CN111393451B - 一种基于黄柏酮的化合物 - Google Patents
一种基于黄柏酮的化合物 Download PDFInfo
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Abstract
Description
技术领域
本发明属于化学医药技术领域,具体涉及一种基于黄柏酮的化合物。
背景技术
糖皮质激素是由肾上腺皮质中束状带分泌的一类甾体激素,生理剂量的糖皮质激素具有调节糖、脂肪、蛋白质的生物合成和代谢的作用,超剂量使用还具有抑制免疫应答、抗炎、抗毒、抗休克等药理作用,应用非常广泛。其中,由于其良好的抗炎、抗过敏作用,使得其在许多疾病的治疗中具有不可替代的作用。然而,过量应用糖皮质激素副作用严重,如肾上腺皮质醇增多症(向心性肥胖、满月脸、水牛背、皮肤紫纹、痤疮、多毛等类柯兴综合征表现)、代谢紊乱(激素性糖尿病、高血压、负氮平衡、水电解质紊乱)、诱发或加重感染、溃疡、骨质疏松、骨无菌性坏死、类固醇肌病及糖皮质激素性白内障或青光眼等。由此可见,糖皮质激素是一把典型的“双刃剑”。而目前临床滥用糖皮质激素的情况也非常突出,不仅造成了药物的浪费,也导致各种不良反应。因此,一方面应加强糖皮质激素的临床合理用药,另一方面,如果能通过某种物质增加糖皮质激素药物的生物学效应,在不影响其疗效的情况下减少药物用量,那么就将大大降低其毒副作用的发生。因此,寻找并开发疗效显著、安全可靠的糖皮质激素增效剂对改善糖皮质激素药物的临床用量、减少毒副作用具有重要意义。同时,由于糖皮质激素临床应用的广泛性,开发新型糖皮质激素增效剂具有极大的应用潜力和临床价值。
目前,关于糖皮质激素增效剂的研究报道相对较少,尤其从中药及天然产物中寻找糖皮质激素增效剂的报道更是凤毛麟角,仅有关于人参皂苷可以增强糖皮质激素抗炎活性的报道。
例如,中国专利申请200710041868.6中公开了一种糖皮质激素增效剂,其使用人参总皂苷作为增效剂,其配比分别如下:人参总皂苷200-1200mg,地塞米松0.75-187.5mg;人参总皂苷200-1200mg,倍他米松0.75-187.5mg;人参总皂苷200-1200mg,强的松5-1250mg;人参总皂苷200-1200mg,强的松龙5-1250mg;人参总皂苷200-1200mg,甲强龙4-1000mg;人参总皂苷200-1200mg,可的松25-6250mg;人参总皂苷200-1200mg,氢化可的松20-5000mg。人参总皂苷作为一种糖皮质激素增强剂,可在包括系统性红斑狼疮、肾病综合征、多发性肌炎、类风湿性关节炎等在内的需要长期或大量使用糖皮质激素治疗的疾病中得以应用。
黄柏酮(obacunone,OBA)是一种柠檬苦素类三萜化合物,主要分布于芸香科柑橘属植物以及能清热解毒燥湿的黄柏、白鲜皮等中药中,有研究表明黄柏酮能够结合前列腺表面特异性抗体和雄激素受体,下调Cox-2以及IL-6表达,说明OBA具有增强糖皮质激素的作用,本发明为了进一步提高黄柏酮的增强糖皮质激素的作用,以黄柏酮为原料合成了多种化合物,使其具有更好的抑制NO,以及TNF-α 和IL-6的效果。
发明内容
基于现有技术中的问题,本发明提供了一种基于黄柏酮的化合物。
其中,所述的的化合物,其为如式(1)所示的化合物,或式(1)所示的化合物的立体异构体,几何异构体、互变异构体、氮氧化合物、水合物、溶剂化物、代谢产物、药学上可接受的盐或者前药;
其中:
m为1或2;
其中:
R1和R2各自独立选自以下取代基:H、C1-C6烷基、C3-C8环烷基、卤代芳基、C4-C8 杂环基C1-C4烷基;
n为1-6;
R3选自以下取代基:H、羟基、氰基、氨基、卤素、硝基、C1-C4烷基、氯代C1-C4烷基、巯基、C1-C4烷氧基、C1-C4烷氨基、芳基、芳基C1-C4烷基、杂芳基、杂芳基C1-C4 烷基、C4-C8杂环基、C4-C8杂环基C1-C4烷基、C3-C8环烷基和C3-C8环烷基C1-C4烷基中的一种或多种;
X选自O或N;
当X为O时,R4不存在;
当X为N时,R4选自以下取代基:C1-C4烷基、卤代C1-C4烷基、卤代芳基酰基、羟基C1-C4烷基、芳基、芳基C1-C4烷基、杂芳基、杂芳基C1-C4烷基、C4-C8杂环基、C4-C8 杂环基C1-C4烷基、C3-C8环烷基和C3-C8环烷基C1-C4烷基中的一种或多种。
在一个优选实施方案中,所述的R1和R2各自独立选自H、C1-C4烷基、C3-C8环烷基、卤代芳基、C4-C8杂环基C1-C4烷基。
在一个优选实施方案中,所述的R3选自以下取代基:H、氨基、C1-C4烷基、氯代C1-C4 烷基、C1-C4烷氧基、C1-C4烷氨基中的一种或多种。
在一个优选实施方案中,当X代表N时,所述的R4选自以下取代基:C1-C4烷基、卤代芳基、卤代C1-C4烷基、酰基、芳基、芳基C1-C4烷基、杂芳基、杂芳基C1-C4烷基、杂环基、杂环基C1-C4烷基、环烷基和环烷基C1-C4烷基中的一种或多种。
所述的R1和R2各自独立选自H、C1-C4烷基、C3-C5环烷基、卤代芳基、C4-C5杂环基C1-C4烷基;
所述的R3选自以下取代基:H、氨基、C1-C4烷基、C1-C4烷氧基、C1-C4烷氨基中的一种或多种;
