CN117247358A - 一种具有hdac6抑制活性的苯并二氮杂卓类化合物及其制备方法和应用 - Google Patents
一种具有hdac6抑制活性的苯并二氮杂卓类化合物及其制备方法和应用 Download PDFInfo
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
本发明提供了一种苯并二氮杂卓类化合物及其制备方法和应用,苯并二氮杂卓类化合物结构通式如式(Ⅰ)所示,或其异构体,或其药学上可接受的盐、酯或前药。本发明所述苯并二氮杂卓类化合物结构新颖,可较好地抑制HDAC6\HDAC1,对多种肿瘤细胞显示较高抗增殖活性,对正常细胞毒性低,潜在心脏毒性小,动物急性毒性低,作为高效低毒抗肿瘤治疗剂具有开发前景。
Description
技术领域
本发明涉及药物技术领域,尤其涉及兼具HDAC6/HDAC1抑制活性的苯并二氮杂卓类化合物及其制备方法及应用。
背景技术
组蛋白去乙酰化酶(histone deacetylases,HDACs)和组蛋白乙酰转移酶(histone acetyltransferases,HATs)共同调节细胞内乙酰化水平,从而调节基因的表达。HDACs是基因表达的关键调节因子,迄今为止有18HDAC亚型在哺乳动物中被鉴定,基于他们对酵母蛋白的同源性分为四类:I类(HDAC1、HDAC2、HDAC3、HDAC8)通常存在于细胞核中,并且在各种细胞系和组织中具有普遍存在的表达;II类进一步分为IIa(HDAC4、HDAC5、HDAC7、HDAC9)和IIb(HDAC6、HDAC10)两个亚家族对酵母蛋白具有同源性,主要在细胞核和细胞质之间的穿梭;IV类(HDAC11)作为其唯一成员,存在细胞核和细胞质中,与I类和II类酶的催化部位相似。这三类代表Zn2+依赖性脱乙酰酶。III类(Sirt1~Sirt7)NAD+-依赖脱乙酰酶,需要NAD+的酵母蛋白SiR2的活性和同源物。
目前已上市的组蛋白去乙酰化酶抑制剂(HDACi)共有5个,分别为伏立诺他(vorinostat)、贝利司他(belinostat)、帕比司他(panobinostat)、罗米地辛(romidepsin)和西达本胺(chidamide),前三者均为广谱型抑制剂,后两者选择性作用于I类亚型。伏立诺他和罗米地辛用于治疗皮肤T细胞淋巴瘤(CTCL),贝利司他和西达苯胺用于治疗复发及难治性外周T细胞淋巴瘤(PTCL),帕比司他与硼替佐米和地塞米松联用治疗多发性骨髓瘤(MM)。
尽管上述HDAC抑制剂在临床上已取得良好疗效,但广谱HDAC抑制剂普遍存在如下缺点:
(1)较强的毒副作用,如恶心、呕吐、骨髓抑制等;
(2)基因毒性;
(3)药代动力学特性差,生物利用度低、半衰期短等。
以上缺点既为肿瘤患者造成不便,也阻碍广谱HDAC抑制剂在肿瘤治疗以外领域的应用。
目前HDACs亚型选择性抑制剂成为该领域的研究热点,HDAC6因其独特的结构和功能,成为肿瘤治疗的新热点。
HDAC6一种广泛表达的细胞质蛋白去乙酰化酶,主要靶点包括a-微管蛋白和HSP90。通过对这些底物和其他细胞质靶点的翻译后修饰,参与几个关键的细胞过程有关,包括原代细胞纤毛、细胞内信号传导和DNA损伤反应,抑制HDAC6会导致细胞纤毛的恢复和恶性表型的衰减,与它在细胞调节中的作用一致。同时抑制HDAC6已被证明可以减少致癌的Hedgehog信号通路(Hedgehog信号通路控制细胞命运、增殖与分化,该信号通路被异常激活时,会引起肿瘤的发生与发展。)HDAC6通过与信号中介体的相互作用或通过调节HSP90直接地与细胞内信号传导,是一个重要的细胞内伴侣。总的来说,这些研究将HDAC6与多种致癌过程联系起来,并强调了HDAC6抑制剂诱导细胞和免疫介导的抗肿瘤活性的潜力。
目前临床在研的HDAC6抑制剂都是用于肿瘤的治疗,临床研究显示其副作用相对广谱的HDAC抑制剂有明显的改善,目前还未有剂量限制毒性报道,对肿瘤的治疗具有潜在的应用前景。
文献(Oncologist,2021.26(3):184-e366.)报道ACY-1215是首创的HDAC6抑制剂(IC50=5nM),目前已进入临床II期研究,与硼替佐米协同作用,对复发和难治性淋巴瘤患者具有高度良好的安全性。在ACY-1215的临床研究中,该药物耐受性良好,未观察到剂量限制毒性,最常见的1-2级毒性反应(腹泻、恶心、疲劳、咳嗽、呕吐和疼痛),症状轻微且易于控制。然而,ACY-1215的药代动力曲线中,其血清浓度在较高剂量时趋于稳定。
文献(Blood(2015)126(23):3040.)报道ACY-241是第二代选择性HDAC6抑制剂(IC50=2.6nM),用于多发性骨髓瘤(MM)的治疗,在临床研究中发现在相同剂量下,可获得比ACY-1215更高的血清浓度,没有关于任何剂量限制毒性的报告,用于晚期实体肿瘤患者的治疗,对肿瘤治疗有着潜在的治疗前景。
文献(Clin Cancer Res.2021,27(13))报道KA2507是一种有效的选择性HDAC6抑制剂,其对HDAC6的抑制IC50值达到2.5nmmol,而对其他HDAC亚型抑制较差。临床前模型中KA2507显示出抗肿瘤疗效和免疫调节作用。在I期临床研究中,KA2507在一部分患者中显示出选择性的靶点参与,并延长了疾病稳定,且其耐受性良好,没有剂量限值毒性或其他显著毒性的报道,这些结果表明,KA2507是一个很好的候选药物,值得进一步临床研究。
HDAC6是肿瘤治疗的潜在靶标,以上研究表明选择性HDAC6抑制剂有望开发成为全新的高效低毒的抗肿瘤药物。文献(J.Am.Chem.Soc.2010,132,31,10842-10846)报道TubastainA是一种在研较好的HDAC6抑制剂(IC50=15nM),但其理化性质不佳、成药性差。
发明内容
本发明提供了一种结构新颖的苯并二氮杂卓类化合物,可较好地抑制HDAC6\HDAC1,对多种肿瘤细胞显示较高抗增殖活性,对正常细胞毒性低,潜在心脏毒性小,动物急性毒性低,作为高效低毒抗肿瘤治疗剂具有开发前景。
