CN106866581B - 一种具有药物活性的1，3，4-硒二唑类化合物 - Google Patents

一种具有药物活性的1，3，4-硒二唑类化合物 Download PDF

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CN106866581B
CN106866581B CN201510929374.6A CN201510929374A CN106866581B CN 106866581 B CN106866581 B CN 106866581B CN 201510929374 A CN201510929374 A CN 201510929374A CN 106866581 B CN106866581 B CN 106866581B
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阮奔放
阮健昵福
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Hangzhou Jennifer Biotech Co ltd
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Abstract

本发明属于生物医药领域，具体涉及到一种具有药物活性的1，3，4‑硒二唑类化合物。由于硒杂环的种类不多，基于BPTES(噻二唑类化合物)具有很强的抑制肿瘤生长功能，我们用新的合成方法合成了有多种官能团取代的硒二唑类化合物，并通过测试证实了这些化合物对肿瘤的抑制作用，抗氧化作用和细胞保护功能；使硒二唑可以作为噻二唑的生物电子等排体进行取代；目前有很多药物都含有噻二唑，因此合成带多种官能团的硒二唑衍生物，进一步优化药用噻二唑类化合物活性，这将为新药物开发和应用等方面具有重要意义。

Description

一种具有药物活性的1，3，4-硒二唑类化合物
技术领域
本发明属于生物医药领域，具体涉及到一种具有药物活性的1，3，4-硒二唑类化合物。
背景技术
含硒的杂环具有抗氧化剂，抗炎，抗菌，抗病毒，抗肿瘤功效。硒化合物的抗肿瘤机制一般包括以下几个方面:具有细胞毒性作用,能够清除自由基,阻断癌细胞分裂增殖的信息传递,诱导细胞凋亡,调节机体免疫功能,抑制新生血管的生成和改变某些致癌物代谢的过程等。
有机硒化合物包括含硒杂环、二硒醚、硒醚、硒氰、甲基硒酸、含硒氨基酸(蛋白)、硒糖等几大类。含硒杂环化合物是有机硒化合物中的一大类,因其潜在的药理学活性引起越来越多的重视.比如依布硒啉(Ebselen)是最成功模拟谷胱甘肽过氧化物酶的小分子化合物，现已经进入三期临床研究。硒氰是硒化合物的一类，最早的硒氰要数4-亚苯基双(亚甲基)硒代氰酸酯(P-XSC)。硒唑呋喃对小鼠H1210白血病具有明显的抑制作用，硒唑呋喃也进入了I期临床的研究。1，3，4-硒二唑化合物对MCF-7人乳腺癌细胞表现出很好的抑制作用。硒形式的毒性较低，对小鼠的体重，肝毒性和肾毒很少，但却保留了硒对癌细胞的毒副作用。
发明内容
由于硒杂环的种类不多，基于BPTES(噻二唑类化合物)具有很强的抑制肿瘤生长功能，我们用新的合成方法合成了有多种官能团取代的硒二唑类化合物，并通过测试证实了这些化合物对肿瘤的抑制作用，抗氧化作用和细胞保护功能。使硒二唑可以作为噻二唑的生物电子等排体进行取代；目前有很多药物都含有噻二唑，因此合成带多种官能团的硒二唑衍生物，进一步优化药用噻二唑类化合物活性，这将为新药物开发和应用等方面具有重要意义；同时，我们也研究了一系列的取代硒脲化合物与取代羧酸在温和的条件下合成得到硒二唑的反应方法，这些各种不同的取代硒二唑类衍生物包括芳香族类衍生物等等都有良好的细胞抗氧化效果
本发明提供了一种具有药物活性的1，3，4-硒二唑类化合物，所述的化合物的化学结构式如下：
Figure GDA0002086670080000021
