,OCH2CH2 N(CH2CH3)2),3.43(q,2H,J=7.6赫兹,SO2CH2 CH3),3.37(q,4H,J=7.2赫兹,OCH2CH2N(CH2 CH3)2),1.51(t,3H,J=7.6赫兹,SO2CH2CH3 ),1.40(t,6H,J=7.2赫兹,OCH2CH2N(CH2CH3 )2)。
化合物60及61的合成
反应方案10
从α-溴甲基-苯乙腈合成化合物60及61。在α-溴甲基-苯乙腈(15.3毫摩尔)于甲苯(30毫升)中的溶液中,在30分钟内,于0℃下加入于THF中的DIBAL-H(1.0M,1.4当量)。在0℃下搅拌2小时后,将该反应混合物倾入40毫升二氯甲烷与100毫升10%HCl的混合物中。搅拌所得的混合物1小时,以水然后盐水清洗有机层,及以二氯甲烷萃取水层两次。在Na2SO4上干燥后,过滤及浓缩,将所获得的半油状产物贮存在冰箱中,以定量的产率提供3-(溴甲基)苯甲醛,如为白色结晶固体。遵循叙述在反应方案4中的程序,使所产生的化合物与丙酮在乙醇中反应产生化合物61,如为浅黄色结晶固体。ESI MS m/z:420.9[M+H]+;1H NMR(400MHz,CDCl3)δ:7.71(d,2H,J=16.0赫兹,H-1,5),7.63-7.60(m,2H,芳香环H),7.54-7.50(m,2H,芳香环H),7.44-7.37(m,4H,芳香环H),7.08(d,2H,J=16.0赫兹,H-2,4),4.50(s,4H,-CH2 Br)。
通过使在CH2Cl2中的化合物61与乙磺酰基氯(2当量)、亚硫酸钠(4当量)、碳酸氢钠(4当量)在水中的混合物反应获得化合物60。在35-36℃下搅拌所得的混合物过夜。以二氯甲烷稀释该反应混合物,以水然后盐水清洗,及在Na2SO4上干燥。以CombiFlash系统使用正己烷类/EtOAc冲提液来纯化粗产物以获得想要的产物,如为浅黄色固体。产率:44%。ESIMS m/z:447.1[M+H]+;1H NMR(400MHz,CDCl3)δ:7.55(d,2H,J=16.0赫兹,H-1,5),7.53(br,2H,芳香族的H),7.47-7.25(m,2H,芳香环H),7.42-7.38(m,4H,芳香环H),6.70(d,2H,J=16.0赫兹,H-2,4),4.57(s,4H,-CH2 SO2CH2CH3),2.82-2.70(m,4H,-CH2SO2CH2 CH3),1.30(t,6H,J=7.2赫兹,-CH2SO2CH2 CH3 )。
生物学试验
在人类Lernert’s T细胞淋巴瘤KT-3的增生上的抑制效应
如下列所描述般测量本发明的化合物在人类Lennert’s T细胞淋巴瘤KT-3细胞(一种IL-6相依性细胞株)生长上的抑制效应。简单地说,将KT-3细胞转移至96井板的井中(2.5×103/井),及在包含盘尼西林(25U/毫升)、链霉素(25微克/毫升)、10%热灭活的胎牛血清(FBS)及hIL-6(2.5纳克/毫升,R&D系统)的RPMI-1640培养基(Gibco)中培养。在实验井中,在将细胞平板化后,立即加入多种浓度的测试化合物(一式三份)。在对照井中,加入等体积的媒剂DMSO(0.1%v/v)。在以化合物或于媒剂中培养该等细胞48小时后,使用CellTiter Glo Luminescent Cell Viability Assay Kit(Promega,Madison,WI)评估细胞生存能力。使用Microplate冷光仪LB96V(EG&G BERTH HOLD),根据制造商的协议来定量所产生的发光。通过将经化合物处理的细胞的发光值除以经媒剂处理的细胞的值来计算细胞存活比例。
化合物1-79在IL-6引发的KT-3细胞增生上全部显示出抑制效应。某些化合物(即,化合物6、16、18、19、26、27、35、36、45-51、56、57及79)未预期地具有IC50值(抑制细胞生长50%的化合物浓度)等于或甚至低于0.05M。此外,化合物1-79全部以剂量相依方式抑制KT-3细胞增生。
抑制多种人类肿瘤细胞株的生长
如下列所描述般测量化合物6在下列细胞的生长上的抑制效应:结肠癌细胞(HCT116、HT29、SW480及SW620)、结肠腺癌细胞(Colo205)、前列腺腺癌细胞(PC-3及Dul45)、前列腺癌细胞(CWR22RV及LNCap)、非小细胞肺癌细胞(NCI-H1299)、肺腺癌细胞(A549)、大细胞肺癌细胞(NCI-H460)、乳房转移性癌细胞(MDA-MB-453)、乳腺管癌细胞(T-47D)、乳房腺癌细胞(MCF7)、肝细胞癌细胞(Huh-7及HepG2)、胰脏癌细胞(PANC-1)、子宫颈腺癌细胞(Hela)、IL-6相依性的Lennert’s T细胞淋巴瘤细胞(KT-3)、IL-6相依性的多发性骨髓瘤细胞(INA-6)、多发性骨髓瘤细胞(KMM-1及U266)、骨髓性白血病细胞(HL-60)及T细胞白血病细胞(Jurkat)。简单地说,以1×103至4×103/井的密度范围将肿瘤细胞播种在96井Microtest III组织培养板(Falcon,NJ)中。在包含盘尼西林(25单位/毫升)、链霉素(25微克/毫升)及10%热灭活的FBS的DMEM(Gibco)中培养12小时后,以多种浓度范围(从0至5μM)的化合物6处理细胞72小时。然后,使用以四唑鎓为基底的量热分析(MTT)来评估肿瘤细胞的生存能力,如在Su等人,J Mol Cell Cardiol.1998;30:587-598中所描述。在37℃下,以该MTT染料(5毫克/毫升)培养该等细胞3小时。以MTT溶解缓冲液(50%DMF,24mM HCl,2%醋酸,5%SDS)溶解所产生的甲瓒结晶,及使用Benchmark微板读出器(Bio-Rad,Hercules,CA)测量在595纳米处的吸收度。通过经化合物处理的细胞的吸收值对经媒剂处理的细胞来计算细胞存活比例。
