CN117624139A - 二芳基类化合物及其制备方法和用途 - Google Patents
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Abstract
本发明公开了一种二芳基类化合物及其制备方法和用途。本发明的二芳基类化合物为如式I所示化合物或其药学上可接受的盐。所述化合物能够抑制人皮肤鳞状细胞癌细胞,具有较好的药代动力学性质,成药前景良好。
Description
技术领域
本发明属于医药领域,具体地,本发明涉及到一种二芳基类化合物及其制备方法和用途。
背景技术
微管是真核细胞中细胞骨架的重要组成部分,在维持细胞形态、信号传递、细胞器运输、细胞运动、细胞分裂和有丝分裂等多种细胞功能中发挥着重要作用。
微管由两种类型的微管蛋白亚基,即α-微管蛋白和β-微管蛋白组成,α-微管蛋白和β-微管蛋白形成微管蛋白异二聚体,是微管装配的基本单位。微管靶向剂(Microtubule-targeting agents,MTAs)能破坏微管的动力学稳定性和结构,干扰有丝分裂纺锤体的形成,诱导细胞周期阻滞于G2/M期,促使细胞凋亡。
微管参与很多重要的细胞过程,已成为治疗过度增殖性疾病最重要的药物靶点之一,美国FDA批准的几种微管靶向剂如长春花碱和紫杉烷类化合物被广泛用于治疗多实体肿瘤和血液系统恶性肿瘤,但微管靶向药物的耐药性和剂量限制性毒性限制了其临床疗效。双靶点抑制剂与单靶点药物相比克服了耐药性,可以改善治疗效果,已成为研究热点,如:微管蛋白-SRC双靶点抑制剂、微管蛋白-受体酪氨酸激酶(receptortyrosine kinasesinhibitor,RTK)双靶点抑制剂、微管蛋白-组蛋白去乙酰化酶(histone deacetylasesinhibitor,HDAC)双靶点抑制剂等。
光化性角化病(Actinic keratosis,AK)是一种与长时间暴露在紫外线下有关的皮肤病,在美国AK是皮肤科医生第二常见的疾病,特征是突变的角质形成细胞不受控制的增殖,其被认为是一种癌前病变,如果不及时治疗,20%的病例可能会发展为皮肤鳞状细胞癌(cutaneous squamous cell carcinoma,SCC)。目前微管蛋白-SRC双靶点抑制剂Tirbanibulin临床上局部治疗AK效果显著(NCT03285477),已被FDA批准上市,这表明开发新的具有更好效果的微管蛋白-SRC双靶点抑制剂局部治疗AK可能是一个有潜力的方向。
发明内容
本发明的目的是提供一种二芳基类化合物及其制备方法和用途。本发明中所述的式I所示化合物或其药学上可接受的盐能够抑制人皮肤鳞状细胞癌细胞,具有较好的药代动力学性质,体内代谢快,潜在毒性小以及成药性良好的优势。
本发明第一方面,提供了一种式I所示化合物或其药学上可接受的盐,具有结构:
其中,W为-O-、-S-、-NH-或-N(C1-C6烷基)-;
L不存在或为C1-C6亚烷基;
Q为被m个R2取代的3或4元杂环烷基;
R1、R2和R3各自独立地为氢、卤素、-CN、-NR11R12、C1-C6烷基、C2-C6烯基、C2-C6炔基、3-8元环烷基、4-8元杂环烷基、6-10元芳基、5-8元杂芳基、-O-R21、-C1-C6烷基-O-R22、-COO-R23、-CO-R24或-S(O)2-R25;
当R1为多个时,所述R1相同或不同;
当R2为多个时,所述R2相同或不同;
当R3为多个时,所述R3相同或不同;
其中,R11、R12、R21、R22、R23、R24和R25各自独立地为氢、C1-C6烷基、3-8元环烷基、4-8元杂环烷基、6-10元芳基或5-6元杂芳基;
所述-NR11R12、C1-C6烷基、C2-C6烯基、C2-C6炔基、3-8元环烷基、4-8元杂环烷基、6-10元芳基、5-6元杂芳基、-O-R21、-C1-C6烷基-O-R22、-COO-R23、-CO-R24和-S(O)2-R25各自独立地任选地被一个或多个选自下列的取代基取代:卤素、-OH、-NH2、-CN、C1-C6烷基、-O-C1-C6烷基、3-6元环烷基和4-8元杂环烷基;当取代基为多个时,所述取代基相同或不同;
m、n和t各自独立地为1、2或3。
在一优选实施方式中,各上述4-8元杂环烷基和上述5-6元杂芳基中的杂原子为N、S和O中的一种或多种,个数为1、2或3个。
在一优选实施方式中,W为-O-。
在一优选实施方式中,L为-CH2-或-CH2CH2-。
在一优选实施方式中,n为1;R1为氢、卤素、-CN、C1-C6烷基或C1-C6卤代烷基。较佳地,R1为氢、卤素或C1-C6烷基。
在一优选实施方式中,R1为-H、-F、-Cl、-CN、-CH3或-CF3。较佳地,R1为-H、-F、或-CH3。
在一优选实施方式中,为/>
在一优选实施方式中,为
较佳地,为/>
在一优选实施方式中,式I具有式Ia或Ib结构:
其中,W、L、R1和Q的定义如第一方面中所述;
p为0、1、2或3;
较佳地,R1为-H、-F、-Cl、-CN、-CH3、-CF3、-OH、-OCH3、-NH2、-NHCH3或-N(CH3)2。更佳地,R1为-H、-F、-C1、-CN、-CH3或-CF3。
较佳地,Q为4元杂环烷基。更佳地,Q为
较佳地,式Ib中,p为1或2;
R1为氢、卤素或C1-C6烷基;
Q为m为1或2;R2独立地为卤素、C1-C6烷基或-O-R21,R21为C1-C6烷基。
在一优选实施方式中,式I具有式Ic或Id结构:
各m为1或2;
式Ic中,R2独立地为C1-C3烷基;优选为甲基;
式Id中,当R1为H时,R2独立地为卤素;当R1为卤素或C1-C6烷基时,R2独立地为-O-R21,R21为C1-C6烷基。
在一优选实施方式中,所述3或4元杂环烷基的杂原子选自N、O和S,例如O或N。
较佳地:当所述3或4元杂环烷基的杂原子为O时,所述3或4元杂环烷基通过碳原子与L连接;当所述3或4元杂环烷基的杂原子为N时,所述3或4元杂环烷基通过N或碳原子与L连接。
在一优选实施方式中,所述3或4元杂环烷基的杂原子为1、2或3个,例如1个。
在一优选实施方式中,所述3或4元杂环烷基的选自N、O和S,个数为1、2或3个;较佳地选自O和N,个数为1个。
较佳地,所述3或4元杂环烷基为氧杂环丁烷基或氮杂环丁烷基。
在一优选实施方式中,所述Q为
较佳地,所述Q为
在一优选实施方式中,R2中,所述C1-C6烷基和所述-C1-C6烷基-O-R22中的C1-C6烷基独立地为C1-C3烷基,还可为甲基、乙基、正丙基或异丙基,例如甲基或乙基。
在一优选实施方式中,R2中,所述3-8元环烷基中的环烷基为单环的环烷基。
在一优选实施方式中,R2中,所述3-8元环烷基为3-6元的单环的环烷基,还可为环丙基、环丁基、环戊基或环己基,例如环丙基。
在一优选实施方式中,R2中,所述4-8元杂环烷基为4或5元杂环烷基,杂原子为O,个数为1个,还可为氧杂环丁烷基(例如)。
在一优选实施方式中,R11、R12、R21、R22、R23、R24和R25中,所述C1-C6烷基为甲基、乙基、正丙基或异丙基,例如甲基。
在一优选实施方式中,R2为氢、卤素、-CN、-NR11R12、C1-C6烷基、-O-R21、-C1-C6烷基-O-R22、3-6元环烷基或4-8元杂环烷基;其中,R11、R12、R21和R22各自独立地为氢、C1-C6烷基、3-8元环烷基、4-8元杂环烷基、6-10元芳基或5-6元杂芳基;