当X代表N时,所述的R4选自以下取代基:C1-C4烷基、卤代芳基、卤代C1-C4烷基、酰基、芳基、芳基C1-C4烷基中的一种或多种。
所述的化合物(1)的可以为以下化合物中的一种:
本发明还提供了一种上述化合物的制备方法,所述的方法为:以黄柏酮为起始原料,在还原条件下得到黄柏酮7位醇羟基产物2,接着进行酰化反应得中间体3,最后在碱性条件下与取代的胺类化合物反应得到产物1。
上述的还原为在含硼氢化钠的条件下还原。
上述的酰化为在加入卤代乙酰氯或者卤代丙酰氯的条件下酰化。
上述的碱性条件为含碳酸钾的条件。
上述的取代的胺类化合物为吗啉、N-甲基哌嗪、哌啶、四氢吡咯、正丙胺、二乙胺、正丁胺、异丁胺、环戊胺、N-乙基哌嗪、1-(4-氟苯基)哌嗪、N-乙酰基哌嗪、叔丁胺、二甲胺、异丙胺、4-氯苄胺或1-(3-氨基丙基)咪唑。
优选地,所述的取代的胺类化合物为N-甲基哌嗪、正丙胺、正丁胺、二甲胺、异丙胺或 1-(3-氨基丙基)咪唑。
本发明还提供了上述化合物在制备糖皮质激素增效剂药物中的应用。
优选地,所述的糖皮质激素增效剂药物所针对的疾病包括但不限于支气管哮喘、急性淋巴细胞性白血病、原发性肾病综合征、类风湿性关节炎、系统性红斑狼疮或恶性肿瘤晚期。
有益效果:与现有技术相比,本发明涉及的药物组合物具有如下优点和显著的进步:
(1)本发明公开的化合物(1)具有增强糖皮质激素的效果,并且毒副作用更小;
(2)本发明公开的化合物(1)是以黄柏酮为原料合成的,该化合物可以有效的抑制NO 的生成,从而起到更好的增效糖皮质激素的作用;
(3)本发明公开的化合物(1)是以黄柏酮为原料合成的,该化合物可以剂量依赖性的抑制内毒素小鼠血清中TNF-α 和IL-6的释放,进而可以更好增效糖皮质激素。
附图说明
图1 1b化合物剂量依赖性的抑制内毒素小鼠血清中TNF-α 释放的示意图;
图2 1b化合物能剂量依赖性的抑制内毒素小鼠血清中IL-6释放的示意图。
具体实施方式
基础实施例
化合物2的制备
将黄柏酮(1.0g,2.2mmol)溶于150mL甲醇中,冷却至-5℃,分批次加入硼氢化钠(167.2 mg,4.4mmol),加毕,-5℃下反应10m3n。TLC检测反应完全,加入10mL盐酸(1mol/L)淬灭反应,加入蒸馏水(100mL),用二氯甲烷(100mL×3)萃取,合并有机相,无水硫酸钠干燥,过滤,浓缩,硅胶柱色谱纯化,洗脱剂:石油醚-乙酸乙酯=2:1(V/V),得白色固体800mg,收率80%。
化合物3的制备
将化合物2(500.0mg,1.1mmol),4-二甲氨基吡啶(269.0mg,2.2mmol)和吡啶(105.0 mg,1.3mmol)溶于15mL二氯甲烷中,冷却至0℃。将氯乙酰氯(248.5mg,2.2mmol)滴加至反应液中。滴毕,室温搅拌反应12h。TLC检测反应完全,停止反应,加蒸馏水(100mL),用二氯甲烷(100mL×3)萃取,合并有机相,无水硫酸钠干燥,过滤,浓缩,硅胶柱色谱纯化,洗脱剂:石油醚-乙酸乙酯=2:1(V/V),得白色固体463mg,收率79%。
实施例1
化合物1a的制备
将化合物3(30.0mg,0.06mmol),碳酸钾(15.0mg,0.12mmol),溶于2mL乙腈中。将吗啉(10.4mg,0.12mmol)加至反应液中。加毕,室温反应。TLC检测反应完全,停止反应,加蒸馏水(50mL),二氯甲烷(500mL×3)萃取,合并有机相,无水硫酸钠干燥,过滤,浓缩,硅胶柱色谱纯化,洗脱剂:石油醚-乙酸乙酯=1:2(V/V),得白色固体1a。收率:88%;
mp:93.2-94.0℃;
1H NMR(600MHz,CDCl3)δ7.41-7.39(m,2H),6.48(d,J=11.8Hz,1H),6.34(s,1H),5.90(d,J=11.8Hz,1H),5.50(s,1H),5.13(dd,J=10.5Hz,5.0Hz,1H),3.81(s,1H),3.79-3.72 (m,4H),3.31(d,J=17.3Hz,1H),3.27(d,J=17.3Hz,1H),2.71-2.66(m,2H),2.63-2.57(m,2H), 2.31(dd,J=12.7Hz,5.0Hz,1H),1.89-1.78(m,6H),1.51-1.46(m,1H),1.44(s,3H),1.43(s,3H), 1.30(s,3H),1.27(s,3H),1.02(s,3H);
13C NMR(150MHz,CDCl3)δ169.8,167.4,167.1,157.5,143.3,141.1,122.6,120.1,109.9, 84.7,78.3,76.5,68.1,66.9,59.6,54.6,53.5,52.0,48.3,44.0,43.2,38.7,32.4,32.3,30.1,27.0,21.0, 19.5,16.3,12.7;
C32H42NO9[M+H]+的高效液相质谱质荷比理论值为584.2860;
实际测试值为584.2867。
实施例2
化合物1b的制备:
以化合物3和N-甲基哌嗪为原料,操作同化合物1a的合成方法,得白色固体1b,收率: 59%;
mp:123.0-124.0℃;
