CN115040503B - 螺环二烯酮型木脂素类化合物在制药中的应用 - Google Patents
螺环二烯酮型木脂素类化合物在制药中的应用 Download PDFInfo
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- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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Abstract
本发明公开了如结构式（1）所示的螺环二烯酮型木脂素类化合物在制备治疗或预防焦虑症和抑郁症的药物中的应用。同时公开了以该类化合物为有效成分的药物组合物，和其制备方法。属于药物技术领域。药理活性试验证明：本发明的化合物1和2对皮质酮所致大鼠肾上腺髓质嗜铬瘤分化细胞（PC12细胞）的损伤具有保护作用，可用于预防和治疗焦虑症或抑郁症。
Description
技术领域：
本发明属于药物技术领域，具体涉及螺环二烯酮型木脂素类化合物1或2在制备治疗或预防焦虑症或抑郁症相关药物或保健食品中的应用，同时涉及以其为有效成分的药物组合物，和其制备方法，
背景技术：
当前治疗焦虑和抑郁症的药物主要以化学合成药物为主，但存在副作用大、复发率高等缺点,临床应用具有局限性。因此，开发可长期服用、疗效好且毒性小的药物依然是目前药学研究的热点。
药用植物中分离和发现的活性天然产物一直是创新药物或药物先导化合物发现的重要源泉。从药用植物中也发现众多抗焦虑和抑郁好的活性天然产物，如贯叶连翘(Hypericum perforatum)中发现的间苯三酚类化合物贯叶金丝桃素(Hyperforin)(LifeSciences,1998,63, 499-510)。
大鼠肾上腺髓质嗜铬瘤分化细胞株PC12是一种具有典型神经元特征，并具有高水平肾上腺皮质合成糖皮质激素(glucocorticoids， GCs)受体的细胞系，已被用作模拟高浓度皮质酮刺激时海马神经元损伤的经典模型。与此同时，啮齿动物体内的GCs主要是皮质酮(中草药，2022，53，1093-1099)。抑郁症的重要表现包括过高的皮质酮水平，可诱发神经元和胶质细胞相关的凋亡、自噬和突触可塑性的改变等病理变化。因此可采用皮质酮刺激神经元细胞来模拟焦虑、抑郁的内环境，建立焦虑、抑郁症体外细胞模型(中草药，2022，53，3385-3393；中国药理学与毒理学杂志，2019，33，866)。
紫玉兰(Magnolia liliflora)为木兰科(Magnoliaceae)木兰属 (Magnolia)落叶灌木。紫玉兰与玉兰(Magnolia denudata)同为我国两千多年的传统花卉，在我国大部分城市均有栽培，并已被引种至欧美各国，其树皮、叶和花蕾均可入药，常用作镇痛消炎剂。据《新华本草纲要》记载，紫玉兰具有祛风散寒，通鼻窍的功效，用于治疗鼻塞、鼻渊、风寒头痛、浊涕等症，是民间药材辛夷的重要来源之一 (《新华本草纲要》,上海科学技术出版社,1990,468-469.)。紫玉兰化学成分研究较少，仅见少量木脂素类成分报道(Phytochemistry, 1983,22,763-766；Phytochemistry,1982,21,747–750)并发现部分化合物具有抗炎和抗氧化活性(Industrial Crops and Products,2018,125, 416-424)。
迄今为止，未发现螺环二烯酮型木脂素类化合物1或2的药理活性的报道。
发明内容：
针对现有技术存在的上述不足之处，本发明的目的在于：提供2 个螺环二烯酮型木脂素类化合物，以其为活性成分的药物组合物，其制备方法，以及该类化合物及药物组合物在制备治疗或预防焦虑症和抑郁症的药物及保健食品中的应用。药理活性试验证明本发明的化合物1和2对皮质酮所致大鼠肾上腺髓质嗜铬瘤分化细胞(PC12细胞) 的损伤具有保护作用。
为了实现本发明的上述目的，本发明提供了如下的技术方案：
如下结构式所示的螺环二烯酮型木脂素类化合物1或2在制备治疗或预防焦虑症和抑郁症的药物中的应用，
螺环二烯酮型木脂素类化合物1或2在制备治疗或预防焦虑症和抑郁症的保健食品中的应用。
