CN103382204A - 含苯并1,4-噁二烷的1,3,4-噁二唑衍生物的制备方法及其用途 - Google Patents
含苯并1,4-噁二烷的1,3,4-噁二唑衍生物的制备方法及其用途 Download PDFInfo
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- CN103382204A CN103382204A CN2013101165810A CN201310116581A CN103382204A CN 103382204 A CN103382204 A CN 103382204A CN 2013101165810 A CN2013101165810 A CN 2013101165810A CN 201310116581 A CN201310116581 A CN 201310116581A CN 103382204 A CN103382204 A CN 103382204A
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- oxadioxane
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- oxadiazole
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- 238000002360 preparation method Methods 0.000 title claims abstract description 60
- 150000005072 1,3,4-oxadiazoles Chemical class 0.000 title claims abstract description 18
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- 230000003078 antioxidant effect Effects 0.000 claims abstract description 19
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 17
- 125000005605 benzo group Chemical group 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000011161 development Methods 0.000 claims description 4
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- 239000002244 precipitate Substances 0.000 claims description 4
- 238000004809 thin layer chromatography Methods 0.000 claims description 4
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- OHDRQQURAXLVGJ-HLVWOLMTSA-N azane;(2e)-3-ethyl-2-[(e)-(3-ethyl-6-sulfo-1,3-benzothiazol-2-ylidene)hydrazinylidene]-1,3-benzothiazole-6-sulfonic acid Chemical compound [NH4+].[NH4+].S/1C2=CC(S([O-])(=O)=O)=CC=C2N(CC)C\1=N/N=C1/SC2=CC(S([O-])(=O)=O)=CC=C2N1CC OHDRQQURAXLVGJ-HLVWOLMTSA-N 0.000 description 7
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Abstract
含苯并1,4-噁二烷的1,3,4-噁二唑衍生物的制备方法及其用途。一类含苯并1,4-噁二烷的1,3,4-噁二唑化合物,其特征是它有如下通式:
Description
技术领域
本发明涉及一类含苯并1,4-噁二烷的1,3,4-噁二唑类衍生物制备方法与作为抗氧化物质的用途。
背景技术
需氧生物在进行生命活动的过程中,不可避免地会在生物体内产生活性氧(reactive oxygen species,ROS),正常情况下,生物体存在一套防御体系阻止这些活性氧对生物大分子的氧化损伤,但是当活性氧过量产生,生物体内的防御体系不足以抵御时,这些活性氧分子产生的氧化作用,会损伤人体内的脂质、蛋白质、糖类以及细胞与器官中的DNA,从而导致细胞膜的损伤,或生物大分子如DNA和酶的交联结构被破坏,甚至可能因为DNA的断裂以及脂质过氧化而引发细胞凋亡。由此产生的直接后果是诱发多种疾病,如:肿瘤、炎症、动脉粥样硬化、心血管疾病等。因此,关于活性氧与生物体之间的作用的研究就显得尤为重要。