化合物6在全部经测试的肿瘤细胞的生长上显示出剂量相依的抑制效应,且具有范围0.02至5.5μM的IC50值。
在KT-3细胞中的MRG、STAT1、STAT3及STAT5蛋白质的西方印迹法(Western blot)分析
如在Kawashima等人,J.Immunol.2001,167:3652-3660中所描述般进行西方印迹法分析,伴随着少量修改。简单地说,以1、5或20μM化合物6或媒剂单独在上述包含IL-6的培养基中处理KT-3细胞。在培养后的不同时间点处(即,在处理后的0.5、1、3及6小时处)采集细胞,及使用溶解缓冲液(1.0%Triton X-100,50mM Tris-HCl(pH 7.5),0.1mM EDTA,150mM NaCl,200μM Na3VO4,50mM NaF,1mM二硫苏糖醇,0.4mM苯基甲基砜基氟,3微克/毫升的抗蛋白酶肽,2微克/毫升的胃蛋白酶抑制素A,1微克/毫升的亮肽素(leupeptin)),以2×107细胞/毫升,于冰上溶解细胞30分钟。通过在12,000×克下离心15分钟采集细胞溶成物。使该样品(1×105细胞当量/泳道)接受硫酸十二烷酯钠-聚丙烯酰胺凝胶电泳,随后转移到Immobilon过滤器(Millipore)上。在以5%BSA阻断后,以抗-pSTAT3、STAT3、STAT5、STAT1、MRG或肌动蛋白Abs探测该过滤器。从Santa Cruz Biotechnology购得该兔多株抗-STAT3、抗-STAT5、抗-STAT1及抗肌动蛋白抗体(Abs)、及老鼠单株抗-pSTAT3Ab(B-7)。如先前在Hirose等人,J.Biol.Chem.276:5821-5828中所描述般制备经亲和纯化的抗-MRG Ab。该过滤器进一步以结合HRP的二级抗体培养。最后,使用增强型化学发光(EnhancedChemiluminescence)(ECL)系统(Amersham)显现出蛋白质。
结果显示出化合物6以时间及剂量相依的方式向下调节MRG(MgcRacGAP,一种演化保守(evolutionarily conserved)的GTP酶-活化)蛋白质、STAT3及STAT5蛋白质,及抑制在KT-3细胞中的STAT3蛋白质的磷酸化。比较上,此化合物于测试条件下在KT3细胞中的STAT1的表达上不具有效应。
在老鼠异种移植物模型中于人类结肠癌(HCT-116)上的抑制效应
在机构动物照顾及使用委员会(Institutional Animal Care and UseCommittee)认可的协议下并遵循动物适合且人道使用在研究机构指导方针来进行活体内实验。从Harlan Laboratory购买六周大的无胸腺母裸小鼠。八只老鼠每只在左侧齿面皮下注射1x106与Matrigel(BD Bioscience)混合的HCT-116细胞。在注射后,于治疗前,允许肿瘤生长5天至可摸到的大小(体积~100立方毫米)。将老鼠随机分成二组(n=每组4只)。对照组仅注射媒剂溶液(即,10%DMSO及90%玉米胚芽油),同时实验组从第0(起始注射日)至4天及从第7至10天接受每日注射(i.p.)化合物6(以剂量40毫克/公斤体重,溶解在媒剂溶液中)。使用光标卡尺一周测量肿瘤大小两次且使用下式计算:长度×宽度×高度×0.5236,如在Rockwell等人,J Natl.Cancer Inst.1972;49:735-747中所描述。
结果显示出化合物6在异种移植物老鼠模型中抑制人类结肠癌生长。其它具体实例
在本专利说明书中所揭示的全部特征可以任何组合结合。在本专利说明书中所揭示的每种特征可由提供相同、相当或类似目的的另一种特征置换。因此,除非有明确地描述,否则所揭示的每种特征仅为相等或类似特征的一般是列的实施例。
本领域技术人员可从上述容易地查明本发明的基本特征,及可没有离开其精神及范围制得本发明的多种改变及改质,以使其适应多种用途及条件。因此,其它具体实例也在所附权利要求书的范围内。
Claims (3)
1.一种式(II)的化合物,
其中
X及Y各自独立地是H、烷基或卤基,或X与Y一起是-CH2-、-(CH2)2-、-(CH2)CRaRb(CH2)-、-(CH2)NRa(CH2)-或-(CH2)O(CH2)-,Ra及Rb各自独立地是H、烷基、-C(O)-烷基、-C(O)-环烷基、-C(O)-NH-烷基或-C(O)-NH-环烷基;以及
R1、R2、R3、R4、R5、R1’、R2’、R3’、R4’及R5’各自独立地是H、烷基、卤基、OH、Rc-O-、RdS(O)2-O-、(Rd)2P(O)-O-或(RdO)2P(O)-O-,Rc是未经取代的烷基或经卤基、OH、烷氧基、胺基、环烷基、杂环烷基、芳基或杂芳基取代的烷基,及Rd是H、OH、烷基、烷氧基、胺基或芳基;其中R1、R2、R3、R4、R5、R1’、R2’、R3’、R4’及R5’中的至少一者是RdS(O)2-O-、(Rd)2P(O)-O-、或(RdO)2P(O)-O-;以及
