CN110526811A - 一种α-葡萄糖苷酶抑制剂及其合成方法与应用 - Google Patents
一种α-葡萄糖苷酶抑制剂及其合成方法与应用 Download PDFInfo
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Landscapes
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Abstract
本发明公开了一种α‑葡萄糖苷酶抑制剂及其合成方法与应用;旨在提供一种具有较好降血糖作用的α‑葡萄糖苷酶抑制剂;其结构式为:R1选自H或者CH3;R2选自属于医药技术领域。
Description
技术领域
本发明属医药技术领域,具体涉及一种α-葡萄糖苷酶抑制剂及其合成方法与应用。
背景技术
据国际糖尿病组织报道,全球的糖尿病患者在2030年将达到5.52亿人,已成为继肿瘤和心脑血管病之后,第三大严重威胁人类生命健康的慢性疾病。这导致了医疗支出和相关社会问题的增加。糖尿病最可怕的是其引发的并发症,其发病范围广泛,几乎遍及全身各个组织器官,而且病程长,难治愈,并且致死、致残率非常高。
根据发病机制不同,糖尿病分为I型糖尿病(胰岛素依赖型)、II型糖尿病(非胰岛素依赖型)和妊娠糖尿病,其中II型糖尿病患者人数占糖尿病患者总数的90%。在目前的医疗水平还无法从根本上治愈糖尿病的情况下,糖尿病患者的日益增多将逐步扩大糖尿病用药的市场规模。糖尿病用药主要包括口服降糖药、胰岛素及其类似物。对于大多数患者而言,口服降糖药是经济、实用、便利的治疗方案。口服降糖药主要有四大类:(1)胰岛素增敏剂类;(2)胰岛素增泌剂类;(3)氨基酸相似物类;(4)α-葡萄糖苷酶抑制剂类。
α-葡萄糖苷酶抑制剂是一种有效的口服降糖药,能够与小肠中的α-葡萄糖苷酶的中心活性部位结合,阻抑酶活性的发挥,阻滞双糖水解为单糖,吸收时间后延从而对降低餐后高血糖起到有益的作用。α-葡萄糖苷酶抑制剂除了对糖尿病及糖尿病并发症的预防和治疗有很好的效果外,还能抑制蛋白及脂类糖基化。但是目前用于临床的α-葡萄糖苷酶抑制剂(阿卡波糖、伏格列波糖和米格列醇),都存在不同程度的不良反应,例如腹胀、肠鸣、腹痛、腹泻。因此,开发新的低毒、高效的α-葡萄糖苷酶抑制剂越来越受到人们的重视。
发明内容
针对上述问题,本发明的第一个目的是提供一种具有较好降血糖作用的α-葡萄糖苷酶抑制剂。
本发明的第二个目的是提供上述抑制剂的合成方法。
本发明的第三个目的是提供上述抑制剂的应用。
针对上述问题,本发明提供的第一个技术方案是这样的:
一种α-葡萄糖苷酶抑制剂,其结构式如式1所示:
其中:R1选自下述取代基的其中之一:
H、CH3;
R2选自下述取代基的其中之一:
上述n为:1~15。
本发明的第二个技术方案是提供该α-葡萄糖苷酶抑制剂的合成方法,该方法依次包括下述步骤:
1)将2,5二羟基-1,4苯醌溶于极性有机溶剂中,缓慢滴加无机酸,室温搅拌8~15个小时,然后抽滤浓缩得到黄色固态的中间产物1;
其中所述的化合物2,5二羟基-1,4苯醌、无机酸的摩尔比为1:1~5;
2)将所得中间产物1溶于水中,加入连二亚硫酸钠,在80~120℃下,反应回流8~15分钟,于-4~4℃下冷却结晶,抽滤得到粉白色晶状中间产物2;
其中所述中间产物1和连二亚硫酸钠的摩尔比是1:1~5;
3)将中间产物2溶于有机溶剂中,加入无机碱将反应液的pH调至8~9,室温搅拌15~30分钟,逐滴加入碘甲烷,室温搅拌8~15小时。反应液用无机酸溶液调节pH至5~6,采用有机溶剂萃取后,合并有机相,再依次用蒸馏水、饱和食盐水洗涤,干燥,减压浓缩,所得粗产品过柱纯化,得到白色晶状化中间体A;
其中所述中间产物2、无机碱、碘甲烷的摩尔比是1:1~5:1~5;