抗氧化剂是有助于捕获并中和活性氧,从而消除其对生物体损害的一类物质。在相对较低的可氧化物(糖类、脂质、DNA或蛋白质)浓度下,能有效地延缓或阻止此类物质发生氧化反应的物质。因此,开发抗氧化剂对于治疗各种与氧化相关的疾病有着重要意义。
含苯并1,4-噁二烷骨架结构的化合物由于其在化学、医药研究中所表现的的良好活性一直被广泛关注,已被多项研究证明具有保肝、抑制肿瘤细胞生长等活性。1,3,4-噁二唑杂环化合物具有杀菌、止痛、消炎、抗肿瘤等生物活性。1,3,4-噁二唑硫醇外环的-SH与各种亲电试剂进行反应,可以生成硫醚,或进一步转化为砜或亚砜类化合物,具有广泛的应用。同时,1,3,4-噁二唑环上的活泼氢还可以与醛、仲胺或伯胺的盐酸盐缩合,生成具有广泛生物活性的杂环曼尼希碱。
本发明利用含有1,4-苯并噁二烷的1,3,4-噁二唑,通过曼尼希反应引入各种取代苯胺,制成含有1,4-苯并噁二烷的1,3,4-噁二唑衍生物,并研究它们的抗氧化活性,为新型抗氧化药物的研发提供研究基础。
发明内容
本发明的目的在于提供一类新型含苯并1,4-噁二烷的1,3,4-噁二唑类衍生物以及它们的制备方法与用途。
本发明的技术方案如下:
一类含苯并1,4-噁二烷的1,3,4-噁二唑衍生物,其特征是它有如下通式:
一种制备上述含苯并1,4-噁二烷的1,3,4-噁二唑类衍生物的方法,它由下列步骤组成:
步骤1.将按通法制备的含苯并1,4-噁二烷的1,3,4-噁二唑溶于适量乙醇溶液中,加入40%甲醛水溶液,搅拌10分钟后,再分多次缓慢滴加含各种取代苯胺的乙醇溶液,必要时可用冰浴保持反应体系温度,反应1小时,用薄层色谱(TLC)跟踪反应。
步骤2.将步骤1所得反应液冷却、结晶,将析出的沉淀物过滤,用冰乙醇洗涤三次,再用加入大量乙醇,微热(<50℃)使其全部溶解,放置进行重结晶,即得到本发明所述的含苯并1,4-噁二烷的1,3,4-噁二唑衍生物。
上述制法所述步骤1中的40%甲醛溶液的用量可以是每毫摩尔含苯并1,4-噁二烷的1,3,4-噁二唑加入105μL40%甲醛溶液(相当于甲醛1mmol)。
上述制法所述步骤1中的各种取代的苯胺用量可以是每毫摩尔含苯并1,4-噁二烷的1,3,4-噁二唑加入10mL含1mmol各种取代苯胺的乙醇溶液。
本发明所制得的含苯并1,4-噁二烷的1,3,4-噁二唑类衍生物,通过DPPH、ABTS、FRAP法测试,有着明显的体外抗氧化作用,并在抑制小鼠肝微粒体脂质过氧化(lipid peroxidation,LPO)实验中验证了其抗氧化作用。因此,本发明的含苯并1,4-噁二烷的1,3,4-噁二唑类衍生物可以应用于制备新型抗氧化剂。
具体实施方式
实施例一:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物1)的制备
将1mmol新制得的含苯并1,4-噁二烷的1,3,4-噁二唑溶于30mL乙醇中,加入105μL40%甲醛水溶液,室温搅拌10min,分多次缓慢滴加10mL含1mmol苯胺的乙醇溶液,反应1小时后停止。所得反应液置入冰箱4℃结晶,经过12小时后将析出的沉淀物过滤,用冰乙醇进行洗涤,每次30mL,洗涤三次,在微热(<50℃)条件下用大量乙醇溶解沉淀物,放置重结晶,得到白色针状晶体的目标化合物。产率63%。Mp:147℃.1H-NMR(400MHz,CDCl3)δ7.41-7.44(m,2H,),7.27(t,J=8.0Hz,2H),6.94-7.02(m,3H),6.87(t,1H,J=7.3Hz),5.59(s,2H),5.18(br s,1H),4.33-4.36(m,4H).MS(ESI):342.08(C17H15N3O3S,[M+H]+).
实施例二:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(2-氟苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物2)的制备
制备方法同实施例一。以2-氟苯胺替代苯胺,得到无色针状晶体的目标化合物。产率77%。Mp:171℃.1H-NMR(400MHz,CDCl3)δ7.37-7.42(m,2H),7.22(td,1H,J=8.04,1.32Hz),7.02-7.04(d,1H,J=8.56Hz),6.97-7.00(m,1H),6.93(d,1H,J=8.36Hz),6.73-6.78(m,1H),5.55(s,2H),5.32(br s,1H),4.28-4.32(m,4H).MS(ESI):359.07(C17H14FN3O3S,[M+H]+).
