CN114539263B - 一类含氮并杂环化合物及其药用组合物和应用 - Google Patents
一类含氮并杂环化合物及其药用组合物和应用 Download PDFInfo
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- CN114539263B CN114539263B CN202111329003.6A CN202111329003A CN114539263B CN 114539263 B CN114539263 B CN 114539263B CN 202111329003 A CN202111329003 A CN 202111329003A CN 114539263 B CN114539263 B CN 114539263B
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- nitrogen
- pharmaceutically acceptable
- containing heterocyclic
- heterocyclic compound
- acceptable salt
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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Abstract
本发明提供了一种具有式Ⅰ所示结构的含氮并杂环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子及其药物组合物和应用。本发明涉及的化合物及其药学上可接受的盐可以有效抑制多种肿瘤细胞的生长,可用于制备抗肿瘤药物。
Description
技术领域
本发明涉及化学医药技术领域,具体涉及一类含氮并杂环化合物及其药用组合物和应用。
背景技术
恶性肿瘤(癌症)是一类威胁人类健康的重大恶性疾病。常规治疗癌症的方法,包括放疗、化疗、手术切除以及药物治疗等。但这些方法往往存在副作用大、治疗效果欠佳,肿瘤预后复发、转移等弊端。因此,迫切需要发展新的治疗技术来解决癌症治疗中的这些问题。个体化治疗和靶向治疗是近年来被看作是突破目前癌症治疗瓶颈的希望所在。
肿瘤分子靶向治疗基于对肿瘤生长密切相关的关键信号通路,通过化学或生物学手段进行调控而发展的一种新的治疗方法。靶向小分子药物具有特异性高,选择性强,毒副作用较轻等特点;可以单独或者与现有药物联合用于癌症的治疗。从2001年以伊马替尼甲磺酸盐(Novartis)为代表的小分子靶向药物得以应用以来,肿瘤靶向治疗在过去二十年中得到了迅速发展,目前已有数十种蛋白激酶小分子靶向药物上市,成为癌症治疗中的一类重要药物,为肿瘤化疗开创了一个新时代。
RIO蛋白激酶(RIOKs)目前已发现包括三种亚型,RIOK1,RIOK2以及RIOK3。是广泛存在于所有真核生物、大部分古细菌以及原核生物中的一类进化上较为保守的非典型蛋白激酶。其中RIOK1,RIOK2被发现存在于所有真核生物中,RIOK3存在于一些较高等的真核生物中。RIOKs激酶是40s核糖体前体的组成成分,并在40S核糖体生成过程中的不同阶段分别发挥其不同功能,例如RIOK1或RIOK2的缺失将阻止40S核糖体的成熟。RIOKs具有蛋白激酶的结构域,但缺乏其他真核蛋白激酶中所存在的底物结合区域,包括活化环。研究表明,RIOKs主要是作为ATP水解酶来发挥功能。RIOK2在多类的癌症中呈现高表达。在非小细胞肺癌患者中,RIOK2的高表达与最终结果的恶性程度呈现明显的相关性。细胞周期的正常进行依赖于蛋白的翻译,但RIOK2是简单的通过高表达来增强核糖体的组装能力从而促进蛋白合成,还是获得了其他的促进核糖体组装的致癌性功能还有待深入研究。目前已有一些证据表明,RIOK1和RIOK2能促进细胞增殖和存活,其表达与致癌的AKT信号通路相关。RIOK1和RIOK2可能还在PI3Ks激酶和包括EGFR在内的受体酪氨酸激酶等下游信号通路中发挥作用。
由于RIOK2在多种类型癌症中高表达,并且其生物功能并不完全清楚,因此发展RIOK2激酶小分子抑制剂,有助于了解RIOK家族在细胞中的生物功能,并有望以此为基础发展新的靶向药物。2019年牛津大学、礼来公司、巴西西亚瓦斯城市大学的研究人员合作报道了人类RIOK2蛋白与小分子抑制剂结合的晶体结构(Wang,J.et al,Open Biol.2019,9,190037),为开发RIOK2小分子抑制剂奠定了基础。但他们所报道的小分子抑制剂与RIOK2蛋白的结合常数(Kd)在150nM以上,活性相对较弱。因此,发展具有新骨架、高活性的RIOK家族小分子抑制剂,具有迫切的需要。
发明内容
针对上述问题,本发明提供了一类新的含氮并杂环化合物,这类新的含氮并杂环化合物的核心部分主要为喹喔啉酮并五元杂环结构或类似物。这类新的含氮并杂环化合物在有机溶剂中具有较好的溶解度,能够高活性的抑制RIOK2蛋白激酶的活性,从而能够抑制多种肿瘤细胞的增殖。
具体技术方案如下:
具有式(Ⅰ)所示结构的含氮并杂环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子:
其中,
A1、A2、B1、B2、D和E分别独立地选自:N、CR4;
X任选自:O、S、NR5;
n选自:0或1;
Ar1和Ar2分别独立选自:取代或未取代的C6~C10芳基、取代或未取代的5~10元杂芳基;
R1任选自:H、C1~C6烷基、C3~C6环烷基、3~6元杂环烷基、C1~C8酰基、磺酰基、C6~C18芳基、C6~C18芳基取代的C1~C6烷基、5~18元杂芳基;当R1不为氢时,所述R1独立任选地被1个或多个R6取代;
各R4分别独立地选自:H、卤素、C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、氨基、羟基、氰基、硝基、酯基、酰胺基、磺酰基、磺酰氨基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基、5~18元杂芳基;当R4选自C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基或5~18元杂芳基时,所述R4独立任选地被1个或多个R6取代;
R5任选自:H、C1~C18烷基、C6~C18芳基取代的C1~C18烷基、C3~C18环烷基、C6~C18芳基取代的C3~C18环烷基、C1~C8酰基、磺酰基;当R5不为氢时,所述R5独立任选地被1个或多个R6取代;
各R6分别独立地选自:H、羟基、氨基、氰基、三氟甲基、二氟甲基、硝基、卤素、C1~C6烷氧基、C1~C6烷基胺基、C1~C6烷基酰胺基、C1~C6烷基;
R2、R3分别独立地选自:H、C1~C6烷基、C3~C6环烷基、3~6元杂环烷基、C1~C8酰基、磺酰基、C6~C18芳基、C6~C18芳基取代的C1~C6烷基、5~18元杂芳基,或者R2、R3和与其相连的碳原子一起组成3~6元环烷基、3~6元杂环烷基、或者3~6元杂环脲基;当R2、R3不为氢时,所述R2、R3独立任选地被1个或多个R6取代。
在其中一些实施例中,Ar1和Ar2分别独立地任选自:苯基、噻唑基、呋喃基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、吲哚基、苯并噻唑基、苯并咪唑基、苯并呋喃基;所述Ar1和Ar2分别独立任选地被一个或多个取代基取代,或者未被取代基取代。
在其中一些实施例中,所述的含氮并杂环类化合物具有式(Ⅱ)或者式(III)所示结构:
其中,n选自:0或1;
X1、X2、X3、X4、X5分别独立地选自:N、CR7;
X6、X7、X8、X9和X10分别独立地选自:N、CR8、CR;并且X6、X7、X8、X9和X10中至少有一个选自CR;
