CN116253743B - (+)-Paeoveitol衍生物及其药物组合物与其制备方法和其应用 - Google Patents
(+)-Paeoveitol衍生物及其药物组合物与其制备方法和其应用 Download PDFInfo
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- CN116253743B CN116253743B CN202111513524.7A CN202111513524A CN116253743B CN 116253743 B CN116253743 B CN 116253743B CN 202111513524 A CN202111513524 A CN 202111513524A CN 116253743 B CN116253743 B CN 116253743B
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Abstract
本发明提供结构式(I)所示的(+)‑paeoveitol衍生物1‑20,其药物组合物和其制备方法与其应用，属于药物技术领域。药理实验结果显示，本发明的(+)‑paeoveitol衍生物1‑20（化合物1‑20）或药物组合物能用作为褪黑素受体激动剂，能用在制备治疗或者预防抑郁症药物中。
Description
技术领域
本发明属于药物技术领域，具体涉及到结构式(I)所示的(+)-paeoveitol衍生物1-20(化合物1-20),其药物组合物和其制备方法，以及该类衍生物或药物组合物用作为褪黑素受体激动剂，及它们在制备治疗或者预防抑郁症药物中的应用。
背景技术
抑郁症是最常见的一种精神疾病，以心境显著持久低落为基本临床表现，患者呈情绪低落、悲观绝望、无快感、睡眠紊乱等症状，重者甚至出现***倾向。据世界卫生组织2017年发布的报告显示，全球范围内约有4.3％的人患抑郁症，患者数已达3.22亿，其中中国有5400-9600万患者。现代药理学研究认为抑郁症的发病与遗传、心理、神经内分泌等因素诱发中枢5-羟色胺(5-hydroxytryptamine，5-HT)、去甲肾上腺素(noradrenaline，NA)、多巴胺(dopamine，DA)、乙酰胆碱(acetylcholine，ACh)和神经肽等神经递质含量降低及受体功能下降有关。
随着现代药理学对抗抑郁药物作用机制研究的不断深入，多种新型抗抑郁药物被不断开发出来并被广泛应用于临床，主要包括：单胺氧化酶抑制剂(monoamin-oxidaseinhibitor，MAOIs)、选择性NA再摄取抑制剂(NA selective reuptake inhibitors，NARIs)、选择性5-HT再摄取抑制剂(5-HT selective reuptake inhibitors，SSRIs)、选择性NA和5-HT再摄取抑制剂(NA and 5-HT selective reuptake inhibitors，SNRIs)。三环类化合物作为经典的抗抑郁药物在临床上使用，其主要通过抑制突触前膜对5-HT及NA的再摄取，提高5-HT、NA在突触间隙中的浓度，加强神经传导，产生抗抑郁作用。作用于褪黑素受体的阿戈美拉汀褪黑素受体激动剂阿戈美拉汀(agomelatine)因安全、有效，广泛应用治疗抑郁症。2019年3月5日，美国食品和药物管理局(FDA)批准了的艾***(esketamine)鼻喷雾剂作为快速起效新型抗抑郁症药物上市。艾***作用于谷氨酸受体，可能通过影响脑区NMDA受体功能和突触可塑性发挥抗抑郁作用，具有起效较快的特点。然而艾***作为K粉的一种异构体，有被滥用的风险，且长期使用可能会存在成瘾性。同年，FDA批准别孕烯醇酮(brexanolone)静脉输注剂型(商品名Zulresso)治疗产后抑郁，该药是第一种也是目前唯一获得产后抑郁适应证的药物，该药作用于突触和突触外GABAA受体(γ-氨基丁酸A型受体)，静脉注射48小时后可发挥抗抑郁作用。该药价格昂贵，一个疗程费用高达3.6万美元(约24万元人民币)，且存在会导致患者过度镇静或失去意识等副作用。
综上，目前临床使用的抗抑郁药物主要通过影响脑内5-羟色胺和去甲肾上腺素发挥作用，取得了一定疗效，但存在起效慢、副作用明显、易产生耐药性、停药后易反弹等缺点，不能满足治疗需要。
川赤芍为芍药科(Paeoniaceae)芍药属(Paeonia)植物川赤芍(Paeoniaveitchii)的干燥根，具有活血化瘀，怡神通络的功效，它作为一味传统中药在很多具有疏肝解郁功效的复方中使用。为了从川赤芍中寻找新的抗抑郁活性成分，本发明人前期川赤芍中分离鉴定了60个化合物，包括一对具有6/5/6/6四环体系C19新颖骨架的降二萜(+)-和(-)-paeoveitol(Organic Letters 2014,16,2,424–427)。本发明人前期首次完成了paeoveitol的不对称催化合成(Organic Letters 2017,19,3,429–431)。
(+)-paeoveitol衍生物1-20是以(+)-paeoveitol为原料通过化学合成的方法首次得到，现有技术未见关于(+)-paeoveitol衍生物1-20的报道，也未见关于其生物活性的报道。
发明内容
本发明目的在于提供式(I)所示的(+)-paeoveitol衍生物1-20(化合物1-20)，以其为活性成分的药物组合物，其作为褪黑素受体激动剂，及其在治疗或预防抑郁症药物中的应用，以及它们的制备方法。
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(I)所示的(+)-paeoveitol衍生物1-20(化合物1-20)：
本发明同时提供了药物组合物，含有式(I)所示的(+)-paeoveitol衍生物1-20及可药用载体或赋形剂。
本发明同时提供了式(I)所示的(+)-paeoveitol衍生物1-20在制备褪黑素受体激动剂中的应用。
式(I)所示的(+)-paeoveitol衍生物1-20在制备治疗或者预防抑郁症药物中的应用。
本发明同时提供了所述的药物组合物在制备褪黑素受体激动剂中的应用。
所述的药物组合物在制备治疗或者预防抑郁症药物中的应用。
其中，所述的“抑郁症”是根据美国精神病学会出版的《精神疾病的诊断和统计手册第四版》(DSM-IV)或国际疾病分类第10版(ICD-10)，包括了不同亚型的精神疾病或障碍：1)、抑郁症(Depression)和情感障碍(Mood disorders)类型如抑郁型、狂燥型、抑郁和狂燥混合型、轻微狂燥型；2)、抑郁症样障碍(Depressive disorders)如抑郁样障碍、心情恶劣；3)、其它情感障碍如身体健康状态导致的情感障碍包括具有抑郁症样特征的各种精神疾病或障碍的亚型和由于物质(如成瘾性药物)或治疗(如手术、放疗或化了等)等导致的情感障碍；4)、双相抑郁症或双相情感障碍包括反复发作的抑郁型和轻微狂燥型、抑郁和狂燥交替发作型。