1H NMR(600MHz,CDCl3)δ7.41-7.39(m,2H),6.48(d,J=11.8Hz,1H),6.34(s,1H),5.91 (d,J=11.8Hz,1H),5.50(s,1H),5.12(dd,J=10.1Hz,5.3Hz,1H),3.83(s,1H),3.31(s,2H), 2.84-2.64(m,4H),2.63-2.46(m,4H),2.34(s,3H),2.30(dd,J=12.3Hz,5.3Hz,1H),1.90-1.78 (m,6H),1.52-1.46(m,1H),1.45(s,3H),1.44(s,3H),1.31(s,3H),1.27(s,3H),1.03(s,3H);
13C NMR(150MHz,CDCl3)δ170.0,167.5,167.1,157.5,143.3,141.2,122.6,120.2,109.9, 84.7,78.3,76.5,68.2,59.3,54.9,54.6,52.9,52.1,48.3,45.9,44.1,43.2,38.7,32.4,32.3,30.1,27.1, 21.1,19.5,16.4,12.7;
C33H45N2O8[M+H]+的高效液相质谱质荷比理论值为597.3176;
实际测试值为597.3183。
实施例3
化合物1c的制备:
以化合物3和哌啶为原料,操作同化合物1a的合成方法,得白色固体1c,收率:77%;
mp:104.5-105.2℃;
1H NMR(600MHz,CDCl3)δ7.42-7.39(m,2H),6.48(d,J=11.8Hz,1H),6.34(s,1H),5.90(d,J=11.8Hz,1H),5.50(s,1H),5.11(dd,J=7.7Hz,7.5Hz,1H),3.83(s,1H),3.29(d,J= 17.3Hz,1H),3.23(d,J=17.3Hz,1H),2.64-2.56(m,2H),2.54-2.47(m,2H),2.34-2.28(m,1H), 1.90-1.79(m,6H),1.67-1.58(m,4H),1.51-1.46(m,1H),1.45-1.42(m,8H),1.30(s,3H),1.27(s, 3H),1.03(s,3H);
13C NMR(150MHz,CDCl3)δ170.4,167.5,167.1,157.6,143.3,141.2,122.6,120.2,109.9, 84.8,78.3,76.3,68.2,60.2,54.6,52.1,48.3,44.0,43.2,38.7,32.4,32.3,30.1,27.1,26.0,24.0,21.1, 19.5,16.3,12.7;
C33H44NO8[M+H]+的高效液相质谱质荷比理论值为582.3067;
实际测试值为582.3068。
实施例4
化合物1d的制备:
以化合物3和四氢吡咯为原料,操作同化合物1a的合成方法,得白色固体1d,收率:63%;
mp:100.0-101.9℃;
1H NMR(600MHz,CDCl3)δ7.42-7.38(m,2H),6.48(d,J=11.8Hz,1H),6.35(s,1H),5.90 (d,J=11.8Hz,1H),5.51(s,1H),5.14(dd,J=7.9Hz,7.5Hz,1H),3.78(s,1H),3.54(d,J=17.2 Hz,1H),3.35(d,J=17.2Hz,1H),2.79-2.73(m,2H),2.69-2.63(m,2H),2.34-2.29(m,1H), 1.91-1.79(m,10H),1.52-1.46(m,1H),1.45(s,3H),1.44(s,3H),1.31(s,3H),1.28(s,3H),1.04(s, 3H);
13C NMR(150MHz,CDCl3)δ170.5,167.5,167.1,157.6,143.3,141.2,122.6,120.2,109.9, 84.8,78.3,76.4,68.3,57.0,54.6,54.3,52.2,48.3,44.0,43.2,38.7,32.4,32.2,30.1,27.1,24.0,21.1, 19.5,16.3,12.8;
C32H42NO8[M+H]+的高效液相质谱质荷比理论值为568.2910;
实际测试值为568.2913。
实施例5
化合物1e的制备:
以化合物3和正丙胺为原料,操作同化合物1a的合成方法,得白色固体1e,收率:67%;
mp:85.2-86.8℃;
1H NMR(600MHz,CDCl3)δ7.41-7.38(m,2H),6.47(d,J=11.8Hz,1H),6.34(s,1H),5.90(d,J=11.8Hz,1H),5.50(s,1H),5.16(dd,J=10.7Hz,4.7Hz,1H),3.70(s,1H),3.52(d,J= 17.6Hz,1H),3.48(d,J=17.6Hz,1H),2.62(t,J=7.2Hz,2H),2.30(dd,J=13.1Hz,4.4Hz,1H), 1.91-1.78(m,6H),1.57-1.51(m,2H),1.50-1.46(m,1H),1.44(s,3H),1.43(s,3H),1.30(s,3H), 1.28(s,3H),1.03(s,3H),0.94(t,J=7.4Hz,3H);
