CN111116572B - 噁二唑衍生物及其制备方法和用途 - Google Patents
噁二唑衍生物及其制备方法和用途 Download PDFInfo
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- CN111116572B CN111116572B CN201811286332.5A CN201811286332A CN111116572B CN 111116572 B CN111116572 B CN 111116572B CN 201811286332 A CN201811286332 A CN 201811286332A CN 111116572 B CN111116572 B CN 111116572B
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Abstract
本发明涉及噁二唑衍生物及其制备方法和用途。本发明的噁二唑衍生物具有式(I)所示的结构:其中,R1、X和R2如说明书部分所定义。
Description
发明领域
本发明属于医药技术领域,涉及噁二唑衍生物及其制备方法和用途,具体涉及噁二唑衍生物、包含其的药物组合物、其制备方法及其在医药研究中的应用。
背景技术
色氨酸(TRP)是生物所需要的一种必须氨基酸。吲哚胺-2,3-双加氧酶1(Indoleamine 2,3-dioxygenase 1,IDO1)是机体内天然存在的免疫调节酶。色氨酸(TRP)分解代谢为犬尿酸(KYN)主要由IDO和TDO控制,其催化犬尿酸路径色氨酸分解代谢第一步,即吲哚环2,3位氧化开环裂解,是犬尿酸路径(KP)的限速步骤(Leklem JE,Am J ClinNutr,1971,24(6):659-672)。犬尿酸途径在免疫调节过程中具有重要作用,与肿瘤免疫耐受、免疫调节异常等疾病相关(Barth H.et al Crit Rev Microbiol,2014,40(4):360-368)。
IDO于1967首次作为D-Trp代谢酶分离;为单体含亚铁血红素酶(Hayaishi O.etal Science,1969,164,389-396);氧化裂解几个吲哚环底物,包括D-和L-Trp,色胺,5-HT,血清素和褪黑素。IDO广泛分布在人和其它哺乳动物的肝外组织,主要见于胸腺髓质和次级淋巴器官内,并散布于胎盘、附睾、眼前房及胃肠道黏膜等免疫豁免组织中。IDO在成纤维细胞、B细胞等多种细胞内均有表达,但是表达量最高的细胞为抗原提呈细胞,如树突细胞(DC)和巨噬细胞。
近来,IDO涉及诱发免疫耐受性作用受到很多关注。除胎盘组织外,正常情况下IDO在多数组织细胞内基本不表达。在炎症发生区域,干扰素γ等炎性细胞因子可诱导IDO表达量升高(Vécsei L.et al Nat Rev Drug Discov,2013,12(1):64-82)。有关哺乳动物怀孕、慢性感染、自身免疫性疾病和肿瘤免疫逃逸的研究表明,IDO的高表达,可导致该组织微环境的免疫系统被抑制。胎盘组织IDO高表达可防止对胎儿的免疫排斥反应。炎症区域IDO高表达可防止过度的免疫反应,防止细胞受到过度损伤。表达IDO的细胞可抑制T细胞反应并提高耐受性。
IDO可能通过2种机制参与诱导肿瘤微环境中的免疫耐受。一种是IDO高度表达导致局部的色氨酸耗竭,被周围淋巴细胞通过GCN2机制感受到,诱导T细胞停滞于G1期,引起T细胞发生细胞周期停滞或凋亡(Munn DH.et al Immunity,2015,22(5):633-642);色氨酸的缺乏还能够抑制氨基酸感应激酶1(master amino acid-sensing kinase 1,GLK1),进而抑制m-TOR信号分子,触发T细胞免疫无能和自噬(Metz R.et al Oncoimmunology,2012,1(9):1460-1468),下调机体的免疫能力。另一种是IDO依赖性的色氨酸降解导致犬尿酸水平的提高,犬尿酸进入附近的淋巴细胞结合AHR转录因子对T细胞和调节性Treg细胞进行调节,一方面诱导氧自由基介导的T细胞凋亡;另一方面调节性Treg细胞数量增多且被激活,增强调节T细胞的免疫抑制功能,促使机体对肿瘤特异性抗原免疫耐受(Munn DH.et alTrends Immunol,2013,34(3):137-143)。
众多研究发现,生理条件下IDO呈低水平表达状态,但在多种肿瘤组织表现为组成性高表达(Théate I.et al Cancer Immunol Res,2015,3(2):161-172),包括血液肿瘤和直结肠癌、肝癌、乳腺癌、宫颈癌、肺癌、胰腺癌、咽喉癌等实体瘤。IDO异常高表达在临床上与肿瘤不良预后呈正相关(Godin-Ethier J.et al Clin Cancer Res,2011,17(22):6985-6991)。肿瘤细胞逃脱免疫监控室癌变和癌症进一步发展的关键一步,肿瘤中IDO的异常高表达可能是肿瘤细胞逃避免疫监控的一种主要机制,抑制IDO的活性有可能激活被抑制的免疫系统,从而达到抑制肿瘤生长的效果。因此,IDO是一个具有潜力的抗肿瘤免疫疗法小分子调控靶点。
目前IDO抑制剂的研发均处于早期,Incyte公司开发的口服小分子IDO抑制剂Epacadostat、NewLink Genetics公司开发的口服小分子IDO抑制剂Indoximod和BMS公司开发的口服小分子IDO抑制剂BMS-986205同样处于临床III期。主要用于治疗白血病和肾细胞癌、皮肤癌、头颈癌、膀胱癌、NSCLC等多种实体瘤。除此之外,还有Pfizer、Roche、EliLilly、Flexus、Iomet、iTeos、Curadev等公司的IDO抑制剂处于临床I期研究阶段。抑制剂Epacadostat、Indoximod和BMS-986205的结构式如下:
尽管公开的选择性抑制IDO的抑制剂专利申请包括WO2004094409、WO2006122150、WO2007075598、WO2010005958、WO2014066834、WO2008147283、WO2013174947、WO2017106062、WO2017101884、WO2017152857、WO2018044663等,但是目前并未找到很好的IDO抑制剂可以作为上市药物。
发明内容
为了达到更好的肿瘤治疗效果的目的,更好的满足市场需求,我们设计合成了一系列新型的选择性IDO抑制剂,具有优异的IDO抑制活性,特别是从动物水平考察了血浆犬尿酸/色氨酸比值变化情况,从而从机理上进一步筛选出具有优异的生物活性化合物。
因此,本发明的一个目的是提供一种选择性IDO抑制剂。
本发明的另一个目的是提供所述抑制剂的制备方法。
本发明的再一个目的是提供包含所述抑制剂的药物组合物。
本发明的又一个目的是提供所述抑制剂用于制备治疗多种疾病的药物中的用途。
本发明的上述目的是采用如下技术方案来实现的。
一方面,本发明提供具有式(I)所示结构的化合物、其立体异构体或其药学上可接受的盐,