所述-NR11R12、C1-C6烷基、-O-R21、-C1-C6烷基-O-R22、3-6元环烷基和4-8元杂环烷基各自独立地任选地被一个或多个选自下列的取代基取代:卤素、-OH、-NH2、-CN、C1-C3烷基、-O-C1-C3烷基、3-6元环烷基和4-8元杂环烷基;当取代基为多个时,所述取代基相同或不同。
在一优选实施方式中,R2独立地为氢、-CN、卤素、-C1-C3烷基-CN、-C1-C3烷基、-O-C1-C3烷基、-C1-C3烷基-O-C1-C3烷基、-N(C1-C3烷基)(C1-C3烷基)、-C1-C3烷基-O-环丙基、3-6元环烷基或4-6元杂环烷基。
较佳地,R2独立地为卤素、-C1-C3烷基、-O-C1-C3烷基、-C1-C3烷基-O-C1-C3烷基或-N(C1-C3烷基)(C1-C3烷基)。
在一优选实施方式中,所述R2独立地为氢、-CN、-F、-CH2CN、-CH3、-OCH3、-CH2OCH3、-N(CH3)2、-CH2O-环丙基或氧杂环丁基(例如)。
较佳地,R2独立地为-F、-CH3、-OCH3、-CH2OCH3或-N(CH3)2。
在一优选实施方式中,Q为
较佳地,Q为
在一优选实施方式中,-L-W-为-C1-C6亚烷基-O-。
较佳地,-L-W-为-CH2O-或-CH2CH2O-。
在一优选实施方式中,Q-L-W-为
在一优选实施方式中,R3为氢。在一优选实施方式中,所述式I所示化合物或其药学上可接受的盐,所述式I所示化合物为如下任一化合物:
本发明第二方面,提供了一种药物组合物,包括如第一方面所述的如式I所示化合物或其药学上可接受的盐,和任选的药学上可接受的载体和/或其他活性药物。
或者,所述药物组合物,包括如第一方面的如式I所示化合物或其药学上可接受的盐,和任选的药学上可接受的载体和/或辅料。
本发明第三方面,提供了如第一方面所述的如式I所示化合物或其药学上可接受的盐的用途,或如第二方面所述的药物组合物的用途,所述用途包括:
1)抑制微管蛋白聚合和/或Src激酶、
2)预防、治疗微管蛋白聚合和/或Src激酶相关的疾病、
3)制备微管蛋白聚合和/或Src激酶抑制剂、
4)制备预防、治疗与微管蛋白聚合和/或Src激酶相关的疾病的药物、药物组合物或制剂。
较佳地,所述用途包括:抑制微管蛋白聚合;和/或,预防和/或治疗微管蛋白聚合介导的疾病;和/或,制备微管蛋白聚合抑制剂,和/或预防和/或治疗与微管蛋白聚合介导的疾病的药物、药物组合物或制剂。
较佳地,所述用途包括:抑制Src激酶;和/或,预防和/或治疗Src激酶介导的疾病;和/或,制备Src激酶抑制剂;和/或,制备预防和/或治疗与Src激酶介导的疾病的药物、药物组合物或制剂。
本发明第四方面,还提供了如第一方面所述的如式I所示化合物或其药学上可接受的盐,或如第二方面所述的药物组合物治疗与微管蛋白聚合和/或Src激酶相关的疾病的用途。
在一优选实施例中,所述微管蛋白聚合和/或Src激酶相关的疾病包括肿瘤、皮肤疾病和/或其它疾病的一种、两种或更多种;
较佳地,所述肿瘤包括:实体瘤、肉瘤、血液系统癌症,亚型有乳腺癌、卵巢癌、前列腺癌、子宫颈癌、睾丸癌、结肠癌、结肠直肠癌、肝癌、非小细胞肺癌、鳞状细胞癌(SCC)、小细胞肺癌、胃癌、胃肠道间质瘤、胰腺癌、膀胱癌、生殖细胞瘤、肥大细胞瘤、肥大细胞增多症、胶质母细胞瘤、神经母细胞瘤、星形细胞瘤、黑色素瘤、B细胞淋巴瘤、T细胞淋巴瘤、缓慢进展淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性髓细胞性白血病、急性淋巴细胞性白血病、慢性髓细胞性白血病、慢性淋巴细胞性白血病、骨髓瘤和/或骨髓增生异常综合症;
较佳地,所述皮肤疾病包括:光化性角化病、银屑病、异位性皮炎、牛皮癣、白癜风、玫瑰疹和/或系统性红斑狼疮;
较佳地,所述皮肤疾病还可包括鳞状细胞癌。
较佳地,所述其他疾病包括:自身免疫型糖尿病、糖尿病视网膜病变、肝纤维化、肺纤维化、肾纤维化、阿尔茨海默病、帕金森病、亨廷顿舞蹈症、肌萎缩侧索硬化、脊髓小脑退行性病变、动脉粥样硬化、贫血、镰刀形红细胞贫血症、地中海贫血症、骨关节炎、类风湿性关节炎、疟疾、锥形虫病、蠕虫病、原虫感染、多发性硬化症、狼疮、哮喘、过敏性鼻炎和/或炎性肠病。
本发明第五方面,还提供了如第一方面所述如式I所示化合物或其药学上可接受的盐,或如第二方面所述的药物组合物在制备的用途,所述的用途为制备治疗和/或预防光化性角化病或鳞状细胞癌的药物。
在本发明第六方面,提供一种治疗和/或预防上述的防光化性角化病或鳞状细胞癌的治疗方法,其包括给需要的对象施用如本发明第一方面中所述的式I所示化合物或其药学上可接受的盐或本发明第二方面所述的药物组合物。
在本发明第七方面,提供一种上述式I所示化合物或其药学上可接受的盐的制备方法,其为方法1或方法2:
方法1:其包括如下步骤:在碱性试剂(例如碳酸钾)存在下,将化合物II和化合物II在溶剂中进行反应,得到所述式I所示化合物;
方法2:其包括如下步骤:在碱性试剂(例如碳酸钾)存在下(还优选在碘化钾存在下),将化合物II和化合物II在溶剂中进行反应,得到所述式I所示化合物;
其中,式III′中Q-H中H为氢原子,X1和X2独立地为卤素(例如溴);Q、L、W、R1、R2、n和t的定义如上所述。
本发明的附加方面和优点将在下面的描述中部分给出,部分将从下面的描述中变得明显,或通过本发明的实践了解到。
术语和定义
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当属于本申请说明书记载的范围内。
除非另有定义,否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明,本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义,以本章的定义为准。
应理解,上述简述和下文的详述为示例性且仅用于解释,而不对本发明主题作任何限制。在本申请中,除非另有具体说明,否则使用单数时也包括复数。必须注意,除非文中另有清楚的说明,否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意,除非另有说明,否则所用“或”、“或者”表示“和/或”。此外,所用术语“包括”以及其它形式,例如“包含”、“含”和“含有”并非限制性。
除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,CH2O等同于OCH2。如本文所用,表示基团的连接位点。
本文所用的章节标题仅用于组织文章的目的,而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文,均通过引用方式整体并入本文。
除前述以外,当用于本申请的说明书及权利要求书中时,除非另外特别指明,否则以下术语具有如下所示的含义。
本申请说明书和权利要求书记载的数值范围,当该数值范围被理解为“整数”时,应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如,“1~6的整数”应当理解为记载了0、1、2、3、4、5和6的每一个整数。
在本申请中,在单独或作为其他取代基一部分时,术语“卤素”是指氟、氯、溴、碘。