4)将中间体A放入圆底烧瓶中,置于真空干燥箱中干燥15~30分钟,加入HMPA,换气2~5次,再加入四氢呋喃作溶剂,在-50℃~-30℃下无水无氧反应5~15分钟,缓慢加入正丁基锂,将温度调至-15℃~-5℃反应40~80分钟,逐滴加入溴代烃,继续反应5~15分钟。置于室温反应10~15小时。减压浓缩得到粗产品,有机溶剂溶解后,用无机酸溶液调节pH至5~6,有机相依次用蒸馏水、饱和食盐水洗涤,干燥,减压浓缩,所得粗产品过柱纯化,得到油状中间体B;
其中所述中间体A、HMPA、正丁基锂、溴代烃的摩尔比是1:0.3~0.5:1~1.5:1~1.5;
5)将中间体B溶于有机溶剂,用一定比例的有机水溶液溶解硝酸铈铵,在-10℃~2℃冰盐浴中逐滴加入硝酸铈铵于化合物B中,搅拌10分钟。在室温下反应1~2小时。减压浓缩得到粗产品,用有机溶剂溶解后,依次用蒸馏水、饱和食盐水洗涤,干燥,减压浓缩,所得粗产品过柱纯化,得到固体成品C和D;
其中所述中间体B、硝酸铈铵的摩尔比是1:2~4,有机溶剂与水的比例为8/1~7/3;
6)将成品C或D溶于有机醇,加入氢氧化钠,于70℃~90℃下蒸发回流1.5~2.5小时,减压浓缩,有机溶剂溶解,用无机酸调节pH值至5~6,有机相依次用蒸馏水、饱和食盐水洗涤,干燥,减压浓缩,所得粗产品用低极性的有机溶剂冲洗抽滤,得到最终产物E;
其中所述成品C或D与无机碱的摩尔比是1:40~50。
优选的,上述的α-葡萄糖苷酶抑制剂的合成方法,步骤1)所述的无机酸为浓盐酸、浓硫酸。
优选的,上述的α-葡萄糖苷酶抑制剂的合成方法,步骤3)、步骤4)、步骤6)所述的无机酸为稀盐酸或饱和氯化铵。
优选的,上述的α-葡萄糖苷酶抑制剂的合成方法,步骤3)所述的无机碱为氢氧化钠或氢氧化钾。
优选的,上述的α-葡萄糖苷酶抑制剂的合成方法,步骤1)、步骤2)、步骤3)、步骤4)、步骤5)、步骤6)所述的有机溶剂为乙酸乙酯或二氯甲烷。
优选的,上述的α-葡萄糖苷酶抑制剂的合成方法,所述的溴代烃为1-溴-3-甲基丁烷、或1-溴-3,7-二甲基辛烷、或1-溴-7-苯基庚烷、或2-溴乙基环己烷、或2-(溴甲基)萘。
本发明的最后一个目的是提供上述的α-葡萄糖苷酶抑制剂作为降血糖药物或保健品的应用。
与现有技术相比,本发明提供的技术方案具有如下技术优点:该产品由由天然来源的化合物通过结构改造修饰反应制备,更为安全。该产品对α-葡萄糖苷酶具有较好的抑制活性,在医药、保健、食品领域具有良好的应用前景。
附图说明
图1是中间体A的1HNMR检测谱图;
图2是中间体B1的1HNMR检测谱图;
图3是成品E1的1HNMR检测谱图;
图4是中间体B2的1HNMR检测谱图;
图5是成品E2的1HNMR检测谱图;
图6是中间体B3的1HNMR检测谱图;
图7是成品E3的1HNMR检测谱图;
图8是成品E1及E3对α-葡萄糖苷酶的抑制效应分析图;
图9是成品E1及E3对α-葡萄糖苷酶的抑制机制分析图;
图10是成品E1对α-葡萄糖苷酶的抑制动力学分析图;
图11是成品E3对α-葡萄糖苷酶的抑制动力学分析图。
具体实施方式
为了使本发明的目的、技术方案和有益技术效果更加清晰,以下结合实施例,对本发明进行进一步详细说明。应当理解的是,本说明书中描述的实施例仅仅是为了解释本发明,并非为了限定本发明,实施例的参数、比例可因地制宜做出选择而对结果并无实质性影响。
实施例1
1,2,4,5-四甲氧基苯(中间体A)的合成