本发明所述抑郁症的症状除《精神疾病的诊断和统计手册第四版》(DSM-IV)或国际疾病分类第10版(ICD＝10)所描述的症状外，还涉及昼夜节律紊乱、睡眠障碍、焦虑症、慢性应激、急性应激损伤或认知功能损伤或障碍。
本发明此外还提供了式(I)所示的(+)-paeoveitol衍生物1-20(化合物1-20)的制备方法，该方法包括以下步骤：
(+)-paeoveitol在适当乙酰化试剂作用下制备得到化合物1-3，所述的适当乙酰化试剂包括乙酰氯，乙酸酐，1-乙酰-1H-1,2,3-***[4,5-B]吡啶等。二乙酰化-(+)-paeoveitol在氧化剂作用下制备得到醛中间体，醛中间体与伯胺或仲胺在适当的反应溶剂中在适当的还原剂作用下，经还原胺化及去乙酰化得到化合物4-20，所述的适当的反应溶剂为二氯甲烷或氯仿或甲醇或乙醇，适当的还原剂为硼氢化钠或三乙酰基硼氢化钠或氰基硼氢化钠。
同时提供了所述药物组合物的制备方法，该方法先制备(+)-paeoveitol衍生物1-20(化合物1-20)，然后将上述(+)-paeoveitol衍生物1-20任其一种或任其任意组合加入至少一种可药用载体或赋形剂。
所述药物组合物包括上述的式(I)所示的化合物1-20任其一种或任其组合和至少一种和药学上可接受的载体或赋型剂。
本发明提供的药物组合物，包括上述式(I)所示的化合物1-20中的至少一种或任意组合和药学上可接受的载体或赋型剂。在本发明中，所述药学上可接受的载体或赋型剂优选为固体、半固体或液体稀释剂，填料以及药物制品辅剂。本发明对所述药学上可接受的载体或赋型剂没有特殊的限定，选用本领域熟知的、对人和动物无毒且惰性的药学上可接受的载体和/或赋型剂即可。
本发明对所述药物组合物的制备方法没有特殊的限定，直接将化合物1-20中的至少一种与药学上可接受的载体或赋型剂混合即可，本发明对所述混合的过程没有特殊的限定，选用本领域熟知的过程能够得到药物组合物即可。
在本发明中，当所述化合物1-20或药物组合物用作褪黑素受体激动剂或药物时，可以直接使用，或者以药物组合物的形式使用，所述组合物在药物中的含量优选为0.1～99％；在所述药物组合物中，所述化合物1-20中的至少一种在药物组合物中的含量优选为0.5～90％。本发明的药物组合物优选以单位体重服用量的形式使用。在本发明中，所制备的药物优选可经注射(静注、肌注)和口服两种形式给药。
与现有技术相比，本发明具备如下优益性：本发明提供了新的(+)-paeoveitol衍生物，其作为有效成分的药物组合物，同时提供了(+)-paeoveitol衍生物及其药物组合物在制备与褪黑素受体激动剂及抗抑郁药物中的应用，并提供(+)-paeoveitol衍生物的制备方法。
附图说明：
图1为本发明(+)-paeoveitol衍生物1-20(化合物1-20)的结构示意图。
具体实施方式
为了更好地理解本发明，下面结合附图，以本发明的具体实施例来进一步说明本发明的实质性内容，但并不以此来限制本发明。
实施例1
化合物1和2的制备：
室温下，将(+)-paeoveitol(328mg,1mmol)溶于4mL四氢呋喃，向其中加入1M氢氧化钠溶液(1mL,1mmol)，室温搅拌5min后再向其中加入1-乙酰-1H-1,2,3-***[4,5-B]吡啶(162mg,1mmol)，室温反应30min。加入5mL水稀释反应液，使用1M盐酸溶液调节pH值至中性，乙酸乙酯萃取(3×10mL)，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩除去溶剂，粗产品经硅胶柱层析(丙酮-石油醚,15:85)分离得到181mg化合物1，收率49％，95mg化合物2，收率23％。
化合物1的结构数据：
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(500MHz,CD3OD)δ7.00(s,1H,H-1),6.63(s,1H,H-4),6.42(s,1H,H-15),6.37(s,1H,H-12),5.10(d,J＝3.0Hz,1H,H-8),4.14(d,J＝11.5Hz,1H,H-18a),3.98(d,J＝11.5Hz,1H,H-18b),3.07-3.02(m,1H,H-7),2.24(s,3H,H-19),2.01(s,3H,H-16),1.95(s,3H,-OAc),1.54(d,J＝7.5Hz,3H,H-17)；13C NMR(125MHz,CD3OD)δ171.8(OAc),159.8(C-11),151.6(C-2),148.0(C-5),144.2(C-14),134.2(C-13),128.4(C-6),126.6(C-10),123.9(C-2),120.9(C-4),118.9(C-15),113.2(C-1),112.2(C-12),91.0(C-8),89.5(C-9),67.1(C-18),33.7(C-7),20.7(OAc),16.7(C-16),16.0(C-19),13.6(C-17).
高分辨质谱(ESI)计算值C21H23O6[M+H]+:371.1495,测定值为371.1503.
化合物2的结构数据：
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(400MHz,CDCl3)δ6.94(s,1H,H-15),6.81(s,1H,H-1),6.56(s,1H,H-4),6.47(s,1H,H-12),5.10(d,J＝3.2Hz,1H,H-8),4.20(d,J＝12.0Hz,1H,H-18a),3.96(d,J＝13.6Hz,1H,H-18a),3.06-3.03(m,1H,H-7),2.28(s,3H,-OAc),2.26(s,3H,-OAc),2.03(s,3H,H-19),2.00(s,3H,H-16),1.55(d,J＝6.8Hz,3H,H-17)；13C NMR(100MHz,CDCl3)δ169.7(C＝O),169.6(C＝O),158.3(C-11),151.3(C-5),144.5(C-2),142.9(C-14),133.5(C-13),129.0(C-6),127.0(C-10),124.2(C-3)120.0(C-4),119.3(C-1),117.5(C-15),112.0(C-12),89.4(C-8),88.0(C-9),67.1(C-18),32.6(C-7),20.8(OAc),20.7(OAc),16.8(C-19),15.9(C-16),13.1(C-17).
