CN114502530A - 抑制组蛋白乙酰转移酶p300的新型化合物及其抗纤维化组合物 - Google Patents
抑制组蛋白乙酰转移酶p300的新型化合物及其抗纤维化组合物 Download PDFInfo
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Abstract
本发明涉及一种新型化合物,通过对HAT p300的结构分析,所述化合物能够与组蛋白乙酰转移酶(HAT)p300的特定氨基酸位置形成额外的氢键。本发明的新型化合物对HAT p300活性具有优异的抑制作用,因此可以非常有效地用于预防、改善或治疗与HAT p300活化相关的纤维化疾病。
Description
技术领域
本发明涉及一种用于抑制组蛋白乙酰转移酶p300的新化合物;一种包含该新化合物的抗纤维化组合物;及其各种用途。
背景技术
组织与细胞外基质结合,包括被血管网络包围的高度组织化的细胞群。纤维化或纤维离析是由损伤或炎症引起的胶原基质异常积累的过程,从而引起各种组织的结构和功能变化。在纤维化的情况下,大多数病因属于取代正常组织的纤维***(例如胶原蛋白基质)的过度积累,而与纤维化发生的部位无关。肾脏、肝脏、脂肪、肺、心脏、骨骼或骨髓、皮肤等的进行性纤维化是死亡或疼痛的主要原因。
特别是,在纤维化的类型中,肺纤维化是指在肺部发展的纤维化,它是指一种疾病,其诱导组织纤维化导致肺组织的严重结构变化,同时使慢性炎症细胞浸润到肺组织的肺泡壁中。当引起纤维化的任意因素导致纤维化进行时,肺组织***,肺泡壁变厚,从而减少了通过血液的氧气供应量,这使得患者呼吸困难。近年来,在医学领域,还没有能够完全恢复纤维化已经进展的肺组织的治疗方法。因此,除非在进展的早期或没有任何肺移植的情况下发现纤维化,否则纤维化症状会发展,并最终导致患者在3至5年内死亡。
在纤维化进展早期发现的治疗肺纤维化的方法包括使用类固醇类药物如类固醇、硫唑嘌呤、环磷酰胺的治疗方法;使用抗氧化剂如乙酰半胱氨酸的治疗方法;以及涉及施用生长因子如细胞因子、干扰素-γ(IFN-γ)的治疗方法等。虽然使用类固醇药物和抗氧化剂的治疗方法已经自2000年起被持续研究和报道,但目前还没有明确证明其疗效的药物。据报道,当前可用的药物在长时间给药时会引起全身副作用或引起诸如耐药性等副作用。作为最近受到广泛关注的治疗方法,涉及施用生长因子的治疗方法是相对基本的治疗方法,其使用“干扰素”抑制被称为肺纤维化的重要因子的转化生长因子-β(TGF-β)的产生。由于这种治疗方法是基于对本疾病病因的分析,与使用基于类固醇的药物或抗氧化剂的治疗方法相比,该方法副作用较少且疗效优越,因此使用注射剂、气溶胶等的各种类型的治疗方法已被报道。然而,由于到目前为止尚不清楚肺纤维化的确切原因,单一剂组分(例如干扰素等)可能具有暂时的治疗作用,并且可能仅在某些患者中有效。因此,需要进行持续的研究和临床试验。
蛋白质翻译后修饰作为一个调节多种蛋白质(包括在转录中起直接作用的转录因子)功能的机制,根据这一需要,进行了蛋白质翻译后修饰的相关成分的研究,例如组蛋白乙酰化,其在构成蛋白质的基本单元的氨基酸中的赖氨酸残基的控制下对例如蛋白质的表达等的现象有影响。然而,对具有优异效果的物质的研究仍然不足。
发明详述
技术问题
本发明的目的是提供一种能够抑制组蛋白乙酰转移酶(HAT)p300的新型化合物。
本发明还涉及提供一种用于预防、改善或治疗与HAT p300相关的疾病的组合物,其包括所述的抑制HAT p300的新型化合物。
本发明还涉及提供一种使用抑制HAT p300的新型化合物预防、改善或治疗与HATp300相关的疾病的方法。
然而,本发明要解决的技术问题不限于上述问题,本领域普通技术人员将从以下描述中充分理解在此未描述的其他问题。
技术方案
根据本发明的一个实施方式,提供了一种化合物,所述化合物选自下式1所示的化合物及其药学上可接受的盐、光学异构体、水合物和溶剂化物:
[式1]
其中:
p和q各自独立地为1到5的整数;
r为从1到4的整数;
m和n各自独立地为从1到3的整数,前提是m+n不大于4;
R1为氨基甲酰基(-C(=O)(NH2))或卤素,其中当R1以复数形式存在时,它们彼此相同或不同;
R2和R3各组独立地为C1-C6烷氧基或卤素,其中当每个R2和R3以复数形式存在时,它们彼此相同或不同;和
R4包括选自由C1-C6烷氧基、胺基(-NH2)、氨基甲酰基和羟基(-OH)组成的组中的任意一个,其中当R4以复数形式存在时,它们彼此相同或不同。
除非在本发明中另有说明,否则术语“卤素”是指氟、氯、溴或碘,除非另有说明。
除非在本发明中另有说明,术语“烷氧基”是指与氧连接的烷基,并且可以包括例如甲氧基、乙氧基等,但是本发明不限于此。
在本发明中,术语“烷基”是指直链或支链的饱和单价烃基。在这种情况下,所述烷基可以任选地被一个或多个如本发明所述的取代基取代。烷基的示例可以包括甲基、乙基、丙基(包括其所有类型的异构体)、正丙基、异丙基、丁基(包括其所有类型的异构体)、正丁基、异丁基、仲丁基、叔丁基、戊基(包括其所有类型的异构体)、和己基(包括其所有类型的异构体),但本发明不限于此。
在本发明中,所述“药学上可接受的盐”应该对人体具有低毒性,并且对母体化合物的生物学活性和理化性质没有不利影响。药学上可接受的游离酸和式1的碱性化合物的酸加成盐可用作药学上可接受的盐,但本发明不限于此。
根据本发明化合物的优选的盐的类型可以包括具有无机酸或有机酸的盐。在这种情况下,盐酸、硫酸、硝酸、磷酸、高氯酸、溴酸等可被用作无机酸。另外,乙酸、甲磺酸、乙磺酸、对甲苯磺酸、富马酸、马来酸、丙二酸、邻苯二甲酸、琥珀酸、乳酸、柠檬酸、葡萄糖酸、酒石酸、水杨酸、苹果酸、草酸、苯甲酸、扑酸(embonic acid)、天冬氨酸、谷氨酸等可被用作有机酸。可用于制备有机碱加成盐的有机碱包括三(羟甲基)甲胺、二环己胺等。可用于制备氨基酸加成盐的氨基酸包括天然氨基酸如丙氨酸、甘氨酸等。对于本领域普通技术人员来说显而易见的是,除了示例性的无机酸、有机酸、有机碱和氨基酸之外,还可以使用其它酸和碱。
本发明的盐可以使用常规方法制备。例如,本发明的盐可以通过以下方法制备:将上述式1的化合物溶解在可与水混合的溶剂中,例如甲醇、乙醇、丙酮、1,4-二恶烷等,向其添加游离酸或游离碱,并使所得混合物结晶。
在本发明中,因为“光学异构体”可以具有不对称的碳中心,所以从本发明的化合物获得的所有类型的光学异构体和混合物,如R或S异构体或外消旋化合物,都落在本发明的范围内。
在本发明中,所述化合物可以由下式2表示:
[式2]
其中:
每个R1,R2,R3,R4,和q如上述式1中所定义。
根据本发明的一个优选实施方式,p和q可以各自独立地为1至3的整数。优选地,p可以为1或2的整数,并且q可以为2至4的整数。
根据本发明的一个优选实施方式,r可以为1至3的整数,优选为1或2的整数。
根据本发明的一个优选实施方式,m和n可以各自独立地为1或2的整数。优选地,m和n都可以是1的整数。
根据本发明的一个优选实方式,R1可以是氨基甲酰基(-C(=O)(NH2))。
根据本发明的一个优选实施方式,R4可以是胺基(-NH2)、氨基甲酰基或羟基(-OH)。
本发明的化合物可以包括选自由以下化合物组成的组中的一种或多种,但本发明不限于此:
根据本发明的一个优选实施方式,所述化合物可以是以下化合物中的一种,但本发明不限于此:
与现有的组蛋白乙酰基转移酶抑制剂相比,本发明的化合物在抑制组蛋白乙酰基转移酶方面具有优异的效果,因为化合物的效果得到改善,使得可以与组蛋白乙酰基转移酶p300的R1410、T1411和W1466;或R1410和T1411形成额外的氢键。
根据本发明的另一个实施方式,提供了一种用于抑制组蛋白乙酰转移酶p300的化合物,其如式1所示。
在根据本发明的用于抑制HAT p300的化合物中,所述化合物、组蛋白乙酰基转移酶p300等如先前针对所述化合物所述,并且因此将省略其描述以避免说明书过于冗杂。
根据本发明的另一个实施方式,提供了一种用于预防、改善或治疗组蛋白乙酰基转移酶p300相关疾病的组合物。
本发明的组合物可以用作药物组合物、食品组合物或化妆品组合物。
本发明的组合物包含选自本发明式1所示的新化合物及其药学上可接受的盐、光学异构体、水合物和溶剂化物的化合物作为活性成分。据此,由于本发明的组合物包含有效抑制HAT p300的新型化合物作为活性成分,因此所述组合物可具有预防、改善或治疗患有组蛋白乙酰转移酶p300相关疾病(其中HAT p300的表达增加,例如纤维化)的患者。
在本发明的组合物中,与活性成分相对应的化合物如前所述,因此为了避免说明书过于冗杂,将省略其描述。
本发明的组蛋白乙酰基转移酶p300相关疾病可包括与疾病未发展的正常对照相比,当HAT p300的表达水平过度增加或HAT p300活性过度增加时发展的所有类型的疾病。
在本发明中,术语“纤维化”是指由成纤维细胞引发的细胞外基质异常产生、积累和沉积的疾病,并且可以包括所有类型器官的纤维化,只要胶原蛋白基质因损伤或炎症而异常积累,这可能导致各种组织的结构和功能变化。优选地,所述纤维化可以是选自由肾脏、肝脏、肺、心脏、骨或骨髓和皮肤组成的组中的至少一个器官中的纤维化,但本发明不限于此。出于本发明的目的,纤维化可以通过以下现象诱导,在该现象中,与转化生长因子-β(TGF-β)(其表达水平通过乙酰基转移酶p300增加)引起的纤维化相关的基因(例如胶原蛋白基因)的表达被促进,或纤维化可以通过在缺少能够从损伤中恢复细胞的酶(纤维化可以通过该损伤被诱导)的情况下来诱导,但是本发明不限于此。
本发明的纤维化可以包括选自下组的一种或多种:肺纤维化、子宫肌瘤、骨髓纤维化、肝纤维化、心脏纤维化、多发性硬化、肾脏纤维化、囊性纤维化、中性粒细胞减少症、骨骼肌纤维化、硬皮病、皮肌炎、纵隔纤维化、和由镰状细胞性贫血引起的脾纤维化,并且可以优选为肺纤维化,但是本发明不限于此。
在本发明中,术语“肺纤维化”是指由于肺中的纤维***的过度形成和发展(纤维化)而产生疤痕的(纤维状)组织发展过程。具体地,肺纤维化是一种慢性疾病,会导致肺泡和肺间质组织肿胀和疤痕。当健康组织被这样的疤痕组织取代时,可能会引起炎症。因此,慢性炎症可以被认为是纤维化的先兆。对肺组织的这种损害可能会使肺变得僵硬,并使受试者难以自发呼吸。
在本发明中,肺纤维化可包括特发性肺纤维化(Idiopathic PulmonaryFibrosis,IPF)、非特异性间质肺炎、急性间质肺炎、隐源性机化性肺炎、呼吸性细支气管炎相关间质性肺病、脱屑性间质肺炎、淋巴间质肺炎、间质性肺纤维化和弥漫性肺纤维化。优选地,所述肺纤维化可以是特发性肺纤维化,但本发明不限于此。
本发明的肺纤维化可由各种原因引起,例如,由吸入细颗粒(石棉、岩石粉尘、金属粉尘、存在于香烟烟雾中的颗粒、二氧化硅粉尘等)引起的肺部的微小损伤。此外,肺纤维化可由其他疾病(自身免疫性疾病,病毒或细菌感染等)的继发作用发展,并且也可由某些药物例如细胞毒性剂(博来霉素、白消安、甲氨蝶呤等);抗生素(呋喃妥因、柳氮磺吡啶等);抗心律失常剂(胺碘酮、托卡尼等);抗炎药(金、青霉胺等);和管制药物(麻醉品、***、***等)引起。此外,除上述原因外,特发性肺纤维化还可能由其他未知原因引起。
