CN113135891B - N-芳基-n′-(2-噻吩基)硫脲(脲)衍生物及其制备方法和用途 - Google Patents
N-芳基-n′-(2-噻吩基)硫脲(脲)衍生物及其制备方法和用途 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及医药卫生和化工领域,具体涉及一种N-芳基-N′-(2-噻吩基)硫脲(脲)衍生物及其制备方法和用途。
背景技术
免疫系统是机体执行免疫应答及免疫功能的重要系统。免疫系统的功能在于识别和排除抗原性异物来维持机体内环境稳定和生理平衡。主要有Toll样受体 (TLRs),维甲酸诱导基因I样受体(RLRs),NOD样受体(NLRs)和C型凝集素受体(CLRs)。其中,Toll样受体是识别病原微生物中最具有代表性的一类。 Toll样受体(TLRs)是一类高度保守的跨膜蛋白,它们通过选择识别微生物保守的病原相关分子模式(PAMPs)来触发免疫应答反应以抵抗病原体的入侵,包括固有性免疫与获得性免疫。TLR家族成员可与其自身或其他TLR二聚化以形成同型或异型二聚体,连同衔接蛋白介导下游信号传导,例如TLR1-TLR2和TLR2- TLR6。
在TLR家族中,TLR2是识别病原体谱最广的,可以介导格兰阳性菌感染的脂蛋白等的信号转导,使IL-1和IL-12相关蛋白激酶、肿瘤坏死因子相关因子等信号转导分子的表达增加,并进一步促进IL-1和IL-12等效应因子的合成和释放增加引发炎症反应,诱导细胞增殖转化和凋亡等基因的表达,从而介导机体的天然免疫防御作用。
TLR2是Toll样受体家族中表达范围最广,识别病原微生物种类最多的成员,它可以单独或协同其它Toll家族成员完成对病原体相关分子模式的识别,触发机体对病原微生物的级联免疫应答。一直以来,TLR2激活/抑制剂的研发都是自身免疫性疾病或抗炎药物研发的热门领域。研究发现,TLR的调节剂可用于人体免疫调节或肿瘤免疫治疗,目前,以TLR4、TLR7为作用靶点,已有药物上市; TLR2的激活剂云芝多糖在临床II期,用于乳腺癌的治疗;TLR1/2的激动剂细菌性脂蛋白(BLP)可以抑制肺癌,白血病,黑色素瘤等;Diprovocim与PD1/PDL1 的抑制剂单抗联用,可以提高其抗肿瘤作用。
本发明涉及的式I所示化合物在选择性激活TLR1-TLR2中的用途属于首次公开。
发明内容
本发明的目的在于提供一种N-芳基-N′-(2-噻吩基)硫脲(脲)衍生物及其制备方法和在制备选择性激活TLR1-TLR2的药物中的应用,具有重要的研发价值和开发意义。
本发明一个方面提供了一种N-芳基-N′-(2-噻吩基)硫脲(脲)衍生物,其结构如式I所示,
其中:A为碳环或杂环;X为S、O中任意一个;Y为C、N中任意一个; Z为O、N中任意一个;R1选自氢,含1-6个碳原子的直链、支链或环状烷基,苄基或苯乙基;R2选自氢,含1-6个碳原子的烷基,酰基,苯基或苄基;R3选自氢,卤素,含1-6个碳原子的直链、支链或环状烷基,烷氧基,氨基,硝基,三氟甲基,羧基或羧酸酯;n为1、2或3。
进一步地,所述A为选自A1、A2、A3、A4、A5、A6中任意一个的环,
其中式I所示的化合物,不包括式II所示化合物,
本发明另一个方面提供了式I所示化合物的制备方法:
其中式I化合物中X为硫原子,制备方法如下:
实验方法详述如下:
将A溶于二氯甲烷中,加入三乙胺,冰浴冷却至0℃,滴加硫光气。薄层色谱跟踪反应至结束,减压旋干溶剂,往残留物中加入二氯甲烷,水洗两次,无水硫酸钠干燥。减压除溶剂,加入C,乙醇做溶剂,回流搅拌至反应结束。减压旋干溶剂,残留物用硅胶柱层析分离,得目标产物。
其中式I化合物中X为氧原子,制备方法如下:
实验方法详述如下:
将A溶于碳酸二甲酯中,加入固体光气,90℃反应,薄层色谱跟踪反应至结束。减压除溶剂,加入C,乙醇做溶剂,回流搅拌至反应结束。减压旋干溶剂,残留物用硅胶柱层析分离,得目标产物。
本发明另一个方面提供了式I所示化合物或其药物可接受盐在制备TLR2选择性激动剂或激活TLR1-TLR2的激动剂中的应用,
其中,R1选自氢,含1-6个碳原子的直链、支链或环状烷基,苄基或苯乙基; R2选自氢,含1-6个碳原子的烷基,酰基,苯基或苄基;R3选自氢,卤素,含1- 6个碳原子的直链、支链或环状烷基,烷氧基,氨基,硝基,三氟甲基,羧基或羧酸酯;n为1、2或3;A为碳环或杂环;X为S、O中任意一个;Y为C、N 中任意一个;Z为O、N中任意一个;
优选地,R1选自氢、甲基、乙基、正丙基、异丙基、环丙基、丁基、异丁基、叔丁基或苯乙基;
优选地,R2选自氢、甲基、乙基、丙基或苄基;
优选地,A选自A1、A2、A3、A4、A5、A6中任意一个。
本发明另一个方面提供了式I所示化合物或其药物可接受盐在制备刺激分泌TNF-α的药物中的用途,
