CN117229229A - 一种抑制hdac6的苯并噻二嗪类化合物及其制备方法及应用 - Google Patents
一种抑制hdac6的苯并噻二嗪类化合物及其制备方法及应用 Download PDFInfo
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- CN117229229A CN117229229A CN202210640872.9A CN202210640872A CN117229229A CN 117229229 A CN117229229 A CN 117229229A CN 202210640872 A CN202210640872 A CN 202210640872A CN 117229229 A CN117229229 A CN 117229229A
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Abstract
本发明提供一种抑制组蛋白去乙酰化酶的苯并噻二嗪类化合物及其制备方法及应用,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。本发明所述苯并噻二嗪类化合物结构新颖,作为组蛋白去乙酰化酶HDAC6和HDAC1抑制剂,可有效抑制K562(人慢性髓系白血病细胞)和NCI‑H929(人骨髓瘤细胞)增殖,对正常细胞毒性小、潜在心脏风险低,有望作为高效低毒抗肿瘤治疗剂。
Description
技术领域
本发明涉及药物技术领域,尤其涉及一种抑制组蛋白去乙酰化酶的苯并噻二嗪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)能够催化组蛋白和非组蛋白的去乙酰化过程,和组蛋白乙酰转移酶(histone acetyltransferases,HATs) 共同调节细胞内乙酰化水平,从而调控基因的表达。目前,已知哺乳动物HDACs有18个亚型,分为四类:I类(HDAC1、HDAC2、HDAC3、HDAC8); II类:IIa(HDAC4、HDAC5、HDAC7、HDAC9)和IIb(HDAC6、HDAC10); III类(Sirt1~Sirt7);IV类(HDAC11)。
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)。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HDAC抑制剂在临床上已取得良好疗效,但仍存在如下缺点:(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。因此,开发高效低毒的新型 HDAC抑制剂仍然存在挑战。
HDAC6是HDAC家族中最大的成员,与其它HDAC成员不同,HDAC6 是唯一含有两个催化结构域的组蛋白去乙酰化酶(CD1和CD2),主要分布在胞质内而不是细胞核内,并且在组蛋白的翻译后修饰中无明显的作用。 HDAC6具有强的组蛋白去乙酰化酶活性,能够介导非组蛋白的脱乙酰化进程,其主要作用底物有α-微管蛋白(α-tubulin)、热休克蛋白90(heatshock protein 90,HSP90)和皮层肌动蛋白(cortactin)等。由于HDAC6独特的结构和底物多样性,可参与细胞内的多种生理过程,包括细胞运动、内吞作用、细胞自噬、细胞凋亡以及蛋白质转运和降解。大量研究证实HDAC6的过度表达与多种疾病密切相关,如癌症、自身免疫性疾病或神经退行性疾病等。
目前Celgene公司研发的HDAC6抑制剂Ricolinostat(ACY-1215)已进入临床二期,Phase Ib结果显示Ricolinostat是一种安全且耐受良好的选择性 HDAC6抑制剂,可单独使用或与来那度胺和地塞米松配合使用,用于治疗复发或难治性多发性骨髓瘤。
发明内容
本发明提供了一种新型抑制HDAC6活性的苯并噻二嗪类化合物及其制备方法和应用,对HDAC6和HDAC1均有较强的抑制活性,对肿瘤细胞选择性好,潜在心脏毒性小,,有望作为高效低毒抗肿瘤治疗剂。
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噻二嗪类化合物,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选自氢、卤素、烷基、烷氧基、苄基、芳基、杂芳基、氰基、酰基、酰胺基、烷胺基、磺酰基或含有0-2个N、O和S中的一种或多种杂原子的 5-7元环,其可任选的被取代;
R2选自氢、烷基、酰基、酰胺基、磺酰基或含有0-2个N、O和S中的一种或多种杂原子的5-7元环,其可任选的被取代。
优选的,所述烷基选自C1-C6烷基,其可任选的被1-3个卤素取代;