其中,R1为-NH-或-S-;
X选自取代或未取代的烷基,环烷基,氨基,亚胺基或杂环基,其中所述取代的烷基,环烷基,氨基,亚胺基或杂环基分别独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C1-4烷基,C2-4链烯基,C2-4链炔基、氨基C1-4烷基、氨基C2-4链烯基、C3-8环烷基、C5-8杂环基和氨基C5-8杂环基的取代基所取代;
R2为:-(P=O)n(R3)t或-S(O)mR4;
n=0或1,其中,当n=0时,t=1;当n=1时,t=2。
m=0或2;
R3选自氢原子,羟基,氨基,烷基,杂环烷基,卤代烷基,卤代杂环烷基,芳基和杂芳基;任选进一步被一个或多个选自卤素、羟基、氰基、硝基、C1-4烷基、C1-4烷氧基和氨基C5-10杂环芳基的取代基所取代;
R4选自羟基,氨基,烷基,卤代烷基,其中氨基,烷基,卤代烷基分别独立地任选被选自烷基、羟基、卤素、硝基、氨基、C1-4烷基和C1-4烷氧基中的一个或多个取代基所取代。
在一个优选的实施方案中,所述式(I)所示结构的化合物为式(II)所示结构的化合物(即当在式(I)中,R2为:-(P=O)n(R3)t时的情形):
其中,R1为-NH-或-S-;
n为0或1,其中,当n=0时,t=1;当n=1时,t=2;
X选自取代或未取代的烷基,环烷基或杂环基,其中所述取代的烷基,环烷基或杂环基分别独立地被一个或多个选自卤素、羟基、氰基、氨基、C1-4烷基,氨基C1-4烷基、氨基C2-4链烯基、C3-8环烷基、C5-8杂环基和氨基C5-8杂环基的基团所取代;
R3选自烷基,羟基,氨基,卤代烷基,3-8元杂环基,卤代3-8元杂环烷基,芳基和杂芳基;任选进一步被一个或多个选自卤素、羟基、氰基、羰基、硝基、C1-4烷基、C1-4烷氧基、C1-4杂环基、氮取代C1-4杂环基、C5-10杂环芳基和氨基C5-10杂环芳基的取代基所取代。
优选地,在上述式(II)所示的化合物中,X选自C1-4的低级烷基和包含1或2个N原子的杂环基,优选选自-CH2-CH2-CH2-、-CH2-CH2-、
优选地,在上述式(II)所示的化合物中,R3选自C1-4的低级烷基,3-8元氮杂环基和杂芳基,优选选自CH3-、
在一个具体实施方案中,在上述式(II)所示的化合物中,R1为-NH-或-S-,n为0或1,其中,当n=0时,t=1;当n=1时,t=2,X选自C1-4的低级烷基和包含1或2个N原子的杂环基,优选选自-CH2-CH2-CH2-、-CH2-CH2-、
在另一个优选的实施方案中,所述式(I)所示结构的化合物为式(III)所示结构的化合物(即当在式(I)中,R2为:-S(O)mR4(m=2)时的情形):
其中,R1为-NH-或-S-;
X选自取代或未取代的烷基,环烷基,氨基,亚胺基或杂环基,其中所述取代的烷基,环烷基,氨基,亚胺基或杂环基分别独立地被一个或多个选自卤素、羟基、氰基、硝基、氨基、羰基、C1-4烷基、C2-4链烯基,C2-4链炔基、氮取代C1-4烷基、氨基C2-4链烯基、C3-8环烷基和氨基C5-8杂环基的基团所取代;
R4选自烷基,羟基,氨基和卤代烷基,其中烷基,氨基,卤代烷基分别独立地任选被选自烷基、羟基、卤素、硝基和氨基中的一个或多个取代基所取代。
优选地,在上述式(III)所示的化合物中,X选自C1-4低级烷基、氨基取代的烷基、烷基取代的氨基,烷基取代的亚胺基,烷基取代的酰胺基或包含1或2个N原子的杂环基,优选选自CH2-CH2-、-NH-CH2-CH2-NH-、-CH2-CH2-NH-、-N=CH-CH2-NH-、-NH-CO-CH2-NH-、
优选地,在上述式(III)所示的化合物中,R4选自氨基,甲氨基和甲基,优选为甲基。
在一个具体实施方案中,在上述式(III)所示的化合物中,R1为-NH-,X选自C1-4低级烷基,例如甲基、乙基,R4选自氨基、取代氨基,例如氨基或甲基氨基。
在一个具体的实施方案中,所述式(I)所示结构的化合物选自如下化合物:
另一方面,本发明提供上述式(I)所示化合物的制备方法,该制备方法包括使式(IV)所示的化合物在碱性条件下直接开环,得到式(I)所示化合物,
其中,X、R1、R2如前述所定义;优选地,所述反应在有机溶剂中进行,所述有机溶剂选自四氢呋喃、乙腈、N,N-二甲基甲酰胺、卤代烃、乙二醇二甲醚、二氯乙烷、甲醇、乙醇、石油醚、正己烷、乙醚和乙酸乙酯中的一种或多种;优选地,所述卤代烃为二氯甲烷,二氯乙烷,氯仿或四氯甲烷。
优选地,所述的碱选自碳酸钾、碳酸钠、碳酸镁、碳酸氢钠、碳酸铯、碳酸锂、氢氧化钠、氢氧化钾、氢氧化锂、氢氧化镁、氢氧化铯、三乙胺,二异丙基乙胺,哌啶、吡咯、吡啶、二甲基吡啶和二甲氨基吡啶中的一种或多种。
再一方面,本发明提供一种药物组合物,该药物组合物包含前述式(I)-(III)所示的化合物、其立体异构体或其药学上可接受的盐以及药学上可接受的辅料。
又一方面,本发明提供一种前述式(I)-(III)所示的化合物、其立体异构体或其药学上可接受的盐在制备用于预防和/或治疗癌症、肿瘤、病毒感染、抑郁症、神经性病症、创伤、年龄相关的白内障、器官移植排斥或自身免疫疾病的药物中的用途;其中,优选地,所述癌症或肿瘤选自肺癌、骨癌、胃癌、胰腺癌、皮肤癌、头颈癌、子宫癌、卵巢癌、睾丸癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、胰腺癌、脑癌、垂体腺瘤,黑素瘤、表皮样癌、T细胞淋巴瘤、慢性和急性白血病。
为了清晰性和一致性,下述定义将在专利文件中自始至终贯穿使用。
术语“烷基”指一价饱和脂肪族烃基团,包含1至20个碳原子的直链或支链基团,例如“C1~6烷基”指的是该基团为烷基,且碳链上的碳原子数量在1~6之间。包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、新戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、正庚基、正辛基等。在本发明中,该术语包括取代或未取代的烷基。
术语“取代或未取代的”指所述基团的H被一个或多个取代基所取代。优先选自下组的取代基:卤素、羟基、硝基、氨基、氰基、苯基、苄基、C1~4烷基、C1~4卤代烷基、C1~4烷氧基、C2~4链烯基、C2~4炔基、C3~6环烷基。
术语“环烷基”指的是具有特定碳原子数的单环饱和脂烃基,优选地指取代或未取代的C3~12环烷基。例如环丙基、环己基、甲基环丙基、2-乙基-环戊基、二甲基环丁基等。
术语“烷氧基”指-O-烷基,所述烷基可以是饱和或不饱和的、支链的、直链的或环状的。优选地,具有1~10个碳原子,较佳地1~6个碳原子。代表的例子包括甲氧基、乙氧基、丙氧基、叔丁氧基。
术语“卤素”或“卤代”是指F、Cl、Br、I。术语“卤代烷基”是指本文所定义的烷基中一个、两个或多个氢原子被卤素取代。卤代烷基的代表性例子包括CCl3、CF3、CHCl2、CH2CF3、CF2CF3等。
