CN115215858A - 一类2,3-双取代小檗碱衍生物及其制备方法和应用 - Google Patents
一类2,3-双取代小檗碱衍生物及其制备方法和应用 Download PDFInfo
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Abstract
Description
技术领域
本发明属于医药领域,具体涉及一类2,3-双取代小檗碱衍生物及其制备方法,还涉及该类化合物在制备降血脂的药物中的应用。
背景技术
研究表明,高血脂是导致心血管疾病的一个主要因素。目前,临床上用于降血脂的药物主要分为五类:他汀类、烟酸类、纤维酸衍生物、胆汁酸螯合剂和胆固醇吸收抑制剂,但这些降血脂药物都存在一定的副作用,如横纹肌溶解,肠胃不适等,因此新型降血脂药物的开发一直是国内外医药界的研究热点。
盐酸小檗碱亦称黄连素,是一种天然的异喹啉类生物碱,为黄色粉末,存在于许多的药用植物中,如黄连和黄柏等,其结构式如下所示:
近年来,国内外研究人员发现盐酸小檗碱具有广泛的药理活性,包括降脂、降糖、抗菌、抗肿瘤和抗炎等。但是由于其脂溶性差,口服生物利用度低,大大限制了其临床应用,因此基于盐酸小檗碱进行适当的结构修饰以提高其药理活性具有重大的研究价值。
发明内容
本发明的目的在于提供一类2,3-双取代小檗碱衍生物及其制备方法及其在制备降血脂的药物中的应用。
本发明所提供的2,3-双取代小檗碱衍生物,其结构式如式(A)所示:
其中,R1选自Br-﹑I-或三氟甲基磺酸根离子;
R2选自氢、C1-C10烷基或R3”-R3’-,其中R3’表示C1-C10亚烷基,R3”表示卤素、C1-C6烷氧基、取代或未取代的含氮五元环或六元环中的至少一种,其中,取代的含氮五元环或六元环中的取代基为C1-C6烷基、C1-C6烷氧基、卤素中的任意一种;
R3选自氢、C1-C10烷基或R3”-R3’-,其中R3’表示C1-C10亚烷基,R3”表示卤素、C1-C6烷氧基、取代或未取代的含氮五元环或六元环中的至少一种,其中,取代的含氮五元环或六元环中的取代基为C1-C6烷基、C1-C6烷氧基、卤素中的任意一种;
或,R2与R3之间形成饱和碳链,或者形成含杂原子的链,其中,所述杂原子为N、O或S,或者形成包含不饱和键的链;
具体地,R2、R3相同,为R3”-R3’-,其中R3’表示C2-C6亚烷基,R3”表示 C1-C4烷氧基或C2-C4烷氧基;
或,R2、R3相同,为R3”-R3’-,其中R,’表示C3-C6亚烷基,R3”表示三氮唑。
式(A)所示2,3-双取代小檗碱衍生物具体可为如下化合物中的任意一种:
进一步的,本发明还提出了上述通式(A)所示化合物的制备方法,所述制备方法包括如下步骤:
1)盐酸小檗碱(化合物Ⅰ)在三氟甲烷磺酸存在下,脱去氧桥键,得到化合物Ⅱ(去亚甲基小檗碱);
2)化合物Ⅱ与二卤代烷(X-R2-R3-X,其中,R2与R3之间形成饱和碳链,或者形成含杂原子的链,或者形成包含不饱和键的链;X表示卤素,优选氯或溴) 在碱性条件下反应,其中,化合物Ⅱ与二卤代烷的摩尔比为1:1-10,得到通式 (A)所示化合物,具体可为Ⅲ-1-Ⅲ-3所示化合物;
或
化合物Ⅱ与X-R2及R3-X(R2、R3选自C1-C10烷基或R3”-R3’-,其中R3’表示 C1-C10亚烷基,R3”表示C1-C6烷氧基;X表示卤素,优选氯或溴)在碱性条件下反应,其中,化合物Ⅱ与X-R2及R3-X的摩尔比为1:1-5:1-5,得到通式(A) 所示化合物,具体可为Ⅲ-4-Ⅲ-10所示化合物或Ⅴ-2-Ⅴ-9所示化合物;
或
化合物Ⅱ与X-R2或R3-X(R2、R3选自C1-C10烷基,X表示卤素,优选氯或溴) 在碱性条件下反应,其中,化合物Ⅱ与X-R2或R3-X的摩尔比为1:1-1.2,得到通式(A)所示化合物,具体可为Ⅳ-1-Ⅳ-5所示化合物;
或
式Ⅳ-1所示化合物与X-R2或R3-X(R2、R3选自C1-C10烷基,X表示卤素,优选氯或溴)在碱性条件下反应,其中,化合物Ⅱ与X-R2或R3-X的摩尔比为1: 1-1.2,得到通式(A)所示化合物,具体可为Ⅴ-2-Ⅴ-9所示化合物;
或
式Ⅳ-1所示化合物与二卤代烷(X-R3’-X,R2、R3’选自C1-C10亚烷基,X表示卤素,优选氯或溴)在碱性条件下反应,其中,化合物Ⅱ与X-R3’-X的摩尔比为1:1-1.2,得到如下式a所示化合物,具体可为Ⅵ-1-Ⅵ-5所示化合物;
或
式a所示化合物与R3”-H(R3”表示取代或未取代的含氮五元环或六元环中的至少一种)反应,得到通式(A)所示化合物,具体可为Ⅶ-1-Ⅶ-8所示化合物。
上述方法步骤2)中,所述反应在有机溶剂中进行,所述有机溶剂具体可为乙腈,
所述反应的温度可为60-70℃,反应的时间可为1-8小时,
所述碱性条件具体可由无水碳酸钾提供;
化合物Ⅱ与无水碳酸钾的摩尔比可为1:4-6,优选1:5。
上述通式(A)所示化合物2,3-双取代小檗碱衍生物在制备降血脂的药物中的应用也属于本发明的保护范围。
本发明还提供一种药物组合物,其包括通式(A)所示化合物2,3-双取代小檗碱衍生物。
优选的,所述药物组合物为降血脂药物。
本发明以天然产物小檗碱为母体进行化学修饰,得到一系列与小檗碱结构相似的衍生物,经细胞实验证明,所得化合物具有较好的降血脂作用,且一些衍生物的活性优于母体化合物小檗碱,体现了本发明的创新性。
附图说明
图1为本发明化合物10μmol/L时的体外细胞存活率。
图2为本发明化合物20μmol/L时的体外细胞存活率。
图3为本发明化合物20μmol/L时的细胞水平降脂活性。
具体实施方式
以下结合附图对本发明的优选实施例进行说明,应当理解,此处所描述的优选实施例仅用于说明和解释本发明,并不用于限定本发明。
实施例1、化合物Ⅱ的合成
称取盐酸小檗碱10.00g(26.90mmol)置于500mL干燥的单口圆底烧瓶中,并加入100mL二甲苯,室温搅拌。边搅拌边滴加三氟甲烷磺酸14.28mL (161.37mmol),滴加完毕后室温搅拌反应1小时。待反应完成后,在0℃条件下向反应体系中添加1M HCl,直至不再产生黄色沉淀。抽滤所得混合体系,滤饼依次用少量蒸馏水和石油醚洗涤,然后在真空干燥箱中干燥,得黄色固体Ⅱ,产率为87%。
1H NMR(600MHz,DMSO-d6)δ9.82(overlap,3H),8.74(s,1H),8.16 (d,J=9.0Hz,1H),8.04(d,J=9.0Hz,1H),7.50(s,1H),6.81(s, 1H),4.89(t,J=5.6Hz,2H),4.09(s,3H),4.06(s,3H),3.12(t,J =5.6Hz,2H).