Y选自:O、S、NR5;
各R7、R8分别独立地选自:H、卤素、C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、氨基、羟基、氰基、硝基、酯基、酰胺基、磺酰基、磺酰氨基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基、5~18元杂芳基;当R7或R8选自C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基或5~18元杂芳基时,所述R7、R8独立任选地被1个或多个R6取代;
各R9、R10分别独立地任选自:H、C1~C8烷基,羟基取代的C1~C8烷基,C1~C8烷氧基取代的C1~C8烷基、C3~C8环烷基、C1~C8酰基、烯基酰基、磺酰基、5~18元杂芳基、取代或者未取代的3-10元杂环基、取代或者未取代的3-10元杂环基取代的酰基;或者R9、R10与和其相连的N原子一起形成取代或者未取代的3-10元杂环基。
在其中一些实施例中,所述的含氮并杂环类化合物具有式(IV)或(V)所示结构:
在其中一些实施例中,所述的含氮并杂环类化合物具有式(VI)所示结构:
在其中一些实施例中,各R9、R10分别独立地任选自:H、C1~C8烷基,羟基取代的C1~C8烷基,C1~C8烷氧基取代的C1~C8烷基、C3~C8环烷基、C1~C8酰基、烯基酰基、磺酰基、5~18元杂芳基;或者各R9、R10分别独立地任选自如下结构:
各R11分别独立地任选自:H、卤素、C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、氨基、羟基、氰基、硝基、酯基、C1~C6酰基、C1~C6胺基酰基、酰胺基、磺酰基、磺酰氨基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基、5~18元杂芳基、5-18元杂芳酰基;当R11选自C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基或5~18元杂芳基时,所述R11独立任选地被1个或多个R6取代;
R12选自:H、C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、酯基、酰基、胺基酰基、磺酰基、胺基磺酰基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基、5~18元杂芳基、5-18元杂芳酰基;当R12选自C1~C18烷基、C3~C18环烷基、3~18元杂环烷基、C1~C18烷氧基、C1~C18烷胺基、C6~C18芳基、C6~C18芳基取代的C1~C18烷基或5~18元杂芳基时,所述R12独立任选地被1个或多个R13取代;
各R13分别独立地任选自:H、羟基、氨基、氰基、硝基、卤素、C1~C6烷氧基、C1~C6烷基、磷酸基、二甲基胺基、3~8元杂环烷基、R14取代的3~8元杂环烷基;R14选自:C1~C6烷基、3~8元杂环烷基。
在其中一些实施例中,各R11分别独立地任选自:H、C1~C6烷基、C3~C8环烷基、3~8元杂环烷基、C1~C6烷氧基、C1~C6烷胺基、氨基、羟基、氰基、硝基、酯基、C1~C6酰基、C1~C6胺基酰基、酰胺基、磺酰基、磺酰氨基、C6~C10芳基、C6~C10芳基取代的C1~C10烷基、5~10元杂芳基、5-10元杂芳酰基;当R11选自C1~C6烷基、C3~C8环烷基、3~8元杂环烷基、C1~C6烷氧基、C1~C6烷胺基、C6~C10芳基、C6~C10芳基取代的C1~C6烷基或5~10元杂芳基时,所述R11独立任选地被1个或多个R6取代;
各R12分别独立地任选自:H、C1~C6烷基、C3~C8环烷基、3~8元杂环烷基、C1~C6烷氧基、C1~C6烷胺基、酯基、C1~C6酰基、C1~C6胺基酰基、磺酰基、C1~C6胺基磺酰基、C6~C10芳基、C6~C10芳基取代的C1~C10烷基、5~10元杂芳基、5-10元杂芳酰基;当R12选自C1~C6烷基、C3~C8环烷基、3~8元杂环烷基、C1~C6烷氧基、C1~C6烷胺基、C6~C10芳基、C6~C10芳基取代的C1~C6烷基或5~10元杂芳基时,所述R12独立任选地被1个或多个R13取代。
在其中一些实施例中,各R11分别独立地任选自:H、C1~C3烷基;
各R12分别独立地任选自:H、C1~C6烷基、羟基取代的C1~C6烷基、5~6元杂芳酰基。
在其中一些实施例中,各R7分别独立地任选自:H、卤素、C1~C6烷基、C3~C8环烷基、3~8元杂环烷基、C1~C6烷氧基、C1~C6烷胺基、氨基、羟基、氰基、硝基、酯基、酰胺基、磺酰基、磺酰氨基、C6~C10芳基、C6~C10芳基取代的C1~C6烷基、5~10元杂芳基;当R7选自C1~C6烷基、C3~C8环烷基、3~8元杂环烷基、C1~C6烷氧基、C1~C6烷胺基、C6~C10芳基、C6~C10芳基取代的C1~C6烷基或5~10元杂芳基时,所述R7独立任选地被1个或多个R6取代。
在其中一些实施例中,各R7分别独立地任选自:H、C1~C6烷基、C1~C6烷氧基、羟基、C1~C6烷基胺基、C1~C6烷基酰胺基。
在其中一些实施例中,各R8分别独立地任选自:H、卤素、C1~C6烷基、C3~C8环烷基、3~8元杂环烷基、C1~C6烷氧基、C1~C6烷胺基、氨基、羟基、氰基、硝基、酯基、酰胺基、磺酰基、磺酰氨基、C6~C10芳基、C6~C10芳基取代的C1~C6烷基、5~10元杂芳基;当R8选自C1~C6烷基、C3~C8环烷基、3~8元杂环烷基、C1~C6烷氧基、C1~C6烷胺基、C6~C10芳基、C6~C10芳基取代的C1~C6烷基或5~10元杂芳基时,所述R8独立任选地被1个或多个R6取代。
在其中一些实施例中,各R8分别独立地任选自:H、卤素、C1~C6烷基、C1~C6烷氧基、三氟甲基。
在其中一些实施例中,A1和B1中至少有1个为N;A2、B2、D和E均为CR4;X为O。
在其中一些实施例中,R1任选自:H、C1~C6烷基、羟基取代的C1~C6烷基、C3~C6环烷基、对甲氧基苄基。
本发明还提供了上述的含氮并杂环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子的应用。
具体技术方案如下:
上述的含氮并杂环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备RIOK2抑制剂中的应用。
上述的含氮并杂环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备预防或者治疗肿瘤的药物中的应用。
在其中一些实施例中,所述肿瘤为:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、胶质瘤。
本发明还提供了一种预防或者治疗肿瘤的药用组合物。
具体技术方案如下:
一种预防或者治疗肿瘤的药用组合物,由活性成分和药学上可接受的辅料制备得到,所述活性成分包括上述的含氮并杂环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
本发明的含氮并杂环类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子,是一类新颖的具有高活性、高选择性的RIOK2抑制剂,并对某些其他蛋白激酶产生抑制作用,可以有效抑制多种肿瘤细胞的生长,可用于制备抗肿瘤药物,可用于治疗人类及其它哺乳动物的肿瘤等过渡增殖性疾病。
具体实施方式