为了实现上述发明目的,本发明的第一方面提供了一种苯并二氮杂卓类化合物,结构通式如式(Ⅰ)所示,或其异构体,或其药学上可接受的盐、酯或前药;
其中,
R1和R2独立地选自氢、氘、羟基、卤素、烷基、烷氧基、环烷基、苄基、杂环烷基、芳基、杂芳基、氰基、卤代烷基、酰基、磺酰基或氨基烷基,其各个可任选被取代。
优选的,所述的烷基为含有1~4个碳原子的烷基,其可任选地被0~3个卤素取代;
优选的,所述的环烷基为含有3~6个碳原子的环烷基,岂可任选地被0~3个卤素取代;
优选的,所述的杂环烷基选自吡咯基、吗啉基、哌啶基、哌嗪环、四氢喹啉基、四氢三唑并吡嗪基、二氮杂环庚烷基或哌嗪基,其可任选地被取代;
优选的,所述的芳基或杂芳基选自苯基、萘基、蒽基、吡啶基、嘧啶基、吡嗪基、吲哚基、咪唑基、苯并噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、三唑基、异噁唑基、喹啉基、吡咯基、吡唑基或5,6,7,8-四氢异喹啉;其可任选地被取代;
优选的,所述的酰基选自乙酰基、丙酰基、异丁酰基或芳基酰基,其可任选地被取代;
优选的,所述的磺酰基选自甲磺酰基或芳基磺酰基,其可任选地被取代;
优选的,所述的氨基烷基选自二甲氨基烷基、甲基氨基烷基、哌嗪烷基或哌啶烷基,其可任选地被取代;
优选的,所述的卤素选自氟、氯、溴;
优选的,所述的烷氧基选自含有1~4个碳原子的烷氧基。
优选的,式(Ⅰ)化合物药学上可接受的盐包括式(Ⅰ)化合物与盐酸、氢溴酸、硫酸、醋酸、三氟醋酸、柠檬酸、酒石酸、马来酸、富马酸、甲磺酸、苹果酸、对甲苯磺酸或草酸反应生成的阴离子盐;或式(Ⅰ)化合物与钠离子溶液、钾离子溶液反应生成的阳离子盐。
优选的,R1和R2独立地选自氢、甲基、F、Cl、Br或甲氧基。
在本发明的一些具体实施方式中,苯并二氮杂卓类化合物包括以下化合物或其异构体,或其药学上可接受的盐、酯或前药:
表1
本发明的第二方面提供了上述技术方案所述苯并二氮杂卓类化合物的制备方法,包括以下步骤:
S1,氮气保护下,式(Ⅱ)化合物与4-溴甲基苯甲酸甲酯反应得到式(Ⅲ)化合物;
其中,R1和R2如上述技术方案所示;
S2,式(Ⅲ)化合物与碱性羟胺溶液反应得到式(Ⅰ)化合物;
优选的,步骤S1的反应温度为60~100℃,反应时间为1.5~4h。
优选的,式(Ⅱ)化合物的制备方法包括下述任意一种方法:
方法1包括以下步骤:
A1,式(Ⅳ)化合物与丙烯酸在酸性条件下反应得到式(Ⅱ)化合物;
方法2包括以下步骤:
B1,式(Ⅴ)化合物与丙烯酸加热反应,得到式(Ⅵ)化合物;
B2,式(Ⅵ)化合物在Pt/C催化下与氢气反应生成式(Ⅶ)化合物,或,式(Ⅵ)化合物与在Zn催化下与浓盐酸反应生成式(Ⅶ)化合物;
B3,式(Ⅶ)化合物与浓盐酸在加热条件下反应得到式(Ⅱ)化合物;
优选的,步骤A1中,式(Ⅴ)化合物、丙烯酸与浓盐酸混合,在60~85℃下反应10~16h;
优选的,步骤B1中,反应温度为120~145℃,反应时间6~10h;
优选的,步骤B2中,式(Ⅶ)化合物、Pt/C溶解在有机溶剂中,通入氢气1.5~3h,反应生成式(Ⅷ)化合物;
优选的,步骤B2中,式(Ⅶ)化合物、浓盐酸、有机溶剂混合后,缓慢加入锌粉至反应终止;
优选的,步骤B3中,反应温度为60~80℃,反应时间为3~6h。
本发明的第三方面提供了一种用于制备前述技术方案所述苯并二氮杂卓类化合物的中间体化合物,包括式(Ⅱ)化合物或其异构体、药学上可接受的盐、酯或前药:
和/或,式(Ⅲ)化合物或其异构体、药学上可接受的盐、酯或前药:
和/或,式(Ⅳ)化合物或其异构体、药学上可接受的盐、酯或前药:
和/或,式(Ⅴ)化合物或其异构体、药学上可接受的盐、酯或前药:
和/或,式(Ⅵ)化合物或其异构体、药学上可接受的盐、酯或前药:
和/或,式(Ⅶ)化合物或其异构体、药学上可接受的盐、酯或前药:
其中,R1、R2如前述技术方案所示。
本发明的第四方面提供了前述技术方案所述苯并二氮杂卓类化合物、前述技术方案所述制备方法得到的苯并二氮杂卓类化合物或上述技术方案所述的中间体化合物在制备组蛋白去乙酰化酶抑制剂或抗肿瘤药物中的应用。
优选的,所述组蛋白去乙酰化酶抑制剂为HDAC6和/或HDAC1抑制剂。
优选的,所述抗肿瘤药物包括抗乳腺癌、结肠癌、肝癌、多发性骨髓瘤、肉瘤、肺癌、前列腺癌、直肠癌、肾癌、胰腺癌、血癌、成神经细胞瘤、神经胶质瘤、头癌、颈癌、甲状腺癌、卵巢癌、外阴癌、子宫颈癌、子宫内膜癌、睾丸癌、膀胱癌、食管癌、胃癌、鼻咽癌、颊癌、口腔癌、胃肠道间质瘤、皮肤癌的药物;进一步优选的,包括抗骨髓瘤、神经母细胞瘤、慢性髓系白血病的药物。
本发明的第五方面提供了一种药物组合物,包括至少一种活性组分以及一种或多种药学上可接受的辅料;所述活性组分包括前述技术方案所述苯并二氮杂卓类化合物或上述技术方案所述制备方法得到的苯并二氮杂卓类化合物。
优选的,所述药学上可接受的辅料包括稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂、香味剂和甜味剂中的一种或多种。
本发明所述药物组合物可以制成片剂,粉剂,粒剂,胶囊,口服液及注射用药等多种形式,上述各剂型的药物均可以按照药学领域的常规方法制备。本发明所述药物组合物中的活性组分还可以与其他具有治疗效果或增强治疗效果、降低毒副作用、延长代谢时间的有效成分共同组成药物组合物。
与现有技术相比,本发明的有益效果:
本发明以TubastatinA为先导化合物,对其帽状区域改造得到如式(Ⅰ)化合物所示的苯并二氮杂卓类化合物,具有HDAC6/HDAC1强抑制作用,低毒高效,是一类对肿瘤具有一定治疗作用、成药性好的候选药物。
1)本发明所述苯并二氮杂卓类化合物对HDAC6和HDAC1均具有较强的抑制活性,大多数化合物对HDAC6抑制活性优于HDAC6抑制剂临床I/II期在研药物Rocilinostat(ACY-1215);本发明所述苯并二氮杂卓类化合物多数对HDAC1抑制活性优于Rocilinostat;