其中,R1选自氢,含1-6个碳原子的直链、支链或环状烷基,苄基或苯乙基; R2选自氢,含1-6个碳原子的烷基,酰基,苯基或苄基;R3选自氢,卤素,含1- 6个碳原子的直链、支链或环状烷基,烷氧基,氨基,硝基,三氟甲基,羧基或羧酸酯;n为1、2或3;A为碳环或杂环;X为S、O中任意一个;Y为C、N 中任意一个;Z为O、N中任意一个;
优选地,R1选自氢、甲基、乙基、正丙基、异丙基、环丙基、丁基、异丁基、叔丁基或苯乙基;
优选地,R2选自氢、甲基、乙基、丙基或苄基;
优选地,A选自A1、A2、A3、A4、A5、A6中任意一个。本发明另一个方面提供了一种用于选择性激活TLR2的药物组合物,其含有作为活性物质的式I所示化合物或其药物可接受盐;
其中,R1选自氢,含1-6个碳原子的直链、支链或环状烷基,苄基或苯乙基; R2选自氢,含1-6个碳原子的烷基,酰基,苯基或苄基;R3选自氢,卤素,含1- 6个碳原子的直链、支链或环状烷基,烷氧基,氨基,硝基,三氟甲基,羧基或羧酸酯;n为1、2或3;A为碳环或杂环;X为S、O中任意一个;Y为C、N 中任意一个;Z为O、N中任意一个;
优选地,R1选自氢、甲基、乙基、正丙基、异丙基、环丙基、丁基、异丁基、叔丁基或苯乙基;
优选地,R2选自氢、甲基、乙基、丙基或苄基;
优选地,A选自A1、A2、A3、A4、A5、A6中任意一个。
本发明另一个方面提供了一种用于激活TLR1-TLR2的药物组合物,其含有作为活性物质的式I所示化合物或其药物可接受盐;
其中,R1选自氢,含1-6个碳原子的直链、支链或环状烷基,苄基或苯乙基; R2选自氢,含1-6个碳原子的烷基,酰基,苯基或苄基;R3选自氢,卤素,含1- 6个碳原子的直链、支链或环状烷基,烷氧基,氨基,硝基,三氟甲基,羧基或羧酸酯;n为1、2或3;A为碳环或杂环;X为S、O中任意一个;Y为C、N 中任意一个;Z为O、N中任意一个;
优选地,R1选自氢、甲基、乙基、正丙基、异丙基、环丙基、丁基、异丁基、叔丁基或苯乙基;
优选地,R2选自氢、甲基、乙基、丙基或苄基;
优选地,A选自A1、A2、A3、A4、A5、A6中任意一个。
本发明另一个方面提供了一种用于刺激分泌TNF-α的药物组合物,其含有作为活性物质的式I所示化合物或其药物可接受盐;
其中,R1选自氢,含1-6个碳原子的直链、支链或环状烷基,苄基或苯乙基; R2选自氢,含1-6个碳原子的烷基,酰基,苯基或苄基;R3选自氢,卤素,含1- 6个碳原子的直链、支链或环状烷基,烷氧基,氨基,硝基,三氟甲基,羧基或羧酸酯;n为1、2或3;A为碳环或杂环;X为S、O中任意一个;Y为C、N 中任意一个;Z为O、N中任意一个;
优选地,R1选自氢、甲基、乙基、正丙基、异丙基、环丙基、丁基、异丁基、叔丁基或苯乙基;
优选地,R2选自氢、甲基、乙基、丙基或苄基;
优选地,A选自A1、A2、A3、A4、A5、A6中任意一个。
在本发明的技术方案中,所述药物组合物为注射制剂、口服制剂或外用制剂。
在本发明的技术方案中,所述药物组合物为片剂、胶囊剂、散剂、丸剂、颗粒剂、注射剂或乳剂。
附图说明
图1为SMU-C80对TLR2的激活作用。
图2为SMU-C80激活TLR1-TLR2的抗体实验。
图3为SMU-C80上调TLR2蛋白表达及TNF-α释放实验。
具体实施方式
为了更好地理解本发明的内容,下面结合具体实施方法对本发明内容作进一步说明,但本发明的保护内容不局限以下实施例。
N-(1-萘基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸乙酯))脲
将(1mmol)溶于5mL碳酸二甲酯中,加入固体光气(1 mmol),90℃反应,薄层色谱(TLC)跟踪反应至结束。减压蒸除溶剂,加入 5mL乙醇,加入(1mmol),回流反应至结束。减压旋干溶剂,残留物用硅胶柱层析分离,得目标产物,产率92%。
1H NMR(400MHz,CDCl3)δ10.54(s,1H),8.07-8.09(m,1H),7.91-7.93(m, 1H),7.84(d,J=8.4Hz,1H),7.74(d,J=7.2Hz,1H),7.54-7.58(m,3H),4.10(q,2H), 2.75-2.86(m,4H),2.31-2.38(m,4H),1.20(t,J1=14.4Hz,J2=7.2Hz,3H).13C NMR (101MHz,CDCl3)δ165.7,153.9,153.2,141.0.134.3,132.3,130.5,129.3,128.3, 126.9,126.4,126.2,125.6,123.3,122.2,106.7,60.0,30.4,28.6,27.7,14.1.ESI-MS: m/z 381.1([M+H]+).