13C NMR(150MHz,CDCl3)δ172.1,167.4,167.1,157.4,143.3,141.1,122.5,120.1,109.8, 84.7,78.3,76.4,68.2,54.6,52.2,51.6,51.2,48.2,44.0,43.2,38.7,32.4,32.1,30.1,27.0,23.2,20.9, 19.4,16.3,12.6,11.8;
C31H42NO8[M+H]+的高效液相质谱质荷比理论值为556.2910;
实际测试值为556.2914。
实施例6
化合物1f的制备:
以化合物3和二乙胺为原料,操作同化合物1a的合成方法,得白色固体1f,收率:80%;
mp:89.8-90.5℃;
1H NMR(600MHz,CDCl3)δ7.40-7.38(m,2H),6.47(d,J=11.8Hz,1H),6.33(s,1H),5.90(d,J=11.8Hz,1H),5.50(s,1H),5.10(dd,J=8.2Hz,7.1Hz,1H),3.76(s,1H),3.38(s,2H), 2.72-2.61(m,4H),2.30(dd,J=10.3Hz,7.4Hz,1H),1.91-1.77(m,6H),1.51-1.46(m,1H),1.44 (s,6H),1.30(s,3H),1.27(s,3H),1.08(t,J=7.2Hz,6H),1.04(s,3H);
13C NMR(150MHz,CDCl3)δ171.3,167.5,167.0,157.5,143.3,141.1,122.5,120.2,109.9, 84.7,78.3,76.3,68.4,54.7,54.5,52.3,48.2,47.8,44.0,43.2,38.7,32.4,32.0,30.0,27.0,21.0,19.4, 16.3,12.8,12.3;
C32H44NO8[M+H]+的高效液相质谱质荷比理论值为570.3067;
实际测试值为570.3073。
实施例7
化合物1g的制备:
以化合物3和正丁胺为原料,操作同化合物1a的合成方法,得白色固体1g,收率:75%;
mp:78.5-79.0℃;
1H NMR(600MHz,CDCl3)δ7.41-7.38(m,2H),6.48(d,J=11.8Hz,1H),6.34(s,1H),5.91 (d,J=11.8Hz,1H),5.51(s,1H),5.16(dd,J=10.8Hz,4.7Hz,1H),3.70(s,1H),3.52(d,J=17.6 Hz,1H),3.48(d,J=17.6Hz,1H),2.68-2.63(m,2H),2.31(dd,J=13.1Hz,4.4Hz,1H),1.91-1.78 (m,6H),1.53-1.47(m,3H),1.45(s,3H),1.44(s,3H),1.41-1.34(m,2H),1.31(s,3H),1.29(s,3H), 1.03(s,3H),0.92(t,J=7.4Hz,3H);
13C NMR(150MHz,CDCl3)δ172.2,167.5,167.2,157.5,143.3,141.2,122.6,120.2,109.9, 84.7,78.4,76.5,68.3,54.7,52.3,51.4,49.5,48.3,44.1,43.2,38.8,32.4,32.3,32.2,30.1,27.0,21.0, 20.5,19.4,16.3,14.1,12.7;
C32H44NO8[M+H]+的高效液相质谱质荷比理论值为570.3067;
实际测试值为570.3076。
实施例8
化合物1h的制备:
以化合物3和异丁胺为原料,操作同化合物1a的合成方法,得白色固体1h,收率:94%;
mp:80.0-81.0℃;
1H NMR(600MHz,CDCl3)δ7.41-7.38(m,2H),6.48(d,J=11.8Hz,1H),6.34(s,1H),5.90(d,J=11.8Hz,1H),5.51(s,1H),5.16(dd,J=10.8Hz,4.7Hz,1H),3.71(s,1H),3.51(d,J= 17.6Hz,1H),3.47(d,J=17.6Hz,1H),2.47(d,J=6.8Hz,2H),2.30(dd,J=13.1Hz,4.5Hz,1H), 1.91-1.79(m,6H),1.78-1.72(m,1H),1.52-1.46(m,1H),1.44(s,3H),1.44(s,3H),1.30(s,3H), 1.28(s,3H),1.03(s,3H),0.95-0.92(m,6H);
13C NMR(150MHz,CDCl3)δ172.2,167.5,167.1,157.5,143.3,141.1,122.6,120.2,109.9, 84.7,78.3,76.4,68.3,57.7,54.6,52.2,51.5,48.3,44.1,43.2,38.7,32.4,32.2,30.1,28.6,27.0,21.0, 20.7,20.7,19.4,16.3,12.7;
C32H44NO8[M+H]+的高效液相质谱质荷比理论值为570.3067;
实际测试值为570.3073。
实施例9
化合物3i的制备:
以化合物3和环戊胺为原料,操作同化合物1a的合成方法,得白色固体1i,收率:94%;
