CN114349758A - 一种母核为吡啶并咪唑的化合物及其制备方法和应用 - Google Patents
一种母核为吡啶并咪唑的化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种母核为吡啶并咪唑的化合物及其制备方法和应用。本发明提供的母核为吡啶并咪唑的化合物结构新颖,制备方法简单,可通过特异性抑制NLRP3炎症小体的活化,减少白介素IL‑1β的成熟分泌,从而减轻炎性损伤,改善炎症微环境,具有显著的抗炎活性,同时对THP‑1细胞无明显毒性。本发明化合物可制备成抗炎药物并用于炎症相关疾病的治疗,包括风湿性关节炎,类风湿性关节炎,炎性肠道疾病,痛风,动脉粥样硬化,非酒精性脂肪肝病,冷吡啉相关周期性综合征,慢性肾脏疾病,糖尿病和神经退行性疾病等。
Description
技术领域
本发明属于医药领域,具体涉及一种母核为吡啶并咪唑的化合物及其制备方法和应用。
背景技术
炎症小体是一种由多种蛋白组成的复合物,当细胞受到感染或刺激时可被激活。先天免疫系统通过模式识别受体(pattern recognition receptor,PRR)来识别病原体相关分子模式(pathogen associated molecular patterns,PAMP)或损伤相关的分子模式(damage associated molecular patterns,DAMP)。人们已经发现多种PRR,其中就包括核苷酸结合寡聚域(nucleotide-binding oligomerization domain,NOD)样受体(NOD-likereceptor,NLR)。NLR家族又包括众多成员,其中,包含吡啶结构域3的NOD样受体(NOD likereceptor containing pyrin domain 3,NLRP3)的研究最为透彻。
NLRP3包含三个结构域:热蛋白结构域(pyrin domain,PYD),核苷酸结合结构域(nucleoside triphosphatase domain,NACHT),以及亮氨酸富集结构域(leucine-richrepeat,LRR)。当NLRP3被激活后,随即发生寡聚,通过PYD的同型相互作用引起ASC的寡聚,再通过ASC的CARD结构域引起procaspase-1的聚集,并将其水解为成熟的caspase-1,随后caspase-1再将pro-IL-1β和pro-IL-18水解为成熟的IL-1β和IL-18,引发炎症风暴,导致细胞焦亡。NLRP3炎症小体的活化可以分启动和激活两个阶段。在启动阶段,微生物成分或内源性细胞因子刺激Toll样受体(Toll-like receptor,TLR),激活转录因子NF-κB,NF-κB上调NLRP3和pro-IL-1β的表达。在激活阶段,ATP、K+离子载体、血红素、病原体相关RNA、细菌和真菌毒素等刺激物激活NLRP3,引起NLRP3炎症小体的组装。
NLRP3及其炎症小体是治疗多种疾病的潜在靶点,包括风湿性关节炎,类风湿性关节炎,通风性关节炎,炎性肠道疾病,痛风,动脉粥样硬化,非酒精性脂肪肝病,冷吡啉相关周期性综合征,慢性肾脏疾病,糖尿病,帕金森症,多发性硬化症,阿尔兹海默症,亨廷顿病,系统性红斑狼疮等。NLRP3炎症小体水平的异常升高,有可能导致以上疾病,因此,开发出NLRP3抑制剂有望为解决以上疾病带来突破。
针对NLRP3炎症小体相关疾病,目前已经有一些药物用于临床,如阿那白滞素(anakinra),卡那津单抗(canakinumab),列洛西普(rilonacept)。但这些药物都针对通路下游的IL-1或IL-1受体,这会产生两个问题。一方面,导致这些疾病的炎症因子不止这一种,无法从根本上消除疾病;另一方面,产生这种炎症因子的通路不止这一条,因此会造成免疫抑制。所以,特异性针对NLRP3信号通路的抑制剂有望避免上述问题。目前,人们已经发现多个针对NLRP3信号通路的小分子。16673-34-0通过改变NLRP3蛋白的构象或抑制NLRP3与ASC的结合来抑制NLRP3炎症小体的形成;Bay 11-7082可抑制NLRP3的ATPase活性和ASC寡聚活性,此外还可抑制IKκB激酶从而抑制NF-κB通路的激活;β-羟基丁酸(BHB)通过抑制K+外排从而减少ASC的寡聚,抑制NLRP3炎症小体的形成,最终降低IL-1β和IL-18的产生;CY-09可与NLRP3作用,阻止其与ATP的结合,从而抑制炎症小体的形成;FC11A-2可抑制casepase-1的成熟,从而抑制IL-1β的生成;格列本脲可抑制ATP敏感的K+通道,同时抑制ASC的聚集;异甘草素通过抑制TLR4/MD-2复合物阻断NF-κB通路;JC124可降低NLRP3、ASC、caspase-1、pro-IL-1β的表达,抑制炎症小体的生成;MCC950是目前最高效的NLRP3抑制剂,可直接与NLRP3的NACHT结构域作用,阻断ATP水解而激活NLRP3,达到抑制炎症小体生成的目的;MNS可直接与NLRP3结合,抑制其ATP酶活性;小白菊内酯(Parthenolide)可直接作用于NLRP3的ATP酶结构域,同时抑制casepase-1的激活。尽管已有不少化合物能抑制NLRP3通路,但有些是针对通路中下游的信号分子,不止影响这一条通路,有些虽针对NLRP3本身,但同时有其它生物活性,副作用巨大,有些针对NLRP3本身且选择性很好,比如MCC950,但因为肝毒性而无法成为药物。因此,发现新颖的靶向NLRP3炎症小体的特异性抑制剂,对于治疗NLRP3炎症小体相关的疾病更有研究意义。
发明内容
针对现有问题的不足,本发明的目的是提供一种母核为吡啶并咪唑的化合物及其制备方法和应用。本发明涉及以吡啶并咪唑为母核的一类新型NLRP3炎症小体抑制剂的发现,此类化合物在抑制IL-1β的分泌和治疗由NLRP3炎症小体异常激活引起的相关疾病的应用;本发明还包括此类抑制剂的制备过程和新型抑制剂的药效团组成以及在抗炎领域的应用。
本发明解决其技术问题采用的技术方案是:
一种母核为吡啶并咪唑的化合物,结构如式Ⅰ所示:
式中,R1为C1~C30的烷基、芳基、杂芳基、C1~C30烷基芳基、C1~C30烷基杂芳基或C1~C12杂环;该C1~C12杂环被以下一个或多个相同或不同的取代基取代:C1~C30的烷基,烷氧基,烷氨基,酰胺基,硝基,卤素,苄基,腈基,氨基,羧基,羰基,三氟甲基;
R2为氢、C1~C30的烷基、芳基、杂芳基、C1~C30烷基芳基、C1~C30烷基杂芳基或C1~C12杂环;该C1~C12杂环被以下一个或多个相同或不同的取代基取代:C1~C30的烷基,烷氧基,烷氨基,酰胺基,硝基,卤素,苄基,腈基,氨基,羧基,羰基,三氟甲基。
优选:R3-R7中有一个或两个为烷基、烷氧基、卤素、氰基、羰基、羧基、酰基、磺酰基、氨基、硝基、羟基、酯基、三氟甲基,且其余为H;
进一步优选:R3为H或氟;R4为H、氟、甲基或硝基;R5为H、溴、氰基、硝基、三氟甲基、甲基或甲氧基;R6为H、氟或甲基,R7为H;
优选:Y1-Y3中有一个或两个为N,其余为CH,R8为H、烷基、烷氧基、卤素、氰基、羰基、羧基、酰基、磺酰基、氨基、硝基、羟基、酯基、三氟甲基;
进一步优选:Y1-Y3中有一个为N,其余为CH,R8为H、烷基、烷氧基、卤素、氰基、羰基、羧基、酰基、磺酰基、氨基、硝基、羟基、酯基、三氟甲基;
最优选:Y1-Y3中有一个为N,其余为CH,R8为H、F;
或:所述的R1为C1-C30烷基、卤代烷基、环烷基、卤代环烷基、杂环烷基;
优选:R1为C1-C10烷基、卤代烷基、环烷基、卤代环烷基、杂环烷基;
进一步优选:R1为C3-C6烷基、环烷基;
优选:Z1-Z2至多有一个为N,另外的为CH,R9-R10有且仅有一个为烷基、烷氧基、卤素、羰基、羧基、酰基、磺酰基、亚胺基、硝基、羟基、酯基,且另一个为H;
更优选的:Z1-Z2为CH,R9为H,R10为烷基、烷氧基、羰基、羧基、酰基、磺酰基、亚胺基、硝基、羟基、酯基;
最优选:Z1-Z2为CH,R9为H,R10为酰基、亚胺基;
在一些具体的技术方案中,所述的化合物结构式如下:
一种母核为吡啶并咪唑的化合物及其药学上可接受的盐,所述的化合物结构式如下:
一种母核为吡啶并咪唑的化合物的制备方法,包括如下步骤:
步骤1,化合物Ⅱ成环,得到化合物Ⅲ;
步骤2,将所述化合物Ⅲ在碱性条件下发生亲核取代反应,得到化合物Ⅳ;
步骤3,将所述化合物Ⅳ在碱性条件下发生亲核取代反应,得到化合物I;
式中,R1为C1~C30的烷基、芳基、杂芳基、C1~C30烷基芳基、C1~C30烷基杂芳基或C1~C12杂环;该C1~C12杂环被以下一个或多个相同或不同的取代基取代:C1~C30的烷基,烷氧基,烷氨基,酰胺基,硝基,卤素,苄基,腈基,氨基,羧基,羰基,三氟甲基;