将2,5二羟基-1,4苯醌(5g,3.6mmol)溶于200mL甲醇溶液中,缓慢加入38%浓盐酸(6mL,72.0mmol),室温搅拌过夜。反应完成后(TLC),抽滤浓缩得到黄色固态中间产物1;将所得中间产物1溶于50mL水中,加入连二亚硫酸钠(10g,57.4mmol),在120℃下,反应回流8分钟,于-4℃下冷却结晶,对混合物进行抽滤后得到粉白色晶状中间产物2(4.5g,73.5%);将中间产物2(1.7g,10mmol)溶于10mLDMSO,加入氢氧化钾(1.4g,25mmol),室温搅拌15分钟,逐滴加入碘甲烷(1.88mL,25mmol),反应过夜。以TLC检测反应终点(展开剂:石油醚/乙酸乙酯=5/1),反应完成后,用饱和氯化铵溶液调节反应液的pH为5~6后进行萃取,所得有机相分别用蒸馏水、饱和食盐水洗涤,无水硫酸镁干燥,并减压浓缩得到粗产品;采用硅胶层析法(石油醚/乙酸乙酯=10/1)对粗品进行纯化,得到白色晶状的中间体A(2.8g,53.4%),检测谱图参阅图1。
1HNMR(400MHz,Chloroform-d)δ6.69(s,2H),3.71(s,12H).
实施例2
1,2,4,5-四甲氧基-3-(7-苯基庚基)-苯(中间体B1)的合成
将中间体A(1g,5.1mmol)加入圆底烧瓶中,真空干燥30分钟,加入HMPA(353μL,2mmol),换气2~5次,再加入60mL的四氢呋喃作溶剂,在-40℃下无水无氧反应15分钟,缓慢加入正丁基锂(2.44mL,6.12mmol),将温度调至-10℃反应1小时,逐滴加入1-溴-7-苯基庚烷,继续反应10分钟。然后将混合物置于室温反应10小时。将反应液减压浓缩后,用有机溶剂溶解,饱和氯化铵溶液调节pH至5~6,有机相分别用蒸馏水、饱和食盐水洗涤,收集有机相并用无水硫酸镁干燥,过滤、减压浓缩得到粗产品,通过硅胶柱进行纯化得到中间体B1(223.1mg,22.3%),检测谱图参阅图2。
1HNMR(500MHz,Chloroform-d)δ7.30-7.23(m,2H),7.19-7.14(m,3H),6.41(s,1H),3.84(s,6H),3.76(s,6H),2.64-2.56(m,4H),1.66-1.57(m,2H),1.56-1.49(m,2H),1.42-1.31(m,6H).
2,5-二甲氧基-3-(7-苯基庚基)-1,4-苯醌(成品C1)和2-羟基-5-甲氧基-3-(7-苯基庚基)-1,4-苯醌(成品D1)的合成
将中间体B1(200.0mg,0.546mmol)溶于4mL乙腈,用5mL乙腈/水(3/2)溶液溶解硝酸铈铵(748.8mg,1.37mmol),在-10℃冰盐浴中逐滴加入硝酸铈铵,搅拌10分钟后,置于室温下反应2小时。以TLC检测反应终点(展开剂:石油醚/乙酸乙酯=5/1),反应完成后,减压浓缩得到粗产品,有机溶剂溶解反应液,分别用蒸馏水、饱和食盐水洗涤,收集有机相并用无水硫酸镁干燥,过滤、减压浓缩得到粗产品,过柱纯化得到成品C1(51.4mg,25.5%)和成品D1(59.6mg,29.8%)。
2,5-二羟基-3-(7-苯基庚基)-1,4-苯醌(成品E1)的合成
将成品C1(20mg,0.060mmol)和D1(30mg,0.0937mmol)溶于乙醇,加入3.6mL氢氧化钠(2M,6.91mmol),于70℃下蒸发回流2.5小时,减压浓缩,溶于乙酸乙酯,用饱和氯化铵溶液调节pH值至5~6,有机相依次用蒸馏水、饱和食盐水洗涤;收集有机相,将有机相用无水硫酸镁干燥,过滤,然后减压浓缩得到粗产品,然后用石油醚冲洗抽滤得到最终产品E1(20mg,42.3%),检测谱图参阅图3。
1HNMR(500MHz,Acetone)δ7.28-7.21(m,2H),7.21-7.08(m,3H),5.88(s,1H),2.63-2.54(m,2H),2.46-2.38(m,2H),1.66-1.54(m,2H),1.52-1.41(m,2H),1.40-1.26(m,6H);13CNMR(126MHz,Acetone)δ143.57,129.17,129.04,126.38,123.09,117.89,115.92,103.76,36.48,32.34,30.24,30.09,29.90,28.71,23.00.