高分辨质谱(ESI)计算值C23H25O7[M+H]+:413.1600,测定值为413.1604.
实施例2
化合物3的制备：
将(+)-paeoveitol(32.8mg,0.1mmol)溶于1mL吡啶，搅拌下向其中加入1mL乙酸酐，室温反应过夜。加入10mL水淬灭反应液，乙酸乙酯萃取(3×10mL)，合并有机相，以依次用5％HCl溶液、饱和碳酸氢钠和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，粗产品经硅胶柱层析(乙酸乙酯-石油醚，10:90)分离得到43mg目标化合物，收率为94％。
化合物3的结构数据：
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(500MHz,CDCl3)δ6.97(s,1H,H-15),6.80(s,1H,H-1),6.58(s,1H,H-4),6.49(s,1H,H-12),5.02(d,J＝3.0Hz,1H,H-8),4.75(d,J＝14.4Hz,1H,H-18a),4.48(d,J＝13.6Hz,1H,H-18b),3.11-3.09(m,1H,H-7),2.29(s,3H,OAc),2.27(s,3H,OAc),2.09(s,3H,OAc),2.05(s,3H,H-19),2.00(s,3H,H-19),1.56(d,J＝8.4Hz,3H,H-17)；13C NMR(100MHz,CDCl3)δ170.6(C＝O),169.6(C＝O),169.5(C＝O),158.0(C-11),151.1(C-2),144.5(C-14),143.1(C-5),133.8(C-13),129.1(C-10),126.5(C-6),123.9(C-2),120.1(C-4),119.3(C-1),117.7(C-12),112.0(C-15),89.2(C-8),86.0(C-9),67.1(C-18),32.2(C-7),20.8(OAc),20.8(OAc),20.8(OAc),16.8(C-19),15.9(C-16),13.2(C-17).
实施例3
化合物4的制备：
氮气保护下，将化合物2(20.6mg,0.05mmol)溶于1mL二氯甲烷(10mL)，冰浴下缓慢加入戴斯-马丁试剂(31.8mg,0.075mmol,0.75equiv)，加料完毕室温反应4h，加入饱和硫代硫酸钠溶液猝灭反应，二氯甲烷萃取，合并有机相，饱和食盐水洗涤，减压浓缩除去溶剂后得到醛中间体。将所得醛溶于1mL二氯甲烷，搅拌下，依次向其中加入0.075mmol二甲胺、15.9mg三乙酰基硼氢化钠(0.075mmol)及1μL乙酸，室温反应24h，待反应结束后，加入1mL2M氢氧化钠溶液搅拌6h,使用稀盐酸调节反应液pH值到中性，乙酸乙酯萃取(3×10mL)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩除去溶剂，粗产品经硅胶柱层析(三乙胺-乙酸乙酯-石油醚,1:30:70)分离得到12.2mg目标化合物，收率69％。
化合物3的结构数据：
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(400MHz,pyridine-d5)δ7.43(s,1H,H-15),7.11(s,1H,H-1),6.81(s,1H,H-4),6.61(s,1H,H-12),5.36(d,J＝2.8Hz,1H,H-8),3.33-3.30(m,1H,H-7),3.22(d,J＝13.6Hz,1H,H-18a),2.94(d,J＝13.6Hz,1H,H-18b),2.36(s,6H,N-Me),2.25(s,3H,H-19),2.19(s,3H,H-16),1.61(d,J＝7.2Hz,3H,H-17)；13C NMR(100MHz,pyridine-d5)δ153.6(C-11),151.7(C-2),150.5(C-14),147.0(C-5),127.8(C-13),127.7(C-6),126.9(C-10),122.9(C-3),120.1(C-4),112.8(C-1),111.6(C-12),110.7(C-15),89.7(C-8),89.3(C-9),65.9(C-18),47.8(N-Me),32.9(C-7),16.9(C-19),16.1(C-16),13.5(C-17).
高分辨质谱(ESI)计算值C21H26NO4[M+H]+:356.1856,测定值为356.1838.
实施例4
化合物5的制备：
除了将二甲胺换成二乙胺外，其余所需原料、试剂及制备方法同实施例3，得14mg目标化合物，收率71％。
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(500MHz,pyridine-d5)δ7.46(s,1H,H-15),7.13(s,1H,H-1),6.82(s,1H,H-4),6.62(s,1H,H-12),5.33(d,J＝2.5Hz,1H,H-8),3.44-3.35(m,2H,H-7,H-18a),3.06(d,J＝14.0Hz,1H,H-18b),2.84-2.77(m,2H,H-1′),2.65-2.58(m,2H,H-1′),2.25(s,3H,H-19),2.19(s,3H,H-16),1.65(d,J＝7.0Hz,3H,H-17),1.00-0.97(m,6H,H-2′)；13C NMR(125MHz,pyridine-d5)δ153.8(C-11),151.9(C-2),150.7(C-14),147.3(C-5),128.0(C-13),127.3(C-6),127.3(C-10),123.1(C-2),120.3(C-4),113.0(C-1),111.9(C-11),111.0(C-15),90.1(C-8),90.0(C-9),60.7(C-18),46.6(C-1′),33.1(C-2′),17.2(C-19),16.3(C-16),13.8(C-17).
高分辨质谱(ESI)计算值C23H30NO4[M+H]+:384.2169,测定值为384.2146.
实施例5
化合物6的制备：
除了将二甲胺换成二丙胺外，其余所需原料、试剂及制备方法同实施例3，得13mg目标化合物，收率65％。
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(500MHz,pydidine-d5)δ7.45(s,1H,H-15),7.14(s,1H,H-1),6.83(s,1H,H-4),6.62(s,1H,H-12),5.33(d,J＝3.0Hz,1H,H-8),3.44-3.40(m,2H,H-7,H-18a),3.06(,J＝13.0Hz,1H,H-18b),2.73-2.65(m,2H,H-1′),2.52-2.48(m,2H,H-1′),2.25(s,3H,H-19),2.18(s,3H,H-16),1.68(d,J＝7.0Hz,3H,H-17),1.45-1.39(m,4H,H-2′),0.82(t,J＝7.0Hz,6H,H-3′)；13C NMR(125MHz,pydidine-d5)δ153.9(C-11),151.9(C-2),150.7(C-14),147.4(C-5),128.0(C-13),127.3(C-6),127.3(C-6),123.1(C-3),120.3(C-4),113.0(C-1),111.8(C-12),111.0(C-15),90.2(C-8),90.1(C-9),62.1(C-18),59.2(C-1′),33.1(C-7),20.7(C-2′),17.2(C-19),16.4(C-16),13.8(C-17),11.1(C-3′).