mp:86.0-87.0℃;
1H NMR(600MHz,CDCl3)δ7.42-7.38(m,2H),6.48(d,J=11.8Hz,1H),6.34(s,1H),5.91(d,J=11.8Hz,1H),5.51(s,1H),5.16(dd,J=10.6Hz,4.9Hz,1H),3.71(s,1H),3.51(d,J= 17.8Hz,1H),3.48(d,J=17.7Hz,1H),3.16-3.10(m,1H),2.31(dd,J=12.8Hz,4.7Hz,1H), 1.91-1.79(m,8H),1.74-1.67(m,2H),1.59-1.52(m,2H),1.51-1.46(m,1H),1.45(s,3H),1.44(s, 3H),1.42-1.35(m,2H),1.31(s,3H),1.28(s,3H),1.04(s,3H);
13C NMR(150MHz,CDCl3)δ172.2,167.5,167.2,157.5,143.3,141.1,122.6,120.2,109.9, 84.7,78.4,76.5,68.3,59.5,54.6,52.3,50.1,48.3,44.1,43.2,38.8,33.2,33.0,32.4,32.1,30.1,27.0, 24.1,24.1,21.0,19.4,16.3,12.7;
C33H44NO8[M+H]+的高效液相质谱质荷比理论值为582.3067;
实际测试值为582.3072。
实施例10
化合物1j的制备:
以化合物3和N-乙基哌嗪为原料,操作同化合物1a的合成方法,得白色固体1j,收率: 95%;
Mp:108.7-109.5℃;
1H NMR(600MHz,CDCl3)δ7.40-7.38(m,2H),6.47(d,J=11.8Hz,1H),6.33(s,1H),5.90(d,J=11.8Hz,1H),5.49(s,1H),5.11(dd,J=10.0Hz,5.5Hz,1H),3.82(s,1H),3.31(d,J= 17.4Hz,1H),3.28(d,J=17.4Hz,1H),2.80-2.49(m,8H),2.47(q,J=7.2Hz,2H),2.30(dd,J= 12.1Hz,5.7Hz,1H),1.89-1.79(m,6H),1.51-1.45(m,1H),1.44(s,3H),1.43(s,3H),1.30(s,3H), 1.26(s,3H),1.09(d,J=7.2Hz,3H),1.02(s,3H);
13C NMR(150MHz,CDCl3)δ170.0,167.4,167.1,157.5,143.3,141.1,122.5,120.2,109.9, 84.7,78.3,76.5,68.2,59.4,54.6,53.0,52.5,52.3,52.1,48.3,44.0,43.2,38.7,32.4,32.2,30.0,27.0, 21.0,19.4,16.3,12.7,11.8;
C34H47N2O8[M+H]+的高效液相质谱质荷比理论值为611.3332;
实际测试值为611.3331。
实施例11
化合物1k的制备:
以化合物3和1-(4-氟苯基)哌嗪为原料,操作同化合物1a的合成方法,得白色固体1k,收率:73%;
mp:111.0-112.0℃;
1H NMR(600MHz,CDCl3)δ7.41-7.39(m,2H),6.96(dd,J=9.0Hz,8.4Hz,2H),6.88(dd, J=9.1Hz,4.6Hz,2H),6.48(d,J=11.8Hz,1H),6.35(s,1H),5.91(d,J=11.8Hz,1H),5.51(s, 1H),5.16(dd,J=10.3Hz,5.1Hz,1H),3.85(s,1H),3.40(d,J=17.4Hz,1H),3.34(d,J=17.4Hz, 1H),3.22-3.14(m,4H),2.86(ddd,J=11.2Hz,6.4Hz,3.1Hz,2H),2.78(ddd,J=11.2Hz,6.4Hz, 3.2Hz,2H),2.32(dd,J=12.5Hz,5.2Hz,1H),1.91-1.80(m,6H),1.52-1.47(m,1H),1.45(s,3H), 1.45(s,3H),1.31(s,3H),1.29(s,3H),1.04(s,3H);
13C NMR(150MHz,CDCl3)δ169.9,167.4,167.2,157.6,157.3(d,J=237.7Hz),148.0, 143.3,141.2,122.6,120.1,118.0(d,J=7.7Hz),115.6(d,J=22.0Hz),109.9,84.7,78.3,76.5, 68.1,59.3,54.6,53.2,52.0,50.2,48.4,44.1,43.2,38.7,32.4,32.3,30.1,27.1,21.1,19.5,16.4,12.7;
C38H46FN2O8[M+H]+的高效液相质谱质荷比理论值为677.3238;
实际测试值为677.3245。
实施例12
化合物1l的制备:
以化合物3和N-乙酰基哌嗪为原料,操作同化合物1a的合成方法,得白色固体1l,收率:92%;
mp:102.8-103.4℃;
