CN111763139B - 银松素、银松素的用途及其制备方法 - Google Patents
银松素、银松素的用途及其制备方法 Download PDFInfo
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- C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
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Abstract
本发明提供一种银松素,为晶体化合物,m.p.153~155℃;EI‑MS m/Z:212(M+)。银松素用于制备治疗少弱精症的药物,还可以用于制成医疗上可接受的口服制剂、注射剂、颗粒剂、丸剂、胶囊剂、散剂、缓释剂、控释制剂、靶向制剂及其它给药途径的制剂。本发明的发明人经长期研究,发现银松素对少弱精症有明显的作用,经过进一步研究发现:银松素在小鼠中对少弱精症模型小鼠有明显治疗作用,连续给药两周后少弱精症小鼠的***数量及浓度有明显提高,不同浓度下银松素对小鼠***浓度和活力有促进作用。
Description
技术领域
本发明属于中药制剂技术领域,具体涉及一种银松素、银松素的用途及其制备方法。
背景技术
银松素是一种自然反式1, 2- 二苯乙烯的衍生物, 出现在松树和桉树的木材纸浆及茶叶油和草本药物中, 是一种芪。
由于银松素存在于天然的松子以及松针植物中,其含量极少且在实验室中提纯非常困难,目前对银松素尚无广泛的药理研究,但二苯乙烯衍生物通过非泌尿途径消除在体内被广泛地葡萄糖醛酸化,因而具有良好的抗氧化作用,有大量研究支持。二苯乙烯其它衍生物如白藜芦醇等已进行了较为广泛的药理研究,是各类抗氧化产品研究开发的热点。银松素对于很多种菌类有十分有效抗菌活性,当树木受到真菌感染时,树木就会分泌银松素作为一种植物抗毒素,因此银松素对动物的抗氧化、抗菌作用研究开发前景广阔。但是,迄今为止有关银松素的其他更加高效和确切的作用靶点、机制等尚未被发现。
临床上目前对于少弱精症患者暂无明显作用药物,科学研究白藜芦醇对少弱精症有促进作用但结构不够稳定。
发明内容
本发明要解决的技术问题是提供一种银松素、银松素的用途及其制备方法,实验证明银松素晶体可以抗氧化,具有提高***活力浓度作用。
所述晶体化合物为无色针晶,m.p. 153~155 ℃;EI-MS m/Z: 212 (M+)。
本发明还提供一种银松素的用途,用于制备治疗少弱精症的药物。
其中,所述银松素用于制备治疗少弱精症药物时,有效剂量的范围为0.01ug/mL-10ug/ml。
其中,所述的银松素还用于制成医疗上可接受的口服制剂、注射剂、颗粒剂、丸剂、胶囊剂、散剂、缓释剂、控释制剂、靶向制剂及其它给药途径的制剂。
所述制备方法包括如下步骤:
(1)将0.2mmol的化合物A0.025mmol的双(1,5-环辛二烯)氯化铱(I)二聚体,0.04mmol的1,2-双(二苯基膦)乙烷氮气保护下加入到15ml耐压管,再加入4mmol的EtOH和1.5mL的THF,反应液120℃、搅拌22h;待反应完毕,冷却至室温,加入10ml的乙酸乙酯稀释;反应混合液饱和食盐水洗涤3次,有机相乙酸乙酯萃取,有机相无水硫酸钠干燥,减压浓缩粗产物柱层析纯化,得白色产物B,白色固体 38 mg,反应收率 80%;
(2)将0.2mmol的白色产物B氮气保护下加入6mL的无水二氯甲烷溶解,-20℃下搅拌并缓慢滴加1.34mmol的三溴化硼,混合液氮气保护下搅拌,并缓慢升至室温反应4~5h,反应完毕加入10ml的水,二氯甲烷萃取3次,再用食盐水洗涤,然后无水硫酸钠干燥;减压浓缩粗产物柱层析纯化,制得银松素,白色固体35mg,反应收率83%。
其中,步骤(1)中柱层析纯化时,乙酸乙酯和石油醚的体积比为1/4。步骤(2)中柱层析纯化时,正己烷和丙酮的体积比为6/4。
本发明的上述技术方案的有益效果如下:
本发明的发明人经长期研究,发现银松素对少弱精症有明显的作用,经过进一步研究发现:银松素在小鼠中对少弱精症模型小鼠有明显治疗作用,连续给药两周后少弱精症小鼠的***数量及浓度有明显提高,不同浓度下银松素对小鼠***浓度和活力有促进作用。
附图说明
图1为本发明中化合物E-1,2-双(4-甲氧基苯基)乙烯基)苯氢谱谱图;
图2为本发明中化合物E-1,2-双(4-甲氧基苯基)乙烯基)苯碳谱谱图;
图3为本发明制备的银松素的氢谱谱图;
图4为本发明制备的银松素的碳谱谱图;
图5为本发明中银松素及其晶体对小鼠少弱精症促进作用的实验结果图。
具体实施方式
为使本发明要解决的技术问题、技术方案和优点更加清楚,下面将结合附图及具体实施例进行详细描述。
本发明的发明人经长期研究,发现银松素对少弱精症有明显的作用,经过进一步研究发现:银松素在小鼠中对少弱精症模型小鼠有明显治疗作用,连续给药两周后少弱精症小鼠的***数量及浓度有明显提高,不同浓度下银松素对小鼠***浓度和活力有促进作用。临床上目前对于少弱精症患者暂无明显作用药物,科学研究白藜芦醇对少弱精症有促进作用,银松素与白藜芦醇结构类似且二级结构更加稳定。
所述晶体化合物为无色针晶,m.p. 153~155 ℃;EI-MS m/Z: 212 (M+)。
本发明还提供一种银松素的用途,用于制备治疗少弱精症的药物。所述银松素用于制备治疗少弱精症药物时,有效剂量的范围为0.01ug/mL-10ug/ml。
所述的银松素还可用于制成医疗上可接受的口服制剂、注射剂、颗粒剂、丸剂、胶囊剂、散剂、缓释剂、控释制剂、靶向制剂及其它给药途径的制剂。