如本文所用,在单独或作为其他取代基一部分时,术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至6个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基,叔丁基,戊基,异戊基,新戊基和己基。烷基可以是未取代的或被一个或多个合适的取代基取代。烷基也可以是富含碳和/或氢的同位素(即氘或氚)的天然丰度烷基的同位素异构体。如本文所用,术语“烯基”表示无支链或支链的单价烃链,其含有一个或多个碳-碳双键。如本文所用,术语“炔基”是指无支链或支链的一价烃链,其含有一个或多个碳-碳三键。
在单独或作为其他取代基一部分时,术语“C1-C6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地,所述基团具有1、2或3个碳原子(“C1-C3烷基”),例如甲基、乙基、正丙基或异丙基。
在单独或作为其他取代基一部分时,术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。亚烷基基团的实例包括亚甲基(-CH2-),亚乙基(包括-CH2CH2-或-CH(CH3)-),亚异丙基(包括-CH(CH3)CH2-或-C(CH3)2-)等等。
在单独或作为其他取代基一部分时,术语“环烷基”或“碳环基”是指一种环状烷基。术语“m-n元环烷基”或者“Cm-Cn环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的碳环。例如,“3-15元环烷基”或者“C3-C15环烷基”是指含有3至15,3至9,3至6或3至5个碳原子的环状烷基,它可能包含1至4个环。“5-8元环烷基”则含有5-8个碳原子。包括单环、二环、三环、螺环或桥环。未取代的环烷基的实例包括但不限于环丙基,环丁基,环戊基,环己基和金刚烷基,或者是双环烃基如十氢化萘环。环烷基可以被一个或多个取代基取代。在一些实施方案中,环烷基可以是与芳基或杂芳基稠合的环烷基。术语“C3-C6环烷基”应理解为表示饱和的一价单环或双环烃环,其具有3~6个碳原子,包括稠合或桥接的多环系统。例如环丙基、环丁基、环戊基、环己基。
在单独或作为其他取代基一部分时,“卤代烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基(如-CvFw,其中v=1至3,w=1至(2v+1))。卤代烷基的实例包括,但不限于三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。
在单独或作为其他取代基一部分时,“3或4元杂环烷基”应理解为表示具有3个或4个原子的饱和的含有杂原子的杂环;较佳地,杂原子选自N、O和S。例如3元杂环烷基包括环氧乙烷、环氮乙烷;4元杂环烷基包括氮杂丁烷、氧杂环丁烷、硫杂环丁烷。
在单独或作为其他取代基一部分时,“C2-C6烯基”应理解为表示直连或支链的一价烃基,其包含一个或多个双键并且具有2、3、4、5或6个碳原子,较佳地例如具有2或3个碳原子(即,C2-C3烯基)。应理解,在所述烯基包含多于一个双键的情况下,所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
术语“C2-C6炔基”应理解为表示直连或支链的一价烃基,其包含一个或多个三键并且具有2、3、4、5或6个碳原子,较佳地例如具有2或3个碳原子(“C2-C3炔基”)。所述炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1-乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-异丙基丙-2-炔基、2,2-二甲基丁-3-炔基。特别地,所述炔基是乙炔基、丙-1-炔基或丙-2-炔基。
在本申请中,“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生,且该描述同时包括该事件或状况发生和不发生的情况。例如,“任选地被取代的芳基”表示芳基被取代或未被取代,且该描述同时包括被取代的芳基与未被取代的芳基。
在本申请中,术语“盐”或“药学上可接受的盐”,包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。除了药学可接受的盐外,本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。
在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。
在本申请中,“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氘(2H),氚(3H),碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性,即通过增加流动性和/或粘着性使制剂更适于直接压缩。
本文所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即,使该疾病或病症的状态消退;或者
(iv)减轻该疾病或病症所造成的症状。
在本申请中,“皮肤鳞状细胞癌”与“鳞状细胞癌”可互换使用,是发生于表皮或附属器细胞的一种恶性肿瘤,癌细胞有不同程度的角化。多见于有鳞状上皮覆盖的部位,如皮肤、口腔、唇、食管、子宫颈、阴道等处。此外,有些部位如支气管、膀胱、肾盂等处虽无鳞状上皮覆盖,但可通过鳞状上皮化生而形成鳞状细胞癌。
各步骤的反应,反应温度可因溶剂、起始原料、试剂等适宜选择,反应时间也可因反应温度、溶剂、起始原料、试剂等适宜选择。各步骤反应结束后,目标化合物可按常用方法自反应体系中进行分离、提纯等步骤,如过滤、萃取、重结晶、洗涤、硅胶柱层析等方法。在不影响下一步反应的情况下,目标化合物也可不经过分离、纯化直接进入下一步反应。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明人经过广泛而深入地研究,意外地开发了本发明的化合物。本发明所述化合物能明显抑制人皮肤鳞状细胞癌细胞,具有较好的药代动力学性质,体内代谢快,潜在毒性小,成药性良好;进一步地,对人皮肤鳞状细胞癌具有更好的抑制活性。
具体实施方式
以下结合具体实施例,进一步说明本发明。需理解,以下的描述仅为本发明的最优选实施方式,而不应当被认为是对于本发明保护范围的限制。在充分理解本发明的基础上,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,本领域技术人员可以对本发明的技术方案作出非本质的改动,这样的改动应当被视为包括于本发明的保护范围之中的。
中间体A1、A2的制备
合成路线如下所示:
第一步:N-苄基-2-(5-(4-羟基苯基)吡啶-2-基)乙酰胺(中间体A1)的制备
将原料4-羟基苯硼酸频哪醇酯(6.0g,27.26mmol),N-苄基-2-(5-溴吡啶-2-基)乙酰胺(9.15g,29.99mmol)和碳酸钾(11.30g,81.79mmol)以及[1,1′-双(二苯基膦)二茂铁]二氯化钯(1.96g,2.73mmol)溶于1,4-二氧六环(120mL)和水(3mL)中,反应液升温至85℃搅拌12小时。反应液中加入水(200mL)稀释,用乙酸乙酯(200mL×3)萃取,分液,合并有机相。有机相用无水硫酸钠干燥,过滤,浓缩,残留物用层析柱分离纯化(石油醚∶乙酸乙酯(V/V)=3∶1),得到N-苄基-2-(5-(4-羟基苯基)吡啶-2-基)乙酰胺(中间体A1,5.5g,产率64%)。