R2为氢、C1~C30的烷基、芳基、杂芳基、C1~C30烷基芳基、C1~C30烷基杂芳基或C1~C12杂环;该C1~C12杂环被以下一个或多个相同或不同的取代基取代:C1~C30的烷基,烷氧基,烷氨基,酰胺基,硝基,卤素,苄基,腈基,氨基,羧基,羰基,三氟甲基。
作为本申请的优选技术方案,所述步骤1为:将化合物II与二硫化碳加入乙醇中,加热回流4h,得到化合物III;
一种药物组合物,包括:含有治疗有效量的前述的母核为吡啶并咪唑的化合物、药学上可接受的盐、水合物或溶剂合物及药学上可接受的载体。
本发明还保护上述母核为吡啶并咪唑的化合物或者其药学上可接受的盐,或者上述的药物组合物在制备NLRP3炎症小体抑制剂以及在制备治疗炎症相关疾病的药物中的应用。
作为本申请的优选技术方案,所述炎症相关疾病选自风湿性关节炎,类风湿性关节炎,炎性肠道疾病,痛风,动脉粥样硬化,非酒精性脂肪肝病,冷吡啉相关周期性综合征,慢性肾脏疾病,糖尿病和神经退行性疾病。
作为本申请的优选技术方案,所述神经退行性疾病选自帕金森症,多发性硬化症,阿尔兹海默症,亨廷顿病。
本发明还提供了以吡啶并咪唑的化合物在抑制促炎因子IL-1β释放中的应用。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
C1-C30烷基是指含有一个至十二个碳原子的直链或支链的烃链,可选地被C1-C30烷基取代;
取代是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀(Ca~Cb)烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,C1-C30烷基是指包含1~30个碳原子的烷基。
芳基表示芳基碳环基团,具有单一环、多个环或多个稠环,其中至少一个是芳族的,C1~C30的烷基,烷氧基,烷氨基,酰胺基,硝基,卤素,苄基,腈基,氨基,羧基,羰基,三氟甲基等单-、二-、三-、四-、五-取代。
杂芳基表示一个或多个5-、6-或7-元的芳香族环系,至少含有一个选自氮、氧或硫的杂原子,它们可以被卤素、硝基、三氟甲基、腈基、C1-C12烷基等单-、二-、三-、四-、五-取代。
C1-C30烷基芳基表示含有C1-C30的烷基与芳基相连,可选地被C1-C30烷基取代。
C1-C30烷基杂芳基表示含有C1-C30的烷基与杂芳基相连,可选地被C1-C30取代。
杂环是指稳定的含杂原子或杂原子团的单环、双环或三环,它们可以是饱和的,部分不饱和或者不饱和的。
烷氧基是指相应的醇少掉一个氢原子而成的基团。
卤素是指氟、氯、溴和碘。
本发明化合物指式I所示的化合物。该术语还包括式I化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物及药学上可接受的载体。
许多化合物可以与溶剂形成复合物,在这种溶剂中,它们进行反应,或它们从其中沉淀或结晶出来,这些复合物被称为“溶剂合物”。例如与水形成的复合物被称为水合物。
药物上可接受的载体是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质。
本发明所述的化合物可以添加药学上可接受的载体制成常见的药用制剂,如片剂,胶囊,粉剂,糖浆,悬浮剂,针剂,可以加入香料,甜味剂,液体或固体填料或稀释剂等常用药用辅料。
本发明所述的化合物在临床上的给药方式可以采用口服、注射等方式。
“治疗有效量”或“有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。
本发明达到的有益效果:
本发明提供了一种吡啶并咪唑为母核的化合物。此类化合物结构新颖,制备方法简单,通过特异性抑制NLRP3炎症小体的活化,对白介素IL-1β的释放具有显著的抑制活性,从而减轻炎性损伤,改善炎症微环境,具有潜在的抗炎活性,同时对THP-1细胞无明显毒性。可用于制备成抗炎药物,并用于许多炎症相关疾病的炎性损伤,这些疾病包括冷吡啉相关周期性综合征,炎性肠道疾病,慢性阻滞性肺部疾病,糖尿病,风湿性关节炎,类风湿性关节炎,痛风,非酒精性脂肪肝病,慢性肾脏疾病,动脉粥样硬化,神经退行性疾病如阿尔兹海默症,帕金森症,亨廷顿病,多发性硬化症。
附图说明
图1为实施例45所得化合物Ⅰ-20的免疫印迹试验(Western Blot)试验结果。
具体实施方式
下面通过具体实施方式对本发明做进一步详细说明,但是并不是对本发明的限制,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。所用试剂或者仪器设备未注明生产厂商的,均视为可以通过市场购买的常规产品。
仪器和试剂:熔点采用WRS-2微机熔点仪测定,薄层色谱用硅胶GF254购于阿拉丁试剂公司(aladdin,上海晶纯生化科技股份有限公司);柱色谱用硅胶FCP(200~300目)购于国药集团化学试剂有限公司;其他所用试剂和溶剂均为国产分析纯,根据需要经无水干燥处理后使用。
实施例1合成化合物III
称量3,4-二氨基吡啶(8g,0.0733mol)于反应瓶,向其依次加入无水乙醇60ml,二硫化碳(15.9ml,0.264mol),80℃回流反应4h后,TLC监测原料消失。将反应液冷却至室温,抽滤,用乙酸乙酯洗涤滤饼,干燥后得米白色固体10.2g,收率:92.0%。1H NMR(300MHz,DMSO-d6)δ12.87(s,2H),8.37(d,J=1.0Hz,1H),8.23(d,J=5.4Hz,1H),7.16(dd,J=5.4,1.0Hz,1H).
实施例2合成化合物IV-1
2-(苄基硫)-3-氢-咪唑并[4,5-c]吡啶(IV-1)
称量化合物III(500mg,3.31mmol)于反应瓶,向其依次加入N,N-二甲基甲酰胺5ml,无水碳酸钠(701.04mg,6.61mmol),40℃加热反应1h后,缓慢滴加溴苄(412μl,3.47mmol),继续反应4h,TLC监测原料消失。将反应液冷却至室温,倒入分液漏斗,加大量水稀释,用正丁醇萃取,饱和氯化钠洗涤,无水硫酸钠干燥后,减压浓缩除去溶剂,用二氯甲烷/甲醇柱层析分离纯化,得到白色固体519.6mg,收率:65.11%。
2-(苄基硫)-3-氢-咪唑并[4,5-c]吡啶(IV-1).白色固体,收率:65.11%。1H NMR(300MHz,DMSO-d6)δ8.75(s,1H),8.17(d,J=5.7Hz,1H),7.50–7.42(m,3H),7.34–7.19(m,3H),4.60(s,2H).
实施例3合成化合物IV-2
2-((2-氟苄基)硫代)-3-氢-咪唑并[4,5-c]吡啶(IV-2).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),2-氟溴苄(419μl,3.47mmol)为原料,得到白色固体527.6mg,收率61.52%。1H NMR(300MHz,DMSO-d6)δ13.18(s,1H),8.77(s,1H),8.18(d,J=5.7Hz,1H),7.58(td,J=7.7,1.8Hz,1H),7.50(d,J=4.9Hz,1H),7.39–7.29(m,1H),7.27–7.18(m,1H),7.15(td,J=7.4,1.3Hz,1H),4.64(s,2H).
实施例4合成化合物IV-3
2-((3-氟苄基)硫代)-3-氢-咪唑并[4,5-c]吡啶(IV-3).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),3-氟溴苄(426μl,3.47mmol)为原料,得到白色固体543.5mg,收率63.38%。1H NMR(300MHz,DMSO-d6)δ8.77(d,J=0.9Hz,1H),8.17(d,J=5.7Hz,1H),7.47(dd,J=5.7,0.9Hz,1H),7.35–7.26(m,3H),7.09–7.00(m,1H),4.61(s,2H).
实施例5合成化合物IV-4
2-((4-氟苄基)硫代)-3-氢-咪唑并[4,5-c]吡啶(IV-4).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),4-氟溴苄(418.89μl,3.47mmol)为原料,得到白色固体527.6mg,收率61.52%。1H NMR(300MHz,DMSO-d6)δ13.10(s,1H),8.74(s,1H),8.16(d,J=5.7Hz,1H),7.54–7.47(m,2H),7.46(d,J=5.8Hz,1H),7.17–7.08(m,2H),4.58(s,2H).