其中R1、R2每一个独立的取代基包含1～20个选自C、H、N、O、S、P、Si和卤素原子的原子，包括芳香环，芳香类杂环，取代烷基，酰胺，醚，脂类，卤素，硅烷类，硫醚，胺类，磷酸基团，亚砜类，磺酰基，氨基酸，含COOH官能团的天然产物；
其中Cn代表1-20个碳的碳链；
其中Cn1代表0-8个碳的碳链；
其中X为N、O、S中的一种。
优选地，所述的具有药物活性的1，3，4-硒二唑类化合物的化学结构式如下：
Figure GDA0002086670080000022
或者
Figure GDA0002086670080000023
或者
Figure GDA0002086670080000024
或者
Figure GDA0002086670080000025
或者
Figure GDA0002086670080000031
其中R3、R4、R5、R6、R7、R8每一个独立的取代基包含1～20个选自C、H、N、O、S、P、Si和卤素原子的原子，包括氢原子、芳香环，芳香类杂环，取代烷基，酰胺，羰基，醚，脂类，卤素，硅烷类，硫醚，胺类，磷酸基团，亚砜类，磺酰基，氨基酸，含COOH官能团的天然产物。
优选地，所述的具有药物活性的1，3，4-硒二唑类化合物的化学结构式如下：
Figure GDA0002086670080000032
其中R9为独立的取代基包含1～20个选自C、H、N、O、S、P、Si和卤素原子的原子，包括芳香环，芳香类杂环，取代烷基，酰胺，醚，脂类，卤素，硅烷类，硫醚，胺类，磷酸基团，亚砜类，磺酰基，氨基酸，含COOH官能团的天然产物。
优选地，所述的具有药物活性的1，3，4-硒二唑类化合物的化学结构式如下：
Figure GDA0002086670080000033
或者
Figure GDA0002086670080000034
其中R1’、R2’、R3’、R4’、R5’、R1”、R2”、R3”、R4”、R5”每一个独立的取代基包含1～50个选自C、H、N、O、S、P、Si和卤素原子的原子，包括氢原子、芳香类杂环，取代烷基，酰胺，醚，脂类，卤素，硅烷类，硫醚，胺类，磷酸基团，亚砜类，磺酰基，氨基酸，含COOH官能团的天然产物。
本发明还提供了如下具有药物活性的1，3，4-硒二唑类化合物，所述的化合物的化学结构式如下：
Figure GDA0002086670080000041
或者
Figure GDA0002086670080000042
其中R1’、R2’、R3’、R4’、R5’、R1”、R2”、R3”、R4”、R5”每一个独立的取代基包含1～50个选自C、H、N、O、S、P、Si和卤素原子的原子，包括氢原子、芳香类杂环，取代烷基，酰胺，醚，脂类，卤素，硅烷类，硫醚，胺类，磷酸基团，亚砜类，磺酰基，氨基酸，含COOH官能团的天然产物。
其中Cn4代表1-20个碳的碳链；
本发明提供了一类具有药物活性的1，3，4-硒二唑类化合物，所述的化合物的化学结构式如下：
Figure GDA0002086670080000051
Figure GDA0002086670080000061
Figure GDA0002086670080000071
上述任一所述的具有药物活性的1，3，4-硒二唑类化合物在制备具有抗氧化功能以及细胞保护功能的药物中的应用。
本发明还提供了一系列的具有药物活性的1，3，4-硒二唑类化合物，其化学结构式如下：
Figure GDA0002086670080000081
Figure GDA0002086670080000091
Figure GDA0002086670080000101
该类1，3，4-硒二唑类化合物的制备方法，制备化学方程式如下：
Figure GDA0002086670080000102
制备方法过程以苯基硒脲为例列举如下：
取代苯基硒脲(1mmol；或其它硒脲)，带羧酸基团化合物(0.2～4mmol)，与5mlPOCl3混合均匀搅拌。升温至50-80℃，反应0.5-12h，停止油浴加热，将反应液减压抽干，缓慢倒入冰水，抽滤得滤饼，柱层析分离，干燥。得到0.08g产物，产率87％。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动性的前提下，还可以根据这些附图获得其他的附图。