LC-MS,M/Z(ESI):319.1[M+H]+
第二步:N-苄基-2-(5-(4-(2-溴乙氧基)苯基)吡啶-2-基)乙酰胺(中间体A2)的制备
将N-苄基-2-(5-(4-羟基苯基)吡啶-2-基)乙酰胺(中间体A1,4.0g,12.56mmol),1,2-二溴乙烷(14.16g,75.38mmol)和碳酸钾粉末(10.42g,75.38mmol)置于乙腈(50mL)中,升温至85℃搅拌12小时。往反应液中加入水(50mL)稀释,用乙酸乙酯(50mL×3)萃取,分液,合并有机相。有机相用无水硫酸钠干燥,过滤,浓缩,残留物用层析柱分离纯化(二氯甲烷∶甲醇(V/V)=10∶1),得N-苄基-2-(5-(4-(2-溴乙氧基)苯基)吡啶-2-基)乙酰胺(中间体A2,3.5g,产率66%)。
LC-MS,M/Z(ESI):437.1[M+H]+
中间体A3的制备
合成路线如下所示:
第一步:3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚的制备
室温下将化合物4-溴-3-氟苯酚(5.0g,24.10mmol),KOAc(9.99g,72.3mmol),和联硼酸频那醇酯(12.24g,48.2mmol),1,1′-二(二苯膦基)二茂铁二氯化钯(II)(1.76g,2.41mmol)加入到二氧六环(80mL)中,氮气保护下85℃搅拌12h。待反应完全,加入水(100mL)稀释,用乙酸乙酯(50mL×3)萃取,分液,合并有机相,有机相用无水硫酸钠干燥,过滤,浓缩,残留物用薄层硅胶板分离纯化(石油醚∶乙酸乙酯(V/V)=2∶3)得化合物3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚(3.8g,产率60.1%)。
第二步:N-苄基-2-(5-(2-氟-4-羟基苯基)吡啶-2-基)乙酰胺的制备
将化合物3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚(2.1g,8.25mmol),N-苄基-2-(5-溴吡啶-2-基)乙酰胺(2.77g,9.08mmol),碳酸钾(3.42g,24.75mmol)和1,1-双(二苯基膦)二茂铁二氯化钯(0.065g,0.089mmol)加入到二氧六环中(30mL)中,置换氮气,升温至85℃搅拌10h。加入水(100mL)稀释,用乙酸乙酯(30mL×3)萃取,分液,合并有机相。有机相用无水硫酸钠干燥,过滤,浓缩,残留物用层析柱分离纯化(石油醚∶乙酸乙酯(V/V)=3∶2)得化合物N-苄基-2-(5-(2-氟-4-羟基苯基)吡啶-2-基)乙酰胺(2.6g,产率42.4%)。
LC-MS,M/Z(ESI):337.3[M+H]+
第三步:N-苄基-2-(5-(4-(2-溴乙氧基)-2-氟苯基)吡啶-2-基)乙酰胺的制备
将N-苄基-2-(5-(2-氟-4-羟基苯基)吡啶-2-基)乙酰胺(0.14g,0.416mmol),1,2-二溴乙烷(0.469g,2.497mmol)和碳酸钾(0.345g,2.497mmol)置于乙腈(3mL)中,升温至85℃搅拌12h。加入水(5mL)稀释,用乙酸乙酯(5mL×3)萃取,分液,合并有机相。有机相用无水硫酸钠干燥,过滤,浓缩,残留物用柱层析纯化(石油醚∶乙酸乙酯(V/V)=3∶1),得化合物N-苄基-2-(5-(4-(2-溴乙氧基)-2-氟苯基)吡啶-2-基)乙酰胺(0.14g,产率76%)。
中间体A4的制备
合成路线如下所示:
第一步:3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚的制备
室温下将化合物4-溴-3-甲基苯酚(5g,26.7mmol)和联硼酸频那醇酯(10.2g,40.1mmol)加入到1,4-二氧六环(70mL)中,然后加入醋酸钾(6.56g,66.8mmol),氮气保护下加入1,1′-二(二苯膦基)二茂铁二氯化钯(II)(950mg,1.3mmol),加热至95℃,搅拌6h。反应液冷却至室温,加入水(50mL)稀释,用乙酸乙酯(50mL×3)萃取,分液,合并有机相,有机相用无水硫酸钠干燥,过滤,浓缩,残留物用薄层硅胶板分离纯化(石油醚∶乙酸乙酯(V/V)=5∶1)得化合物2-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基)丁-2-醇(6.1g,产率97%)。
第二步:N-苄基-2-(5-(4-羟基-2-甲基苯基)吡啶-2-基)乙酰胺的制备
室温下将化合物3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚(1.15g,4.92mmol)和N-苄基-2-(5-溴吡啶-2-基)乙酰胺(1.0g,3.33mmol)加入到1,4-二氧六环/水(10mL/1mL)中,然后加入氟化钾(0.760g,13.1mmol),氮气保护下加入1,1′-二(二苯膦基)二茂铁二氯化钯(II)(117mg,0.16mmol),加热到90℃搅拌10h。反应液冷却至室温,加入水(50mL)稀释,用乙酸乙酯(20mL×3)萃取,分液,合并有机相,有机相用无水硫酸钠干燥,过滤,浓缩,残留物经柱层析硅胶纯化(CH2Cl2∶MeOH(V/V)=95∶5),得化合物N-苄基-2-(5-(4-(3-羟基-3-甲基丁氧基)苯基)吡啶-2-基)乙酰胺(850mg,产率78%)。
第三步:N-苄基-2-(5-(4-(2-溴乙氧基)-2-甲基苯基)吡啶-2-基)乙酰胺的制备
室温下将N-苄基-2-(5-(2-甲基-4-羟基苯基)吡啶-2-基)乙酰胺(0.6g,1.8mmol)和碳酸钾(1.5g,10.7mmol)加入到无水乙腈中(15mL),加热到80℃搅拌1h,然后加入1,2-二溴乙烷(2.01g,10.7mmol),继续在80℃下搅拌10h。反应液冷却到室温,浓缩除去溶剂得到粗品,用硅胶柱分离纯化(DCM∶MeOH(V/V)=95∶5)得化合物N-苄基-2-(5-(4-(2-溴乙氧基)-2-氟苯基)吡啶-2-基)乙酰胺(0.55g,产率69%)。
实施例1化合物I-1的制备
合成路线如下所示:
将N-苄基-2-(5-(4-羟基苯基)吡啶-2-基)乙酰胺(中间体A1,0.2g,0.629mmol)和碳酸钾(0.26g,1.885mmol)置于乙腈(3mL)中,升温至85℃搅拌0.5h,再将3-(2-溴乙基)-3-甲基氧杂环丁烷(0.168g,0.942mmol)加入上述体系中,继续搅拌12h,反应完全后向反应体系中加水(5mL)稀释,用乙酸乙酯(5mL×3)萃取,分液,合并有机相。有机相用无水硫酸钠干燥,过滤,浓缩,残留物用高效液相色谱制备分离,纯化得到N-苄基-2-(5-(4-(2-(3-甲基氧杂环丁烷-3-基)乙氧基)苯基)吡啶-2-基)乙酰胺(I-1)(0.12g,产率47.7%)。
LC-MS,M/Z(ESI):417.2[M+H]+
1H NMR(400MHz,CDCl3)δ8.72-8.68(m,1H),7.81(dd,1H),7.63(s,1H),7.52-7.46(m,2H),7.31(ddd,3H),7.26-7.23(m,3H),7.00-6.95(m,2H),4.63(d,2H),4.49(d,2H),4.41(d,2H),4.10(t,2H),3.82(s,2H),2.18(t,2H),1.42(s,3H).