实施例6合成化合物IV-5
2-((4-氯苄基)硫代)-3-氢-咪唑并[4,5-c]吡啶(IV-5).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),4-氯溴苄(454μl,3.47mmol)为原料,得到白色固体461.7mg,收率50.6%。1H NMR(300MHz,DMSO-d6)δ8.75(s,1H),8.18(d,J=5.7Hz,1H),7.54–7.46(m,3H),7.38(d,J=8.5Hz,2H),4.60(s,2H).
实施例7合成化合物IV-6
2-((4-溴苯基)硫代)-3-氢-咪唑[4,5-c]吡啶(IV-6).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),4-溴溴苄(475μl,3.47mmol)为原料,得到白色固体639.4mg,收率60.38%。1H NMR(300MHz,DMSO-d6)δ8.75(s,1H),8.18(d,J=5.7Hz,1H),7.54–7.41(m,5H),4.58(s,2H).
实施例8合成化合物IV-7
4-((3-氢-咪唑[4,5-c]吡啶-2-基)硫代)甲基)苯甲腈(IV-7).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),4-氰基溴苄(440μl,3.47mmol)为原料,得到白色固体598.3mg,收率67.93%。1H NMR(300MHz,DMSO-d6)δ8.73(s,1H),8.15(d,J=5.8Hz,1H),7.76(d,J=8.2Hz,2H),7.66(d,J=8.1Hz,2H),7.46(d,J=5.7Hz,1H),4.66(s,2H).
实施例9合成化合物IV-8
2-((4-硝基苄基)硫代)-3-氢-咪唑并[4,5-c]吡啶(IV-8).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),4-硝基溴苄(454μl,3.47mmol)为原料,得到黄色固体611.2mg,收率64.55%。1H NMR(300MHz,DMSO-d6)δ8.72(s,1H),8.19–8.10(m,3H),7.74(d,J=8.7Hz,2H),7.47(d,J=5.8Hz,1H),4.71(s,2H).
实施例10合成化合物IV-9
2-((4-(三氟甲基)苄基)硫代)-3-氢-咪唑[4,5-c]吡啶(IV-9).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),4-三氟甲基溴苄(537μl,3.47mmol)为原料,得到白色固体652.3mg,收率63.77%。1H NMR(300MHz,DMSO-d6)δ8.73(d,J=0.9Hz,1H),8.15(d,J=5.8Hz,1H),7.72–7.62(m,4H),7.47(dd,J=5.8,0.9Hz,1H),4.67(s,2H).
实施例11合成化合物IV-10
2-((4-甲基苄基)硫代)-3-氢-咪唑并[4,5-c]吡啶(IV-10).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),4-甲基溴苄(485μl,3.47mmol)为原料,得到白色固体609.5mg,收率72.18%。1H NMR(300MHz,DMSO-d6)δ8.74(d,J=0.9Hz,1H),8.17(d,J=5.7Hz,1H),7.45(dd,J=5.6,1.0Hz,1H),7.33(d,J=8.1Hz,2H),7.10(d,J=7.8Hz,2H),4.55(s,2H),2.24(s,3H).
实施例12合成化合物IV-11
2-((4-甲氧基苄基)硫代)-3-氢-咪唑[4,5-c]吡啶(IV-11).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),4-甲氧基溴苄(506μl,3.47mmol)为原料,得到白色固体589.7mg,收率65.72%。1H NMR(300MHz,DMSO-d6)δ8.76(s,1H),8.18(d,J=5.6Hz,1H),7.46(dd,J=5.7,1.0Hz,1H),7.37(d,J=8.6Hz,2H),6.85(d,J=8.7Hz,2H),4.54(s,2H),3.69(s,3H).
实施例13合成化合物IV-12
2-((3-甲基苄基)硫代)-3-氢-咪唑并[4,5-c]吡啶(IV-12).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),3-甲基溴苄(469μl,3.47mmol)为原料,得到白色固体577.4mg,收率68.38%。1H NMR(300MHz,DMSO-d6)δ13.07(s,1H),8.74(s,1H),8.17(d,J=5.7Hz,1H),7.45(d,J=5.7Hz,1H),7.28–7.14(m,3H),7.06(d,J=7.2Hz,1H),4.55(s,2H),2.26(s,3H).
实施例14合成化合物IV-13
2-((3-硝基苄基)硫代)-3-氢-咪唑并[4,5-c]吡啶(IV-13).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),3-硝基溴苄(445μl,3.47mmol)为原料,得到黄色固体632.7mg,收率66.82%。1H NMR(300MHz,DMSO-d6)δ8.74(d,J=0.9Hz,1H),8.37(t,J=2.0Hz,1H),8.14(d,J=5.8Hz,1H),8.04(ddd,J=8.3,2.4,1.1Hz,1H),7.91(dt,J=7.8,1.3Hz,1H),7.54(t,J=8.0Hz,1H),7.47(dd,J=5.8,0.9Hz,1H),4.70(s,2H).
实施例15合成化合物IV-14
2-((3,5-二氟苄基)硫代)-3-氢-咪唑[4,5-c]吡啶(IV-14).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),3,5-二氟溴苄(449μl,3.47mmol)为原料,得到白色固体601.8mg,收率65.62%。1H NMR(300MHz,DMSO-d6)δ8.76(d,J=0.9Hz,1H),8.17(d,J=5.8Hz,1H),7.50(dd,J=5.8,0.9Hz,1H),7.28–7.17(m,2H),7.10(tt,J=9.5,2.4Hz,1H),4.61(s,2H).
实施例16合成化合物IV-15
2-((3,5-二甲基苄基)硫代)-3-氢-咪唑[4,5-c]吡啶(IV-15).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),3,5-二甲基溴苄(534μl,3.47mmol)为原料,得到白色固体587.7mg,收率65.97%。1H NMR(300MHz,DMSO-d6)δ8.77(d,J=1.0Hz,1H),8.19(d,J=5.6Hz,1H),7.48(dd,J=5.6,1.0Hz,1H),7.06(s,2H),6.88(s,1H),4.53(s,2H),2.22(s,6H).
实施例17合成化合物IV-16
2-((6-氟吡啶-3-基)甲基)硫代)-3-氢-咪唑[4,5-c]吡啶(IV-16).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),5-溴甲基-2-氟吡啶氢溴酸盐(941mg,3.47mmol)为原料,得到紫红色固体324.5mg,收率37.70%。1HNMR(300MHz,DMSO-d6)δ8.73(s,1H),8.34(d,J=2.5Hz,1H),8.19–8.05(m,2H),7.47(d,J=5.8Hz,1H),7.12(dd,J=8.5,2.9Hz,1H),4.59(s,2H).
实施例18合成化合物IV-17
2-((吡啶-4-基甲基)硫代)-3-氢-咪唑[4,5-c]吡啶(IV-17).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),4-溴甲基吡啶氢溴酸盐(878mg,3.47mmol)为原料,得到紫红色固体304.6mg,收率38.01%。1H NMR(300MHz,DMSO-d6)δ8.73(d,J=0.9Hz,1H),8.52–8.46(m,2H),8.15(d,J=5.8Hz,1H),7.50–7.45(m,3H),4.60(s,2H).
实施例19合成化合物IV-18
2-((吡啶-3-基甲基)硫代)-3-氢-咪唑[4,5-c]吡啶(IV-18).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),3-溴甲基吡啶氢溴酸盐(878mg,3.47mmol)为原料,得到紫红色固体298.3mg,收率37.23%。
实施例20合成化合物IV-19
2-((吡啶-2-基甲基)硫代)-3-氢-咪唑[4,5-c]吡啶(IV-19).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),2-溴甲基吡啶氢溴酸盐(878mg,3.47mmol)为原料,得到紫红色固体337.1mg,收率42.07%。
实施例21合成化合物IV-20
2-((环己基甲基)硫代)-3-氢-咪唑并[4,5-c]吡啶(IV-20).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),溴甲基环己烷(485μl,3.47mmol)为原料,得到白色固体703.7mg,收率86.02%。1H NMR(300MHz,DMSO-d6)δ8.72(s,1H),8.18(d,J=5.6Hz,1H),7.44(d,J=5.6Hz,1H),3.24(d,J=6.8Hz,2H),1.84(d,J=12.5Hz,2H),1.73–1.56(m,4H),1.26–0.98(m,5H).
实施例22合成化合物IV-21
2-((环戊基甲基)硫代)-3-氢-咪唑并[4,5-c]吡啶(IV-21).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),溴甲基环戊烷(445μl,3.47mmol)为原料,得到白色固体534.1mg,收率69.21%。1H NMR(300MHz,DMSO-d6)δ12.98(s,1H),8.72(s,1H),8.18(d,J=5.6Hz,1H),7.43(d,J=5.6Hz,1H),2.25(hept,J=7.5Hz,1H),1.86–1.75(m,2H),1.68–1.45(m,5H),1.37–1.21(m,3H).