本发明所述化合物中,当任何变量(例如R等)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如,“C1-C6烷基”中“C1-C6”的定义包括以直链或支链排列的具有1、2、3、4、5或6个碳原子的基团。例如,“C1-C6烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、环丁基、环戊基或环己基等。术语“烷氧基”指具有-O-烷基结构的基团,如-OCH3、-OCH2CH3、-OCH2CH2CH3、-O-CH2CH(CH3)2、-OCH2CH2CH2CH3、-O-CH(CH3)2等。术语“杂环烷基”为饱和或部分不饱和的单环或多环环状取代基,其中一个或多个环原子选自N、O或S(O)m(其中m是0-2的整数)的杂原子,其余环原子为碳,例如:吗啉基、哌啶基、四氢吡咯基、吡咯烷基、二氢咪唑基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、四氢呋喃基、四氢噻吩基等,及其N-氧化物,杂环取代基的连接可通过碳原子或通过杂原子实现。术语“杂芳基”指含有1个或多个选自O、N或S的杂原子的芳香环,本发明范围内的杂芳基包括但不限于:喹啉基、吡唑基、吡咯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、三氮唑基、咪唑基、噁唑基、异噁唑基、哒嗪基;“杂芳基”也理解为包括任何含有氮的杂芳基的N-氧化物衍生物。
正如本领域技术人员所理解的,本文中所用“卤素”(“halo”)或“卤”意指氯、氟、溴和碘。
除非另有定义,烷基、环烷基、芳基、杂芳基和杂环烷基取代基可为未被取代的或取代的。例如,C1-C6烷基可被一个、两个或三个选自OH、卤素、烷氧基、二烷基氨基或杂环基例如吗啉基、哌啶基等的取代基取代。
本发明包括式Ⅰ-VI化合物的游离形式,也包括其药学上可接受的盐及立体异构体。本文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐,也包括所有式Ⅰ-VI化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如,可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别,但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此,本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐,也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2一乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐.得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2一二乙基氨基乙醇、2一二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N一乙基吗啉、N一乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
Berg等,“Pharmaceutical Salts,”J.Pharm.Sci.’1977:66:1-19更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。
由于在生理条件下化合物中脱质子化的酸性部分例如竣基可为阴离子的,而这种带有的电荷然后可被内部带有阳离子的质子化了的或烷基化的碱性部分例如四价氮原子平衡抵消,所以应注意本发明化合物是潜在的内盐或两性离子。
在一个实施方案中,本申请提供了一种利用具有式Ⅰ-VI的化合物及其药学可接受的盐治疗人或其它哺乳动物肿瘤等过渡增殖性疾病或症状。
在一个实施方案中,本申请的化合物及其药学可接受的盐可以用于治疗或控制非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、胶质瘤等过渡增殖性疾病。
药物代谢物及前药
本申请所涉及的化合物及其药学可接受的盐的代谢产物,以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药,也包含在本申请的权利要求中。
联合用药
式Ⅰ-VI化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时,原来药物的给药方式&剂量保持不变,而同时或随后服用式Ⅰ-VI化合物。当式Ⅰ-VI化合物与其它一种或几种药物同时服用时,优选使用同时含有一种或几种已知药物和式I-VI化合物的药用组合物。药物联用也包括在重叠的时间段服用式Ⅰ-VI化合物与其它一种或几种已知药物。当式Ⅰ-VI化合物与其它一种或几种药物进行药物联用时,式Ⅰ-VI化合物或已知药物的剂量可能比它们单独用药时的剂量较低。
可以与式Ⅰ-VI化合物进行药物联用的药物或活性成分包括但不局限为:
雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂,细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂,c-Kit抑制剂,Met抑制剂,Raf抑制剂,MEK抑制剂,MMP抑制剂,拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂,Bcl-2家族蛋白抑制剂,MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53、p53激活剂、VEGF抗体、EGF抗体等。
在一个实施方案中,可以与式Ⅰ-VI化合物进行药物联用的药物或活性成分包括但不局限为:阿地白介素、阿仑膦酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗或tice卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠制剂、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿来佐单抗注射剂、卡培他滨、卡铂、康士得、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、顺铂、克拉屈滨、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米松、磷酸地塞米松、戊酸雌二醇、地尼白介素2、狄波美、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、钦-166-壳聚糖复合物、eligard、拉布立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇制剂、17-β-雌二醇、雌莫司汀磷酸钠、炔雌醇、氨磷汀、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非那司提、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷一磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-β-D-阿糖呋喃糖胞噻啶-5’-硬脂酰磷酸酯、福莫司汀、氟维司群、丙种球蛋白、吉西他滨、吉妥单抗、甲磺酸伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素-α2、干扰素α-2A、干扰素α-2B、干扰素α-nl、干扰素α-n3、干扰素β、干扰素γ-la、白细胞介素-2、内含子A、易瑞沙、依立替康、凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