13C NMR(151MHz,DMSO)δ150.00,149.17,145.57,145.12,143.47, 138.26,133.31,127.23,126.68,123.49,121.20,119.10,117.81,114.85, 112.69,61.85,57.05,55.56,25.77.
ESI-MS m/z:324.2(M-O3SCF3)+.
实施例2化合物Ⅲ-1的合成
称取黄色固体Ⅱ1.00g(2.11mmol),无水碳酸钾1.47g(10.57mmol) 置于250mL干燥的单口圆底烧瓶中,并加入100mL乙腈,然后加入1,2-二溴乙烷1.83mL(21.13mmol),60-70℃搅拌反应2小时。用TLC法检测反应完毕,减压条件下旋干有机溶剂得粗产物,然后经硅胶柱层析纯化,洗脱剂V(二氯甲烷):V(甲醇)=40:1。目标组分旋干,得黄色固体Ⅲ-1,产率为98%。
1H NMR(600MHz,DMSO-d6)δ9.86(s,1H),8.91(s,1H),8.18(d, J=9.1Hz,1H),7.99(d,J=9.1Hz,1H),7.72(s,1H),6.98(s,1H), 4.92(t,J=6.1Hz,2H),4.36(t,J=4.3Hz,2H),4.33(t,J=4.3 Hz,2H),4.09(s,3H),4.06(s,3H),3.18(t,J=6.1Hz,2H).
13C NMR(151MHz,DMSO)δ150.35,146.15,145.40,143.59,143.37, 137.33,132.98,128.66,126.69,123.51,121.43,120.13,119.94,116.57, 114.33,64.63,64.14,61.89,57.03,55.43,25.69.
ESI-MS m/z:350.2(M-Br)+.
实施例3化合物Ⅲ-2的合成
制法同实施例2,得黄色固体Ⅲ-2,产率为86%。
1H NMR(600MHz,DMSO-d6)δ9.89(s,1H),8.99(s,1H),8.20(d, J=9.1Hz,1H),8.01(d,J=9.1Hz,1H),7.85(s,1H),7.08(s,1H), 4.94(t,J=6.1Hz,2H),4.26(t,J=5.4Hz,2H),4.23(t,J=5.4 Hz,2H),4.10(s,3H),4.07(s,3H),3.20(t,J=6.1Hz,2H),2.19(m,2H).
13C NMR(151MHz,DMSO)δ153.43,150.64,150.53,145.54,143.66, 136.93,132.89,130.58,126.72,123.63,121.86,121.55,121.11,120.53, 118.98,70.71,70.62,61.90,57.05,55.33,31.03,25.61.
ESI-MS m/z:364.2(M-Br)+.
实施例4化合物Ⅲ-3的合成
制法同实施例2,得黄色固体Ⅲ-3,产率为46%。
1H NMR(600MHz,DMSO-d6)δ9.88(s,1H),8.97(s,1H),8.20(d, J=9.1Hz,1H),8.01(d,J=9.1Hz,1H),7.88(s,1H),7.04(s,1H), 4.94(t,J=6.2Hz,2H),4.49(t,J=5.5Hz,2H),4.29(t,J=5.3 Hz,2H),4.10(s,3H),4.07(s,3H),3.20(t,J=6.2Hz,2H),1.94(m,2H),1.81(m,2H).
13C NMR(151MHz,DMSO)δ153.23,150.42,147.00,145.44,143.63, 137.10,132.95,131.33,126.76,123.55,121.49,121.32,121.24,120.48, 120.29,74.05,71.09,61.90,57.05,55.29,27.40,25.69,24.44.
ESI-MS m/z:378.2(M-Br)+.
实施例5化合物Ⅲ-4的合成
称取黄色固体Ⅱ1.00g(2.11mmol),无水碳酸钾1.47g(10.57mmol) 置于250mL干燥的单口圆底烧瓶中,并加入100mL乙腈,然后加入2-溴乙基乙醚2.38mL(21.13mmol),60-70℃搅拌反应5小时。用TLC法检测反应完毕,减压条件下旋干有机溶剂得粗产物,然后经硅胶柱层析纯化,洗脱剂V(二氯甲烷):V(甲醇)=30:1。目标组分旋干,得黄色固体Ⅲ-4,产率为76%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.99(s,1H),8.21(d, J=9.0Hz,1H),8.01(d,J=9.0Hz,1H),7.74(s,1H),7.12(s,1H), 4.94(t,J=5.9Hz,2H),4.27(t,J=4.4Hz,2H),4.21(t,J=4.4 Hz,2H),4.10(s,3H),4.07(s,3H),3.78(t,J=4.6Hz,2H),3.75(t, J=4.6Hz,2H),3.56(m,4H),3.21(t,J=5.9Hz,2H),1.15(q,6H).
13C NMR(151MHz,DMSO)δ151.09,150.25,148.07,145.43,143.63, 137.63,133.06,128.92,126.80,123.36,121.36,119.90,119.14,112.83, 110.85,68.80,68.39,68.35,68.14,65.81,61.89,57.03,55.36,54.90, 25.95,15.13,15.10.
ESI-MS m/z:468.3(M-Br)+.