实施例三:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(3-氟苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物3)的制备
制备方法同实施例一。以3-氯苯胺替代苯胺,得到无色至浅白色针状晶体的目标化合物。产率54.2%。Mp:149-150℃.1H NMR(400MHz,CDCl3)δ7.38-7.44(m,2H),7.15(dd,1H,J=15.0 7.8Hz),6.93(d,J=8.52Hz,1H),6.67(dd,1H,J=9.72 1.32Hz),6.51(m,1H),5.48(s,2H),5.22(br s,1H),4.28-4.33(m,4H).MS(ESI):359.07(C17H14FN3O3S,[M+H]+).
实施例四:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(4-氟苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物4)的制备
制备方法同实施例一。以4-氯苯胺替代苯胺,得到无色针状晶体的目标化合物。产率54.2%。Mp:189-190℃.1H NMR(400MHz,CDCl3)δ7.37-7.40(m,3H),6.89-6.95(m,2H),6.84-6.87(m,2H),6.01(s,1H),5.47(s,2H),4.23-4.37(m,4H).MS(ESI):359.07(C17H14FN3O3S,[M+H]+).
实施例五:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(2,6-二氟苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物5)的制备
制备方法同实施例一。以2,6-二氟苯胺替代苯胺,得到白色针状晶体的目标化合物。产率50.1%。Mp:148℃.1H NMR(400MHz,CDCl3)δ7.37-7.39(m,2H),6.94-6.98(m,2H),6.86-6.89(m,2H),5.62(s,2H),5.09(br s,1H),4.32-4.37(m,4H).MS(ESI):378.07(C17H13F2N3O3S,[M+H]+).
实施例六:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(3,4,5-三氟苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物6)的制备
制备方法同实施例一。以3,4,5-三氟苯胺替代苯胺,得到白色针状晶体的目标化合物。产率67.4%。Mp:203-204℃.1H NMR(400MHz,CDCl3)δ7.41-7.49(m,3H,H-),6.99(d,1H,J=8.8),5.71(t,1H,J=7.5),5.57(d,2H,J=7.6),4.33-4.38(m,4H).MS(ESI):396.05(C17H13F2N3O3S,[M+H]+).
实施例七:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(2-三氟甲基苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物7)的制备
制备方法同实施例一。以2-三氟甲基苯胺替代苯胺,得到白色针状晶体的目标化合物。产率80.2%。Mp:185℃.1H NMR(400MHz,CDCl3)δ7.33-7.40(m,3H),6.90-6.94(m,2H),6.81-6.85(m,3H),5.58(s,2H),5.05(br s,1H),4.33-4.37(m,4H).MS(ESI):410.07(C18H14F3N3O3S,[M+H]+).
实施例八:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(3-三氟甲基苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物8)的制备
制备方法同实施例一。以3-三氟甲基苯胺替代苯胺,得到白色针状晶体的目标化合物。产率84.5%。Mp:201℃.1H NMR(400MHz,CDCl3)δ7.37-7.40(m,3H),7.32(t,1H,J=7.9Hz),7.20(s,1H),7.08(t,1H,J=8.6Hz),6.93(dd,1H,J=7.9,0.9Hz),5.53(s,2H),5.31(br s,1H),4.28-4.32(m,4H).MS(ESI):410.07(C18H14F3N3O3S,[M+H]+).
实施例九:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(2,5-二三氟甲基苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物9)的制备
制备方法同实施例一。以3,5-二三氟甲基苯胺替代苯胺,得到白色粉末目标化合物。产率77.3%。Mp:177-178℃.1H NMR(400MHz,CDCl3)δ7.38-7.40(m,1H),7.33-7.35(m,2H), 6.91(dd,1H,J=8.6,0.8Hz),6.81-6.85(m,2H)5.58(s,2H),5.05(br s,1H),4.27-4.33(m,4H).MS(ESI):478.08(C19H13F6N3O3S,[M+H]+).