实施例2化合物I-2的制备
合成路线如下所示:
将N-苄基-2-(5-(4-羟基苯基)吡啶-2-基)乙酰胺(中间体A1,0.2g,0.628mmol)和碳酸钾(0.260g,1.885mmol)置于乙腈(3mL)中,升温至85℃搅拌0.5h,再将3-(溴甲基)-3-甲基-1-氧杂环丁烷(0.156g,0.942mmol)加入上述反应液中,继续搅拌12h。将反应液冷至室温,加入水(5mL)稀释,用乙酸乙酯(5mL×3)萃取,分液,合并有机相。有机相用无水硫酸钠干燥,过滤,浓缩,残留物用制备高效液相色谱分离,纯化得到N-苄基-2-(5-(4-((3-甲基氧杂环丁烷-3-基)甲氧基)苯基)吡啶-2-基)乙酰胺(I-2)(0.12g,产率47.7%)。
LC-MS,M/Z(ESI):403.2[M+H]+
1H NMR(400MHz,CDCl3)δ8.71(d,1H),7.82(dd,1H),7.63(s,1H),7.54-7.48(m,2H),7.36-7.22(m,6H),7.08-7.02(m,2H),4.65(d,2H),4.49(dd,4H),4.08(s,2H),3.83(s,2H),1.47(s,3H).
实施例3:化合物I-3的制备
合成路线如下所示:
将N-苄基-2-(5-(4-(2-溴乙氧基)苯基)吡啶-2-基)乙酰胺(中间体A2,0.4g,0.940mmol),3,3-二氟氮杂环丁烷盐酸盐(0.146g,1.129mmol)和碳酸钾(0.390g,2.82mmol)置于乙腈(6mL)中,升温至85℃搅拌12h。反应液冷至室温,加入水(5mL)稀释,用乙酸乙酯(5mL×3)萃取,分液,合并有机相。有机相用无水硫酸钠干燥,过滤,浓缩,残留物用制备高效液相色谱分离纯化,得到N-苄基-2-(5-(4-(2-(3,3-二氟氮杂环丁烷-1-基)乙氧基)苯基)吡啶-2-基)乙酰胺(I-3)(85mg,产率21%)。
LC-MS,M/Z(ESI):483.2[M+H]+
1H NMR(400MHz,CDCl3)δ8.70(d,1H),7.81(dd,1H),7.62(s,1H),7.53-7.45(m,2H),7.36-7.21(m,6H),7.03-6.95(m,2H),4.49(d,2H),4.09(t,2H),3.82(s,2H),3.75(t,4H),3.01(t,2H).
实施例4:化合物I-4的制备
合成路线如下所示:
将N-苄基-2-(5-(4-(2-溴乙氧基)苯基)吡啶-2-基)乙酰胺(中间体A2,0.5g,1.18mmol),3-甲氧基氮杂环丁烷(0.17g,1.38mmol)和碳酸钾(0.48g,3.53mmol)置于乙腈(5.0mL)中,反应液升温至85℃搅拌12h。加入水(5mL)稀释,用乙酸乙酯(5mL×3)萃取,分液,合并有机相。有机相用无水硫酸钠干燥,过滤,浓缩,残留物用制备高效液相色谱分离,得到N-苄基-2-(5-(4-(2-(3-甲氧基氮杂环丁烷-1-基)乙氧基)苯基)吡啶-2-基)乙酰胺(I-4)(250mg,产率51%)。
LC-MS,M/Z(ESI):432.2[M+H]+
1H NMR(400MHz,CDCl3)δ8.70(d,1H),7.81(dd,1H),7.64(s,1H),7.51-7.45(m,2H),7.31(ddd,3H),7.26-7.22(m,2H),4.49(d,2H),4.09(dd,1H),4.04(dd,2H),3.82(s,2H),3.78-3.72(m,2H),3.27(s,3H),3.08-3.02(m,2H),2.91(t,2H).
实施例5:化合物I-5的制备
合成路线如下所示:
将N-苄基-2-(5-(4-(2-溴乙氧基)苯基)吡啶-2-基)乙酰胺(中间体A2,0.5g,1.18mmol),氮杂环丁烷盐酸盐(0.13g,1.41mmol)和碳酸钾(0.48g,3.53mmol)置于乙腈(5.0mL)中,反应液升温至85℃搅拌12h。加入水(5mL)稀释,用乙酸乙酯(5mL×3)萃取,分液,合并有机相。有机相用无水硫酸钠干燥,过滤,浓缩,残留物用制备高效液相色谱分离,得到2-(5-(4-(2-(氮杂环丁烷-1-基)乙氧)苯基)吡啶-2-基)-N-苄基乙酰胺(I-5)(80mg,产率51%)。
LC-MS,M/Z(ESI):402.2[M+H]+
1H NMR(400MHz,CDCl3)δ8.70(d,1H),7.81(dd,1H),7.64(s,1H),7.51-7.44(m,2H),7.35-7.28(m,3H),7.24(d,3H),7.02-6.97(m,2H),4.49(d,2H),4.01(t,2H),3.82(s,2H),3.35(t,4H),2.86(t,2H),2.21-2.08(m,2H).