实施例3
1,2,4,5-四甲氧基3-(2-环己基乙基)苯(中间体B2)的合成
将中间体A(1g,5.1mmol)加入圆底烧瓶中,真空干燥30分钟,加入HMPA(353μL,2mmol),换气2~5次,再加入60mL的四氢呋喃作溶剂,在-40℃下无水无氧反应15分钟,缓慢加入正丁基锂(2.44mL,6.12mmol),将温度调至-10℃反应1小时,逐滴加入2-溴乙基环己烷,继续反应10分钟。然后将混合物置于室温反应10小时。将反应液减压浓缩后,用有机溶剂溶解,饱和氯化铵溶液调节pH至5~6,有机相分别用蒸馏水、饱和食盐水洗涤,收集有机相并用无水硫酸镁干燥,过滤、减压浓缩得到粗产品,通过硅胶柱进行纯化得到中间体B2(652mg,65.2%),检测谱图参阅图4。
1HNMR(600MHz,Chloroform-d)δ6.40(s,1H),3.84(s,6H),3.77(s,6H),2.66–2.58(m,2H),1.85–1.77(m,2H),1.74–1.60(m,3H),1.45–1.38(m,2H),1.36–1.11(m,4H),0.99–0.90(m,2H);13CNMR(151MHz,Chloroform-d)δ148.98,141.15,131.67,96.77,61.08,56.38,38.68,38.27,33.37,26.89,26.50,22.29.
2,5-二甲氧基-3-(2-环己基乙基)-1,4-苯醌(成品C2)和2-羟基-5-甲氧基-3-(2-环己基乙基)-1,4-苯醌(成品D2)的合成
将中间体B2(200.0mg,0.546mmol)溶于4mL乙腈,用5mL乙腈/水(3/2)溶液溶解硝酸铈铵(748.8mg,1.37mmol),在-10℃冰盐浴中逐滴加入硝酸铈铵,搅拌10分钟后,置于室温下反应2小时。以TLC检测反应终点(展开剂:石油醚/乙酸乙酯=5/1),反应完成后,减压浓缩得到粗产品,有机溶剂溶解反应液,分别用蒸馏水、饱和食盐水洗涤,收集有机相并用无水硫酸镁干燥,过滤、减压浓缩得到粗产品,过柱纯化得到成品C2(48.4mg,24.2%)和成品D2(65.4mg,32.7%)。
1HNMR(500MHz,Chloroform-d)δ5.71(s,1H),4.03(s,3H),3.79(s,3H),2.46–2.38(m,2H),1.81–1.71(m,2H),1.70–1.65(m,2H),1.64–1.58(m,1H),1.28–1.09(m,6H),0.96–0.82(m,2H);13CNMR(126MHz,Chloroform-d)δ183.72,182.53,158.85,155.86,131.26,105.46,61.48,56.51,37.81,36.40,33.21,26.73,26.38,20.73.
1HNMR(500MHz,Chloroform-d)δ5.83(s,1H),3.85(s,3H),2.47–2.41(m,2H),1.81–1.72(m,2H),1.71–1.65(m,2H),1.65–1.57(m,1H),1.36–1.09(m,8H),0.94–0.84(m,2H);13CNMR(126MHz,Chloroform-d)δ182.96,181.80,161.19,151.55,119.71,102.26,56.89,37.73,35.61,33.20,26.75,26.40,20.26.
2,5-二羟基-3-(2-环己基乙基)-1,4-苯醌(成品E2)的合成
将成品C2(20mg,0.060mmol)和D2(60mg,0.1874mmol)溶于乙醇,加入5.57mL氢氧化钠(2M,11.133mmol),于70℃下蒸发回流2.5小时,减压浓缩,溶于乙酸乙酯,用饱和氯化铵溶液调节pH值至5~6,有机相依次用蒸馏水、饱和食盐水洗涤;收集有机相,将有机相用无水硫酸镁干燥,过滤,然后减压浓缩得到粗产品,然后用石油醚冲洗抽滤得到最终产品E2(21.6mg,27%),检测谱图参阅图5。
1HNMR(500MHz,Acetone-d6)δ5.87(s,1H),2.46–2.40(m,2H),1.82–1.75(m,2H),1.72–1.66(m,2H),1.65–1.59(m,1H),1.37–1.30(m,2H),1.28–1.13(m,4H),0.96–0.85(m,2H);13CNMR(126MHz,Acetone-d6)δ118.23,103.77,38.45,36.36,33.92,27.34,27.02,20.59.