2)本发明所述苯并二氮杂卓类化合物对人骨髓瘤细胞(NCI-H929)、人神经母细胞瘤细胞(SH-SY5Y)、人慢性髓系白血病细胞(K562)等多株肿瘤细胞均具有良好的抑制效果,对正常细胞的抑制作用弱,表现出较好的细胞选择抑制活性;
3)本发明所述苯并二氮杂卓类化合物对hERG抑制活性弱,潜在心脏毒性较小;大鼠口服单次灌胃耐受性高,急性毒性低。
具体实施方式
在本发明中,所称“异构体”包括但不限于对映异构体、非对映异构体、对映异构体和非对映异构体的混合物、互变异构体、外消旋混合物与非对映异构体的混合物,及其药学上可接收的盐。除非另做说明,当未具体指明异构体组分时,包括所有可能的异构体。
在本发明中,所述“药学上可接受的盐”是指通过形成本发明所述苯并噻二嗪化合物酸式或碱式盐修饰的化合物,包括但不限于无机酸的盐,选自例如,盐酸盐、磷酸盐、磷酸氢盐、氢溴酸盐、硫酸盐、亚硫酸盐和硝酸盐;以及有机盐的盐,选自例如苹果酸盐、马来酸盐、延胡索酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、2-羟基乙基磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐、链烷酸盐如乙酸盐,以及HOOC-(CH2)n-COOH的盐,其中n可以是0-4中的任意整数。如果化合物作为酸加成盐获得,则游离碱可以通过碱化酸式盐的溶液而获得。相反地,如果产物是游离碱,加成盐(例如药学上可接受的加成盐)可以通过将游离碱溶于合适的有机溶剂并且用酸处理溶液而制备,与由碱性化合物制备酸加成盐的常规过程一致。本领域技术人员应了解无需过度实验而可用于制备无毒的药学上可接受的加成盐的各种合成方法。类似地,所述“药学上可接受的酯”是指通过形成本发明所述小分子抑制剂的酯类衍生物,所述“药学上可接受的前药”包括具有在体内外形成本发明所述小分子抑制剂的前体化合物。
在本发明中,所述“芳环”或“芳基”是指5-12个碳原子的全碳单环或稠合多环基团,具有完全共轭的π电子系统。芳环的非限制性实例有:苯环、联苯、萘环和蒽环。芳环可以是无取代或取代的。芳环的取代基可以选自卤素、硝基、氨基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C6环烷基、卤代C3-C6环烷基。
在本发明中,所述“杂芳基”是指5-12个环原子的不饱和的碳环,其中一个或多个碳被杂原子例如氧、氮、硫等置换。杂芳环可以是单环,也可以是双环,即通过两个环稠合而成。具体的杂环芳基可以是:吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基、吡咯基、吗啉基、哌啶基或哌嗪基、噻吩基、苯并噻吩基、吡唑基、苯并吡唑基、吲哚基、二氧戊环基、苯并[1,3]二氧戊环基、噁唑基、苯并噁唑基、呋喃基、苯并呋喃基、噻唑基或苯并噻唑基等。杂环芳基可以是无取代或取代的。杂环芳基的取代基可以选自卤素、硝基、氨基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C6环烷基、卤代C3-C6环烷基。
在本发明中,所述“烷氧基”是指-O-烷基基团,其中烷基如上所定义。本发明所用“烷氧基”的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基和叔丁氧基,烷氧基可以是无取代或取代的。
在本发明中,所述“卤素”或“卤代”表示氟、氯、溴或碘。
在本发明中,所述药学上可接受的辅料包括但不限于药学领域的常规稀释剂,赋形剂,填充剂,粘合剂,湿润剂,崩解剂,吸收促进剂,表面活性剂,吸附载体,润滑剂等,必要时还可以加入香味剂,甜味剂等。本发明所述药物组合物可以制成片剂,粉剂,粒剂,胶囊,口服液及注射用药等多种形式,上述各剂型的药物均可以按照药学领域的常规方法制备。
在本发明的一些具体实施方式中,本发明的化合物可采用如下合成路线进行制备:
路线一:
路线二:
路线三:
采用上述任意一种合成路线得到式(I)化合物,式(I)化合物可进一步与无机酸、有机酸在溶剂中反应,冷却析出相应的式(I)结构化合物的盐。
下面结合实施例对本发明提供的技术方案进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。所有原料未注明合成方法的均购自探索平台、阿拉丁、Sigma-Aldrich等厂家,均为分析纯。
实施例1:4-((4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)-N-羟基苯甲酰胺(T-1)的制备
按照路线1进行制备,合成路线图如下:
1,3,4,5-四氢-2H-苯并[b][1,4]二氮卓-2-酮(1-2)的合成
于500ml三颈瓶中依次加入1,2-苯二胺(4g,36.99mmol,1eq)、丙烯酸(4g,1.5eq),浓盐酸10ml,水50ml,70℃搅拌12h。冷却至室温,加碳酸氢钠调PH7-8,加100ml乙酸乙酯萃取,分出有机相浓缩至干,柱层析分离得白色固体3.2g收率53.3%。1H NMR(600MHz,DMSO-d6)δ9.40(s,1H),6.87(dd,J=7.9,1.5Hz,1H),6.82(ddd,J=8.5,7.2,1.5Hz,1H),6.75(dd,J=8.0,1.5Hz,1H),6.61(td,J=7.5,1.5Hz,1H),5.81–5.68(m,1H),3.43(dtd,J=5.7,4.0,1.8Hz,2H),2.50–2.46(m,2H).ESI-MS(+)m/z=163.3[M+H]+。
4-((4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)苯甲酸甲酯(1-3)的合成