N-(1-萘基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸异丙酯))硫脲
将(1mmol)溶于5mL二氯甲烷中,加入0.5mL三乙胺,冰浴冷却至0℃,滴加硫光气(1mmol)。薄层色谱(TLC)跟踪反应至结束,减压旋干溶剂,往残留物中加入50mL二氯甲烷,水洗两次(2×5mL),无水硫酸钠干燥。减压除溶剂,加入5mL乙醇,加入(1mmol),回流反应至结束。减压旋干溶剂,残留物用硅胶柱层析分离,得目标产物,产率92%。
1H NMR(400MHz,CDCl3)δ11.79(s,1H),7.94-8.08(m,4H),7.55-7.61(m, 4H),4.75-4.81(m,1H),2.78-2.84(m,4H),2.28-2.35(m,2H),1.10(d,J=6.4Hz,6H). 13C NMR(101MHz,CDCl3)δ176.9,165.5,153.3,141.2,134.7,132.3,131.4,130.0, 129.3,128.5,127.5,126.9,125.8,125.7,122.2,109.5,51.1,30.2,28.8,27.7.ESI-MS: m/z 411.2([M+H]+).
N-(1-萘基)-N′-(2-(4,5,6,7-四氢-苯并[b]噻吩-3-甲酸异丙酯))硫脲
1H NMR(400MHz,CDCl3)δ12.09(s,1H),8.17(s,1H),8.02-8.04(m,1H),7.93- 7.97(m,2H),7.54-7.59(m,4H),4.76(m,1H),2.63(m,4H),1.70-1.78(m,4H),1.10 (d,J=6.4Hz,6H).13C NMR(101MHz,CDCl3)δ177.4,165.7,149.5,134.8,131.6, 130.6,130.0,129.2,128.4,127.3,126.7,126.6,125.7,125.6,122.3,113.4,67.8,26.3, 24.3,22.9,22.8,21.6(2C).ESI-MS:m/z 425.3([M+H]+).
N-(1-萘基)-N′-(2-(5,6,7,8-四氢-4H-环庚烯并[b]噻吩-3-甲酸异丙酯))硫脲
1H NMR(400MHz,CDCl3)δ11.88(s,1H),7.93-8.04(m,4H),7.56-7.60(m, 4H),4.72-4.78(m,1H),2.88-2.90(m,2H),2.71-2.73(m,2H),1.78-1.83(m,2H),1.62- 1.68(m,2H),1.52-1.57(m,2H),1.08(d,J=6.4Hz,6H).13C NMR(101MHz,CDCl3) δ177.3,165.8,147.1,136.1,134.8,131.5,130.8,130.1,129.2,128.4,127.3,126.7, 125.7,122.3,115.0,68.2,32.0,28.4,28.2,27.7,26.7,21.5.ESI-MS:m/z 439.2 ([M+H]+).
N-(1-萘基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸正丙酯))硫脲
1H NMR(400MHz,CDCl3)δ11.73(s,1H),7.94-8.05(m,4H),7.56-7.62(m, 4H),3.85(t,J1=12.8Hz,J2=6.4Hz,2H),2.80-2.85(m,4H),2.29-2.36(m,2H),1.50- 1.55(m,2H),0.88(t,J1=14.4Hz,J2=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ177.0,165.5,153.4,141.1,134.7,132.2,131.4,129.9,129.2,128.5,127.4,126.8,125.8, 125.6,122.1,109.8,65.7,30.3,28.8,27.7,21.8,10.5.ESI-MS:m/z 411.2([M+H]+).
N-(1-萘基)-N′-(2-(4,5,6,7-四氢-苯并[b]噻吩-3-甲酸正丙酯))硫脲
1H NMR(400MHz,CDCl3)δ11.98(s,1H),7.93-8.11(m,4H),7.54-7.61(m, 4H),3.81(t,J1=12.8Hz,J2=6.4Hz,2H),2.62-2.67(m,4H),1.73-1.79(m,4H),1.46- 1.52(m,2H),0.86(t,J1=14.4Hz,J2=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ 177.3,165.9,149.6,134.7,131.6,130.7,130.0,129.2,128.4,127.3,126.7,126.6,125.7, 122.3,113.0,65.8,26.2,24.2,22.9,22.8,21.8,10.5.ESI-MS:m/z 425.2([M+H]+).