实施例十:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(2-氯苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物10)的制备
制备方法同实施例一。以2-氯苯胺替代苯胺,得到白色粉末目标化合物。产率60.7%。Mp:139-140℃.1H NMR(400MHz,CDCl3)δ7.43-7.54(m,4H),7.34(d,1H,J=8.2Hz),6.98(d,1H,J=8.0Hz),6.93(t,1H,J=7.6Hz),5.74(t,1H,J=7.2Hz),5.61(d,2H,J=7.6,Hz),4.33-4.37(m,4H).MS(ESI):375.04(C17H14ClN3O3S,[M+H]+).
实施例十一:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(3-氯苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物11)的制备
制备方法同实施例一。以3-氯苯胺替代苯胺,得到白色粉末目标化合物。产率60.7%。Mp:139-140℃.1H NMR(400MHz,CDCl3)δ7.43-7.54(m,4H),7.34(d,1H,J=8.2Hz),6.98(d,1H,J=8.0Hz),6.93(t,1H,J=7.6Hz),5.74(t,1H,J=7.2Hz),5.61(d,2H,J=7.6,Hz),4.33-4.37(m,4H).MS(ESI):375.04(C17H14ClN3O3S,[M+H]+).
实施例十二:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(4-氯苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物12)的制备
制备方法同实施例一。以4-氯苯胺替代苯胺,得到白色粉末目标化合物。产率70.7%。Mp:216℃.1H NMR(400MHz,CDCl3)δ7.40-7.43(m,2H),7.15(t,1H,J=8.0Hz),6.95-6.97(m,2H),6.80-6.83(m,2H),5.50(s,2H),5.22(br s,1H),4.31-4.35(m,4H).MS(ESI):375.04(C17H14ClN3O3S,[M+H]+).
实施例十三:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(2,4-二氯苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物13)的制备
制备方法同实施例一。以2,4-二氯苯胺替代苯胺,得到白色粉末目标化合物。产率88.6%。Mp:155-156℃.1H NMR(400MHz,CDCl3)δ7.38-7.40(m,2H),7.28(d,1H,J=1.6Hz),7.14 -7.20(m,2H),6.93(d,1H,J=8.1Hz),5.65(t,1H,J=7.7Hz),5.54(d,2H,J=7.6Hz),4.28-4.32(m,4H).MS(ESI):410.01(C17H13Cl2N3O3S,[M+H]+).
实施例十四:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(2,5-二氯苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物14)的制备
制备方法同实施例一。以2,5-二氯苯胺替代苯胺,得到白色粉末目标化合物。产率61.3%。Mp:166-167℃.1H NMR(400MHz,CDCl3)δ7.40-7.42(m,2H),7.32(d,1H,J=2.5Hz),7.18(d,1H,J=8.4Hz),6.95(d,1H,J=8.5Hz),6.74(dd,1H,J=8.3 2.2Hz),5.72(t,1H,J=7.6,Hz),5.54(d,2H,J=7.7Hz),4.29-4.33(m,4H).MS(ESI):410.01(C17H13Cl2N3O3S,[M+H]+)..
实施例十五:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(3,4-二氯苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物15)的制备
制备方法同实施例一。以3,4-二氯苯胺替代苯胺,得到白色粉末目标化合物。产率51.0%。Mp:168-169℃.1H NMR(400MHz,CDCl3)δ7.38-7.40(m,2H),7.24(s,1H),7.06(d,1H,J=2.7Hz),6.94(d,1H,J=4.6Hz),6.78(dd,1H,J=4.7 2.8Hz),5.46(s,2H),5.18(br s,1H),4.29-4.33(m,4H).MS(ESI):410.01(C17H13Cl2N3O3S,[M+H]+).
实施例十六:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(2-溴苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物16)的制备
制备方法同实施例一。以2-溴苯胺替代苯胺,得到浅黄色粉末目标化合物。产率80.5%。Mp:158-159℃.1H NMR(400MHz,CDCl3)δ7.38-7.45(m,3H),7.22-7.24(m,2H),6.93(d,1H,J=8.4Hz),6.68-6.72(m,1H),5.69(br s,1H),5.57(s,2H),4.28-4.32(m,4H).MS(ESI):420.00(C17H14BrN3O3S,[M+H]+).