于1L三颈瓶中加入中间体1-2(1g,6.17mmol,1eq),溶于40mlDMF中,加入n-BuOK(0.6919g,1eq),N2保护,室温搅拌30min,加入4-溴甲基苯甲酸甲酯(1.41g,1eq),80℃搅拌3h。冷却至室温,加入100ml水,150ml乙酸乙酯萃取,有机相干燥后柱层析分离得白色固体1.394g,收率73%。1H NMR(600MHz,DMSO-d6)δ7.90–7.74(m,2H),7.47–7.32(m,2H),7.19(dd,J=8.1,1.4Hz,1H),6.99(ddd,J=8.4,7.1,1.4Hz,1H),6.95(dd,J=7.9,1.7Hz,1H),6.89–6.77(m,1H),5.25(t,J=3.0Hz,1H),5.11(s,2H),3.81(s,3H),3.64(td,J=6.6,2.9Hz,2H),2.47(t,J=6.6Hz,2H).ESI-MS(+)m/z=310.23[M+H]+。
4-((4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)-N-羟基苯甲酰胺(1)的合成;
分别将20g盐酸羟胺溶于200ml甲醇,19g氢氧化钾(纯度85%)溶于200ml甲醇,在冰水浴降温条件下缓慢混匀,室温搅拌2h,过滤取滤液得羟胺甲醇溶液。于100ml三颈瓶中加入中间体1-3(1g,3.22mmol)、羟胺甲醇溶液50ml,室温反应过夜。用醋酸调节pH至中性,浓缩后加入乙酸乙酯,用水洗去羟胺,有机相干燥后浓缩至干加入10ml乙醇打浆,过滤得白色固体0.4g,收率40%。1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),9.06(s,1H),7.65(d,J=8.1Hz,2H),7.33(d,J=8.0Hz,2H),7.29–7.22(m,1H),7.08–6.95(m,2H),6.88(td,J=7.5,6.9,1.9Hz,1H),5.30(q,J=5.8,4.4Hz,1H),5.11(s,2H),3.67(td,J=6.6,2.7Hz,2H),2.50(t,J=6.6Hz,2H).ESI-MS(+)m/z=311.2[M+H]+。
实施例2:4-((7,8-二甲基-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)-N-羟基苯甲酰胺(T-2)的制备
按照通法1进行T-2制备。1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),8.97(s,1H),7.60(d,J=8.0Hz,2H),7.30(d,J=8.0Hz,2H),7.02(s,1H),6.73(s,1H),5.05(s,2H),4.98(d,J=2.8Hz,1H),3.58(td,J=6.6,2.8Hz,2H),2.41(t,J=6.6Hz,2H),2.06(d,J=3.2Hz,6H).ESI-MS(+)m/z=340.00[M+H]+。
实施例3:4-((8-甲基-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)-N-羟基苯甲酰胺(T-3)的制备
按照合成通法2进行制备,具体合成路线图如下:
3-((5-甲基-2-硝基苯基)氨基)丙酸(3-2)的合成
于250ml三口瓶中加入5-甲基-2-硝基苯胺(10g,65.29mmol,1eq)、丙烯酸(7.06g,1.5eq),135℃搅拌反应8h。冷却至室温,加15ml二氯甲烷室温搅拌2个小时,过滤得到黄色固体,烘干粗品重7.3g,收率49.9%。
3-((2-氨基-5-甲基苯基)氨基)丙酸(3-3)的合成
于250ml加压釜中加入3-2(7.3g,32.56mmol)、Pt/C 1g,50ml乙醇,充入10psi个氢气,密封室温反应2h,点半检测反应完成,过滤Pt/C,滤液减压浓缩至干得到黑色固体4.79g,不经纯化直接投下一步
7-甲基-1,3,4,5-四氢-2H-苯并[b][1,4]二氮卓-2-酮(3-4)的合成
于100ml三颈瓶中加入4.79g中间体3-3粗品,浓盐酸10ml,纯净水30ml,加热至70℃回流4h。冷却至室温,缓慢加入碳酸氢钠调中性,乙酸乙酯萃取,有机层无水硫酸钠干燥,过滤,滤液减压浓缩至干,柱层析纯化得到白色固体1.23g,两步收率21.43%。1H NMR(600MHz,DMSO-d6)δ9.36(s,1H),6.80(d,J=8.0Hz,1H),6.60(s,1H),6.56–6.46(m,1H),5.62(t,J=3.8Hz,1H),3.47(dt,J=6.8,3.6Hz,2H),2.51(t,J=5.6Hz,2H),2.18(s,3H).ESI-MS(+)m/z=177.00[M+H]+。
4-((8-甲基-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)苯甲酸甲酯(3-5)的合成
于250ml三颈瓶中加入中间体3-4(1g,5.67mmol,1eq),溶于40mlDMF中,加入n-BuOK(0.64g,1eq),N2保护,室温搅拌30min,加入4-溴甲基苯甲酸甲酯(1.3g,1eq),80℃搅拌3h。冷却至室温,加入100ml水,150ml乙酸乙酯萃取,有机相干燥后柱层析分离得白色固体1.13g,收率61.4%。1H NMR(600MHz,DMSO-d6)δ7.90–7.76(m,2H),7.38(d,J=8.1Hz,2H),7.08(d,J=8.1Hz,1H),6.76(d,J=2.1Hz,1H),6.65(dd,J=8.2,2.0Hz,1H),5.16(d,J=3.1Hz,1H),5.09(s,2H),3.81(s,3H),3.62(td,J=6.6,2.9Hz,2H),2.46(t,J=6.5Hz,2H),2.16(s,3H)..ESI-MS(+)m/z=310.23[M+H]+。
4-((8-甲基-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)-N-羟基苯甲酰胺(3)的合成
