CN111410618A - 具有己糖激酶2抑制活性的化合物及用途 - Google Patents
具有己糖激酶2抑制活性的化合物及用途 Download PDFInfo
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Abstract
本发明提供式I所示酰肼取代的亚苄基酚类化合物,各取代基定义如说明书所述。本发明的化合物是有效的己糖激酶2抑制剂,它们可用于治疗肿瘤疾病。
Description
技术领域
本发明涉及酰肼取代的亚苄基酚类化合物,它们是有效的己糖激酶2(HK2)抑制剂。本发明化合物可用于治疗肿瘤疾病,特别是与HK2相关的肿瘤疾病,用于制备治疗肿瘤疾病药物的应用或者用于治疗肿瘤疾病的用途。
背景技术
己糖激酶的英文名称是Hexokinase,本发明中将其缩写为HK。己糖激酶分为四种亚型,包括HK1、HK2、HK3、HK4。其中HK1、HK2、HK3对葡萄糖有较高的亲和力,而HK4对葡萄糖的亲和力较低。己糖激酶的这四种亚型不仅在底物亲和力上有很大差异,而且在组织分布及表达量上也有一定差异。HK1主要分布在线粒体外膜上,且大量表达于胚胎组织上;HK2仅在脂肪、骨骼肌、心肌等组织有相对较高的表达水平;HK3表达量较低;HK4主要分布于胰腺和肝脏组织(J. Exp. Biol., 2003, 206: 2049-2057; Oncotarget, 2013, 4: 1862-1863)。
HK2在正常组织中的表达量较低,但在很多癌细胞中均能检测到HK2的过量表达。目前已证实,HK2在宫颈癌、精原细胞瘤、睾丸淋巴瘤、前列腺癌、卵巢癌、肺癌、直肠癌、乳腺癌、皮肤鳞状细胞癌、结肠癌、肝癌、胰腺癌、胃癌、食管癌、甲状腺癌、膀胱移行上皮癌、白血病、脑瘤、胃癌、腹膜癌、头颈癌、子宫内膜癌、喉癌、肾癌、雌性生殖道癌、原位癌、神经纤维瘤、骨癌、皮肤癌、胃肠道间质瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、胶质瘤、肉瘤均有发现,其中在结直肠癌、胰腺癌、肝癌、胃癌、乳腺癌、卵巢癌、舌鳞状细胞癌、恶性胶质瘤、肺癌、肝外胆管癌、前列腺癌、喉癌、肾癌等多种癌细胞中呈强表达,并且表达量与癌症的恶性程度呈正相关(Clin. Exp. Med., 2014, 14: 345-353)。Rabeh等首次报道了HK2蛋白质的结晶结构(PDB code:2NZT)。人体内的HK2由902个氨基酸构成、相对分子质量约为102kD。
HK2是糖酵解第一步反应的限速酶,在肿瘤细胞中维持着高的糖代谢率,影响癌症的发生、发展。研究表明,系统性敲除非小细胞肺癌小鼠模型中的HK2可抑制肿瘤的发生、发展(Cancer Cell, 2013, 24: 213-228)。因此,HK2有可能作为肿瘤治疗的一个重要靶点,不过目前尚无将HK2作为治疗肿瘤靶点的药物。
本发明针对HK2作为靶点进行研究,新发现一类酰肼取代的亚苄基酚类化合物,为HK2有效的抑制剂。
发明内容
经过本发明人等的研究,本发明涉及具有如下通式I所示的化合物,或其药学上可接受的盐、酯、酰胺或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物和前体药物:
I
其中
Ar为可被取代的4~8元杂环或4~8元碳环或者二者的稠环,其取代基可以为一个或多个独立地选自氢,可被取代的C1~C8烷基或C3~C8环烷基、C1~C8烷氧基、C1~C8酰氧基、C1~C8酰基、氨基、C1~C8烷基胺基、C1~C8酰胺基、C2~C8烷基酰亚胺基、硝基、巯基、烃硫基、酰硫基、卤素、磷酰氧基、磺酰氧基、亚磺酰氧基、脒基、胍基、羧基、膦酸基、磺酸基、亚磺酸基、氰基等基团,以上卤素为氟、氯、溴或碘。
式I化合物中,优选Ar为可被取代的4~8元杂环或4~8元碳环或者二者的稠环,其取代基可以为一个或多个独立地选自氢,C1~C8烷基或C3~C8环烷基、羟基、C1~C8烷氧基、C1~C8酰氧基、C1~C8酰基、氨基、C1~C8烷基胺基、C1~C8酰胺基、C2~C8烷基酰亚胺基、硝基、巯基、卤素、磷酰氧基、磺酰氧基、亚磺酰氧基、脒基、胍基、羧基、膦酸基、磺酸基、亚磺酸基、氰基的基团,以上卤素均指氟、氯、溴或碘。
式I化合物中,m、n各自独立地为0或1,优选n或m其一为0,再优选n和m均为0。
式I化合物中,优选R2、R3相同或不同,各自独立地选自氢、卤素、烷基、芳基、羟基、烷氧基、硝基、巯基、杂环烷基、杂芳基、氰基、环烷基、增溶性基团、-NRR’、-烷基-NRR’的一种或更多种基团取代的杂环基;-NR-CO-R’、-烷基-NR-CO-R’、-CONRR’和SO2NRR’基团;其中,R和R’各自独立地选自氢、烷基、环烷基、芳基、杂环烷基和杂芳基基团;其中卤素指氟、氯、溴或碘。
式I化合物中,再优选R2、R3其一为羟基,更优选R2、R3均为羟基。
本发明确证了酰肼取代的亚苄基酚类化合物为HK2的有效抑制剂,具有抗肿瘤的实用性,可用于治疗肿瘤疾病,包括但不限于诸如结直肠癌、胃肠间质瘤、组织细胞性淋巴 瘤、胰腺癌、肝癌、胃癌、乳腺癌、卵巢癌、舌鳞状细胞癌、恶性胶质瘤、非小细胞肺癌、小细胞 肺癌、肺鳞癌、肺腺癌、肝外胆管癌、前列腺癌、喉癌、肾癌、皮肤癌、上皮细胞癌、宫颈癌、卵 巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、口腔癌、白血病等。化合物通过易合成方法获得,能用多种方法对患者给药。
本发明化合物能够以非溶剂化形式及溶剂化形式存在,包括水合物。一般而言,溶剂化形式包括水合形式等价于非溶剂化形式,也涵盖在本发明范围内。
本发明还包括同位素标记的化合物,它们等同于式I所述化合物,但结构中有一个或多个原子被相应的自然界中常见的同位素原子所替代。可以引入本发明中的同位素实例包括氢、碳、氮、氧、磷、硫、氟和氯,分别对应于例如:2H、3H、11C、13C、14C、15N、17O、18O、31P、32P、35S、18F和36Cl。含有上述同位素和/或其他原子的其他同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。
式I化合物能够进一步生成药学上可接受的形式,包含式I化合物的盐、溶剂化物和N-氧化物,盐包括但不限于酸加成盐和/或碱加成盐。
本发明还提供药物制剂,包含治疗有效量的式I化合物或其治疗学上可接受的盐和其药学上可接受的载体、稀释剂或赋型剂。所有这些形式都属于本发明。
