CN113292570A - 一类含有2,4-噻唑环的化合物及其制备方法和应用 - Google Patents
一类含有2,4-噻唑环的化合物及其制备方法和应用 Download PDFInfo
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- CN113292570A CN113292570A CN202110630883.4A CN202110630883A CN113292570A CN 113292570 A CN113292570 A CN 113292570A CN 202110630883 A CN202110630883 A CN 202110630883A CN 113292570 A CN113292570 A CN 113292570A
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- compound
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- phenyl
- trihalomethyl
- alkyl
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- 125000004953 trihalomethyl group Chemical group 0.000 claims abstract description 27
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- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 22
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- 125000002328 sterol group Chemical group 0.000 claims abstract description 14
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- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims abstract description 12
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Abstract
Description
技术领域
本申请涉及有机合成和药物化学领域,具体涉及一类含有2,4-噻唑环的化合物及其制备方法和应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本申请的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
自身免疫性疾病是自身反应T、B细胞过度活化,对自身抗原发生免疫反应导致自身组织器官损害的一种疾病,例如***性红斑狼疮(SLE)、银屑病等。流行病学调查显示,在我国,***性红斑狼疮患者达数百万人。目前世界范围内,仍没有针对此类自身免疫性疾病的化学新药,临床治疗以糖皮质激素为基础,联合使用非特异性抗炎、免疫抑制剂等,一定程度上延缓了疾病的进程但长期使用会造成病人免疫功能下降,引起多种并发症。
研究证明,B淋巴细胞和T淋巴细胞在自身免疫性疾病方面具有重要的作用。通过开发具有抑制免疫细胞增殖和激活以降低机体异常免疫反应的新药用于治疗自身免疫性疾病是当今医学和药学研究的重要课题。
芳烃受体(AhR)是一种配体激活的转录因子,主要表达于细胞核中,可被一系列化合物激活,如致癌物质2,3,7,8-四氯二苯并对二恶英(TCDD),其被TCDD等激动剂激活后具有促进肿瘤生长、激活免疫细胞的特性。研究显示,AhR是T淋巴细胞Th22的关键转录因子,在机体免疫反应中具有重要作用,因此AhR受体在治疗自身免疫性疾病研究中具有极大的潜力。
在没有配体的情况下,AhR位于细胞质中,作为由热休克蛋白90、p23和AhR相互作用蛋白组成的蛋白复合物的一部分。在结合配体如TCDD时,AhR复合物被激活,之后复合物转位到细胞核,从伴侣蛋白中释放,并与ARNT相互作用。伴侣蛋白可以保护AhR免受蛋白质水解,并保留一个有利于配体结合的结构。AhR-ARNT异源二聚体与信号因子(如染色质重塑因子、组蛋白乙酰转移酶和转录因子)相关,最终与DREs或AHREs结合以促进转录调控。设计以AhR为靶点的免疫调节剂对治疗自身免疫性疾病具有十分重要的意义。
发明内容
本申请的目的是提供一种结构中含有2,4-噻唑环的化合物及其药学上可接受的盐或异构体,所述的化合物毒副作用小,且对免疫细胞的活性具有抑制作用。
具体地,本发明提供了下述的技术特征,以下技术特征的一个或多个的结合构成本发明的技术方案。
在本发明的第一方面,本发明提供了一种含有2,4-噻唑环的化合物或其药学上可接受的盐或异构体,所述化合物具有式X所示结构:
其中,A结构为吡唑并嘧啶或者吲哚;
并且,所述化合物符合式X1或式X2所示结构:
R1为氢或C1-6烷基;
R2选自C1-C3烷基、C5-C15烯基、炔基、5-10元杂环基、C6-C12芳基、5-12元杂芳基、甾醇基和5-10元环烷基;Y与R2直接相连,或者Y与R2相连成环;
R3选自氢、卤素、氨基、羟基、乙酰基、3-10元杂环基、C6-C12芳基、5-12元杂芳基、3-10元环烷基、酯基、羧基、三卤甲基和金刚烷基;
R2或R3是未被取代的,或者是被选自C1-C6烷基、羟基、卤素、三卤甲基、羧基、苯基中的一种或多种所取代的;
其中,R2为C1-C3烷基时,R3不为氢。
以及,在X2化合物中,R2为烷基时,R3不为羟基。
需要特别说明的是,现有的化合物在对免疫细胞的活性具有抑制作用的同时往往也具有毒副作用,比如在一些实施方式中,R2为C1-C3烷基、R3为氢以及,在式X2结构下,R2为烷基R3为羟基时,往往会出现这种状况。而本发明的化合物在测试浓度下未见明显的毒性,具有较高的安全指数,并且具有良好的口服生物利用度,成药性良好。
在本发明中,术语“C1-C6烷基”是指链上具有1至6个碳原子的直链饱和烃基,非限制性地包括甲基、乙基、丙基等。
术语“C5-C15烯基”是指链上具有5至15个碳原子的直链或支链含1个或多个双键的烃基。
术语“3-10元杂环基”是指含有一个或多个饱和和/或部分饱和环,其中包括3-10个环原子,其中一个或多个环原子选自氮、氧或S(0)m(其中m是整数0至2)的杂原子,其余环原子为碳;例如,环氧丙烷、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。
术语“C6-C12芳基”是指包含6-10个环原子,但环原子中不含杂原子的芳香族环基,如苯基、萘基、联苯基等。
术语“5-12元杂芳基”是指包含5-12个环原子且在环原子中含有1-4个杂原子作为环成员的芳香环基团。杂原子可以选自氮、氧或硫。杂芳基可以是具有5-7个环原子的单环杂芳基或者具有7-12个环原子的双环杂芳基。所述双环杂芳基中只要一个环是杂芳基即可,另一个可以是芳香环或非芳香环,含杂原子的或不含杂原子的。此外,所述双环杂芳基既可以是并环结构,也可以是两个杂环直接相连。杂芳基的例子包括但不限于吡咯基、吡唑基、咪唑基、三氮唑基、噁唑基、吡啶基、嘧啶基、呋喃基、噻吩基、异噁唑基、吲哚基等。
术语“甾醇基”是指由三个己烷环及一个环戊烷稠合而成的环戊烷多氢菲衍生物基团,如谷甾醇基、胆甾醇基、麦角甾醇基、澳洲茄胺基、薯蓣皂苷基等。
术语“3-10元环烷基”是指含有一个或多个饱和和/或部分饱和环、所有成环原子均为碳原子的基团,其包括3至10个碳原子;例如,环丙基、环丁基、环戊基、环己基、环己烯基、环庚烯基、环庚三烯基、金刚烷基等。
术语“卤素”是指氟、氯、溴、碘。
术语“三卤甲基”是指被卤素取代的甲基,可以是一取代、二取代或三取代,包括三氟甲基、溴甲基等。
在本发明的一些实施方式中,所述药学上可接受的盐为可以是所述化合物的盐酸盐、硫酸盐、磷酸盐、马来酸盐、富马酸盐、枸橼酸盐、甲磺酸盐、对甲苯磺酸盐或酒石酸盐等等。
在本发明的一些实施方式中,R2选自C1-C3烷基、C5-C15一烯基、C5-C15二烯基、C5-C15三烯基、炔基、5-6元环烷基、苯基、5-6元杂环基、5-6元杂芳基、甾醇基;其中,Y与R2直接相连,或者Y与R2相连成环;
R2是未被取代的,或者是被选自C1-C6烷基、羟基、卤素、三卤甲基、羧基、苯基中的一种或多种所取代的。
进一步地,在本发明的一些实施方式中,R2选自甲基、乙基、丙基、C5一烯基、C10二烯基、C15三烯基、炔基、环戊烷基、环己烷基、三氮唑基、苯基、哌啶基、哌嗪基、吡咯烷基、吡啶基、嘧啶基、甾醇基;其中,Y与R2直接相连,或者Y与R2相连成环;
R2是未被取代的,或者是被选自C1-C6烷基、羟基、卤素、三卤甲基、羧基、苯基中的一种或多种所取代的;
在本发明的一些实施方式中,R3选自氢、卤素、氨基、乙酰基、5-6元杂环基、苯基、联苯基、萘基、5-6元杂芳基、5-6元环烷基、酯基、羧基、酰胺基、三卤甲基、金刚烷基;
R3是未被取代的,或者是被选自C1-C6烷基、羟基、卤素、三卤甲基、羧基、苯基中的一种或多种所取代的。
进一步地,在本发明的一些实施方式中,R3选自氢、卤素、氨基、羟基、乙酰基、苯基、联苯基、萘基、环戊烷基、环己烷基、哌啶基、哌嗪基、吡咯烷基、吡啶基、嘧啶基、酯基、羧基、酰胺基、三卤甲基、金刚烷基;
R3是未被取代的,或者是被选自C1-C6烷基、羟基、卤素、三卤甲基、羧基、苯基中的一种或多种所取代的。