实施例6化合物Ⅲ-5的合成
称取黄色固体Ⅱ1.00g(2.11mmol),无水碳酸钾730mg(5.28mmol) 置于100mL干燥的单口圆底烧瓶中,并加入50mL乙腈,然后加入碘甲烷329 μL(5.28mmol),60-80℃搅拌反应4-5小时。用TLC法检测反应完毕,减压条件下旋干有机溶剂得粗产物,然后经硅胶柱层析纯化,洗脱剂V(二氯甲烷):V(甲醇)=30:1。目标组分旋干,得黄色固体Ⅲ-5,产率为51%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.99(s,1H),8.20(d, J=9.1Hz,1H),8.02(d,J=9.1Hz,1H),7.69(s,1H),7.09(s,1H), 4.95(t,J=5.8Hz,2H),4.11(s,3H),4.07(s,3H),3.94(s,3H),3.87 (s,3H),3.23(t,J=5.8Hz,2H).
13C NMR(151MHz,DMSO)δ151.50,150.23,148.73,145.43,143.62, 137.69,133.07,128.62,126.78,123.37,121.34,119.82,118.89,111.28, 108.68,61.89,57.02,56.12,55.85,55.38,25.97.
ESI-MS m/z:352.2(M-I)+.
实施例7化合物Ⅲ-6的合成
称取黄色固体Ⅱ2.00g(4.23mmol),无水碳酸钾1.46g(10.56mmol) 置于250mL干燥的单口圆底烧瓶中,并加入100mL乙腈,然后加入1-溴乙烷 795μL(10.56mmol),60-80℃搅拌反应4-5小时。用TLC法检测反应完毕,减压条件下旋干有机溶剂得粗产物,然后经硅胶柱层析纯化,洗脱剂V(二氯甲烷):V(甲醇)=50:1。目标组分旋干,得黄色固体Ⅲ-6,产率为57%。
1H NMR(600MHz,DMSO-d6)δ9.86(s,1H),8.96(s,1H),8.20(d, J=9.1Hz,1H),8.01(d,J=9.1Hz,1H),7.68(s,1H),7.07(s,1H), 4.93(t,J=6.3Hz,2H),4.19(q,J=7.0Hz,2H),4.14(q,J=7.0 Hz,2H),4.10(s,3H),4.07(s,3H),3.21(t,J=6.3Hz,2H),1.39(m,6H).
13C NMR(151MHz,DMSO)δ151.03,150.22,147.99,145.37,143.61, 137.75,133.12,128.65,126.78,123.39,121.34,119.79,118.79,112.26, 110.17,64.46,64.07,61.90,57.04,55.40,25.98,14.70,14.60.
ESI-MS m/z:380.3(M-Br)+.
实施例8化合物Ⅲ-8的合成
制法同实施例7,得黄色固体Ⅲ-8,产率为43%。
1H NMR(600MHz,DMSO-d6)δ9.86(s,1H),8.97(s,1H),8.20(d, J=9.1Hz,1H),8.02(d,J=9.1Hz,1H),7.70(s,1H),7.08(s,1H), 4.93(t,J=6.3Hz,2H),4.13(t,J=6.4Hz,2H),4.10(s,3H),4.08 (overlap,2H),4.07(s,3H),3.21(t,J=6.3Hz,2H),1.76(m,4H),1.49(m,4H),0.98(t,J=7.4Hz,3H),0.96(t,J=7.4Hz,3H).
13C NMR(151MHz,DMSO)δ151.43,150.21,148.32,145.38,143.60, 137.74,133.11,128.80,126.77,123.40,121.33,119.80,118.87,112.54, 110.68,68.75,68.17,61.89,57.03,55.39,30.87,30.63,25.97,18.79, 18.70,13.74,13.66.
ESI-MS m/z:436.3(M-Br)+.
实施例9化合物Ⅲ-9的合成
制法同实施例7,得黄色固体Ⅲ-9,产率为44%。
1H NMR(600MHz,DMSO-d6)δ9.86(s,1H),8.96(s,1H),8.20(d, J=9.1Hz,1H),8.02(d,J=9.1Hz,1H),7.70(s,1H),7.07(s,1H), 4.93(t,J=5.8Hz,2H),4.12(overlap,2H),4.10(s,3H),4.07(overlap, 5H),3.21(t,J=5.8Hz,2H),1.77(m,4H),1.46(m,4H),1.38(m,4H), 0.92(q,J=6.7Hz,6H).
13C NMR(151MHz,DMSO)δ151.43,150.21,148.32,145.37,143.60, 137.74,133.11,128.78,126.77,123.40,121.33,119.80,118.85,112.50, 110.64,69.03,68.44,61.88,57.03,55.39,28.47,28.27,27.84,27.74, 25.97,21.90,21.86,13.96,13.94.
ESI-MS m/z:464.4(M-Br)+.
实施例10化合物Ⅲ-10的合成
制法同实施例7,得黄色固体Ⅲ-10,产率为57%。
1H NMR(600MHz,DMSO-d6)δ9.86(s,1H),8.96(s,1H),8.20(d, J=9.1Hz,1H),8.02(d,J=9.1Hz,1H),7.69(s,1H),7.07(s,1H), 4.93(t,J=6.3Hz,2H),4.12(overlap,2H),4.10(s,3H),4.07(overlap, 5H),3.20(t,J=6.3Hz,2H),1.76(m,4H),1.47(m,4H),1.34(m,8H), 0.89(m,6H).
13C NMR(151MHz,DMSO)δ151.43,150.21,148.32,145.37,143.60, 137.74,133.10,128.77,126.77,123.39,121.33,119.79,118.84,112.50, 110.63,69.02,68.44,61.88,57.02,55.39,30.99,30.94,28.76,28.55, 25.97,25.26,25.17,22.11,22.10,13.87,13.86.
ESI-MS m/z:492.4(M-Br)+.
实施例11化合物Ⅳ-1的合成
称取黄色固体Ⅱ1.00g(2.11mmol),无水碳酸钾730mg(5.28mmol) 置于100mL干燥的单口圆底烧瓶中,并加入50mL乙腈,然后加入碘甲烷132 μL(2.11mmol),60-80℃搅拌反应4-5小时。用TLC法检测反应完毕,减压条件下旋干有机溶剂得粗产物,然后经硅胶柱层析纯化,洗脱剂V(二氯甲烷):V(甲醇)=30:1。目标组分旋干,得黄色固体Ⅳ-1,产率为22%。
1H NMR(600MHz,DMSO-d6)δ9.85(s,1H),9.38(s,1H),8.80(s, 1H),8.17(d,J=9.1Hz,1H),8.05(d,J=9.1Hz,1H),7.53(s,1H), 7.05(s,1H),4.93(t,J=5.9Hz,2H),4.09(s,3H),4.06(s,3H),3.89 (s,3H),3.20(t,J=5.9Hz,2H).