本发明提供治疗哺乳动物与HK2高表达相关的肿瘤疾病的方法,包括但不限于结 直肠癌、胃肠间质瘤、组织细胞性淋巴瘤、胰腺癌、肝癌、胃癌、乳腺癌、卵巢癌、舌鳞状细胞 癌、恶性胶质瘤、非小细胞肺癌、小细胞肺癌、肺鳞癌、肺腺癌、肝外胆管癌、前列腺癌、喉癌、 肾癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、口 腔癌、白血病等。该方法包含给予所述哺乳动物治疗此类疾病有效量的式I化合物或其药学上可接受的盐。上述哺乳动物,优选人类。
由于本发明化合物对HK2的抑制活性,它们也是有用的研究工具,用于体外和体内研究HK2的作用机理。
优选地,上述治疗方法给予需要治疗的患者治疗有效量的式I化合物。本发明化合物是酰肼取代的亚苄基酚类化合物,它们是有效的HK2抑制剂。这些化合物容易合成,能够借助多种途径给药,包括口服给药和胃肠外给药。本发明化合物具有式I结构。
因此,本发明也提供了式I化合物用于制备治疗哺乳动物肿瘤疾病药物的用途。所述哺乳动物优选人类。本发明提供了用作为HK2抑制剂的式I化合物或其药物组合物,以及用作肿瘤疾病治疗药物的式I化合物或其药物组合物。
本发明化合物的制药用途或者治疗用途所述的与HK2高表达相关的肿瘤,包括但不限于结直肠癌、胃肠间质瘤、组织细胞性淋巴瘤、胰腺癌、肝癌、胃癌、乳腺癌、卵巢癌、舌鳞状细胞癌、恶性胶质瘤、非小细胞肺癌、小细胞肺癌、肺鳞癌、肺腺癌、肝外胆管癌、前列腺癌、喉癌、肾癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、口腔癌、白血病等。
本发明提供治疗哺乳动物、包括人类与HK2高表达相关的肿瘤疾病的方法,包括但不限于结直肠癌、胃肠间质瘤、组织细胞性淋巴瘤、胰腺癌、肝癌、胃癌、乳腺癌、卵巢癌、舌鳞状细胞癌、恶性胶质瘤、非小细胞肺癌、小细胞肺癌、肺鳞癌、肺腺癌、肝外胆管癌、前列腺癌、喉癌、肾癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、口腔癌、白血病等。该方法包含给予所述哺乳动物治疗此类疾病有效量的式I化合物或其药学上可接受的盐。
本发明还提供药物制剂,包含治疗有效量的式I化合物或其治疗学上可接受的盐和其药学上可接受的载体、稀释剂或赋型剂。所有这些形式都属于本发明。
由于本发明化合物对HK2的抑制活性,它们也是有用的研究工具,用于体外和体内研究HK2的作用机理。
优选地,上述治疗方法给予需要治疗的患者治疗有效量的式I化合物。本发明化合物是酰肼取代的亚苄基酚类化合物,它们是有效的HK2抑制剂。这些化合物容易合成,能够借助多种途径给药,包括口服和胃肠外。本发明化合物具有式I结构。
附图说明
图1化合物10与HK2的结合力测定。
图2化合物10对HK1, HK2, GCK的酶抑制作用。
图3不同剂量化合物10对SW1990移植瘤的治疗作用。
图4化合物10对SW1990移植瘤肿瘤组织生长曲线的影响。
图5化合物10对SW1990移植瘤皮下肿瘤重量的影响。
图6化合物10对SW1990移植瘤小鼠体重的影响。
图7不同剂量化合物10对SW480移植瘤的治疗作用。
图8化合物10对SW480移植瘤肿瘤组织生长曲线的影响。
图9化合物10对SW480移植瘤皮下肿瘤重量的影响。
图10化合物10对SW480移植瘤小鼠体重的影响。
具体实施方式
于本文中,若以一范围界定特定数量时,该范围应解读为包括范围的两端点值、范围内的所有子范围以及范围内的所有数值。举例而言,范围C1-C4应包括C1、C2、C3、C4以及C1-C2、C1-C3、C1-C4、C2-C3、C2-C4、C3-C4。
于本文中,用语“烷基”表示含有直链、二级、三级或环碳原子的烃基,例如可为甲基、乙基、1-丙基、2-丙基、1-丁基、2-甲基-1-丙基、2- 丁基、叔丁基、1-戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基等。烷基可为单价烃基团或为二价烃基团(即伸烷基)。
于本文中,用语“芳基”表示具有单环(例如苯基)或多个缩合或稠合环的不饱和芳族碳环基团,其中至少一环为芳族环。
于本文中,用语“烷氧基”表示-O-烷基的基团,其中烷基定义如上所述。较佳的烷氧基包括例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基、1,2-二甲基丁氧基等。
除非另有指明,否则前述官能基均可视需要经一或多个下列基团取代:烷氧基、卤基、卤烷基、羟基、羟基烷基、芳基、杂芳基、杂环、环烷基、烷酰基、烷氧基羰基、胺基、亚胺基、烷基胺基、酰基胺基、硝基、三氟甲基、三氟甲氧基、羧基、羧基烷基、酮基、硫酮基、烷硫基、烷基亚磺酰基、烷基磺酰基、氰基、乙酰胺基、乙酰氧基、乙酰基、苯甲酰胺基、苯亚磺酰基、苯磺酰胺基、苯磺酰基、苯磺酰基胺基、苯甲酰基、苯甲酰基胺基、苯甲酰氧基、苯甲基、苯甲氧基、苯甲氧基羰基、苯甲基硫基、胺甲酰基、胺甲酸基。
本发明化合物可通过如下通用方法制备获得,其中取代基如以上式I中所定义,除非进一步指出。以下描述的合成方法仅仅是示例性的,本发明的化合物可以通过如本领域普通技术人员掌握的替代路线来合成。
酰肼类化合物(A)与羰基物(B)反应得到结构通式(C)化合物。
酰肼类化合物可以通过相应的酸、酯、酸酐、酰卤等形式与肼发生酰化或肼解反应制备得到。
具体来说,酯与水合肼反应,得到酰肼;酰肼和2, 3, 4-三羟基苯甲醛反应,得到(E)-N'-(2,3,4-三羟基苯亚甲基)酰肼。
本发明化合物能够被制成多种口服与胃肠外剂型给药,包括透皮、直肠或者吸入给药。剂型中包含式I化合物或对应的式I化合物的药学上可接受的盐或者溶剂化物。
本发明的药物制剂中包含治疗有效量的式I化合物以及药学上可接受的载体、稀释剂或赋型剂。就制备含有本发明化合物的药物组合物而言,药学上可接受的载体可以是固体或液体。固体形式制备物包括粉剂、片剂、丸剂、胶囊剂、扁囊剂、栓剂、可分散的颗粒剂、吸入剂。固体载体可以是一种或多种物质,它们也可以充当稀释剂、矫味剂、粘合剂、防腐剂、崩解剂或者包封材料。
本发明制剂优选地含有约1%至约90%的活性化合物。适合的载体包括碳酸镁、硬脂酸镁、滑石、蔗糖、乳糖、甘露醇、果胶、糊精、淀粉、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠、硅胶、微晶纤维素、聚维酮、低熔点蜡、可可脂等。可以使用片剂、粉剂、胶囊剂、丸剂、扁囊剂、锭剂和颗粒剂作为适合于口服给药的固体剂型,优选的口服剂型是片剂和胶囊剂。