图1为本发明中相关化合物抗氧化作用示意图。
具体实施方式
下面结合实施例对本发明做进一步的详细说明，以下实施例是对本发明的解释而本发明并不局限于以下实施例。
实施例：
制备方法过程以苯基硒脲为例列举如下：
苯基硒脲(1mmol；或其它硒脲)，带羧酸基团化合物(0.2-4mmol)，与5mlPOCl3混合均匀搅拌。升温至50-80℃，反应0.5-12h，停止油浴加热，将反应液减压抽干，缓慢倒入冰水，抽滤得滤饼，柱层析分离，干燥。得到产物，产率40～95％。
2-溴乙基-N-苯基胺基-1,3,4-硒二唑：
Figure GDA0002086670080000111
m/z 332(100％,M+H+)
1H NMR(500MHz,)δ10.37(s,1H),7.65–7.53(m,2H),7.35(d,J＝9.0Hz,2H),6.99(dt,J＝7.4,3.7Hz,1H),3.6(t,J＝6.5Hz,2H),3.38-3.29(t,J＝6.5Hz,2H)
2-溴乙基-N-苯基胺基-1,3,4-硒二唑：
Figure GDA0002086670080000112
取代硒脲(1mmol；或其它硒脲)，与多官能团羧酸化合物(0.2-4mmol)，与5mlPOCl3混合均匀搅拌；升温至50-80℃，反应0.5-12h，停止油浴加热，将反应液缓慢倒入冰水、沉淀、柱层析分离，干燥；得到产物，产率40-95％。
m/z 332(100％,M+H+)
1H NMR(500MHz,)δ10.37(s,1H),7.65–7.53(m,2H),7.35(d,J＝9.0Hz,2H),6.99(dt,J＝7.4,3.7Hz,1H),3.6(t,J＝6.5Hz,2H),3.38-3.29(t,J＝6.5Hz,2H)
为了进一步探索各个反应条件对反应产率的影响，选取一组反应物在不同的反应条件下进行了探索，具体反应数据如下：
Figure GDA0002086670080000121
各种不同的反应物及其反应方程式如下，需要特别说明的是下述反应中的反应条件均在前述反应所提供的反应条件内及多官能团羧酸化合物(0.2～4mmol)，与5mlPOCl3混合均匀搅拌；升温至50～80℃，反应0.5～12h，停止油浴加热，将反应液缓慢倒入冰水、沉淀、柱层析分离，干燥；得到产物，反应产率在40-95％；还有包括说明书中其他未列出的化合物通式也能按此条件进行反应。
2-溴乙基-N-吡啶基胺基-1,3,4-硒二唑：
Figure GDA0002086670080000131
m/z 333(100％,M+H+)
1H NMR(500MHz,)δ10(s,1H),8.9(s,1H),8.1(d,J＝9.0Hz,2H),7.3(m,1H),3.6(t,J＝6.5Hz,2H),3.38-3.29(t,J＝6.5Hz,2H)
2-氯乙基-N-苯基胺基-1,3,4-硒二唑：
Figure GDA0002086670080000132
Mp:109-110℃
m/z 288(100％,M+H+)
1H NMR(500MHz,)δ10.37(s,1H),7.65–7.53(m,2H),7.35(d,J＝9.0Hz,2H),6.99(dt,J＝7.4,3.7Hz,1H),3.96(t,J＝6.5Hz,2H),3.38(t,J＝6.5Hz,2H)
2-氯乙基-N-苯基甲胺基-1,3,4-硒二唑：
Figure GDA0002086670080000133
Mp:109-110℃
m/z 302(100％,M+H+)
1H NMR(500MHz,)δ9(1H),7.65–7.53(m,2H),7.35(d,J＝9.0Hz,2H),6.99(dt,J＝7.4,3.7Hz,1H),3.96(m,J＝6.5Hz,4H),3.38-3.29(t,J＝6.5Hz,2H)