于100ml三颈瓶中加入中间体3-5(1g,3.08mmol)、羟胺甲醇溶液50ml,室温反应过夜。用醋酸调节pH至中性,浓缩后加入乙酸乙酯,用水洗去羟胺,有机相干燥后浓缩至干加入10ml乙醇重结晶,过滤得白色固体0.4g,收率40%。
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.04(s,1H),7.65–7.54(m,2H),7.28(d,J=8.1Hz,2H),7.09(d,J=8.2Hz,1H),6.74(d,J=2.0Hz,1H),6.65(dd,J=8.1,2.0Hz,1H),5.15(q,J=8.1,5.5Hz,1H),5.04(s,2H),3.61(td,J=6.7,2.7Hz,2H),2.44(t,J=6.5Hz,2H),2.15(s,3H).ESI-MS(+)m/z=326.01[M+H]+。
实施例4:4-(9-甲基-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)-N-羟基苯甲酰胺(T-4)的制备
按照通法2进行T-4制备。1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),9.00(s,1H),7.66–7.54(m,2H),7.37–7.28(m,2H),7.09(dd,J=8.1,1.5Hz,1H),6.99–6.90(m,1H),6.80(t,J=7.7Hz,1H),5.05(s,2H),4.57(d,J=2.5Hz,1H),3.67(td,J=6.9,2.1Hz,2H),2.41(t,J=6.8Hz,2H),2.23(s,3H).ESI-MS(+)m/z=326[M+H]+。
实施例5:4-((7-氟-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)-N-羟基苯甲酰胺(T-5)的制备
按照合成通法3进行制备,具体合成路线图如下:
3-((4-氟-2-硝基苯基)氨基)丙酸(5-2)的合成
于250ml三口瓶中加入4-氟-2-硝基苯胺(10g,64.05mmol,1eq)、丙烯酸(6.92g,1.5eq),135℃搅拌反应8h。冷却至室温,加15ml二氯甲烷室温搅拌2个小时,过滤得到黄色固体,烘干粗品重8.1g,收率55.4%。
3-((4-氟-2-胺基苯基)氨基)丙酸(5-3)的合成
于250ml三口瓶中加入5-2(8.1g,35.50mmol)、concd HCl 10ml,乙醇50ml,慢慢加入锌粉,边加边搅拌,当点板检测反应完成,终止锌粉加入,冷却室温,将反应液中的乙醇减压浓缩,不经纯化继续投下一步。
8-氟-1,3,4,5-四氢-2H-苯并[b][1,4]二氮卓-2-酮(5-4)的合成
于100ml三颈瓶中加入上步得到的全部粗品5-3,浓盐酸10ml,纯净水30ml,加热至70℃回流4h。冷却至室温,缓慢加入碳酸氢钠调中性,乙酸乙酯萃取,有机层无水硫酸钠干燥,过滤,滤液减压浓缩至干,柱层析纯化得到白色固体2.1g,两步收率32.8%。1H NMR(400MHz,DMSO-d6)δ9.52(s,1H),6.92–6.59(m,3H),5.55(t,J=3.7Hz,1H),3.40(td,J=5.9,3.7Hz,2H),2.47(s,2H).ESI-MS(+)m/z=181.00[M+H]+。
4-((7-氟-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)苯甲酸甲酯(5-5)的合成
于250ml三颈瓶中加入中间体5-4(1g,5.55mmol,1eq),溶于40mlDMF中,加入n-BuOK(0.623g,1eq),N2保护,室温搅拌30min,加入4-溴甲基苯甲酸甲酯(1.27g,1eq),80℃搅拌3h。冷却至室温,加入100ml水,150ml乙酸乙酯萃取,有机相干燥后柱层析分离得到白色固体0.94g,收率51.6%。1H NMR(600MHz,DMSO-d6)δ7.88–7.76(m,2H),7.38(d,J=8.2Hz,2H),7.17(dd,J=10.4,2.9Hz,1H),6.97(dd,J=8.7,5.9Hz,1H),6.87(td,J=8.4,2.9Hz,1H),5.19–5.16(m,1H),5.14(s,2H),3.81(s,3H),3.61(td,J=6.7,2.7Hz,2H),2.47(t,J=6.7Hz,2H).ESI-MS(+)m/z=329.10[M+H]+。
4-((7-氟-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)-N-羟基苯甲酰胺(5)的合成
于100ml三颈瓶中加入中间体5-5(1g,3.05mmol)、羟胺甲醇溶液50ml,室温反应过夜。用醋酸调节pH至中性,浓缩后加入乙酸乙酯,用水洗去羟胺,有机相干燥后浓缩至干加入10ml乙醇重结晶,过滤得白色固体0.437g,收率43.7%。1H NMR(600MHz,DMSO-d6)δ11.12(s,1H),9.00(s,1H),7.61(d,J=7.5Hz,2H),7.30(d,J=7.4Hz,2H),7.18(d,J=9.7Hz,1H),7.03–6.94(m,1H),6.87(s,1H),5.17(s,1H),5.11(s,2H),3.61(s,2H),2.47(s,2H).ESI-MS(+)m/z=330.6[M+H]+。
实施例6:4-((7-氯-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)-N-羟基苯甲酰胺(T-6)的制备
按照通法3进行T-6的制备。1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),9.02(s,1H),7.70–7.57(m,2H),7.31(d,J=2.3Hz,1H),7.30–7.25(m,2H),7.03(dd,J=8.5,2.3Hz,1H),6.94(d,J=8.5Hz,1H),5.43(q,J=3.3Hz,1H),5.09(s,2H),3.63(td,J=6.5,2.8Hz,2H),2.48(d,J=6.2Hz,2H).ESI-MS(+)m/z=345.9[M+H]+