实施例4
3-(3,7-二甲基辛基)-1,2,4,5-四甲氧基苯(中间体B3)的合成
将中间体A(1g,5.1mmol)加入圆底烧瓶中,真空干燥30分钟,加入HMPA(353μL,2mmol),换气2~5次,再加入60mL的四氢呋喃作溶剂,在-40℃下无水无氧反应15分钟,缓慢加入正丁基锂(2.44mL,6.12mmol),将温度调至-10℃反应1小时,逐滴加入1-溴-3,7-二甲基辛烷,继续反应10分钟。然后将混合物置于室温反应10小时。将反应液减压浓缩后,用有机溶剂溶解,饱和氯化铵溶液调节pH至5~6,有机相分别用蒸馏水、饱和食盐水洗涤,收集有机相并用无水硫酸镁干燥,过滤、减压浓缩得到粗产品,通过硅胶柱进行纯化得到中间体B3(648mg,64.8%),检测谱图参阅图6。
1HNMR(500MHz,Chloroform-d)δ6.43(s,1H),3.87(s,6H),3.80(s,6H),2.69–2.56(m,2H),1.60–1.50(m,3H),1.40–1.30(m,4H),1.22–1.12(m,3H),0.98(d,J=6.4Hz,3H),0.88(d,J=6.6Hz,6H).
3-(3,7-二甲基辛基)-2,5-二甲氧基-1,4-苯醌(成品C3)和3-(3,7-二甲基辛基)-2-羟基-5-甲氧基-1,4-苯醌(成品D3)的合成
将中间体B3(200.0mg,0.546mmol)溶于4mL乙腈,用5mL乙腈/水(3/2)溶液溶解硝酸铈铵(748.8mg,1.37mmol),在-10℃冰盐浴中逐滴加入硝酸铈铵,搅拌10分钟后,置于室温下反应2小时。以TLC检测反应终点(展开剂:石油醚/乙酸乙酯=5/1),反应完成后,减压浓缩得到粗产品,有机溶剂溶解反应液,分别用蒸馏水、饱和食盐水洗涤,收集有机相并用无水硫酸镁干燥,过滤、减压浓缩得到粗产品,过柱纯化得到成品C3(42.4mg,21.2%)和成品D3(60.2mg,30.1%)。
3-(3,7-二甲基辛基)-2,5-二羟基-1,4-苯醌(成品E3)的合成
将成品C3(20mg,0.060mmol)和D3(60mg,0.1874mmol)溶于乙醇,加入5.57mL氢氧化钠(2M,11.133mmol),于70℃下蒸发回流2.5小时,减压浓缩,溶于乙酸乙酯,用饱和氯化铵溶液调节pH值至5~6,有机相依次用蒸馏水、饱和食盐水洗涤;收集有机相,将有机相用无水硫酸镁干燥,过滤,然后减压浓缩得到粗产品,然后用石油醚冲洗抽滤得到最终产品E3(28.4mg,35.5%),检测谱图参阅图7。
1HNMR(500MHz,Acetone-d6)δ5.89(s,1H),2.52–2.37(m,2H),1.62–1.40(m,3H),1.40–1.23(m,4H),1.22–1.09(m,3H),0.95(d,J=6.5Hz,3H),0.88(d,J=6.6Hz,6H);13CNMR(126MHz,Acetone-d6)δ117.34,102.88,39.15,36.82,34.84,32.65,27.79,24.49,22.10,22.04,19.85,19.05.