片剂的制备是通过将活性化合物与适当的辅料混合通过造粒工艺结合,包括湿法、干法、挤出、喷雾等方法,也可以是粉末不经造粒工艺直接混合,然后压制成片。胶囊的制备是将活性化合物与适当的辅料通过造粒工艺结合,包括湿法、干法、挤出、喷雾等方法,也可以是粉末不经造粒工艺直接混合,然后经过填充胶囊而成。粉剂的制备是通过将细粉化的活性化合物和稀释剂、着色剂、矫味剂、稳定剂、增稠剂、分散剂和芳香剂等混合,经过分装而成。颗粒剂的制备是通过将活性化合物和稀释剂、着色剂、矫味剂、稳定剂、增稠剂、分散剂和芳香剂等通过造粒工艺结合,包括湿法、干法、挤出、喷雾等方法,制成具有一定粒度的颗粒,再将颗粒分装而成。栓剂的制备是通过将活性化合物与适宜的基质粉末混合均匀,然后分装于模具内,通过模具挤压而成;也可以是将活性化合物溶解或分散于已经熔融的基质内,然后分装至模具内,冷却凝固而成。吸入剂的制备是通过将活性化合物微粉化,然后附着在适宜的载体上而成,如乳糖、糖醇类等,再借助吸入器装置给药。
液体形式制备物包括溶液、混悬液和乳液,例如水、水/乙醇、水/丙二醇和水/聚乙二醇等溶液。就注射而言,可以将液体制备物配制成在乙醇、丙二醇或者聚乙二醇水溶液、等渗盐水、5%含水葡萄糖等中的溶液。适合于口服的水溶液可以这样制备,将活性组分溶于水,根据需要加入适合的着色剂、矫味剂、稳定剂和增稠剂。适合于口服的水混悬液可以这样制备,将微细粉碎的活性组分分散在水中,再与粘性材料混合,例如天然或合成树脂、树胶、甲基纤维素、羧甲基纤维素钠或其他熟知的悬浮剂。乳剂可以通过将活性化合物分散于或溶解于油相或水相中,例如豆油、蒸馏水,再加入另一相液体和乳化剂,例如吐温80,经过搅拌、超声或其它乳化装置乳化而成。
本发明药物制备物优选地为单位剂型。在此类剂型中,制备物被细分为含有适量活性组分的单位剂量。单位剂型可以是带包装的制备物,该包装含有离散量的制备物,例如小包装片剂、胶囊剂和小瓶或安瓿装粉剂。单位剂型可以是片剂、胶囊剂、扁囊剂或锭剂本身,或者是适当数量的任意这些的带包装形式。
式I化合物的治疗有效剂量从约0.1 mg/Kg至约1000 mg/Kg体重每天不等。典型的剂量是约1 mg至10000 mg每天。根据特定的应用和活性组分的效力,活性组分在单位剂量制备物中的量可以从约1 mg至约10000 mg不等,优选约1 mg至8000 mg。如果需要,组合物还可以含有其它可相容的治疗剂。给予需要用式I化合物治疗的受治疗者约1 mg至约8000mg每天的剂量,在24小时内单次或多次给药,治疗可以按连续间隔反复达必要的时间长度。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的试验方法,通常按照常规条件,或按照生产厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例
合成实施例
参考以下合成实施例会更充分的理解本发明,但其不应该解释为限制本发明的范围。一般来说:所用的全部化学品都是商业试剂级产品。溶剂是无水商业级且使用时无需进一步纯化。通过使用预涂敷硅胶GF 254的TLC层析板在UV光下可视的薄层色谱分析监控反应进程。1 H NMR光谱的多重性显示为单重(s)、宽单重(br s)、双重(d)、三重(t)、四重(q)以及多重(m),NMR光谱在Bruker 400 MHz光谱仪上进行。
实施例1、制备中间体化合物,苯甲酰肼的合成
将苯甲酸甲酯(1.36 g, 10 mmol),80%水合肼(3.1 mL, 5 equiv),20 mL甲醇,加入有磁力搅拌子的50 mL圆底烧瓶中搅拌回流。TLC跟踪反应进度,当绝大多数原料被消耗,将反应液置于旋转蒸发仪上回收大部分甲醇溶剂,加入水,乙酸乙酯,转移至分液漏斗中多次萃取,直至水相TLC检测不含产物点为止,合并乙酸乙酯层,加入无水硫酸钠,浓缩得到苯甲酰肼固体1.2 g,收率88.2%,粗品未经纯化直接用于下一步反应。
使用如上方法,用取代或未取代的(杂)芳环,和水合肼反应,溶剂可以替换为水、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜、四氢呋喃、甲苯、二氯甲烷、乙腈、N,N-二甲基甲酰胺、二氧六环等或其组合物。反应温度为-20 °C~溶剂回流温度。产物未经纯化、或采用重结晶、柱层析等常规纯化方法,得到酰肼。
实施例2、(E)-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼的合成
将苯甲酰肼固体(1.36 g, 10 mmol),2,3,4-三羟基苯甲醛(1.62 g, 1.05 equiv),20mL甲醇,加入有磁力搅拌子的50 mL圆底烧瓶中室温搅拌。当绝大多数原料被消耗,产品析出,抽滤,滤饼以少量甲醇洗涤,滤液浓缩后进一步析出固体产品。得到(E)-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼2.2 g,收率81.0%。
使用如上方法,用酰肼和2,3,4-三羟基苯甲醛反应,反应溶剂可替换为乙醇、异丙醇、吡啶、二氯甲烷、二氯乙烷、氯仿、乙醚、苯、甲苯、二甲苯、氯苯、甲基叔丁基醚、二异丙基醚、四氢呋喃、2-甲基四氢呋喃、1,2-二甲氧基乙烷、1,4-二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺等,或上述溶剂的不同组合,反应温度为-20 °C~溶剂回流温度。产物未经纯化、或采用重结晶、柱层析等常规纯化方法。
依据上述方法制得了下述终化合物:
化合物1:(E)-N'-(2,3,4-三羟基苯亚甲基)喹啉-2-甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 12.42(s, 1H), 11.62(s, 1H), 9.58(s, 1H), 8.77(s, 1H), 8.62(d, J = 8.5 Hz, 1H), 8.57(brs, 1H), 8.24-8.21(m, 2H), 8.11(d, J= 7.8 Hz, 1H), 7.94-7.90(m, 1H), 7.78-7.74(m, 1H) , 6.80(d, J = 8.5 Hz, 1H),6.44(d, J = 8.0 Hz, 1H); 13C NMR(100 MHz, DMSO-d 6) δ 160.77, 152.35, 149.96,149.40, 148.12, 146.51, 138.55, 133.22, 131.21, 129.69, 129.44, 128.86,128.69, 121.95, 119.58, 111.36, 108.22.HRMS (ESI) m/z 324.0981[M + H]+, m/z346.0805[M + Na]+ (calcd for C17H13N3O4, 323.0903).