高分辨质谱(ESI)计算值C25H34NO4[M+H]+:412.2482,测定值为412.2466.
实施例6
化合物7的制备：
除了将二甲胺换成二丁胺外，其余所需原料、试剂及制备方法同实施例3，得13mg目标化合物，收率60％。
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(500MHz,pyridine-d5)δ7.47(s,1H,H-15),7.14(s,1H,H-1),6.84(s,1H,H-4),6.62(s,1H,H-12),5.36(d,J＝3.0Hz,1H,H-8),3.45-3.41(m,2H,H-7,H-18a),3.11(d,J＝14.5Hz,1H,H-18b),2.78-2.73(m,2H,H-1′),2.59-2.53(m,2H,H-1′),2.25(s,3H,H-19),2.18(s,3H,H-16),1.68(d,J＝7.0Hz,3H,H-17),1.45-1.40(m,4H,H-2′),1.2-1.24(m,4H,H-3′),0.85(t,J＝7.0Hz,6H,H-4′)；13C NMR(125MHz,pyridine-d5)δ153.8(C-11),151.9(C-2),150.7(C-14),147.4(C-6),128.0(C-13),128.0(C-6),127.3(C-10),123.1(C-3),120.3(C-4),113.0(C-1),111.9(C-12),111.0(C-15),90.2(C-8),90.1(C-9),62.1(C-18),55.9(C-1′),33.1(C-7),29.8(C-2′),20.8(C-3′),17.2(C-19),16.4(C-16),14.3(C-4′),13.8(C-17).
高分辨质谱(ESI)计算值C27H28NO4[M+H]+:440.2795,测定值为440.2787.
实施例7
化合物8的制备：
除了将二甲胺换成吗啉外，其余所需原料、试剂及制备方法同实施例3，得15mg目标化合物，收率75％。
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(500MHz,pyridine-d5)δ7.59(s,1H,H-15),7.14(s,1H,H-1),6.82(s,1H,H-4),6.62(s,1H,H-12),5.33(d,J＝3.0Hz,1H,H-8),3.68-3.66(m,4H,H-2′),3.37-3.35(m,1H,H-7),3.31(d,J＝14.0Hz,1H,H-18a),2.95(d,J＝14.0Hz,1H,H-18b),2.84-2.80(m,2H,H-1′),2.64-2.60(m,2H,H-1′),2.25(s,3H,H-19),2.20(s,3H,H-16),1.67(d,J＝8.4Hz,H-17)；1H NMR(125MHz,pyridine-d5)δ153.8(C-11),152.1(C-2),150.8(C-14),147.1(C-5),128.2(C-13),128.0(C-6),127.1(C-10),123.3(C-3),120.4(C-4),113.1(C-1),112.0(C-12),110.9(C-15),90.1(C-8),89.7(C-9),67.3(C-2′),65.6(C-18),56.1(C-1′),33.3(C-3),17.2(C-19),16.4(C-16),13.8(C-17).
高分辨质谱(ESI)计算值C23H28NO5[M+H]+:398.1962,测定值为398.1938.
实施例8
化合物9的制备：
除了将二甲胺换成四氢吡咯外，其余所需原料、试剂及制备方法同实施例3，得13mg目标化合物，收率71％。
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(500MHz,pyridine-d5)δ7.44(s,1H,H-15),7.11(s,1H,H-1),6.83(s,1H,H-4),6.61(s,1H,H-12),5.38(d,J＝3.0Hz,1H,H-8),3.39(d,J＝13.5Hz,1H,H-18a),3.31-3.26(m,1H,H-7),3.18(d,J＝13.5Hz,1H,H-18b),2.73-2.62(m,4H,H-1′),2.25(s,3H,H-19),2.20(s,3H,H-16),1.62-1.58(m,7H,H-1′,H-17)；1H NMR(125MHz,pyridine-d5)δ153.9(C-11),151.9(C-2),150.7(C-14),147.3(C-5),128.1(C-13),127.9(C-6),127.2(C-10),123.2(C-3),120.4(C-4),113.1(C-1),111.9(C-12),111.04(C-15),90.0(C-8),89.2(C-9),63.2(C-18),56.8(C-1′),33.1(C-7),23.3(C-2′),17.2(C-19),16.4(C-17),13.8(C-17).
高分辨质谱(ESI)计算值C28H28NO4[M+H]+:382.2013,测定值为382.2007.
实施例9
化合物10的制备：
除了将二甲胺换成N-甲基高哌嗪外，其余所需原料、试剂及制备方法同实施例3，得13mg目标化合物，收率62％。
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(500MHz,pyridine-d5)δ7.44(s,1H,H-15),7.14(s,1H,H-1),6.83(s,1H,H-4),6.62(s,1H,H-12),5.38(d,J＝3.0Hz,1H,H-8),3.54(d,J＝14.5Hz,1H,H-18a),3.44-3.41(m,1H,H-7),3.17(d,J＝14.5Hz,1H,H-18b),3.08-3.05(m,2H,H-1′),2.97-2.93(m,2H,H-2′),2.50-2.52(m,2H,H-3′,H-5′),2.25(s,3H,H-19),2.25(s,3H,H-6′),2.19(s,3H,H-16),1.75-1.71(m,2H,H-4′),1.68(d,J＝7.0Hz,3H,H-17)；13CNMR(125MHz,pyridine-d5)δ154.0(C-11),151.9(C-2),150.7(C-14),147.4(C-5),128.1(C-13),128.0(C-6),127.2(C-10),123.1(C-3),120.4(C-4),113.1(C-1),111.9(C-12),111.0(C-15),90.2(C-9),90.0(C-8),64.9(C-18),58.9(C-2′),57.6(C-1′),57.0(C-3′),56.9(C-5′),47.1(C-6′),33.2(C-7),28.3(C-4′),17.2(C-19),16.4(C-16),13.7(C-17).
高分辨质谱(ESI)计算值C25H33N2O4[M+H]+:425.2435,测定值为425.2387.