在本发明中,术语“预防”可以包括但不限于使用本发明的组合物阻断由组蛋白乙酰基转移酶p300相关疾病(例如纤维化)所引发的症状,或抑制或延缓其症状的所有类型的操作。
在本发明中,术语“治疗”可以包括但不限于使用本发明的组合物以改进或改善由组蛋白乙酰基转移酶p300相关疾病(例如纤维化)所引发的症状而执行的所有类型的操作。
在本发明中,术语“改善”可以包括但不限于使用本发明的组合物改进或改善由组蛋白乙酰基转移酶p300相关疾病(例如纤维化)所引发的症状的所有类型的操作。
本发明的药物组合物可以以口服制剂(如粉末、颗粒、胶囊、丸剂、水性混悬剂等)、外用制剂、栓剂、和根据常规方法的无菌注射溶液的形式配制和使用,但本发明不限于此。优选地,所述药物组合物可以配制成用于给药或吸入给药到所述器官中;或用作注射剂,但本发明不限于此。为了本发明的目的,所述药物组合物优选地被配制成用于吸入给药,使得当在呼吸***如肺中发生纤维化时,所述活性成分能够以合适的剂量到达靶器官以用于预防或治疗。
本发明的药物组合物可以包括药学上可接受的载体。在口服给药时,粘合剂、润滑剂、崩解剂、赋形剂、增溶剂、分散剂、稳定剂、悬浮剂、染色剂、调味剂等可以用作药学上可接受的载体。在注射的情况下,可以与缓冲剂、防腐剂、止痛剂、增溶剂、等渗剂、稳定剂等混合使用。对于局部给药,可以使用碱、赋形剂、润滑剂、防腐剂等。根据本发明的药物组合物的制剂可以与如上所述的药学上可接受的载体混合,然后制备成各种形式。例如,在口服给药时,所述制剂可以制备成例如药丸、药片、胶囊、丹药、悬浮液、糖浆、晶片等。对于注射,所述制剂可以制备成单位剂量安瓿或多剂型。此外,所述制剂可以制备成其它溶液、悬浮液、丸剂、胶囊、缓释制剂等。
同时,适用于本文可使用的制剂的载体、赋形剂和稀释剂的示例包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、***胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁、矿物油等。此外,所述药物组合物还可以包括填充剂、抗结块剂、润滑剂、润湿剂、调味剂、乳化剂、防腐剂等。
根据本发明的药物组合物的给药途径可以包括但不限于口服、静脉内、肌内、动脉内、髓内、鞘内、心内、透皮、皮下、腹膜内、鼻内、肠内、局部、舌下或直肠给药。优选口服或肠胃外给药。
在本发明中,术语“肠胃外”包括皮下、皮内、静脉内、肌内、关节内、囊内、胸骨内、鞘内、病灶内和颅内注射或输注。此外,本发明的药物组合物可以以用于直肠给药的栓剂的形式给药。
本发明的药物组合物可以根据各种因素而变化,包括所使用的特定化合物的活性、患者的年龄、体重、一般健康状况和性别、饮食、给药时间、给药途径、***率、药物制剂,以及要预防或治疗的某种疾病的严重程度,并且所述药物组合物的剂量可以根据患者的状况和体重、疾病的严重程度、药物的类型、给药途径和给药持续时间而变化,但是可以由本领域普通技术人员适当选择,并且可以以每天0.0001至50mg/kg或0.001至50mg/kg给药。本发明的药物组合物可以每天给药一次或分剂量给药数次。该剂量不旨在以任何方式限制本发明的范围。根据本发明的药物组合物可以配制成丸剂、糖衣片剂、胶囊、液体、凝胶、糖浆、浆液或悬浮液。
当本发明的食品组合物以饮料的形式制备时,所述食品组合物的使用没有特别限制,只要所述食品组合物以给定的比率包含在内。像传统饮料一样,所述食品组合物可以含有各种调味剂、天然碳水化合物等作为附加组分。具体地说,所述食品组合物可以包括单糖如葡萄糖等;双糖如果糖等;多糖如蔗糖等;常规糖如糊精、环糊精等;糖醇如木糖醇、山梨醇、赤藓糖醇等作为天然碳水化合物。所述食品组合物可以包括天然调味剂(奇异果甜蛋白、甜叶菊提取物(例如,莱鲍迪苷A(rebaudioside A)、甘草甜素等))、合成调味剂(糖精、阿斯巴甜等)等作为调味剂。
本发明的食品组合物还可以包括各种营养素、维生素、矿物质(电解质)、调味剂(包括合成调味剂和天然调味剂)、着色剂、果胶酸及其盐、藻酸及其盐、有机酸、潜在的胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、醇、用于碳酸饮料的碳酸化剂等。
包含在本发明的食品组合物中的组分可以单独使用或组合使用。添加剂的比例不是本发明的关键因素,但可以在0.1至约50重量份的范围内选择,基于本发明的食品组合物为100重量份,但本发明不限于此。
本发明的化妆品组合物可以制备成面部乳液、滋养乳液、滋养精华、按摩霜、美容沐浴添加剂、身体乳液、身体乳、沐浴油、婴儿油、婴儿爽身粉、沐浴凝胶、沐浴乳、隔离乳、隔离霜、防晒霜、润肤露、护肤霜、防晒化妆品、洁面乳、脱毛剂、面部和身体乳液、面部和身体霜、皮肤美白霜、护手霜、护发乳液、化妆霜、茉莉花油、沐浴皂、液体肥皂、美容皂、洗发水、洗手液(即洗手剂)、非药物香皂、奶油皂、洗面奶、全身清洁剂、头皮清洁剂、洗发液、香皂、牙齿美白凝胶、牙膏等。本发明的组合物还可以包括通常用于制备化妆品组合物的溶剂,或合适的载体、赋形剂或稀释剂。
例如,可以在本文中使用的本发明的化妆品组合物中进一步包括的溶剂的类型可以包括水、盐水、DMSO或其组合。此外,也可以包含纯化水、油、蜡、脂肪酸、脂肪酸醇、脂肪酸酯、表面活性剂、保湿剂、增稠剂、抗氧化剂、粘度稳定剂、螯合剂、缓冲剂、低级醇等作为载体、赋形剂或稀释剂,但本发明不限于此。此外,当有需要时,所述化妆品组合物可以包含增白剂、保湿剂、维生素、防晒霜、香料、染料、抗生素、抗菌剂、抗真菌剂等。
氢化植物油、蓖麻油、棉籽油、橄榄油、棕榈仁油、霍霍巴油、鳄梨油等可用作本发明的油,以及蜂蜡、鲸蜡、棕榈蜡、蜡大戟、褐煤蜡、地蜡、液体石蜡、羊毛脂、等可以用作蜡。
硬脂酸、亚油酸、亚麻酸、油酸等可以用作本发明的脂肪酸,鲸蜡醇、辛基十二烷醇、油醇、泛醇、羊毛脂醇、硬脂醇、十六(烷)醇等可以用作脂肪酸醇,肉豆蔻酸异丙酯、棕榈酸异丙酯、硬脂酸丁酯等可以用作脂肪酸酯。本领域已知的阳离子表面活性剂、阴离子表面活性剂和非离子表面活性剂可用作表面活性剂。在这种情况下,如果可能的话,优选来源于天然产物的表面活性剂。另外,所述化妆品组合物可以包括保湿剂、增稠剂、抗氧化剂等,这些在化妆品领域中是众所周知的。在这种情况下,保湿剂、增稠剂和抗氧化剂的类型和含量是相关领域中已知的。
根据本发明的又一个实施方式,提供了一种预防、改善或治疗组蛋白乙酰转移酶p300相关疾病的方法,其包括向目标受试者施用本发明的组合物。
在本发明中,所述组蛋白乙酰基转移酶p300相关疾病、预防、改善、治疗、化合物和组合物的一般内容如上所述,因此将省略其描述,以避免说明书过于冗杂。
在本发明中,术语“受试者”是疑似发生组蛋白乙酰基转移酶p300相关疾病的受试者。在这种情况下,疑似发生组蛋白乙酰基转移酶p300相关疾病的受试者是指哺乳动物(包括已经发展或可能发展相应疾病的人类),例如大鼠、家畜等。然而,所述受试者包括但不限于可以使用本发明的融合蛋白或包含所述融合蛋白的组合物治疗的受试者。
本发明的方法可以包括施用药学有效量的活性成分。合适的每日总剂量可以由医生在合理的医学判断范围内确定,一次性给药或分成几个剂量给药。然而,出于本发明的目的,特定患者的特定治疗有效量优选取决于各种因素,包括待完成的反应的类型和程度、特定组合物(包括是否可以任选地与另一种制剂一起使用)、患者的年龄、体重、一般健康状况、性别和饮食、给药时间、给药途径、组合物的分泌速率、治疗持续时间以及与所述特定组合物一起或同时使用的药物,以及在医学领域中公知的类似因素。
应当理解,本文使用的“组合”是指同时、单独或顺序给药。在顺序给药或单独给药的情况下,次要成分的给药间隔应使得组合疗法的有益效果不会丧失。
在本发明中,本发明的融合蛋白的给药剂量可以在大约0.0001μg-500mg每kg患者体重的范围内,但本发明不限于此。
有利效果
本发明涉及一种新型化合物,通过对HAT p300的结构分析,所述化合物能够与组蛋白乙酰转移酶(HAT)p300的特定氨基酸位置形成额外的氢键。本发明的新型化合物对HATp300活性具有优异的抑制作用,因此可以非常有效地用于预防、改善或治疗与HAT p300活化相关的疾病,例如纤维化。
附图说明
图1至图3显示了根据本发明的一个实施方式,通过免疫组织化学染色确认在来自患有特发性肺纤维化的患者的组织中的组蛋白乙酰基转移酶(HAT)蛋白(即p300(组蛋白乙酰转移酶p300;图1),GCN5(组蛋白乙酰转移酶GCN5;图2)和PCAF(P300/CBP相关因子;图3)的表达水平的结果。
图4显示了根据本发明的一个实施方式,确认PCAF抑制剂的候选物1至67、HAT-24、HAT-26和HAT-28的HAT活性抑制程度的结果。
图5显示了根据本发明的一个实施方式,确认候选物1至14的HAT活性抑制程度的结果。
图6显示了根据本发明的一个实施方式,使用分子对接模拟的HAT p300结构域和底物抑制剂的Lys-CoA分子模型。
图7显示了根据本发明的一个实施方式,使用分子对接模拟来分析参与形成HATp300结构域与底物抑制剂之间的分子间键的主要残基的结果。
图8显示了根据本发明的一个实施方式,使用分子对接模拟分析参与形成候选物12和HAT p300结构域之间的键的主要残基的结果。
图9显示了根据本发明的一个实施方式,确认合成实施例1至19(A1至A19)的组蛋白乙酰基转移酶活性抑制程度的结果。
图10显示了根据本发明的一个实施方式,确认合成实施例6和9(A25和A27)的组蛋白乙酰基转移酶活性抑制程度的结果。
图11A至图11C显示了根据本发明的一个实施方式,使用分子对接模拟来分析参与形成合成实施例6和8(A25和A27)与HAT p300结构域之间的键的主要残基的结果。
[最佳方式]
根据本发明的一个实施方式,提供了一种化合物,所述化合物选自下式1所示的化合物及其药学上可接受的盐、光学异构体、水合物和溶剂化物:
[式1]
其中,p和q各自独立地为1至5的整数;r为1至4的整数;m和n各自独立地为1至3的整数,前提是m+n不大于4;R1为氨基甲酰基(-C(=O)(NH2))或卤素,其中当R1以复数形式存在时,它们彼此相同或不同;R2和R3各自独立地为C1-C6烷氧基或卤素,其中当每个R2和R3以复数形式存在时,它们彼此相同或不同;以及R4包括选自下组的任何一个:C1-C6烷氧基、胺基(-NH2)、氨基甲酰基和羟基(-OH),其中当R4以复数形式存在时,它们彼此相同或不同。
根据本发明的另一个实施方式,提供了一种用于预防、改善或治疗HAT p300相关疾病的组合物,其包括选自式1所示的化合物、及其药学上可接受的盐、光学异构体、水合物和溶剂化物的化合物作为活性成分。