实施例7:4-((7-甲基-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)-N-羟基苯甲酰胺(T-7)的制备
按照通法2进行T-7的制备。1H NMR(600MHz,DMSO-d6)δ11.13(s,1H),9.01(s,1H),7.62(d,J=7.8Hz,2H),7.32(d,J=8.0Hz,2H),7.07(s,1H),6.87(d,J=8.0Hz,1H),6.82(d,J=7.9Hz,1H),5.07(s,3H),3.60(t,J=6.7Hz,2H),2.44(t,J=6.7Hz,2H),2.16(s,3H).ESI-MS(+)m/z=326[M+H]+。
实施例8:4-((8-氟-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)-N-羟基苯甲酰胺(T-8)的制备
按照通法3进行T-8的制备。1H NMR(600MHz,DMSO-d6)δ11.13(s,1H),9.00(s,1H),7.62(d,J=8.2Hz,2H),7.27(d,J=8.2Hz,2H),7.23(d,J=2.9Hz,1H),6.73(dd,J=10.3,2.9Hz,1H),6.63(td,J=8.5,2.9Hz,1H),5.56(s,1H),5.05(s,2H),3.68–3.62(m,2H),2.49(d,J=6.5Hz,2H).ESI-MS(+)m/z=330[M+H]+。
实施例9:4-((7-溴-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)-N-羟基苯甲酰胺(T-9)的制备
按照通法3进行T-9的制备。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),9.17(s,1H),7.62(d,J=7.9Hz,2H),7.47–7.38(m,1H),7.27(d,J=7.9Hz,2H),7.14(dd,J=8.3,2.3Hz,1H),6.89(d,J=8.5Hz,1H),5.46(s,1H),5.09(s,2H),3.63(q,J=5.7Hz,2H),2.48(d,J=7.0Hz,2H).ESI-MS(+)m/z=391.9[M+H]+。
实施例10:4-((6-甲基-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)-N-羟基苯甲酰胺(T-10)的制备
按照通法2进行T-10的制备。1H NMR(600MHz,DMSO-d6)δ11.07(s,1H),9.05(s,1H),7.57(d,J=7.9Hz,2H),7.37(d,J=7.9Hz,2H),6.98(t,J=7.6Hz,1H),6.82(t,J=7.0Hz,2H),5.33(d,J=15.8Hz,1H),5.06(d,J=4.9Hz,1H),4.28(d,J=15.9Hz,1H),3.54(ddd,J=14.0,10.0,4.9Hz,1H),3.45(dt,J=10.9,5.8Hz,1H),2.53(dd,J=13.1,7.1Hz,1H),2.28(s,3H),2.15(dd,J=12.7,4.7Hz,1H).ESI-MS(+)m/z=326[M+H]+。
实施例11:4-((8-甲氧基-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)-N-羟基苯甲酰胺(T-11)的制备
按照通法2进行T-11的制备。1H NMR(400MHz,DMSO)δ11.10(s,1H),8.96(s,1H),7.61(d,J=8.2Hz,2H),7.29(d,J=8.2Hz,2H),7.12(d,J=8.8Hz,1H),6.51(d,J=2.8Hz,1H),6.41(dd,J=8.8,2.8Hz,1H),5.27(s,1H),5.02(s,2H),3.65(s,3H),3.61(d,J=2.2Hz,2H),2.45(t,J=6.4Hz,2H)..ESI-MS(+)m/z=343.4[M+H]+.
实施例12:4-((7,8-二氟-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)-N-羟基苯甲酰胺(T-12)的制备
按照通法1进行T-12的制备。1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.97(s,1H),7.69–7.55(m,2H),7.43(dd,J=12.3,8.3Hz,1H),7.34–7.21(m,2H),6.93(dd,J=12.0,8.3Hz,1H),5.37(d,J=2.9Hz,1H),5.08(s,2H),3.61(td,J=6.6,2.8Hz,2H),2.47(d,J=6.6Hz,2H).ESI-MS(+)m/z=348.40[M+H]+.
实施例13:4-((7,8-二氯-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮卓-1-基)甲基)-N-羟基苯甲酰胺(T-13)的制备
按照通法1进行T-13的制备。1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),8.98(s,1H),7.68–7.57(m,2H),7.51(s,1H),7.25(d,J=8.1Hz,2H),7.13(s,1H),5.68(t,J=3.1Hz,1H),5.10(s,2H),3.64(td,J=6.4,3.0Hz,2H),2.53(d,J=6.3Hz,2H).ESI-MS(+)m/z=378.90[M+H]+.