2-氯乙基-N-苯基乙胺基-1,3,4-硒二唑：
Figure GDA0002086670080000141
Mp:109-110℃
m/z 316(100％,M+H+)
1H NMR(500MHz,)δ9(1H),7.65–7.53(m,2H),7.35(d,J＝9.0Hz,2H),6.99(dt,J＝7.4,3.7Hz,1H),3.6(m,J＝6.5Hz,4H),3.38-3.29(t,J＝6.5Hz,4H)
2-氯乙基-N-二乙酸酯基苯基乙胺基-1,3,4-硒二唑：
Figure GDA0002086670080000142
Mp:109-110℃
m/z 316(100％,M+H+)
1H NMR(500MHz,)δ9(1H),7.65–7.53(m,3H),3.6(m,J＝6.5Hz,4H),3.38-3.29(t,J＝6.5Hz,4H),2.4(s,6H)
2-胍基-N-苯胺基-1,3,4-硒二唑：
Figure GDA0002086670080000143
Mp:109-110℃
m/z 296(100％,M+H+)
1H NMR(500MHz,)δ10.6(1H),7.65–7.53(m,2H),7.35(d,J＝9.0Hz,2H),6.99(dt,J＝7.4,3.7Hz,1H),3.2(2H)
5,5’-二乙基硫醚-二苯氨基-1,3,4-硒二唑
Figure GDA0002086670080000151
Mp＝172-174℃，m/z 534.4(100％,M+H+)
1H NMR(500MHz,DMSO-d6)δ10.37(d,J＝70.4Hz,2H),7.65–7.53(m,4H),7.35(d,J＝9.0Hz,4H),6.99(dt,J＝7.4,3.7Hz,2H),3.24(t,J＝7.2Hz,2H),3.06(t,J＝7.2Hz,2H),2.88(dt,J＝27.2,7.2Hz,4H)
二苯氨基-1,3,4-硒二唑
Figure GDA0002086670080000152
N5，N5′-diphenyl-[2，2′-bi(1，3，4-selenadiazole)]-5，5′-diamine
m/z 447(100％,M+H+)
1H NMR(500MHz,)δ10.26(s,2H),7.58(dd,J＝30.9,7.6Hz,4H),7.33(t,J＝7.9Hz,4H),6.99(t,J＝7.3Hz,2H),
5,5’-甲基-二苯氨基-1,3,4-硒二唑
Figure GDA0002086670080000153
Mp＝130-132℃
m/z 461(100％,M+H+)
1H NMR(500MHz，)δ10.15(s，2H)，7.51(d，J＝8.0Hz，4H)，7.24–7.17(m，4H)，6.90(t，J＝5.6Hz，2H)，3.45–3.35(s，2H).
5，5’-乙烷基-二苯氨基-1，3，4-硒二唑
Figure GDA0002086670080000161
Mp＝160-161℃
m/z 475(100％，M+H+)
1H NMR(500MHz，)δ10.25(s，2H)，7.61(d，J＝8.0Hz，4H)，7.34–7.27(m，4H)，6.98(t，J＝5.6Hz，2H)，1.32–1.20(m，4H).
5，5’-丙基-二苯氨基-1，3，4-硒二唑
Figure GDA0002086670080000162
5，5′-(propane-1，3-diyl)bis(N-phenyl-1，3，4-selenadiazol-2-amine)
Mp：198-201℃
m/z 489(100％，M+H+)
1H NMR(500MHz，)δ9.97(s，2H)，7.62(d，J＝8-0Hz，4H)，7.33(t，J＝7.5Hz，4H)，6.99(t，J＝7.0Hz，2H)，3.02(t，J＝7.2Hz，4H)，2.15–2.07(m，2H).