实施例10
化合物11的制备：
除了将二甲胺换成N-乙酰哌嗪外，其余所需原料、试剂及制备方法同实施例3，得10mg目标化合物，收率52％。
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(500MHz,pyridine-d5)δ7.45(s,1H,H-15),7.14(s,1H,H-11),6.82(s,1H,H-4),6.61(s,1H,H-12),5.35(d,J＝3.0Hz,1H,H-8),3.39-3.38(m,1H,H-7),3.33(d,J＝14.0Hz,1H,H-18a),2.96(d,J＝14.0Hz,1H,H-18b),2.89-2.85(m,6H,H-2′,H-1′),2.64-2.62(m,2H,H-1′),2.24(s,3H,H-19),2.19(s,3H,H-16),1.66(d,J＝7.0Hz,3H,H-17)；13C NMR(125MHz,pyridine-d5)δ153.8(C-11),152.0(C-2),150.8(C-14),147.2(C-5),128.1(C-13),128.0(C-6),127.2(C-10),123.2(C-3),120.4(C-4),113.1(C-1),111.9(C-12),110.9(C-15),90.1(C-8),89.8(C9),65.8(C-18),56.8(C-1′),46.6(C-2′),33.2(C-7),17.2(C-19),16.3(C-16),13.8(C-17).
高分辨质谱(ESI)计算值C23H28N2O4[M+H]+:397.2122,测定值为397.2106.
实施例11
化合物12的制备：
除了将二甲胺换成N-甲基哌嗪外，其余所需原料、试剂及制备方法同实施例3，得16mg目标化合物，收率78％。
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(400MHz,CD3OD)δ6.73(s,1H,H-15),6.59(s,1H,H-1),6.33(s,1H,H-4),6.27(s,1H,H-12),5.03(d,J＝3.2Hz,1H,H-8),3.14(d,J＝14.0Hz,1H,H-18a),3.07-3.04(m,1H,H-7),2.87-2.84(m,3H,H-18b,H-1′),2.64-2.49(m,6H,H-1′,H-2′),2.28(s,3H,H-3′),2.06(s,3H,H-19),2.01(s,3H,H-16),1.52(d,J＝7.2Hz,3H,H-17)；13C NMR(100MHz,CD3OD)δ153.3(C-11),149.9(C-2),148.7(C-14),146.6(C-5),127.3(C-13),127.2(C-6),125.8(C-10),122.2(C-3),119.3(C-4),111.9(C-1),110.6(C-12),109.5(C-15),89.5(C-8),89.1(C-9),63.9(C-18),54.9(C-1′),54.2(C-2′),44.6(C-3′),32.5(C-7),15.5(C-19),14.6(C-16),12.4(C-17).
高分辨质谱(ESI)计算值C24H30N2O4[M+H]+:411.2278,测定值为411.2248.
实施例12
化合物13的制备：
除了将二甲胺换成N-乙基哌嗪外，其余所需原料、试剂及制备方法同实施例3，得17mg目标化合物，收率79％。
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(500MHz,pyridine-d5)δ7.45(s,1H,H-15),7.14(s,1H,H-1),6.82(s,1H,H-4),6.62(s,1H,H-12),5.34(d,J＝3.0Hz,1H,H-8),3.41-3.38(m,1H,H-7),3.34(d,J＝13.5Hz,1H,H-18a),2.99(d,J＝13.5Hz,1H,H-18b),2.91-2.89(m,2H,H-1′),2.73-2.71(m,2H,H-1′),2.40-2.34(m,4H,H-2′),2.25(s,3H,H-19),2.24(q,2H,J＝7.5Hz,H-3′),2.19(s,3H,H-16),1.67(d,J＝6.0Hz,3H,H-17),0.98(t,3H,J＝7.5Hz,H-3′)；13C NMR(125MHz,pyridine-d5)δ153.8(C-11),152.0(C-2),150.8(C-14),147.2(C-5),128.1(C-13),128.0(C-6),127.2(C-10),123.2(C-3),120.4(C-4),113.1(C-1),111.9(C-12),110.9(C-15),90.1(C-8),89.7(C-9),65.9(C-18),55.8(C-1′),53.5(C-2′),52.4(C-3′),33.2(C-7),17.2(C-19),16.3(C-16),13.8(C-17),12.4(C-4′).
高分辨质谱(ESI)计算值C25H32N2O4[M+H]+:425.2435,测定值为425.2393.
实施例13
化合物14的制备：
除了将二甲胺换成1-(2-甲氧苯基)哌嗪外，其余所需原料、试剂及制备方法同实施例3，得15mg目标化合物，收率61％。
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(500MHz,pyridine-d5)δ7.48(s,1H,H-15),7.15(s,1H,H-1),7.07-7.00(m,2H,H-5′,H-7′),6.96-6.93(m,2H,H-6′,H-8′),6.85(s,1H,H-4),6.63(s,1H,H-12),5.37(d,J＝3.0Hz,1H,H-8),3.75(s,3H,OMe),3.43-3.37(m,2H,H-7,H-18a),3.14-3.04(m,7H,H-18b,H-1′,H-2′),2.88-2.85(m,2H,H-1′),2.26(s,3H,H-19),2.20(s,3H,H-16),1.68(d,J＝7.0Hz,3H,H-17)；13C NMR(125MHz,pyridine-d5)δ153.8(C-11),153.0(C-3′),152.0(C-2),150.8(C-14),147.2(C-5),142.3(C-4′),128.1(C-13),128.0(C-6),127.2(C-10),123.8,123.2(C-8′),122.9(C-3),121.5(C-6′),120.4(C-7′),118.6(C-4′),113.1(C-5′),112.5(C-1),111.9(C-12),111.0(C-15),90.1(C-9),89.7(C-8),65.2(C-18),55.9(C-2′),55.5(OMe),51.1(C-1′),33.2(C-7),17.2(C-19),16.4(C-16),13.8(C-17).
高分辨质谱(ESI)计算值C30H35N2O5[M+H]+:503.2540,测定值为503.2506.