化合物2:(E)-4-(2-羟乙基)-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 11.86(s, 1H), 11.61(s, 1H), 9.49(s, 1H), 8.51(s, 1H), 8.44(s, 1H), 7.90(d, J = 8.8 Hz, 2H), 7.08(d, J = 8.9 Hz, 2H), 6.77(d, J = 8.5 Hz, 1H), 6.40(d, J = 8.0 Hz, 1H), 4.95(brs, 1H), 4.08(t, J = 4.9Hz, 2H), 3.75(t, J = 4.8 Hz, 2H); 13C NMR(100 MHz, DMSO-d 6) δ162.48, 162.05,150.11, 149.08, 147.91, 133.16, 129.94, 125.25, 121.62, 114.74, 111.35,108.06, 70.26, 59.92. HRMS (ESI) m/z 333.1073[M + H]+, m/z 355.0906[M + Na]+.(calcd for C16H16N2O6, 332.0995).
化合物3:(E)-4-(甲磺酰基)-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 12.20(s, 1H), 11.36(s, 1H), 9.59(s, 1H), 8.56(s, 1H), 8.50(s, 1H), 8.16(d, J = 8.5 Hz, 2H), 8.10(d, J = 8.5 Hz, 2H), 6.84(d, J = 8.5 Hz, 1H), 6.42(d, J = 8.4 Hz, 1H), 3.30(s, 3H); 13C NMR(100 MHz,DMSO-d 6) δ 161.75, 151.36, 149.46, 148.05, 143.81, 137.92, 133.19, 129.08,127.69, 121.71, 111.23, 108.23, 43.73. HRMS (ESI) m/z 351.0652[M + H]+, m/z373.0472 [M + Na]+.(calcd for C15H14N2O6S, 350.0574).
化合物4:(E)-3-(甲磺酰基)-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼
1H NMR (400 MHz, DMSO-d 6) δ 12.23(s, 1H), 11.38(s, 1H), 9.57(s, 1H), 8.56(brs, 1H), 8.51(s, 1H), 8.46(t, J = 1.5 Hz, 1H), 8.27(d, J = 7.9 Hz, 1H),8.16(d, J = 9.4 Hz, 1H), 7.84(t, J = 7.8 Hz, 1H), 6.84(d, J = 8.5 Hz, 1H),6.42(d, J = 8.5 Hz, 1H), 3.30(s, 3H); 13C NMR(100 MHz, DMSO-d 6) δ 161.46,151.25, 149.43,148.03, 141.69, 134.42, 133.20, 133.09, 130.59, 130.45,126.42, 121.65, 111.27, 108.23, 43.93. HRMS (ESI) m/z 351.0639[M + H]+, m/z373.0467[M + Na]+.(calcd for C15H14N2O6S, 350.0561).
化合物5:(E)-4-丁基-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 11.91(s, 1H), 11.57(s, 1H), 9.50(s, 1H), 8.51(brs, 1H), 8.45(s, 1H), 7.85(d, J = 8.2 Hz, 2H), 7.36(d, J = 8.2 Hz, 2H),6.78(d, J = 8.5 Hz, 1H), 6.40(d, J = 8.4 Hz, 1H), 2.68(t, J = 7.6 Hz, 2H),1.62-1.55(m, 2H), 1.36-1.27(m, 2H), 0.91(t, J = 7.3 Hz, 3H); 13C NMR(100 MHz,DMSO-d 6) δ 162.92, 150.42, 149.16, 147.95, 147.16, 133.17, 130.77, 128.90,128.06, 121.64, 111.31, 108.09, 35.15, 33.31, 22.19, 14.22.HRMS (ESI) m/z329.1485[M + 2H]+, m/z 351.1314[M + Na]+.(calcd for C18H20N2O4, 327.1329).
化合物6:(E)-3-氯-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 12.06(s, 1H), 11.40(s, 1H), 9.56(s, 1H), 8.55(s, 1H), 8.47(s, 1H), 7.97(t, J = 1.8 Hz, 1H), 7.90-7.88(m, 1H), 7.70-7.67(m,1H), 7.58(t, J = 7.9 Hz, 1H), 6.82(d, J = 8.5 Hz, 1H), 6.41(d, J = 8.4 Hz,1H); 13C NMR(100 MHz, DMSO-d 6) δ 161.56, 151.05, 149.37, 148.01, 135.39,133.80, 133.18, 132.15, 131.07, 127.72, 126.87, 121.67, 111.25, 108.19. HRMS(ESI) m/z 307.0494[M + H]+, m/z 329.0311[M + Na]+. (calcd for C14H11ClN2O4,306.0416).
化合物7:(E)-4-氯-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 12.04(s, 1H), 11.46(s, 1H), 9.55(s, 1H), 8.54(s, 1H), 8.47(s, 1H), 7.96-7.94(m, 2H), 7.62(d, J = 8.6 Hz, 2H), 6.81(d, J =8.5 Hz, 1H), 6.41(d, J = 8.4 Hz, 1H); 13C NMR(100 MHz, DMSO-d 6) δ 161.95,150.89, 149.32, 148.00, 137.15, 133.18, 132.10, 129.96, 129.12, 121.68,111.26, 108.16. HRMS (ESI) m/z 307.0494[M + H]+, m/z 329.0309[M + Na]+.(calcdfor C14H11ClN2O4, 306.0416).
化合物8:(E)-4-甲基-N'-(2,3,4-三羟基苯亚甲基)苯甲磺酰肼
1H NMR(400 MHz, DMSO-d 6) δ 11.28(s, 1H), 10.06(s, 1H), 9.57(s, 1H), 8.50(s, 1H), 8.02(s, 1H), 7.73(d, J=8.3 Hz, 2H), 7.43(d, J=8.1 Hz, 2H), 6.73(d, J= 8.6 Hz, 1H), 6.34(d, J = 8.5 Hz, 1H), 2.37(s, 3H); 13C NMR (100 MHz, DMSO-d 6) δ 150.32, 149.23, 147.24, 144.17, 136.10, 133.05, 130.28, 127.62, 120.49,111.34, 108.19, 21.47. HRMS (ESI) m/z 323.0699[M + H]+, m/z 345.0531[M + Na]+.(calcd for C14H14N2O5S, 322.0621).
化合物9:(E)-4-甲氧基-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 11.86(s, 1H), 11.62(s, 1H), 9.49(s, 1H), 8.52(s, 1H), 8.45(s, 1H), 7.92(d, J = 8.8 Hz, 2H), 7.08(d, J = 8.9 Hz, 2H), 6.77(d, J = 8.5 Hz, 1H), 6.40 (d, J = 8.4 Hz, 1H), 3.84(s, 3H); 13C NMR(100 MHz,DMSO-d 6) δ 162.56, 162.45, 150.12, 149.09, 147.92, 133.17, 129.94, 125.36,121.61, 114.27, 111.35, 108.06, 55.91. HRMS (ESI) m/z 303.0984[M + H]+, m/z325.0812[M + Na]+.(calcd for C15H14N2O5, 302.0906).
