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CN105384736A - 一种ⅳ型胶原酶抑制剂及合成方法 - Google Patents

一种ⅳ型胶原酶抑制剂及合成方法 Download PDF

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CN105384736A
CN105384736A CN201510709786.9A CN201510709786A CN105384736A CN 105384736 A CN105384736 A CN 105384736A CN 201510709786 A CN201510709786 A CN 201510709786A CN 105384736 A CN105384736 A CN 105384736A
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CN105384736B (zh
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涂国刚
李少华
匡滨海
刘亚
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Nanchang University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms

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Abstract

一种Ⅳ型胶原酶抑制剂，化学通式如下，R1=呋喃环，苯环；X=CH2，O；n=0,1；m=0，1；R2，R3，R4，R5为F，Cl，I，NO2，OCH3,1至5个碳原子的直链或支链烷烃。本发明还涉及到该Ⅳ型胶原酶抑制剂的合成方法，所设计的化合物均为小分子拟肽类化合物，合成工艺路线短，原材料易得，生产成本低。

Description

一种Ⅳ型胶原酶抑制剂及合成方法
技术领域
本发明涉及一种Ⅳ型胶原酶抑制剂及合成方法。
背景技术
基质金属蛋白酶是一类典型的含金属锌离子的蛋白酶，其活性催化中心含有催化锌离子。基质金属蛋白酶可由成纤维细胞、软骨细胞、成骨细胞、中性粒细胞或巨噬细胞产生，也可由肿瘤细胞产生。内源性组织抑制剂通过调节金属蛋白酶的活性而维持机体的内环境稳定。因此，基质金属蛋白酶表达增加或基质金属蛋白酶与组织抑制剂失衡将导致疾病，如肿瘤转移、类风湿性关节炎多发性硬化症等。研究发现基质金属蛋白酶抑制剂能抑制肿瘤的生长及转移。基底膜主要由Ⅳ型胶原组成并能阻止肿瘤细胞的侵袭。Ⅳ型胶原酶通过分解基底膜血管而使肿瘤细胞发生侵袭和转移。所以Ⅳ型胶原酶抑制剂能有效的阻止肿瘤细胞的侵袭和转移，Ⅳ型胶原酶抑制剂是寻找和开发抗肿瘤物的新领域。
发明内容
本发明的目的是提供一种Ⅳ型胶原酶抑制剂及合成方法。
本发明是这样来实现的，其化学通式为：
R1=呋喃环，苯环；X=CH2，O；n=0,1；m=0，1；R2，R3，R4，R5为F，Cl，I，NO2，OCH3,1至5个碳原子的直链或支链烷烃。
本发明的合成方法步骤是：
(1)5-(2,4-二氯苯基)-1,3,4-噻二唑-2-胺的制备：将2,4-二氯苯甲酸、硫代氨基脲、POCl3放于带有回流装置的圆底烧瓶中，回流反应1h，冷却至室温，用恒压滴液漏斗缓慢向圆底烧瓶中加入水，回流反应4h,冷却至室温，用氢氧化钠溶液调PH值，用循环水式真空泵趁热抽滤，固体用乙醇重结晶，干燥后得目的物。
(2)N-[2-[5-(2,4-二氯苯基)-1,3,4-噻二唑]]-2-呋喃酰胺的制备：将糠酸、氯化亚砜放于带回流装置的圆底烧瓶中，回流反应2h，放置室温，旋转蒸发器除去剩余的氯化亚砜，用无水二氯甲烷洗2次。冰浴下缓慢滴入含有5-(2,4-二氯苯基)-1,3,4-噻二唑-2-胺、无水三乙胺、二氯甲烷做溶剂的圆底烧瓶中，室温密封反应过夜，旋干，固体依次用水、1mol/LHCl、水、饱和碳酸氢钠、水、乙醇洗，干燥，用DMF、水重结晶,得固体目的物。
本发明的优点是：所设计的化合物均为小分子拟肽类化合物，合成工艺路线短，原材料易得，生产成本低。
具体实施方式
实施例：
(1)5-(2,4-二氯苯基)-1,3,4-噻二唑-2-胺的制备：
将9.74g（50mmol）2,4-二氯苯甲酸、4.65g（50mmol）硫代氨基脲、13mlPOCl3放于带有回流装置的圆底烧瓶中，在75℃下回流反应1h，冷却至室温，用恒压滴液漏斗缓慢向圆底烧瓶中加入55ml水，于110℃回流反应4h,冷却至室温，用50%氢氧化钠溶液调PH值至8，用循环水式真空泵趁热抽滤，固体用乙醇重结晶，干燥后得浅黄色目的物6.21g，产率：50.36%；mp:154-156℃.
(2)N-[2-[5-(2,4-二氯苯基)-1,3,4-噻二唑]]-2-呋喃酰胺的制备：
将1.71g(15mmol)糠酸、12ml氯化亚砜放于带回流装置的圆底烧瓶中，回流反应2h，放置室温，旋转蒸发器除去剩余的氯化亚砜，用无水二氯甲烷洗2次。冰浴下缓慢滴入含有3.7g(15mmol)5-(2,4-二氯苯基)-1,3,4-噻二唑-2-胺、9ml无水三乙胺、二氯甲烷做溶剂的圆底烧瓶中，室温密封反应过夜，旋干，固体依次用水、1mol/LHCl、水、饱和碳酸氢钠、水、乙醇洗，干燥，用DMF、水重结晶,得白色固体2.9g,产率：56.86%，mp:294-295℃。IR(KBr,cm-1):3126,1680,1533,1507,1321,1091;1HNMR(400MHz,DMSO)δ13.25(s,1H),8.17(d,J=8.4Hz,1H),8.08(s,1H),7.92(d,J=24.4Hz,1H),7.76(s,1H),7.62(d,J=8.5Hz,1H),6.78(d,J=1.6Hz,1H)；ESI-MS:m/z[M+H]+340.3.
(3)(2R)-N-[2-[5-苯基-1,3,4-噻二唑]]-2-羟基-苯乙酰胺的制备
将1.52g(10mmol)(R)-(-)-扁桃酸、1.7mL(20.5mmol)吡啶、20mL二氯甲烷和催化剂DMAP置于干燥的圆底烧瓶中，待完全溶解后逐滴加入2.6mL(20.5mmol)三甲基氯硅烷，室温搅拌4h。冷却至0°C，加入0.75mL(10.3mmol)二氯亚砜和两滴DMF，0℃搅拌1h，室温搅拌30min。冷却至0°C，加入1.95g(11mmol)5-苯基-1,3,4-噻二唑-2-胺和2.7mL(33mmol)吡啶，室温搅拌2h。将2.11g(11mmol)柠檬酸用20mL甲醇溶解，加入到反应瓶中，室温搅拌30min后倒入分液漏斗，用乙酸乙酯稀释，依次用1mol/L盐酸、饱和碳酸氢钠溶液和饱和食盐水各洗两遍，将有机相溶剂蒸除，用乙酸乙酯重结晶，干燥后得目标化合物。同样方法制备。黄色固体，产率80.6%,m.p.232-234°C;IR(KBr,ν):3300,2730,1703,1676,1549,1501cm-1;1HNMR(DMSO-d 6,400MHz)δ:12.75(1H,s,NH),7.94–7.89(2H,m,Ar-H),7.53(5H,dd,J=9.8,5.8Hz,Ar-H),7.38(2H,t,J=7.3Hz,Ar-H),7.31(1H,dd,J=8.4,6.1Hz,Ar-H),6.42(1H,d,J=4.8Hz,OH),5.38(1H,d,J=4.6Hz,7-CH);ESI-MSm/z312.1(M)+。
体外抑酶活性
底物MOCAc-Pro-Leu-Gly-Leu-Dap(Dnp)-Ala-Arg-NH2中具有荧光物质MOCAc，可用荧光分光光度计检测，底物中的Dap(Dnp)为荧光熄灭物，在没有明胶酶加入的情况下底物不显荧光，当在适宜的条件下加入明胶酶，明胶酶能分解底物，底物分解后Dap(Dnp)对MOCAc的荧光熄灭作用消失，释放出的荧光物MOCAc发出荧光，可通过荧光分光光度计检测其荧光的强度，从而可以确定明胶酶的活性，通过加入对明胶酶有抑制作用的目标化合物间接的反应Ⅳ型胶原酶抑制剂的活性大小。
96孔黑色酶标板，每孔加入20uL(5nmol/L)酶，然后加入5uL(100umol/L)化合物，混匀，37°C孵育15分钟。然后加入10uL(50umol/L)底物，再加入15uL缓冲液(50mmol/LHEPES,pH7.5,150mmol/LNaCl,5mmol/LCaCl2,0.01%Brij-35,1%DMSO)，混匀，37°C孵育15分钟。用酶标仪检测荧光信号，激发波长为328nm，发射波长为393nm。目标化合物对酶的抑制率={1-[(Flu化合物-Flu本底)/(Flu酶-Flu本底)]}×100%。
表1化合物的体外抑酶活性
表2化合物的体外抑酶活性

