CN102875479B - 喹唑啉二酮衍生物及其制备方法、其药物组合物及用途 - Google Patents
喹唑啉二酮衍生物及其制备方法、其药物组合物及用途 Download PDFInfo
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- CN102875479B CN102875479B CN201210408391.1A CN201210408391A CN102875479B CN 102875479 B CN102875479 B CN 102875479B CN 201210408391 A CN201210408391 A CN 201210408391A CN 102875479 B CN102875479 B CN 102875479B
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Abstract
本发明涉及一类具有式（I）结构的喹唑啉二酮衍生物及其药学上可接受的盐、其制备方法、含有其药物制剂的药物组合物及其医药用途。本发明的结构如式（I）所示的化合物对HDAC活性的半数抑制浓度普遍在10-7mol.L-1以下。该系列化合物可用于癌症、纤维化疾病、炎症性疾病、免疫紊乱相关疾病、神经退行性疾病等。预防和治疗。
Description
技术领域
本发明涉及生物医药领域，特别涉及一类具有式（I）结构的喹唑啉二酮衍生物及其药学上可接受的盐、其制备方法、含有其药物制剂的药物组合物及其医药用途。
背景技术
组蛋白乙酰化是最早被发现的与转录相关的组蛋白修饰方式之一，是一种可逆的蛋白共价修饰形式，组蛋白的乙酰化有利于DNA与组蛋白八聚体的解离、核小体结构松弛，从而使各种转录因子和协同转录因子与DNA结合位点特异性结合，激活基因的转录。组蛋白低乙酰化状态时，核小体结构紧密，使各种促进细胞生长、分化和凋亡的基因转录受到抑制，和肿瘤的发生密切相关。
组蛋白的低乙酞化和组蛋白去乙酰化酶(histone deacetylases，HDACs)的过度表达是大多数癌症的基本特征。乙酰化状态的组蛋白H4的减少是癌症的共同特点之一，该过程发生在肿瘤形成的早期阶段，在肿瘤发展过程中起到至关重要的作用。这为采用组蛋白去乙酰化酶抑制剂(HDACi)抑制HDACs的作用能够恢复异常的表观基因至正常水平提供了一个依据。除了与早期肿瘤的形成密切相关外，H4低乙酰化也牵涉到肿瘤的入侵和转移中。用组蛋白去乙酞化酶抑制剂TSA处理胃肠癌细胞后，引起被抑制了的控制肿瘤入侵和转移的基因的重新表达。
HDACs的表达异常与多种人类肿瘤密切相关。在人类的许多肿瘤细胞中都发现了基因表达的改变以及HDACs的异常表达现象，而通过干扰RNA技术敲除过度表达的HDACs后，体外培养的肿瘤细胞增殖得到抑制。对培养的肿瘤细胞以及人肿瘤组织的标本进行研究，都发现了HDACs与正常细胞相比过度表达的现象。研究胃癌、食道癌、卵巢癌、肺癌、前列腺癌和甲状腺癌患者的组织样本中的表达情况，发现超过75％的癌组织和其周围的正常上皮细胞中HDACs过度表达。
HDACs的表达或活性的调节异常与肿瘤的形成、入侵和转移密切相关，而小分子的组蛋白去乙酰化酶抑制剂HDACi应用到患有恶性肿瘤的病人身上己经获得了抗肿瘤效果且安全特性好。因此HDACs引起人们的广泛研究兴趣，以HDACs为靶标将是癌症治疗一种有效的策略，HDACi已成为是目前研究的最有潜力的抗肿瘤药物之一。
发明内容
本发明的目的是在现有技术的基础上提供一种结构如式（I）所示的喹唑啉二酮衍生物或其药学上可接受的盐。
本发明的另一目的是提供一种结构如式（I）所示的喹唑啉二酮衍生物的制备方法。
本发明的再以目的是提供一种含有结构如式（I）所示的喹唑啉二酮衍生物或其药学上可接受的盐的药物组合物及该药物组合物的用途。