术语“烯基”指具有2~10个碳原子的,含一个或多个碳-碳双键的烷基。这类基团例如有乙烯基、1-丙烯基、2-丙烯基、丁-3-烯基等。
术语“芳基”是指具有共轭的π电子体系的6至20个(较佳6-14个)碳原子的单价芳香族碳环基团,它具有单环(如苯基)或稠环(如奈基或蒽基)形式,优选的芳基包括苯基和萘基。
术语“杂芳基”代表环中多达6个原子的稳定的单环或每个环中多达6个原子的双环碳环,其中至少一个环为芳香环且含有1~4个选自O、N和S的杂原子。单环杂芳基的代表性例子包括但不限于:呋喃基、咪唑基、吡啶基、哒嗪酮基、嘧啶基、吡嗪基、吡唑基、吡咯基、噻吩基、三唑基和三嗪基。双环杂芳基的代表性例子包括但不限于苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并咪唑基、喹啉基、萘啶基、吡啶并咪唑基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基,包含3~20个环原子,其中一个或多个环原子选自N、O或S,其余环原子为C。优选包含3~12个环原子,其中1~4个是杂原子;最优选包含3~8个环原子,其中1~3个是杂原子。单环杂环基的实例包括吡咯烷基、咪唑烷基、四氢呋喃基、二氢吡咯基、哌啶基、哌嗪基、吡喃基等。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“药物上可接受的盐”是指在合理医学判断范围内适用于与哺乳动物特别是人的组织接触而无过度毒性、刺激、过敏反应等并与合理的效益/风险比相称的盐,比如胺、羧酸和其他类型化合物的医学上可接受的盐在所属领域中是被熟知的。
术语“盐”包含得自无机酸例如盐酸、硫酸、亚硫酸、硝酸、磷酸、氢溴酸等的盐,也包括自有机酸如乙酸、丙酸、琥珀酸、乳酸、苹果酸、酒石酸、柠檬酸、甲磺酸、马来酸、富马酸、水杨酸等制备的盐。如果本发明的化合物为酸性的,则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、锌盐等,得自有机无毒碱的盐包括伯胺盐、仲胺盐、叔胺盐等。
与现有技术相比较,本申请有何种有益的技术效果。
本发明从作用机制角度筛选出具有高抑制活性的化合物,重点考察侧链改构对化合物活性的影响,因此我们设计合成了一系列新型的选择性IDO抑制剂,通过改构侧链的结构,发现基于氨基磺酰基衍生物的侧链(ZQY-13)具有高的抑制活性。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。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者按照制造厂商所建议的条件。除非另行定义,文中所使用的所有专业与科学用语与本领域专业人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法之中。文中所示的较佳实施方法与材料仅做示范之用。
制备实施例
在下述制备实施例中,包括母核1,母核2及中间体的制备方法如下所述:
制备例1:4-(3-溴-4-氟苯基)-3-(4-硝基-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮的制备(母核1)
步骤1:4-氨基-N′-羟基-1,2,5-噁二唑-3-甲脒氯的制备
在500ml的反应瓶中,将4-氨基-N′-羟基-1,2,5-噁二唑-3–甲脒(8.44g,59mmol)溶于50ml的冰醋酸中,然后依次加入270ml的水和30ml的6M盐酸,然后升温44℃搅拌至溶清,然后加入NaCl(10.4g,178mmol),冰浴条件下,滴加NaNO2(4.08g,59mmol)水溶液40ml,滴加完毕后,室温搅拌1小时,反应结束后,过滤,将固体溶于乙酸乙酯中,水洗有机相,分离有机相,有机相减压蒸馏得到4-氨基-N′-羟基-1,2,5-噁二唑-3-甲脒氯,类白色固体3.80g,收率50.0%。
步骤2:4-氨基-N-(3-溴-4-氟苯基)-N′-羟基-1,2,5-噁二唑-3-甲脒的制备
将4-氨基-N-羟基-1,2,5-噁二唑-3-甲脒氯(3.80g,23.4mmol)溶于50ml水中,升温至60℃,加入3-溴-4-氟苯胺(4.88g25.8mmol),反应20分钟,缓慢滴加碳酸氢钠(2.94g,35.2mmol)水溶液30ml,滴加完毕后,控温搅拌20分钟,反应完毕后,冷却至室温,加入乙酸乙酯和水,水洗有机相,分离有机相,有机相减压蒸馏得到4-氨基-N-(3-溴-4-氟苯基)-N′-羟基-1,2,5-噁二唑-3-甲脒,淡黄色固体7.40g,收率99.0%。
步骤3:3-(4-氨基-1,2,5-噁二唑-3-基)-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮的制备
将4-氨基-N-(3-溴-4-氟苯基)-N′-羟基-1,2,5-噁二唑-3-甲脒(7.40g,1.28mmol)和羰基二咪唑(5.68g,35.2mmol)溶于80ml乙酸乙酯中,升温至60℃,控温搅拌,反应完毕后,反应液冷却至室温,水洗,加入乙酸乙酯,水洗有机相,分离有机相,有机相减压蒸馏经柱层析纯化(石油醚乙酸乙酯=41)得到3-(4-氨基-1,2,5-噁二唑-3-基)-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮,白色固体,5.60g,收率70.0%。
步骤4:4-(3-溴-4-氟苯基)-3-(4-硝基-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮的制备
将3-(4-氨基-1,2,5-噁二唑-3-基)-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(5.60g,16.2mmol)溶于100ml的H2O2和200ml的三氟乙酸中,升温至60℃,控温搅拌,反应完毕后,减压除去大部分的三氟乙酸,水洗反应液,加入乙酸乙酯,分离有机相,有机相减压蒸馏得到4-(3-溴-4-氟苯基)-3-(4-硝基-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮,淡黄色固体,3.36g,收率55.0%。
制备例2:4-(3-溴-4-氟苯基)-3-(4-肼基-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮的制备(母核2)
将母核1(1.00g,2.7mmol)溶于30ml乙腈中,室温条件下,滴加80%的水合肼乙腈溶液10ml,滴加完毕后,TLC监控反应完毕后,反应液直接减压蒸馏得到4-(3-溴-4-氟苯基)-3-(4-肼基-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮,淡黄色固体0.90g,产品未经纯化直接进行下一步反应。