在本发明的一些实施方式中,所述化合物具有式I或式II所述结构:
其中,X、Y、R1、R2、R3同上文中所定义。
R1为氢或C1-C2烷基;
R2选自甲基、乙基、C5一烯基、C10二烯基、环己烷基、苯基、、吡啶基;其中,Y与R2直接相连,或者Y与R2相连成环;
R3选自氢、苯基、吡啶基、嘧啶基、酯基、三卤甲基;
R2或R3是未被取代的,或者是被选自C1-C6烷基、羟基、卤素、三卤甲基、羧基中的一种或多种所取代的。
R2选自甲基、乙基、丙基、C5一烯基、C10二烯基、C15三烯基、炔基、环戊烷基、环己烷基、苯基、三氮唑基、吡啶基、甾醇基;其中,Y与R2直接相连,或者Y与R2相连成环;
R3选自氢、卤素、氨基、羟基、乙酰基、苯基、联苯基、萘基、环戊烷基、环己烷基、吡咯烷基、吡啶基、嘧啶基、酯基、羧基、酰胺基、三卤甲基、金刚烷基;
R2或R3是未被取代的,或者是被选自C1-C6烷基、羟基、卤素、三卤甲基、羧基、苯基中的一种或多种所取代的。
在本发明的一些实施方式中,X为O时,所述化合物具有式IA或式IIA所示结构:
其中,Y、R1、R2、R3同上文中所定义,Y与R2直接相连,或者Y与R2相连成环。
在本发明的一些实施方式中,X为S时,所述化合物具有IB所示结构:
其中,Y为-NH-,R1、R2、R3同上文中所定义;
进一步地,在一些实施方式中,在IB化合物中,R2选自甲基、乙基和吡啶基;R3选自氢、吡啶基和嘧啶基。
其中,Y为-O-或-NH-时,Y与R2可直接相连;
所述化合物具有IA1、IA2、IA3、IIA1、IIA2或IIA3所示结构:
作为示例,本发明提供了一系列化合物,所述化合物选自以下结构:
在本发明的第二方面,本发明提供了一种制备上述第一方面中所述的化合物或其药学上可接受的盐或异构体的方法,所述方法包括:
以化合物1与化合物2进行环化反应得到化合物3,化合物3经酯键水解得到化合物4,化合物4酰氯化、氨化得到化合物5,化合物5经硫取代得到化合物6,化合物6经过环化反应得到化合物8,化合物8经酯键水解得到化合物9,化合物9和化合物10经过酰胺缩合或酯键缩合得到式IA化合物;
或者,进一步地,式IA化合物经氧硫交换制备得到式IB化合物;
其中,化合物1-10如下所示,
R1、R2、R3、Y同上述第一方面中所定义。
以及,在本发明的一些实施方式中,所述方法包括:化合物11与草酰氯反应得到化合物12,化合物12经过氨化得到化合物13,化合物13经过氧化反应得到化合物14,化合物14经过环化反应得到化合物16,化合物16经过氧化反应得到化合物17,化合物17经过酯键水解得到化合物18,化合物18与化合物19经过缩合反应得到化合物IIA。
其中,化合物11-19的如下所示:
R1、R2、R3、Y同上述第一方面中所定义。
本领域技术人员可根据本申请公开了的制备方法通过实验选取适宜的反应条件,包括反应溶剂、反应温度、是否加入催化剂等。
在本发明的第三方面,本发明提供了一种药物组合物或药物制剂,其包含上述第一方面中所述的化合物或其药学上可接受的盐或异构体;
或者,进一步地,所述药物组合物或者所述药物制剂包含药学上可接受的辅料或药物载体。
所述药学上可接受的辅料是指药物组合物中除有效成分之外的成分,其对受试者无毒。药学上可接受的辅料比如赋形剂,其包括但不限于溶剂、助溶剂、填充剂、润滑剂、崩解剂、缓冲剂、稳定剂或防腐剂等。
所述药物载体可以是药学上可接受的溶剂、悬浮剂或载体,用于将化合物递送至动物或人体内。载体可以是液体或固体,并按照计划的给药方式进行选择。蛋白和脂质体也可以是药物载体。
本领域技术人员可使用本领域公知的技术将本发明的化合物配制成药物组合物或药物制剂。比如可根据由沈阳药科大学主编的现代药物制剂丛书进行药物制剂的制备。除本文提到以外,合适的药用辅料是本领域已知的,例如参见2005年版的药用辅料手册(原著第四版),作者(英)R.C.罗(RaymondCRowe)(美)P.J.舍斯基(PaulJSheskey)。
在本发明的第四方面,本发明提供了上述第一方面中所述的化合物或其药学上可接受的盐或异构体·,或者上述第二方面所述的药物组合物或药物制剂在制备用于预防和/或治疗与防活化免疫***有关的疾病或病症的药物中的用途;
或者,上述第一方面中所述的化合物或其药学上可接受的盐或异构体,或者上述第二方面所述的药物组合物或药物制剂在制备免疫抑制剂药物中的应用。
在本发明的实施方式中,所述疾病或病症选自:器官、组织或细胞移植的排异反应;通过移植造成的移植物抗宿主病;以及自身免疫综合症;以及与细胞因子风暴有关的疾病或病症。
进一步地,所述自身免疫综合症包括狼疮、***性红斑狼疮、银屑病、湿疹、皮炎、关节炎、类风湿性关节炎、脊柱关节炎、痛风性关节炎或其他关节炎性病症、多发性硬化症、皮肤真菌并、抗磷脂抗体综合征、淋巴瘤性甲状腺肿、淋巴细胞性甲状腺炎、多发性硬化、重症肌无力、Ⅰ型糖尿病、葡萄膜炎、巩膜表外层盐、巩膜炎、川崎(Kawasaki’s)疾病、葡萄膜视网膜盐、后葡萄膜炎、与***有关的葡萄膜炎、眼色素膜脑膜炎综合征、兵营行脑脊髓炎、慢性异源移植血管病变、后感染性自身免疫疾病,图风湿热和后感染性血管球性肾炎、炎症性和细胞增生型皮肤病、牛皮癣、牛皮癣关节炎、特应性皮炎、肌病、肌炎、骨髓炎、接触性皮炎、湿疹性皮炎、脂溢性皮炎、扁平苔癣、天疱疮、荨麻疹、血管性水肿、血管炎、红疹、粉刺、肥大细胞病。
进一步地,所述与细胞因子风暴有关的疾病或病症为因感染性疾病引起的细胞因子风暴综合征,所述因感染性疾病引起的细胞因子风暴综合征包括但不限于因肿瘤、炎症、新型冠状病毒等感染性疾病引起的细胞因子风暴综合征。
在本发明的第五方面,本发明提供了一种预防和/或治疗与活化免疫***有关的疾病或病症的方法,其包括向受试者施用治疗有效量的上述第一方面中所述的化合物或其药学上可接受的盐或异构体、或者上述第三方面中所述的药物组合物或药物制剂。
其中,所述受试者是指需要治疗、观察或实验的动物,或者正在治疗、观察或实验的动物,或者已经接受过治疗、观察或实验的动物;所述动物尤其指哺乳动物,特别是人、牛、大鼠、小鼠。
所述治疗有效量是指所使用的本发明的上述第一方面中所述的化合物或其药学上可接受的盐或异构体、或者包含该所述化合物或其药学上可接受的盐或异构体的药物组合物或药物制剂的量,该量可引起研究者、兽医、医生或其他医疗人员所追求的组织***、动物或人的生物学或医学响应,这包括减轻或部分减轻受治疗的疾病、综合征、病症或障碍的症状。
相较于现有技术,本发明的优势在于:
本发明提供了一系列含有2,4-噻唑环的化合物,结构新颖,合成路线操作简便,收率高,毒副性低,且对T淋巴细胞及B淋巴细胞具有显著抑制作用,可用于制备免疫抑制剂药物。
附图说明
构成本申请的一部分的说明书附图用来提供对本申请的进一步理解,本申请的示意性实施例及其说明用于解释本申请,并不构成对本申请的不当限定。以下,结合附图来详细说明本申请的实施方案,其中:
图1示意出本发明部分示意化合物的IC50曲线。
图2示出了本发明部分示意化合物在5、2.5、1.25、0.625μM测试浓度下对淋巴细胞活力影响结果。
图3示出了实施例6中各组小鼠血清中IL-6,IL-2,TNF-a,IFN-y含量;
图4示出了实施例6中各组小鼠肺组织H&E组织染色。
图5示出了实施例7中各组小鼠血清中IL-6,IL-2和TNF-a含量。
具体实施方式
下面结合具体实施例,进一步阐述本申请。应理解,这些实施例仅用于说明本申请而不用于限制本申请的范围。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熟练人员所熟悉的意义相同。本申请所使用的试剂或原料均可通过常规途径购买获得,如无特殊说明,本申请所使用的试剂或原料均按照本领域常规方式使用或者按照产品说明书使用。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申请方法中。文中所述的较佳实施方法与材料仅作示范之用。
所有实施例中,1H NMR及13C NMR由AvanceⅢ-400或AvanceⅢ-600型核磁共振仪记录,化学位移以δ(ppm)表示;质谱由MS质谱-LCQ-DECA离子阱质谱仪(ESI/LR)与MS质谱-Q-TOF四极杆飞行时间质谱仪(ESI-HR)记录;化合物分离选用国药集团化学试剂有限公司的200-300目硅胶。
本发明提供了一类含有2,4-噻唑环的化合物,本发明所述的一系列化合物可通过如下所示的方法制备:
制备路线一:
其中,R1、R2、R3、Y如本发明发明内容部分所定义。
所述反应步骤包括:
(a)化合物1与化合物2经过环化反应得到化合物3;环化反应为在有机溶剂中,酸性条件下进行,所述的有机溶剂为有机酸。
(b)化合物3经过酯键水解反应得到化合物4;酯键水解反应在有机溶剂、碱性条件或酸性条件的存在下进行。所述的有机溶剂为甲醇或四氢呋喃。
(c,d)化合物4经过酰氯化、氨化得到化合物5;步骤(c)中,酰氯化反应在有机溶剂、酰氯化试剂条件的存在下进行;所述的有机溶剂为二氯甲烷、二氯乙烷、甲苯或酰氯化试剂;所述的酰氯化试剂为氯化亚砜、三氯化磷、光气或草酰氯;步骤(d)中,氨化反应在氨水中进行。
(e)化合物5经过硫取代得到化合物6;硫代反应在有机溶剂中进行;所述的有机溶剂为甲苯;硫代试剂为劳森试剂。
(f)化合物6经过环化反应得到化合物8;环化反应在有机溶剂中进行;所述有机溶剂为乙醇。
(g)化合物8经过酯键水解得到化合物9;所述的酯键水解反应与步骤(b)类似。
(h)化合物9与化合物10经过酰胺缩合或酯键缩合得到化合物ⅠA;酰胺缩合反应在有机溶剂中由缩合剂及碱催化进行;所述的有机溶剂为二氯甲烷或N,N-二甲基甲酰胺(DMF);所用缩合剂为2-(7-偶氮苯并三氮唑)-四甲基脲六氟磷酸酯(HATU)或二环己基碳二亚胺(DCC);所述的碱为N,N-二异丙基乙胺(DIPEA)或4-二甲氨基吡啶(DMAP)。