为了实现前述目的，本发明采用如下的技术方案：
一种结构通式如式（I）所示的喹唑啉二酮衍生物或其药学上可接受的盐：
式（I）
其中，R1、R2可彼此相同或不同，各自独立地选自氢、卤素、胺基、硝基、氰基、酰胺基、羟基、烷氧基、C1-C6烷基、C3-C8全碳单环环烷基、C6-C10芳基或C5-C10杂芳基，其中所述胺基、酰胺基、烷氧基、C1-C6烷基、C3-C8全碳单环环烷基、C6-C10芳基或C5-C10杂芳基独立可选地被一个或多个选自卤素、胺基、硝基、氰基、酰胺基、羟基、烷氧基、C1-C6烷基、C3-C8全碳单环环烷基、C6-C10芳基、C5-C10杂芳基的取代基所取代。
本发明的另一方面，所述R1和R2通过键连接形成5至8元环，所述5至8元环是饱和或不饱和的；所述5至8元环中可含有一个或多个O、S或N等杂原子；所述5至8元环独立可选地被一个或多个自卤素、胺基、硝基、氰基、酰胺基、羟基、烷氧基、C1-C6烷基、C3-C8全碳单环环烷基、C6-C10芳基、C5-C10杂芳基的取代基所取代。
在一个优选的实施方式中，所述R1、R2各自独立地选自氢、卤素、氰基、C1-C6烷基、C3-C8全碳单环环烷基；其中所述C1-C6烷基、C3-C8全碳单环环烷基独立可选地被一个或多个选自卤素、胺基、硝基、氰基、酰胺基、羟基、烷氧基、C1-C6烷基、C3-C8全碳单环环烷基、C6-C10芳基、C5-C10杂芳基的取代基所取代。
在一个更优选的实施方式中，所述R1、R2各自独立地选自氢、卤素、甲基、三氟甲基、乙基、氰基、环丙基；或者R1和R2通过键连接形成5至8元环是饱和或不饱和的，该5至8元环为C5-C8全碳单环环烷基、C5-C8杂环基、C6-C10芳基或C5-C10杂芳基，所述C5-C8全碳单环环烷基、C5-C8杂环基、C6-C10芳基或C5-C10杂芳基独立可选地被一个或多个自卤素、胺基、硝基、氰基、酰胺基、羟基、烷氧基、C1-C6烷基、C3-C8全碳单环环烷基、C6-C10芳基、C5-C10杂芳基的取代基所取代。
在一个最优选的实施方式中，所述喹唑啉二酮衍生物为以下四种结构式所示的化合物：
一种前述式（I）所示的喹唑啉二酮衍生物的制备方法，包括以下步骤：
1）将式（2）的尿嘧啶或被取代的尿嘧啶通过HMDS进行硅烷化保护后，加入4-溴甲基肉桂酸甲酯进行烷基化反应得到式（3）中间体，停止反应后浓缩柱层析得白色固体的式（3）中间体；
其中R1、R2可彼此相同或不同，各自独立地选自氢、卤素、胺基、硝基、氰基、酰胺基、羟基、烷氧基、C1-C6烷基、C3-C8全碳单环环烷基、C6-C10芳基或C5-C10杂芳基，其中所述胺基、酰胺基、烷氧基、C1-C6烷基、C3-C8全碳单环环烷基、C6-C10芳基或C5-C10杂芳基独立可选地被一个或多个选自卤素、胺基、硝基、氰基、酰胺基、羟基、烷氧基、C1-C6烷基、C3-C8全碳单环环烷基、C6-C10芳基、C5-C10杂芳基的取代基所取代；
2）将式（3）中间体与氢氧化锂碱性环境下水解得到相应的醇，酸化得到白色固体式（4）的中间体；
3）将式（4）中间体与BOP、盐酸羟胺、DIPEA混合，加入DMF溶剂，室温搅拌反应，浓缩，柱层析后得到式（1）所示的喹唑啉二酮衍生物。
式(2) 式(3)
式(4) 式(1)
一种药物组合物，包括前述式（1）的喹唑啉二酮衍生物或其药学上可接受的盐和药学上可接受的载体或稀释剂。
所述的药物组合物的用途，用于抑制HDAC的活性，预防和/或治疗因HDAC活性抑制而改善的疾病。
所述因HDAC活性抑制而改善的疾病包括癌症、纤维化疾病、炎症性疾病、免疫紊乱相关疾病、神经退行性疾病。
所述药物组合物用作癌症治疗的辅助手段或者与其他抗肿瘤药物的组合用药，用于对肿瘤细胞的抑制和/或杀灭。