优选的,所述卤素选自F、Cl或Br;
优选的,所述5-7元环选自吡咯基、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,其可任选的被取代;
优选的,所述杂芳基选自萘基、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,其可任选被取代;
优选的,所述酰基选自C1-C4烷基取代的酰基或芳基取代酰基;
优选的,所述磺酰基选自C1-C4烷基取代的磺酰基或芳基取代磺酰基;
优选的,所述烷胺基选自二甲氨基烷基、甲基氨基烷基、哌嗪烷基或哌啶烷基,其可任选的被取代。
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。
进一步优选的,R1选自氢、卤素、C1-C6烷基或含有1-6个C原子的烷氧基,其可任选的被取代;
进一步优选的,R2选自氢、苄基、C1-C6烷基或含有1-6个C原子的酰基。
在本发明的一些具体实施方式中,苯并噻二嗪类化合物可以是以下化合物或其异构体,或其药学上可接受的盐、酯或前药:
本发明的第二方面提供了一种上述技术方案所述苯并噻二嗪类化合物的制备方法,包括以下步骤:
S1,式(Ⅱ)化合物与氯磺酰异氰酸酯经过傅克酰基化反应和缩合成环反应得到式(Ⅲ)化合物;
其中,R1选自氢、卤素、烷基、烷氧基、苄基、芳基、杂芳基、氰基、酰基、酰胺基、烷胺基、磺酰基或含有0-2个N、O和S中的一种或多种杂原子的5-7元环,其可任选的被取代;
S2,式(Ⅲ)化合物与4-溴甲基苯甲酸甲酯经过第一取代反应得到式(Ⅳ) 化合物;
其中,式(Ⅵ)化合物中的X为卤素;
S3,若R2为氢,则式(Ⅳ)化合物与羟胺进行羟胺化反应,得到式(Ⅰ) 化合物;
若R2不为氢,则式(Ⅳ)化合物与式(Ⅴ)化合物进行第二取代反应得到式(Ⅵ)化合物,式(Ⅵ)化合物与羟胺进行羟胺化反应得到式(Ⅰ) 化合物;
其中,R2如权利要求1、2、4或5所示的非氢基团;
其中,式(Ⅴ)化合物中的X为卤素。
优选的,步骤S1中,傅克酰基化反应包括以下步骤:在-45℃~-30℃下将式(Ⅱ)化合物与氯磺酰异氰酸酯混合进行取代反应,以氯化铝为催化剂在105℃~120℃下进行缩合成环反应。
优选的,步骤S2中,所述第一取代反应包括以下步骤:以碳酸钾为催化剂,式(Ⅲ)化合物与4-溴甲基苯甲酸甲酯进行取代反应,脱水,得到式 (Ⅳ)化合物。
优选的,步骤S3中,所述羟胺化反应以烷基醇盐为催化剂;所述第二取代反应以碳酸钾为催化剂,反应温度为-5℃~5℃。
本发明的第三方面提供了一种制备前述技术方案所述苯并噻二嗪类化合物的中间体化合物,包括式(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(Ⅵ)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一种前述技术方案所述苯并噻二嗪类化合物、前述技术方案所述制备方法得到的苯并噻二嗪类化合物或上述技术方案所述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,所述抗肿瘤药物包括抗多发性骨髓瘤药物。
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噻二嗪类化合物或前述技术方案所述制备方法得到的苯并噻二嗪类化合物。
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:
1.本发明提供的苯并噻二嗪类化合物结构新型,对HDAC6及HDAC1抑制活性高(nM级别),部分化合物对HDAC6显示一定的HDAC6选择性抑制作用(相较于HDAC1);
2.本发明提供的苯并噻二嗪类化合物对人慢性髓系白血病细胞K562、人骨髓瘤细胞NCI-H929等显示出较强的抗增殖活性,同时对人胚肺成纤维细胞 MRC-5毒性,表现较好的肿瘤细胞选择性抑制作用;
3.本发明提供的苯并噻二嗪类化合物对hERG抑制活性弱,潜在心脏毒性较小。
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,所述苯并噻二嗪化合物可以按照下述通式制备得到:
以R1为取代基的苯胺为原料,与氯磺酰异氰酸酯经过傅克酰基化和缩合成环反应得到关键中间体化合物苯并噻二嗪二氧化物(式(Ⅲ)化合物)。苯并噻二嗪二氧化物的4位N与4-溴甲基苯甲酸甲酯发生亲核取代反应生成式(Ⅳ)化合物,式(Ⅳ)化合物直接经羟胺化或2位N经亲核取代成酯再羟胺化后得式(Ⅰ)化合物。
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-((1,1-二氧化物-3-氧代-3,4-二氢-2H-苯并[e][1,2,4]噻二嗪 -2-基)甲基)-N-羟基苯甲酰胺(T1)的制备