实施例十七:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(3-溴苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物17)的制备
制备方法同实施例一。以3-溴苯胺替代苯胺,得到白色粉末目标化合物。产率77.8%。Mp:150-151℃.1H NMR(400MHz,CDCl3)δ7.38-7.41(m,2H),7.05-7.11(m,2H),6.93- 6.95(m,2H),6.83(dd,1H,J=4.0 1.6Hz),5.47(d,2H,J=4.0Hz),5.17(br s,1H),4.29-4.33(m,4H).MS(ESI):420.00(C17H14BrN3O3S,[M+H]+).
实施例十八:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(4-溴苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物18)的制备
制备方法同实施例一。以4-溴苯胺替代苯胺,得到白色晶体目标化合物。产率59.0%。Mp:205-206℃.1H NMR(400MHz,CDCl3)δ7.37-7.40(m,2H),7.05-7.11(m,2H),6.93-6.94(m,2H),6.84(dd,1H,J=4.1 1.7Hz),5.47(d,2H,J=5.2Hz),5.18(br s,1H),4.28-4.32(m,4H).MS(ESI):420.00(C17H14BrN3O3S,[M+H]+).
实施例十九:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(2,4-二溴苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物19)的制备
制备方法同实施例一。以2,4-二溴苯胺替代苯胺,得到白色晶体目标化合物。产率76.2%。Mp:187-188℃.1H NMR(400MHz,CDCl3)δ7.62(d,1H,J=2.2Hz),7.42-7.45(m,2H),7.38(dd,1H,J=8.7 2.1Hz),7.16(d,1H,J=8.8Hz),6.98(dd,1H,J=8.2 0.4Hz),5.72(t,1H,J=7.7Hz),5.58(d,2H,J=7.8Hz),4.33-4.37(m,4H).MS(ESI):497.90(C17H13Br2N3O3S,[M+H]+).
实施例二十:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(2-硝基苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物20)的制备
制备方法同实施例一。以2-硝基苯胺替代苯胺,得到黄色粉末目标化合物。产率84.1%。Mp:192-193℃.1H NMR(400MHz,CDCl3)δ8.80(t,1H,J=6.6Hz),8.20(d,1H,J=8.4Hz),7.55(t,1H,J=7.1Hz),7.48(d,1H,J=8.5Hz),7.39-7.42(m,2H),6.94(d,1H,J=8.4Hz),6.85(t,1H,J=8.1Hz),5.66(d,2H,J=7.8Hz),4.33-4.37(m,4H).MS(ESI):387.07(C17H14N4O5S,[M+H]+).
实施例二十一:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(3-硝基苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物21)的制备
制备方法同实施例一。以3-硝基苯胺替代苯胺,得到黄色粉末目标化合物。产率85.0%。 Mp:181-181℃.1H NMR(400MHz,CDCl3)δ7.84(t,1H,J=2.1Hz),7.65(dd,1H,J=10.5 0.6Hz),7.39-7.41(m,2H),7.35(d,1H,J=8.0Hz),7.22(dd,1H,J=7.6 0.8Hz),5.56(d,2H,J=7.9Hz),5.44(t,1H,J=4.2Hz),4.28-4.32(m,4H).MS(ESI):387.07(C17H14N4O5S,[M+H]+).
实施例二十二:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(4-硝基苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物22)的制备
制备方法同实施例一。以4-硝基苯胺替代苯胺,得到黄色粉末目标化合物。产率82.7%。Mp:234-234℃.1H NMR(400MHz,CDCl3)δ7.40-7.42(m,2H),7.32(d,1H,J=2.2Hz),7.18(d,1H,J=8.4Hz),6.96(d,1H,J=8.8Hz),6.73(dd,1H,J=8.4 2.2Hz),5.71(t,1H,J=7.6Hz),5.54(d,2H,J=7.7Hz),4.29-4.33(m,4H).MS(ESI):387.07(C17H14N4O5S,[M+H]+).