根据本发明的式（1）的喹唑啉二酮衍生物或其药学上可接受的盐组成的药物组合物可以用来抑制HDAC的活性，预防和/或治疗因HDAC活性抑制而改善的疾病。
根据本发明的式（1）的喹唑啉二酮衍生物或其药学上可接受的盐组成的药物组合物对HDAC活性的半数抑制浓度普遍在10-7mol.L-1以下。该系列化合物可用于癌症、纤维化疾病、炎症性疾病、免疫紊乱相关疾病、神经退行性疾病等。
具体实施方式
本发明公开了一种化合物及该化合物作为HDAC抑制剂的应用，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
式（I）
其中，
R1、R2选自氢、卤素、胺基、硝基、氰基、酰胺基、羟基、烷氧基、C1-C6烷基、C3-C8全碳单环环烷基、C6-C10芳基、C5-C10杂芳基。其中所述胺基、酰胺基、烷氧基、C1-C6烷基、C3-C8全碳单环环烷基、C6-C10芳基、C5-C10杂芳基可以进一步被一个或多个选自卤素、胺基、硝基、氰基、酰胺基、羟基、烷氧基、C1-C6烷基、C3-C8全碳单环环烷基、C6-C10芳基、C5-C10杂芳基的取代基所取代；
或R1和R2通过键连接形成5至8元环，所述5至8元环是饱和或不饱和的；该5至8元环中可含有一个或多个O、S或N等杂原子；所述5至8元环独立可选地被一个或多个自卤素、胺基、硝基、氰基、酰胺基、羟基、烷氧基、C1-C6烷基、C3-C8全碳单环环烷基、C6-C10芳基、C5-C10杂芳基的取代基所取代；
进一步地优选，R1、R2选自氢、卤素、氰基、C1-C6烷基、C3-C8全碳单环环烷基。其中所述C1-C6烷基、C3-C8全碳单环环烷基可以进一步被一个或多个选自卤素、胺基、硝基、氰基、酰胺基、羟基、烷氧基、C1-C6烷基、C3-C8全碳单环环烷基、C6-C10芳基、C5-C10杂芳基的取代基所取代；
或R1和R2通过键连接形成5至8元环，所述5至8元环是饱和或不饱和的；该5至8元环中可含有一个或多个O、S或N等杂原子；所述5至8元环独立可选地被一个或多个自卤素、胺基、硝基、氰基、酰胺基、羟基、烷氧基、C1-C6烷基、C3-C8全碳单环环烷基、C6-C10芳基、C5-C10杂芳基的取代基所取代；
再进一步地优选，R1、R2选自氢、卤素、甲基、三氟甲基、乙基、氰基、环丙基；或者R1和R2通过键连接形成5至8元环是饱和或不饱和的，该5至8元环为C5-C8全碳单环环烷基、C5-C8杂环基、C6-C10芳基或C5-C10杂芳基，所述C5-C8全碳单环环烷基、C5-C8杂环基、C6-C10芳基或C5-C10杂芳基可被一个或多个自卤素、胺基、硝基、氰基、酰胺基、羟基、烷氧基、C1-C6烷基、C3-C8全碳单环环烷基、C6-C10芳基、C5-C10杂芳基的取代基所取代；
本发明通式（I）所示的化合物最优选地包括但不限于：
本发明中，术语“C1-C6烷基”是指具有直链或支链部分并含有1至6个碳原子的饱和一价烃基。此类基团的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基和叔丁基。
术语“C3-C8全碳单环环烷基”是指具有总共3至8个碳原子的饱和的、单环的环结构。此类基团的实例包括但不限于环丙基、环丁基、环戊基。
术语“C6-C10芳基”是指含有6至10个碳原子的衍生至芳烃的基团。此类基团的实例包括但不限于苯基、苄基、萘基。
术语“C5-C10杂芳基”是指在其环中含有5至10个碳原子并含有1至4个各自独立地选自O、S和N的杂原子的芳族杂环基团。条件是所述基团的环上不含两个相邻的O原子或两个相邻的S原子。该杂环基团包括苯并稠环体系。C5-C10杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、二氮杂萘基、异吲哚基、嘌呤基、苯并噻吩基、苯并噻唑基。所述C5-C10杂芳基在可能的情况下可以为C-连接的或N连接的。