13C NMR(151MHz,DMSO)δ150.64,150.21,146.40,145.35,143.56, 137.80,133.16,127.08,126.69,123.58,121.35,119.59,119.13,112.24, 111.41,61.90,57.07,55.92,55.56,25.98.
ESI-MS m/z:338.2(M-I)+.
实施例12化合物Ⅳ-3的合成
称取黄色固体Ⅱ1.00g(2.11mmol),无水碳酸钾730mg(5.28mmol) 置于100mL干燥的单口圆底烧瓶中,并加入50mL乙腈,然后加入1-溴丙烷 192μL(2.11mmol),60-80℃搅拌反应4-5小时。用TLC法检测反应完毕,减压条件下旋干有机溶剂得粗产物,然后经硅胶柱层析纯化,洗脱剂V(二氯甲烷):V(甲醇)=30:1。目标组分旋干,得黄色固体Ⅳ-3,产率为29%。
1H NMR(600MHz,DMSO-d6)δ9.85(s,1H),9.23(s,1H),8.79(s, 1H),8.18(d,J=9.1Hz,1H),8.05(d,J=9.1Hz,1H),7.55(s,1H), 7.04(s,1H),4.92(t,J=6.3Hz,2H),4.09(s,3H),4.06(s,3H),4.05 (overlap,2H),3.18(t,J=6.3Hz,2H),1.80(m,2H),1.02(t,J=7.4 Hz,3H).
13C NMR(151MHz,DMSO)δ150.19,150.02,146.50,145.32,143.55, 137.84,133.17,127.09,126.69,123.57,121.33,119.52,118.95,112.25, 112.22,69.98,61.88,57.05,55.55,25.95,21.94,10.38.
ESI-MS m/z:366.2(M-Br)+.
实施例13化合物Ⅳ-4的合成
制法同实施例12,得黄色固体Ⅳ-4,产率为35%。
1H NMR(600MHz,DMSO-d6)δ9.84(s,1H),9.23(s,1H),8.78(s, 1H),8.17(d,J=9.1Hz,1H),8.04(d,J=9.1Hz,1H),7.53(s,1H), 7.04(s,1H),4.92(t,J=6.3Hz,2H),4.09(s,3H),4.07(overlap, 2H),4.06(s,3H),3.18(t,J=6.3Hz,2H),1.76(m,2H),1.48(m,2H), 0.95(t,J=7.4Hz,3H).
13C NMR(151MHz,DMSO)δ150.19,150.06,146.50,145.32,143.56, 137.85,133.18,127.10,126.69,123.58,121.34,119.52,118.94,112.23, 112.21,68.19,61.89,57.06,55.57,30.64,25.96,18.66,13.71.
ESI-MS m/z:380.2(M-Br)+.
实施例14化合物Ⅳ-5的合成
制法同实施例12,得黄色固体Ⅳ-5,产率为25%。
1H NMR(600MHz,DMSO-d6)δ9.84(s,1H),9.23(s,1H),8.79(s, 1H),8.17(d,J=9.0Hz,1H),8.05(d,J=9.0Hz,1H),7.54(s,1H), 7.04(s,1H),4.92(t,J=6.2Hz,2H),4.09(s,3H),4.08(overlap, 2H),4.06(s,3H),3.18(t,J=6.2Hz,2H),1.78(m,2H),1.43(m,2H), 1.37(m,2H),0.92(t,J=7.0Hz,3H).
13C NMR(151MHz,DMSO)δ150.20,150.06,146.50,145.33,143.56, 137.86,133.18,127.10,126.69,123.58,121.34,119.52,118.94,112.23, 112.21,68.48,61.89,57.06,55.57,28.28,27.59,25.96,21.92,13.95.
ESI-MS m/z:394.3(M-Br)+.
实施例15化合物Ⅴ-2的合成
称取黄色固体Ⅳ-1500mg(1.08mmol),无水碳酸钾297mg(2.15mmol) 置于100mL干燥的单口圆底烧瓶中,并加入30mL乙腈,然后加入1-溴丙烷 196μL(2.15mmol),70-80℃搅拌反应3小时。用TLC法检测反应完毕,减压条件下旋干有机溶剂得粗产物,然后经硅胶柱层析纯化,洗脱剂V(二氯甲烷):V(甲醇)=80:1。目标组分旋干,得黄色固体Ⅴ-2,产率为43%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.98(s,1H),8.21(d, J=9.1Hz,1H),8.03(d,J=9.1Hz,1H),7.69(s,1H),7.09(s,1H), 4.94(t,J=6.3Hz,2H),4.10(s,3H),4.09(overlap,2H),4.07(s, 3H),3.88(s,3H),3.23(t,J=6.3Hz,2H),1.81(m,2H),1.04(t,J=7.4Hz,3H).
13C NMR(151MHz,DMSO)δ151.75,150.23,148.09,145.41,143.61, 137.71,133.10,128.62,126.77,123.40,121.34,119.83,118.90,111.44, 109.83,70.30,61.89,57.02,55.88,55.39,25.99,22.14,10.53.
ESI-MS m/z:380.2(M-Br)+.
实施例16化合物Ⅴ-3的合成
制法同实施例15,得黄色固体Ⅴ-3,产率为44%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.98(s,1H),8.21(d, J=9.1Hz,1H),8.03(d,J=9.1Hz,1H),7.70(s,1H),7.09(s,1H), 4.94(t,J=6.2Hz,2H),4.13(t,J=6.5Hz,2H),4.10(s,3H),4.07 (s,3H),3.87(s,3H),3.22(t,J=6.2Hz,2H),1.78(m,2H),1.50(m,2H),0.98(t,J=7.4Hz,3H).
13C NMR(151MHz,DMSO)δ151.75,150.23,148.13,145.42,143.62, 137.72,133.10,128.61,126.78,123.40,121.35,119.84,118.91,111.43, 109.81,68.47,61.89,57.03,55.89,55.39,30.85,25.99,18.82,13.75.
ESI-MS m/z:394.3(M-Br)+.
实施例17化合物Ⅴ-4的合成
制法同实施例15,得黄色固体Ⅴ-4,产率为48%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.98(s,1H),8.21(d, J=9.1Hz,1H),8.03(d,J=9.1Hz,1H),7.69(s,1H),7.09(s,1H), 4.94(t,J=6.1Hz,2H),4.12(overlap,2H),4.10(s,3H),4.07(s, 3H),3.88(s,3H),3.22(t,J=6.1Hz,2H),1.79(m,2H),1.46(m,2H),1.38(m,2H),0.93(t,J=7.1Hz,3H).