制备例3:4-(3-溴-4-氟苯基)-3-(4-((3-(6-氧代哒嗪-1(6H)-基)丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-1))的制备
步骤1:4-(3-溴-4-氟苯基)-3-(4-((3-羟丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮的制备
将母核1(0.30g,8.1mmol)溶于40ml四氢呋喃中,再加入3-氨基丙醇(0.067g,8.9mmol),室温搅拌,反应完毕后,加入乙酸乙酯和水,分离有机相,有机相减压蒸馏得到油状产物4-(3-溴-4-氟苯基)-3-(4-((3-羟丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮300mg,产品不经纯化直接进行下一步反应。
步骤2:3-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)甲基磺酸丙酯的制备
将4-(3-溴-4-氟苯基)-3-(4-((3-羟丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(0.30g,7.5mmol)溶于30ml二氯甲烷中,冰浴条件下,滴加甲磺酰氯(0.11g,9.0mmol)的二氯甲烷溶液10ml,滴加完毕后,升温至室温反应,反应完毕后,加入乙酸乙酯和水,分离有机相,有机相减压蒸馏得到3-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)甲基磺酸丙酯300mg,产品不经纯化直接进行下一步反应。
步骤3:4-(3-溴-4-氟苯基)-3-(4-((3-(6-氧代哒嗪-1(6H)-基)丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮的制备
将3-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二-3-基)氨基)甲基磺酸丙酯(0.11g,0.23mmol),3(2H)-哒嗪酮(0.10g,1.0mmol)和碳酸钾溶于20ml乙腈中,升温至80℃反应,反应完毕后,加入乙酸乙酯和水,分离有机相,有机相减压蒸馏经柱层析纯化(石油醚:乙酸乙酯=3:1)得到4-(3-溴-4-氟苯基)-3-(4-((3-(6-氧代哒嗪-1(6H)-基)丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-1))70mg,收率63.6%。
制备例4:4-(3-溴-4-氟苯基)-3-(4-((3-(3-甲基-6-氧代哒嗪-1(6H)-基)丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-2))的制备
合成方法同制备例3,只是用6-甲基-3-哒嗪酮替换3(2H)-哒嗪酮,得到4-(3-溴-4-氟苯基)-3-(4-((3-(3-甲基-6-氧代哒嗪-1(6H)-基)丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-2))100mg。
制备例5:4-(3-溴-4-氟苯基)-3-(4-((3-(6-氧代哒嗪-1(6H)-基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-3))的制备
合成方法同制备例3,只是用乙醇胺替换3-氨基丙醇,得到4-(3-溴-4-氟苯基)-3-(4-((3-(6-氧代哒嗪-1(6H)-基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-3))91mg。
制备例6:4-(3-溴-4-氟苯基)-3-(4-((3-(3-甲基-6-氧代哒嗪-1(6H)-基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-4))的制备
合成方法同制备例3,只是用乙醇胺替换3-氨基丙醇,得到4-(3-溴-4-氟苯基)-3-(4-((3-(3-甲基-6-氧代哒嗪-1(6H)-基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-4))58mg。
制备例7:4-(3-溴-4-氟苯基)-3-(4-(4-(二甲基磷酰基)哌嗪-1-基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-5))的制备
步骤1:4-硝基哌嗪-1-羧酸叔丁酯的制备
将1-Boc-哌嗪(5.00g,26.8mmol)溶于40ml的冰醋酸和40ml的水中,冰浴条件下,缓慢加入NaNO2(2.80g,40.6mmol),室温反应5小时后,加入乙酸乙酯和碳酸氢钠洗涤有机相,分离有机相,有机相减压蒸馏得到4-硝基哌嗪-1-羧酸叔丁酯5.40g,未经纯化直接进行下一步反应。
步骤2:4-氨基哌嗪-1-羧酸叔丁酯的制备
将4-硝基哌嗪-1-羧酸叔丁酯(1.20g,2.0mmol)溶于50ml NH4Cl(19.00g,355mmol)的四氢呋喃水溶液中,加入锌粉(15.00g,,229.4mmol),室温反应3小时,加入乙酸乙酯和碳酸氢钠洗涤有机相,分离有机相,有机相减压蒸馏得到4-氨基哌嗪-1-羧酸叔丁酯0.60g,未经纯化直接进行下一步反应。
步骤3:4-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)哌嗪-1-羧酸叔丁酯的制备
将4–氨基哌嗪-1-羧酸叔丁酯(0.60g,3.0mmol)和母核1(1.00g,2.7mmol)溶于40ml四氢呋喃中,室温搅拌2小时,加入乙酸乙酯和水,分离有机相,有机相减压蒸馏得到4-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)哌嗪-1-羧酸叔丁酯1.21g,未经纯化直接进行下一步反应。
步骤4:4-(3-溴-4-氟苯基)-3-(4-(哌嗪-1-氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮的制备
将4-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)哌嗪-1-羧酸叔丁酯(1.21g,2.3mmol)溶于30ml二氯甲烷中,加入3ml的三氟乙酸,室温反应,反应1小时后,减压蒸馏得到4-(3-溴-4-氟苯基)-3-(4-(哌嗪-1-氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮600mg,未经纯化直接进行下一步反应。
步骤5:4-(3-溴-4-氟苯基)-3-(4-(4-(二甲基磷酰基)哌嗪-1-基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮的制备