根据本发明的又一个实施方式,提供了一种预防、改善或治疗HAT p300相关疾病的方法,其包括选自式1所示的化合物、及其药学上可接受的盐、光学异构体、水合物和溶剂化物的化合物作为活性成分。
本发明的实施方式
在下文中,将参照以下实施例对本发明进行详细说明。对于本领域技术人员来说显而易见的是,以下实施例仅是为了举例说明本发明,而不旨在不脱离本发明的范围的情况下限制本发明的范围。
实施例
[实施例1]纤维化患者组织中蛋白质表达水平的确认
将从特发性肺纤维化患者或正常人获得的组织固定在10%***中,并包埋在石蜡中,并将7μm厚的切片附接到载玻片上。然后,使用二甲苯将切片脱蜡,并用高浓度至低浓度的乙醇处理。然后,使用HAT p300(组蛋白乙酰基转移酶p300)、GCN5(组蛋白乙酰基转移酶GCN5)和PCAF(P300/CBP相关因子)的特异性抗体进行免疫染色,并使用光学显微镜测定每种蛋白质的表达水平。结果如图1至3所示。
如图1至3所示,证实在组蛋白乙酰基转移酶(以下称为“HAT”)p300、GCN5和PCAF中,与从正常人获得的组织相比,来自特发性肺纤维化患者的组织中的p300的表达增加。
根据结果,可以看出,当p300的表达或功能被特异性抑制时,纤维化能够得到有效治疗,因为与正常组织相比,特别是组蛋白乙酰基转移酶中的p300在纤维化如特发性肺纤维化中以高水平存在。
[实施例2]p300活性抑制剂的筛选
[2-1]初筛
候选物1至67是基于PCAF结构制造的HAT抑制剂,HAT-24、HAT-26和HAT-28被稀释至100μM,然后根据制造商提供的方法使用测量HAT活性的试剂盒(Biovision,货号K332,美国)测定p300的HAT活性抑制程度(抑制活性)。结果如图4所示。此处,用C646(HAT抑制剂)作为阳性对照处理组织。
如图4所示,候选物1至14抑制了80%的HAT活性,但是候选物15至67、HAT-25、HAT-26和HAT-28仅具有20%至50%的HAT活性抑制作用。
[2-2]复筛
将在[2-1]节中具有良好的HAT活性抑制效果的候选物1至14稀释至0.5μM、1μM、10μM和100μM的浓度。此后,以与[2-1]节相同的方式测定对HAT活性的抑制程度。结果如图5和表1所示。
[表1]
如图5和表1所示,已确认在候选物1至14中,候选物12(HAT-12)的IC50为0.953。
[实施例3]候选物12的结构分析
为了通过分子对接模拟获得有关候选物的构效关系的信息,使用HAT p300结构域及其底物抑制剂Lys-CoA的共晶结构(pdb:3biy)建立了分子模型。最后将Lys-CoA重新对接到由此建立的分子模型中,并比较了共晶结构。结果,确认候选物具有类似的结合模式。根据结果,评估了对接结果的准确性(图6),分析了参与HAT p300结构域与Lys-CoA之间结合的主要残基(图7),并用候选物12(HAT-12)进行分子对接模拟(图8)。
如图6所示,证实了HAT p300结构域-配体(Lys-CoA)的预测结合模式与共晶结构之间存在高度相似性。
如图7所示,证实了当分析参与Lys-CoA和HAT p300结构域之间结合的主要残基时,在R1410、T1411、W1466、Y1467、L1398、S1400、I 1457、W1436和Y1397处观察到氢键。其中,与R1410,T1411,W1466和Y1467的相互作用对于药物抑制活性很重要。特别是,可以看出W1466在药物抑制活性中起着关键作用(参见例如Erin M.Bowers等人,p300/CBP组蛋白乙酰基转移酶的虚拟配体筛选:一种选择性小分子抑制剂的鉴定,Chem Biol.2010年5月28日;17(5):471-82)。
如图8所示,证实了当分析参与候选物12与HAT p300结构域之间结合的主要残基时,未观察到与R1410、T1411、W1466和Y1467的相互作用,但与L1398和S1400形成氢键。
从上述结果可以预测,L1398和S1400在药物抑制活性中也起着重要作用。此外,可以看出,当与R1410、T1411、W1466和Y1467发生额外的氢键结合时,HAT p300的抑制活性进一步增强。
基于这些结果,制备如下所述具有上述特性的合成例1至24(A20至A43)以进一步增强HAT p300抑制活性。
[合成例1至24]抑制组蛋白乙酰基转移酶p300的新型化合物的制备
[方案1]
[合成方法1]化合物1至17
取代的4-羟基苯甲醛(1当量)及其相应的取代的苄基氯(1当量),和K2CO3(1当量)在DMF溶剂中于80℃反应1小时。将反应混合物冷却至室温,并使用乙酸乙酯萃取。提取物用水,NaHCO3,和卤水洗涤,然后用MgSO4干燥。之后,在减压下完全除去溶剂,然后进行硅胶色谱以获得O-苄基化化合物的化合物1-17(参见表2)。
[表2]
[化合物1]3-氯-4-(3-氯苄氧基)-5-甲氧基苯甲醛
使用5-氯香草醛(1.00g,5.36mmol)和3-氯苄基氯(0.70g,5.36mmol)获得化合物1,为象牙色固体(1.50g,96.5%)。
Rf 0.54(乙酸乙酯:正己烷=1:3);1H-NMR(CDCl3,400MHz)δ3.95(s,3H),5.13(s,2H),7.30-7.32(m,2H),7.36(d,J=2.0Hz,1H),7.37-7.39(m,1H),7.51(d,J=2.0Hz,1H),7.53-7.54(m,1H),9.86(s,1H);13C-NMR(CDCl3,100MHz)56.5,74.3,109.6,125.9,126.4,128.5,128.6,129.4,129.9,132.9,134.5,138.7,149.4,154.5,190.1ppm。
[化合物2]3-溴-4-(3-氯苄氧基)-5-甲氧基苯甲醛
使用5-溴苯胺(1.00g,4.33mmol)和3-氯苄基氯(0.58g,5.36mmol)获得化合物2,为象牙色固体(1.50g,96.5%)。
Rf 0.65(乙酸乙酯:正己烷=1:3);1H-NMR(CDCl3,400MHz)δ3.94(s,3H),5.12(s,2H),7.30-7.32(m,2H),7.38(dd,J=8.4,1.2Hz,1H),7.40(d,J=2.0Hz,1H),7.54-7.56(m,1H),7.66(d,J=2.0Hz,1H),9.85(s,1H);13C-NMR(CDCl3,100MHz)56.5,74.2,110.3,118.5,126.5,128.6,129.0,129.9,133.5,134.5,138.7,150.4,154.4,190.0ppm。
[化合物3]4-((3-氯苄基)氧基)-3-碘-5-甲氧基苯甲醛
使用5-碘香草醛(1.00g,3.60mmol)和3-氯苄基氯(0.58g,5.36mmol)获得化合物3,为象牙色固体(1.423g,98.1%)。
Rf 0.67(乙酸乙酯:正己烷=1:3);1H-NMR(CDCl3,400MHz)δ3.94(s,3H),5.10(s,2H),7.31-7.33(m,2H),7.41(dd,J=8.4,1.2Hz,1H),.7.43(d,J=1.6Hz,1H),7.57-7.58(m,1H),7.87(d,J=1.6Hz,1H),9.84(s,1H);13C-NMR(CDCl3,100MHz)56.4,74.0,92.8,111.2,126.6,128.7,128.8,129.9,134.4,134.5,135.1,138.7,152.9,153.2,189.9ppm。
[化合物4]3-((2-氯-4-甲酰基-6-甲氧基苯氧基)甲基)苯甲酸乙酯
使用5-氯香草醛(1.00g,5.36mmol)和3-(氯甲基)苯甲酸乙酯(1.06g,5.36mmol)得到化合物4,为黄色固体(1.18g,63.1%)。
Rf 0.39(乙酸乙酯:正己烷=1:3);1H-NMR(CDCl3,400MHz)δ1.41(t,J=7.2Hz,3H),3.95(s,3H),4.39(q,J=7.2Hz,2H),5.21(s,2H),7.30(ddd,J=7.6,1.2,1.2Hz,1H),7.36(d,J=1.6Hz,1H),7.46(dd,J=7.6,7.6Hz,1H),7.50(d,J=2.0Hz,1H),8.02(ddd,J=7.6,1.2,1.2Hz,1H),8.18(dd,J=1.2,1.2Hz,1H),9.85(s,1H);13C-NMR(CDCl3,100MHz)14.6,56.5,61.3,74.7,109.6,126.0,128.7,129.4,129.6,129.7,130.9,132.8,132.9,137.1,149.5,154.6,166.6,190.2ppm。
[化合物5]3-((2-溴-4-甲酰基-6-甲氧基苯氧基)甲基)苯甲酸乙酯
使用5-溴香草醛(1.00g,4.33mmol)和3-(氯甲基)苯甲酸乙酯(0.86g,4.33mmol)得到化合物5,为淡黄色固体(1.53g,90.1%)。
Rf 0.35(乙酸乙酯:正己烷=1:3);1H-NMR(CDCl3,400MHz)δ1.41(t,J=7.2Hz,3H),3.95(s,3H),4.39(q,J=7.2Hz,2H),5.21(s,2H),7.40(d,J=2.0Hz,1H),7.46(dd,J=7.6,7.6Hz,1H),7.66(d,J=2.0Hz,1H),7.75(ddd,J=7.6,1.2,1.2Hz,1H),8.02(ddd,J=7.6,1.2,1.2Hz,1H),8.19(dd,J=1.2,1.2Hz,1H),9.85(s,1H);13C-NMR(CDCl3,100MHz)14.6,56.5,61.3,74.6,110.3,118.6,128.7,129.0,129.7,130.9,133.0,133.4,137.1,150.6,154.4,166.6,190.0ppm。
[化合物6]3-((4-甲酰基-2-碘-6-甲氧基苯氧基)甲基)苯甲酸乙酯
使用5-碘香草醛(1.00g,3.60mmol)和3-(氯甲基)苯甲酸乙酯(0.71g,3.60mmol)得到化合物6,为淡黄色固体(1.41g,88.8%)。
Rf 0.39(乙酸乙酯:正己烷=1:3);1H-NMR(CDCl3,400MHz)δ1.41(t,J=7.2Hz,3H),3.95(s,3H),4.39(q,J=7.2Hz,2H),5.21(s,2H),7.43(d,J=1.6Hz,1H),7.47(dd,J=7.6,7.6Hz,1H),7.78(ddd,J=7.6,1.2,1.2Hz,1H),7.86(d,J=1.6Hz,1H),8.02(ddd,J=7.6,1.2,1.2Hz,1H),8.22(dd,J=1.6,1.6Hz,1H),9.83(s,1H);13C-NMR(CDCl3,100MHz)14.6,56.3,61.3,74.4,92.8,111.2,128.7,129.7,129.8,130.9,133.1,134.3,135.1,137.1,152.9,153.2,166.6,189.9ppm。