13C NMR(151MHz,DMSO)δ151.74,150.23,148.12,145.42,143.62, 137.72,133.09,128.61,126.78,123.40,121.34,119.83,118.90,111.43, 109.81,68.77,61.89,57.03,55.89,55.39,28.47,27.77,25.99,21.90, 13.94.
ESI-MS m/z:408.3(M-Br)+.
实施例18化合物Ⅴ-5的合成
制法同实施例15,得黄色固体Ⅴ-5,产率为38%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.97(s,1H),8.20(d, J=9.1Hz,1H),8.02(d,J=9.1Hz,1H),7.69(s,1H),7.08(s,1H), 4.94(t,J=6.2Hz,2H),4.12(overlap,2H),4.10(s,3H),4.07(s, 3H),3.87(s,3H),3.22(t,J=6.2Hz,2H),1.78(m,2H),1.47(m,2H),1.34(m,4H),0.90(t,J=6.8Hz,3H).
13C NMR(151MHz,DMSO)δ151.74,150.22,148.12,145.42,143.61, 137.72,133.09,128.60,126.77,123.39,121.34,119.82,118.90,111.43, 109.81,68.79,61.89,57.02,55.89,55.39,31.01,28.74,25.99,25.27, 22.10,13.93.
ESI-MS m/z:422.3(M-Br)+.
实施例19化合物Ⅴ-6的合成
制法同实施例15,得黄色固体Ⅴ-6,产率为35%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.98(s,1H),8.21(d, J=9.1Hz,1H),8.02(d,J=9.1Hz,1H),7.69(s,1H),7.08(s,1H), 4.94(t,J=6.2Hz,2H),4.12(overlap,2H),4.10(s,3H),4.07(s, 3H),3.87(s,3H),3.22(t,J=6.2Hz,2H),1.78(m,2H),1.46(m,2H),1.37(m,2H),1.30(m,4H),0.88(t,J=6.9Hz,3H).
13C NMR(151MHz,DMSO)δ151.74,150.22,148.12,145.42,143.61, 137.72,133.09,128.60,126.77,123.39,121.34,119.83,118.90,111.43, 109.82,68.79,61.89,57.03,55.89,55.39,31.27,28.78,28.47,25.99, 25.57,22.08,13.97.
ESI-MS m/z:436.3(M-Br)+.
实施例20化合物Ⅴ-7的合成
制法同实施例15,得黄色固体Ⅴ-7,产率为37%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.98(s,1H),8.21(d, J=9.1Hz,1H),8.02(d,J=9.1Hz,1H),7.69(s,1H),7.08(s,1H), 4.94(t,J=6.2Hz,2H),4.12(overlap,2H),4.10(s,3H),4.07(s, 3H),3.87(s,3H),3.22(t,J=6.2Hz,2H),1.78(m,2H),1.46(m,2H),1.37(m,2H),1.30(m,6H),0.87(t,J=7.0Hz,3H).
13C NMR(151MHz,DMSO)δ151.75,150.23,148.12,145.42,143.62, 137.72,133.09,128.61,126.78,123.40,121.34,119.83,118.90,111.43, 109.82,68.79,61.89,57.03,55.89,55.39,31.26,28.77,28.76,28.69, 25.99,25.60,22.10,13.97.
ESI-MS m/z:450.3(M-Br)+.
实施例21化合物Ⅴ-8的合成
制法同实施例15,得黄色固体Ⅴ-8,产率为40%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.97(s,1H),8.20(d, J=9.1Hz,1H),8.02(d,J=9.1Hz,1H),7.68(s,1H),7.08(s,1H), 4.94(t,J=6.3Hz,2H),4.12(overlap,2H),4.10(s,3H),4.07(s, 3H),3.87(s,3H),3.22(t,J=6.3Hz,2H),1.78(m,2H),1.46(m,2H),1.36(m,2H),1.28(m,8H),0.86(t,J=7.0Hz,3H).
13C NMR(151MHz,DMSO)δ151.74,150.23,148.12,145.42,143.62, 137.71,133.09,128.60,126.77,123.39,121.34,119.83,118.89,111.42, 109.80,68.78,61.88,57.02,55.88,55.39,31.29,28.99,28.81,28.77, 28.68,25.99,25.58,22.11,13.95.
ESI-MS m/z:464.3(M-Br)+.
实施例22化合物Ⅴ-9的合成
制法同实施例15,得黄色固体Ⅴ-9,产率为43%。
1H NMR(600MHz,DMSO-d6)δ9.86(s,1H),8.96(s,1H),8.20(d, J=9.1Hz,1H),8.02(d,J=9.1Hz,1H),7.68(s,1H),7.08(s,1H), 4.94(t,J=6.3Hz,2H),4.11(overlap,2H),4.10(s,3H),4.07(s, 3H),3.87(s,3H),3.22(t,J=6.3Hz,2H),1.78(m,2H),1.45(m,2H),1.35(m,2H),1.28(m,10H),0.85(t,J=7.0Hz,3H).
13C NMR(151MHz,DMSO)δ151.74,150.22,148.12,145.41,143.61, 137.71,133.09,128.58,126.76,123.39,121.34,119.81,118.88,111.41, 109.78,68.77,61.88,57.02,55.87,55.39,31.32,29.04,28.99,28.80, 28.77,28.72,25.99,25.59,22.10,13.95.
ESI-MS m/z:478.3(M-Br)+.
实施例23化合物Ⅵ-1的合成
称取黄色固体Ⅳ-11g(2.15mmol),无水碳酸钾1.49g(10.75mmol) 置于100mL干燥的单口圆底烧瓶中,并加入80mL乙腈,然后加入1,2-二溴乙烷1.85mL(21.50mmol),60-80℃搅拌反应1-2小时。用TLC法检测反应完毕,减压条件下旋干有机溶剂得粗产物,然后经硅胶柱层析纯化,洗脱剂V(二氯甲烷):V(甲醇)=30:1。目标组分旋干,得黄色固体Ⅵ-1,产率为47%。
1H NMR(600MHz,DMSO-d6)δ9.88(s,1H),8.99(s,1H),8.21(d, J=9.1Hz,1H),8.01(d,J=9.1Hz,1H),7.74(s,1H),7.13(s,1H), 4.95(t,J=5.9Hz,2H),4.49(t,J=5.6Hz,2H),4.11(s,3H),4.07 (s,3H),3.90(s,3H),3.88(overlap,2H),3.24(t,J=5.9Hz,2H);
13C NMR(151MHz,DMSO)δ151.74,150.27,147.23,145.45,143.65, 137.54,133.02,129.44,126.80,123.35,121.36,119.96,118.97,111.75, 110.72,69.12,61.89,57.02,55.97,55.33,31.15,26.00.