实施例23合成化合物IV-22
2-((环丁基甲基)硫代)-3-氢-咪唑并[4,5-c]吡啶(IV-22).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),溴甲基环丁烷(407μl,3.47mmol)为原料,得到白色固体550.9mg,收率75.96%。1H NMR(300MHz,DMSO-d6)δ12.98(s,1H),8.73(s,2H),8.18(d,J=5.6Hz,2H),7.44(d,J=5.6Hz,2H),3.39(d,J=7.6Hz,7H),2.67(hept,J=7.9Hz,2H),2.13–1.98(m,5H),1.87–1.69(m,9H).
实施例24合成化合物IV-23
2-((环丙基甲基)硫代)-3-氢-咪唑并[4,5-c]吡啶(IV-23).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),溴甲基环丙烷(337μl,3.47mmol)为原料,得到白色固体516.2mg,收率76.04%。1H NMR(300MHz,DMSO-d6)δ12.97(s,1H),8.70(s,2H),8.17(d,J=5.6Hz,2H),7.42(d,J=5.6Hz,2H),3.26(d,J=7.2Hz,4H),1.26–1.17(m,2H),0.58–0.51(m,4H),0.36–0.28(m,4H).
实施例25合成化合物IV-24
2-((3-甲基-2-烯-1-基)硫代)-3-氢-咪唑[4,5-c]吡啶(IV-24).合成方法与实施例2相同,以化合物III(500mg,3.31mmol),无水碳酸钠(701.04mg,6.61mmol),1-溴-3-甲基-2-丁烯(401μl,3.47mmol)为原料,得到白色固体537.8mg,收率74.15%。1H NMR(300MHz,DMSO-d6)δ8.71(s,1H),8.17(d,J=5.6Hz,1H),7.43(d,J=5.6Hz,1H),5.39(tt,J=8.0,1.6Hz,1H),3.96(d,J=7.8Hz,2H),1.69(d,J=4.8Hz,6H).
实施例26合成化合物I-1
4-((2-(苄基硫基)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)-N-(3-甲氧基丙基)苯甲酰胺(I-1)
以I-1为例,称量化合物IV-1(400mg,1.66mmol)于反应瓶,向其依次加入N,N-二甲基甲酰胺5ml,氢化钠(60%,69.61mg,1.74mmol),室温反应0.5h后,缓慢加入4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(474.36mg,1.66mmol),继续反应4h,TLC监测原料消失。将反应液冷却至室温,倒入分液漏斗,加大量水稀释,正丁醇萃取,饱和氯化钠洗涤,无水硫酸钠干燥后,减压浓缩除去溶剂。用二氯甲烷/甲醇柱层析分离纯化,得到白色固体418.7mg,收率56.56%。
4-((2-(苄基硫基)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)-N-(3-甲氧基丙基)苯甲酰胺(I-1).白色固体,收率56.56%。m.p.131.3-132.1℃.1H NMR(300MHz,DMSO-d6)δ8.95(d,J=1.5Hz,1H),8.52(t,J=5.6Hz,1H),8.18(dd,J=6.8,1.6Hz,1H),7.87(d,J=8.3Hz,2H),7.59(d,J=6.8Hz,1H),7.53–7.45(m,4H),7.34–7.20(m,3H),5.69(s,2H),4.58(s,2H),3.39–3.27(m,4H),3.23(s,3H),1.76(p,J=6.6Hz,2H).13C NMR(75MHz,DMSO)δ173.33,166.18,156.45,145.68,139.73,139.20,135.21,131.73,129.28,129.15,128.83,128.25,128.21,127.41,110.74,70.16,61.11,58.36,37.05,35.20,29.66.HRMS(ESI)calcd forC25H26N4O2S[M+H]+447.1849,found 447.1855.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=11.34min,>99.15%.
实施例27合成化合物I-2
4-((2-((2-氟苄基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)-N-(3-甲氧基丙基)苯甲酰胺(I-2).合成方法与实施例26相同,以化合物Ⅳ-2(400mg,1.54mmol),氢化钠(64.78mg,1.62mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(441.44mg,1.54mmol)为原料,得到白色固体348.6mg,收率48.64%。m.p.177.4-177.1℃.1H NMR(300MHz,DMSO-d6)δ8.96(d,J=1.5Hz,1H),8.50(t,J=5.6Hz,1H),8.18(dd,J=6.8,1.6Hz,1H),7.86(d,J=8.3Hz,2H),7.71–7.66(m,1H),7.59(d,J=6.8Hz,1H),7.53–7.45(m,3H),7.33–7.23(m,2H),5.69(s,2H),4.67(s,2H),3.33(dt,J=20.1,6.8Hz,4H),3.23(s,3H),1.75(p,J=6.6Hz,2H).13C NMR(75MHz,DMSO)δ172.76,166.13,156.44,145.65,139.72,136.46,135.22,133.70,131.78,131.61,129.81,129.50,129.32,128.24,128.21,127.73,110.84,70.16,61.12,58.37,37.04,33.18,29.67.HRMS(ESI)calcd for C25H25FN4O2S[M+H]+465.1755,found 465.1751.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=13.21min,>97.64%.
实施例28合成化合物I-3
4-((2-((3-氟苄基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)-N-(3-甲氧基丙基)苯甲酰胺(I-3).合成方法与实施例26相同,以化合物Ⅳ-3(400mg,1.54mmol),氢化钠(64.78mg,1.62mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(441.44mg,1.54mmol)为原料,得到白色固体377.1mg,收率52.62%。m.p.147.6-148.1℃.1H NMR(300MHz,DMSO-d6)δ8.98(d,J=1.5Hz,1H),8.52(t,J=5.6Hz,1H),8.19(dd,J=6.8,1.6Hz,1H),7.88(d,J=8.4Hz,2H),7.61(d,J=6.7Hz,1H),7.52(d,J=8.3Hz,2H),7.38–7.30(m,3H),7.12–7.02(m,1H),5.70(s,2H),4.60(s,2H),3.40–3.28(m,4H),3.23(s,3H),1.76(p,J=6.6Hz,2H).13C NMR(75MHz,DMSO)δ172.97,166.16,164.07,160.85,156.46,145.68,142.54,142.44,139.71,135.23,131.77,130.74,130.62,129.29,128.25,128.21,125.38,125.34,116.09,115.81,114.32,114.04,110.82,70.16,61.12,58.35,37.05,34.52,29.67.HRMS(ESI)calcd for C25H25FN4O2S[M+H]+465.1755,found 465.1761.HPLC(20%–60%acetonitrilein water,with 0.1%TFA),tR=11.85min,>99.29%.
实施例29合成化合物I-4
4-((2-((4-氟苄基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)-N-(3-甲氧基丙基)苯甲酰胺(I-4).合成方法与实施例26相同,以化合物Ⅳ-4(400mg,1.54mmol),氢化钠(64.78mg,1.62mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(441.44mg,1.54mmol)为原料,得到白色固体359.6mg,收率50.18%。m.p.171.8-173.2℃.1H NMR(300MHz,DMSO-d6)δ8.98(d,J=1.5Hz,1H),8.52(t,J=5.6Hz,1H),8.19(dd,J=6.8,1.6Hz,1H),7.88(d,J=8.4Hz,2H),7.61(d,J=6.7Hz,1H),7.52(d,J=8.3Hz,2H),7.38–7.30(m,3H),7.12–7.02(m,1H),5.70(s,2H),4.60(s,2H),3.40–3.28(m,4H),3.23(s,3H),1.76(p,J=6.6Hz,2H).13C NMR(75MHz,DMSO)δ172.97,166.16,164.07,160.85,156.46,145.68,142.54,142.44,139.71,135.23,131.77,130.74,130.62,129.29,128.25,128.21,125.38,125.34,116.09,115.81,114.32,114.04,110.82,70.16,61.12,58.35,37.05,34.52,29.67.HRMS(ESI)calcd for C25H25FN4O2S[M+H]+465.1755,found 465.1761.HPLC(20%–60%acetonitrilein water,with 0.1%TFA),tR=18.05min,>99.41%.
实施例30合成化合物I-5
4-((2-((4-氯苄基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)-N-(3-甲氧基丙基)苯甲酰胺(I-5).合成方法与实施例26相同,以化合物Ⅳ-5(400mg,1.45mmol),氢化钠(60.92mg,1.52mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(415.11mg,1.45mmol)为原料,得到白色固体406.3mg,收率58.23%。m.p.150.0-151.0℃1H NMR(300MHz,DMSO-d6)δ8.91(d,J=1.5Hz,1H),8.45(s,1H),8.15(dd,J=6.8,1.6Hz,1H),7.82(d,J=8.3Hz,2H),7.55(d,J=6.7Hz,1H),7.49(t,J=8.5Hz,4H),7.10(s,2H),5.65(s,2H),4.52(s,2H),3.21(s,3H),1.71(s,2H).13C NMR(75MHz,DMSO)δ172.95,166.14,156.40,145.64,139.71,138.63,135.22,131.98,131.79,131.09,129.27,128.74,128.25,128.22,110.80,70.16,61.12,58.36,37.04,34.31,29.66.HRMS(ESI)calcd for C25H25ClN4O2S[M+H]+481.1460,found 481.1465.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=13.50min,>97.31%.