实施例14化合物对HDAC抑制活性
化合物的组蛋白去乙酰化酶体外抑制活性测定参照HDAC6和HDAC1抑制剂筛选试剂盒(HDAC6:BPS公司;HDAC1:Active Motif公司)说明书进行。以临床在研HDAC6抑制剂Rocilinostat(ACY-1215)为阳性对照。
实验结果见表2:
表2
实验结果显示,本发明化合物对HDAC6显示较强的抑制活性(IC50<9nM),同时对HDAC1也显示较强抑制活性,除化合物T10外,化合物对HDAC1抑制活性均优于阳性对照Rocilinostat(ACY-1215)。
实施例15体外对肿瘤细胞抗增殖活性测试
采用CCK-8法测定部分本发明化合物对NCI-H929(人骨髓瘤细胞)、SH-SY5Y(人神经母细胞瘤细胞)、K562(人慢性髓系白血病细胞)及MRC-5人正常胚肺成纤维细胞的抗增殖活性,选择Rocilinostat(ACY-1215)为对照。具体结果如表(单位为:Inh%in 20μM和Inh%in 2μM):
实验步骤
(1)细胞培养
收集对数生长期细胞,计数,用完全培养基重新悬浮细胞,调整细胞浓度至合适浓度,接种96孔板,每孔接种100μl细胞悬液。细胞在37℃,100%相对湿度,5%CO2培养箱中孵育12-24小时。
(2)筛选
收集对数生长期细胞,计数,用完全培养基重新悬浮细胞,调整细胞浓度至合适浓度(依照细胞密度优化试验结果确定),接种96孔板,每孔加100μl细胞悬液。细胞在37℃,100%相对湿度,5%CO2培养箱中孵育24小时。
待细胞完全贴壁后,用DMSO将待测化合物稀释至1mM和10mM。按1μl/孔加入细胞使化合物终浓度达到10μM和100μM。DMSO终浓度为1%。
细胞置于37℃,100%相对湿度,5%CO2培养箱中孵育48小时;
加入10μl CCK-8溶液并置于37℃培养箱中孵育4小时。
轻轻震荡后在SpectraMax M5 Microplate Reader上测定450nm波长处的吸光度,以650nm处吸光度作为参比,计算抑制率。
(3)数据处理
按下式计算药物对肿瘤细胞生长的抑制率:肿瘤细胞生长抑制率%=[(Ac-As)/(Ac-Ab)]×100%
As:样品的OA(细胞+CCK-8+待测化合物)
Ac:阴性对照的OA(细胞+CCK-8+DMSO)
Ab:阳性对照的OA(培养基+CCK-8+DMSO)
表3对细胞抗增殖活性测试结果
从上表可见,与阳性对照Rocilinostat相比,本发明化合物对多种肿瘤细胞均显示了良好的体外抗肿瘤细胞增殖活性,对人骨髓瘤细胞(NCI-H929)、人神经母细胞瘤细胞(SH-SY5Y)、人慢性髓系白血病细胞(K562)具有较高的抑制活性;尤其在测试浓度下对SH-SY5Y部分化合物显示明显优于阳性药的抗增殖活性。。
同时,本发明化合物相对于Rocilinostat,对MRC-5人正常胚肺成纤维细胞的抑制活性较弱,具有更低的毒副作用,揭示本发明化合物在对于肿瘤细胞和正常细胞的抑制增殖方面具有更好的选择性,预示其作为抗肿瘤药物使用时,可能具有更低的毒副作用。
实施例16化合物对hERG钾通道影响实验
采用hERG钾离子通道抑制试验初步考察本发明部分化合物体外潜在心脏毒副作用。实验操作如下:
1)细胞准备
CHO-hERG细胞培养于175cm2培养瓶中,待细胞密度生长到60~80%,移走培养液,用7mLPBS洗一遍,然后加入3mL Detachin消化。
待消化完全后加入7mL培养液中和,然后离心,吸走上清液,再加入5mL培养液重悬,以确保细胞密度为2~5×106/mL。
2)电生理记录过程
单细胞高阻抗封接和全细胞模式形成过程全部由Qpatch仪器自动完成,在获得全细胞记录模式后,细胞钳制在-80毫伏,在给予一个5秒的+20毫伏去极化刺激前,先给予一个50毫秒的-50毫伏前置电压,然后复极化到-50毫伏维持5秒,再回到-80毫伏。每15秒施加此电压刺激,记录2min后给予细胞外液记录2min,然后开始给药过程,化合物浓度从最低测试浓度开始,每个测试浓度给予2min,连续给完所有浓度后,给予阳性对照化合物10μMCisapride。每个浓度至少测试3个细胞(n≥3)。
3)化合物准备
将化合物母液用细胞外液进行稀释,取2μL的化合物母液加入998μL细胞外液,然后在含0.2%DMSO的细胞外液中依次进行5倍连续稀释得到需要测试的最终浓度。实验数据由XLFit软件进行分析。
实验结果如下表4:
表4
hERG实验结果显示,测试化合物T1~T6,T9,和T10对hERG钾离子通道的抑制活性均大于20μM,提示本发明化合物潜在的心脏毒性较低。
实施例17急性毒性试验
采用张均田主编的《现代药理实验方法》报道的方法,初步筛选,经用Bliss法统计,化合物T-9和T-12小鼠单次灌服的LD50分别为1700mg/kg和1500mg/kg。试验结果表明T-9和T-12的急性毒性风险较低。
实施例18药物组合物1
将实施例9制备的化合物T-9与填充剂、崩解剂、润滑剂混合、制粒、压片,得到以化合物T-9为活性成分的药物组合物1。
实施例19药物组合物2
将实施例12制备的化合物T-12与溶剂、稳定剂混合、过滤、包装,得到以化合物T-12为活性成分的药物组合物2。
实施例20药物组合物3
将实施例2制备的化合物T-2、实施例12制备的化合物T-12与填充剂、崩解剂、润滑剂混合、制粒、压片,得到以化合物T-2和T-12为活性成分的药物组合物3。
以上所述仅是本发明的优选实施方式,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,还可以作出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (15)