[化合物7]3-((2-氯-4-甲酰基-6-甲氧基苯氧基)甲基)苄腈
使用5-氯香草醛(1.00g,5.36mmol)和3-(溴甲基)苄腈乙酯(1.05g,5.36mmol)得到化合物7,为白色固体(1.30g,80.5%)。
Rf 0.25(乙酸乙酯:正己烷=1:3);1H-NMR(CDCl3,400MHz)δ3.96(s,3H),5.17(s,2H),7.38(d,J=2.0Hz,1H),7.50(dd,J=7.6,7.6Hz,1H),7.52(d,J=2.0Hz,1H),7.64(ddd,J=7.6,1.6,1.6Hz,1H),7.75(ddd,J=7.6,1.6,1.6Hz,1H),7.84(dd,J=1.6,1.2Hz,1H),9.87(s,1H);13C-NMR(CDCl3,100MHz)56.6,73.8,109.6,112.8,118.9,126.0,129.4,129.5,131.8,132.1,132.5,133.1,138.4,149.1,154.5,190.1ppm。
[化合物8]3-((2-溴-4-甲酰基-6-甲氧基苯氧基)甲基)苄腈
使用5-溴香草醛(1.00g,4.33mmol)和3-(溴甲基)苄腈乙酯(0.85g,4.33mmol)得到化合物8,为白色固体(1.53g,83.8%)。
Rf 0.24(乙酸乙酯:正己烷=1:3);1H-NMR(CDCl3,400MHz)δ3.95(s,3H),5.16(s,2H),7.42(d,J=2.0Hz,1H),7.50(dd,J=8.0,7.6Hz,1H),7.64(ddd,J=7.6,2.0 1.6Hz,1H),7.67(d,J=1.6Hz,1H),7.70(ddd,J=8.0,1.6,1.2Hz,1H),7.86(dd,J=1.6,1.6Hz,1H),9.86(s,1H);13C-NMR(CDCl3,100MHz)56.5,73.6,110.3,112.8,118.5,118.9,129.0,129.5,131.9,132.1,132.6,133.7,138.4,150.1,154.3,189.9ppm。
[化合物9]3-((4-甲酰基-2-碘-6-甲氧基苯氧基)甲基)苄腈
使用5-碘香草醛(1.00g,3.60mmol)和3-(溴甲基)苄腈乙酯(0.71g,3.60mmol)得到化合物9,为白色固体(1.20g,84.4%)。
Rf 0.27(乙酸乙酯:正己烷=1:3);1H-NMR(CDCl3,400MHz)δ3.95(s,3H),5.15(s,2H),7.44(d,J=2.0Hz,1H),7.51(dd,J=8.0,7.6Hz,1H),7.65(ddd,J=7.6,1.6,1.2Hz,1H),7.78(ddd,J=7.6,1.6,1.2Hz,1H),7.88(d,J=2.0Hz,1H),7.89(dd,J=1.6,1.2Hz,1H),9.85(s,1H);13C-NMR(CDCl3,100MHz)56.4,73.4,92.7,111.3,112.8,118.9,129.5,132.0,132.1,132.7,134.6,135.0,138.3,152.5,153.2,189.8ppm。
[化合物10]3-氯-4-((3-氟苄基)氧基)-5-甲氧基苯甲醛
使用5-氯香草醛(1.00g,5.36mmol)和3-氟苄基氯乙酯(0.78g,5.36mmol)得到化合物10,为白色固体(1.15g,72.8%)。
Rf 0.58(乙酸乙酯:正己烷=1:3);1H-NMR(CDCl3,400MHz)δ3.95(s,3H),5.15(s,2H),7.00-7.05(m,1H),7.24-7.28(m,2H),7.34(dd,J=8.0,2.0Hz,1H),7.37(d,J=2.0Hz,1H),7.51(d,J=2.0Hz,1H),9.85(s,1H);13C-NMR(CDCl3,100MHz)56.5,74.4,109.7,115.3,115.5,123.8,126.0,130.1,132.9,139.3,149.5,154.6,161.8,164.3,190.2ppm。
[化合物11]4-((3-氯苄基)氧基)-3-甲氧基苯甲醛
使用香草醛(1.00g,6.57mmol)和3-甲氧基苄基氯(1.03g,6.57mmol)得到化合物11,为黄色半固体(1.48g,99.6%)。
Rf 0.45(乙酸乙酯:正己烷=1:3);1H-NMR(CDCl3,400MHz)δ3.95(s,3H),5.19(s,2H),6.95(d,J=8.4Hz,1H),7.29-7.32(m,3H),7.39(dd,J=8.0,1.6Hz,1H),7.43-7.44(m,2H),9.84(s,1H);13C-NMR(CDCl3,100MHz)56.2,70.2,109.7,112.6,125.4,126.6,127.4,128.6,130.2,130.7,134.8,138.3,150.3,153.4,191.0ppm。
[化合物12]4-((2-氯-4-甲酰基-6-甲氧基苯氧基)甲基)苯甲酰胺
使用5-氯香草醛(0.18g,0.96mmol)和4-(氯甲基)苯甲酰胺(0.16g,0.96mmol)得到化合物12,为白色固体(0.22g,73.2%)。
Rf 0.25(乙酸乙酯:正己烷=1:1);1H-NMR(400MHz,DMSO-d6)δ3.88(s,3H),5.12(s,2H),7.29(d,J=1.6Hz,1H),7.44(d,J=2.0Hz,1H),7.48(d,J=8.0Hz,2H),7.83(d,J=8.0Hz,2H),9.78(s,1H);13C-NMR(400MHz,DMSO-d6)55.2,73.7,109.5,124.5,127.2,127.4,128.3,132.0,133.2,139.4,148.4,153.7,168.4,189.4ppm。
[化合物13]4-((2-溴-4-甲酰基-6-甲氧基苯氧基)甲基)苯甲酰胺
使用5-溴香草醛(0.18g,0.79mmol)和4-(氯甲基)苯甲酰胺(0.13g,0.79mmol)得到化合物13,为白色固体(0.20g,73.2%)。
Rf 0.16(乙酸乙酯:正己烷=1:1);1H-NMR(400MHz,DMSO-d6)δ3.88(s,3H),5.11(s,2H),7.34(d,J=2.0Hz,1H),7.50(d,J=8.4Hz,2H),7.60(d,J=1.6Hz,1H),7.83(d,J=8.4Hz,2H),9.78(s,1H);13C-NMR(400MHz,DMSO-d6)55.7,73.6,100.1,117.6,127.2,127.4,127.5,132.6,133.2,139.4,149.5,153.5,168.4,189.3ppm。
[化合物14]4-((4-甲酰基-2-碘-6-甲氧基苯氧基)甲基)苯甲酰胺
使用5-碘香草醛(0.26g,0.94mmol)和4-(氯甲基)苯甲酰胺(0.16g,0.94mmol)得到化合物14,为白色固体(0.28g,72.4%)。
Rf 0.10(乙酸乙酯:正己烷=1:1);1H-NMR(400MHz,DMSO-d6)δ3.87(s,3H),5.10(s,2H),7.36(d,J=2.0Hz,1H),7.53(d,J=8.0Hz,2H),7.79(d,J=1.6Hz,1H),7.83(d,J=8.4Hz,2H),9.76(s,1H);13C-NMR(400MHz,DMSO-d6)55.6,73.4,92.1,111.0,127.2,127.6,133.1,133.5,133.6,139.4,151.9,152.3,168.4,189.1ppm。
[化合物15]3-((2-氯-4-甲酰基-6-甲氧基苯氧基)甲基)苯甲酰胺
使用5-氯香草醛(0.40g,2.14mmol)和3-(氯甲基)苯甲酰胺(0.36g,2.14mmol)得到化合物15,为白色固体(0.32g,45.0%)。
Rf 0.10(乙酸乙酯:正己烷=1:1);1H-NMR(CDCl3,400MHz)δ3.88(s,3H),5.11(s,2H),7.30(d,J=2.0Hz,1H),7.37(dd,J=7.6,7.6Hz,1H),7.44(d,J=2.0Hz,1H),7.59(d,J=8.0Hz,1H),7.77(ddd,J=7.6,1.6,1.2Hz,1H),794(dd,J=1.6,1.6Hz,1H),9.78(s,1H););13C-NMR(400MHz,DMSO-d6)56.4,74.1,110.9,124.1,127.2,127.6,127.9,128.2,131.1,132.6,134.4,136.6,148.2,154.0,167.6,191.1ppm。
[化合物16]3-((2-溴-4-甲酰基-6-甲氧基苯氧基)甲基)苯甲酰胺
使用5-溴香草醛(0.18g,0.79mmol)和3-(氯甲基)苯甲酰胺(0.13g,0.79mmol)得到化合物16,为白色固体(0.20g,73.2%)。
Rf 0.16(乙酸乙酯:正己烷=1:1);1H-NMR(DMSO-d6,400MHz)δ3.88(s,3H),5.10(s,2H),7.34(d,J=2.0Hz,1H),7.38(dd,J=8.0,8.0Hz,1H),7.60(d,J=2.0Hz,1H),7.62(ddd,J=7.6,1.2,1.2Hz 1H),7.78(ddd,J=7.6,1.2,1.2Hz 1H),7.96(dd,J=1.2,1.2Hz,1H),9.78(s,1H);13C-NMR(400MHz,DMSO-d6)55.7,73.8,110.0,117.7,126.9,127.2,127.6,127.9,131.0,132.6,133.5,136.3,149.5,153.6,168.5,189.3ppm。
[化合物17]3-((4-甲酰基-2-碘-6-甲氧基苯氧基)甲基)苯甲酰胺
使用5-碘香草醛(0.26g,0.94mmol)和3-(氯甲基)苯甲酰胺(0.16g,0.94mmol)得到化合物17,为白色固体(0.28g,72.4%)。
Rf 0.10(乙酸乙酯:正己烷=1:1);1H-NMR(DMSO-d6,400MHz)δ3.88(s,3H),5.09(s,2H),7.36(d,J=2.0Hz,1H),7.38(dd,J=8.0,8.0Hz,1H),7.65(ddd,J=7.6,1.6,1.6Hz1H),7.78(ddd,J=7.6,1.2,1.2,Hz 1H),7.79(d,J=2.0Hz,1H),7.98(dd,J=1.6,1.6Hz,1H),9.76(s,1H);13C-NMR(400MHz,DMSO-d6)55.6,73.6,92.2,111.0,126.9,127.3,127.8,131.1,133.5,113.6,133.7,136.2,151.9,152.4,168.5,189.1ppm。
[合成方法2]合成例1至24(A20至A43)