ESI-MS m/z:445.1(M-Br)+.
实施例24化合物Ⅵ-2的合成
制法同实施例23,得黄色固体Ⅵ-2,产率为72%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.99(s,1H),8.21(d, J=9.1Hz,1H),8.02(d,J=9.1Hz,1H),7.75(s,1H),7.11(s,1H), 4.95(t,J=6.3Hz,2H),4.25(t,J=5.9Hz,2H),4.10(s,3H),4.07 (s,3H),3.89(s,3H),3.72(t,J=6.4Hz,2H),3.23(t,J=6.3Hz,2H),2.33(m,2H).
13C NMR(151MHz,DMSO)δ151.79,150.25,147.72,145.43,143.62, 137.60,133.05,129.09,126.77,123.39,121.35,119.89,118.97,111.57, 110.33,66.70,61.89,57.02,55.95,55.36,31.96,31.33,26.01.
ESI-MS m/z:459.1(M-Br)+.
实施例25化合物Ⅵ-3的合成
制法同实施例23,得黄色固体Ⅵ-3,产率为82%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.97(s,1H),8.21(d, J=9.0Hz,1H),8.02(d,J=9.0Hz,1H),7.71(s,1H),7.09(s,1H), 4.94(t,J=5.4Hz,2H),4.18(t,J=5.9Hz,2H),4.10(s,3H),4.07 (s,3H),3.88(s,3H),3.67(t,J=6.5Hz,2H),3.23(t,J=5.4Hz,2H),2.03(m,2H),1.92(m,2H).
13C NMR(151MHz,DMSO)δ151.74,150.23,147.91,145.44,143.62, 137.66,133.05,128.78,126.78,123.35,121.34,119.81,118.90,111.47, 110.03,68.02,61.88,57.02,55.92,55.38,34.86,29.18,27.37,25.98.
ESI-MS m/z:473.1(M-Br)+.
实施例26化合物Ⅵ-4的合成
制法同实施例23,得黄色固体Ⅵ-4,产率为76%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.97(s,1H),8.20(d, J=9.1Hz,1H),8.02(d,J=9.1Hz,1H),7.69(s,1H),7.09(s,1H), 4.94(t,J=6.2Hz,2H),4.14(t,J=6.4Hz,2H),4.10(s,3H),4.07 (s,3H),3.88(s,3H),3.60(t,J=6.7Hz,2H),3.23(t,J=6.2Hz,2H),1.92(m,2H),1.82(m,2H),1.60(m,2H).
13C NMR(151MHz,DMSO)δ151.73,150.21,148.04,145.40,143.60, 137.68,133.06,128.66,126.76,123.36,121.32,119.81,118.88,111.43, 109.89,68.69,61.88,57.01,55.89,55.38,35.11,31.95,27.87,25.98, 24.40.
ESI-MS m/z:487.2(M-Br)+.
实施例27化合物Ⅵ-5的合成
制法同实施例23,得黄色固体Ⅵ-5,产率为90%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.97(s,1H),8.21(d, J=7.7Hz,1H),8.02(d,J=7.7Hz,1H),7.69(s,1H),7.09(s,1H), 4.94(br,2H),4.13(overlap,2H),4.10(s,3H),4.07(s,3H),3.88(s, 3H),3.56(br,2H),3.23(br,2H),1.86(br,2H),1.80(br,2H),1.49 (br,4H).
13C NMR(151MHz,DMSO)δ151.75,150.21,148.07,145.41,143.61, 137.69,133.07,128.65,126.77,123.37,121.33,119.82,118.89,111.43, 109.88,68.70,61.88,57.02,55.89,55.38,35.12,32.18,28.59,27.32, 25.98,24.75.
ESI-MS m/z:501.2(M-Br)+.
实施例28化合物Ⅶ-1的合成
称取黄色固体Ⅵ-2200mg(0.371mmol),1,2,4-三氮唑46mg(0.658mmol),无水碳酸钾91mg(0.658mmol)置于50mL干燥的单口圆底烧瓶中,并加入 20mL乙腈,70-80℃搅拌反应4小时。用TLC法检测反应完毕,减压条件下旋干有机溶剂得粗产物,然后经硅胶柱层析纯化,洗脱剂V(二氯甲烷):V(甲醇) =30:1。目标组分旋干,得黄色固体Ⅶ-1,产率为42%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.94(s,1H),8.56(s, 1H),8.20(d,J=9.1Hz,1H),8.01(overlap,1H),8.00(s,2H),7.70 (s,1H),7.11(s,1H),4.94(t,J=6.1Hz,2H),4.41(t,J=6.8Hz, 2H),4.14(t,J=5.8Hz,2H),4.10(s,3H),4.07(s,3H),3.90(s,3H), 3.23(t,J=6.1Hz,2H),2.33(m,2H).
13C NMR(151MHz,DMSO)δ151.88,151.49,150.25,147.72,145.44, 144.20,143.63,137.61,133.04,129.14,126.79,123.38,121.35,119.84, 118.95,111.59,110.49,66.00,61.89,57.03,55.96,55.36,45.70,29.11, 26.01.
ESI-MS m/z:447.2(M-Br)+.
实施例29化合物Ⅶ-2的合成
制法同实施例28,得黄色固体Ⅶ-2,产率为38%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.95(s,1H),8.57(s, 1H),8.21(d,J=9.1Hz,1H),8.02(d,J=9.1Hz,1H),7.98(s,1H), 7.69(s,1H),7.09(s,1H),4.94(t,J=5.8Hz,2H),4.31(t,J=6.8 Hz,2H),4.16(t,J=6.1Hz,2H),4.10(s,3H),4.07(s,3H),3.88(s, 3H),3.23(t,J=5.8Hz,2H),2.00(m,2H),1.74(m,2H).
13C NMR(151MHz,DMSO)δ151.74,151.42,150.23,147.91,145.45, 144.03,143.63,137.66,133.05,128.79,126.79,123.36,121.34,119.80, 118.90,111.46,110.00,68.36,61.88,57.02,55.91,55.38,48.25,26.31, 25.99,25.63.
ESI-MS m/z:461.2(M-Br)+.