1H NMR(600MHz,CDCl3)δ7.41-7.38(m,2H),6.48(d,J=11.8Hz,1H),6.34(s,1H),5.90(d,J=11.8Hz,1H),5.50(s,1H),5.15(dd,J=10.8Hz,4.6Hz,1H),3.78(s,1H),3.71(ddd,J =13.1Hz,6.0Hz,3.5Hz,1H),3.63(ddd,J=12.9Hz,6.6Hz,3.5Hz,1H),3.56-3.47(m,2H), 3.36(d,J=17.4Hz,1H),3.31(d,J=17.4Hz,1H),2.76(ddd,J=11.2Hz,6.4Hz,3.3Hz,1H), 2.64-2.55(m,3H),2.31(dd,J=13.2Hz,4.4Hz,1H),2.08(s,3H),1.90-1.77(m,6H),1.51-1.46 (m,1H),1.44(s,3H),1.44(s,3H),1.30(s,3H),1.28(s,3H),1.01(s,3H);
13C NMR(150MHz,CDCl3)δ169.8,169.1,167.4,167.2,157.5,143.4,141.1,122.6,120.1, 109.9,84.6,78.4,76.5,68.1,59.1,54.6,53.0,52.7,52.0,48.4,46.3,44.1,43.1,41.4,38.7,32.4, 32.4,30.1,27.1,21.5,21.1,19.5,16.4,12.6;
C34H45N2O9[M+H]+的高效液相质谱质荷比理论值为625.3125;
实际测试值为625.3129。
实施例13
化合物1m的制备:
以化合物3和叔丁胺为原料,操作同化合物1a的合成方法,得白色固体1m,收率:72%;
mp:94.5-95.0℃;
1H NMR(600MHz,CDCl3)δ7.42-7.38(m,2H),6.48(d,J=11.8Hz,1H),6.34(s,1H),5.91(d,J=11.8Hz,1H),5.51(s,1H),5.15(dd,J=9.7Hz,5.8Hz,1H),3.75(s,1H),3.54(d,J= 17.3Hz,1H),3.46(d,J=17.3Hz,1H),2.32(dd,J=11.8Hz,6.0Hz,1H),1.91-1.81(m,6H), 1.52-1.46(m,1H),1.45(s,3H),1.44(s,3H),1.31(s,3H),1.28(s,3H),1.15(s,9H),1.04(s,3H);
13C NMR(150MHz,CDCl3)δ172.5,167.5,167.2,157.5,143.3,141.1,122.6,120.2,109.9, 84.8,78.4,76.6,68.3,54.6,52.3,50.4,48.3,45.2,44.1,43.2,38.8,32.4,32.2,30.0,28.9,27.0,21.0, 19.4,16.3,12.7;
C32H44NO8[M+H]+的高效液相质谱质荷比理论值为570.3067;
实际测试值为570.3066。
实施例14
化合物1n的制备:
以化合物3和二甲胺为原料,操作同化合物1a的合成方法,得白色固体1n,收率:73%;
mp:120.0-121.0℃;
1H NMR(600MHz,CDCl3)δ7.42-7.38(m,2H),6.48(d,J=11.8Hz,1H),6.34(s,1H),5.91 (d,J=11.8Hz,1H),5.50(s,1H),5.15(dd,J=10.5Hz,4.9Hz,1H),3.76(s,1H),3.29(d,J=17.1 Hz,1H),3.22(d,J=17.1Hz,1H),2.40(s,6H),2.32(dd,J=12.8Hz,4.9Hz,1H),1.90-1.80(m, 6H),1.52-1.46(m,1H),1.45(s,6H),1.31(s,3H),1.28(s,3H),1.04(s,3H);
13C NMR(150MHz,CDCl3)δ170.4,167.5,167.1,157.6,143.3,141.2,122.6,120.2,109.9, 84.7,78.3,76.3,68.2,60.5,54.6,52.1,48.4,45.6,44.0,43.2,38.7,32.4,32.3,30.1,27.1,21.0,19.5, 16.3,12.7;
C30H40NO8[M+H]+的高效液相质谱质荷比理论值为542.2754;
实际测试值为542.2754。
实施例15
化合物1o的制备:
以化合物3和异丙胺为原料,操作同化合物1a的合成方法,得白色固体1o,收率:71%;
mp:87.5-88.5℃;
1H NMR(600MHz,CDCl3)δ7.42-7.38(m,2H),6.48(d,J=11.8Hz,1H),6.34(s,1H),5.91 (d,J=11.8Hz,1H),5.51(s,1H),5.15(dd,J=10.6Hz,4.9Hz,1H),3.71(s,1H),3.51(s,2H), 2.90-2.83(m,1H),2.31(dd,J=12.8Hz,4.8Hz,1H),1.91-1.79(m,6H),1.52-1.46(m,1H),1.45 (s,3H),1.44(s,3H),1.31(s,3H),1.28(s,3H),1.10(d,J=6.2Hz,3H),1.09(d,J=6.2Hz,3H), 1.04(s,3H);