实施例14
化合物15的制备：
除了将二甲胺换成1-(4-甲基苯基)哌嗪外，其余所需原料、试剂及制备方法同实施例3，得14mg目标化合物，收率59％。
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(500MHz,pyridine-d5)δ7.49(s,1H,H-15),7.15-7.13(m,3H,H-1,H-5′),6.93(d,J＝9.0Hz,H-4′),6.85(s,1H,H-4),6.63(s,1H,H-15),5.33(d,J＝3.0Hz,1H,H-8),3.44-3.34(m,2H,H-7,H-18a),3.11(d,J＝5.0Hz,4H,H-2′),3.10-2.96(m,3H,H-18b,H-1′),2.82-2.7(m,2H,H-1′),2.26(s,1H,H-19),2.23(s,1H,H-7′),2.20(s,1H,H-16),1.67(d,J＝7.0Hz,H-17)；13C NMR(125MHz,pyridine-d5)δ153.8(C-11),152.0(C-2),150.8(C-14),149.9(C-3′),147.0(C-5),130.0(C-5′)128.5(C-6′)128.1(C-13),128.0(C-6),127.1(C-10),123.2(C-2),120.4(C-4),116.4(C-4′),113.1(C-1),112.0(C-12),111.0(C-15),90.1(C-8),89.7(C-9),65.0(C-18),55.5(C-2′),49.8(c-1′),33.2(C-7),20.4(C-7′),17.2(C-19),16.4(C-16),13.8(C-17).
高分辨质谱(ESI)计算值C30H35N2O4[M+H]+:487.2591,测定值为487.2561.
实施例15
化合物16的制备：
除了将二甲胺换成1-(4-联苯基)-哌嗪外，其余所需原料、试剂及制备方法同实施例3，得17mg目标化合物，收率63％。
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(500MHz,pyridine-d5)δ7.74-7.69(m,4H,H-8′,H-9′),7.51(s,1H,H-15),7.49-7.45(m,2H,H-5′),7.34-7.31(m,1H,H-10′),7.16(s,1H,H-1),7.08(d,J＝9.0Hz,2H,H-4′),6.86(s,1H,H-2),6.64(s,1H,H-12),5.34(d,J＝3.0Hz,1H,H-8),3.42-3.35(m,2H,H-7,H-18a),3.20-3.18(m,4H,H-2′),3.05-2.97(m,3H,H-18b,H-1′),2.83-2.80(m,2H,H-1′),2.27(s,3H,H-19),2.17(s,3H,H-16),1.69(d,J＝7.0Hz,H-17)；13C NMR(125MHz,pyridine-d5)δ153.8(C-11),152.1(C-2),151.3(C-3′),150.8(C-14),147.2(C-5),141.3(C-7′),131.7(C-6′),129.3(C-9′),128.1(C-13),128.0(C-6),127.9(C-5′),127.1(C-10),126.8(C-10′),126.7(C-8′),123.3(C-2),120.4(C-4),116.2(C-4′),113.1(C-1),112.0(C-12),111.0(C-15),90.1(C-8),89.7(C-9),65.0(C-18),55.4(C-2′),49.0(C-1′),33.2(C-7),17.2(C-19),16.4(C-16),13.8(C-17).
高分辨质谱(ESI)计算值C35H36N2O4[M+H]+:549.2748,测定值为549.2740.
实施例16
化合物17的制备：
除了将二甲胺换成1-(3-甲基苄基)-哌嗪外，其余所需原料、试剂及制备方法同实施例3，得17mg目标化合物，收率66％。
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(400MHz,CD3OD)δ7.20-7.06(m,4H,H-5′,H-6′,H-7′,H-8′),6.72(s,1H,H-15),6.58(s,1H,H-1),6.31(s,1H,H-4),6.26(s,1H,H-12),5.01(s,1H,H-8),3.36(s,2H,H-3′),3.34(d,J＝14.0Hz,1H,H-18a),3.11(d,J＝14.0Hz,1H,H-18b),3.05-3.03(m,1H,H-7),2.83-2.79(m,2H,H-1′),2.59-2.55(m,6H,H-1′,H-2′),2.31(s,3H,10′),2.04(s,3H,H-19),1.99(s,3H,H-16),1.50(d,J＝7.2Hz,3H,H-17)；13C NMR(100MHz,CD3OD)δ153.3(C-11),149.9(C-2),148.7(C-14),146.7(C-5),137.6(C-4′),136.6(C-6′),130.2(C-5′),127.8(C-7′),127.7(C-8′),127.3(C-13),127.2(C-6),126.6(C-9′),125.8(C-10),122.2(C-3),119.3(C-4),111.9(C-1),110.6(C-12),109.5(C-15),89.5(C-8),89.1(C-9),64.0(C-18),62.7(C-3′),54.3(C-1′),53.0(C-2′),32.4(C-7),20.0(C-10′),15.4(C-19),14.5(C-17),12.3(C-17).
高分辨质谱(ESI)计算值C31H36N2O4[M+H]+:501.2748,测定值为501.2711.
实施例17
化合物18的制备：
除了将二甲胺换成1-(2-嘧啶基)哌嗪外，其余所需原料、试剂及制备方法同实施例3，得16mg目标化合物，收率69％。
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(400MHz,pyridine-d5)δ8.31(d,J＝4.8Hz,2H,H-4′),6.72(s,1H,H-15),6.57(s,1H,H-1),6.49(t,J＝4.8Hz,1H,H-5′),6.40(s,1H,H-4),6.36(s,1H,H-12),5.08(d,J＝3.2Hz,1H,H-8),3.80-3.75(m,4H,H-2′),3.20(d,J＝14.0Hz,1H,H-18a),3.13-3.10(m,1H,H-7),2.91-2.85(m,2H,H-1′),2.80(d,J＝14.0Hz,1H,H-18b),2.60-2.55(m,2H,H-1′),2.09(s,3H,H-19),2.04(s,3H,H-16),1.51(d,J＝6.8Hz,3H,H-17)；13C NMR(100MHz,pyridine-d5)δ161.4(C-3′),157.8(C-4′),153.8(C-11),149.1(C-2),148.0(C-14),147.3(C-5),127.5(C-13),127.0(C-6),126.2(C-10),122.1(C-3),119.9(C-4),112.7(C-1),111.5(C-12),110.1(C-15),109.8(C-5′),89.7(C-8),89.1(C-9),64.9(C-18),55.1(C-1′),44.2(C-2′),32.7(C-7),16.5(C-19),15.6(C-16),13.4(C-17).
高分辨质谱(ESI)计算值C27H31N4O4[M+H]+:475.2340,测定值为475.2311.
