CN105078986A - 组合物89083001030568及其在治疗或预防肾纤维化药物中的应用 - Google Patents
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Abstract
本发明涉及有机合成和药物化学领域,具体涉及组合物89083001030568、制备方法及其在制备预防或治疗肾纤维化药物上的用途。本发明公开了一种组合物89083001030568及其制备方法。药理学实验表明,本发明的组合物89083001030568具有预防或治疗肾纤维化的作用,具有开发预防或治疗肾纤维化药物的价值。
Description
技术领域
本发明涉及有机合成和药物化学领域,具体涉及组合物89083001030568、制备方法及其用途。
背景技术
肾纤维化(包括肾间质纤维化和肾小球硬化)是各种原因引起的肾脏损害最后阶段的主要病理基础,肾纤维化发生机制较为复杂,与多种因素有关,其中主要与细胞外基质细胞产生细胞的增殖和活化,血管活性物质、细胞因子以及细胞外基质转换失衡有关,肾间质纤维化几乎是所以原发或继发肾脏疾病进展到终末期肾衰竭的共同途径。急需研发高效低毒的抗肾纤维化药物。
肾纤维化的治疗目前已有的药物存在毒性大、安全性低的问题,从天然产物中寻找化合物或先导化合物并进行结构修饰获得其衍生物,从而得到高效低毒的潜在药物有重要价值。
本发明涉及的化合物I是一个2011年发表(MengShaoetal.,2010.PsiguadialsAandB,TwoNovelMeroterpenoidswithUnusualSkeletonsfromtheLeavesofPsidiumguajava.OrganicLetters12(2010)5040–5043)的化合物,我们对化合物I进行了结构修饰,获得了两个新的衍生物即化合物III和化合物IV,并用化合物III和化合物IV制备了组合物89083001030568并对该组合物抗肾纤维化活性进行了评价,其具有抗肾纤维化活性。
发明内容
本发明公开了一个新的组合物89083001030568,该组合物由化合物III和化合物IV组成,该组合物中化合物III和化合物IV的质量百分数分别为95%和5%。
本发明公开的组合物可以制成药学上可接受的盐或药学上可接受的载体。
药效学实验表明,本发明的组合物具有较好的抗肾纤维化作用。本发明的药学上可接受的盐具有同样的药效。
以下通过实施例对本发明作进一步详细的说明,但本发明的保护范围不受具体实施例的任何限制,而是由权利要求加以限定。
具体实施方式
实施例1化合物PsiguadialA的制备
化合物PsiguadialA(I)的制备方法参照MengShao等人发表的文献(MengShaoetal.,2010.PsiguadialsAandB,TwoNovelMeroterpenoidswithUnusualSkeletonsfromtheLeavesofPsidiumguajava.OrganicLetters12(2010)5040–5043)的方法。
实施例2PsiguadialA的O-溴乙基衍生物(II)的合成
将化合物I(474mg,1.00mmol)溶于20mL苯,向溶液中加入四丁基溴化铵(TBAB)(0.16g),1,2-二溴乙烷(7.520g,40.00mmol)和12mL的50%氢氧化钠溶液。混合物在35摄氏度搅拌8h。8h之后将反应液倒入冰水中,立即用二氯甲烷萃取两次,合并有机相溶液。然后对有机相溶液依次用水和饱和食盐水洗涤3次,再用无水硫酸钠干燥,最后减压浓缩去除溶剂得到产物粗品。产物粗品用硅胶柱层析纯化(流动相为:石油醚/丙酮=100:0.5,v/v),收集棕色集中洗脱带并挥去溶剂即得到化合物II的棕色粉末(502mg,73%)。
1HNMR(500MHz,DMSO-d6)δ10.44(s,2H),7.24(s,2H),7.20(d,J=10.0Hz,3H),4.31(s,4H),3.89(s,1H),3.74(s,4H),2.30(s,1H),2.12(s,1H),2.02(s,1H),1.92(s,1H),1.79(s,1H),1.73(s,1H),1.51(d,J=19.8Hz,3H),0.99(s,3H),0.95(d,J=4.7Hz,7H),0.85(s,3H),0.53(s,1H),0.43(s,1H).
13CNMR(125MHz,DMSO-d6)δ188.69(s),170.54(s),165.42(s),163.38(s),142.72(s),129.71(s),127.96(s),127.08(s),118.00(s),116.82(s),114.82(s),72.73(s),40.19(s),34.75(s),34.32(s),31.75(s),30.93(s),28.09(s),26.43(s),24.48(s),23.74(s),21.18(s),20.77(s),19.99(s),14.39(s).