化合物10:(E)-4-硝基-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 12.26(s, 1H), 11.33(s, 1H), 9.60(s, 1H), 8.56(brs, 1H), 8.50(s, 1H), 8.38(d, J = 12.0 Hz, 2H), 8.16(d, J = 12.0 Hz, 2H),6.84(d, J = 8.5 Hz, 1H), 6.42(d, J = 8.5 Hz, 1H); 13C NMR(100 MHz, DMSO-d 6) δ161.35, 151.50, 149.77, 149.51, 148.07, 139.09, 133.19, 129.58, 124.18,121.70, 111.22, 108.25. HRMS (ESI) m/z 318.0723[M + H]+, m/z 340.0547[M + Na]+.(calcd for C14H11N3O6, 317.0645).
化合物11:(E)-3-甲氧基-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 11.94(s, 1H), 11.52(s, 1H), 9.53(s, 1H), 8.54(brs, 1H), 8.47(s, 1H), 7.52-7.44(m, 3H), 7.19-7.16(m, 1H), 6.79(d, J = 8.5Hz, 1H), 6.41(d, J = 8.4 Hz, 1H), 3.84(s, 3H); 13C NMR(100 MHz, DMSO-d 6) δ162.74, 159.72, 150.75, 149.25, 147.98, 134.75, 133.17, 130.22, 121.67,120.21, 118.09, 113.24, 111.29, 108.13, 55.83. HRMS (ESI) m/z 303.0972[M + H]+,m/z 325.0789[M + Na]+.(calcd for C15H14N2O5, 302.0894).
化合物12:(E)-2-苯基-N'-(2,3,4-三羟基苯亚甲基)乙酰肼
1H NMR(400 MHz, DMSO-d 6) δ 11.72(s, 1H), 11.30(s, 1H), 9.49(s, 1H), 8.49(s, 1H), 8.23(s, 1H), 7.35-7.27(m, 5H), 6.77(d, J = 8.5 Hz, 1H), 6.38(d, J =8.5 Hz, 1H), 3.54(s, 2H); 13C NMR(100 MHz, DMSO-d 6) δ 166.47, 149.45, 149.12,147.80, 136.00, 133.11, 129.58, 128.83, 127.12, 121.51, 111.17, 108.05,41.36. HRMS (ESI) m/z 287.1036[M + H]+, m/z 309.0866[M + Na]+.(calcd forC15H14N2O4, 286.0958).
化合物13:(E)-3-硝基-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼
1H NMR(400 MHz,DMSO-d 6) δ 12.29(s, 1H), 11.34(s, 1H), 9.59(s, 1H), 8.78(t, J = 1.9 Hz,1H), 8.56(brs, 1H), 8.52(s, 1H), 8.47-8.37(m, 2H), 7.86(t, J =8.0 Hz, 1H), 6.85(d, J = 8.5 Hz, 1H), 6.42(d, J = 8.4 Hz, 1H); 13C NMR(100MHz, DMSO-d 6) δ 160.86, 151.39, 149.48, 148.28, 148.05, 134.80, 134.55,133.20, 130.86, 126.89, 122.69, 121.66, 111.25, 108.24. HRMS (ESI) m/z318.0721[M + H]+, m/z 340.0541[M + Na]+.(calcd for C14H11N3O6, 317.0643).
化合物14:(E)-4-苯基-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 12.06(s, 1H), 11.57(s, 1H), 9.56(s, 1H), 8.57(s, 1H), 8.50(s, 1H), 8.04(d, J = 8.3 Hz, 2H), 7.85(d, J = 8.3 Hz, 2H), 7.76(d, J = 7.4 Hz, 2H), 7.53-7.41(m, 3H), 6.81(d, J = 8.5 Hz, 1H), 6.42(d, J =8.4 Hz, 1H); 13C NMR(100 MHz, DMSO-d 6) δ 162.63, 150.64, 149.24, 147.99,143.84, 139.48, 133.19, 132.08, 129.56, 128.74, 127.40, 127.21, 121.69,111.32, 108.14. HRMS (ESI) m/z 349.1238[M + H]+, m/z 371.0990[M + Na]+.(calcdfor C20H16N2O4, 348.1160).
化合物15:(E)-N'-(2,3,4-三羟基苯亚甲基)-2,3-二氢苯并[b][1,4]二氧六环-2-甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 11.74(s, 1H), 11.18(s, 1H), 9.56(s, 1H), 8.54(s, 1H), 8.41(s, 1H), 7.05-7.02(m, 1H), 6.92-6.85(m, 3H), 6.77(d, J = 8.5 Hz,1H), 6.39(d, J = 8.5 Hz, 1H), 5.00-4.99(m, 1H), 4.43-4.33(m, 2H); 13C NMR(100MHz, DMSO-d 6) δ 163.41, 151.58, 149.44, 147.96, 143.46, 142.58, 133.14,122.20, 122.18, 121.67, 117.85, 117.60, 111.07, 108.20, 72.51, 65.06. HRMS(ESI) m/z 331.0913[M + H]+, m/z 353.0739[M + Na]+.(calcd for C16H14N2O6,330.0835).
化合物16:(E)-6-羟基-N'-(2,3,4-三羟基苯亚甲基)-2-萘甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 12.04(s, 1H), 11.64(s, 1H), 10.16(s, 1H), 9.51(s, 1H), 8.54(brs, 1H), 8.50(s, 1H), 8.43(s, 1H), 7.95-7.89(m, 2H), 7.81(d, J= 8.7 Hz, 1H), 7.21(s, 1H), 7.19(d, J = 8.7 Hz, 2H),6.80(d, J = 8.5 Hz, 1H),6.42(d, J = 8.4 Hz, 1H); 13C NMR(100 MHz, DMSO-d 6) δ 163.15, 157.65, 150.26,149.15, 147.96, 136.84, 133.19, 131.24, 128.51, 127.36, 127.07, 126.73,124.88, 121.63, 120.09, 111.38, 109.18, 108.11. HRMS (ESI) m/z 339.0973[M +H]+, m/z 361.0801[M + Na]+.(calcd for C18H14N2O5, 338.0895).
化合物17:(E)-N-{4-[2-(2,3,4-三羟基苯亚甲基)肼-1-羰基]苯基}环丙甲酰胺
1H NMR(400 MHz, DMSO-d 6) δ 11.88(s, 1H), 11.59(s, 1H), 10.52(s, 1H), 9.50(s, 1H), 8.51(s, 1H),8.44(s, 1H), 7.89(d, J = 8.7 Hz, 2H), 7.73(d, J = 8.8Hz, 2H), 6.78(d, J = 8.5 Hz, 1H), 6.40(d, J = 8.4 Hz, 1H), 1.85-1.79(m, 1H),0.85-0.83(m, 4H); 13C NMR(100 MHz, DMSO-d 6) δ 172.66, 162.44, 150.24, 149.12,147.93, 142.95, 133.16, 129.00, 127.33, 121.63, 118.74, 111.34, 108.08,15.16, 8.01. HRMS (ESI) m/z 356.1240[M + H]+, m/z 378.1059[M + Na]+.(calcd forC18H17N3O5, 355.1162).