实施例二十三:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(2-氯-4-硝基苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物23)的制备
制备方法同实施例一。以2-氯-4-硝基苯胺替代苯胺,得到浅黄色粉末目标化合物。产率59.2%。Mp:167-168℃.1H NMR(400MHz,CDCl3)δ8.24(d,1H,J=2.5Hz),8.14(dd,1H,J=8.3 2.5Hz),7.39-7.41(m,2H),7.35(d,1H,J=9.4Hz),6.95(d,1H,J=8.0Hz),6.21(t,1H,J=7.8Hz),5.64(d,2H,J=7.5Hz),4.29-4.33(m,4H).MS(ESI):421.03(C17H13ClN4O5S,[M+H]+).
实施例二十四:5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-3-(2-甲基苯基氨基甲基)-1,3,4-噁二唑-2(3H)-硫酮(化合物24)的制备
制备方法同实施例一。以2-甲基苯胺替代苯胺,得到无色晶体目标化合物。产率69.7%。Mp:147-147℃.1H NMR(400MHz,CDCl3)δ7.42-7.44(m,2H),7.19(d,1H,J=7.4Hz),7.11-7.15(m,2H),6.97(d,1H,J=8.2Hz),6.81(t,1H,J=5.1Hz),5.62(d,2H,J=5.2Hz),5.15(br s,1H),4.23-4.37(m,4H),2.27(s,3H).MS(ESI):356.10(C18H17N3O3S,[M+H]+).
实施例二十五:分别采用DPPH、ABTS和FRAP法测定含苯并1,4-噁二烷的1,3,4-噁二唑类衍生物体外抗氧化活性,以BHT作为阳性对照。试验方法如下:
DPPH自由基清除法测定抗氧化活性:于96孔板中,分别加入100μL不同浓度的样品溶液和100μL2×10-4mol/L的DPPH溶液(A测),100μL样品溶液中和100μL无水乙醇(A 样),100μL DPPH溶液和100μL无水乙醇(A空白),25℃反应30min后,使用酶标仪测定 517nm处吸光值,重复三次,按照公式SC%=[1-(A测-A样)/A空白]×100%计算清除率。结果以IC50表示,即当达到50%的DPPH自由基清除率时,待测样品液(抗氧化剂)的浓度。
ABTS法测定抗氧化活性:ABTS·+由5mL7mmol/L ABTS溶液和88μL140mmol/LK2S2O8水溶液避光反应12小时后生成,该溶液提前1天配制,并且必须当天使用,使用前用乙醇稀释到吸光值在732nm处为0.70±0.02。20μL样品溶液加到180μLABTS·+溶液中避光反应10min进行吸光值测定,最终结果以IC50表示,即当达到50%的ABTS自由基清除率时,待测样品液(抗氧化剂)的浓度。
FRAP法测定抗氧化活性:配制4mg/mL的样品乙醇溶液备用,采用96孔U底微孔板进行测试。每排的第1孔加入20μL样品液,其它孔(所用总孔数根据IC50范围确定)各加入20μL乙醇,采用二倍稀释法梯度稀释,配制成系列浓度样品液,最后加入180μL FRAP工作液(300mmol/L pH3.6醋酸盐缓冲液25mL,10mmol/L TPTZ2.5mL,20mmol/L FeCl32.5mL,现配现用),37℃反应4min后用酶标仪测定593nm处吸光值,重复三次。空白对照为20μL乙醇加180μL FRAP工作液,样品空白对照为20μL样品溶液加180μL醋酸盐缓冲液,阳性对照为BHT。以FeSO4·7H2O标准曲线作为参考(0.1-1.0mmol/L,n=6,标准曲线为Y=1.2241X+0.0460,R2=0.9963),结果以C0.5FRAP表示,即具有0.5mmol/L FeSO4·7H2O抗氧化能力的样品浓度。