实施例6:化合物I-6的制备
合成路线如下所示:
室温下将原料N-苄基-2-(5-(4-(2-溴乙氧基)-2-氟苯基)吡啶-2-基)乙酰胺(中间体A3,0.6g,1.35mmol)加入到乙腈(10mL)中,然后加入碳酸钾(561mg,4.1mmol)、碘化钾(23mg,0.14mmol)和3-甲氧基氮杂环丁烷盐酸盐(200mg,1.62mmol),反应液在80℃下搅拌8h,反应液浓缩除去溶剂,残留物用硅胶柱分离纯化(CH2Cl2∶MeOH(V/V)=95∶5),得化合物N-苄基-2-(5-(2-氟-4-(2-(3-甲氧基氮杂环丁烷-1-基)乙氧基)苯基)吡啶-2-基)乙酰胺(I-6)(213.5mg,产率38%)。
1H NMR(400MHz,DMSO-d6)δ8.67-8.58(m,2H),7.86(d,1H),7.49(t,IH),7.42(d,1H),7.35-7.20(m,5H),6.99-6.86(m,2H),4.30(d,2H),3.99(m,2H),3.94(m,1H),3.72(s,2H),3.55(m,2H),3.14(s,3H),2.88(m,2H),2.76(t,2H)
LC-MS,M/Z(ESI):450.4[M+H]+
实施例7:化合物I-7的制备
合成路线如下所示:
室温下将原料N-苄基-2-(5-(4-(2-溴乙氧基)-2-甲基苯基)吡啶-2-基)乙酰胺(中间体A4,0.6g,1.37mmol)加入到乙腈(10mL)中,然后加入碳酸钾(566mg,4.1mmol)、碘化钾(23mg,0.14mmol)和3-甲氧基氮杂环丁烷盐酸盐(202mg,1.64mmol),反应液在80℃下搅拌8h,反应液浓缩除去溶剂,残留物用硅胶柱分离纯化(CH2Cl2∶MeOH(V/V)=95∶5)纯化,得到化合物N-苄基-2-(5-(4-(2-(3-甲氧基氮杂环丁烷-1-基)乙氧基)-2-甲基苯基)吡啶-2-基)乙酰胺(I-7)(221.5mg,产率36%).
1H NMR(400MHz,DMSO-d6)δ8.62(t,1H),8.41(d,1H),7.68(m,1H),7.38(d,1H),7.33-7.18(m,5H),7.13(d,1H),6.87(d,1H),6.82(m,1H),4.29(d,2H),3.98-3.89(m,3H),3.71(s,2H),3.57-3.49(m,2H),3.13(s,3H),2.91-2.83(m,2H),2.74(t,2H),2.20(s,3H)
LC-MS,M/Z(ESI):446.4[M+H]+
实施例8:化合物I-8的制备
合成路线如下所示:
室温下将原料N-苄基-2-(5-(4-(2-溴乙氧基)苯基)吡啶-2-基)乙酰胺(中间体A2,0.6g,1.41mmol)加入到乙腈(10mL)中,然后加入碳酸钾(584mg,4.2mmol)、碘化钾(23mg,0.14mmol)和3-(甲氧基甲基)氮杂环丁烷盐酸盐(232mg,1.69mmol),反应液在80℃下搅拌8h,反应液浓缩除去溶剂,残留物用硅胶柱分离纯化(CH2Cl2∶MeOH(V/V)=95∶5),得化合物N-苄基-2-(5-(4-(2-(3-(甲氧基甲基)氮杂环丁烷-1-基)乙氧基)苯基)吡啶-2-基)乙酰胺(I-8)(231.1mg,产率37%).
1H NMR(400MHz,DMSO-d6)δ8.72(d,1H),8.59(t,1H),7.94(m,1H),7.65-7.58(m,2H),7.38(d,1H),7.33-7.18(m,5H),7.04-6.97(m,2H),4.28(d,J=5.9Hz,2H),3.94(t,2H),3.69(s,2H),3.40(t,2H),3.28(d,2H),3.21(s,3H),2.90(t,2H),2.71(t,2H),2.57(m,1H).
LC-MS,M/Z(ESI):446.4[M+H]+
实施例9:化合物I-9的制备
合成路线如下所示:
室温下将原料N-苄基-2-(5-(4-(2-溴乙氧基)苯基)吡啶-2-基)乙酰胺(中间体A2,0.6g,1.41mmol)加入到乙腈(10mL)中,然后加入碳酸钾(584mg,4.2mmol)、碘化钾(23mg,0.14mmol)和N,N-二甲基氮杂环丁烷-3-胺盐酸盐(231mg,1.69mmol),反应液在80℃下搅拌8h,反应液浓缩除去溶剂,残留物用硅胶柱分离纯化(CH2Cl2∶MeOH(V/V)=95∶5),得化合物N-苄基-2-(5-(4-(2-(3-(二甲基氨基)氮杂环丁烷-1-基)乙氧基)苯基)吡啶-2-基)乙酰胺(I-9)(329.5mg,产率52.5%)。
1H NMR(400MHz,DMSO-d6)δ8.73(d,1H),8.61(t,1H),7.95(m,1H),7.63(d,2H),7.39(d,1H),7.34-7.18(m,5H),7.02(d,2H),4.29(d,2H),3.97(t,2H),3.70(s,2H),3.43(d,2H),2.82(t,2H),2.74(t,3H),1.98(s,6H)
LC-MS,M/Z(ESI):445.4[M+H]+
实施例10化合物I-27的制备
合成路线如下所示:
第一步:N-苄基-2-(5-(4-(2-氯乙氧基)-苯基)-吡啶-2-基)-乙酰胺的制备
室温下将原料N-苄基-2-(5-(4-羟基苯基)吡啶-2-基)乙酰胺(中间体A1)(0.6g,1.8mmol)和碳酸钾(1.5g,10.7mmol)加入到无水乙腈中(15mL),加热到80℃下搅拌1h,然后加入1-溴-2-氯乙烷(2.01g,10.7mmol),反应液继续在80℃下搅拌10h。反应完成后,将反应液冷却到室温,减压浓缩除去溶剂,粗品用硅胶柱分离纯化(石油醚∶乙酸乙酯(V/V)=2∶1),得化合物N-苄基-2-(5-[4-(2-氯乙氧基)-苯基]-吡啶-2-基)-乙酰胺(0.55g,产率69%).
第二步:N-苄基-2-(5-(4-(2-(3-甲氧基-3-甲基-氮杂环丁烷-1-基)-乙氧基)-苯基)-吡啶-2-基)乙酰胺的制备
室温下将原料N-苄基-2-{5-[4-(2-氯乙氧基)-苯基]-吡啶-2-基}-乙酰胺(0.1g,0.23mmol)加入到N.N-二甲基甲酰胺(2mL)中,然后加入碳酸钾(91mg,0.9mmol)、碘化钾(150mg,0.9mmol)和3-甲氧基-3-甲基氮杂环丁烷(34mg,0.34mmol),反应液在60℃下搅拌8h。点板检测反应完成后,用制备层析板纯化(二氯甲烷∶甲醇(V/V)=10∶1),得化合物N-苄基-2-(5-{4-[2-(3-甲氧基-3-甲基-氮杂环丁烷-1-基)-乙氧基]-苯基}-吡啶-2-基)乙酰胺(18.9mg,产率18%).