N-(1-萘基)-N′-(2-(4,5,6,7-四氢-苯并[b]噻吩-3-甲酸正丁酯))硫脲
1H NMR(400MHz,CDCl3)δ12.00(s,1H),7.92-8.04(m,4H),7.56-7.61(m, 4H),3.86(t,J1=12.8Hz,J2=6.4Hz,2H),2.65(s,4H),1.74-1.77(m,4H),1.43-1.46 (m,2H),1.25-1.30(m,2H),0.88(t,J1=14.4Hz,J2=7.2Hz,3H).13C NMR(101MHz, CDCl3)δ177.3,165.9,149.5,134.7,131.5,130.7,130.0,129.2,128.4,127.3,126.8, 126.6,125.7,125.7,122.2,113.1,63.9,30.5,26.2,24.2,22.9,22.8,19.1,13.6.ESI- MS:m/z 439.2([M+H]+).
N-(1-萘基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸异丁酯))硫脲
1H NMR(400MHz,CDCl3)δ11.79(s,1H),7.95-8.03(m,4H),7.56-7.62(m, 4H),3.70(d,J=6.4Hz,2H),2.83(t,J1=14.4Hz,J2=7.2Hz,4H),2.32-2.35(m,2H), 1.81-1.84(m,1H),0.88(d,J=6.8Hz,6H).13C NMR(101MHz,CDCl3)δ177.0, 165.7,153.6,141.0,134.8,132.3,131.4,129.9,129.3,128.5,127.4,126.8,125.8,125.7, 122.2,109.8,70.3,30.6,28.9,27.8,27.7,19.2.ESI-MS:m/z 425.2([M+H]+).
N-(1-萘基)-N′-(2-(4,5,6,7-四氢-苯并[b]噻吩-3-甲酸异丁酯))硫脲
1H NMR(400MHz,CDCl3)δ12.06(s,1H),7.94-8.09(m,4H),7.55-7.61(m, 4H),3.67(d,J=6.4Hz,2H),2.63-2.68(m,4H),1.74-1.81(m,5H),0.85(d,J=6.8Hz, 6H).13C NMR(101MHz,CDCl3)δ177.4,166.2,149.8,134.7,131.6,130.6,130.0, 129.2,128.4,127.3,126.7,126.6,125.8,125.7,122.3,113.0,70.4,27.5,26.4,24.3, 22.9,22.8,19.2.ESI-MS:m/z 439.2([M+H]+).
N-(1-萘基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸叔丁酯))硫脲
1H NMR(400MHz,CDCl3)δ11.90(s,1H),7.94-8.03(m,4H),7.55-7.60(m, 4H),2.57-2.83(m,4H),2.29-2.32(m,2H),1.27(s,9H).13C NMR(101MHz,CDCl3) δ176.9,165.1,153.0,141.1,134.9,131.9,131.5,130.1,129.1,128.3,127.3,126.7, 125.8,125.7,122.2,110.9,81.1,30.3,28.8,27.9,27.6.ESI-MS:m/z 425.2([M+H]+).
N-(1-萘基)-N′-(2-(4,5,6,7-四氢-6-甲基-苯并[b]噻吩-3-甲酸异丙酯))硫脲
1H NMR(400MHz,CDCl3)δ12.1(s,1H),7.94-8.04(m,4H),7.55-7.61(m,4H), 4.73-4.80(m,1H),2.69-2.81(m,2H),2.5-2.59(m,1H),2.21-2.27(m,1H),1.80-1.84 (m,2H),1.28-1.36(m,1H),1.04-1.12(m,9H).13C NMR(101MHz,CDCl3)δ177.3, 165.7,149.6,134.8,131.6,130.3,130.1,129.2,128.4,127.3,126.7,126.3,125.7,125.7, 122.3,113.2,67.8,32.3,31.3,29.1,26.0,21.7,21.6,21.3.ESI-MS:m/z 439.2 ([M+H]+).
N-(1-萘基)-N′-(2-(4,5,6,7-四氢-6-甲基-6-氮杂-苯并[b]噻吩-3-甲酸异丙酯))硫脲
1H NMR(400MHz,CDCl3)δ12.08(s,1H),7.94-8.05(m,4H),7.54-7.60(m, 4H),4.75-4.81(m,1H),3.56(s,2H),2.80-2.82(m,2H),2.71-2.72(m,2H),2.98(s, 3H),1.10(d,J=6.0Hz,6H).13C NMR(101MHz,CDCl3)δ177.4,165.4,150.2,134.7, 131.5,130.0,129.2,128.7,128.4,127.3,126.7,125.7,125.6,123.5,122.1,112.7,68.0, 53.0,52.3,45.3,26.6,21.6.ESI-MS:m/z 439.2([M+H]+).