实施例31合成化合物I-6
4-((2-((4-溴苯基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)-N-(3-甲氧基丙基)苯甲酰胺(I-6).合成方法与实施例26相同,以化合物Ⅳ-6(400mg,1.25mmol),氢化钠(52.46mg,1.31mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(357.48mg,1.25mmol)为原料,得到白色固体377.5mg,收率57.51%。m.p.155.4-156.6℃1H NMR(300MHz,DMSO-d6)δ8.97(d,J=1.5Hz,1H),8.55(t,J=5.6Hz,1H),8.20(dd,J=6.8,1.6Hz,1H),7.90(d,J=8.3Hz,2H),7.61(d,J=6.7Hz,1H),7.55–7.43(m,6H),5.71(s,2H),4.56(s,2H),3.41–3.29(m,4H),3.24(s,3H),1.77(p,J=6.6Hz,2H).13C NMR(75MHz,DMSO)δ173.00,166.16,156.46,145.69,139.70,139.07,135.23,131.75,131.65,131.45,129.24,128.26,128.22,120.48,110.81,70.17,61.13,58.37,37.06,34.38,29.68.HRMS(ESI)calcd forC25H25BrN4O2S[M+H]+525.0954,found 525.0956.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=11.051min,>99.99%.
实施例32合成化合物I-7
4-((2-((4-氰基苯)硫基)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)-N-(3-甲氧基丙基)苯甲酰胺(I-7).合成方法与实施例26相同,以化合物Ⅳ-7(400mg,1.50mmol),氢化钠(63.08mg,1.58mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(429.81mg,1.50mmol)为原料,得到白色固体413.6mg,收率58.39%。m.p.168.2-169.2℃1H NMR(300MHz,DMSO-d6)δ8.96(d,J=1.5Hz,1H),8.50(t,J=5.6Hz,1H),8.19(dd,J=6.8,1.6Hz,1H),7.87(d,J=8.3Hz,2H),7.77(d,J=8.4Hz,2H),7.69(d,J=8.4Hz,2H),7.59(d,J=6.7Hz,1H),7.51(d,J=8.3Hz,2H),5.69(s,2H),4.64(s,2H),3.39–3.26(m,4H),3.23(s,3H),1.75(p,J=6.6Hz,2H).13C NMR(75MHz,DMSO)δ172.61,166.13,156.45,145.80,145.65,139.69,135.22,132.71,131.80,130.20,129.38,128.24,119.32,110.89,110.08,70.16,61.12,58.36,37.04,34.61,29.66.HRMS(ESI)calcd for C26H25N5O2S[M+H]+472.1802,found472.1808.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=10.12min,>99.23%.
实施例33合成化合物I-8
N-(3-甲氧基丙基)-4-((2-((4-硝基苄基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)苯甲酰胺(I-8).合成方法与实施例26相同,以化合物Ⅳ-8(400mg,1.47mmol),氢化钠(61.91mg,1.55mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(421.86mg,1.47mmol)为原料,得到淡黄色固体405.6mg,收率57.73%。m.p.161.9-163.0℃1H NMR(300MHz,DMSO-d6)δ8.97(d,J=1.5Hz,1H),8.51(t,J=5.7Hz,1H),8.23–8.13(m,3H),7.87(d,J=8.3Hz,2H),7.77(d,J=8.7Hz,2H),7.60(d,J=6.7Hz,1H),7.51(d,J=8.2Hz,2H),5.70(s,2H),4.70(s,2H),3.39–3.27(m,4H),3.23(s,3H),1.76(p,J=6.6Hz,2H).13C NMR(75MHz,DMSO)δ172.50,166.12,156.46,148.03,146.85,145.66,139.68,135.22,131.81,130.41,129.41,128.23,123.92,110.91,70.16,61.13,58.36,37.04,34.33,29.66.HRMS(ESI)calcd forC25H25N5O4S[M+H]+492.1700,found 492.1697.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=12.59min,>99.27%.
实施例34合成化合物I-9
N-(3-甲氧基丙基)-4-((2-((4-(三氟甲基)苄基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)苯甲酰胺(I-9).合成方法与实施例26相同,以化合物Ⅳ-9(400mg,1.29mmol),氢化钠(54.31mg,1.36mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(370.07mg,1.29mmol)为原料,得到白色固体379.4mg,收率57.02%。m.p.132.9-134.1℃1H NMR(300MHz,DMSO-d6)δ8.97(d,J=1.6Hz,1H),8.52(t,J=5.6Hz,1H),8.20(dd,J=6.8,1.6Hz,1H),7.91–7.83(m,2H),7.76–7.63(m,4H),7.60(d,J=6.7Hz,1H),7.55–7.48(m,2H),5.70(s,2H),4.66(s,2H),3.40–3.28(m,4H),3.23(s,3H),1.76(p,J=6.6Hz,2H).13CNMR(75MHz,DMSO)δ172.77,166.13,156.47,145.68,144.66,144.64,139.70,135.23,131.78,129.98,129.34,128.24,128.22,127.77,126.55,125.71,125.66,125.61,125.56,122.95,110.86,70.16,61.12,58.34,37.04,34.48,29.66.HRMS(ESI)calcd forC26H25F3N4O2S[M+H]+515.1723,found 515.1724.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=11.74min,>99.28%.
实施例35合成化合物I-10
N-(3-甲氧基丙基)-4-((2-((4-甲基苄基)硫代)-3-氢-咪唑并[4,5-c]吡啶-3-基)甲基)苯甲酰胺(I-10).合成方法与实施例26相同,以化合物Ⅳ-10(400mg,1.57mmol),氢化钠(65.79mg,1.64mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(448.30mg,1.57mmol)为原料,得到白色固体388.3mg,收率53.82%。m.p.152.7-152.8℃1H NMR(300MHz,DMSO-d6)δ8.93(d,J=1.5Hz,1H),8.49(t,J=5.6Hz,1H),8.16(dd,J=6.8,1.6Hz,1H),7.85(d,J=8.4Hz,2H),7.56(d,J=6.8Hz,1H),7.49(d,J=8.3Hz,2H),7.34(d,J=8.1Hz,2H),7.10(d,J=7.6Hz,2H),5.67(s,2H),4.51(s,2H),3.37–3.25(m,4H),3.22(s,3H),2.26(s,3H),1.74(p,J=6.7Hz,2H).13C NMR(75MHz,DMSO)δ173.43,166.12,156.43,145.68,139.76,136.54,136.02,135.20,131.69,129.39,129.28,129.19,129.09,128.23,128.20,110.69,70.16,61.06,58.37,37.03,34.98,29.66,21.15.HRMS(ESI)calcdfor C26H28N4O2S[M+H]+461.2006,found 461.2004.HPLC(20%–60%acetonitrile inwater,with 0.1%TFA),tR=20.68min,>99.99%.
实施例36合成化合物I-11
4-((2-((4-甲氧基苄基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)-N-(3-甲氧基丙基)苯甲酰胺(I-11).合成方法与实施例26相同,以化合物Ⅳ-11(400mg,1.47mmol),氢化钠(61.91mg,1.55mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(421.86mg,1.47mmol)为原料,得到白色固体376.5mg,收率53.59%。m.p.144.2-144.4℃1H NMR(300MHz,DMSO-d6)δ8.93(d,J=1.5Hz,1H),8.53(t,J=5.6Hz,1H),8.16(dd,J=6.8,1.5Hz,1H),7.91–7.83(m,2H),7.58(d,J=6.7Hz,1H),7.50(d,J=8.3Hz,2H),7.39(d,J=8.6Hz,2H),6.85(d,J=8.7Hz,2H),5.68(s,2H),4.52(s,2H),3.71(s,3H),3.38–3.27(m,4H),3.21(s,3H),1.75(p,J=6.6Hz,2H).13C NMR(75MHz,DMSO)δ173.55,166.21,158.76,156.44,145.70,139.73,135.22,131.72,130.90,130.45,129.07,128.26,128.20,114.23,110.69,70.17,61.12,58.35,55.47,37.07,34.74,29.66.HRMS(ESI)calcd for C26H28N4O3S[M+H]+477.1955,found 477.1953.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=11.49min,>99.21%.
实施例37合成化合物I-12
N-(3-甲氧基丙基)-4-((2-((3-甲基苄基)硫代)-3-氢-咪唑并[4,5-c]吡啶-3-基)甲基)苯甲酰胺(I-12).合成方法与实施例26相同,以化合物Ⅳ-12(400mg,1.57mmol),氢化钠(65.79mg,1.64mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(448.3mg,1.57mmol)为原料,得到白色固体401.8mg,收率55.69%。m.p.130.6-131.7℃1H NMR(300MHz,DMSO-d6)δ8.93(d,J=1.6Hz,1H),8.47(t,J=5.6Hz,1H),8.16(dd,J=6.7,1.6Hz,1H),7.84(d,J=8.3Hz,2H),7.57(d,J=6.7Hz,1H),7.49(d,J=8.2Hz,2H),7.25(d,J=7.7Hz,2H),7.18(t,J=7.9Hz,1H),7.04(d,J=7.4Hz,1H),5.67(s,2H),4.52(s,2H),3.36–3.24(m,4H),3.22(s,3H),2.27(s,3H),1.74(p,J=6.6Hz,2H).13C NMR(75MHz,DMSO)δ173.39,166.15,156.45,145.69,139.78,138.92,137.96,135.22,131.74,129.89,129.16,128.78,128.25,128.22,128.11,126.41,110.74,70.17,61.10,58.39,37.03,35.24,29.67,21.44.HRMS(ESI)calcd for C26H28N4O2S[M+H]+461.2006,found 461.2002.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=13.32min,>97.13%.