术语“C5-C8杂环基”是指非芳族的、单环或多环或螺环基团，该基团在其环体系中具有5至8个碳原子与1至4个各自独立地选自O、S和N的杂原子，条件是所述基团的环不含两个相邻的O原子或两个相邻的S原子。当C5-C8杂环基含有硫原子时，所述硫原子可以被一个或两个氧原子氧化。C5-C8杂环基的实例包括但不限于哌嗪子基指基团吗啉代基哌啶子基吡咯烷基四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基。
术语“卤素”和“卤代”是指氟、氯、溴、碘。
术语“C6-C10芳氧基”是指-O-C6-C10芳基。
术语“C1-C6烷氧基”是指-O-C1-C6烷基。
所谓“各自独立地”的意思是指R1和R2两个基团独立地选自某个基团，两者互不影响且相互独立，即R1和R2有可能相同，也有可能不同。
所谓“可选地”的意思是指后续描述的事件或情形可能会也可能不会发生，并且该描述包括事物或情形可能会也可能不会发生，并且该描述包括事物或情形发生和不发生两种情况。
在一些实施方案中，“被一个或多个基团取代”是指在指定的原子或基团中的一个、两个、三个或四个氢原子分别被指定范围的基团中选出的相同或不同的基团替换。
本发明还提供了上述各化合物的药学上可接受的盐。“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括：
（1）与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸包括盐酸、氢溴酸、氢碘酸、硝酸、亚硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸包括乙酸、丙酸、丙烯酸、草酸、（D）或（L）苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
（2）存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属例子例如碱金属离子、碱土金属离子或铝离子，有机碱，例如乙胺、二乙胺、二环己胺、三乙胺、丁胺、乙二胺、乙醇胺、二乙醇胺、三乙醇胺、哌嗪、苄胺、苯基苄胺、胆碱、葡甲胺、氨丁三醇、N-甲基葡糖胺等。
本发明还涉及一种药用组合物，包含本发明提供的通式（I）所示的化合物和药学上可接受的载体或稀释剂。
“药物组合物”指将本发明中的化合物中的一个或多个或其药学上可接受的盐与别的化学成分形成的组合物，例如药学上可接受的载体，混合。药物组合物的目的是促进给药给动物的过程。
“药学上可接受的载体”指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的药物组合物中的非活性成分，例如包括但不限于：碳酸钙、磷酸钙、各种糖（例如乳糖、甘露醇等）、淀粉、环糊精、硬脂酸镁、纤维素、碳酸镁、丙烯酸聚合物或甲基丙烯酸聚合物、凝胶、水、聚乙二醇、丙二醇、乙二醇、蓖麻油或氢化蓖麻油或多乙氧基氢化蓖麻油、芝麻油、玉米油、花生油等。
前述的药物组合物中，除了包括药学上可接受的载体外，还可以包括在药（剂）学上常用的辅剂，例如：抗细菌剂、抗真菌剂、抗微生物剂、保质剂、调色剂、增溶剂、增稠剂、表面活性剂、络合剂、蛋白质、氨基酸、脂肪、糖类、维生素、矿物质、微量元素、甜味剂、色素、香精或它们的结合等。
本发明中的“可选进一步被……基团所取代”是指前面所指的各基团可以“被……基团所取代”，也可以不“被……基团所取代”。
本发明涉及的通式（I）所示的化合物提供用在人或动物体治疗方法中。
本发明的另一方面在于提供本发明所定义的通式化合物（I）在制备用于抑制PARP活性的药物中的用途。