Claims (2)

1.一种Ⅳ型胶原酶抑制剂，其特征是化学通式为：
R1=呋喃环，苯环；X=CH2，O；n=0,1；m=0，1；R2，R3，R4，R5为F，Cl，I，NO2，OCH3,1至5个碳原子的直链或支链烷烃。
2.一种权利要求1所述的Ⅳ型胶原酶抑制剂的合成方法，其特征是合成方法步骤为：
(1)5-(2,4-二氯苯基)-1,3,4-噻二唑-2-胺的制备：将2,4-二氯苯甲酸、硫代氨基脲、POCl3放于带有回流装置的圆底烧瓶中，回流反应1h，冷却至室温，用恒压滴液漏斗缓慢向圆底烧瓶中加入水，回流反应4h,冷却至室温，用氢氧化钠溶液调PH值，用循环水式真空泵趁热抽滤，固体用乙醇重结晶，干燥后得目的物；(2)N-[2-[5-(2,4-二氯苯基)-1,3,4-噻二唑]]-2-呋喃酰胺的制备：将糠酸、氯化亚砜放于带回流装置的圆底烧瓶中，回流反应2h，放置室温，旋转蒸发器除去剩余的氯化亚砜，用无水二氯甲烷洗2次；冰浴下缓慢滴入含有5-(2,4-二氯苯基)-1,3,4-噻二唑-2-胺、无水三乙胺、二氯甲烷做溶剂的圆底烧瓶中，室温密封反应过夜，旋干，固体依次用水、1mol/LHCl、水、饱和碳酸氢钠、水、乙醇洗，干燥，用DMF、水重结晶,得固体目的物。
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CN113527225A (zh) * 2021-07-15 2021-10-22 南昌大学 一种丙烯酰噻二唑衍生物及其制备方法和应用
CN115925572A (zh) * 2022-12-12 2023-04-07 南京安杰新生物医药有限公司 一锅法合成米拉贝隆杂质

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CN113527225A (zh) * 2021-07-15 2021-10-22 南昌大学 一种丙烯酰噻二唑衍生物及其制备方法和应用
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