所述式(II)的化合物选自由以下组成的群组:
化合物6
化合物18
化合物26以及
化合物27
2.一种根据权利要求1所述的化合物在制造用于治疗癌症的药物中的用途。
3.根据权利要求2所述的用途,其中该癌症是结肠癌、前列腺癌、肺癌、肾脏癌、膀胱癌、乳房癌、肝癌、胰癌、胃癌、子宫颈癌、卵巢癌、神经胶质瘤、黑素瘤、淋巴瘤、多发性骨髓瘤及白血病。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US37553410P | 2010-08-20 | 2010-08-20 | |
US61/375,534 | 2010-08-20 | ||
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EP3045445B1 (en) * | 2010-08-20 | 2019-08-07 | The University Of Tokyo | 1,5-diphenyl-penta-1,4-dien-3-one compounds |
US9884825B2 (en) | 2012-08-03 | 2018-02-06 | Georgia State University Research Foundation, Inc. | Curcumin analogs and methods of making and using thereof |
CN103910616A (zh) * | 2014-03-20 | 2014-07-09 | 浙江工业大学 | 一种姜黄素衍生物及其制备与应用 |
CN104974038B (zh) * | 2014-04-13 | 2019-04-30 | 江苏康缘药业股份有限公司 | 一种含羧基单羰基姜黄素衍生物及其制备方法和应用 |
CN103922911A (zh) * | 2014-04-17 | 2014-07-16 | 上海应用技术学院 | 一种(1e,4e)-1,5-二(邻溴间甲氧基苯基)-1,4-戊二烯酮化合物及合成方法 |
US11708329B2 (en) | 2018-01-30 | 2023-07-25 | The Regents Of The University Of California | Inhibitors of the WNT/beta-catenin pathway |
KR20200130389A (ko) * | 2018-03-08 | 2020-11-18 | 피아이 테라퓨틱스 리미티드 | 단백질 분해를 저해하기 위한 화합물 및 암의 치료에서의 이의 사용 방법 |
CN108864188B (zh) * | 2018-09-06 | 2020-06-23 | 贵州大学 | 一种含亚磷酸酯的1,4-戊二烯-3-酮类衍生物、其制备方法及应用 |
CN109942540B (zh) * | 2019-04-22 | 2021-06-18 | 贵州大学 | 一种含噻吩磺酸酯的1,4-戊二烯-3-酮类衍生物、其制备方法及应用 |
CN109970704B (zh) * | 2019-04-22 | 2022-01-28 | 贵州大学 | 一种含噻吩磺酸酯的查耳酮类衍生物、其制备方法及应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08299777A (ja) * | 1995-05-11 | 1996-11-19 | Lion Corp | 分散剤 |
CN101711231A (zh) * | 2007-01-08 | 2010-05-19 | 安德鲁科技有限公司 | 具有(取代苯基)-丙烯醛部分的化合物、它们的衍生物、生物活性及其用途 |
US20100152493A1 (en) * | 2005-06-27 | 2010-06-17 | Hiroyuki Shibata | BIS(ARYLMETHYLIDENE)ACETONE COMPOUND, ANTI-CANCER AGENT, CARCINOGENESIS-PREVENTIVE AGENT, INHIBITOR OF EXPRESSION OF Ki-Ras, ErbB2, c-Myc AND CYCLINE D1, BETA-CATENIN-DEGRADING AGENT, AND p53 EXPRESSION ENHANCER |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU7963691A (en) * | 1990-05-17 | 1991-12-10 | Baylor College Of Medicine | Growth inhibitors and methods of treating cancer and cell proliferative diseases |
JPH0829977A (ja) * | 1994-07-18 | 1996-02-02 | Nippon Zeon Co Ltd | ポジ型レジスト組成物 |
WO2001040188A1 (en) | 1999-12-03 | 2001-06-07 | Emory University | Curcumin analogues for treating cancer |