1HNMR(400MHz,DMSO-d6)δ8.75(d,1H),8.63(t,1H),7.96(dd,1H),7.64(d,2H),7.40(d,1H),7.35-7.19(m,5H),7.04(d,2H),4.31(d,2H),4.00(t,2H),3.72(s,2H),3.20(dd,2H),3.09(s,3H),3.03(d,2H),2.80(t,2H),1.37(s,3H)
LC-MS,M/Z(ESI):446.2[M+H]+
下列化合物的制备参考上述实施例的制备方法得到。
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本发明测试例中的对照化合物(商品名Tirbanibulin)是一种双重作用的Src激酶和微管蛋白聚合抑制剂,已被FDA和欧盟获批用于面部或头皮光化性角化病的局部治疗。对照化合物的制备参考专利WO 2008/002676 A2,对照化合物结构如下:
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测试例1:抑制微管蛋白单体聚合试验
采用Tubulin Polymerization Assay Kit(cytoskeleton,Cat.#BK011P)开展化合物抑制微管蛋白单体聚合试验。
试验前先将试剂盒配套的96孔板(Corning Costar,Cat.#3686)放置于酶标仪(MD,SpectraMax M5)中加热至37℃,维持10min,取出96孔板,加入5μl的10×的化合物溶液或空白溶液,再将96孔板放入酶标仪37℃孵育1min,使化合物溶液升温至37℃,取出96孔板于每孔迅速加入按照供应商说明书配置的反应混合物,1min内完成加样并避免产生气泡,然后立即将96孔板放入酶标仪,震荡5s,使用Kinetic mode在激发光360nm、发射光420nm条件下,37℃连续检测30min-60min,每30s检测一次,以检测时间为X轴,荧光信号值为Y轴得到微管蛋白单体聚合曲线。
化合物对微管蛋白聚合抑制试验结果表明,本发明化合物能明显抑制微管蛋白单体的聚合。
测试例2:化合物抑制细胞增殖试验
采用人皮肤鳞状细胞癌细胞A-431(ATCC,CRL-1555)、人胚胎肾上皮细胞293T(中国典型培养物保藏中心,GDC0187)和小鼠胚胎成纤维细胞3T3-Swiss(ATCC,CCL-92)增殖试验检测小分子化合物对细胞增殖抑制作用。
A-431细胞、293T细胞和3T3-Swiss细胞培养于含10%胎牛血清的DMEM培养基中,于37℃,5%CO2培养箱中生长。将对数期细胞按照1000个细胞/孔,每孔100μl接种于96孔细胞培养板,置于37℃,5%CO2培养箱培养过夜。第二天每孔再加入100μl梯度稀释的2×待测化合物溶液,DMSO作为阳性对照,另设置10μM十字孢碱(阿拉丁,S102392)作为阴性对照组,加完化合物的培养板继续于37℃,5%CO2培养箱中孵育4天。孵育完成后使用luciferase assay system(Promega,G9243)并按照供应商提供的说明书在Envision 2104Multilabel Reader上测定荧光信号值。通过以下公式计算抑制率,然后以抑制剂的浓度Log值为X轴,抑制率为Y轴绘制曲线,用Graphpad 8.0计算得出IC50。
Inhibition%=(阳性对照组信号-测试孔信号)/(阳性对照组信号-阴性对照组信号)*100
表1测试化合物对不同细胞增殖活性抑制结果
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化合物对细胞增殖抑制试验结果表明,本发明化合物能明显抑制细胞增殖,尤其是化合物I-2、I-6和I-7,相比于对照化合物,将细胞增殖抑制活性提升了至少1倍以上,甚至可达3倍以上。
测试例3:药代动力学试验
小鼠药代动力学试验,使用3只雄性ICR小鼠,20-25g,禁食过夜,尾静脉注射给药(5mg/kg)。在给药前和给药后15、30min以及1、2、4、8、24h采血。血液样品于6800g,2-8℃离心6min,收集血浆,于-80℃保存。取各时间点血浆,加入3-5倍量含内标的乙腈溶液混合,涡旋混合1分钟,13000转/min下于4℃离心10min,取上清液加入3倍量水混合,取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。
表2小鼠药代动力学试验结果
小鼠药代动力学试验结果表明,本发明化合物符合皮肤局部给药的药代动力学性质,体内代谢快,潜在毒性小,成药性良好。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (11)
1.一种式I所示化合物或其药学上可接受的盐,其特征在于:式I具有如下结构:
其中,其中,W为-O-、-S-、-NH-或-N(C1-C6烷基)-;
L不存在或为C1-C6亚烷基;
Q为被m个R2取代的3或4元杂环烷基;
R1、R2和R3各自独立地为氢、卤素、-CN、-NR11R12、C1-C6烷基、C2-C6烯基、C2-C6炔基、3-8元环烷基、4-8元杂环烷基、6-10元芳基、5-8元杂芳基、-O-R21、-C1-C6烷基-O-R22、-COO-R23、-CO-R24或-S(O)2-R25;
当R1为多个时,所述R1相同或不同;
当R2为多个时,所述R2相同或不同;
当R3为多个时,所述R3相同或不同;
其中,R11、R12、R21、R22、R23、R24和R25各自独立地为氢、C1-C6烷基、3-8元环烷基、4-8元杂环烷基、6-10元芳基或5-6元杂芳基;
所述-NR11R12、C1-C6烷基、C2-C6烯基、C2-C6炔基、3-8元环烷基、4-8元杂环烷基、6-10元芳基、5-6元杂芳基、-O-R21、-C1-C6烷基-O-R22、-COO-R23、-CO-R24和-S(O)2-R25各自独立地任选地被一个或多个选自下列的取代基取代:卤素、-OH、-NH2、-CN、C1-C6烷基、-O-C1-C6烷基、3-6元环烷基和4-8元杂环烷基;当取代基为多个时,所述取代基相同或不同;
m、n和t各自独立地为1、2或3。
2.如权利要求1所述的式I所示化合物或其药学上可接受的盐,其特征在于:W为-O-;
和/或,L为-CH2-或-CH2CH2-;
和/或,n为1;R1为氢、卤素、-CN、C1-C6烷基或C1-C6卤代烷基;