按照合成通法进行制备T1,合成路线如下:
具体合成操作如下:
1)-40℃条件下,将苯胺(270mmol)溶解于100mL硝基甲烷中,然后用滴管漏斗滴加到氯磺酰异氰酸酯(26mL,300mmol)的200mL硝基甲烷溶液中。添加完成后,将反应混合物再搅拌30分钟并添加氯化铝(39g, 300mmol)。然后在搅拌下将混合物加热至110℃并保持1小时。然后将粗物质倒入冰中,抽滤收集沉淀,用冷水和无水乙醚洗涤,无水乙醇打浆,得到中间体2a。
2)将中间体2a(10mmol)、碳酸钾(12mmol)加入到30mL的N,N- 二甲基甲酰胺中,并滴加4-溴甲基苯甲酸甲酯的乙腈溶液(10mmol/20mL),室温搅拌4小时。反应完成后,将反应液倒入200mL水中,有固体析出,过滤分离所得固体。滤饼用水冲洗并真空干燥以产生区域异构烷基化产物的混合物,通过柱层析(石油醚:乙酸乙酯体系)得到中间体4-((1,1-二氧化-3- 氧代-3,4-二氢-2H-1,2,4-苯并噻二嗪-2-基)甲基)苯甲酸甲酯(3a)。ESI-MS (m/z):346.90[M+H]+。1H NMR(600MHz,DMSO)δ11.54(s,1H),7.92(dd,J =22.7,8.0Hz,3H),7.77–7.72(m,1H),7.48(d,J=8.1Hz,2H),7.38–7.30(m, 2H),5.06(s,2H),3.84(s,3H).
3)将中间体3a(2mmol)加入到羟胺/甲醇钠的甲醇溶液(20mmol) 中。并在冰水浴条件下,滴加甲醇钠甲醇溶液(10mmol),反应4-6小时。反应完成后,加入2倍体积的水,并用2M的HCI水溶液调PH为7-8,有固体析出,过滤,甲醇打浆,得到目标化合物T1。mp>250℃。ESI-MS(m/z): 348.50[M+H]+。1H NMR(400MHz,DMSO)δ7.80(d,J=7.9Hz,1H),7.75– 7.62(m,3H),7.38(p,J=6.8,5.6Hz,2H),7.24(t,J=7.6Hz,2H),4.98(s,2H).
实施例2:4-((7-氟-1,1-二氧基-3-氧代-3,4-二氢-2H-苯并[e][1,2,4]噻二嗪-2-基)甲基)-N-羟基苯甲酰胺(T2)的制备
按照通法制备T2。mp 170.6-172.1℃。ESI-MS(m/z):366.60[M+H]+。 1H NMR(400MHz,DMSO)δ12.57(s,1H),7.71(dd,J=11.7,8.4Hz,3H), 7.54(td,J=8.8,3.0Hz,1H),7.37(dd,J=13.5,7.9Hz,2H),7.26(dd,J=9.1, 4.4Hz,1H),4.98(s,2H).
实施例3:N-羟基-4-((7-甲基-1,1-二氧基-3-氧代-3,4-二氢-2H-苯并 [e][1,2,4]噻二嗪-2-基)甲基)苯甲酰胺(T3)的制备
按照通法制备T3。mp 204.1-208.8℃。ESI-MS(m/z):377.90[M+H]+。 1H NMR(600MHz,DMSO-d6)δ11.25(s,1H),9.05(s,1H),7.70(d,J=8.1Hz, 2H),7.39(d,J=8.1Hz,2H),7.33(d,J=2.8Hz,2H),7.25(d,J=8.6Hz,1H), 5.01(s,2H),3.84(s,3H).
实施例4:4-((7-氯-1,1-二氧基-3-氧代-3,4-二氢-2H-苯并[e][1,2,4]噻二嗪-2-基)甲基)-N-羟基苯甲酰胺(T4)的制备
按照通法制备T4。mp 164.1-166.2℃。ESI-MS(m/z):381.80[M+H]+。1H NMR(600MHz,DMSO-d6)δ11.14(s,1H),9.06(s,1H),7.93(d,J=2.4Hz, 1H),7.74(dd,J=8.8,2.5Hz,1H),7.71–7.68(m,2H),7.39(d,J=8.0Hz,2H), 7.28(d,J=8.8Hz,1H),5.00(s,2H).
实施例5:N-羟基-4-((7-甲氧基-1,1-二氧基-3-氧基-3,4-二氢-2H-苯并 [e][1,2,4]噻二嗪-2-基)甲基)苯甲酰胺(T5)的制备
按照通法制备T5。mp 204.1-208.8℃。ESI-MS(m/z):377.90[M+H]+。 1H NMR(600MHz,DMSO-d6)δ11.25(s,1H),9.05(s,1H),7.70(d,J=8.1Hz, 2H),7.39(d,J=8.1Hz,2H),7.33(d,J=2.8Hz,2H),7.25(d,J=8.6Hz,1H), 5.01(s,2H),3.84(s,3H).