其中,式IA化合物经氧硫交换制备得到式IB化合物,可进行如下反应。
制备路线二:
其中,R1、R2、R3、Y如本发明发明内容部分所定义。
(j)化合物11与草酰氯反应得到化合物12;反应在有机溶剂中进行;所述的有机溶剂为***。
(k)化合物12经过氨化得到化合物13;所述的氨化水解反应与反应(d)类似。
(l)化合物13经过氧化反应得到化合物14;氧化反应在有机溶剂、氧化剂的条件下进行;所述的有机溶剂为N,N-二甲基甲酰胺(DMF);所述的氧化剂为二氯亚砜。
(m)化合物14经过环化反应得到化合物16;环化反应在有机溶剂、碱性催化剂下进行;所述的有机溶剂为N,N-二甲基甲酰胺(DMF);所述的碱性催化剂为1,8-二氮杂二环十一碳-7-烯(DBU)。
(n)化合物16经过氧化反应得到化合物17;所述的氧化反应在有机溶剂、氧化剂条件下进行;所述的有机溶剂为四氢呋喃;所述的氧化剂为二氧化锰。
(o)化合物17经过酯键水解得到化合物18;所述的酯键水解反应与反应(b)类似。
(p)化合物18与化合物19经过缩合反应得到化合物IIA;所述的酰胺缩合反应与反应(h)类似。
具体地,本发明下述实施例中给出了示例化合物的制备方法和相关活性和药用实验。本领域技术人员根据本发明的公开能够制备得到符合本发明通式结构的更多化合物。
实施例1化合物IA-1
(a)取化合物1(3-氨基-4-甲氧基羰基吡唑)溶于乙酸中,加入化合物2(1,1,3,3-四甲氧基丙烷),加热搅拌至反应完全,冷却至室温,减压蒸干溶剂,用乙酸乙酯和饱和碳酸氢钠水溶液萃取洗涤三次。有机相用饱和食盐水洗涤一次后,用无水硫酸钠干燥,过滤浓缩,过柱,分离纯化,得化合物3。
(b)取化合物3溶于甲醇,加入氢氧化钠水溶液,搅拌至反应完全,盐酸酸化,过滤,干燥,得化合物4。
(c)取化合物4,加入二氯甲烷中形成混悬液,加入二氯亚砜及催化量DMF,加热至反应完全,减压蒸干溶剂,得酰氯化产物;
(d)取氢氧化钾固体、氯化铵固体,溶于水中,加入(c)步骤所得化合物,搅拌至反应完全,过滤,水洗滤饼,干燥,得化合物5。
(e)取化合物5溶于无水甲苯中,加入劳森试剂,加热至反应完全后,冷却至室温,过滤,甲苯洗涤滤饼,干燥后得化合物6。
(f)取化合物6溶于乙醇中,加入溴代丙酮酸甲酯,加热至反应完全后,冷却至室温,减压蒸干溶剂,水和乙酸乙酯萃取洗涤三次,合并有机相,用饱和食盐水洗涤一次后,用无水硫酸钠干燥,过滤浓缩,过柱分离纯化,得化合物8。
(g)取化合物8溶于甲醇,加入氢氧化钠水溶液,搅拌至反应完全,盐酸酸化,过滤,干燥,得化合物9。
(h)取化合物9,溶于二氯甲烷,加入HATU,低温条件下滴加DIEA,搅拌10min后,加入化合物10,室温搅拌30min,加水淬灭,二氯甲烷萃取三次,合并有机相,氯化钠饱和水溶液洗涤,无水硫酸钠干燥,过滤浓缩,过柱,分离纯化,得化合物IA。
以含有不同取代基的胺或醇为化合物10,按照类似前述的步骤制备以下实施例,具体胺或醇即化合物10参考表1:
表1
化合物IA-1:黄色固体,收率为87.2%;1H NMR(400MHz,CDCl3)δ9.29–9.21(m,2H),8.83(dd,J=15.0,3.1Hz,1H),8.64–8.60(m,1H),8.47–8.39(m,1H),7.88(s,1H),7.65(dt,J=15.0,3.1Hz,1H),7.28(td,J=14.9,4.7Hz,2H),4.74–4.66(m,1H),4.04(dt,J=19.8,13.3Hz,1H),3.81(dt,J=24.8,13.2Hz,1H),2.24(dtd,J=12.0,8.8,1.6Hz,1H),2.13–1.88(m,3H)。
化合物IA-2:黄色固体,收率为85.3%;1H NMR(400MHz,CDCl3)δ9.25(dd,J=15.0,2.9Hz,1H),8.98(s,1H),8.83(dd,J=15.0,2.9Hz,1H),8.62(m,1H),8.43(m,1H),8.38(s,1H),7.65(dt,J=15.0,3.1Hz,1H),7.29(m,3H),4.23(s,2H)。
化合物IA-3:黄色固体,收率为86.5%;1H NMR(400MHz,CDCl3)δ8.76(d,J=7.0Hz,1H),8.71(dd,J=5.5,3.5Hz,2H),8.67(s,1H),8.56(dd,1H),8.16(s,1H),7.93(s,1H),7.81(d,J=7.8Hz,1H),7.33(t,1H),7.01(t,1H),4.72(d,J=5.9Hz,2H),2.46(s,J=1.2Hz,1H)。
化合物IA-4:黄色固体,收率为89.8%;1H NMR(400MHz,DMSO-d6)δ9.38(dd,J=7.1,1.7Hz,1H),8.92(dd,J=4.1,1.7Hz,1H),8.88(s,1H),8.55(s,1H),7.35(dd,J=7.0,4.2Hz,1H),5.51(td,1H),4.88(d,J=7.3Hz,2H),1.83(dd,J=3.0,1.3Hz,6H)。
化合物IA-5:黄色固体,收率为82.3%;1H NMR(400MHz,Chloroform-d)δ8.75(d,J=7.0Hz,2H),8.72–8.68(m,1H),8.14(s,1H),7.87(t,J=6.4Hz,1H),7.45(m,J=8.0Hz,1H),6.99(dd,J=7.1,4.2Hz,1H),6.84(m,J=9.6,9.0Hz,2H),4.69(d,J=6.3Hz,2H)。
化合物IA-6:黄色固体,收率为85.5%;1H NMR(400MHz,CDCl3)δ8.89(s,1H),8.74(dd,J=7.0,1.8Hz,1H),8.67(dd,J=4.1,1.7Hz,1H),8.17(s,1H),6.96(dd,J=7.0,4.1Hz,1H),5.49(t,J=6.7Hz,1H),5.08(t,J=6.1Hz,1H),4.90(d,J=7.1Hz,2H),2.08(td,J=9.8,7.5,4.3Hz,5H),1.76(s,3H),1.66(s,3H),1.58(s,3H)。
化合物IA-7:黄色固体,收率为85.4%;1H NMR(400MHz,CDCl3)δ9.25(m,2H),8.83(dd,J=15.0,3.1Hz,1H),7.88(s,1H),7.28(t,J=15.0Hz,1H),5.34(dddt,J=14.3,10.3,4.0,2.0Hz,1H),5.15(dddt,J=14.3,10.3,4.0,2.0Hz,1H),4.67(d,J=12.4Hz,2H),2.02(m,4H),1.82(d,J=2.0Hz,3H),1.70(d,J=2.0Hz,3H),1.66(d,J=2.0Hz,3H)。
化合物IA-8:黄色固体,收率为79.4%;1H NMR(400MHz,CDCl3)δ9.24(m,2H),8.83(dd,J=7.5,1.4Hz,1H),7.89(d,J=12.1Hz,2H),7.75(d,J=1.4Hz,1H),7.25(m,3H),4.23(s,2H)。
化合物IA-9:黄色固体,收率为87.3%;1H NMR(400MHz,CDCl3)δ8.82(s,1H),8.77(dd,J=7.1,1.8Hz,1H),8.71(dd,J=6.8,1.9Hz,3H),8.64(dd,J=4.1,1.7Hz,2H),8.29(s,2H),8.09(s,1H),7.84(s,2H),7.37–7.25(m,10H),7.23–7.15(m,7H),6.99(dd,J=7.0,4.1Hz,1H),6.94(dd,J=7.0,4.1Hz,2H),6.01(dd,J=7.7,2.2Hz,2H),5.44(dd,J=7.8,4.4Hz,1H),4.44(dt,J=12.2,6.6Hz,1H),4.29(dt,J=11.6,6.9Hz,1H),3.98(dd,J=8.6,5.6Hz,4H),2.42(ddt,J=14.6,7.4,3.4Hz,4H),2.16–1.86(m,11H)。
化合物IA-10:黄色固体,收率为89.5%;1H NMR(400MHz,DMSO-d6)δ9.37(dd,J=7.0,1.6Hz,1H),9.11(d,J=2.3Hz,1H),9.02(s,1H),8.91(dd,J=4.1,1.6Hz,1H),8.49(s,1H),8.45–8.40(m,1H),8.37(dd,J=8.3,2.1Hz,1H),7.52(dd,J=8.3,4.7Hz,1H),7.34(dd,J=7.0,4.1Hz,1H)。
化合物IA-11:黄色固体,收率为82.6%;1H NMR(400MHz,CDCl3)δ8.66(d,J=5.2Hz,2H),8.64–8.59(m,1H),8.08(s,1H),7.82(s,1H),7.33(d,J=7.5Hz,2H),7.28(t,J=7.2Hz,2H),7.24–7.18(m,1H),6.94–6.87(m,1H),4.62(d,J=5.9Hz,2H)。
化合物IA-12:黄色固体,收率为84.9%;1H NMR(400MHz,Chloroform-d)δ8.72(d,J=7.0Hz,1H),8.65(s,2H),8.52(s,1H),8.47(d,J=4.1Hz,1H),8.06(s,1H),7.61(d,J=7.5Hz,2H),7.24(d,J=6.7Hz,1H),6.98–6.92(m,1H),3.71(q,J=6.8Hz,2H),2.97(t,J=7.1Hz,2H)。