HRMS(ESI)m/z[M+H]+calcdforC34H41Br2O5:689.1300;found689.1303.
实施例3PsiguadialA的O-(二乙胺基)乙基衍生物(III)的合成
将化合物II(344mg,0.5mmol)溶于20mL乙腈当中,向其中加入无水碳酸钾(690mg,5.0mmol),碘化钾(168mg,1.0mmol)和二乙胺(2920mg,40mmol),混合物加热回流9h。反应结束后将反应液倒入冰水中,用等量二氯甲烷萃取4次,合并有机相。依次用水和饱和食盐水洗涤合并之后的有机相,再用无水硫酸钠干燥,减压浓缩去除溶剂得到产物粗品。产物粗品用硅胶柱层析纯化(流动相为:石油醚/丙酮=100:1.5,v/v),收集黄色集中洗脱带并挥去溶剂即得到化合物III的黄色粉末(231.8mg,69%)。
1HNMR(500MHz,DMSO-d6)δ10.40(s,2H),7.20(s,2H),7.16(d,J=10.0Hz,3H),4.01(s,4H),3.92(s,1H),2.80(s,8H),2.58(s,4H),2.07(s,1H),1.87(d,J=8.4Hz,2H),1.77(s,1H),1.63(d,J=16.8Hz,2H),1.46(s,1H),1.40(s,2H),1.21(s,1H),1.09(s,12H),0.92(s,3H),0.86(s,6H),0.83(s,3H),0.48(s,1H),0.22(s,1H).
13CNMR(125MHz,DMSO-d6)δ188.13(s),170.24(s),165.66(s),163.19(s),142.21(s),129.74(s),127.81(s),127.13(s),117.32(s),116.78(s),114.65(s),69.32(s),52.18(s),47.25(s),40.16(s),34.49(s),34.15(s),30.26(s),28.31(s),26.33(s),24.11(s),23.47(s),21.56(s),20.83(s),19.14(s),14.25(s),12.17(s).
HRMS(ESI):m/z[M+H]+calcdforC42H61N2O5:673.4580;found:673.4576。
实施例4PsiguadialA的O-(哌啶基)乙基衍生物(IV)的合成
将化合物II(344mg,0.5mmol)溶于20mL乙腈当中,向其中加入无水碳酸钾(690mg,5.0mmol),碘化钾(168mg,1.0mmol)和哌啶(1704mg,20mmol),混合物加热回流10h。反应结束后将反应液倒入25mL冰水中,用等量二氯甲烷萃取4次,合并有机相。依次用水和饱和食盐水洗涤合并之后的有机相,再用无水硫酸钠干燥,减压浓缩去除溶剂得到产物粗品。产物粗品用硅胶柱层析纯化(流动相为:石油醚/丙酮=100:1.0,v/v),收集黄色集中洗脱带即得到Cleistanone的O-(哌啶基)乙基衍生物(IV)的黄色胶状固体(212.3mg,61%)。
1HNMR(500MHz,DMSO-d6)δ10.58(s,2H),7.36(s,2H),7.30(d,J=10.0Hz,3H),4.20(s,1H),4.12(s,4H),2.68(s,4H),2.51(s,8H),2.34(s,1H),2.06(d,J=9.1Hz,2H),1.99(d,J=5.5Hz,2H),1.75(s,1H),1.57(d,J=8.5Hz,10H),1.51(s,1H),1.45(d,J=8.0Hz,5H),1.07(s,3H),1.01(s,6H),0.99(s,3H),0.65(s,1H),0.35(s,1H).
13CNMR(125MHz,DMSO-d6)δ188.11(s),170.25(s),165.46(s),163.73(s),142.84(s),129.97(s),127.32(s),127.54(s),117.68(s),116.17(s),114.32(s),69.59(s),54.43(d,J=16.3Hz),40.76(s),34.92(s),34.84(s),30.65(s),28.33(s),26.21(s),24.37(d,J=10.4Hz),23.88(s),23.41(s),21.97(s),20.48(s),19.26(s),14.11(s).