实施例38合成化合物I-13
N-(3-甲氧基丙基)-4-((2-((3-硝基苄基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)苯甲酰胺(I-13).合成方法与实施例26相同,以化合物Ⅳ-13(400mg,1.40mmol),氢化钠(58.67mg,1.47mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(399.80mg,1.40mmol)为原料,得到淡黄色固体397.1mg,收率58.72%。m.p.170.8-171.3℃1H NMR(300MHz,DMSO-d6)δ8.99(d,J=1.6Hz,1H),8.49(t,J=5.6Hz,1H),8.41(t,J=2.0Hz,1H),8.21(dd,J=6.8,1.6Hz,1H),8.11(ddd,J=8.3,2.4,1.1Hz,1H),7.97(dt,J=7.7,1.3Hz,1H),7.87(d,J=8.3Hz,2H),7.65–7.57(m,2H),7.52(d,J=8.2Hz,2H),5.71(s,2H),4.70(s,2H),3.38–3.27(m,4H),3.25(s,3H),1.76(p,J=6.6Hz,2H).13C NMR(75MHz,DMSO)δ172.47,166.12,156.34,148.11,145.58,142.33,139.68,136.05,135.23,130.26,129.51,128.24,123.85,122.36,110.96,70.16,61.14,58.37,37.02,34.12,29.65.HRMS(ESI)calcd forC25H25N5O4S[M+H]+492.1700,found 492.1696.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=11.51min,>96.62%.
实施例39合成化合物I-14
4-((2-((3,5-二氟苄基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)-N-(3-甲氧基丙基)苯甲酰胺(I-14).合成方法与实施例26相同,以化合物Ⅳ-14(400mg,1.44mmol),氢化钠(60.58mg,1.51mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(412.80mg,1.44mmol)为原料,得到白色固体389.7mg,收率55.98%。m.p.146.1-146.6℃1H NMR(300MHz,DMSO-d6)δ8.95(d,J=1.6Hz,1H),8.47(t,J=5.6Hz,1H),8.16(dd,J=6.8,1.6Hz,1H),7.84(d,J=8.4Hz,2H),7.57(d,J=6.7Hz,1H),7.48(d,J=8.2Hz,2H),7.26–7.17(m,2H),7.06(tt,J=9.4,2.4Hz,1H),5.67(s,2H),4.55(s,2H),3.36–3.25(m,4H),3.20(s,3H),1.73(p,J=6.6Hz,2H).13C NMR(75MHz,DMSO)δ172.62,166.16,164.32,164.15,161.07,160.89,156.45,145.65,144.48,144.36,139.70,135.24,131.82,129.44,128.26,128.23,112.52,112.29,112.19,110.90,103.20,102.86,102.52,70.16,61.13,58.35,37.04,34.20,29.66.HRMS(ESI)calcd for C25H24F2N4O2S[M+H]+483.1661,found 483.1659.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=12.38min,>97.79%.
实施例40合成化合物I-15
4-((2-((3,5-二甲基苄基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)-N-(3-甲氧基丙基)苯甲酰胺(I-15).合成方法与实施例26相同,以化合物Ⅳ-15(400mg,1.48mmol),氢化钠(62.36mg,1.48mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(424.95mg,1.48mmol)为原料,得到白色固体411.2mg,收率58.34%。m.p.170.7-170.9℃1H NMR(300MHz,DMSO-d6)δ8.96(d,J=1.5Hz,1H),8.52(t,J=5.6Hz,1H),8.18(dd,J=6.7,1.6Hz,1H),7.89(d,J=8.3Hz,2H),7.60(d,J=6.8Hz,1H),7.52(d,J=8.2Hz,2H),7.08(s,2H),6.88(s,1H),5.70(s,2H),4.52(s,2H),3.41–3.29(m,4H),3.25(s,3H),2.25(s,6H),1.77(p,J=6.6Hz,2H).13C NMR(75MHz,DMSO)δ173.52,166.15,156.48,145.73,139.76,138.61,137.83,135.22,131.69,129.10,128.91,128.25,128.19,127.04,110.70,70.17,61.09,58.37,37.05,35.30,29.68,21.32.HRMS(ESI)calcd for C27H30N4O2S[M+H]+475.2162,found 475.2159.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=14.79min,>98.62%.
实施例41合成化合物I-16
4-((2-((6-氟吡啶-3-基)甲基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)-N-(3-甲氧基丙基)苯甲酰胺(I-16).合成方法与实施例26相同,以化合物Ⅳ-16(400mg,1.54mmol),氢化钠(64.54mg,1.61mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(439.77mg,1.54mmol)为原料,得到淡黄色固体314.2mg,收率43.92%。m.p.178.8-180.3℃1H NMR(300MHz,DMSO-d6)δ8.96(d,J=1.5Hz,1H),8.49(t,J=5.6Hz,1H),8.36(d,J=2.9Hz,1H),8.18(dd,J=6.8,1.6Hz,1H),8.10(td,J=8.2,2.6Hz,1H),7.85(d,J=8.3Hz,2H),7.59(d,J=6.8Hz,1H),7.50(d,J=8.4Hz,2H),7.12(ddd,J=8.4,2.9,0.6Hz,1H),5.68(s,2H),4.56(s,2H),3.37–3.26(m,4H),3.23(s,3H),1.74(p,J=6.6Hz,2H).13C NMR(75MHz,DMSO)δ172.53,166.12,164.04,160.93,156.39,147.92,147.72,145.61,142.97,142.86,139.70,135.22,134.03,133.97,131.82,129.42,128.23,110.89,109.93,109.43,70.15,61.11,58.36,37.02,31.16,29.65.HRMS(ESI)calcd for C24H24FN5O2S[M+H]+466.1708,found 466.1706.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=8.20min,>98.93%.
实施例42合成化合物I-17
N-(3-甲氧基丙基)-4-((2-((吡啶-4-基甲基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)苯甲酰胺(I-17).合成方法与实施例26相同,以化合物Ⅳ-17(400mg,1.65mmol),氢化钠(69.33mg,1.73mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(472.42mg,1.65mmol)为原料,得到黄色固体297.4mg,收率40.25%。m.p.183.2-184.8℃1H NMR(300MHz,DMSO-d6)δ8.95(d,J=1.5Hz,1H),8.54–8.42(m,3H),8.17(dd,J=6.8,1.6Hz,1H),7.84(d,J=8.2Hz,2H),7.58(d,J=6.7Hz,1H),7.51–7.44(m,4H),5.67(s,2H),4.54(s,2H),3.36–3.24(m,4H),3.19(s,3H),1.72(p,J=6.6Hz,2H).13C NMR(75MHz,DMSO)δ172.36,166.17,156.29,150.01,148.65,145.55,139.66,135.25,131.92,129.50,128.26,124.33,110.91,70.17,61.17,58.36,37.05,33.85,29.66.HRMS(ESI)calcd forC24H25N5O2S[M+H]+448.1802,found 448.1798.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=14.68min,>97.11%.
实施例43合成化合物I-18
N-(3-甲氧基丙基)-4-((2-((吡啶-3-基甲基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)苯甲酰胺(I-18).合成方法与实施例26相同,以化合物Ⅳ-18(400mg,1.65mmol),氢化钠(69.33mg,1.73mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(472.42mg,1.65mmol)为原料,得到淡黄色固体278.4mg,收率37.68%。m.p.180.1-182.7℃1H NMR(300MHz,DMSO-d6)δ9.58(d,J=1.3Hz,1H),8.95(s,1H),8.76(dd,J=6.8,1.3Hz,1H),8.68(s,1H),8.56(t,J=5.6Hz,1H),8.35(d,J=8.1Hz,1H),8.08(d,J=6.7Hz,1H),7.87(d,J=8.3Hz,2H),7.70(dd,J=8.0,5.2Hz,1H),7.57(d,J=8.1Hz,2H),5.89(s,2H),4.78(s,2H),3.30(dt,J=17.7,6.4Hz,4H),3.19(s,3H),1.72(p,J=6.6Hz,2H).13C NMR(75MHz,DMSO)δ165.98,162.36,159.58,159.12,147.72,146.37,145.12,142.02,140.04,138.46,137.31,136.17,135.53,133.70,128.64,128.32,125.82,111.20,70.13,62.47,58.29,37.03,32.14,29.62.HRMS(ESI)calcd for C24H25N5O2S[M+H]+448.1802,found 448.1809.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=16.65min,>99.52%.