本发明的其他方面在于提供如本发明所定义的通式化合物（I）在药物制备用于预防和/或治疗因HDAC活性抑制而改善的疾病中的用途，包括但不限于癌症、纤维化疾病（包括肺纤维化、肾纤维化）、炎症性疾病（包括关节炎、回肠炎、肾炎、接触性皮炎等）、免疫紊乱相关疾病、神经退行性疾病等。
本发明的另一方面在于提供如本发明所定义的通式化合物（I）在药物制备中的用途，该药物用作癌症治疗脑癌、肾癌、肝癌、乳腺癌、胃癌、白血病、卵巢癌、前列腺癌等等。
下面结合实施例，进一步阐述本发明：
实施例1：(E)-3-(4-((2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)甲基)苯基)-N-羟基酰胺F1的制备
将尿嘧啶（0.25g，2.2mmol）、六甲基二硅胺烷（HMDS）（10mL）、浓硫酸1滴加入100mL茄形瓶中，氮气保护，120℃搅拌反应4h后浓缩除去HMDS。向反应瓶中加入4-溴甲基肉桂酸甲酯（0.51g，2mmol）、1，2-二氯乙烷20mL，氮气保护，升温回流反应8h，停止反应后浓缩柱层析得白色固体（E1-1）370mg，产率65％。HPLC：97.5%，MS(ESI)m/z：[M+H]+=287.4。
1H-NMR(400M,DMSO-d6)δ11.36(s,1H),7.77(d,1H),7.72(d,2H),7.65(d,1H),7.34(d,2H),6.63(d,1H),5.62(dd,1H),4.90(s,2H),3.73(s,3H)ppm。
将中间体E1-1（286mg，1mmol）、一水合氢氧化锂（105mg，2.5mmol）、水20mL加到100mL茄型瓶中，氮气保护，室温搅拌24h，酸化得白色固体（E1-2）245mg，产率90％。MS(ESI)m/z：[M-H]-=271.0。
将中间体E1-2（200mg，0.74mmol）、苯并三氮唑-1-基氧基三（二甲基氨基）磷鎓六氟磷酸盐(BOP)（490mg，1.11mmol）、盐酸羟胺（78mg，1.11mmol）、N，N-二异丙基乙胺（DIPEA）（478mg，3.71mmol）、DMF（25mL）加至100mL茄形瓶中，氮气保护，室温搅拌反应12h，浓缩，柱层析后得(E)-3-(4-((2，4-二氧代-3,4-二氢嘧啶-1(2H)-基)甲基)苯基)-N-羟基酰胺F1（127mg），产率60％。MS(ESI)m/z：[M+H]+=288.1，HPLC：98.4％。
1H-NMR(400M,DMSO-d6)δ11.36(s,1H),10.81(s,1H),9.09(brs,1H),8.00(d,1H),7.67(d,2H),7.58(d,1H),7.42(d,2H),6.44(d,1H),5.62(dd,1H),4.89(s,2H)ppm。
实施例2：(E)-3-(4-((5-乙基-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)甲基)苯基)-N-羟基酰胺F2的制备
采用制备化合物F1相类似的方法可制得化合物F2（97mg，74%）。HPLC：97.03%，MS:[M+H]+=316.1.
1H-NMR(400M,DMSO-d6)δ11.34(s,1H),10.80(s,1H),9.05(brs,1H),7.60(s,1H),7.57(d,2H),7.43(d,1H),7.32(d,2H),6.47(d,1H),4.89(s,2H),2.23(q,2H),1.03(t,3H)ppm。
实施例3：(E)-3-(4-((5，6-二甲基-2，4-二氧代-3，4-二氢嘧啶-1(2H)-基)甲基)苯基)-N-羟基酰胺的制备
采用制备化合物F1相类似的方法可制得化合物F3（75mg，58%）。HPLC：94.33%，MS:[M+H]+=316.4.