实施例6:4-((7-溴-1,1-二氧基-3-氧-3,4-二氢-2H-苯并[e][1,2,4]噻二嗪 -2-基)甲基)-N-羟基苯甲酰胺(T6)的制备
按照通法制备T6。mp 197.6-202.2℃。ESI-MS(m/z):425.70[M+H]+。 1H NMR(600MHz,DMSO-d6)δ12.44(s,1H),11.27(s,1H),9.07(s,1H),7.93 (d,J=2.2Hz,1H),7.83(dd,J=8.8,2.2Hz,1H),7.80(d,J=8.2Hz,2H),7.57 (d,J=8.1Hz,2H),7.22(d,J=8.8Hz,1H),5.42(s,2H).
实施例7:4-((4-苄基-7-氯-1,1-二氧基-3-氧-3,4-二氢-2H-苯并[e][1,2,4] 噻二嗪-2-基)甲基)-N-羟基苯甲酰胺(T7)的制备
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按照通法制备T7。mp 135.8-137.8℃。ESI-MS(m/z):445.90[M+H]+。 1H NMR(600MHz,DMSO-d6)δ7.66(d,J=7.8Hz,2H),7.53(d,J=2.6Hz, 1H),7.32(d,J=6.0Hz,4H),7.24(d,J=7.5Hz,3H),6.71(t,J=5.6Hz,1H), 6.62(d,J=9.0Hz,1H),4.43(d,J=5.7Hz,2H),4.03(s,2H).
实施例8:4-((7-氯-4-(环丙基甲基)-1,1-二氧基-3-氧基-3,4-二氢-2H- 苯并[e][1,2,4]噻二嗪-2-基)甲基)-N-羟基苯甲酰胺(T8)的制备
按照通法制备T8。mp 164.4-166.4℃。ESI-MS(m/z):410.00[M+H]+。 1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),7.63(d,J=7.8Hz,2H),7.50(d, J=2.7Hz,1H),7.33(dd,J=8.9,2.7Hz,1H),7.23(d,J=7.9Hz,2H),6.74(d,J =9.0Hz,1H),6.17(t,J=5.2Hz,1H),4.02(s,2H),3.00(t,J=5.9Hz,2H),1.09 (t,J=7.0Hz,1H),0.51–0.46(m,2H),0.24(t,J=5.0Hz,2H).
实施例9:4-((4-乙酰基-1,1-二氧基-3-氧基-3,4-二氢-2H-苯并[e][1,2,4] 噻二嗪-2-基)甲基)-N-羟基苯甲酰胺(T9)的制备
按照通法制备T9。mp 150.1-152.4℃。ESI-MS(m/z):390.02[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.25(s,1H),9.05(s,1H),7.70(d,J=8.1Hz, 2H),7.39(d,J=8.1Hz,2H),7.33(d,J=2.8Hz,2H),7.25(d,J=8.6Hz,1H), 5.01(s,2H),3.84(s,3H).
实施例10:4-((6-氯-1,1-二氧基-3-氧代-3,4-二氢-2H-苯并[e][1,2,4]噻二嗪-2-基)甲基)-N-羟基苯甲酰胺(T10)的制备
按照通法制备T10。mp 168.2-170.1℃。ESI-MS(m/z):381.66[M+H]+。 1H NMR(600MHz,DMSO-d6)δ11.13(s,1H),9.06(s,1H),7.93(d,J=2.4Hz, 1H),7.74(dd,J=8.8,2.5Hz,1H),7.71–7.68(m,2H),7.39(d,J=8.0Hz,2H), 7.28(d,J=8.8Hz,1H),4.98(s,2H).