化合物IA-13:黄色固体,收率为87.9%;1H NMR(400MHz,Chloroform-d)δ8.74–8.68(m,2H),8.63(dt,J=6.0,1.7Hz,2H),8.55(dd,J=4.0,1.8Hz,1H),8.51–8.46(m,2H),8.45–8.39(m,2H),8.09(s,1H),8.02(s,1H),7.94(s,1H),7.21(d,J=5.4Hz,2H),7.13–7.07(m,2H),6.91(dd,J=7.0,4.1Hz,1H),6.86(dd,J=7.0,4.0Hz,1H),6.07(dd,J=7.9,2.1Hz,1H),5.29(dd,J=8.1,5.0Hz,1H),4.38(dt,J=11.7,6.7Hz,1H),4.24(dt,J=11.6,7.0Hz,1H),3.96–3.85(m,2H),2.39(tdt,J=15.0,12.6,7.2Hz,2H),1.96(dtt,J=12.6,9.9,7.6,3.6Hz,5H),1.80(dtd,J=22.6,11.7,11.3,8.0Hz,2H)。
化合物IA-14:黄色固体,收率为81.2%;1H NMR(400MHz,CDCl3)δ8.76(dd,J=7.1,1.7Hz,1H),8.66(d,J=4.0Hz,2H),8.12(s,1H),7.00(dd,J=7.0,4.1Hz,1H),4.07(q,J=9.1Hz,2H)。
化合物IA-15:黄色固体,收率为86.3%;1H NMR(400MHz,DMSO-d6)δ9.29–9.25(m,2H),8.88–8.80(m,3H),8.66(s,1H),8.26(s,1H),8.23(s,1H),7.26–7.21(m,2H),5.41(t,J=7.9Hz,1H),5.18(d,J=3.8Hz,1H),5.13(d,J=3.4Hz,1H),4.58(t,J=8.4Hz,1H),4.41(s,1H),4.32(q,J=3.8Hz,1H),4.17–3.99(m,3H),3.74(dt,J=12.3,2.1Hz,1H),3.69–3.59(m,5H),3.51(s,3H),2.37(td,J=10.7,8.7,3.2Hz,1H),2.26–2.07(m,2H),1.96(ddd,J=13.2,9.2,4.4Hz,1H)。
化合物IA-16:黄色固体,收率为86.4%;1H NMR(400MHz,CDCl3)δ9.29–9.21(m,2H),8.83(dd,J=15.0,3.1Hz,1H),7.88(s,1H),7.28(t,J=15.0Hz,1H),4.87(t,J=6.2Hz,1H),3.68–3.42(m,5H),2.35–2.17(m,1H),2.09–1.90(m,1H),1.87–1.52(m,4H)。
化合物IA-17:黄色固体,收率为83.5%;1H NMR(400MHz,CDCl3)δ9.28–9.21(m,2H),8.83(dd,J=7.5,1.4Hz,1H),7.88(s,1H),7.28(t,J=7.5Hz,1H),7.24–7.06(m,3H),4.59(t,J=4.6Hz,1H),4.06(dt,J=13.0,6.6Hz,1H),3.88–3.79(m,1H),2.30–2.15(m,3H),2.07–1.97(m,1H)。
化合物IA-18:黄色固体,收率为82.3%;1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.78(d,J=3.2Hz,1H),8.45(dd,J=6.2,2.6Hz,1H),8.33(s,1H),7.28(t,J=15.0Hz,1H),3.74(dd,J=12.6,6.3Hz,2H),2.52–2.36(m,2H)。
化合物IA-19:黄色固体,收率为89.3%;1H NMR(400MHz,MeOD)δ9.06(dd,J=7.0,1.4Hz,1H),8.81(s,1H),8.78(dd,J=4.0,1.4Hz,1H),8.19(s,1H),7.19(dd,J=7.0,4.1Hz,1H),4.35–4.23(m,1H),3.86(dd,J=13.9,3.9Hz,1H),3.56(dd,J=13.9,8.5Hz,1H)。
化合物IA-20:黄色固体,收率为85.7%;1H NMR(400MHz,CDCl3)δ8.81–8.73(m,2H),8.70(dd,J=4.0,1.5Hz,1H),8.10(s,1H),7.40(d,J=8.1Hz,1H),6.99(dd,J=7.0,4.1Hz,1H),3.96(tdt,J=11.9,8.2,3.9Hz,1H),2.23(d,J=10.3Hz,2H),2.03(m,J=10.0Hz,4H),1.51(dt,J=14.4,12.3Hz,2H),1.42–1.28(m,2H)。
化合物IA-21:黄色固体,收率为83.4%;1H NMR(400MHz,CDCl3)δ8.77(dd,J=7.1,1.8Hz,1H),8.70–8.64(m,2H),8.52(d,J=4.9Hz,1H),8.06(s,1H),7.65(td,J=7.7,1.8Hz,1H),7.29(d,J=5.7Hz,1H),7.21–7.15(m,1H),6.99(dd,J=7.1,4.1Hz,1H),3.82(t,J=7.0Hz,2H),3.34(s,1H),3.12(t,J=7.0Hz,2H)。
化合物IA-22:黄色固体,收率为88.6%;1H NMR(400MHz,DMSO-d6)δ9.31(dd,J=7.0,1.6Hz,1H),9.15(t,J=6.1Hz,1H),9.10(s,1H),8.86(dd,J=4.1,1.6Hz,1H),8.81(s,2H),8.27(s,1H),7.29(dd,J=7.0,4.1Hz,1H),4.55(d,J=6.1Hz,2H)。
化合物IA-23:黄色固体,收率为85.5%;1H NMR(400MHz,CDCl3)δ8.77(dt,J=6.2,3.1Hz,1H),8.74–8.68(m,2H),8.34(d,J=1.9Hz,1H),8.12(t,J=4.7Hz,1H),8.00(s,1H),7.44(dt,J=8.6,6.8Hz,2H),7.00(dt,J=8.9,4.5Hz,1H),3.41–3.32(m,4H),3.30–3.22(m,4H)。
化合物IA-24:黄色固体,收率为73.5%;1H NMR(400MHz,CDCl3)δ8.79(s,1H),8.76(dd,J=7.0,1.5Hz,1H),8.71(dd,J=3.9,1.4Hz,1H),8.11(s,1H),7.47(s,1H),7.00(dd,J=7.0,4.1Hz,1H),5.34(t,J=6.6Hz,1H),5.10(t,J=6.6Hz,1H),4.10(t,J=6.2Hz,2H),2.19–2.09(m,2H),2.08–2.02(m,2H),1.75(s,3H),1.68(s,3H),1.61(s,3H)。
化合物IA-25:黄色固体,收率为82.2%;1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.61–8.49(m,3H),8.10(s,1H),7.66(t,J=8.2Hz,2H),7.31(dd,J=7.8,4.7Hz,1H),3.77(q,J=7.0Hz,2H),3.02(t,J=7.2Hz,2H),2.46(s,3H)。
化合物IA-26:黄色固体,收率为83.5%;1H NMR(400MHz,CDCl3)δ8.78–8.71(m,2H),8.69(dd,J=4.0,1.7Hz,1H),8.59(d,J=4.2Hz,1H),8.13(s,1H),8.05(d,J=7.9Hz,1H),7.99(t,J=6.3Hz,1H),7.47(dd,J=7.9,4.7Hz,1H),6.99(dd,J=7.0,4.1Hz,1H),4.88(d,J=6.4Hz,2H)。
化合物IA-27:黄色固体,收率为79.0%;1H NMR(400MHz,CDCl3)δ8.65(dt,J=11.8,6.5Hz,4H),8.09(s,1H),8.03(t,J=6.4Hz,N-H),7.85(d,J=8.2Hz,1H),7.56(d,J=8.0Hz,1H),6.93(dd,J=7.0,4.1Hz,1H),4.68(d,J=4.4Hz,2H)。
化合物IA-28:黄色固体,收率为81.3%;1H NMR(400MHz,DMSO-d6)δ9.29(dd,J=7.1,1.7Hz,1H),9.13(t,J=6.3Hz,1H),8.84(dd,J=4.1,1.7Hz,1H),8.81(s,1H),8.59(dd,J=8.9,2.0Hz,2H),8.26(s,1H),8.02(t,J=2.1Hz,1H),7.27(dd,J=7.0,4.1Hz,1H),4.54(d,J=6.2Hz,2H)。
化合物IA-29:黄色固体,收率为73.3%;1H NMR(400MHz,CDCl3)δ8.79–8.68(m,3H),8.22(d,J=1.2Hz,1H),8.16(s,1H),8.03(t,J=5.9Hz,1H),7.56(dd,J=8.5,1.7Hz,1H),7.01(dd,J=7.0,4.1Hz,1H),4.67(d,J=6.4Hz,2H)。
化合物IA-30:黄色固体,收率为83.5%;1H NMR(400MHz,CDCl3)δ8.79–8.68(m,1H),8.23(s,1H),8.17(d,J=5.8Hz,1H),7.94(s,1H),7.87(d,J=5.4Hz,1H),7.00(dd,J=7.0,4.1Hz,1H),6.93(d,J=4.1Hz,1H),4.68(d,J=6.3Hz,1H)。