[方案2]
使用10mL乙醇作为溶剂,将取代的O-苄基化苯甲醛衍生物与苯乙酮衍生物混合,并向其中添加50%NaOH(2.0至5.0当量)。此后,将混合物在室温下搅拌24小时,并进一步向其中加入水。然后,使用乙酸乙酯萃取混合物,并用水,NaHCO3,和卤水洗涤提取物,然后用MgSO4干燥。之后,在减压下完全除去溶剂,然后进行硅胶色谱,从而获得合成例1至24(参见表3)。
[表3]
[合成例1](E)-3-((4-(3-氨基苯基)-3-氧代丙基-1-烯-1-基)-2-氯-6-甲氧基苯氧基)甲基)苯甲酰胺(A20)
使用化合物15(200mg,0.63mmol)和3-氨基苯乙酮(85mg,0.63mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:乙酸乙酯:二氯甲烷=4:1),从而获得合成例1(A20),为黄色固体(78mg,28.6%)。
Rf 0.42(乙酸乙酯:二氯甲烷=4:1);1H-NMR(400MHz,DMSO-d6)δ3.95(s,3H),5.11(s,2H),5.36(s,2H),6.86(ddd,J=7.6,2.0,0.8Hz,1H),7.21(dd,J=8.0,7.6Hz,1H),7.27(dd,J=2.0,2.0Hz,1H),7.37-7.39(m,2H),7.47(dd,J=8.0,7.6Hz,1H),7.56(d,J=1.6Hz,1H),7.62(d,J=1.6Hz,1H),7.63(d,J=15.6Hz,1H),7.64(d,J=8.0Hz,1H),7.83(d,J=15.6Hz,1H),7.86(ddd,J=7.6,1.6,1.2Hz,1H),8.00(br s,2H)。
[合成例2](E)-3-((4-(3-氨基苯基)-3-氧代丙基-1-烯-1-基)-2-溴-6-甲氧基苯氧基)甲基)苯甲酰胺(A21)
使用化合物16(150mg,0.41mmol)和3-氨基苯乙酮(49mg,0.36mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:乙酸乙酯:二氯甲烷=4:1),从而获得合成例2(A21),为黄色固体(35mg,20.1%)。
Rf 0.29(乙酸乙酯:二氯甲烷=4:1);1H-NMR(400MHz,DMSO-d6)δ3.95(s,3H),5.09(s,2H),5.36(s,2H),6.85(ddd,J=8.0,2.4,1.2Hz,1H),7.21(dd,J=8.0,7.6Hz,1H),7.26(dd,J=2.0,2.0Hz,1H),7.37-7.39(m,2H),7.48(dd,J=7.6,7.6Hz,1H),7.60(d,J=1.6Hz,1H),7.62(d,J=16.0Hz,1H),7.67(d,J=8.0Hz,1H),7.75(d,J=1.6Hz,1H),7.82(d,J=15.6Hz,1H),7.85(ddd,J=8.0,1.2,1.2Hz,1H),8.00(br s,2H);13C-NMR(100MHz,DMSO-d6)51.7,69.1,107.8,108.2,111.8,112.7,114.0,118.3,120.2,122.4,122.8,123.4,124.4,126.3,127.7,129.6,132.1,133.6,137.0,141.1,144.4,148.8,162.9,184.7ppm。
[合成例3](E)-3-((4-(3-氨基苯基)-3-氧代丙基-1-烯-1-基)-2-碘-6-甲氧基苯氧基)甲基)苯甲酰胺(A22)
使用化合物17(150mg,0.36mmol)和3-氨基苯乙酮(49mg,0.36mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:乙酸乙酯:二氯甲烷=4:1),从而获得合成例3(A22),为黄色固体(13mg,6.8%)。
Rf 0.38(乙酸乙酯:二氯甲烷=4:1);1H-NMR(400MHz,DMSO-d6)δ3.94(s,3H),5.06(s,2H),5.35(s,2H),6.85(ddd,J=7.6,2.0,0.8Hz,1H),7.21(dd,J=7.6,7.6Hz,1H),7.26(dd,J=2.0,2.0Hz,1H),7.36-7.39(m,2H),7.49(dd,J=7.6,7.6Hz,1H),7.60(d,J=16.0Hz,1H),7.61(d,J=1.6Hz,1H),7.70(d,J=8.0Hz,1H),7.80(d,J=15.6Hz,1H),7.85(ddd,J=8.0,1.6,1.2Hz,1H),7.90(d,J=1.6Hz,1H),8.06(br s,2H)。
[合成例4](E)-3-(4-((3-氨基甲酰基苄基)氧基)-3-氯-5-甲氧基苯基)丙烯酰基)苯甲酰胺(A23)
使用化合物15(100mg,0.31mmol)和3-氨基甲酰基苯乙酮(51mg,0.31mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:甲醇:二氯甲烷=1:10),从而获得合成例4(A23),为淡黄色固体(60mg,41.3%)。
Rf 0.50(甲醇:二氯甲烷=1:9);1H-NMR(400MHz,DMSO-d6)δ3.89(s,3H),5.06(s,2H),7.12(d,J=2.0Hz,1H),7.32(d,J=1.6Hz,1H),7.37(dd,J=8.0,7.6Hz,1H),7.52(dd,J=8.0,7.6Hz,1H),7.57(d,J=16.0Hz,1H),7.61(d,J=8.0,1.6Hz,1H),7.63(d,J=16.0Hz,1H),7.78(d,J=8.0,1.6,1.2Hz,1H),7.95(dd,J=2.0,1.2Hz,1H),8.09-8.13(m,2H),8.55(dd,J=1.6,1.6Hz,1H);13C-NMR(100MHz,DMSO-d6)56.5,74.0,112.5,122.1,122.6,127.1,127.3,127.6,127.7,128.2,128.9,131.1,131.2,131.6,132.0,134.3,134.9,136.9,137.5,143.0,145.0,153.8,167.2,167.7,188.8ppm。
[合成例5](E)-3-(3-溴-4-((3-氨基甲酰基苄基)氧)-5-甲氧基苯基)丙烯酰基)苯甲酰胺(A24)
使用化合物16(100mg,0.27mmol)和3-氨基甲酰基苯乙酮(45mg,0.31mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:甲醇:二氯甲烷=1:10),从而获得合成例5(A24),为淡黄色固体(40mg,28.5%)。
Rf 0.50(甲醇:二氯甲烷=1:9);1H-NMR(400MHz,DMSO-d6)δ3.89(s,3H),5.05(s,2H),7.15(d,J=2.0Hz,1H),7.38(dd,J=8.0,7.6Hz,1H),7.47(d,J=1.6Hz,1H),7.52(dd,J=8.0,7.6Hz,1H),7.58(d,J=15.6Hz,1H),7.61(d,J=8.0,1.6Hz,1H),7.63(d,J=15.6Hz,1H),7.64(d,J=7.6,2.0,1.2Hz,1H),7.78(ddd,J=8.0,1.6,1.2Hz,1H),7.97(dd,J=2.0,2.0Hz,1H),8.09-8.13(m,2H),8.55(dd,J=1.6,1.6Hz,1H);13C-NMR(100MHz,DMSO-d6)56.5,73.9,113.1,117.5,122.6,125.0,127.1,127.4,127.6,128.2,128.9,131.1,131.2,132.0,132.3,134.3,134.9,136.9,137.6,142.9,146.1,153.6,167.2,167.7,188.8ppm。
[合成例6](E)-3-(4-((3-氨基甲酰基苄基)氧)-3-碘-5-甲氧基苯基)丙烯酰基)苯甲酰胺(A25)
使用化合物17(100mg,0.24mmol)和3-氨基甲酰基苯乙酮(40mg,0.24mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:甲醇:二氯甲烷=1:10),从而获得合成例6(A25),为淡黄色固体(35mg,25.9%)。
Rf 0.50(甲醇:二氯甲烷=1:9);1H-NMR(400MHz,DMSO-d6)δ3.94(s,3H),5.05(s,2H),7.42(dd,J=7.6,7.6Hz,1H),7.48(d,J=2.0Hz,1H),7.58(dd,J=7.6,7.6Hz,1H),7.65(d,J=15.6Hz,1H),7.67(dd,J=8.0,2.0Hz,1H),7.82(d,J=2.0Hz,1H),7.83(ddd,J=7.6,1.6,1.2Hz,1H),7.84(d,J=15.6Hz,1H),8.01(dd,J=2.0,1.6Hz,1H),8.12-8.15(m,1H),8.21(ddd,J=8.0,1.6,1.2Hz,1H),8.58(ddd,J=1.6,1.6Hz,1H);13C-NMR(100MHz,DMSO-d6)56.3,73.6,93.7,113.8,122.3,127.1,127.3,127.6,128.2,128.9,130.8,131.1,131.2,132.0,133.1,134.3,134.8,136.9,137.6,142.8,148.7,152.4,167.2,167.7,188.8ppm。
[合成例7](E)-3-((2-氯-4-(3-羟基苯基)-3-氧代丙基-1-烯-1-基)-6-甲氧基苯氧基)甲基)苯甲酰胺(A26)
使用化合物15(200mg,0.63mmol)和1-(2-((四氢-2H-吡喃-2-基)氧基)苯基)乙烷-1-酮(138mg,0.63mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:乙酸乙酯:二氯甲烷=4:1),从而获得合成实施例7(A26),为黄色固体(35mg,12.8%)。
Rf 0.45(乙酸乙酯:二氯甲烷=4:1);1H-NMR(400MHz,DMSO-d6)δ3.96(s,3H),5.11(s,2H),7.07(ddd,J=8.0,2.4,0.8Hz,1H),7.36-7.40(m,2H),7.47(dd,J=8.0,7.6Hz,1H),7.49(dd,J=1.6,1.6Hz,1H),7.59(d,J=16.0Hz,1H),7.63-7.67(m,4H),7.85(ddd,J=8.0,1.6,1.2Hz,1H),7.90(d,J=15.6Hz,1H),7.98-8.01(m,2H);13C-NMR(100MHz,DMSO-d6)56.5,74.0,112.0,114.7,119.7,120.4,122.3,122.8,127.1,127.5,127.6,128.2,129.8,131.1,131.7,134.3,136.9,138.9,142.4,144.9,153.8,157.7,167.7,189.0ppm。