HRMS(ESI):m/z[M+H]+calcdforC44H61N2O5:697.4580;found:697.4576。
实施例5组合物对单侧输尿管结扎大鼠肾间质纤维化的影响
1.1材料
贝那普利,北京诺华制药有限公司生产;羟脯氨酸(HYP)试剂盒,南京建成生物公司;纤维连结蛋白(FN)试剂盒购自上海生物制品所。
组合物89083001030568的制备:将95mg化合物III的粉末和5mg化合物IV的粉末装入带盖的小管中并用涡轮搅拌仪混合即得到100mg组合物89083001030568。
实验动物:普通级Wistar大鼠,雄性,体重150-200g,SD大鼠。
1.2试验方法与结果
大鼠60只,随机分6组,即假手术组、模型组、苯那普利灌胃10mg/kg组、组合物灌胃10mg/kg组、化合物III灌胃10mg/kg组、化合物IV灌胃10mg/kg组,动物喂养1周,各大鼠以10%水合氯醛3.0mL/kg腹腔注射麻醉后,将大鼠右侧卧位固定与手术台上,剪毛后用碘酒、75%酒精消毒手术区,行左侧腹切口,逐层切开皮肤、肌肉及腹壁各层,暴露并分离左侧输尿管,假手术组仅切开腹腔并游离左侧输尿管,但不结扎和剪断,其他各组大鼠用4-0丝线结扎两道,上一道结扎点位于左肾下极水平,然后在两道结扎点剪断输尿管,逐层缝合,术后10天10%水合氯醛麻醉后处死各组动物,取血,按纤维连结蛋白测定说明测定说明纤维联接蛋白(FN)。生理盐水反复灌洗后留取左侧肾脏,肾组织经4%的多聚甲醛缓冲液固定。切取适量肾组织,按羟脯氨酸试剂盒测定说明测定羟脯氨酸。
常规病理学检①肉眼观察:假手术组肾脏颜色鲜红,表明光滑,包膜光泽,无粘连。模型对照组肾脏体积增大,颜色苍白,表明呈颗粒状,类似人体大白肾,少数区域肾包膜粘连。②光镜检查:假手术组肾单位结果清晰,肾小球囊无扩张或炎细胞浸润。模型对照组大片肾小管坏死,肾间质纤维细胞增生,肾小管扩张,内有大量棕黄色遮光物质或坏死脱落的上皮细胞,肾小球数目减少,部分肾小球纤维化并与包曼氏囊壁粘连,囊腔消失。组合物给药组病变与模型对照组类似,但均有不同程度的形态学改善,与模型对照组比较有明显差异。而化合物III给药组和化合物IV给药组与模型对照组无显著性差异。
表1组合物对单侧输尿管结扎大鼠肾间质纤维化的影响
*p<0.05,与模型组相比较
对各组FN、HYP进行T检验。结果见表1,组合物灌胃10mg/kg显著降低FN、HYP水平(与模型对照组比较,P<0.05);而化合物III和化合物IV灌胃10mg/kg未能显著降低FN、HYP水平。
结论:组合物能够显著降低肾间质纤维化FN、HYP水平的升高,抑制肾间质纤维化,可以用来制备抗肾纤维化药物。化合物III和化合物IV不能够显著降低肾间质纤维化FN、HYP水平的升高,不能抑制肾间质纤维化,不可以用来制备抗肾纤维化药物。
实施例6本发明所涉及组合物89083001030568片剂的制备
取2克组合物89083001030568,加入制备片剂的常规辅料18克,混匀,常规压片机制成100片。
实施例7本发明所涉及组合物89083001030568胶囊的制备
取2克组合物89083001030568,加入制备胶囊剂的常规辅料如淀粉18克,混匀,装胶囊制成100粒。
Claims (7)
1.一种组合物89083001030568,其特征为该组合物由化合物III和化合物IV组成,该组合物中化合物III和化合物IV的质量百分数分别为95%和5%。
2.如权利要求1所述的组合物89083001030568的制备方法,其特征为:将化合物III的粉末和化合物IV的粉末按照质量百分数分别为95%和5%充分混合。
3.一种如权利要求1所述的组合物89083001030568在治疗肾纤维化药物中的应用。
4.如权利要求3所述的组合物89083001030568在治疗肾纤维化药物中的应用,其特征为:所述肾纤维化为肾间质纤维化。
5.如权利要求4所述的组合物89083001030568在治疗肾纤维化药物中的应用,其特征为:所述肾间质纤维化为单侧输尿管阻塞形成的肾间质纤维化。
6.如权利要求3所述的组合物89083001030568在治疗肾纤维化药物中的应用,其特征为:所述组合物降低肾纤维化引起的纤维连结蛋白FN的升高。
7.如权利要求3所述的组合物89083001030568在治疗肾纤维化药物中的应用,其特征为:所述组合物降低肾纤维化引起的羟脯氨酸的升高。
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