化合物IA-31:黄色固体,收率为83.6%;1H NMR(400MHz,CDCl3)δ8.76(d,J=7.0Hz,1H),8.72(d,J=4.4Hz,2H),8.42(s,1H),8.16(s,1H),7.93(s,1H),7.74(dd,J=8.1,1.8Hz,1H),7.30(t,J=7.3Hz,1H),7.01(dd,J=6.9,4.1Hz,1H),4.68(d,J=6.3Hz,2H)。
实施例2化合物IB-1
(i)取化合物IA-1溶于无水甲苯中,加入劳森试剂,加热至反应完全,冷却至室温,过滤,甲苯洗涤滤饼,干燥后得化合物IB-1。
以含有不同取代基的化合物IA为原料,按照类似前述的步骤制备以下实施例,具体化合物IA见下表:
化合物IB-1:黄色固体,收率为69.2%;1H NMR(400MHz,CDCl3)δ9.25(dd,J=15.0,3.1Hz,1H),8.83(dd,J=15.0,3.1Hz,1H),8.62(m,1H),8.43(m,2H),7.88(s,1H),7.65(dt,J=15.02,3.06 1H),7.28(td,J=14.9,4.7Hz,2H),4.40(s,2H)。
化合物IB-2:黄色固体,收率为77.3%;1H NMR(400MHz,CDCl3)δ9.25(dd,J=7.4,1.5Hz,1H),8.83(dd,J=7.5,1.4Hz,1H),8.50(d,J=1.3Hz,1H),8.44(s,1H),8.13(dd,J=7.5,1.3Hz,1H),7.88(s,1H),7.27(dt,J=9.7,7.5Hz,2H),7.09(dt,J=7.5,1.5Hz,1H)。
化合物IB-3:黄色固体,收率为73.7%;1H NMR(400MHz,CDCl3)δ9.41(s,1H),9.25(dd,J=15.0,3.1Hz,1H),8.83(dd,J=15.0,3.1Hz,1H),8.61(s,2H),8.54(s,1H),8.44(s,1H),7.88(s,1H),7.26(d,J=15.0Hz,1H),4.40(s,2H)。
化合物IB-4:黄色固体,收率为75.0%;1H NMR(400MHz,CDCl3)δ9.25(dd,J=7.4,1.5Hz,1H),9.00(s,1H),8.83(dd,J=7.5,1.4Hz,1H),8.42(m,3H),7.88(s,1H),7.46(dt,J=7.5,1.4Hz,1H),7.28(t,J=7.5Hz,1H),7.16(t,J=7.5Hz,1H),3.54(t,J=7.6Hz,2H),2.81(t,J=7.6Hz,2H)。
实施例3化合物IIA-1
(j)取化合物11溶于无水***中,滴加草酰氯,搅拌至反应完全。过滤,***洗涤滤饼,干燥,得化合物12。
(k)取氢氧化钾固体、氯化铵固体,溶于水中,加入化合物12,搅拌至反应完全,过滤,水洗滤饼,干燥,得化合物13。
(l)取化合物14,溶于DMF,加入二氯亚砜,搅拌至反应完全,加水淬灭,乙酸乙酯萃取,有机相用水洗涤,无水硫酸钠干燥,过滤浓缩,过柱,分离纯化,得化合物14。
(m)取化合物14,溶于DMF,加入半胱氨酸甲酯后,滴加1,8-二氮杂二环十一碳-7-烯(DBU),加热至反应完全,冷却至室温,加入稀盐酸酸化,过滤,水洗滤饼,烘干,得化合物16;
(n)取化合物16溶于四氢呋喃,加入二氧化锰,加热至反应完全,过滤,滤液用无水硫酸钠干燥,过滤浓缩,得化合物17;
(o)取化合物17溶于甲醇,加入氢氧化钠水溶液,搅拌至反应完全,盐酸酸化,过滤,干燥,得化合物18。
(p)取化合物18,溶于二氯甲烷,加入EDCI,HOBt,DIEA,搅拌10min后,加入化合物19,室温搅拌30min,加水淬灭,二氯甲烷萃取三次,合并有机相,氯化钠饱和水溶液洗涤,无水硫酸钠干燥,过滤浓缩,过柱,分离纯化,得化合物IIA。
以含不同取代基的胺或醇为化合物19,按照类似前述的步骤制备以下实施例,具体胺或醇即化合物19参考下表:
表3
化合物IIA-1:黄色固体,收率为65.2%;1H NMR(400MHz,CDCl3)δ10.13(s,1H),9.41(s,1H),8.90(d,J=3.0Hz,1H),8.62(s,2H),8.47(dd,J=28.3,5.9Hz,3H),8.30(d,J=4.9Hz,2H),8.18(s,1H),7.73(d,J=7.9Hz,1H),7.54(d,J=7.8Hz,1H),7.48–6.88(m,10H),5.83(d,J=7.2Hz,1H),5.46–5.27(m,1H),4.46–4.07(m,1H),4.07–3.78(m,3H),3.00–2.19(m,2H),1.93(tddd,J=31.4,25.2,12.5,6.2Hz,5H),1.69(dt,J=16.2,11.2Hz,1H)。
化合物IIA-2:黄色固体,收率为79.5%;1H NMR(400MHz,CDCl3)δ9.73(s,1H),8.26(dd,J=14.7,3.3Hz,1H),8.22(s,1H),7.97(s,1H),7.53(dd,J=14.6,3.3Hz,1H),7.27(td,J=14.9,3.4Hz,1H),7.18(td,J=14.8,3.3Hz,1H),5.33(tdd,J=12.5,4.0,2.0Hz,1H),5.14(tdd,J=12.5,1.9,1.1Hz,2H),4.66(d,J=12.3Hz,2H),2.18(m,6H),1.96(m,2H),1.82(d,J=1.8Hz,3H),1.70(d,J=2.0Hz,3H),1.66(d,J=2.0Hz,6H)。
化合物IIA-3:黄色固体,收率为83.6%;1H NMR(400MHz,DMSO-d6)δ12.34(d,J=3.3Hz,1H),9.07(d,J=3.3Hz,1H),8.83(s,1H),8.37–8.28(m,1H),7.67–7.51(m,1H),7.28(q,J=4.8Hz,2H),5.02(d,J=2.5Hz,2H),3.64(s,1H)。
化合物IIA-4:黄色固体,收率为84.8%;1H NMR(400MHz,CDCl3):δ9.75(s,1H),8.31–8.23(m,2H),7.98(s,1H),7.54(dd,J=14.7,3.4Hz,1H),δ7.28(td,J=14.9,3.4Hz,1H),7.19(td,J=14.8,3.2Hz,1H),5.34(dddt,J=14.4,12.5,4.0,2.0Hz,1H),4.67(d,J=12.4Hz,2H),1.82(d,J=2.0Hz,3H),1.70(d,J=2.0Hz,3H)。
化合物IIA-5:黄色固体,收率为90.0%;1H NMR(400MHz,CDCl3)δ9.75(s,1H),8.26(m,2H),7.98(s,1H),7.54(dd,J=14.6,3.4Hz,1H),7.23(dtd,J=47.6,14.8,3.3Hz,2H),5.34(tdd,J=12.5,4.0,2.0Hz,1H),5.15(dddt,J=14.3,10.3,4.0,2.0Hz,1H),4.67(d,J=12.4Hz,2H),2.12(m,4H),1.82(d,J=2.0Hz,3H),1.70(d,J=2.0Hz,3H),1.66(d,J=2.0Hz,3H)。
化合物IIA-6:黄色固体,收率为71.2%;1H NMR(400MHz,CDCl3)δ9.47–9.35(m,2H),8.66(s,1H),8.62(s,1H),8.48(d,J=3.6Hz,1H),8.33(d,J=6.0Hz,1H),7.79(d,J=7.7Hz,1H),7.57(d,J=6.4Hz,1H),7.38(dd,J=7.4,4.9Hz,1H),7.29(dd,J=9.1,5.3Hz,2H),4.60(d,J=6.0Hz,2H)。
化合物IIA-7:黄色固体,收率为81.3%;1H NMR(400MHz,CDCl3)δ9.75(s,1H),8.27(m,2H),7.98(s,1H),7.54(dd,J=7.5,1.6Hz,1H),7.28(td,J=7.5,1.5Hz,1H),7.19(td,J=7.5,1.5Hz,1H),5.27(t,J=6.2Hz,1H),4.84(p,J=7.2Hz,1H),4.36(dt,J=9.9,7.3Hz,1H),3.50(dd,J=12.5,2.0Hz,1H),3.25(dd,J=12.5,2.0Hz,1H),2.78(ddd,J=12.4,7.1,0.6Hz,1H),2.19(ddd,J=12.3,8.4,6.2Hz,1H),2.08(dq,J=12.7,6.9Hz,1H),1.59(m,18H),0.97(m,12H),0.80(d,J=6.4Hz,3H)。
化合物IIA-8:黄色固体,收率为84.5%;1H NMR(400MHz,CDCl3)δ9.75(s,1H),8.27(dd,J=15.0,3.1Hz,2H),7.98(s,1H),7.54(dd,J=14.7,3.4Hz,1H),7.23(dtd,J=47.4,14.9,3.2Hz,2H),5.27(tt,J=12.5,2.0Hz,1H),4.84(p,J=14.7Hz,1H),2.47(ddd,J=24.7,14.7,1.9Hz,1H),2.21(m,3H),1.53(m,23H),90(m,15H),0.49(dt,J=22.7,18.5Hz,1H)。