[合成例8](E)-3-((2-溴-4-(3-羟基苯基)-3-氧代丙基-1-烯-1-基)-6-甲氧基苯氧基)甲基)苯甲酰胺(A27)
使用化合物16(100mg,0.27mmol)和1-(2-((四氢-2H-吡喃-2-基)氧基)苯基)乙烷-1-酮(60mg,0.27mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:甲醇:二氯甲烷=1:10),从而获得合成实施例8(A27),为淡黄色固体(38mg,28.9%)。
Rf 0.56(乙酸乙酯:二氯甲烷=1:9);1H-NMR(400MHz,DMSO-d6)δ3.96(s,3H),5.09(s,2H),7.07(ddd,J=7.6,2.0,1.2Hz,1H),7.38(dd,J=8.0,8.0Hz,1H),7.39(br s,1H),7.48(dd,J=8.0,7.6Hz,1H),7.49(d,J=2.4Hz,1H),7.63(d,J=2.0Hz,1H),7.65(d,J=15.6Hz,1H),7.67(dd,J=7.6,1.6Hz,1H),7.79(d,J=1.6Hz,1H),7.85(ddd,J=7.6,1.6,1.2Hz,1H),7.89(d,J=15.6Hz,1H),8.00(br s,1H);13C-NMR(100MHz,DMSO-d6)56.5,73.9,112.6,114.7,117.4,119.7,120.3,122.8,125.1,127.1,127.6,128.2,129.8,131.1,132.4,134.3,136.9,138.9,142.3,145.9,153.6,157.7,167.7,188.9ppm。
[合成例9](E)-3-((4-(3-羟基苯基)-3-氧代丙基-1-烯-1-基)-2-碘-6-甲氧基苯氧基)甲基)苯甲酰胺(A28)
使用化合物17(200mg,0.49mmol)和1-(2-((四氢-2H-吡喃-2-基)氧基)苯基)乙烷-1-酮(107mg,0.49mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:甲醇:二氯甲烷=1:20),从而获得合成实施例9(A28),为黄色固体(136mg,52.9%)。
Rf 0.53(甲醇:二氯甲烷=1:9);1H-NMR(400MHz,DMSO-d6)δ3.87(s,3H),5.02(s,2H),7.00(ddd,J=7.6,2.0,1.2Hz,1H),7.13(d,J=1.6Hz,1H),7.22(dd,J=8.0,8.0Hz,1H),7.35-7.41(m,4H),7.53(d,J=15.6Hz,1H),7.59(d,J=2.0Hz,1H),7.66(d,J=7.6Hz,1H),7.78(dd,J=8.0,1.6Hz,1H),7.99(dd,J=1.6,1.6Hz,1H))。
[合成例10](E)-3-(3-氯-4-((3-氯苄基)氧基)-5-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(A29)
使用化合物1(100mg,0.32mmol)和3,4,5-三甲氧基苯乙酮(67.4mg,0.32mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:乙酸乙酯:正己烷=1:3),从而获得合成例10(A29),为灰白色固体(30mg,18.6%)。
Rf 0.19(乙酸乙酯:正己烷=1:3);1H-NMR(400MHz,CDCl3)δ3.93(s,3H),3.95(s,3H),3.96(s,6H),5.07(s,2H),7.04(d,J=2.0Hz,1H),7.26(d,J=2.4Hz,2H),7.30-7.32(m,2H),7.34(d,J=2.0Hz,1H),7.37(d,J=15.6Hz,1H),7.37-7.39(m,1H),7.55(dd,J=0.8,0.8Hz,1H),7.68(d,J=15.6Hz,1H);13C-NMR(100MHz,CDCl3)56.5,56.7,61.2,74.4,106.1,106.5,111.5,121.9,122.4,126.5,128.5,128.6,129.4,129.9,131.9,133.5,134.5,139.0,143.3,146.0,153.4,154.2,189.1ppm。
[合成例11](E)-3-(3-溴-4-((3-氯苄基)氧基)-5-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(A30)
使用化合物2(100mg,0.28mmol)和3,4,5-三甲氧基苯乙酮(59mg,0.28mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:乙酸乙酯:正己烷=1:3),从而获得合成例11(A30),为黄色固体(55mg,35.8%)。
Rf 0.26(乙酸乙酯:正己烷=1:3);1H-NMR(400MHz,CDCl3)δ3.94(s,3H),3.95(s,3H),3.96(s,6H),5.06(s,2H),7.08(d,J=2.0Hz,1H),7.26(d,J=2.4Hz,2H),7.31-7.34(m,2H),7.36(d,J=15.6Hz,1H),7.41(ddd,J=8.4,1.2,1.2Hz,1H),7.51(d,J=1.6Hz,1H),7.57(br s,1H),7.68(d,J=15.6Hz,1H);13C-NMR(100MHz,DMSO-d6)56.3,56.5,60.2,73.2,106.4,113.4,117.4,122.6,124.6,126.7,127.9,128.0,130.2,132.4,132.9,139.3,142.1,142.3,145.7,152.9,153.4,187.9ppm。
[合成例12](E)-3-(4-((3-氯苄基)氧基)-3-碘-5-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(A31)
使用化合物3(100mg,0.25mmol)和3,4,5-三甲氧基苯乙酮(52mg,0.25mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:乙酸乙酯:正己烷=1:3),从而获得合成例12(A31),为淡黄色固体(57mg,38.7%)。
Rf 0.23(乙酸乙酯:正己烷=1:3);1H-NMR(400MHz,CDCl3)δ3.93(s,3H),3.95(s,3H),3.96(s,6H),5.05(s,2H),7.12(d,J=2.0Hz,1H),7.26(d,J=2.0Hz,2H),7.32-7.34(m,2H),7.35(d,J=15.6Hz,1H),7.44(ddd,J=7.2,1.6,1.2Hz,1H),7.59(dd,J=1.2,1.2Hz,1H),7.67(d,J=15.6Hz,1H),7.71(d,J=2.0Hz,1H);13C-NMR(100MHz,DMSO-d6)56.3,56.4,60.2,72.9,93.6,106.4,114.0,122.4,126.7,127.9,130.2,130.6,132.8,132.9,133.2,139.3,142.1,142.2,148.4,152.3,152.9,187.9ppm。
[合成例13](E)-3-((2-氯-6-甲氧基-4-(3-氧-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)苯氧基)甲基)苯甲酰胺(A32)
使用化合物15(170mg,0.53mmol)和3,4,5-三甲氧基苯乙酮(112mg,0.53mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:乙酸乙酯:正己烷=2:1),从而获得合成例13(A32),为淡黄色固体(140mg,51.3%)。
Rf 0.13(乙酸乙酯:正己烷=2:1);1H-NMR(400MHz,DMSO-d6)δ3.84(s,3H),3.87(s,3H),3.88(s,6H),5.05(s,2H),7.06(d,J=1.6Hz,1H),7.22(s,2H),7.29(d,J=2.0Hz,1H),7.38(dd,J=7.6,7.6Hz,1H),7.39(d,J=15.6Hz,1H),7.58(d,J=15.6Hz,1H),7.60(dd,J=7.6,7.6Hz,1H),7.77(ddd,J=7.6,1.6,1.2Hz,1H),7.95(dd,J=1.6,1.2Hz,1H);13C-NMR(100MHz,DMSO-d6)56.0,56.1,60.5,74.1,105.9,110.9,121.5,122.0,127.1,127.4,128.1,128.5,131.2,131.3,133.0,133.6,136.8,142.2,142.6,145.3,152.8,153.7,168.8,188.4ppm。
[合成例14](E)-3-((2-溴-6-甲氧基-4-(3-氧-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)苯氧基)甲基)苯甲酰胺(A33)
使用化合物16(100mg,0.27mmol)和3,4,5-三甲氧基苯乙酮(58mg,0.27mmol)进行合成,并萃取所得产物,从而获得合成例14(A33),为淡黄色固体(100mg,65.4%)。
Rf 0.13(乙酸乙酯:正己烷=2:1);1H-NMR(400MHz,CDCl3)δ3.84(s,3H),3.88(s,9H),5.04(s,2H),7.11(d,J=1.6Hz,1H),7.22(s,2H),7.29(d,J=2.0Hz,1H),7.38(dd,J=8.0,8.0Hz,1H),7.40(d,J=15.6Hz,1H),7.44(d,J=1.6Hz,1H),7.58(d,J=15.6Hz,1H),7.63(d,J=8.0Hz,1H),7.78(ddd,J=7.6,1.6,1.2Hz,1H),7.97(dd,J=1.6,1.2Hz,1H);13C-NMR(100MHz,DMSO-d6)55.7,55.9,60.3,73.8,105.7,111.3,117.7,121.8,124.2,126.8,127.2,127.8,131.0,131.7,132.7,133.4,136.6,141.9,142.2,146.1,152.5,153.3,168.6,188.1ppm。