13C NMR(150MHz,CDCl3)δ172.3,167.5,167.2,157.4,143.3,141.2,122.6,120.2,109.9, 84.7,78.4,76.6,68.3,54.6,52.3,49.0,48.6,48.3,44.1,43.2,38.8,32.4,32.1,30.1,27.0,23.1,22.6, 21.0,19.4,16.3,12.7;
C31H42NO8[M+H]+的高效液相质谱质荷比理论值为556.2910;
实际测试值为556.2905。
实施例16
化合物1p的制备:
以化合物3和4-氯苄胺为原料,操作同化合物1a的合成方法,得白色固体1p,收率:62%;
mp:88.6-89.2℃;
1H NMR(600MHz,CDCl3)δ7.41-7.40(m,2H),7.32(d,J=8.6Hz,2H),7.30(d,J=8.7Hz,2H),6.48(d,J=11.8Hz,1H),6.35(s,1H),5.91(d,J=11.8Hz,1H),5.51(s,1H),5.19(dd,J =10.9Hz,4.5Hz,1H),3.87(d,J=13.4Hz,1H),3.82(d,J=13.3Hz,1H),3.69(s,1H),3.51(d,J =17.7Hz,1H),3.46(d,J=17.7Hz,1H),2.31(dd,J=13.3Hz,4.3Hz,1H),1.91-1.74(m,7H), 1.52-1.47(m,1H),1.45(s,6H),1.31(s,3H),1.30(s,3H),1.01(s,3H);
13C NMR(150MHz,CDCl3)δ172.0,167.4,167.2,157.5,143.4,141.1,138.1,133.0,129.7, 128.7,122.6,120.1,109.9,84.7,78.4,76.5,68.2,54.7,52.6,52.2,50.4,48.3,44.1,43.2,38.8,32.4, 32.3,30.1,27.0,21.0,19.4,16.3,12.6;
C35H41ClNO8[M+H]+的高效液相质谱质荷比理论值为638.2521;
实际测试值为638.2527。
实施例17
化合物1q的制备:
以化合物3和1-(3-氨基丙基)咪唑为原料,操作同化合物1a的合成方法,得白色固体1q,收率:58%;
mp:82.8-83.5℃;
1H NMR(600MHz,CDCl3)δ7.51(s,1H),7.42-7.39(m,2H),7.05(s,1H),6.94(s,1H),6.48(d,J=11.8Hz,1H),6.35(s,1H),5.91(d,J=11.8Hz,1H),5.51(s,1H),5.20(dd,J=11.0Hz, 4.4Hz,1H),4.13-4.05(m,2H),3.66(s,1H),3.49(d,J=17.7Hz,1H),3.44(d,J=17.7Hz,1H), 2.68-2.60(m,2H),2.31(dd,J=13.4Hz,4.2Hz,1H),1.98-1.92(m,2H),1.91-1.78(m,6H), 1.76-1.73(m,1H),1.52-1.47(m,1H),1.45(s,3H),1.45(s,3H),1.31(s,3H),1.30(s,3H),1.01(s, 3H);
13C NMR(150MHz,CDCl3)δ172.1,167.4,167.3,157.6,143.4,141.2,137.5,129.4,122.7, 120.1,119.0,109.9,84.7,78.5,76.4,68.0,54.7,52.0,51.1,48.4,46.0,44.5,44.2,43.2,38.8,32.5, 32.4,31.4,30.3,27.1,21.1,19.5,16.4,12.5;
C34H44N3O8[M+H]+的高效液相质谱质荷比理论值为622.3128;
实际测试值为622.3129。
实施例18
化合物1r的制备:
以化合物3和(S)-3-(Boc-氨基)哌啶为原料,操作同化合物1a的合成方法,得白色固体 1r,收率:71%;
1H NMR(600MHz,CDCl3)δ7.41-7.39(m,2H),6.49(d,J=11.8Hz,1H),6.35(t,J=1.2Hz, 1H),5.91(d,J=11.8Hz,1H),5.51(s,1H),5.13(dd,J=10.8Hz,4.5Hz,1H),5.06(s,1H),3.78(s, 1H),3.77-3.71(m,1H),3.34-3.24(m,2H),2.80-2.73(m,1H),2.71-2.63(m,1H),2.51-2.40(m, 2H),2.31(dd,J=13.3Hz,4.3Hz,1H),1.94-1.69(m,8H),1.63-1.56(m,2H),1.54-1.47(m,1H), 1.46(s,3H),1.45(s,3H),1.43(s,9H),1.31(s,3H),1.28(s,3H),1.04(s,3H);