所述制备方法包括如下步骤:
(1)将0.2mmol的(1-(2-(3,5-二甲氧基苯基)乙炔基))苯,0.005mmol的双(1,5-环辛二烯)氯化铱(I)二聚体,0.04mmol的1,2-双(二苯基膦)乙烷氮气保护下加入到15ml耐压管,再加入4mmol的EtOH ( 232mL)和1.5mL的THF,反应液120℃、搅拌22h;待反应完毕,冷却至室温,加入10ml的乙酸乙酯稀释;反应混合液饱和食盐水洗涤3次,有机相乙酸乙酯萃取,有机相无水硫酸钠干燥,减压浓缩粗产物柱层析纯化(乙酸乙酯/石油醚=1/4),得白色产物(E-1,2-双(4-甲氧基苯基)乙烯基)苯,白色固体 38 mg,反应收率 80%;1H NMR (400 MHz,CDCl3): 7.51 - 7.49 (m, 2H),7.37 -7.33 (m, 2H),7.28 - 7.24 (m, 1H),7.09 (d, J= 16.4 Hz, 1H),7.03 (d, J = 16.4 Hz, 1H),6.7 (d, J = 2.4 Hz, 2H),6.40 (t, J =2.0 Hz, 1H),3.82 (s, 6H);13C NMR (100 MHz, CDCl3): 161.1, 139.5, 137.3,129.3, 128.8, 128.8, 127.9, 126.7, 104.7, 100.1, 55.5。
(2)将0.2mmol的(E-1,2-双(4-甲氧基苯基)乙烯基)苯氮气保护下加入6mL的无水二氯甲烷溶解,-20℃下搅拌并缓慢滴加1.34mmol的三溴化硼 (0.34 g, 30%溶解于无水二氯甲烷中),混合液氮气保护下搅拌,并缓慢升至室温反应4~5h,反应完毕加入10ml的水,二氯甲烷萃取3次,再用食盐水洗涤,然后无水硫酸钠干燥;减压浓缩粗产物柱层析纯化(正己烷/丙酮=6/4),制得银松素,白色固体35mg,反应收率83%。1H NMR (400 MHz, (CD3)2CO):7.57 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.2 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H),7.10 (s, 2H), 6.60 (d, J = 2.0 Hz, 2H), 6.32 (t, J = 2.4 Hz, 1H); 13C NMR (100MHz, (CD3)2CO): 159.6, 140.4, 138.4, 129.8, 129.5, 129.2, 128.3, 127.3,105.9, 103.1。
下面结合具体实施例进一步证明银松素及其晶体改善少弱精症的作用。
实验步骤如下:
步骤一、将40只成熟的8周龄的ICR雄性小鼠适用性饲养3天后,将其随机分为模型组、空白组、银松素高剂量组、银松素中剂量组、银松素低剂量组、白藜芦醇高剂量对照组、白藜芦醇中剂量对照组、白藜芦醇低剂量对照组共8组,每组各5只。
步骤二、将白消安配成浓度为6mg/mL的溶液,除空白组小鼠不做处理外,其余各组均给予睾丸注射,剂量为6mg/kg,造成少弱***症小鼠模型。两周后,银松素高剂量组、银松素中剂量组、银松素低剂量组分别给予不同浓度银松素灌胃治疗,灌胃剂量分别为高剂量组为100mg/kg体重、中剂量组为10mg/kg体重、低剂量组为1mg/kg体重,白藜芦醇高剂量对照组、白藜芦醇中剂量对照组、白藜芦醇低剂量对照组分别给予不同浓度白藜芦醇灌胃治疗,灌胃剂量分别为高剂量组为100mg/kg体重、中剂量组为10mg/kg体重、低剂量组为1mg/kg体重,而模型组和空白组每日均给予1mL的溶剂灌胃,每组均连续灌胃14天。
步骤三、实验过程中观察小鼠一般状态(如毛色、活动、体态等),测日饮水量及进食量。
步骤四、实验结束后将小鼠全部处死,股动脉取血、分离血清、摘取睾丸、性腺及***称重,提取附睾***,采用CASA计算机辅助***质量分析***检测小鼠的***密度、***活动率、前向运动***百分率;检测小鼠的体重、睾丸及附睾的质量;Elisa试剂盒检测小鼠睾丸中ROS、MDA、SOD1的水平;Elisa试剂盒检测各组小鼠的血清性腺激素睾酮(T)及***(LH)水平、***(FSH)。
结果如图5所示:
***计数和***活动力检测结果比较 空白组与模型组相比,差异显著具有统计学意义(P<0.05),与模型组相比,银松素高剂量组、银松素中剂量组、白藜芦醇高剂量对照组、白藜芦醇中剂量对照组各药物治疗组***计数和***活动力显著提高,差异显著具有统计学意义(P<0.05),高剂量组***计数和***活动力明显高于中剂量组、低剂量组,差异显著具有统计学意义(P<0.05)。与空白组相比,各组小鼠睾丸湿重与附睾湿重均降低,差异显著具有统计学意义(P<0.05),与模型组相比,银松素高剂量组、银松素中剂量组、白藜芦醇高剂量对照组、白藜芦醇中剂量对照组均升高,差异显著具有统计学意义(P<0.05),低剂量组与模型组相比无明显差异(P>0.05)。
以上所述是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明所述原理的前提下,还可以作出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
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