、氮芥、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化雌激素、6-琉基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸甲酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢氢化可的松口服溶液剂、奥沙利铂、紫杉醇、泼尼松磷酸钠制剂、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸匹鲁卡品、毗柔比星、普卡霉素、卟吩姆钠、泼尼莫司汀、司替泼尼松龙、泼尼松、倍美力、丙卡巴脐、重组人类红细胞生成素、雷替曲塞、利比、依替膦酸铼-186、美罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、奥曲肽、沙莫司亭、司莫司汀、西佐喃、索布佐生、唬钠甲强龙、帕福斯酸、干细胞治疗、链佐星、氯化锶-89、左旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、甲睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁膦酸、拓扑替康、托瑞米芬、托西莫单抗、曲妥珠单抗、曲奥舒凡、维A酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、干扰素r-lb、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、BAY 43-9006、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、地西他滨、DN-101、阿霉素-MTC、dSLIM、度他雄胺、edotecarin、依氟鸟氨酸、依喜替康、芬维A胺、组胺二盐酸盐、组氨瑞林水凝胶植入物、钬-166DOTMP、伊班膦酸、干扰素γ、内含子-PEG、ixabepilone、匙孔形血蓝蛋白、L-651582、兰乐肽、拉索昔芬、libra、lonafamib、米泼昔芬、米诺屈酸酯、MS-209、脂质体MTP-PE、MX-6、那法瑞林、奈莫柔比星、新伐司他、诺拉曲特、奥利默森、onco-TCS、osidem、紫杉醇聚谷氨酸酯、帛米酸钠、PN-401、QS-21、夸西洋、R-1549、雷洛昔芬、豹蛙酶、13-顺维A酸、沙铂、西奥骨化醇、T-138067、tarceva、二十二碳六烯酸紫杉醇、胸腺素αl、嘎唑呋林、tipifarnib、替拉扎明、TLK-286、托瑞米芬、反式MID-lo7R、伐司朴达、伐普肽、vatalanib、维替泊芬、长春氟宁、Z-100和唑来麟酸或它们的组合。
下列实施例中所用试剂均可购买得到。
以下实施例对本发明做进一步的描述,但该实施例并非用于限制本发明的保护范围。
实施例中所用试剂的英文简称对应的中文名称如下:
英文简称 | 中文名称 |
DMSO | 二甲基亚砜 |
THF | 四氢呋喃 |
1,4-dioxane | 1,4-二氧六环 |
<![CDATA[H<sub>2</sub>O]]> | 水 |
EtOH | 乙醇 |
CDI | N,N’-羰基-二咪唑 |
TFA | 三氟乙酸 |
PMBCl | 对甲氧基苄氯 |
实施例1
8-(6-甲氧基吡啶-3-基)-1-(4-(哌嗪-1-基)-3-三氟甲基苯基)-咪唑[1,5-a]喹喔啉-4(5H)-酮(RI-101)
8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)imidazo[1,5-a]quinoxalin-4(5H)-one(RI-101)
化合物1-2a的合成:在500ml反应瓶中,将化合物1-1a(24g,100mmol)、N-Boc-哌嗪(22.35g,120mmol)和K2CO3(20.73g,150mmol)加入DMSO(100ml)中,120℃加热反应24h。反应结束,加水淬灭,用乙酸乙酯萃取(200ml×3),水和饱和氯化钠溶液洗涤,合并有机层,无水硫酸钠干燥,减压旋蒸得到粗品,经柱层析纯化(乙酸乙酯:石油醚=1:10),得到化合物1-2a白色固体13g,收率31%。1H NMR(400MHz,CDCl3)δ7.75(d,J=2.4Hz,1H),7.63(dd,J=8.4Hz,2.4Hz,1H),7.20(d,J=8.8Hz,1H),3.55(t,J=4.8Hz,4H),2.83(t,J=4.8Hz,4H),1.48(s,9H);ESI-MS:m/z 409.1[M+H]+.
化合物1-7a的合成:在-78℃,氩气保护下,将化合物1-2a(6g,14.67mmol)加入250ml反应瓶中,再加入70ml甲苯/THF(1:1),反应1h。再将3.7ml硼酸三乙酯缓慢滴入上述混合液中,继续反应3h。然后将温度缓慢升至0℃,加入20ml饱和氯化铵,转室温搅拌30min。反应结束,用乙酸乙酯萃取(100ml×3),饱和氯化钠溶液洗涤,合并有机层,无水硫酸钠干燥,减压旋蒸得到粗品1-3a,直接用于下一步反应。
将化合物1-3a(5.6g,15mmol)、化合物1-4a(1.47g,10mmol)、Pd(PPh3)2Cl2(700mg,1mmol)和Cs2CO3(6.5g,20mmol)加入250ml反应瓶,氩气保护,再加入100ml1,4-dioxane/H2O(4:1),100℃回流反应过夜。反应结束,减压除去溶剂,加水,用乙酸乙酯萃取(100ml×3),减压除去乙酸乙酯,再用30ml乙酸乙酯/石油醚(1:2)洗涤,得到粗品1-5a,直接用于下一步反应。
在250ml反应瓶中,将粗品化合物1-5a(4g,10mmol)、化合物1-6a(2.6g,12mmol)和Cs2CO3(4.88g,15mmol)加入乙腈(80ml)中,回流反应过夜。反应结束,减压除去溶剂,加水,用乙酸乙酯萃取(100ml×3),饱和氯化钠溶液洗涤,合并有机层,无水硫酸钠干燥,减压旋蒸得到粗品,经柱层析纯化(乙酸乙酯:石油醚=1:1.5),得到化合物1-7a,浅黄色固体4.7g,收率79%。1H NMR(400MHz,CDCl3)δ7.89(d,J=8.4Hz,1H),7.79(d,J=8.4Hz,1H),7.67(s,1H),7.52-7.55(m,2H),7.32(s,1H),7.19(d,J=8.0Hz,1H),7.10(s,1H),3.53(t,J=4.4Hz,4H),2.86(t,J=4.8Hz,4H),1.47(s,9H);ESI-MS:m/z 596.1[M+H]+.
化合物1-8a的合成:在250ml反应瓶中,将化合物1-7a(6g,10mml),铁粉(2.79g,50mmol),氯化铵(4.28g,80mmol)溶于EtOH/H2O(80ml,4:1)中,80℃回流反应过夜。反应结束,用硅藻土抽滤,加水,再用碳酸钠调pH至碱性,二氯甲烷萃取(100ml×3),合并有机层,无水硫酸钠干燥,减压旋蒸得到粗品,重结晶得化合物1-8a,浅黄色固体4.64g,收率82%。1H NMR(400MHz,CDCl3)δ7.86(d,J=2.0Hz,1H),7.65(dd,J=8.4Hz,2.0Hz,1H),7.38(dd,J=8.8Hz,2.0Hz,1H),7.32(d,J=1.2Hz,1H),7.19(d,J=2.0Hz,1H),7.17(d,J=8.8Hz,1H),7.04(d,J=1.2Hz,1H),6.73(d,J=8.4Hz,1H),3.76(brs,2H),3.53(t,J=4.8Hz,4H),2.86(t,J=4.8Hz,4H),1.47(s,9H);ESI-MS:m/z 566.1[M+H]+.