实施例30化合物Ⅶ-3的合成
制法同实施例28,得黄色固体Ⅶ-3,产率为31%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.96(s,1H),8.53(s, 1H),8.20(d,J=9.0Hz,1H),8.02(d,J=9.0Hz,1H),7.96(s,1H), 7.68(s,1H),7.08(s,1H),4.94(t,J=5.6Hz,2H),4.24(t,J=6.8 Hz,2H),4.11(overlap,2H),4.10(s,3H),4.07(s,3H),3.87(s,3H), 3.22(t,J=5.6Hz,2H),1.89(m,2H),1.81(m,2H),1.41(m,2H).
13C NMR(151MHz,DMSO)δ151.71,151.32,150.22,148.03,145.41, 143.94,143.62,137.69,133.07,128.66,126.78,123.37,121.33,119.82, 118.89,111.43,109.85,68.60,61.88,57.02,55.88,55.38,48.43,29.01, 28.15,25.98,22.55.
ESI-MS m/z:475.3(M-Br)+.
实施例31化合物Ⅶ-4的合成
制法同实施例28,得黄色固体Ⅶ-4,产率为17%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.97(s,1H),8.52(s, 1H),8.20(d,J=8.2Hz,1H),8.02(d,J=8.2Hz,1H),7.95(s,1H), 7.68(s,1H),7.08(s,1H),4.94(br,2H),4.19(br,2H),4.10(overlap, 5H),4.07(s,3H),3.87(s,3H),3.22(br,2H),1.83(br,2H),1.77(br, 2H),1.48(br,2H),1.31(br,2H).
13C NMR(151MHz,DMSO)δ151.75,151.29,150.22,148.06,145.41, 143.88,143.61,137.69,133.08,128.65,126.77,123.38,121.34,119.81, 118.89,111.43,109.86,68.67,61.88,57.02,55.88,55.38,48.50,29.19, 28.55,25.98,25.58,25.01.
ESI-MS m/z:489.3(M-Br)+.
实施例32化合物Ⅶ-5的合成
制法同实施例28,得黄色固体Ⅶ-5,产率为51%。
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.98(s,1H),8.21(d, J=9.1Hz,1H),8.02(d,J=9.1Hz,1H),7.70(s,1H),7.09(s,1H), 4.94(t,J=6.2Hz,2H),4.18(t,J=6.1Hz,2H),4.10(s,3H),4.07 (s,3H),3.88(s,3H),3.60(br,4H),3.23(t,J=6.2Hz,2H),2.41(br,6H),1.97(br,2H);
13C NMR(151MHz,DMSO)δ151.78,150.23,148.00,145.42,143.62, 137.68,133.07,128.77,126.78,123.38,121.34,119.84,118.92,111.48, 110.06,67.16,66.10(overlap2),61.88,57.02,55.90,55.38,54.90, 53.34(overlap2),26.00(overlap2).
ESI-MS m/z:465.3(M-Br)+.
实施例33化合物Ⅶ-6的合成
制法同实施例28,得黄色固体Ⅶ-6,产率为36%。
1H NMR(600MHz,DMSO-d6)δ9.89(s,1H),8.97(s,1H),8.22(d, J=9.0Hz,1H),8.01(d,J=9.0Hz,1H),7.74(s,1H),7.13(s,1H), 4.94(t,J=6.0Hz,2H),4.24(t,J=5.7Hz,2H),4.11(s,3H),4.08 (s,3H),3.89(s,3H),3.64(br,2H),3.36(overlap,2H),3.24(t,J=6.0Hz,2H),3.09(br,2H),2.19(m,2H),1.98(br,4H);
13C NMR(151MHz,DMSO)δ151.71,150.30,147.56,145.58,143.70, 137.58,133.02,129.26,126.85,123.33,121.39,119.80,118.97,111.56, 110.29,66.48,61.91,57.04,56.00,55.38,53.49(overlap2),51.81, 26.00,25.43,22.59(overlap2).
ESI-MS m/z:449.3(M-Br)+.
实施例34化合物Ⅶ-7的合成
制法同实施例28,得黄色固体Ⅶ-7,产率为27%。
1H NMR(600MHz,DMSO-d6)δ9.89(s,1H),8.97(s,1H),8.22(d, J=9.0Hz,1H),8.01(d,J=9.0Hz,1H),7.75(s,1H),7.13(s,1H), 4.94(t,J=6.7Hz,2H),4.23(t,J=5.0Hz,2H),4.11(s,3H),4.08 (s,3H),3.89(s,3H),3.54(br,2H),3.25(overlap,4H),2.96(br,2H), 2.21(m,2H),1.85(br,2H),1.70(overlap,4H).
13C NMR(151MHz,DMSO)δ151.72,150.30,147.56,145.58,143.70, 137.58,133.02,129.27,126.85,123.33,121.38,119.80,118.96,111.57, 110.37,66.60,61.90,57.04,55.97,55.38,53.86,52.34(overlap2), 26.00,23.60,22.76(overlap2),21.27.
ESI-MS m/z:463.3(M-Br)+.
实施例35化合物Ⅶ-8的合成
制法同实施例28,得黄色固体Ⅶ-8,产率为27%。
1H NMR(600MHz,DMSO-d6)δ9.89(s,1H),8.97(s,1H),8.22(d, J=9.1Hz,1H),8.01(d,J=9.1Hz,1H),7.75(s,1H),7.14(s,1H), 4.94(t,J=6.1Hz,2H),4.23(t,J=5.5Hz,2H),4.11(s,3H),4.08 (s,3H),3.89(s,3H),3.55(br,2H),3.24(overlap,4H),2.96(br,2H), 2.21(m,2H),1.85(overlap,2H),1.64(br,1H),1.34(m,2H),0.95(d, J=5.9Hz,3H);
13C NMR(151MHz,DMSO)δ151.71,150.30,147.56,145.58,143.70, 137.58,133.02,129.26,126.85,123.32,121.38,119.80,118.96,111.57, 110.35,66.58,61.90,57.04,55.96,55.38,54.90,53.91,52.20, 31.12(overlap2),28.07,26.00,21.08.
ESI-MS m/z:477.3(M-Br)+.