1H-NMR(400M,DMSO-d6)δ11.38(s,1H),10.89(s,1H),9.10(brs,1H),7.60(d,2H),7.41(d,1H),7.29(d,2H),6.53(d,1H),4.89(s,2H),2.23(q,2H),2.23(m,3H)，1.98(m,3H)ppm。
实施例4：(E)-3-(4-((2，4-二氧代-5-(三氟甲基)-3，4-二氢嘧啶--1(2H)-基)甲基)苯基)-N-羟基酰胺的制备
采用制备化合物F1相类似的方法可制得化合物F4（105mg，63%）。HPLC：95.10%，MS:[M+H]+=356.0.
1H-NMR(400M,DMSO-d6)δ11.36(s,1H),10.81(s,1H),9.09(brs,1H),8.29(d,1H),7.57(d,2H),7.38(d,1H),7.29(d,2H),6.91(d,1H),4.84(s,2H)ppm。
实施例5：HDAC抑制剂生化水平筛选
实验目的：
建立HDAC抑制剂筛选模型，为以后筛选有HDAC抑制作用的化合物奠定基础，同时以阳性药物验证模型稳定性，可靠性。
实验原理：
本实验采用两步反应：第一步：底物1Boc-Lys(Ac)MCA（H4一段序列），在HDAC作用下，生成去乙酰化底物2，lysine ε-NH2暴露；第二步：去乙酰化底物被Trypsin降解，释放出荧光基团3，而未去乙酰化底物不被胰酶降解，通过测定化合物在ex 380nm，em 460nm荧光强度，测定化合物的HDAC抑制作用并计算IC50值。
注：为防止HDAC在第二步反应对结果的影响，第二步加入的胰酶混合物中加入2μM TSA。
实验操作：
1.化合物配置：根据具体情况将化合物溶于DMSO中，配置成10-1、10-2M储备液。
2.各组分终浓度：substrate 50μM（储备液50mM,临用前应用assay buffer稀释至工作浓度），HDAC（30×）（应用前应用assay buffer稀释30倍，15μl/well加入96well plate），TSA 10-7---10-11M.（储备液DMSO配置，2mg/ML（6.6*10-3M），实验前应用HDAC buffer配置至所需浓度）。
3.各组分加入量及反应时间（以96孔板为例,100μl体系）
第一步：
| Sample | Assay buffer | HDAC(dilution) | Compound(5×) | Substrate(2×) |
| Blank | 25μl | 0 | 0 | 25μl |
| Control | 10μl | 15μl | 0 | 25μl |
| TSA | 0 | 15μl | 10μl | 25μl |
| Test sample | 0 | 15μl | 10μl | 25μl |
注：Compound（5×）：化合物配置浓度为最终测试浓度的5倍
Substrate（2×）：化合物配置浓度为最终测试浓度的2倍，即若底物终浓度为50μM,则加入浓度为100μM。
各组分按顺序加入后，37℃孵育1h
第二步：
加入developer 50μl/well（其中TSA含量为2μM,直接加入developer中，若应用商业化developer，应用assay buffer稀释后加入TSA），37℃孵育20min
于Ex：380nm，Em460nm处测荧光值。本发明提供结构如式Ⅰ所示化合物对PARP酶活性的半数抑制浓度（IC50）见表1：
表1化合物对PARP酶活性的半数抑制浓度（IC50）
| 化合物 | F1 | F2 | F3 | F4 |
| 活性强度 | +++ | +++ | ++ | +++ |
+++表示IC50<100nM；++表示IC50范围为100-500nM；+表示IC50范围为500nM-5μM；-表示未测试。
以上关于本发明的具体描述，仅用于说明本发明而并非受限于本发明实施例索描述的技术方案，本领域的普通技术人员应当理解，仍然可以对本发明进行修改或等同替换，已达到相同技术效果；只要满足使用需要，都在本发明的保护范围之内。
Claims (2)
1. 一种喹唑啉二酮衍生物的制备方法，其特征在于，包括以下步骤：
1）将式（2）的尿嘧啶或被取代的尿嘧啶通过HMDS进行硅烷化保护后，加入4-溴甲基肉桂酸甲酯进行烷基化反应得到式（3）中间体，停止反应后浓缩柱层析得白色固体的式（3）中间体；
其中R1、R2可彼此相同或不同，各自独立地选自氢、C1-C6烷基、C3-C8全碳单环环烷基，其中所述C1-C6烷基、C3-C8全碳单环环烷基独立可选地被一个或多个选自卤素的取代基所取代；
2）将式（3）中间体与氢氧化锂碱性环境下水解后，再酸化得到白色固体式（4）的中间体；
3）将式（4）中间体与BOP、盐酸羟胺、DIPEA混合，加入DMF溶剂，室温搅拌反应，浓缩，柱层析后得到式（1）所示的喹唑啉二酮衍生物，
。
2.根据权利要求1所述的一种喹唑啉二酮衍生物的制备方法，其特征在于，所述R1、R2选自氢、甲基、乙基或三氟甲基。