化合物18:(E)-5-羟基-N'-(2,3,4-三羟基苯亚甲基)-3H-吲哚-2-甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 11.93(s, 1H), 11.54(s, 1H), 11.49(s, 1H), 9.51(s, 1H), 8.91(s, 1H), 8.52(s, 1H), 8.45(s, 1H), 7.28(d, J = 8.8 Hz, 1H),7.07-7.10(m, 1H), 6.93(d, J = 2.2 Hz, 1H), 6.82-6.77(m, 2H), 6.41(d, J = 8.4Hz, 1H); 13C NMR (100 MHz, DMSO-d 6) δ 157.67, 151.76, 149.62, 149.10, 147.83,133.19, 132.16, 130.30, 128.17, 121.47, 115.69, 113.39, 111.45, 108.13,104.83, 103.10. HRMS (ESI) m/z 328.0928[M + H]+, m/z 350.0745[M + Na]+.(calcdfor C16H13N3O5, 327.0850).
化合物19:(E)-N'-(2,3,4-三羟基苯亚甲基)烟酰肼
1H NMR(400 MHz, DMSO-d 6) δ 12.20(s, 1H), 11.44(s, 1H), 9.60(s, 1H), 9.16(m, 1H), 8.86(dd, J = 4.9, 1.7 Hz, 1H), 8.60(s, 1H), 8.55(s, 1H), 8.35(dt, J= 8.0, 2.0 Hz, 1H), 7.65-7.68(m, 1H), 6.91(d, J = 8.5 Hz, 1H), 6.49(d, J =8.4 Hz, 1H); 13C NMR(100 MHz, DMSO-d 6) δ 161.52, 152.81, 151.06, 149.41,149.01, 148.02, 135.84, 133.18, 129.22, 124.11, 121.65, 111.22, 108.20. HRMS(ESI) m/z 274.0811[M + H]+, m/z 296.0613[M + Na]+.(calcd for C13H11N3O4,273.0750).
化合物20:(E)-2-羟基-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 11.93(s, 1H), 11.86(s, 1H), 11.38(s, 1H), 9.53(s, 1H), 8.52(d, J = 1.6 Hz, 2H), 7.89(dd, J = 7.9, 1.7 Hz, 1H), 7.43-7.47(m,1H), 7.02-6.92(m, 2H), 6.82(d, J = 8.5 Hz, 1H), 6.41(d, J = 8.4 Hz, 1H); 13CNMR(100 MHz, DMSO-d 6) δ 164.68, 159.55, 151.39, 149.44, 148.05, 134.35,133.18, 128.84, 121.69, 119.44, 117.77, 115.92, 111.24, 108.20. HRMS(ESI) m/z289.0776[M + H]+, m/z 311.0603[M + Na]+.(calcd for C14H12N2O5, 288.0746).
化合物21:(E)-4-氟-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 11.96(s, 1H), 11.48(s, 1H), 9.46(s, 1H), 8.47(s, 1H), 8.05-7.96(m, 2H), 7.38(t, J = 8.8 Hz, 2H), 6.80(d, J = 8.4 Hz, 1H),6.41(d, J = 8.4 Hz, 1H); 13C NMR(100 MHz, DMSO-d 6) δ 163.41, 161.91, 150.67,149.26, 147.98, 133.18, 130.78, 130.69, 129.89, 129.86, 121.63, 116.11,115.89, 111.28, 108.13. HRMS(ESI) m/z 291.0739[M + H]+, m/z 313.0575[M + Na]+.(calcd for C14H11FN2O4, 290.0703).
化合物22:(E)-4-氯-3-硝基-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 12.21(s, 1H), 11.24(s, 1H), 9.53(s, 1H), 8.60(d, J = 2.1 Hz, 1H), 8.50(d, J = 7.9 Hz, 2H), 8.23(dd, J = 8.4, 2.2 Hz, 1H),7.99(d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.42 (d, J = 8.5 Hz, 1H);13C NMR(100 MHz, DMSO-d 6) δ 160.00, 151.36, 149.54, 148.05, 147.84, 133.50,133.19, 133.17, 132.63, 128.82, 125.22, 121.58, 111.23, 108.26. HRMS(ESI) m/z352.0306[M + H]+, m/z 374.0109[M + Na]+.(calcd for C14H10ClN3O6, 351.0258).
化合物23:(E)-N'-(2,3,4-三羟基苯亚甲基)噻吩-2-甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 11.99(s, 1H), 11.34(s, 1H), 9.49(s, 1H), 8.52(s, 1H), 8.44(s, 2H), 7.89(dd, J = 4.3, 2.8 Hz, 2H), 7.26-7.22(m, 1H), 6.81(d, J = 8.5 Hz, 1H), 6.40(d, J = 8.4 Hz, 1H); 13C NMR(100 MHz, DMSO-d 6) δ157.69, 150.22, 149.25, 147.88, 138.21, 133.18, 132.35, 129.39, 128.64,121.49, 111.34, 108.15. HRMS(ESI) m/z 279.0465[M + H]+, m/z 301.0269[M + Na]+.(calcd for C12H10N2O4S, 278.0361).
化合物24:(E)-N'-(2,3,4-三羟基苯亚甲基)异烟酰肼
1H NMR(400 MHz, DMSO-d 6) δ 12.18(s, 1H), 11.29(s, 1H), 9.56(s, 1H), 8.79-8.81(m, 2H), 8.55(s, 1H), 8.50(s, 1H), 7.83-7.85(m, 2H), 6.84(d, J = 8.5 Hz,1H), 6.42(d, J = 8.5 Hz, 1H); 13C NMR(100 MHz, DMSO-d 6) δ 161.40, 151.52,150.83, 149.52, 148.07, 140.51, 133.19, 133.17, 121.92, 121.66, 111.21,108.25. HRMS(ESI) m/z 274.0822[M + H]+, m/z 296.0672[M + Na]+.(calcd forC13H11N3O4, 273.0750).
化合物25:(E)-2,5-二羟基-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 11.84(s, 1H), 11.44(s, 1H), 11.10(s, 1H), 9.51(s, 1H), 9.13(s, 1H), 8.49(s, 1H), 7.28(d, J = 3.0 Hz, 1H), 6.90(dd, J = 8.8,3.0 Hz, 1H), 6.85-6.76(m, 2H), 6.40(d, J = 8.5 Hz, 1H); 13C NMR(100 MHz, DMSO-d 6) δ 164.23, 151.89, 151.25, 150.01, 149.36, 148.02, 133.16, 121.94, 121.73,118.34, 116.19, 114.27, 111.25, 108.16. HRMS(ESI) m/z 305.0779[M + H]+, m/z327.0618[M + Na]+.(calcd for C14H12N2O6, 304.0695).
化合物26:(E)-N'-(2,3,4-三羟基苯亚甲基)苯甲酰肼
1H NMR(400 MHz, DMSO-d 6) δ 11.94(s, 1H), 11.52(s, 1H), 9.46(s, 1H), 8.49(s, 1H), 8.44(s, 1H), 7.91-7.88(m, 2H), 7.59-7.55(m, 1H), 7.53-7.49(m, 2H),6.76(d, J = 8.5 Hz,1H), 6.37(d, J = 8.5 Hz, 1H); 13C NMR(100 MHz, DMSO-d 6) δ162.90, 150.57, 149.18, 147.93, 133.34, 133.13, 132.28, 128.97, 127.98,121.60, 111.24, 108.07.