螺环二烯酮型木脂素类化合物1或2的制备方法，包括以下工艺步骤：取晒干后的紫玉兰叶，粉碎并用95％乙醇冷浸提取三次，合并三次提取液，减压浓缩，得到总浸膏。该浸膏分散于水中用于乙酸乙酯萃取，萃取物经反相中压液相色谱(MCI树脂)进行分离，用甲醇水系统梯度洗脱(30:70、40:60、50:50、60:40、70:30、80:20、90:10 和100:0)，经检测合并成13个组份Fr.1～Fr.13。组份4经硅胶柱层析，用石油醚/乙酸乙酯(4:1)洗脱，得到9个亚组分Fr.4.1～Fr.4.9。组分Fr.4.6经高压液相色谱(HPLC)分离(乙腈/水，35：65)，得到化合物1。组份6经硅胶柱层析，用石油醚/乙酸乙酯(4:1)洗脱，得到6个亚组分Fr.6.1～Fr.6.6。组分Fr.6.3经硅胶柱层析(石油醚/丙酮，7:3)和凝胶Sephdex LH-20柱层析(氯仿/甲醇，1:1)，分离得到化合物2。
螺环二烯酮型木脂素类化合物1和2通过显著改善皮质酮所致 PC12细胞的损伤从而实现其抗焦虑和抗抑郁的作用，从而实现在制备治疗或预防焦虑症和抑郁症药物及保健食品中的应用。
本发明此外还提供了包含螺环二烯酮型木脂素类化合物和至少一种药学上可接受的载体的药物组合物。
上面所述的药学上可接受的载体是指药学领域常规的药物载体，例如，水、葡萄糖、乳糖、阿拉伯胶等和适合在制备固体、半固体、液体或气溶胶形式的制剂中使用的其他载体。组合物可以另外含有稳定剂，增稠剂，和/或着色剂和香料。
本发明的螺环二烯酮型木脂素类化合物及其药学上可接受的载体制备而成的组合物可经口或不经过口给药，给药量因药物不同而各有不同，对成人来说，每天1-100mg较合适。
经口服给药时，首先使化合物与常规的药用辅剂如赋形剂、解剂、黏合剂、润滑剂、抗氧化剂、包衣剂、着色剂、芳香剂、表面活性剂等混合，将其制成颗粒剂、胶囊、片剂等形式给药：非经口给药时可以注射液、输液剂或栓剂等形式给药。制备上述制剂时，可使用常规的制剂技术。
附图说明：
图1为本发明的螺环二烯酮型木脂素类化合物的结构示意图；
图2为本发明的化合物2的单晶X衍射结构示意图；
图3为化合物1和2对皮质酮诱导PC12神经损伤的保护作用，图中，Blank：空白对照组；NC：模型组；DIM：阳性对照组。
具体实施方式：
下面结合附图，用本发明的实施例来进一步说明本发明的实质性内容，但并不以此来限定本发明。根据本发明的实质对本发明进行的改进都属于本发明的范围。
实施例1：
螺环二烯酮型木脂素类化合物1和2的制备及结构鉴定：
制备方法：取晒干后的紫玉兰叶，粉碎并用95％乙醇冷浸提取三次，合并三次提取液，减压浓缩，得到总浸膏。该浸膏分散于水中用于乙酸乙酯萃取，萃取物经反相中压液相色谱(MCI树脂)进行分离，用甲醇水系统梯度洗脱(30:70、40:60、50:50、60:40、70:30、80:20、 90:10和100:0)，经检测合并成13个组份Fr.1～Fr.13。组份4经硅胶柱层析，用石油醚/乙酸乙酯(4:1)洗脱，得到9个亚组分Fr.4.1～Fr.4.9。组分Fr.4.6经高压液相色谱(HPLC)分离(乙腈/水，35：65)，得到化合物1。组份6经硅胶柱层析，用石油醚/乙酸乙酯(4:1)洗脱，得到6个亚组分Fr.6.1～Fr.6.6。组分Fr.6.3经硅胶柱层析(石油醚/丙酮，7:3)和凝胶Sephdex LH-20柱层析(氯仿/甲醇，1:1)，分离得到化合物2。
结构鉴定：本发明所述化合物分子结构式(1)分别对应化合物 1和2：
化合物1(Magnoflorin D)：白色无定型粉末；(c 0.01, MeOH)；UV(MeOH)λmax(logε)200(5.01)；CD(MeOH)λmax(Δε):210 (-14.33),262(+15.37),322(-10.85)nm；IR(KBr)νmax 3410,2928,1732, 1651,1608,1517,1453,1375,1246,1144,869cm–1；1H and 13C NMR spectroscopic data,see Table 2；HREIMS m/z 365.1356[M+Na]+(calc. for C20H22O5Na,365.1359).