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| US11993580B1 (en) | 2022-12-02 | 2024-05-28 | Neumora Therapeutics, Inc. | Methods of treating neurological disorders |
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| CN1764648A (zh) * | 2003-01-13 | 2006-04-26 | 安斯泰来制药有限公司 | 作为组蛋白脱乙酰酶(hdac)抑制剂的异羟肟酸衍生物 |
| CN1795175A (zh) * | 2003-08-20 | 2006-06-28 | Axys药物公司 | 作为组蛋白脱乙酰基酶抑制剂的乙炔衍生物 |
| CN1882529A (zh) * | 2003-09-24 | 2006-12-20 | 梅特希尔基因公司 | 组蛋白脱乙酰基酶抑制剂 |
| WO2008053863A1 (fr) * | 2006-10-30 | 2008-05-08 | Santen Pharmaceutical Co., Ltd. | Nouveau composé ayant un squelette de 1,4-benzothiazin-3-one ou un squelette de 3,4-dihydroquinolin-2-one |
| US20110053925A1 (en) * | 2009-08-28 | 2011-03-03 | Novartis Ag | Hydroxamate-Based Inhibitors of Deacetylases |
| US20110060009A1 (en) * | 2009-08-28 | 2011-03-10 | Novartis Ag | Hydroxamate-Based Inhibitors of Deacetylases |
| WO2012025155A1 (en) * | 2010-08-26 | 2012-03-01 | Novartis Ag | Hydroxamate-based inhibitors of deacetylases |
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| CN1764648A (zh) * | 2003-01-13 | 2006-04-26 | 安斯泰来制药有限公司 | 作为组蛋白脱乙酰酶(hdac)抑制剂的异羟肟酸衍生物 |
| CN1795175A (zh) * | 2003-08-20 | 2006-06-28 | Axys药物公司 | 作为组蛋白脱乙酰基酶抑制剂的乙炔衍生物 |
| CN1882529A (zh) * | 2003-09-24 | 2006-12-20 | 梅特希尔基因公司 | 组蛋白脱乙酰基酶抑制剂 |
| WO2008053863A1 (fr) * | 2006-10-30 | 2008-05-08 | Santen Pharmaceutical Co., Ltd. | Nouveau composé ayant un squelette de 1,4-benzothiazin-3-one ou un squelette de 3,4-dihydroquinolin-2-one |
| US20110053925A1 (en) * | 2009-08-28 | 2011-03-03 | Novartis Ag | Hydroxamate-Based Inhibitors of Deacetylases |
| US20110060009A1 (en) * | 2009-08-28 | 2011-03-10 | Novartis Ag | Hydroxamate-Based Inhibitors of Deacetylases |
| WO2012025155A1 (en) * | 2010-08-26 | 2012-03-01 | Novartis Ag | Hydroxamate-based inhibitors of deacetylases |
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| Optimization of the in Vitro Cardiac Safety of Hydroxamate-Based Histone Deacetylase Inhibitors;Michael D. Shultz等;《Journal of Medicinal Chemistry》;20110608;第54卷(第13期);第4752-4772页 * |
| S. Vadivelan等.Pharmacophore modeling and virtual screening studies to design some potential histone deacetylase inhibitors as new leads.《Journal of Molecular Graphics & * |
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