实施例18
化合物19的制备：
除了将二甲胺换成1-(2-吡嗪基)哌啶外，其余所需原料、试剂及制备方法同实施例3，得14mg目标化合物，收率59％。
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(400MHz,pyridine-d5)δ8.07-8.06(m,2H,H-5′,H-6′),7.82(d,J＝2.8Hz,1H,H-4′),6.76(s,1H,H-15),6.59(s,1H,H-1),6.41(s,1H,H-4),6.35(s,1H,H-12),5.06(d,J＝2.8Hz,1H,H-8),3.52-3.50(m,4H,H-2′),3.18(d,J＝14.0Hz,1H,H-18a),3.11-3.05(m,1H,H-7),2.92-2.87(m,2H,H-1′),2.84(d,J＝14.0Hz,1H,H-18b),2.66-2.62(m,2H,H-1′),2.10(s,3H,H-19),2.04(s,3H,H-16),1.51(d,J＝7.2Hz,3H,H-17)；13C NMR(100MHz,pyridine-d5)δ155.1(C-3′),153.7(C-11),149.5(C-14),148.3(C-2),147.1(C-5),142.0(C-6′),132.4(C-5′),130.6(C-4′),127.4(C-13),127.4(C-6),126.0(C-10),122.4(C-3),119.8(C-4),112.7(C-1),111.4(C-12),110.4(C-15),89.7(C-8),89.0(C-9),64.7(C-18),54.6(C-2′),44.7(C-1′),32.7(C-7),16.6(C-19),15.7(C-16),13.4(C-17).
高分辨质谱(ESI)计算值C27H30N4O4[M+H]+:475.2340,测定值为475.2341.
实施例19
化合物20的制备：
除了将二甲胺换成喹哌嗪外，其余所需原料、试剂及制备方法同实施例3，得12mg目标化合物，收率56％。
性状：白色粉末
1H-NMR和13C-NMR数据：1H NMR(400MHz,pyridine-d5)δ7.86(d,J＝9.2Hz,H-5′),7.74(d,J＝8.4Hz,H-7′),7.59(d,J＝8.0Hz,H-7′),7.52(dd,J＝7.2,7.2Hz,1H,H-9′),7.23(dd,J＝7.6,7.2Hz,1H,H-8′),6.91(d,J＝9.2Hz,H-4′),6.75(s,1H,H-15),6.53(s,1H,H-1),6.41(s,1H,H-4),6.35(s,1H,H-12),5.08(d,J＝2.8Hz,1H,H-8),3.70-3.61(m,4H,H-2′),3.14(d,J＝14.0Hz,1H,H-18a),3.11-3.08(m,1H,H-7),2.91-2.86(m,2H,H-1′),2.81(d,J＝14.0Hz,1H,H-18b),2.65-2.60(m,2H,H-1′),2.08(s,3H,H-19),2.04(s,3H,H-16),1.47(d,J＝7.2Hz,3H,H-17)；13C NMR(100MHz,pyridine-d5)δ157.7(C-3′),153.8(C-11),149.1(C-2),147.9(C-14),147.6(C-5),147.3(C-11′),137.7(C-5′),129.8(C-9′),127.5(C-13),127.3(C-7′),127.2(C-6),126.3(C-10),126.2(C-8′),123.1(C-3),122.6(C-8′),122.3(C-6′),119.8(C-4),112.8(C-4′),111.5(C-1),110.4(C-12),109.9(C-15),89.7(C-8),89.0(C-9),64.6(C-18),55.0(C-1′),45.6(C-2′),32.7(C-7),16.6(C-19),15.6(C-16),13.4(C-17).
高分辨质谱(ESI)计算值C32H34N3O4[M+H]+:524.2544,测定值为524.2516.
实施例20
本发明(+)-paeoveitol衍生物1-20对MT1和MT2受体的激动活性。
1材料和方法
1.1材料
褪黑素受体MT1和MT2激动活性筛选使用的细胞株分别对应人体肾上皮细胞HEK293-MT1和HEK293-MT2；含有10％胎牛血清的细胞培养基(Dulbecco’s Modified EageMedium，DMEM)；免洗钙流试剂盒。
1.2仪器
CO2恒温培养箱Thermo Forma 3310(美国)；倒置生物显微镜XD-101型(南京)：Flexstation 3Benchtop Multi-Mode Microplate Reader(Molecular Devices,Sunnyvale,California,USA)。
1.3实验过程
将96孔黑壁透底细胞培养板利用基质BD Matrigel包被，于37℃恒温培养箱1h，吸取上清液，以4×10孔的密度，将对应HEK293细胞接种于96孔黑壁透底细胞培养板中，于CO2浓度为5％的37℃恒温培养箱中培养16～24h；弃去原培养基，加入新鲜配置的染液100μL/孔，于37℃避光孵育60min。待测样品的配制：配制不同浓度的待测样品。将特定体积的待测样品加入到细胞中，加入样品体积为50μL/孔，利用Flexstation 3多功能酶标仪测定样晶对褪黑素受体的激动作用。利用Graphpad prism 5软件对实验结果进行分析。
2结果
在测试浓度为1.0mM时，化合物11和14对MT1和MT2受体具有一定的激动活性；化合物16对MT1受体具有较好的激动作用，激动率为56.4％；化合物10同时对MT1和MT2受体具有较好激动活性，激动率分别为58.9％和62.2％。化合物12对MT1和MT2受体具有强的激动作用，激动率分别为95.3％和74.5％。
3结论
实验结果显示，化合物10和12对MT1和MT2受体具有激动作用，能作为新型的褪黑素受体激动剂，以及能治疗或改善与褪黑素受体相关的中枢神经***疾病。
表1化合物1-20对MT1和MT2受体的激动作用
注：阿戈美拉汀作为阳性对照，以褪黑素(MT)的最大激动率设为100％，化合物的测试浓度为1.0mM。
实施例22：
化合物12对小鼠强迫游泳实验不动时间的影响。
1材料和方法
药品与试剂
羧甲基纤维素钠(CMCNa)和阳性药物氟西汀购自于萨恩化学技术(上海)有限公司，受试药物(化合物12)由实施例11所制得
实验仪器
徐州博纳信息技术有限公司XQT小鼠强迫游泳硬件、美国Any-Maze动物行为记录跟踪软件。
实验动物