依据上述方法制得到化合物001-036:
<u>011</u> | <u>2-OH</u> | <u>3-OH</u> | <u>303</u> | |
<u>012</u> | <u>2-OH</u> | <u>3-OH</u> | <u>287</u> | |
<u>013</u> | <u>2-OH</u> | <u>3-OH</u> | <u>318</u> | |
<u>014</u> | <u>2-OH</u> | <u>3-OH</u> | <u>349</u> | |
<u>015</u> | <u>2-OH</u> | <u>3-OH</u> | <u>331</u> | |
<u>016</u> | <u>2-OH</u> | <u>3-OH</u> | <u>339</u> | |
<u>017</u> | <u>2-OH</u> | <u>3-OH</u> | <u>356</u> | |
<u>018</u> | <u>2-OH</u> | <u>3-OH</u> | <u>328</u> | |
<u>019</u> | <u>2-H</u> | <u>3-OH</u> | <u>274</u> | |
<u>020</u> | <u>2-OH</u> | <u>3-OH</u> | <u>289</u> | |
<u>021</u> | <u>2-OH</u> | <u>3-OH</u> | <u>291</u> | |
<u>022</u> | <u>2-OH</u> | <u>3-OH</u> | <u>352</u> | |
<u>023</u> | <u>2-OH</u> | <u>3-OH</u> | <u>279</u> | |
<u>024</u> | <u>2-OH</u> | <u>3-OH</u> | <u>274</u> | |
<u>025</u> | <u>2-OH</u> | <u>3-OH</u> | <u>305</u> | |
<u>026</u> | <u>2-OH</u> | <u>3-OH</u> | <u>273</u> | |
<u>027</u> | <u>2-OH</u> | <u>3-OH</u> | <u>323</u> | |
<u>028</u> | <u>2-OH</u> | <u>3-OH</u> | <u>291</u> | |
<u>029</u> | <u>2-H</u> | <u>3-OH</u> | <u>337</u> | |
<u>030</u> | <u>2-OH</u> | <u>3-OH</u> | <u>329</u> | |
<u>031</u> | <u>2-OH</u> | <u>3-H</u> | <u>340</u> | |
<u>032</u> | <u>2-OH</u> | <u>3-H</u> | <u>336</u> | |
<u>033</u> | <u>2-OH</u> | <u>3-H</u> | <u>275</u> | |
<u>034</u> | <u>2-OH</u> | <u>3-H</u> | <u>305</u> | |
<u>035</u> | <u>2-OH</u> | <u>3-H</u> | <u>326</u> | |
<u>036</u> | <u>2-OH</u> | <u>3-OH</u> | <u>339</u> |
生物活性测试实施例
测试例1、本发明化合物与HK2受体结合实验
1、HK2蛋白表达和纯化
(1) HK2基因(Genebank: BC021116.1)转入pET26b质粒,将构建好的测序正确的质粒转入表达宿主BL21(DE3)感受态细胞(货号:C600003,ThermoFisher),挑取单克隆子至5 mL含有相应抗性的LB培养基中,37 ℃,200 rpm,摇床过夜培养。次日按1:100(体积比)接入含有相应抗性的1L LB液体培养基中,继续摇床培养至对数期,使OD 600=0.8,加入IPTG至终浓度0.4 mM,转移至20 ℃,200 rpm继续诱导培养过夜。
(2)离心收集细胞,加入适量体积的裂解液(200 mM NaCl, 10%甘油,100 mMTris-HCl, 1%曲那通),超声破碎细胞,将破碎液体4℃,14000 rpm 离心30 min,分离上清和沉淀,利用AKTA Pure蛋白纯化系统,分别采用亲和层析、离子交换层析和分子筛层析纯化得到HK2蛋白,供结合实验使用。
、MST(微量热泳动仪)测定化合物与HK2酶的结合能力
待测化合物用DMSO溶解,配制成50 mM母液,随后用缓冲液(20 mM HEPES)稀释成1.0mM的初始工作液1,测定缓冲液为含10% DMSO的20 mM HEPES(pH7.5)。初始工作液1作为结合力测定的最高浓度,然后用测定缓冲液倍比稀释工作液1,共稀释9次,得到10个工作液,工作液10的浓度为1.953 μM。各工作液加入20 nM HK2酶蛋白,在微量热泳动仪上测定平衡解离常数Kd。待测化合物和HK2酶蛋白结合的平衡解离常数为Kd参见图1、表二。
测试例2、酶活性试验
1. 反应体系
2. 酶活性实验
按照上述酶反应体系,将10 μL重组人HK2蛋白(0.1 mg/mL)与5 μL合成的测试化合物于37 ℃恒温震荡培养箱中共孵育10 min,然后加入剩余的85 μL反应体系,然后将96孔板放入Synergy H4全功能酶标仪。酶标仪参数设置:检测波长为340 nm,读数时间为20 min,读数间隔为2 min。化合物设置浓度梯度,每个浓度做三个副孔,用GraphPad Prism 5计算出相应化合物的酶活性半数抑制浓度(IC50),结果参见图2、表二。
结果显示,本发明化合物可有效抑制HK2酶活性。
测试例3、体外肿瘤增值抑制测定
于DMEM高糖培养基中加入10%的胎牛血清(品牌:四季青),1%的青链霉素混合液作为细胞培养液。37 ℃水浴复苏SW1990 (ATCC CRL-2172TM、SW480 (ATCC CCL-228TM)细胞,加入到含有5 mL细胞培养液的T25细胞培养瓶中,置于二氧化碳细胞培养箱(37 ℃、5% CO2)中培养。待细胞占据培养瓶面积的80%左右时,用0.25% Trypsin-EDTA消化细胞,接种于96孔板(5000个/孔)中,待细胞贴壁生长之后,给予不同浓度的化合物处理,每个浓度梯度设置三个副孔,48 h后,加入含10% CCK8的培养基,放置细胞培养箱15-20 min,450 nm下测定吸光度,计算细胞存活率(IC50),结果参见表二。
注:n.b.表示未检测出结合
经测定,本发明化合物对受试瘤株均有抑制作用。
测试例4、体内抗肿瘤试验
一、SW1990移植瘤模型
1. 将24只接种SW1990细胞的荷瘤CB-17/SCID鼠(北京华阜康,16-18 g)随机等分为高剂量组(8只),低剂量组(8只)和对照组(8只)三组,其中低剂量组,高剂量组小鼠分别给予每日一次75 mg/Kg, 150 mg/Kg化合物10,对照组只给予空白载体,给药开始后每两天给小鼠称重一次;每两天测量肿瘤大小,连续给药17天后处死,量取肿瘤组织,测量实验组和对照组肿瘤块。如图3所示,与对照组相比,给药组能明显抑制SW1990肿瘤组织的生长。图4为给药期间肿瘤组织的生长曲线,亦反映了药物对肿瘤组织的抑制作用。图5为在实验终点各组小鼠肿瘤组织的重量柱状图。对照组、低剂量组和高剂量组小鼠肿瘤组织的平均质量分别为:0.77 g,0.51 g,0.28 g,低剂量组与高剂量组对肿瘤组织的抑制率分别为33.7%,63.6% (**P<0.01)。图6为给药期间各组小鼠体重的平均值,结果显示在给药期间,给药组小鼠无明显下降,显示该化合物对小鼠的毒性较低。