N-(4-溴-1-萘基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸异丙酯))硫脲
1H NMR(400MHz,CDCl3)δ11.87(s,1H),8.34(d,J=8.0Hz,1H),8.05(d,J= 8.0Hz,1H),7.90-7.92(m,2H),7.62-7.68(m,2H),7.48(d,J=8.0Hz,1H),4.78-4.85 (m,1H),2.79-2.85(m,4H),2.31-2.36(m,2H),1.14(d,J=6.4Hz,6H).13C NMR(101 MHz,CDCl3)δ176.8,165.2,153.1,141.2,133.2,132.3,131.5,131.1,129.8,128.2, 128.1,127.9,125.9,123.7,122.7,110.2,67.9,30.3,28.8,27.7,21.7.ESI-MS:m/z 473.1([M+H]+).
N-(4-溴-1-萘基)-N′-(2-(4,5,6,7-四氢-苯并[b]噻吩-3-甲酸异丙酯))硫脲
1H NMR(400MHz,CDCl3)δ12.19(s,1H),8.34(d,J=8.0Hz,1H),8.04(d,J= 8.0Hz,1H),7.91(s,1H),7.90(d,J=8.0Hz,1H),7.60-7.70(m,2H),7.46(d,J=8.0 Hz,1H),4.77-4.83(m,1H),2.64(s,4H),1.71-1.79(m,4H),1.13(d,J=8.0Hz,6H). 13C NMR(101MHz,CDCl3)δ177.2,165.9,149.4,133.2,131.5,131.2,130.7,129.8, 128.1,127.9,126.8,126.0,123.7,122.7,113.4,68.1,26.2,24.3,22.9,22.8,21.6.ESI- MS:m/z 487.1([M+H]+).
N-(4-氟-1-萘基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸异丙酯))硫脲
1H NMR(400MHz,CDCl3)δ11.76(s,1H),819-8.21(m,1H),8.01-8.04(m,1H), 7.93(s,1H),7.54-7.67(m,3H),725(d,1H),4.75-4.81(m,1H),2.77-2.84(m,4H), 2.28-2.35(m,2H),1.12(d,6H).13C NMR(101MHz,CDCl3)δ177.7,165.1,158.8, 156.3,154.1,140.8,131.6,128.3,127.6,126.6,124.0,123.4,120.8,110.2,108.9,68.1, 30.5,28.8,27.5,21.9.ESI-MS:m/z 429.1([M+H]+).
N-(5-喹啉基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸异丙酯))硫脲
1H NMR(400MHz,CDCl3)δ11.82(s,1H),8.98(s,1H),8.31-8.46(m,2H),8.24 (d,J=8.4Hz,1H),7.83(t,J=7.7Hz,1H),7.67(d,J=7.1Hz,1H),7.40-7.56(m, 1H),4.75(s,0H),2.80(q,5H),2.17-2.43(m,2H),1.11(d,J=5.9Hz,6H).13C NMR (101MHz,CDCl3)δ176.9,165.2,153.0,150.9,149.0,141.2,132.3,131.6,131.2, 130.5,129.4,126.2,125.6,122.0,110.1,67.9,30.3,28.8,27.6,21.7.ESI-MS:m/z 412.1([M+H]+).
N-(8-喹啉基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸异丙酯))硫脲
1H NMR(400MHz,CDCl3)δ12.41(s,1H),10.44(s,1H),8.89-8.92(m,2H), 8.28(d,1H),7.65-7.66(m,2H),7.55-7.58(m,1H),5.21-5.28(m,1H),2.86-2.97(m, 4H),2.37-2.44(m,2H),1.38(d,6H).13C NMR(101MHz,CDCl3)δ173.5,166.0, 153.7,148.4,141.2,139.0,136.3,134.2,132.0,128.2,126.7,122.5,121.9,117.0,109.5, 68.1,30.5,28.9,27.7,22.0.ESI-MS:m/z 412.1([M+H]+).
N-(2-萘基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸异丙酯))硫脲
1H NMR(400MHz,CDCl3)δ7.96-7.84(m,4H),7.58-7.51(m,2H),7.40(d,J= 8.7Hz,1H),4.94-4.84(m,1H),2.87(dd,J=13.4Hz,6.6Hz,4H),2.37(dd,J=14.0 Hz,6.9Hz,2H),1.19(d,J=6.2Hz,6H).13C NMR(101MHz,CDCl3)δ176.73,165.23, 153.15,141.14,133.14,132.25,131.56,131.12,129.76,128.11,128.07,127.88, 125.91,123.64,122.79,110.10,77.30,77.19,76.99,76.67,67.90,30.28,28.81,27.64, 21.67.ESI-MS:m/z411.1([M+H]+).
N-(1-萘基)-N′-(2-(4,5,6,7-四氢-苯并[b]噻吩-3-甲酸苯乙酯))硫脲
1H NMR(400MHz,CDCl3)δ11.70(s,1H),7.93-8.05(m,4H),7.56-7.62(m, 4H),7.30-7.32(m,2H),7.22-7.25(m,1H),7.14(d,J=7.2Hz,2H),4.11(t,J1=14.4 Hz,J2=7.2Hz,2H),2.79-2.83(m,4H),2.69(t,J1=13.6Hz,J2=6.8Hz,2H),2.25- 2.33(m,2H).13CNMR(101MHz,CDCl3)δ177.0,165.3,153.7,141.0,137.6,134.7, 132.2,131.4,130.0,129.3,128.7,128.5,128.4,127.4,126.8,126.5,125.8,125.7,122.2, 109.5,64.7,34.8,30.3,28.8,27.7.ESI-MS:m/z 487.1([M+H]+).