昆明小鼠，SPF级，体重18-20g，购自于北京华阜康生物科技股份有限公司。动物合格证号：SCXK(京)2014-0004。小鼠每笼6只群养，自由摄食饮水，室温21±1℃，每天接受12h光照/12h黑暗，动物在新饲养环境适应7天后开始实验。实验开始前12h禁食，自由饮水。
2实验过程
取小鼠按体重均衡随机分为7组，空白对照组(0.5％CMCNa)，氟西汀阳性对照组(20mg/kg)，化合物12剂量组1(5mg/kg)，化合物12剂量组2(10mg/kg)，化合物12剂量组3(20mg/kg)，化合物12剂量组4(40mg/kg)，化合物12剂量组5(80mg/kg)，每组12只。测试前24h和1h灌胃给药后进行强迫游泳实验。将小鼠放入直径15cm、高25cm、水深10cm的玻璃容器中，水温25±1℃，视频摄像记录小鼠6min的运动情况，使用Any-Maze行为跟踪软件统计小鼠后4min内的不动时间，作为抗抑郁活性指标。
3结果
在10,20,40和80mg/kg剂量时，化合物12能够缩短小鼠强迫游泳的不动时间，且呈一定的剂量依赖关系，在20,40mg/kg剂量时，活性最为显著，提示其有抗抑郁活性。
表2化合物12小鼠强迫游泳实验数据结果
实施例22：
制剂实施例
1.取(+)-paeoveitol衍生物1-20(化合物1-20)任其一种或任意组合，用少量的DMSO溶解后，按常规加注射用水，精滤，灌封灭菌制成注射液。
2.取(+)-paeoveitol衍生物1-20(化合物1-20)任其一种或任意组合，用少量的DMSO溶解后，将其溶于无菌注射用水中，搅拌使溶解，用无菌抽滤漏斗过滤，再无菌精滤，分装于安甑中，低温冷冻干燥后无菌熔封得粉针剂。
3.取(+)-paeoveitol衍生物1-20(化合物1-20)任其一种或任意组合，按其与赋形剂重量比为9：1的比例加入赋形剂，制成粉剂。
4.取(+)-paeoveitol衍生物1-20(化合物1-20)任其一种或任意组合，按其与赋形剂重量比为5：1的比例加入赋形剂，制粒压片。
5.取(+)-paeoveitol衍生物1-20(化合物1-20)任其一种或任意组合，按常规口服液制法制成口服液。
6.取(+)-paeoveitol衍生物1-20(化合物1-20)任其一种或任意组合，按其与赋形剂重量比为5：1的比例加入赋形剂，制成胶囊。
7.取(+)-paeoveitol衍生物1-20(化合物1-20)任其一种或任意组合，按其与赋形剂重量比为3：1的比例加入赋形剂，制成胶囊。
8.取(+)-paeoveitol衍生物1-20(化合物1-20)任其一种或任意组合，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。
由以上实施例可知，本发明提供了一系列(+)-paeoveitol衍生物，它们的制备方法和应用，药物组合物及其应用。本发明提供的(+)-paeoveitol衍生物对MT1和MT2受体具有一定的激动活性，特别是化合物12在小鼠强迫游泳实验中，能够显著缩短小鼠强迫游泳不动时间，具有抗抑郁活性，能够与可药用载体或赋型剂组成药物组合物，能够用于抗抑郁症的治疗。
以上所述仅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，在不脱离本发明原理的前提下，还可以做出若干改进，这些改进也应视为本发明的保护范围。
Claims (10)
1.如下结构式所示的(+)-paeoveitol衍生物1-20，
2.权利要求1所述的结构式所示的(+)-paeoveitol衍生物1-20的制备方法，其特征在于：该方法包括下述步骤：(+)-paeoveitol在适当乙酰化试剂作用下制备得到化合物1-3，所述的适当乙酰化试剂为乙酰氯，乙酸酐，1-乙酰-1H-1,2,3-***[4,5-B]吡啶；二乙酰化-(+)-paeoveitol在氧化剂作用下制备得到醛中间体，醛中间体与伯胺或仲胺在适当的反应溶剂中在适当的还原剂作用下，经还原胺化及去乙酰化得到化合物4-20，所述的适当的反应溶剂为二氯甲烷或氯仿或甲醇或乙醇，适当的还原剂为硼氢化钠或三乙酰基硼氢化钠或氰基硼氢化钠。
3.权利要求1所述的结构式所示的(+)-paeoveitol衍生物1-20在制备褪黑素受体激动剂中的应用。
4.权利要求1所述的结构式所示的(+)-paeoveitol衍生物1-20在制备治疗或者预防抑郁症药物中的应用。
5.根据权利要求4所述的应用，其特征在于：所述抑郁症的症状为昼夜节律紊乱、睡眠障碍、焦虑症、慢性应激、急性应激损伤或认知功能损伤或障碍。
6.药物组合物，含有权利要求1所述的结构式所示的(+)-paeoveitol衍生物1-20及可药用载体或赋形剂。
7.权利要求6所述的药物组合物在制备褪黑素受体激动剂中的应用。
8.权利要求6所述的药物组合物在制备治疗或者预防抑郁症药物中的应用。
9.根据权利要求8所述的应用，其特征在于：所述抑郁症的症状为昼夜节律紊乱、睡眠障碍、焦虑症、慢性应激、急性应激损伤或认知功能损伤或障碍。
10.权利要求6所述的药物组合物的制备方法，其特征在于该方法包括下述步骤：(+)-paeoveitol在适当乙酰化试剂作用下制备得到化合物1-3，所述的适当乙酰化试剂为乙酰氯，乙酸酐，1-乙酰-1H-1,2,3-***[4,5-B]吡啶；二乙酰化-(+)-paeoveitol在氧化剂作用下制备得到醛中间体，醛中间体与伯胺或仲胺在适当的反应溶剂中在适当的还原剂作用下，经还原胺化及去乙酰化得到化合物4-20，所述的适当的反应溶剂为二氯甲烷或氯仿或甲醇或乙醇，适当的还原剂为硼氢化钠或三乙酰基硼氢化钠或氰基硼氢化钠；然后将上述(+)-paeoveitol衍生物1-20即化合物1-20任其一种或任其组合加入至少一种可药用载体或赋形剂。
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| Title |
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| (±)-Paeoveitol, a Pair of New Norditerpene Enantiomers from Paeonia veitchii;Liang, Wen-Juan;;Organic Letters;第16卷(第2期);424-427 * |
| A Total Synthesis of Paeoveitol;Xu, Lun;;Organic Letters;第18卷(第15期);3698-3701 * |
| Biomimetic Total Synthesis of Paeoveitol;Zhang, Yuhan;;Organic Letters;第18卷(第18期);4578-4581 * |
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