较佳地,R1为氢、卤素或C1-C6烷基;
和/或,R2独立地为氢、卤素、-CN、-NR11R12、C1-C6烷基、-O-R21、-C1-C6烷基-O-R22、3-6元环烷基或4-8元杂环烷基;其中,R11、R12、R21和R22各自独立地为氢、C1-C6烷基、3-8元环烷基、4-8元杂环烷基、6-10元芳基或5-6元杂芳基;
所述-NR11R12、C1-C6烷基、-O-R21、-C1-C6烷基-O-R22、3-6元环烷基和4-8元杂环烷基各自独立地任选地被一个或多个选自下列的取代基取代:卤素、-OH、-NH2、-CN、C1-C3烷基、-O-C1-C3烷基、3-6元环烷基和4-8元杂环烷基;当取代基为多个时,所述取代基相同或不同;
较佳地,R2独立地为氢、-CN、卤素、-C1-C3烷基-CN、-C1-C3烷基、-O-C1-C3烷基、-C1-C3烷基-O-C1-C3烷基、-N(C1-C3烷基)(C1-C3烷基)、-C1-C3烷基-O-环丙基、3-6元环烷基或4-6元杂环烷基;
更佳地,R2独立地为卤素、-C1-C3烷基、-O-C1-C3烷基、-C1-C3烷基-O-C1-C3烷基或-N(C1-C3烷基)(C1-C3烷基);
和/或,R3为氢。
3.如权利要求2所述的式I所示化合物或其药学上可接受的盐,其特征在于:n为1;R1为-H、-F、-Cl、-CN、-CH3或-CF3;
较佳地,R1为-H、-F、或-CH3;和/或,R2独立地为氢、-CN、-F、-CH2CN、-CH3、-OCH3、-CH2OCH3、-N(CH3)2、-CH2O-环丙基或氧杂环丁基;
较佳地,R2独立地为-F、-CH3、-OCH3、-CH2OCH3或-N(CH3)2。
4.如权利要求1所述的式I所示化合物或其药学上可接受的盐,其特征在于:式I具有式Ia或Ib结构:
其中,W、L、R1和Q的定义如权利要求1中所述;
p为0、1、2或3。
5.如权利要求4所述的式I所示化合物或其药学上可接受的盐,其特征在于:式Ib为情形1或2:
情形1:式Ib中,p为1或2;
R1为氢、卤素或C1-C6烷基;
Q为m为1或2;R2为卤素、C1-C6烷基或-O-R21,R21为C1-C6烷基;
情形2:式Ib具有式Ic或Id结构:
各m为1或2;
式Ic中,R2独立地为C1-C3烷基;优选为甲基;
式Id中,当R1为H时,R2独立地为卤素;当R1为卤素或C1-C6烷基时,R2独立地为-O-R21,R21为C1-C6烷基。
6.如权利要求1或4所述的式I所示化合物或其药学上可接受的盐,其特征在于:各所述4-8元杂环烷基和所述5-6元杂芳基中的杂原子为N、S和O中的一种或多种,个数为1、2或3个;
和/或,所述3或4元杂环烷基的杂原子选自N、O和S,个数为1、2或3个;较佳地选自O和N,个数为1个;更佳地为氧杂环丁烷基或氮杂环丁烷基;
和/或,R2中,所述C1-C6烷基和所述-C1-C6烷基-O-R22中的C1-C6烷基独立地为C1-C3烷基,还可为甲基、乙基、正丙基或异丙基,例如甲基或乙基;
和/或,R2中,所述3-8元环烷基中的环烷基为单环的环烷基;
和/或,R2中,所述4-8元杂环烷基为4或5元杂环烷基,杂原子为O,个数为1个,还可为氧杂环丁烷基,例如
和/或,R11、R12、R21、R22、R23、R24和R25中,所述C1-C6烷基为甲基、乙基、正丙基或异丙基,例如甲基。
7.如权利要求1或4所述的式I所示化合物或其药学上可接受的盐,其特征在于:为/>
较佳地,为/>
更佳地,为/>
和/或,Q为
较佳地,Q为
更佳地,Q为
和/或,-L-W-为-C1-C6亚烷基-O-;
较佳地,-L-W-为-CH2O-或-CH2CH2O-。
8.如权利要求1所述的式I所示化合物或其药学上可接受的盐,其特征在于:所述式I所示化合物为如下任一化合物:
9.一种药物组合物,其特征在于:其包括如权利要求1-8中任一项所述的如式I所示化合物或其药学上可接受的盐,和任选的药学上可接受的载体和/或辅料。
10.一种物质A的用途,其特征在于,所述的物质A为如权利要求1-8中任一项的如式I所示化合物、其药学上可接受的盐或如权利要求9所述的药物组合物;
所述的用途包括如下任一种用途:
1)抑制微管蛋白聚合和/或Src激酶;
2)制备微管蛋白聚合和/或Src激酶抑制剂;
3)制备预防、治疗与微管蛋白聚合和/或Src激酶相关的疾病的药物、药物组合物或制剂;
和,4)制备治疗和/或预防光化性角化病或鳞状细胞癌的药物;
较佳地,所述的与微管蛋白聚合和/或Src激酶相关的疾病包括肿瘤、皮肤疾病和/或其它疾病的一种、两种或更多种;
所述肿瘤较佳地包括:实体瘤、肉瘤、血液系统癌症,亚型有乳腺癌、卵巢癌、前列腺癌、子宫颈癌、睾丸癌、结肠癌、结肠直肠癌、肝癌、非小细胞肺癌、鳞状细胞癌、小细胞肺癌、胃癌、胃肠道间质瘤、胰腺癌、膀胱癌、生殖细胞瘤、肥大细胞瘤、肥大细胞增多症、胶质母细胞瘤、神经母细胞瘤、星形细胞瘤、黑色素瘤、B细胞淋巴瘤、T细胞淋巴瘤、缓慢进展淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性髓细胞性白血病、急性淋巴细胞性白血病、慢性髓细胞性白血病、慢性淋巴细胞性白血病、骨髓瘤和/或骨髓增生异常综合症;
所述的皮肤疾病较佳地包括:光化性角化病、鳞状细胞癌、银屑病、异位性皮炎、牛皮癣、白癜风、玫瑰疹和/或系统性红斑狼疮;
所述的其它疾病较佳地包括:自身免疫型糖尿病、糖尿病视网膜病变、肝纤维化、肺纤维化、肾纤维化、阿尔茨海默病、帕金森病、亨廷顿舞蹈症、肌萎缩侧索硬化、脊髓小脑退行性病变、动脉粥样硬化、贫血、镰刀形红细胞贫血症、地中海贫血症、骨关节炎、类风湿性关节炎、疟疾、锥形虫病、蠕虫病、原虫感染、多发性硬化症、狼疮、哮喘、过敏性鼻炎和/或炎性肠病。
11.一种如权利要求1-8中任一项所述的式I所示化合物或其药学上可接受的盐的制备方法,其特征在于:所述的制备方法为方法1或方法2:
方法1:其包括如下步骤:在碱性试剂存在下,将化合物II和化合物II在溶剂中进行反应,得到所述式I所示化合物;
方法2:其包括如下步骤:在碱性试剂存在下,将化合物II'和化合物III'在溶剂中进行反应,得到所述式I所示化合物;
其中,X1和X2独立地为卤素;Q、L、W、R1、R2、n和t的定义均如权利要求1-8中任一项所述。
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