二、SW480移植瘤模型
1. 将24只接种SW480细胞的荷瘤CB-17/ SCID鼠(北京华阜康,16-18g)随机等分为高剂量组(8只),低剂量组(8只)和对照组(8只)三组,其中低剂量组,高剂量组小鼠分别给予每日一次75 mg/Kg, 150 mg/Kg化合物10,对照组只给予空白载体,给药开始后每两天给小鼠称重一次;每两天测量肿瘤大小,连续给药17天后处死,量取肿瘤组织,测量实验组和对照组肿瘤块。如图7所示,与对照组相比,给药组能明显抑制SW480肿瘤组织的生长。图8为给药期间肿瘤组织的生长曲线,亦反映了药物对肿瘤组织的抑制作用。图9为在实验终点各组小鼠肿瘤组织的重量柱状图。对照组,低剂量组,高剂量组小鼠肿瘤组织的平均质量分别为:0.37 g,0.23 g,0.13 g。低剂量组与高剂量组对肿瘤组织的抑制率分别为37.8%,64.8%(**P<0.01)。图10为给药期间各组小鼠体重的平均值,结果显示在给药期间,给药组小鼠无明显下降,显示该化合物对小鼠的毒性较低。
以上具体实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (10)
1.一种式I所示的化合物,或其药学上可接受的盐,或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药:
其中,
Ar为可被取代的4~8元杂环或4~8元碳环或者二者的稠环,其取代基可以为一个或多个独立地选自氢,可被取代的C1~C8烷基或C3~C8环烷基、C1~C8烷氧基、C1~C8酰氧基、C1~C8酰基、氨基、C1~C8烷基胺基、C1~C8酰胺基、C2~C8烷基酰亚胺基、硝基、巯基、烃硫基、酰硫基、卤素、磷酰氧基、磺酰氧基、亚磺酰氧基、脒基、胍基、羧基、膦酸基、磺酸基、亚磺酸基、氰基等基团,以上卤素为氟、氯、溴或碘;
R2、R3各自独立地选自氢、取代或未取代C1~C8烷基、取代或未取代C2~C8不饱和链烯基、取代或未取代C3~C8环烷基、取代或未取代芳基、取代或未取代芳基C1~C8烷基,其中芳基为单环或稠环芳烃基,取代基为一个或多个选自C1~C8烷基、C3~C8环烷基、羟基、C1~C8烷氧基、C1~C8酰氧基、C1~C8酰基、氨基、C1~C8烷基胺基、C1~C8酰胺基、C2~C8酰亚胺基、硝基、巯基、C1~C8烷硫基、C1~C8酰硫基、磷酰氧基、磺酰氧基、亚磺酰氧基、脒基、胍基、羧基、膦酸基、磺酸基、亚磺酸基、氰基、卤素的基团,其中卤素指氟、氯、溴或碘。
2.如权利要求1所述的式I化合物,其特征在于,优选Ar为可被取代的苯环,其取代基可以为一个或多个独立地选自氢, C1~C8烷基或C3~C8环烷基、羟基、C1~C8烷氧基、C1~C8酰氧基、C1~C8酰基、氨基、C1~C8烷基胺基、C1~C8酰胺基、C2~C8烷基酰亚胺基、硝基、巯基、卤素、磷酰氧基、磺酰氧基、亚磺酰氧基、脒基、胍基、羧基、膦酸基、磺酸基、亚磺酸基、氰基的基团,以上卤素均指氟、氯、溴或碘。
3.如权利要求2所述的式I化合物,其特征在于,m、n各自独立的为0或1,优选n或m其一为0,更优选n和m均为0。
4.如权利要求3所述的式I化合物,其特征在于,R2、R3相同或不同,各自独立地选自氢、卤素、烷基、芳基、羟基、烷氧基、硝基、巯基、杂环烷基、杂芳基、氰基、环烷基、增溶性基团、-NRR’、-烷基-NRR’的一种或更多种基团取代的杂环基;-NR-CO-R’、-烷基-NR-CO-R’、-CONRR’和SO2NRR’基团;其中,R和R’各自独立地选自氢、烷基、环烷基、芳基、杂环烷基和杂芳基基团;其中卤素指氟、氯、溴或碘。
5.如权利要求4所述的式I化合物,其特征在于,优选R2、R3其一为羟基,更优选R2、R3均为羟基。
6.权利要求1-5任一项的化合物在制备用于治疗肿瘤疾病的药物中的用途。
7.权利要求6的用途,其中被治疗的疾病包括但不限于结直肠癌、胃肠间质瘤、组织细胞性淋巴瘤、胰腺癌、肝癌、胃癌、乳腺癌、卵巢癌、舌鳞状细胞癌、恶性胶质瘤、非小细胞肺癌、小细胞肺癌、肺鳞癌、肺腺癌、肝外胆管癌、前列腺癌、喉癌、肾癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、口腔癌、白血病等。
8.药物组合物,其包含治疗有效量的权利要求1-5任一项的化合物、药物载体、稀释剂或赋型剂。
9.根据权利要求8的药物组合物,用于治疗肿瘤疾病。
10.根据权利要求9的药物组合物,所述肿瘤疾病包括但不限于结直肠癌、胃肠间质瘤、组织细胞性淋巴瘤、胰腺癌、肝癌、胃癌、乳腺癌、卵巢癌、舌鳞状细胞癌、恶性胶质瘤、非小细胞肺癌、小细胞肺癌、肺鳞癌、肺腺癌、肝外胆管癌、前列腺癌、喉癌、肾癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、口腔癌、白血病等。
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WO2022063351A1 (en) | 2020-09-22 | 2022-03-31 | Univerzita Karlova | Azulene hydrazide-hydrazones and their use in the treatment of oncologic diseases |
CN114805588A (zh) * | 2022-06-11 | 2022-07-29 | 北京大学 | 一种己糖激酶2(hk2)乙酰化位点特异性抗体及其制备方法和用途 |
CN116640123A (zh) * | 2022-02-15 | 2023-08-25 | 沈阳药科大学 | 诱导hk2蛋白降解的双功能分子化合物及其合成和用途 |
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WO2022063351A1 (en) | 2020-09-22 | 2022-03-31 | Univerzita Karlova | Azulene hydrazide-hydrazones and their use in the treatment of oncologic diseases |
CZ309818B6 (cs) * | 2020-09-22 | 2023-11-08 | Univerzita Karlova | Azulenové hydrazido-hydrazony a jejich použití k léčbě onkologických onemocnění |
CN116640123A (zh) * | 2022-02-15 | 2023-08-25 | 沈阳药科大学 | 诱导hk2蛋白降解的双功能分子化合物及其合成和用途 |
CN114805588A (zh) * | 2022-06-11 | 2022-07-29 | 北京大学 | 一种己糖激酶2(hk2)乙酰化位点特异性抗体及其制备方法和用途 |
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