为了更好的说明本发明的效果,下面给出实施例中制备的α-葡萄糖苷酶抑制活性评价方法。
以E1、E3为例,测定E1、E3的α-葡萄糖苷酶抑制活性。
实验例1
成品E1和E3的α-葡萄糖苷酶抑制活性测定
将成品E1和E3溶于DMSO中配成不同浓度的溶液;配制浓度为0.1mol/L的PBS缓冲溶液(pH=6.8);用0.1mol/L,pH=6.8的磷酸盐缓冲溶液(PBS)配制0.7U/mL的α-葡萄糖苷酶溶液和1mmol/L的α-对硝基苯酚葡萄糖苷(PNPG)溶液;然后采用96孔板,每孔先加入35μL的pH=6.8的磷酸盐缓冲溶液,再加入10μL,0.7U/mL的α-葡萄糖苷酶溶液,再加入5μL不同浓度的样品溶液,空白对照组加量的DMSO,混匀后,每孔重复4次,然后将板快速转移至多功能酶标仪中37℃孵育10min,其中环形摇震1min。将孵育完成的96孔板取出,用移液枪(排枪)每孔加入50μL的1mmol/L,α-对硝基苯酚葡萄糖苷溶液引发反应,然后将板快速转移至多功能酶标仪中37℃反应30min,其中环形摇震3min。最后,将96孔板取出,每孔加入50μL的1mol/L的Na2CO3溶液终止反应,然后将板快速转移至多功能酶标仪中环形摇震30s,在405nm波长下,测定每孔的OD值。再通过公式:抑制率=(A0-A1)/A0×100%其中,A0为空白对照组,A1为样品组。计算抑制效果,通过抑制剂浓度和抑制效果的关系进行曲线拟合,从曲线计算得到每个样品对α-葡萄糖苷酶的半抑制浓度IC50值。
成品E1和E3对α-葡萄糖苷酶的抑制曲线,如图8所示,使用GraphPad Prism计算出IC50值分别为3.55μM、3.32μM。在同样的测试条件下,阳性对照组阿卡波糖的IC50值为2392μM。因此,实验结果表明成品E1和E3对α-葡萄糖苷酶具有很强的抑制作用。
实验例2
成品E1和E3对α-葡萄糖苷酶的抑制机理
以PNPG为底物研究成品E1和E3对α-葡萄糖苷酶的抑制机理,沿用实验例1中α-葡萄糖苷酶抑制活性评价的反应体系,固定底物浓度为1mM,加入不同浓度的抑制剂,改变α-葡萄糖苷酶的浓度,测得的酶活力对酶量如图9所示,得到一组过原点的直线。随着抑制剂浓度的增加,线的斜率减小,说明了该抑制剂对α-葡萄糖苷酶的抑制是可逆的。在抑制剂存在的情况下,α-葡萄糖苷酶的活力降低,是因为抑制剂抑制了酶的活力,降低了酶的催化效率,而不是因为有效酶量的减少。
实验例3
成品E1和E3对α-葡萄糖苷酶的抑制动力学
以PNPG为底物研究成品E1和E3对α-葡萄糖苷酶的抑制类型,沿用上述α-葡萄糖苷酶抑制活性评价的反应体系,固定α-葡萄糖苷酶的浓度为0.7U/mL,改变底物的浓度,测定加入不同浓度的抑制剂对α-葡萄糖苷酶催化底物的影响。如图10C1及图11B1所示,采用Lineweaver-Burk双倒数作图法,以底物浓度的倒数1/[S]对反应速度的倒数1/V作图,可以得到一组斜率不同但相交于第三象限的直线。随着抑制剂浓度的增大,酶的米氏常数(Km)值和最大反应速度(Vmax)值同时改变,Km值增大而Vmax值减小,说明该抑制剂是混合型抑制剂。换句话说,该抑制剂既可以与游离酶结合,也可以与酶-底物的复合物相结合。且Ki大于Kis。如图10C2、C3及图11B2、B3所示,分别以Lineweaver-Burk双倒数图中的纵轴截距及斜率对抑制剂浓度的作图得到直线E1:Y=5.369+16.03x、Y=12.60+5.248x;E3:Y=12.07+6.264x、Y=2.574x+9.550。根据公式可以求出成品E1:Ki=2.40μM,Kis=0.33μM;成品E3:Ki=3.71μM,Kis=1.93μM。
根据上述实验例的分析结果,可以推测上述的α-葡萄糖苷酶抑制剂可以用来制备降血糖药物或保健品以及减肥药物。