实施例11化合物对HDAC抑制活性
使用已开发建立的实验平台测试条件进行化合物对HDAC6、HDAC1靶点抑制效果的检测,以Rocilinostat(ACY-1215)作为阳性对照化合物。
1)试剂及耗材
2)仪器
3)HDAC酶配置
HDAC6酶抑制实验:将样品配置成stock浓度为40mM的DMSO溶液,避光保存备用。
HDAC1酶抑制实验:化合物配置成stock浓度为20mM的DMSO溶液,均避光保存备用。
4)HDAC6酶学反应过程
a配制1×反应溶液。
b化合物浓度梯度的配制:待测化合物测试终浓度为80nM起始,4倍稀释,5个浓度,设置单孔检测,阳性化合物测试终浓度为3μM起始,3 倍稀释,10个浓度,设置复孔检测。在384孔Source板中梯度稀释成相应 100倍终浓度的溶液,然后用Echo550转移250nL到384孔反应板中待测。 Max孔和Min孔中均转移250nL的100%DMSO。
c用1×反应溶液配制1.67×酶溶液。
d在各孔中加15μL的1.67×酶溶液;在Min孔中加15μL的1.6×反应溶液。室温孵育15分钟。
e用1×反应溶液配制2.5×底物混合溶液。
f反应板各孔中加入10μL的2.5×底物混合溶液,起始反应。
g使用Synergy连续读取荧光信号。
5)HDAC1酶学反应过程
a配制1×反应溶液。
b化合物浓度梯度的配制:待测化合物测试终浓度为2μM起始,10倍稀释,4个浓度,设置单孔检测;阳性药测试浓度为3μM起始,3倍稀释, 10个浓度,设置复孔检测。在384孔Source板中梯度稀释成相应100倍终浓度的溶液,然后用Echo550转移250nL到384孔反应板中待测。Max孔和Min孔中均转移250nL的100%DMSO。
c用1×反应溶液配制1.67×酶溶液。
d在各孔中加15μL的1.67×酶溶液;在Min孔中加15μL的1.6×反应溶液。室温孵育15分钟。
e用1×反应溶液配制2.5×底物混合溶液。
f反应板各孔中加入10μL的2.5×底物混合溶液,起始反应。
g使用Synergy连续读取荧光信号。
6)数据分析
选取线性反应段得到斜率(slope)。进而计算百分比抑制率,计算公式如下:
其中:Mean(Max)是各Max孔(含DMSO和酶)斜率值的均值; Mean(Min)是各Min孔(无酶孔)斜率值的均值;Sample Signal是化合物孔的斜率值。
拟合量效曲线:以化合物浓度的log值作为X轴,对应的百分比抑制率为Y轴,采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线,从而得出各个化合物抑制酶活性的IC50值。
实验结果见表:
实验结果显示,本发明化合物对HDAC6显示较强的抑制活性 (IC50<50nM),同时对HDAC1也显示抑制活性,除化合物T7和T8外,化合物对HDAC1抑制活性均优于阳性对照Rocilinostat(ACY-1215)。
实施例12化合物对肿瘤细胞及人体正常细胞抗增殖活性
采用CCK-8法测试本发明化合物在单浓度(10μM)条件下对K562(人慢性髓系白血病细胞)、NCI-H929(人骨髓瘤细胞)及MRC-5人正常胚肺成纤维细胞的抗增殖活性,选择Rocilinostat(ACY-1215)为阳性对照。
1)细胞株
K562(人慢性髓系白血病细胞)(来源:ATCC);
NCI-H929(人骨髓瘤细胞)(来源:ATCC);
MRC-5人正常胚肺成纤维细胞(来源:ATCC)
2)试剂和耗材
Cell Counting Kit-8(Cat#CK04-13,Dojindo)
96孔培养板(Cat#3599,Corning Costar)
胎牛血清(Cat#10099-141,GIBCO)
培养基(Invitrogen)
台式酶标仪SpectraMax M5 Microplate Reader(Molecular Devices)
3)实验步骤
(1)细胞培养
a)收集对数生长期细胞,计数,用完全培养基重新悬浮细胞,
b)调整细胞浓度至合适浓度(依照大蒜辣素药效学实验中细胞密度优化试验结果确定),接种96孔板,每孔接种100μl细胞悬液。
c)细胞在37℃,100%相对湿度,5%CO2培养箱中孵育12-24小时。
(2)筛选
a)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。
b)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%。
c)细胞置于37℃,100%相对湿度,5%CO2培养箱中孵育48小时;
d)加入10μlCCK-8溶液并置于37℃培养箱中孵育4小时。
e)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)
抗细胞增殖实验结果如表(单位为:Inh%in 10μM):
A:>90%;B:80~90%;C:70~80%;D:50~70%E:<50%
从上表可见,与阳性对照Rocilinostat相比,本发明化合物对肿瘤细胞显示了较好的体外抗肿瘤细胞增殖活性,对K562(人慢性髓系白血病细胞) 抗增殖活性优于阳性对照,对NCI-H929(人骨髓瘤细胞)抗增殖活性优于或相当于阳性对照药。
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13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T1~T6, T9,和T10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7mL PBS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:
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14药物组合物1
将实施例4制备的化合物T4与填充剂、崩解剂、润滑剂混合、制粒、压片,得到以化合物T4为活性成分的药物组合物1。
实施例15药物组合物2
将实施例5制备的化合物T5与溶剂、稳定剂混合、过滤、包装,得到以化合物T5为活性成分的药物组合物2。
实施例16药物组合物3
将实施例2制备的化合物T2、实施例10制备的化合物T10与填充剂、崩解剂、润滑剂混合、制粒、压片,得到以化合物T2和T10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 (13)
1.一种苯并噻二嗪类化合物,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选自氢、卤素、烷基、烷氧基、苄基、芳基、杂芳基、氰基、酰基、酰胺基、烷胺基、磺酰基或含有0-2个N、O和S中的一种或多种杂原子的5-7元环,其可任选的被取代;
R2选自氢、烷基、酰基、酰胺基、磺酰基或含有0-2个N、O和S中的一种或多种杂原子的5-7元环,其可任选的被取代。
2.根据权利要求1所述的苯并噻二嗪类化合物,其特征在于,所述烷基选自C1-C6烷基,其可任选的被1-3个卤素取代;
所述卤素选自F、Cl或Br;
所述5-7元环选自吡咯基、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,其可任选的被取代;
所述杂芳基选自萘基、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,其可任选被取代;
所述酰基选自C1-C4烷基取代的酰基或芳基取代酰基;
所述磺酰基选自C1-C4烷基取代的磺酰基或芳基取代磺酰基;
所述烷胺基选自二甲氨基烷基、甲基氨基烷基、哌嗪烷基或哌啶烷基,其可任选的被取代。
3.根据权利要求1所述的苯并噻二嗪类化合物,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所述的苯并噻二嗪类化合物,其特征在于,
R1选自氢、卤素、C1-C6烷基或含有1-6个C原子的烷氧基,其可任选的被取代;
R2选自氢、苄基、C1-C6烷基或含有1-6个C原子的酰基。
5.根据权利要求4所述的苯并噻二嗪类化合物,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任意一项所述苯并噻二嗪类化合物的制备方法,包括以下步骤:
S1,式(Ⅱ)化合物与氯磺酰异氰酸酯经过傅克酰基化反应和缩合成环反应得到式(Ⅲ)化合物;
其中,R1如权利要求1、2、4或5所示;
S2,式(Ⅲ)化合物与4-溴甲基苯甲酸甲酯经过第一取代反应得到式(Ⅳ)化合物;
其中,R1如权利要求1、2、4或5所示;
S3,若R2为氢,则式(Ⅳ)化合物与羟胺进行羟胺化反应,得到式(Ⅰ)化合物;
若R2不为氢,则式(Ⅳ)化合物与式(Ⅴ)化合物进行第二取代反应得到式(Ⅵ)化合物,式(Ⅵ)化合物与羟胺进行羟胺化反应得到式(Ⅰ)化合物;
其中,R2如权利要求1、2、4或5所示的非氢基团;
其中,式(Ⅴ)化合物中的X为卤素。
7.根据权利要求6所述的制备方法,其特征在于,步骤S1中,在-45℃~-30℃下将式(Ⅱ)化合物与氯磺酰异氰酸酯混合进行取代反应,以氯化铝为催化剂在105℃~120℃下进行缩合成环反应;
和/或,步骤S2中,所述第一取代反应包括以下步骤:以碳酸钾为催化剂,式(Ⅲ)化合物与4-溴甲基苯甲酸甲酯进行取代反应,脱水,得到式(Ⅳ)化合物;
和/或,步骤S3中,所述羟胺化反应以烷基醇盐为催化剂;所述第二取代反应以碳酸钾为催化剂,反应温度为-5℃~5℃。
8.一种制备权利要求1-5任意一项所述苯并噻二嗪类化合物的中间体化合物,包括: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(Ⅵ)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、2、4或5所示。
9.权利要求1-5任意一项所述苯并噻二嗪类化合物、权利要求6-7任意一项所述制备方法得到的苯并噻二嗪类化合物或权利要求8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。
10.根据权利要求9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。
11.根据权利要求9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。
12.一种药物组合物,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任意一项所述苯并噻二嗪类化合物或权利要求6-7任意一项所述制备方法得到的苯并噻二嗪类化合物。
13.根据权利要求12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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