试验例:本发明化合物的体外细胞存活率及体外降脂水平试验
一﹑材料与方法
细胞:A549和HepG2细胞来自哈尔滨医科大学药剂实验室。
药品及试剂:本发明化合物为哈尔滨医科大学药化实验室自制;MTT噻唑蓝(天津阿尔法生物科技有限公司)﹑甘油三酯测试盒(南京建成生物工程研究所)﹑BCA蛋白浓度测定试剂盒(上海碧云天生物技术有限公司)。
(1)细胞培养
从液氮中取出冻存的A549和HepG2细胞,置于37℃的水浴锅中解冻,轻轻摇晃冷冻管使细胞全部融化,移入无菌操作台内。打开冷冻管,将细胞悬液转移到容积为15mL的离心管中,加入10mL含10%胎牛血清的DMEM培养液吹匀。在1000转/分钟转速条件下离心5分钟,去除上清液。加入约4mL含 10%胎牛血清的DMEM培养液使细胞悬浮,转移到培养瓶中。于37℃,5%CO2,饱和湿度的孵箱中进行孵育。
(2)化合物体外细胞存活率检测
从孵箱中取出生长良好的A549细胞,胰酶消化并调整细胞密度至103-104个/mL,将细胞悬液每孔100μL接种于96孔培养板中,四周边缘孔用无菌的 PBS填充。37℃,5%CO2,饱和湿度的孵箱中孵育,至细胞单层铺满96孔培养板板底,加入浓度梯度的化合物。本发明化合物分别用DMSO溶解,最终浓度为10μmol/L,DMSO体积比为总体积的0.02﹪。每个化合物设置3个平行孔并设置3个对照孔:培养孔只加培养液替代给药,同置于孵箱中培养24小时。每孔加入20μL MTT溶液(5mg/mL),然后继续孵育4小时。终止培养,小心吸出孔内培养液,每孔加入150μL DMSO,将96孔培养板置于摇床上低速振荡10分钟使结晶物充分溶解,然后在酶联免疫检测仪490nm处测量各孔的OD 值。最后,计算本发明化合物体外细胞存活率。
(3)化合物体外降脂水平检测
油酸造模液:取5μL油酸溶于63.5μL的无水乙醇中,然后加入274μL 现配的PBS稀释得油酸造模母液。再以油酸造模母液:培养液=1:90的比例配置一定量的油酸造模液。
从孵箱中取出生长良好的HepG2细胞,胰酶消化后加入适量的培养液,用胶头吸管轻轻吹打使细胞悬浮。将细胞悬液每孔100μL接种于24孔培养板中,然后每孔补加300μL的培养液。孵育12小时待细胞完全贴壁,小心吸出孔内培养液并向孔内加入500μL油酸造模液,然后分别向各给药组加入用DMSO溶解的本发明化合物,其终浓度为20μmol/L,DMSO体积比为总体积的0.002%,每个化合物设置3个平行孔。同时另设1个对照组OA(只加油酸造模液替代给药)和1个阴性组NC(只加培养基替代造模液、给药),每组设置3个平行孔。培养48小时后,小心吸出孔内培养液并用PBS清洗。PBS吸干净后向每孔加入 100μL胰酶消化,待消化结束后加入300μL培养基终止消化,轻轻吹打使细胞完全悬浮,然后转移至2mL EP管中,于3500转/分的条件下离心10分钟,结束后吸出上清液。每个EP管中加入1mL PBS清洗并将细胞混匀,于3500 转/分的条件下离心10分钟,结束后吸出上清液。每个EP管中加入100μL异丙醇并置冰上孵育1.5-2小时。孵育结束后于13500转/分的条件下离心15分钟,上清液转移至96孔培养板中(EP管4℃保存备用),吹风机小风冷风吹干至白色颗粒状,然后向每孔加入20μL异丙醇和180μL工作液。校准组设置3个平行孔:每孔加入2μL校准液和198μL工作液,空白组设置3个平行孔:每孔加入相应的DMSO。37℃孵育10分钟后,在酶联免疫检测仪510nm处测量各孔的OD值。上述备用EP管中加入40μL配置好的细胞裂解液并置冰上孵育40分钟,结束后于13500转/分的条件下离心15分钟,分别取10μL 上清液置96孔培养板中,并加入10μL PBS与200μL BCA工作液,于37℃条件下放置30分钟,然后在酶联免疫检测仪562nm处测量各孔的OD值。最后,计算本发明化合物体外降脂水平。
二﹑试验结果
上述化合物的测试结果如图1-图3所示。当化合物浓度为10μmol/L时,除化合物Ⅲ-3﹑Ⅵ-4和Ⅵ-5外,大部分化合物对A549细胞无明显毒副作用;当化合物浓度为20μmol/L时,除化合物Ⅲ-3﹑Ⅵ-1﹑Ⅵ-2﹑Ⅵ-3和Ⅵ-5外,大部分化合物对A549细胞无明显毒副作用;当化合物浓度为20μmol/L时,大部分化合物表现出降脂活性,其中化合物Ⅲ-4﹑Ⅲ-5和Ⅶ-4的降脂活性显著强于化合物Ⅰ(盐酸小檗碱)。
本发明发现了一类新型的2,3-双取代小檗碱衍生物,部分化合物具有较好的降脂活性,具有继续优化开发成新型降脂药物的潜力。
显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (8)
1.2,3-双取代小檗碱衍生物,其结构式如通式(A)所示:
其中,R1选自Br-﹑I-或三氟甲基磺酸根离子;
R2选自氢、C1-C10烷基或R3”-R3’-,其中R3’表示C1-C10亚烷基,R3”表示卤素、C1-C6烷氧基、取代或未取代的含氮五元环或六元环中的至少一种,其中,取代的含氮五元环或六元环中的取代基为C1-C6烷基、C1-C6烷氧基、卤素中的任意一种;
R3选自氢、C1-C10烷基或R3”-R3’-,其中R3’表示C1-C10亚烷基,R3”表示卤素、C1-C6烷氧基、取代或未取代的含氮五元环或六元环中的至少一种,其中,取代的含氮五元环或六元环中的取代基为C1-C6烷基、C1-C6烷氧基、卤素中的任意一种。
2.根据权利要求1所述的2,3-双取代小檗碱衍生物,其特征在于:R2与R3之间形成饱和碳链,或者形成含杂原子的链,其中,所述杂原子为N、O或S,或者形成包含不饱和键的链。
4.根据权利要求1-3中任一项所述的2,3-双取代小檗碱衍生物,其特征在于:R2、R3相同,为R3”-R3’-,其中R3’表示C2-C6亚烷基,R3”表示C1-C4烷氧基或C2-C4烷氧基。
5.根据权利要求1-3中任一项所述的2,3-双取代小檗碱衍生物,其特征在于:R2、R3相同,为R3”-R3’-,其中R3’表示C3-C6亚烷基,R3”表示三氮唑。
7.权利要求1-6中任一项所述的2,3-双取代小檗碱衍生物在制备降血脂的药物中的应用。
8.一种药物组合物,其包括权利要求1-6中任一项所述的2,3-双取代小檗碱衍生物。
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WO2023169567A1 (zh) * | 2022-03-11 | 2023-09-14 | 南京施江医药科技有限公司 | 四环类化合物在治疗肿瘤中的应用 |
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