5，5’-丁烷基-二苯氨基-1，3，4-硒二唑
Figure GDA0002086670080000163
Mp＝205-208℃
m/z 503(100％，M+H+)
1H NMR(500MHz,)δ10.35(s,2H),7.61(d,J＝7.9Hz,2H),7.55(d,J＝8.0Hz,2H),7.33(t,J＝7.6Hz,4H),6.99(t,J＝6.9Hz,2H),3.40 2.96-2.79(m,4H),1.77-1.67(m,4H).
5,5’-戊烷基-二苯氨基-1,3,4-硒二唑
Figure GDA0002086670080000171
Mp＝165-171℃
m/z 517(100％,M+H+)
1H NMR(500MHz,)δ10.34(s,2H),7.61(d,J＝7.8Hz,4H),7.32(t,J＝7.9Hz,4H),6.98(t,J＝7.3Hz,2H),2.91-2.77(t,J＝7.4Hz,4H),1.77–1.67(m,4H),1.51–1.40(m,2H).
2-丁酸甲酯基-5-苯氨基-1,3,4-硒二唑
Figure GDA0002086670080000172
m/z 325(100％,M+H+)
1H NMR(500MHz,)δ10.34(s,1H),7.61(d,J＝7.8Hz,2H),7.32(t,J＝7.9Hz,2H),6.98(t,J＝7.3Hz,1H),3.65(s,3H),2.32(t,J＝7.2Hz,2H),1.9(m,2H),1.5(t,J＝7.2Hz,2H)
2-水杨酰胺戊烷基5-苯胺基-1,3,4-硒二唑
Figure GDA0002086670080000173
m/z 472(100％,M+H+)
1H NMR(500MHz,)δ10.34(s,1H),7.61-6.98(m,9H),2.4(s,3H),3.18-1.3(m,10H),,
苯乙酰胺戊烷基5-苯胺基-1,3,4-硒二唑
Figure GDA0002086670080000181
m/z 428(100％,M+H+)
1H NMR(500MHz,)δ10.34(s,1H),7.61-6.98(m,10H),3.18-1.3(m,10H),,
2-叔丁氧羰基氨基戊烷基-5-萘胺基-1,3,4-硒二唑
Figure GDA0002086670080000182
m/z 460(100％,M+H+)
1H NMR(500MHz,)δ10.34(s,1H),7.61-6.98(m,7H),3.18-1.3(m,10H),,1.4(s,9H).
2-叔丁氧羰基氨基戊烷-5-二硝基苯胺基-1,3,4-硒二唑
Figure GDA0002086670080000183
m/z 500(100％,M+H+)
1H NMR(500MHz,)δ10.34(s,1H),8.5-6.98(m,3H),3.18-1.3(m,10H),,1.4(s,9H).
2-叔丁氧羰基氨基戊烷基5-邻氟基苯胺基-1,3,4-硒二唑
Figure GDA0002086670080000184
m/z 428(100％,M+H+)
1H NMR(500MHz)δ10.34(s,1H),8.06(d,J＝7.8Hz,1H),7.59(m,2H),7.46(m,1H),7.37(d,J＝8.0，1H)，3.18-1.3(m，10H)，1.4(s，9H).
2-叔丁氧羰基氨基戊烷基5-间甲氧基苯胺基-1,3,4-硒二唑
Figure GDA0002086670080000191
m/z 440(100％,M+H+)
1H NMR(500MHz)δ10.34(s,1H),8.06(s,J＝7.8Hz,1H),7.59(m,2H),7.46(d,J＝8.0,1H),7.37(d,J＝8.0,1H),3.8(s,3H),3.18-1.3(m,10H),1.4(s,9H).