US20050069551A1 (en) * | 2002-03-08 | 2005-03-31 | Emory University | Cytotoxic compound-protein conjugates as suppressors of tumor growth and angiogenesis |
US20060276536A1 (en) | 2004-02-12 | 2006-12-07 | Vander Jagt David L | Cancer treatment using curcumin derivatives |
JP2008029977A (ja) * | 2006-07-31 | 2008-02-14 | Ntn Corp | エアロゾル吐出ノズルおよび被膜形成装置 |
US8329757B2 (en) * | 2008-10-14 | 2012-12-11 | Charlesson, Llc | Curcumin analog compositions and related methods |
CN101475455A (zh) * | 2009-02-10 | 2009-07-08 | 贵州大学 | 1,5-二取代芳基-1,4-戊二烯-3-酮衍生物及制备方法和用途 |
EP3045445B1 (en) * | 2010-08-20 | 2019-08-07 | The University Of Tokyo | 1,5-diphenyl-penta-1,4-dien-3-one compounds |
-
2011
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08299777A (ja) * | 1995-05-11 | 1996-11-19 | Lion Corp | 分散剤 |
US20100152493A1 (en) * | 2005-06-27 | 2010-06-17 | Hiroyuki Shibata | BIS(ARYLMETHYLIDENE)ACETONE COMPOUND, ANTI-CANCER AGENT, CARCINOGENESIS-PREVENTIVE AGENT, INHIBITOR OF EXPRESSION OF Ki-Ras, ErbB2, c-Myc AND CYCLINE D1, BETA-CATENIN-DEGRADING AGENT, AND p53 EXPRESSION ENHANCER |
CN101711231A (zh) * | 2007-01-08 | 2010-05-19 | 安德鲁科技有限公司 | 具有(取代苯基)-丙烯醛部分的化合物、它们的衍生物、生物活性及其用途 |
Non-Patent Citations (7)
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EP3045445A1 (en) | 2016-07-20 |
EP2606021A2 (en) | 2013-06-26 |
JP5998139B2 (ja) | 2016-09-28 |
AR112787A2 (es) | 2019-12-11 |
NZ607653A (en) | 2014-09-26 |
CN107253915A (zh) | 2017-10-17 |
CN103459361A (zh) | 2013-12-18 |
AR082856A1 (es) | 2013-01-16 |
AU2011292144B2 (en) | 2016-07-14 |
WO2012024282A3 (en) | 2012-04-26 |
US8822732B2 (en) | 2014-09-02 |
US20140371177A1 (en) | 2014-12-18 |
KR20140107097A (ko) | 2014-09-04 |
EP3045445B1 (en) | 2019-08-07 |
WO2012024282A2 (en) | 2012-02-23 |
US20120046247A1 (en) | 2012-02-23 |
CA2807776A1 (en) | 2012-02-23 |
EP3564204A1 (en) | 2019-11-06 |
KR101907631B1 (ko) | 2018-10-12 |
SG188217A1 (en) | 2013-04-30 |
EP2606021B1 (en) | 2019-07-31 |
EP2606021A4 (en) | 2014-05-07 |
TWI574686B (zh) | 2017-03-21 |
AU2011292144A1 (en) | 2013-03-14 |
CA2807776C (en) | 2018-10-09 |
JP2013536227A (ja) | 2013-09-19 |
TW201212905A (en) | 2012-04-01 |
US9359279B2 (en) | 2016-06-07 |
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