实施例44合成化合物I-19
N-(3-甲氧基丙基)-4-((2-((吡啶-2-基甲基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)苯甲酰胺(I-19).合成方法与实施例26相同,以化合物Ⅳ-19(400mg,1.65mmol),氢化钠(69.33mg,1.73mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(472.42mg,1.65mmol)为原料,得到黄色固体296.7mg,收率40.16%。m.p.182.9.-183.9℃1H NMR(300MHz,DMSO-d6)δ9.57(d,J=1.3Hz,1H),8.76(dd,J=6.8,1.4Hz,1H),8.59–8.50(m,2H),8.08(d,J=6.7Hz,1H),7.91–7.78(m,3H),7.63(dt,J=7.9,1.1Hz,1H),7.56(d,J=8.2Hz,2H),7.36(ddd,J=7.6,4.9,1.2Hz,1H),5.89(s,2H),4.83(s,2H),3.30(dt,J=17.7,6.5Hz,4H),3.19(s,3H),1.72(p,J=6.6Hz,2H).13C NMR(75MHz,DMSO)δ165.98,162.96,159.40,158.95,155.84,148.99,147.71,140.03,138.50,138.46,137.28,135.52,133.55,128.62,128.32,124.03,123.54,118.68,114.77,111.14,70.14,62.45,58.31,37.03,29.63.HRMS(ESI)calcd for C24H25N5O2S[M+H]+448.1802,found 448.1807.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=15.32min,>99.60%.
实施例45合成化合物I-20
4-((2-((环己基甲基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)-N-(3-甲氧基丙基)苯甲酰胺(I-20).合成方法与实施例26相同,以化合物Ⅳ-20(400mg,1.62mmol),氢化钠(67.91mg,1.70mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(462.76mg,1.62mmol)为原料,得到白色固体567.9mg,收率77.59%。m.p.156.6-157.1℃1H NMR(300MHz,DMSO-d6)δ8.89(d,J=1.6Hz,1H),8.50(t,J=5.6Hz,1H),8.15(dd,J=6.8,1.6Hz,1H),7.86(d,J=8.3Hz,2H),7.52(dd,J=11.7,7.5Hz,3H),5.66(s,2H),3.39–3.26(m,4H),3.23(s,3H),3.18(d,J=6.8Hz,2H),1.90–1.80(m,2H),1.75(p,J=6.7Hz,2H),1.70–1.53(m,4H),1.26–1.07(m,3H),1.07–0.92(m,2H).13C NMR(75MHz,DMSO)δ174.14,166.11,156.45,145.71,139.76,135.18,131.54,128.73,128.22,128.19,110.42,70.16,61.03,58.35,38.11,38.02,37.03,32.56,29.67,26.38,26.00.HRMS(ESI)calcd for C25H32N4O2S[M+H]+453.2319,found 453.2319.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=14.35min,>99.33%.
实施例46合成化合物I-21
4-((2-((环戊基甲基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)-N-(3-甲氧基丙基)苯甲酰胺(I-21).合成方法与实施例26相同,以化合物Ⅳ-21(400mg,1.71mmol),氢化钠(71.99mg,1.80mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(490.58mg,1.71mmol)为原料,得到白色固体525.3mg,收率69.8%。m.p.144.3-145.0℃1H NMR(300MHz,DMSO-d6)δ8.92(d,J=1.5Hz,1H),8.56(t,J=5.6Hz,1H),8.17(dd,J=6.8,1.6Hz,1H),7.89(d,J=8.4Hz,2H),7.56(d,J=6.7Hz,1H),7.51(d,J=8.4Hz,2H),5.69(s,2H),3.39–3.27(m,6H),3.23(s,3H),2.26(hept,J=7.5Hz,1H),1.84–1.70(m,4H),1.65–1.43(m,4H),1.36–1.24(m,2H).13C NMR(75MHz,DMSO)δ174.10,166.14,156.43,145.72,139.75,135.19,131.56,128.74,128.23,128.17,110.43,70.17,61.06,58.34,37.05,36.95,32.23,29.67,25.24.HRMS(ESI)calcd for C24H30N4O2S[M+H]+439.2162,found 439.2158.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=12.61min,>97.66%.
实施例47合成化合物I-22
4-((2-((环丁基甲基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)-N-(3-甲氧基丙基)苯甲酰胺(I-22).合成方法与实施例26相同,以化合物Ⅳ-22(400mg,1.82mmol),氢化钠(76.60mg,1.92mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(521.95mg,1.82mmol)为原料,得到白色固体495.4mg,收率63.97%。m.p.145.3-146.7℃1H NMR(300MHz,DMSO-d6)δ8.73(s,1H),8.34(t,J=5.6Hz,1H),7.98(dd,J=6.8,1.6Hz,1H),7.69(d,J=8.2Hz,2H),7.39(d,J=6.7Hz,1H),7.32(d,J=8.3Hz,2H),5.50(s,2H),3.20–3.09(m,6H),3.04(s,3H),2.59–2.39(m,1H),1.92–1.78(m,2H),1.64–1.48(m,6H).13C NMR(75MHz,DMSO)δ173.82,166.15,156.36,145.66,139.75,135.20,131.66,128.85,128.24,128.19,110.51,70.16,61.09,58.35,37.36,37.04,35.25,29.66,27.51,17.83.HRMS(ESI)calcd forC23H28N4O2S[M+H]+425.2006,found 425.2001.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=11.05min,>99.58%.
实施例48合成化合物I-23
4-((2-((环丙基甲基)硫代)-3-氢-咪唑[4,5-c]吡啶-3-基)甲基)-N-(3-甲氧基丙基)苯甲酰胺(I-23).合成方法与实施例26相同,以化合物Ⅳ-23(400mg,1.95mmol),氢化钠(81.83mg,2.05mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(557.62mg,1.95mmol)为原料,得到白色固体486.2mg,收率60.78%。m.p.147.9-148.4℃1H NMR(300MHz,DMSO-d6)δ8.89(d,J=1.6Hz,1H),8.57(t,J=5.6Hz,1H),8.14(dd,J=6.7,1.6Hz,1H),7.88(d,J=8.0Hz,2H),7.55(d,J=6.7Hz,1H),7.48(d,J=8.0Hz,2H),5.68(s,2H),3.37–3.27(m,4H),3.23–3.17(m,5H),1.74(p,J=6.6Hz,2H),1.30–1.13(m,1H),0.54–0.46(m,2H),0.32–0.24(m,2H).13C NMR(75MHz,DMSO)δ174.08,166.28,156.41,145.71,139.70,135.19,131.67,128.77,128.26,128.16,110.49,70.16,61.15,58.31,49.08,37.10,36.74,29.64,11.77,6.05.HRMS(ESI)calcd for C22H26N4O2S[M+H]+411.1849,found 411.1847.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=8.89min,>99.49%.
实施例49合成化合物I-24
N-(3-甲氧基丙基)-4-((2-((3-甲基-2-烯-1-基)硫代)-3-氢-咪唑并[4,5-c]吡啶-3-基)甲基)苯甲酰胺(I-24).合成方法与实施例26相同,以化合物Ⅳ-24(400mg,1.82mmol),氢化钠(76.60mg,1.92mmol),4-(溴甲基)-N-(3-甲氧基丙基)苯甲酰胺(521.95mg,1.82mmol)为原料,得到白色固体517.6mg,收率66.84%。m.p.148.5-150.2℃1HNMR(300MHz,DMSO-d6)δ8.85(d,J=1.5Hz,1H),8.48(t,J=5.6Hz,1H),8.12(dd,J=6.8,1.6Hz,1H),7.82(d,J=8.3Hz,2H),7.52(d,J=6.8Hz,1H),7.45(d,J=8.3Hz,2H),5.65(s,2H),5.40(tt,J=7.7,1.4Hz,1H),3.88(d,J=7.8Hz,2H),3.35–3.23(m,4H),3.19(s,3H),1.76–1.65(m,8H).13C NMR(75MHz,DMSO)δ173.68,166.20,156.39,145.66,139.75,135.74,135.15,131.70,128.92,128.22,128.17,120.51,110.57,70.15,61.08,58.35,49.07,37.04,29.62,29.27,25.83,18.12.HRMS(ESI)calcd for C23H28N4O2S[M+H]+425.2006,found 425.2000.HPLC(20%–60%acetonitrile in water,with 0.1%TFA),tR=20.46min,>97.17%.