将4-(3-溴-4-氟苯基)-3-(4-(哌嗪-1-氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(0.15g,0.35mmol)溶于30ml二氯甲烷中,加入三乙胺(0.055g,0.52mmol),冰浴条件下,滴加二甲基氯氧化磷(0.05g,0.43mmol)的二氯甲烷溶液20ml,滴加完毕后,室温过夜反应,反应结束后,加入二氯甲烷和水,分离有机相,有机相减压蒸馏得到4-(3-溴-4-氟苯基)-3-(4-(4-(二甲基磷酰基)哌嗪-1-基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-5))0.08g,未经纯化直接进行下一步反应。
制备例8:4-(3-溴-4-氟苯基)-3-(4-(4-(甲磺酰基)哌嗪-1-基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-6))的制备
合成方法同制备例7,只是用甲磺酰氯替换二甲基氯氧化磷,得到4-(3-溴-4-氟苯基)-3-(4-(4-(甲磺酰基)哌嗪-1-基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-6))50mg。
制备例9:4-(3-溴-4-氟苯基)-3-(4-(4-(N-甲基氨基磺酰基)哌嗪-1-基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-7))的制备
合成方法同制备例7,只是用甲基氨基磺酰氯替换二甲基氯氧化磷,得到4-(3-溴-4-氟苯基)-3-(4-(4-(N-甲基氨基磺酰基)哌嗪-1-基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-7))28mg。
制备例10:4-(3-溴-4-氟苯基)-3-(4-(4-(氨基磺酰基)哌嗪-1-基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-8))的制备
合成方法同制备例7,只是用N-(叔丁氧基羰基)磺酰氯替换二甲基氯氧化磷,然后脱掉Boc基团后得到4-(3-溴-4-氟苯基)-3-(4-(4-(氨基磺酰基)哌嗪-1-基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-8))26mg。
制备例11:4-(3-溴-4-氟苯基)-3-(4-((1-(甲磺酰基)哌啶-3-基)硫代)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-9))的制备
步骤1:3-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)硫代)哌啶-1-羧酸叔丁酯的制备
将1-N-Boc-3-巯基哌啶(0.24g,1.1mmol)和母核1(0.40g,1.1mmol)溶于40ml四氢呋喃中,加入三乙胺(0.22g,2.2mmol),室温搅拌2小时,加入乙酸乙酯和水,分离有机相,有机相减压蒸馏得到3-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)硫代)哌啶-1-羧酸叔丁酯0.60g,未经纯化直接进行下一步反应。
步骤2:4-(3-溴-4-氟苯基)-3-(4-(哌啶-3-硫基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮的制备
将3-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)硫代)哌啶-1-羧酸叔丁酯(0.50g,0.9mmol)溶于30ml二氯甲烷中,加入3ml的三氟乙酸,室温反应,反应1小时后,减压蒸馏得到4-(3-溴-4-氟苯基)-3-(4-(哌啶-3-硫基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮0.45g,收率95.0%。
步骤3:4-(3-溴-4-氟苯基)-3-(4-((1-(甲磺酰基)哌啶-3-基)硫代)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮的制备
将4-(3-溴-4-氟苯基)-3-(4-(哌啶-3-硫基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(0.15g,0.3mmol)溶于30ml二氯甲烷中,加入三乙胺(0.06g,0.6mmol),冰浴条件下,滴加甲磺酰氯(0.08g,0.6mmol)的二氯甲烷溶液20ml,滴加完毕,室温过夜反应,加入二氯甲烷和水,分离有机相,有机相减压蒸馏得到4-(3-溴-4-氟苯基)-3-(4-((1-(甲磺酰基)哌啶-3-基)硫代)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-9))0.12g,未经纯化直接进行下一步反应。
制备例12:4-(3-溴-4-氟苯基)-3-(4-((1-(二甲基磷酰基)哌啶-3-基)硫代)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-10))的制备
合成方法同制备例11,只是用二甲基氯氧化磷替换甲磺酰氯,得到目标产物4-(3-溴-4-氟苯基)-3-(4-((1-(二甲基磷酰基)哌啶-3-基)硫代)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-10))75mg。
制备例13:4-(3-溴-4-氟苯基)-3-(4-((1-(N-甲基硫酸氨)哌啶-3-基)硫代)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-11))的制备
合成方法同制备例11,只是用甲基氨基磺酰氯替换甲磺酰氯,得到目标产物4-(3-溴-4-氟苯基)-3-(4-((1-(N-甲基硫酸氨)哌啶-3-基)硫代)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-11))87mg。
制备例14:4-(3-溴-4-氟苯基)-3-(4-((1-(1-氨磺酰哌啶-3-基)硫代)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-12))的制备
合成方法同制备例11,只是用N-(叔丁氧基羰基)磺酰氯替换甲磺酰氯,然后脱掉Boc基团后得到目标产物4-(3-溴-4-氟苯基)-3-(4-((1-(1-氨磺酰哌啶-3-基)硫代)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-12))27mg。
制备例15:2-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)乙磺酰胺(化合物(Ⅳ-13))的制备