N-(5-异喹啉基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸异丙酯))硫脲
1H NMR(400MHz,CDCl3)δ11.67(s,1H),11.20(s,1H),9.41(s,1H),8.55(s, 1H),8.17(s,1H),7.80(d,4H),4.94(s,1H),2.79(s,5H),2.29(s,3H),1.22(s,7H). 13C NMR(101MHz,CDCl3)δ177.6,165.1,153.9,152.9,143.4,140.8,133.5,132.7, 131.8,130.3,129.4,128.0,127.7,116.3,109.1,68.2,30.6,28.8,27.6,22.0.ESI-MS: m/z 412.1([M+H]+).
N-(4-碘-1-萘基)-N′-(2-(4,5,6,7-四氢-苯并[b]噻吩-3-甲酸异丙酯))硫脲
1H NMR(400MHz,CDCl3)δ8.20(t,J=7.6,1H),8.04-7.96(m,1H),7.70-7.53 (m,1H),7.33(d,J=7.8,1H),4.80(d,1H),2.64(s,2H),1.85-1.67(m,2H),1.14(d,J =6.3,3H).13C NMR(101MHz,CDCl3)δ176.73,165.23,153.15,141.14,133.14, 132.25,131.56,131.12,129.76,128.11,128.07,127.88,125.91,123.64,122.79,110.10, 77.30,77.19,76.99,76.67,67.90,30.28,28.81,27.64,21.67.ESI-MS:m/z 551.5 ([M+H]+).
N-(1-萘基)-N′-(2-(4,5,6,7-四氢-6-甲基-苯并[b]噻吩-3-甲酸乙酯))硫脲
1H NMR(400MHz,CDCl3)δ11.93(s,1H),7.94-8.05(m,4H),7.56-7.61(m, 4H),3.89(q,2H),2.69-2.83(m,2H),2.53-2.60(m,1H),2.21-2.28(m,1H),1.80-1.88 (m,2H),1.27-1.38(m,1H),1.05-1.11(m,6H).13C NMR(101MHz,CDCl3)δ177.3, 165.7,149.5,134.7,131.5,130.5,130.1,129.2,128.4,127.4,126.8,126.3,125.8,125.7, 122.3,112.9,60.1,32.3,31.0,29.1,25.9,21.3,14.0.HRMS(ESI):calcd for C23H24N2O2S2(M+H)+=425.1357,found 425.1359.
N-(1-萘基)-N′-(2-(4,5,6,7-四氢-6-甲基-6-氮杂-苯并[b]噻吩-3-甲酸乙酯))硫脲
1H NMR(400MHz,CDCl3)δ11.91(s,1H),8.10(s,1H),7.95-8.03(m,3H),7.57- 7.61(m,4H),3.91(q,2H),3.61(s,2H),2.84-2.85(m,2H),2.75-2.77(m,2H),2.53(s, 3H),1.10(t,J1=14.4Hz,J2=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ177.4,165.4, 150.2,134.7,131.5,130.0,129.2,128.8,128.4,127.3,126.8,125.7,125.7,123.4,122.1, 112.4,60.1,52.9,52.2,45.3,26.4,14.0.HRMS(ESI):calcd for C22H23N3O2S2(M+H)+=426.1310,found 426.1315.
N-(1-萘基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸))硫脲
N-(1-萘基)-N′-(2-(4,5,6,7-四氢-苯并[b]噻吩-3-甲酸))硫脲
N-(8-喹啉基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸甲酯))硫脲
1H NMR(400MHz,CDCl3)δ12.34(s,1H),10.33(s,1H),8.89(s,2H),8.22(d, J=8.2Hz,1H),7.65-7.59(m,4H),7.52(dd,J=7.0,3.2Hz,2H),3.90(s,4H),2.91 (d,J=22.7Hz,7H),2.46-2.34(m,4H).13C NMR(101MHz,CDCl3)δ173.6,166.9, 154.1,148.5,141.0,139.0,136.3,134.1,132.1,128.2,126.7,122.6,121.9,117.1,108.8, 51.6,30.4,28.9,27.8.ESI-MS:m/z 384.5([M+H]+).
N-(5-喹啉基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸甲酯))硫脲
1H NMR(400MHz,CDCl3)δ11.67(s,1H),9.01(s,1H),8.40(d,J=8.1Hz,1H), 8.27(d,J=8.5Hz,1H),8.09(s,1H),7.87(t,J=7.6Hz,2H),7.69(d,J=6.7Hz,1H), 7.51(d,J=4.2Hz,1H),3.50(s,4H),2.81(s,5H),2.33(s,3H).13C NMR(101MHz, CDCl3)δ177.7,165.8,154.0,151.3,148.8,140.8,134.3,131.9,131.8,129.7,129.1, 126.3,125.4,122.2,108.6,52.0,30.4,28.8,27.6.ESI-MS:m/z 384.4([M+H]+).