1.一种苯并二氮杂卓类化合物,结构通式如式(Ⅰ)所示,或其异构体,或其药学上可接受的盐、酯或前药;
其中,
R1和R2独立地选自氢、氘、羟基、卤素、烷基、烷氧基、环烷基、苄基、杂环烷基、芳基、杂芳基、氰基、卤代烷基、酰基、磺酰基或氨基烷基,其各个可任选被取代。
2.根据权利要求1所述的苯并二氮杂卓类化合物,其特征在于,所述的烷基为含有1~4个碳原子的烷基,其可任选地被0~3个卤素取代;
和/或,所述的环烷基为含有3~6个碳原子的环烷基,岂可任选地被0~3个卤素取代;
和/或,所述的杂环烷基选自吡咯基、吗啉基、哌啶基、哌嗪环、四氢喹啉基、四氢三唑并吡嗪基、二氮杂环庚烷基或哌嗪基,其可任选地被取代;
和/或,所述的芳基或杂芳基选自苯基、萘基、蒽基、吡啶基、嘧啶基、吡嗪基、吲哚基、咪唑基、苯并噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、三唑基、异噁唑基、喹啉基、吡咯基、吡唑基或5,6,7,8-四氢异喹啉;其可任选地被取代;
和/或,所述的酰基选自乙酰基、丙酰基、异丁酰基或芳基酰基,其可任选地被取代;
和/或,所述的磺酰基选自甲磺酰基或芳基磺酰基,其可任选地被取代;
和/或,所述的氨基烷基选自二甲氨基烷基、甲基氨基烷基、哌嗪烷基或哌啶烷基,其可任选地被取代;
和/或,所述的卤素选自氟、氯、溴;
和/或,所述的烷氧基选自含有1~4个碳原子的烷氧基。
3.根据权利要求1所述的苯并二氮杂卓类化合物,其特征在于,式(Ⅰ)化合物药学上可接受的盐包括式(Ⅰ)化合物与盐酸、氢溴酸、硫酸、醋酸、三氟醋酸、柠檬酸、酒石酸、马来酸、富马酸、甲磺酸、苹果酸、对甲苯磺酸或草酸反应生成的阴离子盐;或式(Ⅰ)化合物与钠离子溶液、钾离子溶液反应生成的阳离子盐。
4.根据权利要求1或2所述的苯并二氮杂卓类化合物,其特征在于,R1和R2独立地选自氢、甲基、F、Cl、Br或甲氧基。
5.根据权利要求4所述的苯并二氮杂卓类化合物,其特征在于,包括以下化合物或其异构体,或其药学上可接受的盐、酯或前药:
6.一种权利要求1-5任意一项所述苯并二氮杂卓类化合物的制备方法,其特征在于,包括以下步骤:
S1,氮气保护下,式(Ⅱ)化合物与4-溴甲基苯甲酸甲酯反应得到式(Ⅲ)化合物;
其中,R1和R2如权利要求1-5任意一项所示;
S2,式(Ⅲ)化合物与碱性羟胺溶液反应得到式(Ⅰ)化合物;
7.根据权利要求6所述的制备方法,其特征在于,步骤S1的反应温度为60~100℃,反应时间为1.5~4h。
8.根据权利要求6所述的制备方法,其特征在于,式(Ⅱ)化合物的制备方法包括下述任意一种方法:
方法1包括以下步骤:
A1,式(Ⅳ)化合物与丙烯酸在酸性条件下反应得到式(Ⅱ)化合物;
方法2包括以下步骤:
B1,式(Ⅴ)化合物与丙烯酸加热反应,得到式(Ⅵ)化合物;
B2,式(Ⅵ)化合物在Pt/C催化下与氢气反应生成式(Ⅶ)化合物,或,式(Ⅵ)化合物与在Zn催化下与浓盐酸反应生成式(Ⅶ)化合物;
B3,式(Ⅶ)化合物与浓盐酸在加热条件下反应得到式(Ⅱ)化合物;
9.根据权利要求6所述的制备方法,其特征在于,步骤A1中,式(Ⅴ)化合物、丙烯酸与浓盐酸混合,在60~85℃下反应10~16h;
和/或,步骤B1中,反应温度为120~145℃,反应时间6~10h;
和/或,步骤B2中,式(Ⅶ)化合物、Pt/C溶解在有机溶剂中,通入氢气1.5~3h,反应生成式(Ⅷ)化合物;
和/或,步骤B2中,式(Ⅶ)化合物、浓盐酸、有机溶剂混合后,缓慢加入锌粉至反应终止;
和/或,步骤B3中,反应温度为60~80℃,反应时间为3~6h。
10.一种用于制备权利要求1-5任意一项所述苯并二氮杂卓类化合物的中间体化合物,包括式(Ⅱ)化合物或其异构体、药学上可接受的盐、酯或前药:
和/或,式(Ⅲ)化合物或其异构体、药学上可接受的盐、酯或前药:
和/或,式(Ⅳ)化合物或其异构体、药学上可接受的盐、酯或前药:
和/或,式(Ⅴ)化合物或其异构体、药学上可接受的盐、酯或前药:
和/或,式(Ⅵ)化合物或其异构体、药学上可接受的盐、酯或前药:
和/或,式(Ⅶ)化合物或其异构体、药学上可接受的盐、酯或前药:
其中,R1、R2如权利要求1-5任意一项所示。
11.权利要求1-5任意一项所述苯并二氮杂卓类化合物、权利要求6-9任意一项所述制备方法得到的苯并二氮杂卓类化合物或权利要求10所述的中间体化合物在制备组蛋白去乙酰化酶抑制剂或抗肿瘤药物中的应用。
12.根据权利要求11所述的应用,其特征在于,所述组蛋白去乙酰化酶抑制剂为HDAC6和/或HDAC1抑制剂。
13.根据权利要求11所述的应用,其特征在于,所述抗肿瘤药物包括抗乳腺癌、结肠癌、肝癌、多发性骨髓瘤、肉瘤、肺癌、前列腺癌、直肠癌、肾癌、胰腺癌、血癌、成神经细胞瘤、神经胶质瘤、头癌、颈癌、甲状腺癌、卵巢癌、外阴癌、子宫颈癌、子宫内膜癌、睾丸癌、膀胱癌、食管癌、胃癌、鼻咽癌、颊癌、口腔癌、胃肠道间质瘤、皮肤癌的药物。
14.一种药物组合物,包括至少一种活性组分以及一种或多种药学上可接受的辅料;所述活性组分包括权利要求1-5任意一项所述苯并二氮杂卓类化合物或权利要求6-9任意一项所述制备方法得到的苯并二氮杂卓类化合物。
15.根据权利要求14所述的药物组合物,其特征在于,所述药学上可接受的辅料包括稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂、香味剂和甜味剂中的一种或多种。
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