将2-氨基乙基磺酰胺(0.06g,0.48mmol)和母核1(0.18g,0.48mmol)溶于40ml四氢呋喃中,加入三乙胺(0.5ml,3.87mmol),室温反应2小时,加入乙酸乙酯和水,分离有机相,有机相减压蒸馏经柱层析纯化(乙酸乙酯:石油醚=2:1)得到2-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)乙磺酰胺(化合物(Ⅳ-13))0.11g,收率50.7%。
制备例16:2-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)-(N-甲基)乙磺酰胺(化合物(Ⅳ-14))的制备
合成方法同制备例15,只是用2-氨基-N-甲基乙烷磺酰胺盐酸盐替换2-氨基乙基磺酰胺,得到2-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)-(N-甲基)乙磺酰胺(化合物(Ⅳ-14)),98mg。
制备例17:N-(2-(4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)肼基)乙基)甲磺酰胺(化合物(Ⅳ-15))的制备
步骤1:N-(2,2-二乙氧基乙基)甲磺酰胺的制备
将氨基乙醛缩二乙醇(0.67g,5.0mmol)溶于40ml二氯甲烷中,加入三乙胺(1.10g,11.0mmol),冰浴条件下,滴加甲磺酰氯(0.58g,5.0mmol)的二氯甲烷溶液10ml,滴加完毕,室温搅拌2小时,加入二氯甲烷和水,分离有机相,有机相减压蒸馏得到N-(2,2-二乙氧基乙基)甲磺酰胺0.80g,未经纯化直接进行下一步反应。
步骤2:N-(2-(4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)肼基)乙基)甲磺酰胺的制备
将母核2(0.30g,0.84mmol)溶于40ml二氯甲烷中,加入1ml的三氟乙酸和200μl的三乙基硅烷,室温下滴加N-(2,2-二乙氧基乙基)甲磺酰胺(0.18g,0.84mmol)的二氯甲烷溶液20ml,滴加完毕后,室温反应,反应4小时,加入二氯甲烷和水,分离有机相,有机相减压蒸馏,经柱层析纯化(乙酸乙酯:石油醚=1:1)得到N-(2-(4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)肼基)乙基)甲磺酰胺(化合物(Ⅳ-15))0.09g,收率21.7%。
制备例18:N-(2-(2-(4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)-1,2,5-噁二唑-3-基)-1-甲磺酰基氨基乙基)乙基)甲磺酰胺(化合物(Ⅳ-16))的制备
合成方法同制备例17,控制N-(2,2-二乙氧基乙基)甲磺酰胺与母核2的摩尔比为3:1,得到(化合物(Ⅳ-16)80mg。
制备例19:N-(2-(2-(4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)肼基)乙基)甲磺酰胺(化合物(Ⅳ-17))的制备
合成方法同制备例17,只是控制第二步反应条件中不添加三乙基硅烷,最后得到N-(2-(2-(4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)肼基)乙基)甲磺酰胺(化合物(Ⅳ-17)0.10g,收率为75.1%。
制备例20:N-(2-(4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)肼基)-2-氧代乙基)甲磺酰胺(化合物(Ⅳ-18))的制备
步骤1:2-(甲磺酰氨基)乙酸甲酯的制备
将甘氨酸甲酯盐酸盐(0.50g,4.1mmol)溶于30ml的二氯甲烷中,冰浴条件下,加入N,N-二异丙基乙胺(1.00g,7.7mmol),滴加甲磺酰氯(0.50g,4.4mmol)的二氯甲烷溶液10ml,滴加完毕后,室温搅拌2小时,反应完毕,酸洗,水洗,加入二氯甲烷和水分离有机相,有机相减压蒸馏得到2-(甲磺酰氨基)乙酸甲酯0.40g,未经纯化直接进行下一步反应。
步骤2:2-(甲磺酰氨基)乙酸的制备
将2-(甲磺酰氨基)乙酸甲酯(0.40g,2.1mmol)溶于30ml甲醇中,加入氢氧化锂(0.24g,10mmol)的水溶液3ml,室温反应,反应1小时后,减压蒸馏除去甲醇,加入水,用3MHCl调节反应液的pH至2,然后加入乙酸乙酯和水,分离有机相,有机相减压蒸馏得到白色固体2-(甲磺酰氨基)乙酸0.20g,未经纯化直接进行下一步反应。
步骤3:2-(甲磺酰氨基)乙酰氯的制备
将2-(甲磺酰氨基)乙酸(0.06g,0.4mmol)溶于20ml SOCl2中,回流反应3小时,减压蒸馏得到淡黄色固体2-(甲磺酰氨基)乙酰氯0.07g,未经纯化直接进行下一步反应。
步骤4:N-(2-(4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)肼基)-2-氧代乙基)甲磺酰胺的制备
将母核2(0.10g,0.28mmol)溶于20ml二氯甲烷中,加入N,N-二异丙基乙胺(0.08g,0.62mmol),然后冰浴滴加2-(甲磺酰氨基)乙酰氯(0.07g,0.41mmol)的10ml二氯甲烷溶液,室温反应1小时,加入二氯甲烷和水,分离有机相,有机相减压蒸馏经柱层析纯化(石油醚:乙酸乙酯=2:1)得到N-(2-(4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)肼基)-2-氧代乙基)甲磺酰胺(化合物(Ⅳ-18))0.05g,收率为36.3%。
以下结合实施例进一步描述本发明,但这些实施例并非限制本发明的范围。
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR的测定是用BrukerAVANCE-600核磁共振仪,测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CD3OD),内标为四甲基硅烷(TMS),化学位移是以10-6(ppm)作为单位给出的。
MS的测定用SCIEX厂商生产的API2000质谱仪。
柱层析硅胶一般使用青岛海洋化工100-200目硅胶为载体,薄层层析硅胶板使用Merck TLC Silica gel 60F254型硅胶板,涂层厚度200μm。
实施例中如无特殊说明,反应中的溶液是指水溶液。
实施例中如无特殊说明,反应的温度为室温。
室温中最适宜的反应温度范围为20℃~30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC),反应所使用的展开剂体系有:二氯甲烷和甲醇体系,乙酸乙酯和石油醚体系,乙酸乙酯和正己烷体系,丙酮体系,溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂体系和薄层色谱法展开剂体系包括:二氯甲烷和甲醇体系,乙酸乙酯和石油醚体系,乙酸乙酯和正己烷体系,正己烷、乙酸乙酯和二氯甲烷体系,乙酸乙酯体系。溶剂的体积比根据化合物的极性不同而进行调节,也可加入少量的三乙胺和酸性或碱性试剂等进行调节。