[合成例15](E)-3-((2-碘-6-甲氧基-4-(3-氧-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)苯氧基)甲基)苯甲酰胺(A34)
使用化合物17(100mg,0.24mmol)和3,4,5-三甲氧基苯乙酮(51mg,0.24mmol)进行合成,并萃取所得产物,从而获得合成例15(A34),为淡黄色固体(75mg,51.2%)。
Rf 0.13(乙酸乙酯:正己烷=2:1);1H-NMR(400MHz,CDCl3)δ3.84(s,3H),3.87(s,3H),3.88(s,6H),5.03(s,2H),7.14(d,J=1.6Hz,1H),7.21(s,2H),7.38(d,J=15.2Hz,1H),7.39(dd,J=7.6,7.6Hz,1H),7.57(d,J=15.6Hz,1H),7.63(d,J=1.6Hz,1H),7.67(d,J=7.6Hz,1H),7.78(ddd,J=8.0,1.6,1.2Hz,1H),7.99(dd,J=1.6,1.2Hz,1H);13C-NMR(100MHz,DMSO-d6)55.6,55.9,60.3,73.6,92.6,105.7,112.3,121.7,126.8,127.3,127.8,130.2,131.1,132.6,132.7,133.5,136.5,141.9,142.1,148.6,152.1,152.5,168.5,188.1ppm。
[合成例16](E)-3-(3-氯-4-((3-氯苄基)氧基)-5-甲氧基苯基)-1-(3-羟基苯基)丙-2-烯-1-酮(A35)
使用化合物1(100mg,0.32mmol)和1-(3-((四氢-2H-吡喃-2-基)氧基)苯基)乙烷-1-酮(70.1mg,0.32mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:乙酸乙酯:正己烷=1:3),从而获得合成实施例16(A35),为象牙色固体(26mg,18.9%)。
Rf0.13(乙酸乙酯:正己烷=1;3);1H-NMR(400MHz,DMSO-d6)δ3.88(s,3H),4.98(s,2H),7.00(ddd,J=8.0,1.6,0.8Hz,1H),7.06(d,J=2.0Hz,1H),7.22-7.26(m,4H),7.30(ddd,J=8.0,2.0,1.6Hz,1H),7.37-7.41(m,2H),7.39(d,J=15.6Hz,1H),7.46(d,J=2.4Hz,1H),7.54(d,J=15.6Hz,1H)。
[合成例17](E)-3-(3-溴-4-((3-氯苄基)氧基)-5-甲氧基苯基)-1-(3-羟基苯基)丙-2-烯-1-酮(A36)
使用化合物2(100mg,0.28mmol)和1-(3-((四氢-2H-吡喃-2-基)氧基)苯基)乙烷-1-酮(62mg,0.28mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:乙酸乙酯:正己烷=1:3),从而获得合成实施例17(A36),为象牙色固体(62mg,46.5%)。
Rf 0.14(乙酸乙酯:正己烷=1;3);1H-NMR(400MHz,DMSO-d6)δ3.95(s,3H),5.07(s,2H),7.07(dd,J=8.0,2.4Hz,1H),7.38(dd,J=8.0,7.6Hz,1H),7.41-7.49(m,4H),7.57(br s,1H),7.62(d,J=2.0Hz,1H),7.64(d,J=8.0Hz,1H),7.65(d,J=16.0Hz,1H),7.79(dd,J=2.0,1.6Hz,1H),7.90(d,J=15.6Hz,1H),9.81(s,1H);13C-NMR(100MHz,DMSO-d6)56.5,73.2,112.6,114.7,117.3,119.7,120.3,122.8,125.1,126.7,127.9,128.0,129.8,130.2,132.4,132.9,138.9,139.3,142.2,145.8,153.5,157.7,188.9ppm。
[合成例18](E)-3-(4-((3-氯苄基)氧基)-3-碘-5-甲氧基苯基)-1-(3-羟基苯基)丙-2-烯-1-酮(A37)
使用化合物3(100mg,0.25mmol)和1-(3-((四氢-2H-吡喃-2-基)氧基)苯基)乙烷-1-酮(55mg,0.25mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:乙酸乙酯:正己烷=1:3),从而获得合成实施例18(A37),为黄色固体(57mg,43.8%)。
Rf 0.15(乙酸乙酯:正己烷=1;3);1H-NMR(400MHz,CDCl3)δ3.84(s,3H),4.94(s,2H),7.00(ddd,J=8.0,2.0,1.2Hz,1H),7.05(d,J=1.6Hz,1H),7.22-7.26(m,3H),7.31(d,J=15.6Hz,1H),7.33-7.36(m,1H),7.38-7.41(m,2H),7.50(br s,1H),7.53(d,J=16.0Hz,1H),7.58(d,J=2.0Hz,1H),9.02(s,1H);13C-NMR(100MHz,DMSO-d6)56.3,72.9,93.6,113.3,114.7,119.7,120.3,122.6,126.7,127.9,128.0,129.8,130.2,131.0,132.9,133.2,138.9,139.3,142.2,148.4,152.3,157.7,188.9ppm。
[合成例19](E)-1-(3-氨基苯基)-3-(3-氯-4-((3-氯苄基)氧基)-5-甲氧基苯基)丙-2-烯-1-酮(A38)
使用化合物1(230mg,0.74mmol)和3-氨基苯乙酮(100mg,0.74mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:乙酸乙酯:正己烷=1:3),从而获得合成例19(A38),为橙色固体(60mg,18.9%)。
Rf 0.06(乙酸乙酯:正己烷=1:3);1H-NMR(400MHz,CDCl3)δ3.72(s,3H),4.82(s,2H),5.36(s,2H),6.91(d,J=2.0Hz,1H),6.91-6.93(m,1H),7.07-7.14(m,5H),7.22(d,J=15.6Hz,1H),7.29(d,J=7.6Hz,1H),7.30(br s,1H),7.33(dd,J=1.6,1.6Hz,1H),7.39(d,J=15.6Hz,1H)。
[合成例20](E)-1-(3-氨基苯基)-3-(3-溴-4-((3-氯苄基)氧基)-5-甲氧基苯基)丙-2-烯-1-酮(A39)
使用化合物2(100mg,0.28mmol)和3-氨基苯乙酮(38mg,0.28mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:乙酸乙酯:正己烷=1:3),从而获得合成例20(A39),为橙色固体(57mg,42.9%)。
Rf 0.07(乙酸乙酯:正己烷=1:3);1H-NMR(400MHz,CDCl3)δ3.93(s,3H),5.05(s,2H),6.91(ddd,J=8.0,1.6,0.8Hz,1H),7.08(d,J=1,6Hz,1H),7.29(dd,J=7.6,7.6Hz,1H),7.31-7.33(m,3H),7.38(d,J=15.6Hz,1H),7.37(dd,J=1.6,1.2Hz,1H),7.40-7.42(m,1H),7.47(d,J=1,6Hz,1H),7.57(br s,1H),7.65(d,J=16.0Hz,1H);13C-NMR(100MHz,DMSO-d6)56.5,73.2,112.5,112.9,116.6,117.3,118.7,123.1,124.9,126.7,127.9,128.0,129.1,130.2,132.5,132.9,138.3,139.3,141.7,145.7,149.1,153.5,189.5ppm。
[合成例21](E)-1-(3-氨基苯基)-3-(4-((3-氯苄基)氧基)-3-碘-5-甲氧基苯基)丙-2-烯-1-酮(A40)
使用化合物3(200mg,0.50mmol)和3-氨基苯乙酮(67mg,0.50mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:乙酸乙酯:正己烷=1:3),从而获得合成例21(A40),为黄色固体(64mg,42.9%)。
Rf 0.08(乙酸乙酯:正己烷=1:3);1H-NMR(400MHz,DMSO-d6)δ3.93(s,3H),5.03(s,2H),5.34(s,2H),6.85(ddd,J=8.0,2.8,0.8,1H),7.21(dd,J=8.0,7.6Hz,1H),7.26(dd,J=2.0,2.0Hz,1H),7.37(ddd,J=7.6,1.6,1.2Hz,1H),7.42-7.46(m,2H),7.48(ddd,J=7.6,1.6,1.2Hz,1H),7.58-7.62(m,3H),7.80(d,J=16.0Hz,1H),7.90(d,J=1.6Hz,1H);13C-NMR(100MHz,DMSO-d6)56.3,72.9,93.6,112.9,113.3,116.5,118.7,122.9,126.7,127.8,127.9,129.1,130.2,130.7,132.9,133.3,138.3,139.3,141.6,148.3,149.1,152.3,189.4ppm。
[合成例22](E)-3-(3-(3-氯-4-((3-氯苄基)氧基)-5-甲氧基苯基)丙烯酰基)苯甲酰胺(A41)
使用化合物1(100mg,0.32mmol)和3-氨基甲酰基苯乙酮(52mg,0.32mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:甲醇:二氯甲烷=1:10),从而获得合成例22(A41),为淡黄色固体(41mg,28.2%)。
Rf 0.72(甲醇:二氯甲烷=1:9);1H-NMR(400MHz,DMSO-d6)δ3.89(s,3H),4.99(s,2H),7.10(d,J=1.6Hz,1H),7.23(dd,J=2.4,2.0Hz,1H),7.25(dd,J=7.2,7.2Hz,1H),7.31(ddd,J=7.2,2.0,1.6Hz,1H),7.32(d,J=2.0Hz,1H),7.46(br s,1H),7.52(dd,J=8.0,7.6Hz,1H),7.57(d,J=15.6Hz,1H),7.63(d,J=15.6Hz,1H),8.11(dd,J=7.6,1.6Hz,2H),8,54(dd,J=1.6,1.6Hz,1H)。
[合成例23](E)-3-(3-(3-溴-4-((3-氯苄基)氧基)-5-甲氧基苯基)丙烯酰基)苯甲酰胺(A42)