化合物2(maglifloenone)：白色无定型粉末；C22H26O6；ESI-MS m/z: 409[M+Na]+。1H-NMR(500MHz,CDCl3)δ:6.37(2H,s,H-2,6),2.53 (1H,m,H-7),2.06(1H,m,H-8),0.61(3H,d,J＝6.0Hz,H-9),5.92(1H, s,H-3'),5.48(1H,s,H-6'),2.37(1H,m,H-7'a),2.00(1H,d,J＝11.4Hz, H-7'b),5.03(1H,t,J＝5.8Hz,H-8'),2.31(1H,m,H-9'a),1.73(1H,dd,J ＝13.7,12.0Hz,H-9'b),3.83(6H,s,3,5-OCH3),3.80(3H,s,4-OCH3), 3.65(3H,s,5'-OCH3)；13C-NMR(125MHz,CDCl3)δ:139.1(C-1), 104.6(C-2,6),153.3(C-3,5),136.7(C-4),46.9(C-7),45.3(C-8),14.6 (C-9),50.4(C-1'),180.2(C-2'),101.4(C-3'),183.2(C-4'),153.3(C-5'), 109.0(C-6'),43.6(C-7'),81.9(C-8'),37.8(C-9'),56.2(3,5-OCH3),60.9(4-OCH3),55.3(5'-OCH3)。经与文献报道maglifloenone (Phytochemistry 1982,21,747-750；Natural Product Sciences,2017,23, 119-124.)的1H和13C核磁数据比对，鉴定为同一个化合物。
表1化合物1的氢谱和碳谱数据(CDCl3)
a Measured at a600 MHz,b150 MHz.
实施例2：
化合物1和2对皮质酮诱导PC12神经损伤的保护作用：
(1)实验方法：
PC12细胞接种于含10％FBS及100U/mL双抗(青霉素-链霉素) 的DMEM高糖溶液中，并于温度37℃，5％CO2培养箱中培养至对数生长期，胰酶消化，制成细胞悬液。细胞悬液吸至15mL离心管中， 800rpm，离心5min弃上清液，然后加入新的培养基调整细胞浓度至1×105个/mL。然后取此PC12细胞接种于96孔板中，每孔0.1mL, 并放入细胞培养箱培养23小时。将待测化合物(终浓度20μM)加入到含皮质酮(终浓度150μM)的96孔板中，同时设置空白对照组(培养基)、模型组(培养基及终浓度150μM皮质酮)、阳性对照组[培养基、终浓度150μM皮质酮和终浓度10μM Desipramine(DIM)]，24小时后，加入MTS，继续培养2小时，然后用酶标仪于570nm波长下测定吸光度值，并计算细胞存活率。实验重复3次。
(2)实验结果：
实验表明与模型组相比(68.09±0.78％)，在20μM浓度下化合物1和2对皮质酮诱导PC12细胞成活率分别为71.5±0.99％和73.0± 1.42％。在相同浓度下，阳性对照药Desipramine(DIM)对皮质酮诱导PC12细胞成活率为90.07±0.45％。该结果提示，化合物1和2 对皮质酮诱导PC12神经损伤的保护作用，具有治疗焦虑症或抑郁症的作用。
实施例3
片剂的制备：
取化合物1和/或2，按其与赋形剂重量比为1:5-1:10的比例加入赋形剂，制粒压片。
实施例4
胶囊剂的制备：
取化合物1和/或2，按其与赋形剂重量比为1:5-1:10的比例加入赋形剂，制成胶囊。
实施例5
口服液制剂的制备：
取化合物1和/或2，以及利用碱金属(锂、钠、钾)或碱土金属(钙、镁)、有机酸(酒石酸，柠檬酸，甲酸，乙二酸等)或无机酸(盐酸，硫酸，磷酸等)制成的盐，按常规口服液制法制成口服液。
实施例6
颗粒剂或冲剂的制备：
取化合物1和/或2，以及利用碱金属(锂、钠、钾)或碱土金属(钙、镁)、有机酸(酒石酸，柠檬酸，甲酸，乙二酸等)或无机酸(盐酸，硫酸，磷酸等)制成的盐，按其与赋形剂重量比为5:1的比例加入赋形剂，制成颗粒剂或冲剂。
Claims (6)
1.如下结构式所示的螺环二烯酮型木脂素类化合物1或2在制备治疗或预防焦虑症和抑郁症的药物中的应用，
。
2.药物组合物，其中含有权利要求1中结构式所示的螺环二烯酮型木脂素类化合物1和药学上可接受的载体。
3.根据权利要求2所述的药物组合物，其特征在于，所述的药物组合物为微粒给药系统。
4.根据权利要求2所述的药物组合物，其特征在于，所述的药物组合物剂型为片剂、胶囊、丸剂、口服液、注射剂、缓释制剂、控释制剂。
5.权利要求2所述的药物组合物在制备治疗或预防焦虑症和抑郁症的药物中的应用。
6.根据权利要求1或5所述的应用，其特征在于，所述的螺环二烯酮型木脂素类化合物1和2通过显著改善皮质酮所致PC12细胞的损伤从而实现抗焦虑和抗抑郁的作用。
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