化合物IIA-9:黄色固体,收率为83.9%;1H NMR(400MHz,CDCl3)δ9.75(s,1H),8.27(q,J=3.2Hz,2H),7.98(s,1H),7.54(dd,J=14.7,3.4Hz,1H),7.23(dtd,J=47.4,14.8,3.2Hz,2H),5.27(tt,J=12.3,2.0Hz,1H),4.82(p,J=14.7Hz,1H),2.45(ddd,J=24.9,14.7,2.0Hz,1H),2.23(m,3H),1.42(m,40H),0.49(dt,J=22.5,18.4Hz,1H)。
化合物IIA-10:黄色固体,收率为89.4%;1H NMR(400MHz,CDCl3)δ9.74(s,1H),8.27(dd,J=6.9,1.9Hz,2H),7.98(s,1H),7.54(dd,J=7.5,1.6Hz,1H),7.28(td,J=7.5,1.5Hz,1H),7.19(td,J=7.5,1.5Hz,1H),6.67(s,1H),5.27(t,J=6.2Hz,1H),4.08(p,J=7.6Hz,1H),3.79(dt,J=10.4,8.0Hz,1H),3.50(dd,J=12.4,8.6Hz,1H),3.25(dd,J=12.4,8.6Hz,1H),2.47(ddd,J=12.5,7.9,0.8Hz,1H),2.18(m,2H),1.64(m,19H),0.89(m,10H),0.77(m,4H)。
化合物IIA-11:黄色固体,收率为84.7%;1H NMR(400MHz,DMSO-d6)δ12.41(d,J=3.3Hz,1H),9.11(d,J=3.3Hz,1H),8.94(s,1H),8.33(dt,J=7.8,3.0Hz,1H),7.60(dd,1H),7.52(dd,1H),7.45(t,J=7.4Hz,2H),7.41–7.37(m,1H),7.36–7.32(m,5H),7.23(dd,J=7.7,1.4Hz,1H),5.51(s,2H),2.28(s,3H)。
化合物IIA-12:黄色固体,收率为78.9%;1H NMR(400MHz,MeOD)δ11.72(s,1H),9.28(d,J=2.6Hz,1H),8.36(s,1H),8.26(dd,J=5.6,3.4Hz,1H),7.45–7.38(m,1H),7.25–7.13(m,2H),3.46(t,J=5.7Hz,2H),3.38(t,J=5.8Hz,2H),1.89(s,4H)。
化合物IIA-13:黄色固体,收率为83.5%;1H NMR(400MHz,MeOD)δ9.20(d,J=1.8Hz,1H),8.54(d,J=1.4Hz,1H),8.41–8.36(dd,1H),7.57–7.48(dd,1H),7.30(m,J=6.3Hz,2H),4.82(t,J=3.8Hz,1H),4.13(dd,J=11.4,4.1Hz,1H),4.04(dd,J=11.4,3.6Hz,1H),3.85(s,3H)。
化合物IIA-14:黄色固体,收率为88.6%;1H NMR(400MHz,CDCl3)δ9.74(s,1H),8.27(dd,J=14.7,3.4Hz,1H),8.18(s,1H),7.98(s,1H),7.54(dd,J=14.7,3.4Hz,1H),7.40(s,1H),7.29(m,2H),7.19(td,J=14.8,3.2Hz,1H),6.96(m,1H),6.87(td,J=16.0,3.0Hz,1H),4.23(s,2H)。
化合物IIA-15:黄色固体,收率为87.1%;1H NMR(400MHz,CDCl3)δ9.74(s,1H),8.27(m,2H),7.98(s,1H),7.54(dd,J=7.5,1.6Hz,1H),7.28(td,J=7.5,1.5Hz,1H),7.19(td,J=7.5,1.5Hz,1H),6.66(s,1H),3.18(t,J=7.7Hz,2H),2.51(m,4H),2.36(t,J=7.6Hz,2H),1.73(m,2H),1.68(m,4H)。
化合物IIA-16:黄色固体,收率为82.3%;1H NMR(400MHz,DMSO-d6)δ12.35(s,N-H),9.45(s,1H),9.36(t,J=6.2Hz,1H),8.68(s,1H),8.39–8.31(m,1H),7.64(d,J=1.8Hz,1H),7.61–7.55(m,1H),7.49–7.38(m,2H),7.36–7.25(m,2H),4.62(d,J=6.0Hz,2H)。
化合物IIA-17:黄色固体,收率为88.4%;1H NMR(400MHz,DMSO)δ12.45(s,1H),10.62(s,1H),9.53(d,J=3.2Hz,1H),9.02(d,J=2.3Hz,1H),8.85(s,1H),8.39(dd,J=4.7,1.2Hz,1H),8.37–8.31(m,1H),8.31–8.24(m,1H),7.64–7.55(m,1H),7.47(dd,J=8.3,4.7Hz,1H),7.35–7.26(m,2H)。
化合物IIA-18:黄色固体,收率为88.8%;1H NMR(400MHz,CDCl3)δ10.39(s,1H),9.44(s,2H),8.92(d,J=3.1Hz,1H),8.50(d,J=7.8Hz,1H),8.42(d,J=7.6Hz,2H),8.25(s,1H),8.05(s,2H),7.82(d,J=3.2Hz,2H),7.66–6.88(m,25H),5.66(d,J=6.9Hz,2H),5.40(dd,J=7.5,4.7Hz,1H),4.19(ddd,J=18.0,12.3,6.5Hz,2H),4.08(dd,J=29.5,8.0Hz,1H),4.03–3.81(m,3H),2.70–2.07(m,4H),2.07–1.49(m,9H)。
化合物IIA-19:黄色固体,收率为87.9%;1H NMR(400MHz,MeOD)δ9.34(s,1H),8.53(s,1H),8.39(d,J=7.3Hz,1H),7.52(d,J=7.0Hz,1H),7.42(d,J=7.5Hz,2H),7.36(t,J=7.3Hz,2H),7.29(t,3H),4.69(s,2H)。
化合物IIA-20:黄色固体,收率为90.1%;1H NMR(400MHz,DMSO)δ12.41(s,1H),9.39(s,1H),8.89(t,J=5.3Hz,1H),8.60(s,1H),8.55(s,1H),8.47(d,J=4.5Hz,1H),8.35(d,J=7.2Hz,1H),7.79(d,J=7.5Hz,1H),7.60(d,J=7.2Hz,1H),7.40(t,1H),7.31(m,2H),3.63(dd,J=13.0,6.5Hz,2H),2.97(dd,2H)。
化合物IIA-21:黄色固体,收率为82.3%;1H NMR(400MHz,CDCl3)δ10.60(s,1H),9.58(s,2H),8.97(d,J=3.1Hz,1H),8.64(d,J=5.0Hz,4H),8.54(t,J=5.9Hz,3H),8.41(d,J=7.3Hz,2H),8.32(s,3H),7.61–7.21(m,16H),7.17(d,J=3.1Hz,2H),5.57(d,J=7.5Hz,2H),5.48–5.28(m,4H),4.70–3.96(m,5H),3.96–3.82(m,2H),2.38(dtd,J=19.9,12.7,7.4Hz,3H),2.16–1.76(m,9H),1.75(d,J=6.7Hz,1H)。
化合物IIA-22:黄色固体,收率为84.0%;1H NMR(400MHz,CDCl3)δ9.68(s,1H),8.22(dd,J=14.7,3.3Hz,1H),8.15(s,1H),7.93(s,1H),7.49(dd,J=14.6,3.4Hz,1H),7.19(dtd,J=47.3,14.8,3.3Hz,2H),4.37(t,J=16.3Hz,1H),3.51(m,2H),2.05(m,1H),1.87(m,1H),1.66(m,4H)。
化合物IIA-23:黄色固体,收率为87.1%;1H NMR(400MHz,CDCl3)δ9.74(s,1H),8.31–8.20(m,2H),7.98(s,1H),7.54(dd,J=14.7,3.4Hz,1H),7.23(dtd,J=47.4,14.8,3.2Hz,2H),4.89(p,J=5.6Hz,1H),4.55(t,J=9.0Hz,1H),3.66(qd,J=24.8,5.4Hz,2H),2.21(ddd,J=22.9,8.0,4.6Hz,1H),2.14(ddd,J=14.7,8.0,4.6Hz,1H)。
化合物IIA-24:黄色固体,收率为83.0%;1H NMR(400MHz,DMSO-d6)δ12.52(d,J=3.3Hz,1H),9.28(d,J=3.2Hz,1H),8.70(s,1H),8.57(d,J=8.1Hz,1H),8.42–8.28(m,1H),7.63–7.52(m,1H),7.31(dd,J=6.4,2.9Hz,2H),4.58(dt,J=8.5,4.3Hz,1H),3.92(qd,J=11.3,4.5Hz,2H)。
化合物IIA-25:黄色固体,收率为87.2%;1H NMR(400MHz,CDCl3)δ9.74(s,1H),8.27(dd,J=14.1,3.9Hz,2H),7.98(s,1H),7.54(dd,J=14.6,3.4Hz,1H),7.28(td,J=14.9,3.4Hz,1H),7.19(td,J=14.8,3.2Hz,1H),4.20(t,J=15.9Hz,1H),3.54(m,5H),2.23(m,1H),1.75(m,5H)。