含苯并1,4-噁二烷的1,3,4-噁二唑类衍生物(化合物1-24)三种化学方法抗氧化结果如表1所示。从中可以看出化合物1、5、6、24具有较好的体外抗氧化活性,化合物20、21、23抗氧化活性相对较弱。
实施例二十六:选取实施实例二十五中具有代表性的化合物(1、5、6、20、21、23和24),采用抑制小鼠肝微粒体脂质过氧化(LPO)方法测定其抗氧化活性。实验方法如下:
小鼠肝微粒体的制备:将6-8周龄ICR小鼠禁食24h后处死,取出肝脏,用预冷的生理盐水清洗,吸干称重并剪碎,按5mL/g肝湿重的比例加入生理盐水,用匀浆器制成匀浆。0-4℃条件下,1×104g,4℃离心30min,取上清于1×105g,4℃离心40min,所得沉淀即为小鼠肝脏微粒体。用PBS缓冲液(加20%甘油)将微粒体重悬起即可进行测试或于-80℃保存。微粒体蛋白含量用考马斯亮蓝法测定。
微粒体Vit C/Fe2+脂质过氧化激发模型:溶液配制所用基本缓冲液为Tris/HCl(0.2mol/L,pH=7.4)与KCl(0.15mol/L)按体积1∶2比例混合。各化合物制成5个不同浓度的剂量组(6.25、12.5、25.0、50.0、100.0μg/mL)。不同浓度的Trolox(6.25-100μg/mL)为阳性对照。反应体系中含50mol/L FeSO4和5mmol/L Vit C各30.0μL,微粒体悬液和不同浓度化合物溶液各40.0μL,37℃水浴15min,加入10%三氯醋酸500μL终止反应,3000r/min离心10min,取上清400μL加入等量的0.67%2-硫代巴比妥酸溶液,100℃水浴15min,冷却,测定535nm OD值。通过与标准曲线比较,计算得到各化合物的抑制中浓度(IC50)即丙二醛产生量为对照的一半时待测样品液的浓度,结果如表2所示。
从表2中可以看出,化合物5、6对小鼠肝微粒体脂质过氧化有很好的抑制活性,强于对照品Trolox,具有很好的开发潜力。
表1含苯并1,4-噁二烷的1,3,4-噁二唑类衍生物体外抗氧化活性(μg/mL)
表2化合物1,5,6,20,21,23,24抑制小鼠肝微粒体LPO活性(μg/mL)
Claims (5)
2.一种权利要求1所述的含苯并1,4-噁二烷的1,3,4-噁二唑衍生物的制备方法,其特征是它由下列步骤组成:
步骤1.将按通法制备的含苯并1,4-噁二烷的1,3,4-噁二唑溶于适量乙醇溶液中,加入40%甲醛水溶液,搅拌10分钟后,再分多次缓慢滴加含各种取代苯胺的乙醇溶液,必要时可用冰浴保持反应体系温度,反应1小时,用薄层色谱(TLC)跟踪反应。
步骤2.将步骤1所得反应液冷却、结晶,将析出的沉淀物过滤,用冰乙醇洗涤三次,再用加入大量乙醇,微热(<50℃)使其全部溶解,放置进行重结晶,即得到权利要求1所述的含苯并1,4-噁二烷的1,3,4-噁二唑衍生物。
3.根据权利要求2所述制法,其特征是:步骤1所述的40%甲醛溶液的用量可以是每毫摩尔含苯并1,4-噁二烷的1,3,4-噁二唑加入105μL40%甲醛溶液(相当于甲醛1mmol)。
4.根据权利要求2所述制法,其特征是:步骤1所述的各种取代的苯胺用量可以是每毫摩尔含苯并1,4-噁二烷的1,3,4-噁二唑加入10mL含1mmol各种取代苯胺的乙醇溶液。
5.一种权利要求2所述的含苯并1,4-噁二烷的1,3,4-噁二唑衍生物在抗氧化药物开发中的相关应用。
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