13C NMR(150MHz,CDCl3)δ170.0,167.3,167.0,157.5,155.1,143.2,141.0,122.4,120.0, 109.7,84.6,79.0,78.2,76.2,67.9,59.4,58.3,54.5,53.3,51.9,48.2,46.3,43.9,43.0,38.5,32.3, 32.2,29.9,29.1,28.4,26.9,22.3,20.9,19.4,16.2,12.6;
实施例19
化合物1s的制备:
以化合物3和(R)-3-(Boc-氨基)哌啶为原料,操作同化合物1a的合成方法,得白色固体 1s,收率:78%;
1H NMR(600MHz,CDCl3)δ7.44-7.38(m,2H),6.48(d,J=11.8Hz,1H),6.35(s,1H),5.91 (d,J=11.8Hz,1H),5.51(s,1H),5.21-5.12(m,2H),3.82-3.75(m,1H),3.73(s,1H),3.34(d,J= 17.1Hz,1H),3.25(d,J=17.1Hz,1H),2.73-2.61(m,2H),2.58-2.47(m,2H),2.31(dd,J=13.3 Hz,4.3Hz,1H),1.92-1.74(m,8H),1.63-1.53(m,2H),1.52-1.47(m,1H),1.45(s,3H),1.45(s, 3H),1.44(s,9H),1.31(s,3H),1.28(s,3H),1.04(s,3H);
13C NMR(150MHz,CDCl3)δ170.1,167.5,167.1,157.5,155.3,143.3,141.2,122.6,120.1, 109.9,84.7,79.1,78.3,76.4,68.2,59.7,58.4,54.7,53.6,52.1,48.4,46.2,44.0,43.2,38.7,32.4, 32.3,30.1,29.0,28.6,27.1,22.1,21.1,19.5,16.3,12.8;
试验例1细胞上清中NO的测定
受试物与地塞米松对LPS活化RAW264.7细胞分泌NO的协同抑制作用
取对数生长期的RAW264.7细胞,刮刀刮下,吹散细胞,在血细胞计数板上进行细胞计数。调整细胞浓度为1×106个/ml,按100μL/孔接种于96孔细胞培养板。加入不同浓度受试物(25 和50μM)和地塞米松(8pM),共50μl/孔,同时加入终浓度为10ng/mL的LPS,50μL/孔,对照孔加等体积的培养基,于孵箱中孵育24h。取上清100μL/孔置酶标板中,再加Gr3ess试剂 100μL/孔,微型振荡器上振荡3m3n,于酶标仪540nm波长处测定个孔吸光度值。
抑制率%=100*(1-给药组OD值/LPS模型组OD值)
表1化合物与地塞米松对LPS活化RAW264.7细胞分泌NO的协同抑制作用
试验例2 1b化合物对LPS致内毒素血症小鼠血清中炎症因子的影响
(1)Balb/c小鼠适应环境两天,分为五组,分别为正常组、模型组、1b大剂量组(150mg/kg,相当于260μmol/kg),中剂量组(75mg/kg,相当于130μmol/kg)和小剂量组(37.5mg/kg,相当于65μmol/kg);
(2)按体重腹腔注射给药:
1b大剂量组:给予实施例2中的1b化合物150mg/kg,相当于260μmol/kg(无菌生理盐水溶解,给药体积0.3mL/只);
1b中剂量组:给予实施例2中的1b化合物75mg/kg,相当于130μmol/kg(无菌生理盐水溶解,给药体积0.3mL/只);
1b小剂量组:给予实施例2中的1b化合物37.5mg/kg,相当于65μmol/kg(无菌生理盐水溶解,给药体积0.3mL/只);
正常组和模型组:给予0.3mL/只的无菌生理盐水;
(3)LPS处理:
给药30min后,1b大剂量组、1b中剂量组、1b小剂量组和模型组按体重尾静脉注射给脂多糖(LPS)10mg/kg,给药体积0.3mL/只;正常组小鼠用等体积无菌生理盐水替代;
(4)检测:
以上五组小鼠,在LPS处理3h后眼球取血,于4度放置过夜,取3000g离心10min以得到上清液,用ELISA试剂盒(购自Biolegend公司)进行检测血清TNF-α 和IL-6。
具体检测结果见附图1和2,根据检测结果可知,1b化合物各剂量组小鼠血清TNF-α和 IL-6明显低于模型组,即能够剂量依赖性的抑制内毒素小鼠血清中TNF-α 和IL-6的释放,并且可以明显的看出1b在150mg/kg剂量下能够有效的抑制血清中的TNF-α 和IL-6。
Claims (6)
2.根据权利要求1所述的化合物,其特征在于:
R1和R2各自独立选自H、C1-C4烷基、环戊基、4-氯苄基或咪唑-1-亚丙基。
5.根据权利要求1-3任一项所述的化合物,或根据权利要求4所述的制备方法制备得到的产物在制备糖皮质激素增效产品中的应用。
6.根据权利要求5所述的应用,其特征在于:所述的糖皮质激素增效产品所针对的疾病为支气管哮喘、急性淋巴细胞性白血病、原发性肾病综合征、类风湿性关节炎、系统性红斑狼疮、恶性肿瘤晚期中的至少一种。
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