N-(4-氨基-1-萘基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸异丙酯))硫脲
1H NMR(400MHz,CDCl3)δ11.64(s,1H),7.96(d,1H),7.88(d,1H),781(s, 1H),750-7.56(m,2H),7.39(d,1H),6.85(d,1H),4.75-4.82(m,1H),2.77-2.84(m, 4H),2.27-2.35(m,2H),1.10(d,H).ESI-MS:m/z 426.6([M+H]+).
N-(4-萘乙酸甲酯-1-基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸异丙酯)) 硫脲
1H NMR(400MHz,CDCl3)δ11.82(s,1H),8.08(t,2H),7.90(s,1H),7.51-7.64 (m,4H),4.77-4.81(m,1H),4.15(d,2H),3.72(s,3H),2.78-2.85(m,4H),2.31-2.34 (m,2H),1.12(d,6H).ESI-MS:m/z 483.1([M+H]+).
N-(2-氟-5-喹啉基)-N′-(2-(5,6-二氢-4H-环戊烯并[b]噻吩-3-甲酸异丙酯))硫脲
1H NMR(400MHz,CDCl3)δ11.81(s,1H),9.04(d,1H),8.37(d,1H),8.18(s, 1H),7.50-7.64(m,3H),4.76-4.81(m,1H),2.77-2.83(m,4H),2.30-2.36(m,2H),1.32 (d,6H).ESI-MS:m/z 430.1([M+H]+).
N-(4-氟-1-萘基)-N′-(2-(4,5,6,7-四氢-苯并[b]噻吩-3-甲酸异丙酯))硫脲
1H NMR(400MHz,CDCl3)δ12.09(s,1H),8.14-8.24(m,1H),8.01(d,J=7.1 Hz,1H),7.92(s,1H),7.62(d,J=6.4Hz,2H),7.54(d,J=8.0,1H),7.22-7.27(m,1H), 4.74-4.80(m,1H),2.62-2.65(m,4H),1.73-1.76(m,4H),1.11(d,J=6.2Hz,6H).13C NMR(101MHz,CDCl3)δ177.53,165.79,149.46,131.65,130.58,128.22,127.69, 126.96,126.63,126.34,124.81,124.64,122.58,121.09,113.27,109.52,109.31,67.94, 26.23,24.25,22.84,21.63.ESI-MS:m/z 443.1([M+H]+).
以下实验中的HEK Blue TLR2细胞,THP-1细胞,THP-1(TLR2-/-)细胞为本科室所有;胎牛血清购自美国GIBICO公司;细胞培养板购自美国康宁公司; DMEM,RPMI 1640培养基购自美国GIBICO公司;Quanti-blue购自美国 InvivoGen公司。
实施例32 化合物1-37对TLR2的激活活性实验:
实验步骤如下:
1、接种HEK Blue TLR2细胞:用含10%胎牛血清(60℃加热30分钟)的 DMEM培养基配成单个细胞悬液,以每孔20000个细胞接种到384孔细胞培养板,每孔接种体积30μL;
2、加入待测化合物,培养:向各个孔加入10μL用含10%胎牛血清(60℃加热30分钟)的DMEM培养基稀释成相应浓度的待测化合物,在37℃,5% CO2培养条件下培养24小时;
3、呈色:培养24小时后,每孔避光加40μL Quanti-blue溶液。
4、测量与计算:在620nm吸光度下15分钟为单位读数4次,以检测细胞上清中SEAP的信号强度。EC50通过Growth/Sigmoidal中的Hill1进行非线性拟合。
SMU-C80对TLR2的激活作用如图1所示,从图1可看出化合物15 (SMU-C80)激活TLR2的EC50为0.031±0.001μM。其它化合物激活TLR2的结果如表1所示。从表1中可知,该系列化合物有较好的激活TLR2的活性,具有良好的开发潜力。
表1 化合物对TLR2的激活活性
化合物 | EC<sub>50</sub>/μM | 化合物 | EC<sub>50</sub>/μM |
1 | 7.60±0.61 | 20 | 0.082±0.01 |
2 | 0.18±0.014 | 21 | 0.056±0.013 |
3 | 0.14±0.03 | 22 | 1.77±0.12 |
4 | 2.22±0.22 | 23 | NA |
5 | 0.82±0.082 | 24 | NA |
6 | 1.05±0.071 | 25 | NA |
7 | NA | 26 | 1.83±0.28 |
8 | 28.21±16.25 | 27 | 1.59±0.42 |
9 | 30.48±15.14 | 28 | 0.103±0.003 |
10 | NA | 29 | 0.11±0.003 |
11 | 1.70±0.52 | 30 | 0.021±0.001 |
12 | NA | 31 | 0.035±0.001 |
13 | 0.039±0.001 | 32 | 3.57±0.58 |
14 | 0.048±0.0046 | 33 | 0.36±0.021 |
15(SMU-C80) | 0.031±0.001 | 34 | 7.33±2.59 |
16 | 0.020±0.001 | 35 | 0.33±0.024 |
17 | 0.102±0.02 | 36 | 5.84±0.21 |
18 | 1.73±0.34 | 37 | 2.35±0.057 |
19 | NA |
NA:no activity.