使用化合物3(100mg,0.25mmol)和3-氨基甲酰基苯乙酮(41mg,0.25mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:甲醇:二氯甲烷=1:10),从而获得合成例23(A42),为淡黄色固体(51mg,37.1%)。
Rf 0.53(甲醇:二氯甲烷=1:9);1H-NMR(400MHz,DMSO-d6)δ3.94(s,3H),5.05(s,2H),7.42-7.44(m,2H),7.48(ddd,J=7.6,0.8Hz,1H),7.56(br s,1H),7.61(br s,1H),7.64(d,J=2.0Hz,1H),7.66(d,J=7.6Hz,1H),7.71(d,J=15.2Hz,1H),7.96(d,J=15.2Hz,1H),7.98(d,J=2.0Hz,1H),8.15(ddd,J=8.0,1.2,1.2Hz,1H),8.20(br s,1H),8.32(ddd,J=7.6,1.2,1.2Hz,1H),8.57(dd,J=2.0,1.6Hz,1H);13C-NMR(100MHz,DMSO-d6)56.3,72.9,93.6,113.8,122.4,126.7,127.3,127.9,128.0,128.8,130.2,130.8,131.2,132.0,132.9,133.1,134.8,137.6,139.3,142.8,148.5,152.3,167.2,188.8ppm。
[合成例24](E)-3-(3-(4-((3-氯苄基)氧基)-3-碘-5-甲氧基苯基)丙烯酰基)苯甲酰胺(A43)
使用化合物3(100mg,0.25mmol)和3-氨基甲酰基苯乙酮(41mg,0.25mmol)进行合成,并通过硅胶柱色谱法萃取所得产物(洗脱:甲醇:二氯甲烷=1:10),从而获得合成例24(A43),为淡黄色固体(51mg,37.1%)。
Rf 0.53(甲醇:二氯甲烷=1:9);1H-NMR(400MHz,DMSO-d6)δ3.94(s,3H),5.05(s,2H),7.42-7.44(m,2H),7.48(ddd,J=7.6,0.8Hz,1H),7.56(br s,1H),7.61(br s,1H),7.64(d,J=2.0Hz,1H),7.66(d,J=7.6Hz,1H),7.71(d,J=15.2Hz,1H),7.96(d,J=15.2Hz,1H),7.98(d,J=2.0Hz,1H),8.15(ddd,J=8.0,1.2,1.2Hz,1H),8.20(br s,1H),8.32(ddd,J=7.6,1.2,1.2Hz,1H),8.57(dd,J=2.0,1.6Hz,1H);13C-NMR(100MHz,DMSO-d6)56.3,72.9,93.6,113.8,122.4,126.7,127.3,127.9,128.0,128.8,130.2,130.8,131.2,132.0,132.9,133.1,134.8,137.6,139.3,142.8,148.5,152.3,167.2,188.8ppm。
[实施例4]合成例1至24对HAT活性抑制程度的确认
将合成例1至24分别稀释至100μM,并按照与第[2-1]节相同的方式测定HAT p300活性的抑制程度。结果如图9所示。此处,用C646和候选物12(HAT-12)代替合成例1至24作为对照处理组织。
如图9所示,证实合成实施例1至24(A20至A43)的HAT活性抑制效果为90%以上,显著高于相应对照的C646和候选物12的活性抑制效果,表明合成例1至24(A20至A43)抑制了HAT p300的活性。另外,合成例6(A25)和合成例8(A27)抑制了几乎100%的HAT p300活性。
基于该结果,可以看出,对应于根据本发明的新合成化合物的合成例1至24对HATp300活性的抑制程度非常优异。从结果可以看出,合成例1至24可以非常有效地用于预防、改善或治疗与HAT p300相关的疾病。
[实施例5]合成例6和8对HAT p300活性抑制程度的确认
将如实施例4所述的具有非常优异的HAT p300抑制效果的合成例6和8稀释至0.5μM、1μM、10μM或100μM,并按照与第[2-1]节相同的方式测定各浓度下HAT p300活性的抑制程度,并从这些结果中推导出IC50值。结果如图10和下表4所示。
[表4]
合成例6(A25) | 合成例8(A27) | |
IC<sub>50</sub>(μM) | 0.87±0.15 | 1.06±0.16 |
如图10和表4所示,合成例6和8的IC50值分别为0.87μM和1.06μM,表明合成例6和8分别有效地抑制了HAT p300活性。
基于该结果,可以看出,根据本发明的新合成化合物非常有效地抑制了HAT p300的活性,因为所述新合成化合物被修饰从而与HAT p300的R1410、T1411、W1466、Y1467形成额外的氢键。
[实施例6]候选物6(A25)和8(A27)的结构分析
对于如实施例5所述的具有最佳HAT抑制效果的候选物6(A25)和候选物8(A27),按照与实施例3相同的方式进行分子对接模拟。结果如图11A至11C所示。
如图11A至11C所示,可以看出,除了在实施例3中从候选物12(HAT-12)确认的与HAT p300的S1400的氢键之外,在合成例6(A25)中进一步期望与R1410、T1411和W1466形成氢键,整个对接模式也类似于Lys-CoA。预期合成例6的HAT p300抑制活性将由于这样的结构显著上升(IC50=0.87±0.15(μM))。此外,在合成例8(A27)中,进一步预期与R1410和T1411形成氢键,并且预期合成例8的HAT p300抑制活性将由于这样的结构而上升(IC50=1.06±0.16(μM))。
基于该结果,可以看出,根据本发明的合成例6和8通过与HAT p300的R1410、T1411和W1466;或R1410和T1411的额外氢键与HAT p300结构域以非常高的水平相互作用,从而非常有效地抑制了HAT p300的活性。
虽然已经参考本发明的示例性实施例详细描述了本发明,但是对于本领域的普通技术人员来说显而易见的是,该具体描述只是优选实施实施方式,并且不旨在限制本发明的范围。因此,应当理解本发明的技术范围应由所附权利要求及其等同物限定。
工业实用性
本发明涉及一种新型化合物,通过对HAT p300的结构分析,所述化合物能够与组蛋白乙酰转移酶(HAT)p300的特定氨基酸位置形成额外的氢键。本发明的新型化合物对HATp300活性具有优异的抑制作用,因此可以非常有效地用于预防、改善或治疗与HAT p300活化相关的纤维化疾病。
Claims (14)
2.根据权利要求1所述的化合物,其中p和q各自独立地为1至3的整数;
r为1或2的整数;
m和n为1或2的整数。
3.根据权利要求1所述的化合物,其中R1为氨基甲酰基(-C(=O)(NH2))。
4.根据权利要求1所述的化合物,其中R4包含选自胺基、氨基甲酰基或羟基的任意一种。
7.一种用于预防或治疗组蛋白乙酰基转移酶p300相关疾病的药物组合物,其包含选自下述式1所示的化合物、以及其药学上可接受的盐、光学异构体、水合物和溶剂化物作为活性成分:
[式1]
其中:
p和q各自独立地为1到5的整数;
r为从1到4的整数;
m和n各自独立地为从1到3的整数,前提是m+n不大于4;
R1为氨基甲酰基(-C(=O)(NH2))或卤素,其中当R1以复数形式存在时,它们彼此相同或不同;
R2和R3各组独立地为C1-C6烷氧基或卤素,其中当每个R2和R3以复数形式存在时,它们彼此相同或不同;和
R4包括选自下组的任意一种:C1-C6烷氧基、胺基(-NH2)、氨基甲酰基和羟基(-OH),其中当R4以复数形式存在时,它们彼此相同或不同。
8.根据权利要求7所述的药物组合物,其中所述组蛋白乙酰基转移酶p300相关疾病是纤维化。
9.根据权利要求8所述的药物组合物,其中所述纤维化包括选自下组的一种或多种:肺纤维化、子宫肌瘤、骨髓纤维化、肝纤维化、心脏纤维化、多发性硬化、肾脏纤维化、囊性纤维化、中性粒细胞减少症、骨骼肌纤维化、硬皮病、皮肌炎、纵隔纤维化、和由镰状细胞性贫血引起的脾纤维化。
10.根据权利要求10所述的药物组合物,其中所述肺纤维化包括选自下组的一种或多种:特发性肺纤维化、非特异性间质肺炎、急性间质肺炎、隐源性机化肺炎、呼吸性细支气管炎相关间质性肺病、脱屑性间质肺炎、淋巴样间质肺炎、间质性肺纤维化和弥漫性肺纤维化。
11.一种用于预防或改善组蛋白乙酰基转移酶p300相关疾病的食品组合物,其包含选自下述式1所示的化合物、其药学上可接受的盐、旋光异构体、水合物和溶剂化物作为活性成分:
[式1]
其中:
p和q各自独立地为1到5的整数;
r为从1到4的整数;
m和n各自独立地为从1到3的整数,前提是m+n不大于4;
R1为氨基甲酰基(-C(=O)(NH2))或卤素,其中当R1以复数形式存在时,它们彼此相同或不同;
R2和R3各组独立地为C1-C6烷氧基或卤素,其中当每个R2和R3以复数形式存在时,它们彼此相同或不同;和
R4包括选自下组的任意一种:C1-C6烷氧基、胺基(-NH2)、氨基甲酰基和羟基(-OH),其中当R4以复数形式存在时,它们彼此相同或不同。
12.一种用于预防或改善组蛋白乙酰基转移酶p300相关疾病的化妆品组合物,其包含选自下述式1所示的化合物、其药学上可接受的盐、旋光异构体、水合物和溶剂化物作为活性成分:
[式1]
其中:
p和q各自独立地为1到5的整数;
r为从1到4的整数;
m和n各自独立地为从1到3的整数,前提是m+n不大于4;
R1为氨基甲酰基(-C(=O)(NH2))或卤素,其中当R1以复数形式存在时,它们彼此相同或不同;
R2和R3各组独立地为C1-C6烷氧基或卤素,其中当每个R2和R3以复数形式存在时,它们彼此相同或不同;和
R4包括选自下组的任意一种:C1-C6烷氧基、胺基(-NH2)、氨基甲酰基和羟基(-OH),其中当R4以复数形式存在时,它们彼此相同或不同。
13.一种预防或治疗组蛋白乙酰基转移酶p300相关疾病的方法,包括:
将选自下述式1所示的化合物及其药学上可接受的盐、旋光异构体、水合物和溶剂化物的化合物施用于目标对象:
[式1]
其中:
p和q各自独立地为1到5的整数;
r为从1到4的整数;
m和n各自独立地为从1到3的整数,前提是m+n不大于4;
R1为氨基甲酰基(-C(=O)(NH2))或卤素,其中当R1以复数形式存在时,它们彼此相同或不同;
R2和R3各组独立地为C1-C6烷氧基或卤素,其中当每个R2和R3以复数形式存在时,它们彼此相同或不同;和
R4包括选自下组的任意一种:C1-C6烷氧基、胺基(-NH2)、氨基甲酰基和羟基(-OH),其中当R4以复数形式存在时,它们彼此相同或不同。
14.根据权利要求13所述的方法,其中所述组蛋白乙酰基转移酶p300相关疾病是纤维化。
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