化合物1-9a的合成:在25ml反应瓶中,将化合物1-8a(0.56g,1mmol)和CDI(0.24g,1.5mmol)加入10ml 1,2-二氯苯中,回流反应3h。反应结束,湿法上柱,经柱层析纯化(乙酸乙酯:石油醚=3:1),得到化合物1-9a,白色固体0.29g,收率50%。1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),8.02(s,1H),7.96-7.99(m,2H),7.79(d,J=7.6Hz,1H),7.49(d,J=8.8Hz,1H),7.26(d,J=8.8Hz,1H),7.03(d,J=2.0Hz,1H),3.56(t,J=4.8Hz,4H),2.96(t,J=4.8Hz,4H),1.44(s,9H);ESI-MS:m/z 592.1[M+H]+.
化合物RI-101的合成:将化合物1-9a(0.59g,1mmol)、化合物1-10a(0.23g,1.5mmol)、Pd(PPh3)2Cl2(70mg,0.1mmol)和Cs2CO3(0.65g,2mmol)加入25ml反应瓶,氩气保护,再加入20ml 1,4-dioxane/H2O(4:1),100℃回流反应过夜。反应结束,减压除去溶剂,加水,用乙酸乙酯萃取(100ml×3),合并有机层,无水硫酸钠干燥,减压旋蒸得到粗品1-11a,直接用于下一步反应。
在25ml反应瓶中,将化合物1-11a(0.62g,1mmol)溶于10ml二氯甲烷中,再加入3ml三氟乙酸,室温搅拌反应1h。反应结束,减压除去溶剂,饱和碳酸氢钠调pH至碱性,抽滤,滤饼经柱层析纯化(二氯甲烷:甲醇=5:1),得到化合物RI-101,白色固体0.4g,收率77%。1HNMR(400MHz,CD3OD)δ8.15(d,J=2.0Hz,1H),8.10(s,1H),8.06(dd,J=8.4Hz,2.0Hz,1H),7.85-7.88(m,2H),7.66(dd,J=8.4Hz,2.4Hz,1H),7.61(dd,J=8.4Hz,2.0Hz,1H),7.43(d,J=8.4Hz,1H),7.24(d,J=2.0Hz,1H),6.79(d,J=8.4Hz,1H),3.92(s,3H),3.46(t,J=4.8Hz,4H),3.37(t,J=4.8Hz,4H);ESI-MS:m/z 521.1[M+H]+.
实施例2
8-(6-乙氧基吡啶-3-基)-1-(4-(哌嗪-1-基)-3-三氟甲基苯基)-咪唑[1,5-a]喹喔啉-4(5H)-酮(RI-102)
8-(6-ethoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)imidazo[1,5-a]quino xalin-4(5H)-one(RI-102)
合成方法如同实施例1,白色固体0.2g,收率72%。
1H NMR(400MHz,CD3OD)δ8.08(s,2H),8.00(d,J=7.6Hz,1H),7.85(s,1H),7.81(d,J=8.0Hz,1H),7.57-7.59(m,2H),7.40(d,J=8.4Hz,1H),7.21(s,1H),6.71(d,J=8.4Hz,1H),4.32(q,J=6.8Hz,2H),3.16-3.21(m,8H),1.39(t,J=6.8Hz,3H);ESI-MS:m/z 535.1[M+H]+.
实施例3
1-(4-(哌嗪-1-基)-3-三氟甲基苯基)-8-(吡啶-3-基)-咪唑[1,5-a]喹喔啉-4(5H)-酮(RI-103)
1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-8-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-4(5H)-one(RI-103)
合成方法如同实施例1,白色固体0.13g,收率78%。
1H NMR(400MHz,CD3OD)δ8.47-8.49(m,1H),8.44(d,J=1.6Hz,1H),8.05-8.08(m,2H),7.98(d,J=8.4Hz,1H),7.75(d,J=8.4Hz,1H),7.66-7.70(m,2H),7.45(d,J=8.4Hz,1H),7.38-7.41(m,1H),7.36(s,1H),2.98-3.11(m,8H);ESI-MS:m/z 491.1[M+H]+.
实施例4
8-(2-甲氧基嘧啶-5-基)-1-(4-(哌嗪-1-基)-3-三氟甲基苯基)-咪唑[1,5-a]喹喔啉-4(5H)-酮(RI-104)
8-(2-methoxypyrimidin-5-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)imidazo[1,5-a]quinoxalin-4(5H)-one(RI-104)
合成方法如同实施例1,白色固体0.21g,收率69%。
1H NMR(400MHz,CD3OD)δ8.37-8.44(m,2H),8.01-8.10(m,3H),7.83(d,J=8.4Hz,1H),7.64-7.94(m,1H),7.42-7.48(m,1H),7.18-7.25(m,1H),4.01(s,3H),3.27-3.32(m,8H);ESI-MS:m/z 522.1[M+H]+.
实施例5
8-(4-甲氧苯基)-1-(4-(哌嗪-1-基)-3-三氟甲基苯基)-咪唑[1,5-a]喹喔啉-4(5H)-酮(RI-105)
8-(4-methoxyphenyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)imidazo[1,5-a]quinoxali n-4(5H)-one(RI-105)
合成方法如同实施例1,白色固体0.14g,收率75%。
1H NMR(400MHz,CD3OD)δ8.15(d,J=2.0Hz,1H),8.09(s,1H),8.03(dd,J=8.4Hz,1.6Hz,1H),7.82(d,J=8.0Hz,1H),7.57(dd,J=8.4Hz,2.0Hz,1H),7.39(d,J=8.4Hz,1H),7.26(d,J=1.6Hz,1H),7.16(d,J=8.4Hz,2H),6.87(d,J=8.4Hz,2H),3.81(s,3H),3.42(t,J=4.4Hz,4H),3.29(t,J=4.4Hz,4H);ESI-MS:m/z 520.1[M+H]+.