实施例33 SMU-C80激活TLR1-TLR2的抗体实验:
1、接种HEK Blue TLR2细胞:用含10%胎牛血清(60℃加热30分钟)的 DMEM培养基配成单个细胞悬液,以每孔20000个细胞接种到384孔细胞培养板,每孔接种体积20μL;
2、加入SMU-C80,h-TLR1、h-TLR2、h-TLR6抗体,培养:向各孔加入10 μL 0.2μM的SMU-C80,再加入10μL稀释成相应浓度的h-TLR1或h-TLR2或 h-TLR6抗体,培养24小时;
3、呈色:培养24小时后,每孔避光加40μL Quanti-blue溶液。
4、测量与计算:在620nm吸光度下15分钟为单位读数4次,以检测细胞上清中SEAP的信号强度。
实验结果如图2所示,结果显示,加入h-TLR1或h-TLR2抗体后,可抑制细胞上清中的SEAP信号,加入h-TLR6抗体后,不能抑制细胞上清中的SEAP 信号。说明SMU-C80可以激活TLR1-TLR2。
实施例34 SMU-C80上调TLR2蛋白表达及激活TNF-α释放的实验:
SMU-C80上调TLR2蛋白表达实验步骤如下:
1、免疫蛋白印迹实验使用6孔板,每孔1×106个细胞,加入3mLDMEM培养基(含10%胎牛血清,60℃加热30分钟),同时加入10μL梯度稀释的SMU- C80,37℃、5%的CO2的培养箱中培养。其中,HEK-Blue TLR2细胞培养24h, THP-1细胞加PMA刺激分化后培养24h。
2、蛋白提取及定量:将培养孔里的上清吸掉,加入1mL的PBS洗两遍,冰上操作。每孔加入150μL裂解液(RIPA:PMSF=100:1,体积比),冰上裂解30 分钟,偶尔振荡摇匀;裂解结束,收集裂解液,转速12000rpm,4℃离心15min,收集上清,即为蛋白液。按BCA试剂盒进行蛋白定量检测,根据蛋白定量结果,加入计算好的蛋白液、水和5×的上样缓冲液,使用封口膜密封好,95℃水浴锅中煮10min,冷却后保存在4℃冰箱中,等待上样。
3、电泳和转膜:配制分离胶,浓缩胶,上样。每胶孔中加入10μL的蛋白液,两侧分别加入1μL和3μL的预染蛋白marker标记上样顺序。上样完毕后,设置电压80V跑20min后,电压调整至120V跑至溴酚蓝到达玻璃板底部约1 cm处,停止电泳。转PVDF膜。
4、抗体孵育:转膜结束,按照marker将所需要的蛋白条带剪出来。用TBST 洗3遍,5%的脱脂奶粉(TBST做溶剂)封闭1小时,接着用TBST洗三遍。封闭结束后进行抗体孵育,加入目标条带蛋白的特异性抗体,在4℃摇床上孵育 12-18h,非特异性二抗用5%的脱脂奶粉稀释,室温摇床上孵育1h。
5、曝光:洗涤结束后,蛋白条带浸泡在TBST溶液中备用。用移液枪将ECL 化学发光液均匀地滴到蛋白条带上,放入曝光机中的暗箱中曝光2min。蛋白灰度值使用Image J软件,蛋白条带的组合使用adobe illustrator软件。
结果如图3A,3B所示,结果显示,SMU-C80可以激活HEK Blue TLR2细胞以及THP-1细胞中TLR2,使TLR2蛋白的表达量上升。
SMU-C80激活TNF-α释放的实验步骤如下:
1、细胞培养:12孔板,每孔1×105个细胞。RPMI 1640全培养基培养,并加刺激剂PMA(100nM)刺激24h使得细胞贴壁;吸掉含有PMA的培养基,用1mL的PBS洗两遍,加入新的1mL培养基,培养24h;吸掉培养基,加1 mL的PBS洗两遍。SMU-C80用RPMI 1640稀释到所需浓度,加入到孔板中。培养24h以后,取孔板中的培养基离心(1000rpm,3min),得上清。
2、按照酶联免疫吸附测定(ELISA,BD)上清中的TNF-α。
结果如图3C,3D所示,结果显示,SMU-C80可以激活野生型THP-1细胞中TNF-α的表达;在THP-1(TLR2-/-)细胞中,SMU-C80不能激活TNF-α的表达。
上述实施例的说明只是用于理解本发明的方法及其核心思想。应当指出,对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也将落入本发明权利要求的保护范围内。
Claims (8)
8.根据权利要求6或7所述的药物组合物,其特征在于,所述药物组合物为注射制剂、口服制剂或外用制剂。
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