需要说明的是,本发明所采用的原料,除特殊说明外,均通过常规手段制备或者通过商业渠道购买。
Claims (8)
1.一种α-葡萄糖苷酶抑制剂,其特征在于,其结构式如式1所示:
其中:
R1选自下述取代基的其中之一:
H、CH3;
R2选自下述取代基的其中之一:
上述n为:1~15。
2.权利要求1所述的α-葡萄糖苷酶抑制剂的合成方法,其特征在于,依次包括下述步骤:
1)将2,5二羟基-1,4苯醌溶于极性有机溶剂中,缓慢滴加无机酸,室温搅拌8~15个小时,然后抽滤浓缩得到黄色固态的中间产物1;
其中所述的化合物2,5二羟基-1,4苯醌与无机酸的摩尔比为1:1~5;
2)将所得中间产物1溶于水中,加入连二亚硫酸钠,在80~120℃下,反应回流8~15分钟,于-4~4℃下冷却结晶,抽滤得到粉白色晶状中间产物2;
其中所述中间产物1和连二亚硫酸钠的摩尔比是1:1~5;
3)将中间产物2溶于有机溶剂中,加入无机碱将反应液的pH调至8~9,室温搅拌15~30分钟,逐滴加入碘甲烷,室温搅拌8~15小时;反应液用无机酸溶液调节pH至5~6,采用有机溶剂萃取后,合并有机相,再依次用蒸馏水、饱和食盐水洗涤,干燥,减压浓缩,所得粗产品过柱纯化,得到白色晶状中间体A;
其中所述中间产物2、无机碱、碘甲烷的摩尔比是1:1~5:1~5;
4)将化合物A放入圆底烧瓶中,置于真空干燥箱中干燥15~30分钟,加入HMPA,换气2~5次,再加入四氢呋喃作溶剂,在-50℃~-30℃下无水无氧反应5~15分钟,缓慢加入正丁基锂,将温度调至-15℃~-5℃反应40~80分钟,逐滴加入溴代烃,继续反应5~15分钟;置于室温反应10~15小时;减压浓缩得到粗产品,有机溶剂溶解后,用无机酸溶液调节pH至5~6,有机相依次用蒸馏水、饱和食盐水洗涤,干燥,减压浓缩,所得粗产品过柱纯化,得到油状中间体B;
其中所述中间体A、HMPA、正丁基锂、溴代烃的摩尔比是1:0.3~0.5:1~1.5:1~1.5;
5)将中间体B溶于有机溶剂,用一定比例的有机水溶液溶解硝酸铈铵,在-10℃~2℃冰盐浴中逐滴加入硝酸铈铵于中间体B中,搅拌10分钟;在室温下反应1~2小时;减压浓缩得到粗产品,用有机溶剂溶解后,依次用蒸馏水、饱和食盐水洗涤,干燥,减压浓缩,所得粗产品过柱纯化,得到固体成品C和D;
其中所述中间体B、硝酸铈铵的摩尔比是1:2~4,有机溶剂与水的比例为8/1~7/3;
6)将成品C或D溶于有机醇,加入氢氧化钠,于70℃~90℃下蒸发回流1.5~2.5小时,减压浓缩,有机溶剂溶解,用无机酸调节pH值至5~6,有机相依次用蒸馏水、饱和食盐水洗涤,干燥,减压浓缩,所得粗产品用低极性的有机溶剂冲洗抽滤,得到最终产物E;
其中所述成品C或D与无机碱的摩尔比是1:40~50。
3.根据权利要求2所述的α-葡萄糖苷酶抑制剂的合成方法,其特征在于,步骤1)所述的无机酸为浓盐酸或浓硫酸。
4.根据权利要求2所述的α-葡萄糖苷酶抑制剂的合成方法,其特征在于,步骤3)、步骤4)、步骤6)所述的无机酸为稀盐酸或饱和氯化铵。
5.根据权利要求2所述的α-葡萄糖苷酶抑制剂的合成方法,其特征在于,步骤3)所述的无机碱为氢氧化钠或氢氧化钾。
6.根据权利要求2所述的α-葡萄糖苷酶抑制剂的合成方法,其特征在于,步骤1)、步骤2)、步骤3)、步骤4)、步骤5)、步骤6)所述的有机溶剂为乙酸乙酯或二氯甲烷。
7.根据权利要求2所述的α-葡萄糖苷酶抑制剂的合成方法,其特征在于,所述的溴代烃为1-溴-3-甲基丁烷、或1-溴-3,7-二甲基辛烷、或1-溴-7-苯基庚烷、或2-溴乙基环己烷、或2-(溴甲基)萘。
8.权利要求1所述的α-葡萄糖苷酶抑制剂作为制备降血糖药物或保健品的应用。
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