2-叔丁氧羰基氨基戊烷基-5-对三氟甲基苯胺基-1,3,4-硒二唑
Figure GDA0002086670080000192
m/z 478(100％,M+H+)
1H NMR(500MHz)δ10.34(s,1H),8.06(d,J＝7.8Hz,2H),7.59(m,1H),7.46(d,J＝7.8,2H),3.18-1.3(m,10H),1.4(s,9H).
2-(N-叔丁氧羰基吡咯烷基5-苯胺基)-1,3,4-硒二唑
Figure GDA0002086670080000193
m/z 394(100％,M+H+)
1H NMR(500MHz)δ10.34(s,1H),8.06(d,J＝7.8Hz,2H),7.59-7.46(m,3H),3.4(m,3H),1.7-1.5(m,4H),1.4(s,9H).
2-(N-叔丁氧羰基氨基戊烷基苯乙基)-5-苯胺基-1,3,4-硒二唑
Figure GDA0002086670080000194
m/z 444(100％,M+H+)
1H NMR(500MHz)δ10.34(s,1H),8.06(m,J＝7.8Hz,4H),7.59-7.46(m,7H),4-3.2(m,3H),1.4(s,9H).
2-(N-叔丁氧羰基氨基戊烷基)对三甲基硅氧基苯乙基-5-苯胺基-1,3,4-硒二唑
Figure GDA0002086670080000201
m/z 532(100％,M+H+)
1H NMR(500MHz)δ10.34(s,1H),8.06(m,J＝7.8Hz,4H),7.59-7.46(m,6H),4-3.2(m,3H),1.4(s,9H),0.2(s,9H)
2-(N-叔丁氧基羰基氨基咪唑乙基)-5-苯胺基-1,3,4-硒二唑
Figure GDA0002086670080000202
m/z 434(100％,M+H+)
1H NMR(500MHz)δ10.34(s,1H),8.06(m,J＝7.8Hz,5H),7.59-7.46(m,3H),4-3(m,3H),1.4(s,9H)
间二苯氨基-1,3,4-硒二唑基苯
Figure GDA0002086670080000203
m/z 523(100％,M+H+)
1H NMR(500MHz)δ9.97(s,2H),8.4(s,1H),8.1(d,J＝7.5,2H),7.62(m,5H),7.33(t,J＝7.5Hz,4H),6.99(t,J＝7.0Hz,2H)
邻二苯氨基-1,3,4-硒二唑基苯
Figure GDA0002086670080000211
m/z 523(100％,M+H+)
1H NMR(500MHz)δ9.97(s,2H),8.1(d,J＝7.5,2H),7.62(m,6H),7.33(t,J＝7.5Hz,4H),6.99(t,J＝7.0Hz,2H)
所述1,3,4-硒二唑的相关衍生化合物的抗氧化作用：
上述的1,3,4-硒二唑的相关衍生化合物都具有抗氧化作用，保护各类细胞生长：PC12细胞(1000个每孔)在双氧水环境或无氧条件下，加1,3,4-硒二唑类化合物(10000nM)，生长3天，观察细胞生长，加化合物可以生长，不加化合物的细胞不存活；具体效果见附图1。
此外，需要说明的是，本说明书中所描述的具体实施例，其化合物等所取名称等可以不同。凡依本发明专利构思及原理所做的等效或简单变化，均包括于本发明专利的保护范围内。本发明所属技术领域的技术人员可以对所描述的具体实施例做各种各样的修改或补充或采用类似的方式替代，只要不偏离本发明的结构或者超越本权利要求书所定义的范围，均应属于本发明的保护范围。

Claims (2)

1.一种具有药物活性的1，3，4-硒二唑类化合物，其特征在于所述的化合物的化学结构式如下：
Figure FDA0002391979580000011
其中R1’、R2’、R3’、R4’、R5’、R1”、R2”、R3”、R4”、R5”均为H。
2.根据权利要求1所述的具有药物活性的1，3，4-硒二唑类化合物在制备具有抗氧化功能以及细胞保护功能的药物中的应用。
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