实施例6
1-(4-(哌嗪-1-基)-3-三氟甲基苯基)-8-(噻唑-3-基)-咪唑[1,5-a]喹喔啉-4(5H)-酮(RI-106)
1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-8-(thiophen-3-yl)imidazo[1,5-a]quinoxalin-4(5H)-one(RI-106)
合成方法如同实施例1,灰白色固体0.1g,收率63%。
1H NMR(400MHz,CD3OD)δ8.13(d,J=1.6Hz,1H),8.09(s,1H),8.02(dd,J=8.0Hz,1.6Hz,1H),7.83(d,J=8.0Hz,1H),7.65(dd,J=8.4Hz,2.0Hz,1H),7.43(dd,J=5.2Hz,2.8Hz,1H),7.37(d,J=8.4Hz,1H),7.33(d,J=1.6Hz,1H),7.24(dd,J=2.8Hz,1.2Hz,1H),6.91(dd,J=5.2Hz,1.2Hz,1H),3.38(t,J=4.8Hz,4H),3.29(t,J=4.8Hz,4H);ESI-MS:m/z496.1[M+H]+.
实施例7
9-(6-甲氧基吡啶-3-基)-1-(4-(哌嗪-1-基)-3-三氟甲基苯基)-4H-苯并[b][1,2,4]三氮唑[4,3-d][1,4]二氮卓-5(6H)-酮(RI-107)
9-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one
化合物7-6a和7-6a’的合成:在250ml反应瓶中,将4-溴-1,2-苯二胺(2g,10.69mmol)溶于20ml二甲苯中,加热至140℃,再将0.1ml冰乙酸加入混合液中,最后缓慢滴加10ml 3,3-甲氧基丙烯酸乙酯(2g,10.69mmol)和二甲苯的混合液,反应2h。反应结束,除去溶剂,乙酸乙酯萃取(50ml×3),水和饱和氯化钠溶液洗涤,合并有机层,无水硫酸钠干燥,减压旋蒸得到粗品,经柱层析纯化(乙酸乙酯:石油醚=1:4),得到白色固体化合物7-6a(0.8g,收率27%),7-6a’,(1.0g,收率33%)。
化合物7-6a:1H NMR(400MHz,CDCl3)δ8.80(s,1H),7.42(d,J=2.4Hz,1H),7.23(dd,J=8.4,2.4Hz,1H),6.93(d,J=8.4Hz,1H),4.31(q,J=7.2Hz,2H),3.19(s,2H),1.36(t,J=7.2Hz,3H);ESI-MS:m/z 283.1[M+H]+.
化合物7-6a’:1H NMR(400MHz,CDCl3)δ8.74(s,1H),7.28(dd,J=8.8,2.4Hz,1H),7.21(d,J=2.0Hz,1H),7.10(d,J=8.8Hz,1H),4.31(q,J=7.2Hz,2H),3.19(s,2H),1.36(t,J=7.2Hz,3H);ESI-MS:m/z 283.1[M+H]+.
化合物7-7a的合成:
在500ml反应瓶中,将化合物7-1a(20g,90mmol),无水哌嗪(11.6g,135mmol)和碳酸钾(25g,180mmol)加入DMSO(100ml)中,90℃下加热反应4h后,加水淬灭。乙酸乙酯萃取(100ml×3),饱和氯化钠溶液洗涤,合并有机层,无水硫酸钠干燥,减压旋蒸得到粗品,经柱层析纯化(二氯甲烷:甲醇=10:1),得到油状物7-2a(17g,收率66%)。1H NMR(400MHz,CDCl3)δ8.28(d,J=2.0Hz,1H),8.13(dd,J=8.4,2.0Hz,1H),7.28(d,J=8.4Hz,1H),3.90(s,3H),2.98-3.03(m,8H);ESI-MS:m/z 289.1[M+H]+.
在500ml反应瓶中,将化合物7-2a(17g,59mmol),碳酸钾(12g,88mmol),TBAI(4g,12mmol)加入100ml乙腈中,再缓慢滴加对甲氧基苄氯(11g,71mmol),室温过夜反应。反应结束,用二氯甲烷萃取(100ml×3),水和饱和氯化钠溶液洗涤,合并有机层,无水硫酸钠干燥,减压旋蒸得到粗品7-3a,重结晶得白色固体,直接用于下一步反应。
在500ml反应瓶中,将化合物7-3a(15g,37mmol)溶于100ml无水乙醇中,再加入14ml50%水合肼,回流反应过夜。反应结束,除去溶剂,加冰水淬灭,搅拌析出固体,抽滤,滤饼干燥,得到白色固体7-4a,直接用于下一步反应。
在25ml反应瓶中,将化合物7-6a(0.5g,1.76mmol)加入10ml冰乙酸中,再加入化合物7-5a(0.74g,1.76mmol),120℃加热反应2h。反应结束,除去溶剂,加入乙酸乙酯,饱和碳酸氢钠中和,乙酸乙酯萃取(20ml×3),水洗,合并有机层,无水硫酸钠干燥,减压旋蒸得到粗品,经柱层析纯化(二氯甲烷:甲醇=10:1),得到白色固体7-7a(0.8g,收率73%)。1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),7.65-7.69(m,2H),7.58-7.61(m,2H),7.32(d,J=8.8Hz,1H),7.24(d,J=8.4Hz,2H),7.18(d,J=2.0Hz,1H),6.89(d,J=8.4Hz,2H),3.93(d,J=14.4Hz,1H),3.78(d,J=14.4Hz,1H),3.74(s,3H),3.47(s,2H),3.28-3.33(m,4H),2.94(t,J=4.4Hz,4H);ESI-MS:m/z 627.1[M+H]+.
化合物RI-107的合成:在25ml反应瓶中,将化合物7-7a(0.3g,0.48mmol)加入5mlTFA和0.2ml三氟甲磺酸中,80℃回流反应过夜。反应结束,除去溶剂,饱和碳酸钠溶液中和,抽滤,滤饼用烘箱干燥得粗品7-8a,直接用于下一步反应。
将化合物7-8a(100mg,0.2mmol)、化合物7-9a(46mg,0.3mmol)、(PPh3)4Pd(23mg,0.02mmol)和碳酸钾(55mg,0.4mmol)加入25ml反应瓶,氩气保护,再加入5ml dioxane/H2O(4:1),100℃回流反应过夜。反应结束,加水淬灭,抽滤,滤饼经柱层析纯化(二氯甲烷:甲醇=5:1),得到白色固体RI-107(50mg,收率47%)。1H NMR(400MHz,MeOD-d4)δ7.83-7.85(m,2H),7.80(d,J=2.4Hz,1H),7.75(dd,J=8.4,2.0Hz,1H),7.69(d,J=8.8Hz,1H),7.64(dd,J=8.8,2.4Hz,1H),7.51(d,J=8.4Hz,1H),7.19(d,J=2.0Hz,1H),6.80(d,J=8.4Hz,1H),3.93-4.04(m,2H),3.91(s,3H),3.36-3.44(m,4H),3.23-3.28(m,4H);ESI-MS:m/z 536.1[M+H]+.