化合物IIA-26:黄色固体,收率为89.1%;1H NMR(400MHz,CDCl3)δ9.74(s,1H),8.27(dd,J=14.7,3.4Hz,1H),8.18(s,1H),7.98(s,1H),7.54(dd,J=14.7,3.4Hz,1H),7.23(dtd,J=47.4,14.8,3.2Hz,2H),4.99(t,J=8.6Hz,1H),4.77(p,J=16.0Hz,1H),4.11(dd,J=24.9,15.7Hz,1H),3.66(s,3H),3.24(dd,J=24.7,15.8Hz,1H),2.60(ddd,J=24.9,16.2,8.6Hz,1H),1.81(ddd,J=24.7,16.2,8.7Hz,1H),1.38(s,1H)。
化合物IIA-27:黄色固体,收率为82.2%;1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),9.43(d,J=1.2Hz,1H),9.31(t,J=6.3Hz,1H),8.75(s,1H),8.35(d,J=6.9Hz,1H),7.59(dd,J=5.8,2.7Hz,1H),7.37–7.25(m,2H),4.17(dt,J=18.7,9.4Hz,2H)。
化合物IIA-28:黄色固体,收率为82.6%;1H NMR(400MHz,CDCl3)δ9.74(s,1H),8.27(dd,J=14.7,3.4Hz,1H),8.19(s,1H),8.07–7.96(m,2H),7.54(dd,J=14.7,3.4Hz,1H),7.23(dtd,J=47.4,14.8,3.2Hz,2H),7.09(dd,J=16.0,10.0Hz,1H),4.88(t,J=8.6Hz,1H),3.86(dt,J=24.8,13.2Hz,1H),3.64(dt,J=24.8,13.1Hz,1H),2.33–2.17(m,1H),2.08–1.93(m,1H),1.86–1.72(m,2H)。
化合物IIA-29:黄色固体,收率为85.9%;1H NMR(400MHz,CDCl3)δ8.77–8.72(m,2H),8.69(dd,J=4.1,1.7Hz,1H),8.11(s,1H),6.98(dd,J=7.0,4.1Hz,1H),3.86–3.66(m,2H),2.51(qt,J=10.8,6.8Hz,2H)。
化合物IIA-30:黄色固体,收率为82.0%;1H NMR(400MHz,CDCl3)δ9.27(s,1H),8.88(s,1H),8.50(d,J=7.3Hz,1H),8.37(s,1H),7.46(d,J=7.6Hz,1H),7.39–7.29(m,3H),7.18(s,1H),5.32(t,J=6.2Hz,1H),5.08(t,J=6.0Hz,1H),4.12(t,J=5.6Hz,2H),2.13–2.01(m,4H),1.74(s,3H),1.66(s,3H),1.59(s,3H)。
实施例4化合物IIB-1
(r)取化合物IIA-3(见表1),溶于叔丁醇中,加入化合物20及催化量叔丁基三氯乙酰亚胺酯(TBTA)后,加入维生素C钠水溶液,室温搅拌5min,滴加硫酸铜水溶液,室温搅拌30min后,水和乙酸乙酯萃取洗涤,合并有机相,饱和食盐水洗涤一次后,用无水硫酸钠干燥,过滤浓缩,过柱分离纯化,得化合物IIB-1。
以含不同取代基的叠氮化合物20为原料,具体叠氮化合物20见表4,制备具有表中所列结构式的化合物:
表4
化合物IIB-1:黄色固体,收率为43.1%;1H NMR(400MHz,CDCl3)δ9.74(s,1H),8.26(dd,J=14.7,3.4Hz,1H),8.20(s,1H),7.97(s,1H),7.53(dd,J=14.6,3.4Hz,1H),7.48(s,1H),7.22(m,7H),5.62(s,2H),4.36(dt,J=55.1,11.2Hz,2H),3.06(t,J=11.2Hz,2H)。
化合物IIB-2:黄色固体,收率为41.0%;1H NMR(400MHz,DMSO-d6)δ12.38(d,J=3.3Hz,1H),9.07(d,J=3.2Hz,1H),8.88(s,1H),8.41(s,1H),8.37–8.26(m,1H),7.98–7.86(m,4H),7.67–7.56(m,1H),7.51(ddd,J=17.4,7.3,2.5Hz,3H),7.36–7.24(m,2H),5.81(s,2H),5.48(s,2H)。
化合物IIB-3:黄色固体,收率为49.3%;1H NMR(400MHz,CDCl3)δ9.75(s,1H),8.27(q,J=3.8Hz,2H),7.98(s,1H),7.54(dd,J=14.7,3.4Hz,1H),7.23(m,3H),5.63(s,2H),4.46(t,J=15.4Hz,2H),3.52(t,J=15.6Hz,2H),1.86(m,4H),1.33(m,4H)。
化合物IIB-4:黄色固体,收率为50.0%;1H NMR(400MHz,CDCl3)δ9.75(s,1H),8.36(s,1H),8.27(dd,J=14.7,3.3Hz,1H),7.98(s,1H),7.54(dd,J=14.6,3.4Hz,1H),7.39(s,1H),7.23(dtd,J=47.6,14.9,3.3Hz,2H),5.63(s,2H),4.46(t,J=10.8Hz,2H),3.62(t,J=9.9Hz,2H),1.95(ddt,J=25.8,15.0,10.8Hz,2H),1.77(s,1H),1.46(m,6H)。
化合物IIB-5:黄色固体,收率为59.3%;1H NMR(400MHz,DMSO-d6)δ12.38(s,1H),9.08(d,J=2.1Hz,1H),8.88(s,1H),8.39–8.27(m,1H),8.16(s,1H),7.63–7.56(m,1H),7.31(qd,J=7.1,3.7Hz,2H),5.49(s,2H),4.08(s,2H),1.99–1.89(m,3H),1.65(d,J=12.2Hz,3H),1.53(d,J=12.1Hz,3H),1.46(d,J=2.8Hz,6H)。
实施例5化合物的体外免疫抑制活性测试
淋巴细胞毒性评价:脊椎法处死大鼠,无菌取其脾脏,磨碎制成单细胞悬液,加入红细胞裂解液2mL去除红细胞后,用含10%胎牛血清FBS的RPMI-1640培养液将细胞浓度调成2×106个/mL。96孔板中加入100μL 2×106个/mL细胞悬液和100μL适当浓度的待测化合物,放入37℃、5%CO2培养箱中培养48小时。结束培养时,每孔加入CCK8 10μL,在培养箱中放置5-7小时后,用酶标仪于450nm处测定OD 450值。
淋巴细胞增殖实验:2×106个/mL新鲜的脾脏细胞按照37℃、5%CO2培养箱中培养48个小时,培养液用5μg/mL的刀豆蛋白A(ConA)来诱导细胞的增殖,同时加入适当浓度的待测化合物以测试其对淋巴细胞增殖的抑制活性。部分化合物测试结果见下列表格及说明书附图:
其中,Tacrolimus为他克莫司;ITE是一种内源性AhR部分激动剂(AHR的天然内源性配体);KYN,即犬尿氨酸(kynurenine),由Trp经双加氧酶TDO、IDO作用代谢生成,是一种AhR激动剂。
本发明实施例中得到的化合物对淋巴细胞增殖具有较好的抑制活性,其中示意部分化合物的IC50值,如下表所示,其中部分化合物的IC50曲线如图1中所示:
此外,本实施例中还测试了化合物对淋巴细胞的毒性测试,测试方法:细胞密度为3*106个/mL,96孔板,每孔100μL,3*105个细胞/孔,未加刺激因子,测试化合物的毒性,其中化合物的浓度为5、2.5、1.25、0.625μM,测试结果显示本发明的化合物在测试浓度下均为见明显毒性,结果如图2所示。
结果表明本发明的化合物对淋巴细胞毒性低,且对淋巴细胞具有显著的抑制增殖作用。其中化合物IA-3对淋巴细胞有尤为显著的抑制作用,且细胞毒性较小,安全指数高。其余化合物对大鼠淋巴细胞增殖物也具有明显的抑制活性,且普遍优于阳性药Tacrolimus。
总而言之,从这些事实可以得出结论,本发明的部分化合物,由于其有效地抑制免疫细胞活性,从而对免疫疾病的预防或治疗是有效的,在制备免疫抑制剂药物时具有非常良好的应用前景。
实施例6化合物抑制LPS诱导的细胞因子风暴实验
取健康雄性小鼠共15只,随机平均分为3组,分别为对照组、模型组、给药组,每组5只,标号并记录体重。分别给药,对照组和模型组分别尾静脉注射生理盐水,给药组尾静脉注射实施例1-4制备的化合物,10mg/kg(2mg/ml;50μl/10g)。一小时后,腹腔注射LPS,3mg/kg(0.3mg/ml,100μl/10g)。5小时后,第二次注射药物。9小时后,将小鼠取血,处死。
取血完成后,ELISA测定血清中,IL-6,IL-2,TNF-a,IFN-y。结果显示本发明的化合物表现出不同程度上的降低LPS诱导的血清中炎症因子IL-6,IL-2,TNF-a和IFN-y的含量的情况,尤其以化合物IA-3对于上述因子的降低作用最为显著,结果如图3所示。
以化合物IA-3组进行组织病理学检查:小鼠肺4%多聚甲醛固定,HE观察组织病理变化。结果显示,LPS组肺损伤严重,表现为炎性细胞浸润、肺泡壁增厚、肺间质充血、出血,而化合物IA-3的治疗降低了肺部病理的严重程度,小鼠肺组织H&E组织染色结果如图4所示。
实施例7化合物制CD-3抗体诱导的细胞因子风暴实验
取健康雄性小鼠共15只,随机平均分为3组,分别为对照组、模型组、给药组,每组5只,标号并记录体重。分别给药,对照组和模型组分别尾静脉注射生理盐水,给药组尾静脉注射化合物实施例1-4中制备的化合物,10mg/kg(2mg/ml;50μl/10g)。0.5小时后,腹腔注射CD-3抗体,100μg/kg。5小时后,第二次注射药物。9小时后,将小鼠取血,处死。