实施例1(ZQY-1的制备):N-(3-溴-4-氟苯基)-N′-羟基-4-((3-(6-氧代哒嗪-1(6H)-基)丙基)氨基)-1,2,5-噁二唑-3-甲脒的制备
将4-(3-溴-4-氟苯基)-3-(4-((3-(6-氧代哒嗪-1(6H)-基)丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(化合物(Ⅳ-1))(0.07g,0.15mmol)溶于20ml四氢呋喃中,加入2M氢氧化钠水溶液5ml,室温搅拌反应,TLC监控反应完毕后,加入乙酸乙酯和水,分离有机相,有机相减压蒸馏经柱层析纯化(石油醚:乙酸乙酯=3:1)得到N-(3-溴-4-氟苯基)-N′-羟基-4-((3-(6-氧代哒嗪-1(6H)-基)丙基)氨基)-1,2,5-噁二唑-3-甲脒50mg,收率为75.5%。
实施例2(ZQY-2的制备):N-(3-溴-4-氟苯基)-N′-羟基-4-((3-(3-甲基-6-氧代哒嗪-1(6H)-基)丙基)氨基)-1,2,5-噁二唑-3-甲脒的制备
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合成方法同实施例1,只是用化合物(Ⅳ-2)替换化合物(Ⅳ-1),得到目标产物N-(3-溴-4-氟苯基)-N′-羟基-4-((3-(3-甲基-6-氧代哒嗪-1(6H)-基)丙基)氨基)-1,2,5-噁二唑-3-甲脒80mg,收率为83.5%。
实施例3(ZQY-3的制备):N-(3-溴-4-氟苯基)-N′-羟基-4-((2-(6-氧代哒嗪-1(6H)-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒的制备
合成方法同实施例1,只是用化合物(Ⅳ-3)替换化合物(Ⅳ-1),得到目标产物N-(3-溴-4-氟苯基)-N′-羟基-4-((2-(6-氧代哒嗪-1(6H)-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒60mg,收率为70.2%。
实施例4(ZQY-4的制备):N-(3-溴-4-氟苯基)-N′-羟基-4-((2-(3-甲基-6-氧代哒嗪-1(6H)-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒的制备
合成方法同实施例1,只是用化合物(Ⅳ-4)替换化合物(Ⅳ-1),得到目标产物N-(3-溴-4-氟苯基)-N′-羟基-4-((2-(3-甲基-6-氧代哒嗪-1(6H)-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒30mg,收率为56.8%。
实施例5(ZQY-5的制备):N-(3-溴-4-氟苯基)-4-((4-(二甲基磷酰基)哌嗪-1-基)氨基)-N′-羟基-1,2,5-噁二唑-3-甲脒的制备
合成方法同实施例1,只是用化合物(Ⅳ-5)替换化合物(Ⅳ-1)得到目标产物N-(3-溴-4-氟苯基)-4-((4-(二甲基磷酰基)哌嗪-1-基)氨基)-N′-羟基-1,2,5-噁二唑-3-甲脒40mg收率为53.0%。
实施例6(ZQY-6的制备):N-(3-溴-4-氟苯基)-N′-羟基4-((4-(甲磺酰基)哌嗪-1-基)氨基)-1,2,5-噁二唑-3-甲脒的制备
合成方法同实施例1,只是用化合物(Ⅳ-6)替换化合物(Ⅳ-1),得到目标产物N-(3-溴-4-氟苯基)-N′-羟基4-((4-(甲磺酰基)哌嗪-1-基)氨基)-1,2,5-噁二唑-3-甲脒30mg,收率为67.0%。
实施例7(ZQY-7的制备):N-(3-溴-4-氟苯基)-N′-羟基4-((4-(N-甲基氨基磺酰基)哌嗪-1-基)氨基)-1,2,5-噁二唑-3-甲脒的制备
合成方法同实施例1,只是用化合物(Ⅳ-7)替换化合物(Ⅳ-1),得到目标产物N-(3-溴-4-氟苯基)-N′-羟基4-((4-(N-甲基氨基磺酰基)哌嗪-1-基)氨基)-1,2,5-噁二唑-3-甲脒20mg,收率为75.0%。
实施例8(ZQY-8的制备):N-(3-溴-4-氟苯基)-N′-羟基4-((4-氨磺酰哌嗪-1-基)氨基)-1,2,5-噁二唑-3-甲脒的制备
合成方法同实施例1,只是用化合物(Ⅳ-8)替换化合物(Ⅳ-1),得到目标产物N-(3-溴-4-氟苯基)-N′-羟基4-((4-氨磺酰哌嗪-1-基)氨基)-1,2,5-噁二唑-3-甲脒10mg,收率为40.0%。
实施例9(ZQY-9的制备):N-(3-溴-4-氟苯基)-N′-羟基-4-((1-(甲磺酰基)哌啶基-3-基)硫代)-1,2,5-噁二唑-3-甲脒的制备
合成方法同实施例1,只是用化合物(Ⅳ-9)替换化合物(Ⅳ-1),得到目标产物N-(3-溴-4-氟苯基)-N′-羟基-4-((1-(甲磺酰基)哌啶基-3-基)硫代)-1,2,5-噁二唑-3-甲脒0.06g,收率为53.0%。
实施例10(ZQY-10的制备):N-(3-溴-4-氟苯基)-4-((1-(二甲基磷酰基)哌啶-3-基)硫代)-N′-羟基-1,2,5-噁二唑-3-甲脒的制备
合成方法同实施例1,只是用化合物(Ⅳ-10)替换化合物(Ⅳ-1),得到目标产物N-(3-溴-4-氟苯基)-4-((1-(二甲基磷酰基)哌啶-3-基)硫代)-N′-羟基-1,2,5-噁二唑-3-甲脒50mg,收率为70.0%。
实施例11(ZQY-11的制备):N-(3-溴-4-氟苯基)-N′-羟基-4-((1-(N-甲基硫酸氨)哌啶-3-基)硫代)-1,2,5-噁二唑-3-甲脒的制备
合成方法同实施例1,只是用化合物(Ⅳ-11)替换化合物(Ⅳ-1),得到目标产物N-(3-溴-4-氟苯基)-N′-羟基-4-((1-(N-甲基硫酸氨)哌啶-3-基)硫代)-1,2,5-噁二唑-3-甲脒50mg,收率为60.0%。
实施例12(ZQY-12的制备):N-(3-溴-4-氟苯基)-N′-羟基-4-((1-(1-氨磺酰哌啶-3-基)硫代)-1,2,5-噁二唑-3-甲脒的制备
合成方法同实施例1,只是用化合物(Ⅳ-12)替换化合物(Ⅳ-1),然后脱掉Boc基团后得到目标产物N-(3-溴-4-氟苯基)-N′-羟基-4-((1-(1-氨磺酰哌啶-3-基)硫代)-1,2,5-噁二唑-3-甲脒10mg,收率为40.0%。
实施例13(ZQY-13的制备):N-(3-溴-4-氟苯基)-N′-羟基-4-((2-氨磺酰)氨基)-1,2,5-噁二唑-3-甲脒的制备
合成方法同实施例1,只是用化合物(Ⅳ-13)替换化合物(Ⅳ-1),得到目标产物N-(3-溴-4-氟苯基)-N′-羟基-4-((2-氨磺酰)氨基)-1,2,5-噁二唑-3-甲脒0.06g,收率为58.0%。
实施例14(ZQY-14的制备):N-(3-溴-4-氟苯基)-N′-羟基-4-((2–(N-甲基磺酰基)乙基)氨基)-1,2,5-噁二唑-3-甲脒的制备