实施例8
8-(6-甲氧基吡啶-3-基)-1-(4-(哌嗪-1-基)-3-三氟甲基苯基)-4H-苯并[b][1,2,4]三氮唑[4,3-d][1,4]二氮卓-5(6H)-酮(RI-108)
8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one
使用化合物7-6a’为原料,合成方法如实施例7,白色固体70mg,收率66%。
1H NMR(400MHz,MeOD-d4)δ8.45(d,J=2.4Hz,1H),8.00(dd,J=8.8,2.4Hz,1H),7.93(d,J=2.0Hz,1H),7.73(dd,J=8.4,2.0Hz,1H),7.66(d,J=2.0Hz,1H),7.62(d,J=8.4Hz,1H),7.43(dd,J=8.4,2.0Hz,1H),7.15(d,J=8.4Hz,1H),6.94(d,J=8.8Hz,1H),3.90-4.05(m,5H),3.39-3.41(m,4H),3.21-3.30(m,4H);ESI-MS:m/z 536.1[M+H]+.
实施例9
8-(6-甲氧基吡啶-3-基)-1-(4-(哌嗪-1-基)-3-三氟甲基苯基)-[1,2,4]三氮唑并[4,3-a]喹喔啉-4(5H)-酮(RI-109)
8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one
化合物9-4a的合成:
在100ml反应瓶中,将化合物9-1a(2g,8.89mmol),和碳酸钾(1.84g,13.33mmol),加入10ml DMF中,再缓慢滴加PMBCl(1.67g,10.67mmol),室温反应过夜。反应结束,加水淬灭,乙酸乙酯萃取(100ml×3),水和饱和氯化钠溶液洗涤,合并有机层,无水硫酸钠干燥,减压旋蒸得到粗品9-2a,重结晶得白色固体,直接用于下一步反应。
将化合物9-2a(2g,5.80mmol)和三氟醋酸碘苯(3.74g,8.70mmol)加入250ml反应瓶,氩气保护,再加入80ml二氯甲烷,最后滴加无水乙醇(2.67g,58mmol),50℃回流反应过夜。反应结束,减压除去溶剂,乙酸乙酯萃取(100ml×3),水和饱和氯化钠溶液洗涤,合并有机层,无水硫酸钠干燥,减压旋蒸得到粗品,经柱层析纯化(乙酸乙酯:石油醚=1:7.5),得到9-3a,白色固体0.5g,收率22%。1H NMR(400MHz,CDCl3)δ7.45(d,J=8.4Hz,1H),7.40(d,J=2.0Hz,1H),7.33(dd,J=8.4,2.0Hz,1H),7.23(d,J=8.8Hz,2H),6.85(d,J=8.8Hz,2H),5.37(s,2H),4.54(q,J=7.2Hz,2H),3.77(s,3H),1.51(t,J=7.2Hz,3H);ESI-MS:m/z389.1[M+H]+.
化合物9-4a的合成:采用化合物9-3a以及7-4a为原料,合成方法同化合物7-7a的合成,得到白色固体0.3g,收率33%。1H NMR(400MHz,CDCl3)δ7.94(d,J=2.0Hz,1H),7.80(dd,J=8.4,2.0Hz,1H),7.58(d,J=2.0Hz,1H),7.47(d,J=8.4Hz,1H),7.26-7.35(m,5H),7.16(dd,J=8.8,1.6Hz,1H),6.89(d,J=2.4Hz,2H),6.87(d,J=2.4Hz,2H),5.48(s,2H),3.81(s,3H),3.78(s,3H),3.53(s,2H),3.03-3.20(m,4H),2.56-2.63(m,4H);ESI-MS:m/z733.1[M+H]+.
化合物RI-109的合成:在25ml反应瓶中,将化合物9-4a(0.3g,0.41mmol)加入5mlTFA和0.2ml三氟甲磺酸中,80℃回流反应过夜。反应结束,除去溶剂,用饱和碳酸钠溶液中和,抽滤,滤饼用烘箱干燥得粗品9-5a,直接用于下一步反应。
将化合物9-5a(80mg,0.16mmol)、化合物(6-甲氧基吡啶-3-基)硼酸(36mg,0.24mmol)、(PPh3)2Cl2Pd(11mg,0.016mmol)和Cs2CO3(156mg,0.48mmol)加入25ml反应瓶,氩气保护,再加入5ml 1,4-dioxane/H2O(4:1),100℃回流反应过夜。反应结束,减压除去溶剂,经柱层析纯化(二氯甲烷:甲醇=5:1),得到RI-109,白色固体30mg,收率36%。1H NMR(400MHz,MeOD-d4)δ8.43(s,1H),8.15(s,1H),8.05(d,J=8.0Hz,1H),7.97(d,J=8.4Hz,1H),7.77(d,J=8.4Hz,1H),7.63(s,1H),7.37(s,2H),6.92(d,J=8.4Hz,1H),3.97(s,3H),3.10-3.20(m,8H);ESI-MS:m/z 522.1[M+H]+.
实施例10
7-(6-甲氧基吡啶-3-基)-1-(4-(哌嗪-1-基)-3-三氟甲基苯基)-[1,2,4]三氮唑并[4,3-a]喹喔啉-4(5H)-酮(RI-110)
7-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-trifluoromethylphenyl)-[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one
合成方法如实施例9,白色固体36mg,收率43%。
1H NMR(400MHz,MeOD-d4)δ8.21(s,1H),8.11(d,J=8.0Hz,1H),7.94(s,1H),7.88(d,J=8.0Hz,1H),7.70(d,J=8.4Hz,1H),7.65(d,J=8.8Hz,1H),7.50(d,J=8.4Hz,1H),7.25(s,1H),6.78(d,J=8.4Hz,1H),3.92(s,3H),3.24-3.30(m,8H);ESI-MS:m/z 522.1[M+H]+.