取血完成后,ELISA测定血清中,IL-6,IL-2,TNF-a,IFN-y。结果显示,本发明的化合物表现出不同程度上的降低CD-3抗体诱导的血清中炎症因子IL-6,IL-2,TNF-a和IFN-y的含量的情况,尤其以化合物IA-3对于上述因子的降低作用最为显著,结果如图5所示。
实施例8化合物的口服生物利用度研究
经过实验验证,本发明的实施例中制备得到的化合物具有较好的口服生物利用度,本实施例以免疫细胞增殖抑制活性表现较为良好的化合物IA-3作为示例,示意将其作为免疫抑制剂进一步在动物模型上进行研究之前,对其口服生物利用度的研究过程,如下:
仪器:Thermo Accela高效液相***
标准系列溶液制备:取化合物IA-3适量,精密称定,置100mL容量瓶中,用乙腈溶解并定容至刻度,摇匀,制得25.0μg/mL储备液。分别量取储备液适量,用乙腈定容稀释制成浓度为5,10,25,50,100,250,500,1000ng/mL的系列标准溶液,4℃冰箱保存,备用。
内标溶液的制备:取内标适量,精密称定,置100mL容量瓶中,用乙腈溶解并定容至刻度,摇匀,制得浓度为25μg/mL储备液。再精密量取储备液适量,加乙腈稀释制成浓度为50ng/mL的内标对照品溶液,4℃冰箱保存,备用。
血浆样品预处理:取大鼠血浆80μL,加内标120μL,涡旋混合2min,离心10min,取上清140μL,离心10min,取10μL进样分析。
标准曲线:取大鼠空白血浆64μL,加入待测物标准系列溶液16μL及含有内标的乙腈溶液120μL,涡旋混合2min,离心10min,取上清140μL,离心10min,取10μL利用HPLC-HR-MS进样分析。仪器求得直线回归方程即为标准曲线。
样品采集:健康雄性wistar大鼠8只,随机分成二组(灌胃组、静脉组),每组4只。给药前禁食12h,自由饮水。灌胃组给予受试药物5mg/kg,静脉组给予1mg/kg,于给药前和给药后5min,15min,30min,1h,1.5h,2h,4h,6h,8h,10h和12h由大鼠眼眶静脉取血约0.4mL,并立即移入肝素化离心管中,离心分离血浆。
样品测定和数据处理:根据采集的大鼠血浆样品按“血浆样品预处理”项下处理后在上述条件下分析测定。应用非房室模型分别处理上述血药浓度测定数据,DAD2.0软件计算药动学参数。根据生物利用度公式F=AUCig*Div/AUCiv*Dig*100%,计算生物利用度。
结果如表5、表6所示:
表5单次注射给药PK(1mg/kg)
表6单次口服给药PK(5mg/kg)
IA-3灌胃给药后,全血暴露量AUC较大,相对口服生物利用度为22.07%,具有潜在的成药性。
以上所述仅为本申请的优选实施例而已,并不用于限制本申请,尽管参照前述实施例对本申请进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。凡在本申请的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本申请的保护范围之内。
Claims (10)
1.一种含有2,4-噻唑环的化合物或其药学上可接受的盐或异构体,所述化合物具有式X所示结构:
其中,A结构为吡唑并嘧啶或者吲哚,所述化合物符合式X1或式X2所示结构:
Z为无或羰基;
X为O或S;
R1为氢或C1-6烷基;
R2选自C1-C3烷基、C5-C15烯基、炔基、5-10元杂环基、C6-C12芳基、5-12元杂芳基、甾醇基和5-10元环烷基;Y与R2直接相连,或者Y与R2相连成环;
R3选自氢、卤素、氨基、羟基、乙酰基、3-10元杂环基、C6-C12芳基、5-12元杂芳基、3-10元环烷基、酯基、羧基、三卤甲基和金刚烷基;
R2或R3是未被取代的,或者是被选自C1-C6烷基、羟基、卤素、三卤甲基、羧基、苯基中的一种或多种所取代的;
其中,R2为C1-C3烷基时,R3不为氢。
2.根据权利要求1所述的化合物或其药学上可接受的盐或异构体,其特征在于,R2选自C1-C3烷基、C5-C15一烯基、C5-C15二烯基、C5-C15三烯基、炔基、5-6元环烷基、苯基、5-6元杂环基、5-6元杂芳基、甾醇基;其中,Y与R2直接相连,或者Y与R2相连成环;
R2是未被取代的,或者是被选自C1-C6烷基、羟基、卤素、三卤甲基、羧基、苯基中的一种或多种所取代的;
优选地,R3选自氢、卤素、氨基、羟基、乙酰基、5-6元杂环基、苯基、联苯基、萘基、5-6元杂芳基、5-6元环烷基、酯基、羧基、酰胺基、三卤甲基、金刚烷基;
R3是未被取代的,或者是被选自C1-C6烷基、羟基、卤素、三卤甲基、羧基、苯基中的一种或多种所取代的。
3.根据权利要求1所述的化合物或其药学上可接受的盐或异构体,其特征在于,R2选自甲基、乙基、丙基、C5一烯基、C10二烯基、C15三烯基、炔基、环戊烷基、环己烷基、三氮唑基、苯基、哌啶基、哌嗪基、吡咯烷基、吡啶基、嘧啶基、甾醇基;其中,Y与R2直接相连,或者Y与R2相连成环;
R2是未被取代的,或者是被选自C1-C6烷基、羟基、卤素、三卤甲基、羧基中的一种或多种所取代的;
优选地,R3选自氢、卤素、氨基、羟基、乙酰基、苯基、联苯基、萘基、环戊烷基、环己烷基、哌啶基、哌嗪基、吡咯烷基、吡啶基、嘧啶基、酯基、羧基、酰胺基、三卤甲基、金刚烷基;
R3是未被取代的,或者是被选自C1-C6烷基、羟基、卤素、三卤甲基、羧基、苯基中的一种或多种所取代的。
4.根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐或异构体,其特征在于,所述化合物具有式I或式II所述结构:
其中,X、Y、R1、R2、R3同权利要求1至3中任一项中所述;
优选地,式I化合物中,
X为O或S;
R1为氢或C1-C2烷基;
R2选自甲基、乙基、C5一烯基、C10二烯基、环己烷基、苯基、、吡啶基;其中,Y与R2直接相连,或者Y与R2相连成环;
R3选自氢、苯基、吡啶基、嘧啶基、酯基、三卤甲基;
R2或R3是未被取代的,或者是被选自C1-C6烷基、羟基、卤素、三卤甲基、羧基中的一种或多种所取代的;
优选地,式II化合物中,
X为O或S;
R2选自甲基、乙基、丙基、C5一烯基、C10二烯基、C15三烯基、炔基、环戊烷基、环己烷基、苯基、三氮唑基、吡啶基、甾醇基;其中,Y与R2直接相连,或者Y与R2相连成环;
R3选自氢、卤素、氨基、羟基、乙酰基、苯基、联苯基、萘基、环戊烷基、环己烷基、吡咯烷基、吡啶基、嘧啶基、酯基、羧基、酰胺基、三卤甲基、金刚烷基;
R2或R3是未被取代的,或者是被选自C1-C6烷基、羟基、卤素、三卤甲基、羧基中的一种或多种所取代的。
8.一种制备权利要求1至7中任一项所述的化合物或其药学上可接受的盐或异构体的方法,其特征在于,所述方法包括:
以化合物1与化合物2进行环化反应得到化合物3,化合物3经酯键水解得到化合物4,化合物4酰氯化、氨化得到化合物5,化合物5经硫取代得到化合物6,化合物6经过环化反应得到化合物8,化合物8经酯键水解得到化合物9,化合物9和化合物10经过酰胺缩合或酯键缩合得到式IA化合物;
或者,进一步地,式IA化合物经氧硫交换制备得到式IB化合物;
其中,化合物1-10如下所示,
R1、R2、R3、Y同权利要求1至7中任一项中所述;
优选地,所述方法包括:化合物11与草酰氯反应得到化合物12,化合物12经过氨化得到化合物13,化合物13经过氧化反应得到化合物14,化合物14经过环化反应得到化合物16,化合物16经过氧化反应得到化合物17,化合物17经过酯键水解得到化合物18,化合物18与化合物19经过缩合反应得到化合物IIA。
其中,化合物11-19的如下所示:
R1、R2、R3、Y同权利要求1至7中任一项中所述。
9.药物组合物或药物制剂,其特征在于,包含权利要求1至7中任一项中所述的化合物或其药学上可接受的盐或异构体;
或者,进一步地,包含药学上可接受的辅料或载体。
10.权利要求1至7中任一项所述的化合物或其药学上可接受的盐或异构体或者权利要求9中所述的药物组合物或药物制剂在制备用于预防和/或治疗与活化免疫***有关的疾病或病症的药物中的用途;
或者,权利要求1至7中任一项所述的化合物或其药学上可接受的盐或异构体或者权利要求9中所述的药物组合物或药物制剂在制备免疫抑制剂药物中的应用;
优选地,所述疾病或病症选自:器官、组织或细胞移植的排异反应;通过移植造成的移植物抗宿主病;以及自身免疫综合症;以及与细胞因子风暴有关的疾病或病症;
优选地,所述自身免疫综合症包括狼疮、***性红斑狼疮、银屑病、湿疹、皮炎、关节炎、类风湿性关节炎、脊柱关节炎、痛风性关节炎或其他关节炎性病症、多发性硬化症、皮肤真菌并、抗磷脂抗体综合征、淋巴瘤性甲状腺肿、淋巴细胞性甲状腺炎、多发性硬化、重症肌无力、I型糖尿病、葡萄膜炎、巩膜表外层盐、巩膜炎、川崎(Kawasaki’s)疾病、葡萄膜视网膜盐、后葡萄膜炎、与***有关的葡萄膜炎、眼色素膜脑膜炎综合征、兵营行脑脊髓炎、慢性异源移植血管病变、后感染性自身免疫疾病,图风湿热和后感染性血管球性肾炎、炎症性和细胞增生型皮肤病、牛皮癣、牛皮癣关节炎、特应性皮炎、肌病、肌炎、骨髓炎、接触性皮炎、湿疹性皮炎、脂溢性皮炎、扁平苔癣、天疱疮、荨麻疹、血管性水肿、血管炎、红疹、粉刺、肥大细胞病;
优选地,所述与细胞因子风暴有关的疾病或病症为因感染性疾病引起的细胞因子风暴综合征。
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