合成方法同实施例1,只是用化合物(Ⅳ-14)替换化合物(Ⅳ-1),得到目标产物N-(3-溴-4-氟苯基)-N′-羟基-4-((2–(N-甲基磺酰基)乙基)氨基)-1,2,5-噁二唑-3-甲脒50mg,收率为53.0%。
实施例15(ZQY-15的制备):N-(3-溴-4-氟苯基)-N′-羟基-4-(2-(甲基磺酰氨基)乙基)肼基)-1,2,5-噁二唑-3-甲脒的制备
合成方法同实施例1,只是用化合物(Ⅳ-15)替换化合物(Ⅳ-1),得到目标化合物N-(3-溴-4-氟苯基)-N′-羟基-4-(2-(甲基磺酰氨基)乙基)肼基)-1,2,5-噁二唑-3-甲脒0.02g,收率为36.0%。
实施例16(ZQY-16的制备):4-(2,2-双(2-(甲磺酰氨基)乙基)肼基)-N-(3-溴-4-氟苯基)-N′-羟基-1,2,5-噁二唑-3-甲脒的制备
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合成方法同实施例1,只是用化合物(Ⅳ-16)替换化合物(Ⅳ-1),得到目标产物N-(3-溴-4-氟苯基)-N′-羟基-4-(2-(氨磺酰氨基)乙基)肼基)-1,2,5-噁二唑-3-甲脒30mg,收率为39.2%。
实施例17(ZQY-17的制备)N-(3-溴-4-氟苯基)-N′-羟基-4-(2-(2-(甲磺酰氨基)亚乙基)肼基)-1,2,5-噁二唑-3-甲脒的制备
合成方法同实施例1,只是用化合物(Ⅳ-17)替换化合物(Ⅳ-1),得到目标产物N-(3-溴-4-氟苯基)-N′-羟基-4-(2-(2-(甲磺酰氨基)亚乙基)肼基)-1,2,5-噁二唑-3-甲脒0.06g,收率为63.4%。
实施例18(ZQY-18的制备)N-(3-溴-4-氟苯基)-N′-羟基-4-(2-(甲基磺酰氨基)乙酰基)肼基)-1,2,5-噁二唑-3-甲脒的制备
合成方法同实施例1,只是用化合物(Ⅳ-18)替换化合物(Ⅳ-1),得到目标产物N-(3-溴-4-氟苯基)-N′-羟基-4-(2-(甲基磺酰氨基)乙酰基)肼基)-1,2,5-噁二唑-3-甲脒0.03g,收率为63.4%。
上述实施例制备得到的化合物的具体物理表征结果如下表所示:
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药效筛选试验
试验例1:化合物在体外细胞水平的生物活性检测
制备浓度为1×105/mL的A375细胞悬液,内含100mM的L-色氨酸,均匀地接种到96孔板中(100μl/孔)。5%CO2,37℃培养24小时后每孔各加入80μl不同浓度梯度的待测化合物,每个药物浓度设2个复孔,并设相应的空白孔与对照孔。30分钟后加20μl人IFN-γ工作液(终浓度50ng/ml),5%CO2,37℃继续培养48小时。转移培养液(140μl/孔)到新的96孔板,每孔加入10μl 6.1N三氯乙酸,50℃孵育30分钟沉淀蛋白。2500rpm离心10分钟。转移上清液(100μl/孔)至新的96孔板,每孔加100uL的2%(w/v)p-二甲氨基苯甲醛的乙酸,用酶标仪(492nm条件下)检测犬尿酸的OD值,计算IC50值。结果如下:
化合物编号 | IC50(μM) |
ZQY-9 | 0.046 |
ZQY-10 | 0.134 |
ZQY-11 | 0.090 |
ZQY-12 | 0.082 |
ZQY-13 | 0.010 |
ZQY-14 | 0.039 |
ZQY-15 | 0.036 |
ZQY-17 | 0.041 |
结果分析:色氨酸是组成机体免疫细胞的重要氨基酸,在吲哚胺-2,3-双加氧酶1(IDO1)的作用下转换成犬尿酸。基于IDO1的该作用机制,本试验采用A375细胞(人恶性黑色素瘤细胞),通过检测犬尿酸水平的变化值和计算IC50值,确认各化合物对IDO1的体外抑制活性。结果显示,ZQY9-15、17化合物显示了良好的抑制活性。
试验例2:化合物在动物体内的生物活性检测(小鼠血浆犬尿酸/色氨酸比值)
雄性C57BL/6小鼠单次口服给予50mg/kg待测化合物或阳性药Epacadostat,给药前0小时以及给药后2小时和5小时时间点采血,3000rmp离心10分钟,取血浆,3倍甲醇沉淀,10000rmp高速离心10分钟,取上清LC-MS相对定量分析。检测设备:Waters Xevo TQ质谱系统,配备ESI电喷雾离子源,Acquity二元高压液相系统。质谱条件:capillary 3.5kv,Desolvation Temp 550℃,Desolvation gas 800L/Hr,Cone gas 50L/Hr。检测离子对Try205.1→188.1,Kyn 209.2→192.1,BLF(IS)207.2→161.1。色谱条件:色谱柱watersAcquity UPLC BEH shield RP18 2.1×100mm,1.7μm,洗脱条件:流动相A乙腈,流动相B为含1mM乙酸铵和0.1%甲酸水溶液。洗脱条件:0-1分钟,10%A,1-2分钟90%A,2-2.5分钟90%A,2.6-3.5分钟10%A。将每只小鼠0小时血浆犬尿酸/色氨酸比值定为1,通过计算给药后(2和5小时)血浆犬尿酸/色氨酸比值的变化值,以推测各化合物对小鼠体内IDO的抑制活性。结果如下:
(注:data=Mean±SD,n=6,*p<0.05vs 5h Epacadostat值;**p<0.0 1vs2h Epacadostat值)
结果分析:各化合物给药小鼠血浆犬尿酸/色氨酸比值均下降,提示各化合物尤其是ZQY-13化合物体内对IDO1均具有抑制活性,ZQY-13化合物体内对IDO1的抑制作用明显优于Epacadostat,具有统计学差异。
Claims (7)
1.具有式(II)所示结构的化合物或其药学上可接受的盐,
其中,R1为-S-,n=1,t=2,X为R3为CH3-。
2.具有式(III)所示结构的化合物或其药学上可接受的盐,
其中,R1为-NH;
X选自-N=CH-CH2-NH-;R4选自氨基,甲氨基和甲基。
3.根据权利要求2所述的化合物或其药学上可接受的盐,其特征在于,R4为甲基。
4.选自如下所述的化合物或其药学上可接受的盐:
5.一种药物组合物,该药物组合物包含权利要求1-4中任一项所述的化合物或其药学上可接受的盐以及药学上可接受的辅料。
6.权利要求1-4中任一项所述的化合物或其药学上可接受的盐在制备用于预防和/或治疗癌症、肿瘤、病毒感染、抑郁症、神经性病症、创伤、年龄相关的白内障、器官移植排斥或自身免疫疾病的药物中的用途;
其中,所述癌症或肿瘤选自肺癌、骨癌、胃癌、皮肤癌、头颈癌、子宫癌、卵巢癌、睾丸癌、输卵管癌、子宫颈癌、阴道癌、胰腺癌、脑癌、垂体腺瘤,黑素瘤、表皮样癌、T细胞淋巴瘤、慢性和急性白血病。
7.根据权利要求6所述的用途,其特征在于,所述癌症或肿瘤选自子宫内膜癌。
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