实施例11
化合物的体外抗肿瘤活性:本实验使用的细胞MKN-1(人胃癌细胞)、U87MG(人恶性胶质母细胞瘤细胞)等细胞系,均来自ATCC或者中国科学院典型培养物保藏委员会细胞库。3000-10000个/孔的上述细胞接种到96孔板中,过夜后,加入不同浓度的化合物(0-30μM)连续处理72小时。然后加入CCK8试剂,继续孵育1-3小时,接着用超级酶标仪测定其在450nm及650nm的吸光值。使用GrapPad prism 5.0软件计算其半数抑制浓度(IC50)。
结果发现,本发明的含氮并杂环类化合物可明显抑制MKN-1和U87MG肿瘤细胞的增殖。具体数据见表1。
表1化合物体外抗肿瘤细胞的活性(IC50/μM)
MKN-1(μM) | U87MG(μM) | |
RI-101 | 8.4 | 4.8 |
RI-102 | 1.0 | 2.8 |
RI-103 | 5.1 | 4.1 |
RI-104 | 5.3 | 4.5 |
RI-105 | 1.3 | 1.7 |
RI-106 | 4.1 | 3.9 |
RI-107 | 3.2 | 5.1 |
RI-108 | 4.2 | 6.8 |
RI-109 | 0.52 | 0.78 |
RI-110 | 4.4 | 3.7 |
实施例12
含氮并杂环类化合物对RIOK2激酶的亲和力Kd测试
KINOMEscanTM技术是业内最全面的检测化合物针对大量人类激酶作用的高通量筛选系统。(Fabian et al.(2005)Nat.Biotechnol.23,329;Karamanet al.(2008)Nat.Biotechnol.26,127)。KINOMEscanTM是基于竞争性结合作用而建立的检测方法,通过化合物与固定化的配体竞争性结合激酶活性位点来定量检测化合物与酶的结合能力。该测试主要包括三个组分:连接有DNA标签的激酶,固定化的配体以及被测化合物。化合物与固定化的配体的竞争能力是通过对激酶上连接的DNA标签进行定量PCR测得的。
激酶活性测试:对大多数实验,在24孔板中,带有激酶标签的T7噬菌体是在BL21来源的大肠杆菌中平行扩增。当大肠杆菌生长到对数生长期时,用冰冻保存的T7噬菌体进行感染(感染复数=0.4),并在32℃下震荡培养直到细菌溶解(90-150分钟)。将溶解物离心(6000x g)并过滤(0.2μm)除去碎片。收集的上清感染HEK293细胞并在其中扩增,由此产生可用于qPCR检测的带DNA标签的激酶。连接了生物素的小分子配体与链霉亲和素包被的磁珠在室温下反应30分钟,为实验提供亲合性的树脂。将配体化的磁珠用过量的生物素封闭,并用封闭缓冲液(SeaBlock(Pierce),1%BSA,0.05%Tween 20,1mM DTT)洗涤以除去未结合的配体,并减少非特异性的噬菌体结合。结合反应是将激酶、结合配体的磁珠,含待测试化合物的1x结合缓冲液(20%SeaBlock,0.17×PBS,0.05%Tween 20,6mM DTT)混合。待测化合物使用100%DMSO配制成100X的储备液,实验时直接稀释到反应体系中。所有的反应都在聚丙烯384孔板中进行,反应终体积为0.02ml。将测试板室温下震荡孵化1小时,将磁珠用冲洗缓冲液(1×PBS,0.05%Tween 20)洗涤磁珠。将磁珠重悬于洗脱液(1×PBS,0.05%Tween 20,0.5μM非生物素化的亲和配体),在室温下震荡孵化30分钟。通过用qPCR方法检测激酶上的DNA标签量来检测激酶的浓度。
结合常数(Kds)采用希尔方程,通过标准的剂量-响应曲线计算得到:
希尔斜率值取-1。
表2中所列为代表性化合物编号以及对应Kd结果。结果发现,本发明的含氮并杂环类化合物与RIOK2激酶的结合能力较强。
表2化合物与RIOK2激酶的结合能力
化合物 | Kd(μM) |
RI-101 | 0.056 |
RI-102 | 0.860 |
RI-103 | >10 |
RI-104 | >10 |
RI-105 | 0.065 |
RI-106 | >10 |
RI-107 | >10 |
RI-108 | >10 |
RI-109 | 0.029 |
RI-110 | >10 |
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对以下实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (11)
1.具有式(II)或者式(III)所示结构的含氮并杂环类化合物或者其药学上可接受的盐:
其中,
A1选自:N、CR4,B1为N;
A2、B2、D和E分别独立地选自:CR4;
X任选自:O、S;
n 选自: 0 或1;
X1、X3、X5分别独立地选自:CR7;
X2、X4分别独立地选自:N、CR7;
X6、X7、X8、X9和X10分别独立地选自:CR8、CR;并且X6、X7、X8、X9和X10中至少有一个选自CR;
Y选自:O、S;
R1、R2、R3、R4均为:H;
各R6分别独立地选自:H、卤素;
各R7 、R8分别独立地选自:H、卤素、C1~C6烷基、C1~C6烷氧基;当R7 或R8选自C1~C6烷基、C1~C6烷氧基时,所述R7 、R8独立任选地被1个或多个R6取代;
R选自:;
R9、R10与和其相连的N原子一起形成如下结构:;其中,m1选自:1、2;m2选自:1、2;Z选自:NR12;
R11选自:H、C1~C3烷基;
R12选自:H。
2.根据权利要求1所述的含氮并杂环类化合物或者其药学上可接受的盐,其特征在于,其具有式(IV)或(V)所示结构:
。
3.根据权利要求2所述的含氮并杂环类化合物或者其药学上可接受的盐,其特征在于,其具有式(VI)所示结构:
。
4.根据权利要求1-3任一项所述的含氮并杂环类化合物或者其药学上可接受的盐,其特征在于,
R11选自:H;
R12选自:H。
5.根据权利要求1-3任一项所述的含氮并杂环类化合物或者其药学上可接受的盐,其特征在于,各R7分别独立地任选自:H、C1~C6烷氧基。
6.根据权利要求1-3任一项所述的含氮并杂环类化合物或者其药学上可接受的盐,其特征在于,各R8分别独立地任选自:H、三氟甲基。
7.根据权利要求1所述的含氮并杂环类化合物或者其药学上可接受的盐,其特征在于,所述含氮并杂环类化合物选自如下化合物:
。
8.权利要求1-7任一项所述的含氮并杂环类化合物或者其药学上可接受的盐在制备RIOK2抑制剂中的应用。
9.权利要求1-7任一项所述的含氮并杂环类化合物或者其药学上可接受的盐在制备预防或者治疗肿瘤的药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述肿瘤为:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、胶质瘤。
11.一种预防或者治疗肿瘤的药用组合物,其特征在于,由活性成分和药学上可接受的辅料制备得到,所述活性成分包括权利要求1-7任一项所述的含氮并杂环类化合物或者其药学上可接受的盐。
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