性能测试
下面是本发明化合物的药理学实验结果,该部分的化合物代号所对应的结构式等同于实施例部分的代号所对应的结构式。
一、用于测定IL-1β含量的ELISA实验
细胞培养上清中IL-1β的分泌使用双抗体夹心法ELISA检测。新鲜收集的血清样本室温静置20min后,于4℃3000g离心10min,上清即可用于检测分析。将样品与标准品分别加入已包被抗体的96孔板中,加入生物素化抗体后置于37℃摇床孵育1h后,洗板5次。加入酶结合工作液,37℃避光孵育30min后,洗板5次。加入显色底物,37℃避光孵育15min。加入终止液终止反应。10min内用全波长酶标仪(Thermo)于450nm波长处测量吸光度值,根据标准曲线换算检测样品浓度。化合物对白介素IL-1β的抑制率计算如下:
抑制率(%)=1-(药物孔OD值-空白孔OD值)/(药物孔OD值-空白孔OD值),以不加药物和诱导因子的细胞孔为空白对照,以不加药物,加LPS和ATP的细胞孔为阴性对照。
本发明以MCC950为阳性对照,DMSO组为阴性对照,细胞裂解液为空白背景,设置3个复孔,化合物对IL-1β抑制率结果表示为为各组数据平均值±SEM。本发明中部分化合物对白介素IL-1β的抑制率如表1所示。
表1:
由表1数据可知,本发明的化合物对白介素IL-1β具有抑制活性,这为开发高效安全结构新颖特异性强的NLRP3抑制剂,及治疗NLRP3介导的炎症相关疾病如风湿性关节炎,类风湿性关节炎,炎性肠道疾病,痛风,动脉粥样硬化,非酒精性脂肪肝病,冷吡啉相关周期性综合征,慢性肾脏疾病,糖尿病和神经退行性疾病等的药物提供了基础。
二细胞毒性评价
通过使用MTT测定确定细胞毒性。MTT购自Sigma(St.Louis,MO)。将其溶解在磷酸盐缓冲盐水(PBS)中至储备溶液浓度为5mg/mL并储存在-20℃。在用测试化合物或DMSO的密度梯度处理细胞24小时后,将20.0μLMTT溶液(5mg/mL)加入到96孔板的每个孔中并孵育4小时。然后,除去溶液并向每个孔中加入150.0μL DMSO以溶解水溶性MTT-甲臢晶体。通过Elx800吸光度酶标仪(BioTek,Vermont,USA)在570nm记录吸光度值(OD值)。化合物对细胞生长抑制率的计算如下:
抑制率(%)=1-(药物孔OD值-空白孔OD值)/(药物孔OD值-空白孔OD值),以不加药物和诱导因子的细胞孔为空白对照。本发明部分化合物的细胞毒性评价如表2所示。
表2:
由表2数据可知,本发明的绝大多数化合物IC50>100μM,细胞毒性小。
三.Western Blot监测化合物对目的蛋白的影响
细胞蛋白制备:吸取六孔板细胞上清,经冰预冷PBS缓冲液漂洗两次后用细胞刮刀将细胞从六孔板中刮下并收集。1000g离心5min,按照1:5(体细胞压积:裂解液体积)比例加入RIPA蛋白裂解液,冰上裂解60min,16000g离心10min,吸取上清即为全细胞蛋白,取4μL进行BCA法测定蛋白浓度,其余蛋白上清按体积加入5×上样缓冲液后沸水浴中变性10min,分装后-20℃保存。
根据BCA定量结果,取40-80μg样品/泳道上样,依据目的蛋白的分子量采用不同胶浓度的SDS-PAGE分离,进行恒压(80V)浓缩25min,恒压(120V)凝胶电泳55min。200mA恒流湿转电转90min使蛋白转移至PVDF膜(Millipore,USA)。将PVDF膜置于3%BSA-TBST室温震荡封闭1h后,加入5%BSA-TBST配置的一抗:人抗IL-1β(1:1000),人抗GAPDH(1:1000,sigma,USA),4℃过夜。TBST漂洗10min×3次后,加入HRP标记的山羊抗兔二抗(1:4000),室温震荡孵育1.5h,TBST漂洗10min×3次后加入ECL(Pierce)发光底物显色。Image Quant LAS4000mini(GE)显影。将目的蛋白灰度值与内参GAPDH灰度值之比进行半定量分析(图1)。
由western blot实验表明,本发明中的化合物I-20可明显抑制NLRP3蛋白的表达,具有浓度依赖性。
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求为保护范围。
Claims (10)
1.一种母核为吡啶并咪唑的化合物及其药学上可接受的盐,其特征在于,所述化合物的结构如式Ⅰ所示:
式中,R1为C1~C30的烷基、芳基、杂芳基、C1~C30烷基芳基、C1~C30烷基杂芳基或C1~C12杂环;该C1~C12杂环被以下一个或多个相同或不同的取代基取代:C1~C30的烷基,烷氧基,烷氨基,酰胺基,硝基,卤素,苄基,腈基,氨基,羧基,羰基,三氟甲基;
R2为氢、C1~C30的烷基、芳基、杂芳基、C1~C30烷基芳基、C1~C30烷基杂芳基或C1~C12杂环;该C1~C12杂环被以下一个或多个相同或不同的取代基取代:C1~C30的烷基,烷氧基,烷氨基,酰胺基,硝基,卤素,苄基,腈基,氨基,羧基,羰基,三氟甲基。
2.根据权利要求1所述的母核为吡啶并咪唑的化合物,其特征在于:
优选的:R3-R7中有一个或两个为烷基、烷氧基、卤素、氰基、羰基、羧基、酰基、磺酰基、氨基、硝基、羟基、酯基、三氟甲基,且其余为H;
进一步优选:R3为H或氟;R4为H、氟、甲基或硝基;R5为H、溴、氰基、硝基、三氟甲基、甲基或甲氧基;R6为H、氟或甲基,R7为H;
优选的:Y1-Y3中有一个或两个为N,其余为CH,R8为H、烷基、烷氧基、卤素、氰基、羰基、羧基、酰基、磺酰基、氨基、硝基、羟基、酯基、三氟甲基;
进一步优选的:Y1-Y3中有一个为N,其余为CH,R8为H、烷基、烷氧基、卤素、氰基、羰基、羧基、酰基、磺酰基、氨基、硝基、羟基、酯基、三氟甲基;
最优选:Y1-Y3中有一个为N,其余为CH,R8为H、F;
或:所述的R1为C1-C30烷基、卤代烷基、环烷基、卤代环烷基、杂环烷基;
优选的:R1为C1-C10烷基、卤代烷基、环烷基、卤代环烷基、杂环烷基;
进一步优选的:R1为C3-C6烷基、环烷基;
3.根据权利要求1所述的母核为吡啶并咪唑的化合物,其特征在于:所述的R2为其中Z1-Z2分别独立地为CH、N,R9-R10有且仅有一个为烷基、烷氧基、卤素、氰基、羰基、羧基、酰基、磺酰基、亚胺基、硝基、羟基、酯基、三氟甲基,且另一个为H;
优选的:Z1-Z2至多有一个为N,另外的为CH,R9-R10有且仅有一个为烷基、烷氧基、卤素、羰基、羧基、酰基、磺酰基、亚胺基、硝基、羟基、酯基,且另一个为H;
更优选的,Z1-Z2为CH,R9为H,R10为烷基、烷氧基、羰基、羧基、酰基、磺酰基、亚胺基、硝基、羟基、酯基;
进一步优选的:Z1-Z2为CH,R9为H,R10为酰基、亚胺基;
6.权利要求1所述的母核为吡啶并咪唑的化合物的制备方法,包括如下步骤:
步骤1,化合物Ⅱ成环,得到化合物Ⅲ;
步骤2,将所述化合物Ⅲ在碱性条件下发生亲核取代反应,得到化合物Ⅳ;
步骤3,将所述化合物Ⅳ在碱性条件下发生亲核取代反应,得到化合物I;
式中,R1为C1~C30的烷基、芳基、杂芳基、C1~C30烷基芳基、C1~C30烷基杂芳基或C1~C12杂环;该C1~C12杂环被以下一个或多个相同或不同的取代基取代:C1~C30的烷基,烷氧基,烷氨基,酰胺基,硝基,卤素,苄基,腈基,氨基,羧基,羰基,三氟甲基;
R2为氢、C1~C30的烷基、芳基、杂芳基、C1~C30烷基芳基、C1~C30烷基杂芳基或C1~C12杂环;该C1~C12杂环被以下一个或多个相同或不同的取代基取代:C1~C30的烷基,烷氧基,烷氨基,酰胺基,硝基,卤素,苄基,腈基,氨基,羧基,羰基,三氟甲基;
优选的,所述步骤1为:将化合物II与二硫化碳加入乙醇中,加热回流4h,得到化合物III;
7.一种药物组合物,其特征在于:该组合物包括:含有治疗有效量的权利要求1-6任一所述的母核为吡啶并咪唑的化合物、药学上可接受的盐、水合物或溶剂合物及药学上可接受的载体。
8.权利要求1-6任一所述的母核为吡啶并咪唑的化合物或者其药学上可接受的盐,或者权利要求7所述的药物组合物在制备NLRP3炎症小体抑制剂中的应用。
9.权利要求1-6任一所述的母核为吡啶并咪唑的化合物或者其药学上可接受的盐,或者权利要求7所述的药物组合物在制备治疗炎症相关疾病的药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述炎症相关疾病选自风湿性关节炎,类风湿性关节炎,炎性肠道疾病,痛风,动脉粥样硬化,非酒精性脂肪肝病,冷吡啉相关周期性综合征,慢性肾脏疾病,糖尿病和神经退行性疾病;优选的,所述神经退行性疾病选自帕金森症,多发性硬化症,阿尔兹海默症,亨廷顿病。
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