CN116253704A - Paeoveitol D衍生物及其药物组合物和其制备方法与其应用 - Google Patents
Paeoveitol D衍生物及其药物组合物和其制备方法与其应用 Download PDFInfo
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- CN116253704A CN116253704A CN202111513606.1A CN202111513606A CN116253704A CN 116253704 A CN116253704 A CN 116253704A CN 202111513606 A CN202111513606 A CN 202111513606A CN 116253704 A CN116253704 A CN 116253704A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract
本发明提供结构式(I)所示的paeoveitol D衍生物1‑27,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 D衍生物1‑27(化合物1‑27)或其药物组合物能用在制备褪黑素受体激动剂中,能用在治疗或预防与褪黑素受体相关的中枢神经系统疾病的药物中。
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 D衍生物1-27(化合物1-27),其药物组合物和其制备方法,以及衍生物1-27或其药物组合物在制备褪黑素受体激动剂中和在治疗或预防与褪黑素受体相关的中枢神经系统疾病的药物中的应用。
背景技术
褪黑素(melatonin,MT)是由松果体分泌的吲哚类内源性激素,对生物体的昼夜节律、免疫、衰老、心脑血管等具有重要的调节作用,在体内主要通过激活相应的褪黑素受体(melatonin receptor)发挥生理功能,褪黑素受体有三个亚型:MT1,MT2和MT3,前两者在人和其他哺乳动物中均有表达。褪黑素受体与多种中枢神经系统疾病,如节律紊乱、睡眠障碍、抑郁症、阿尔茨海默病等密切相关。现代药理学研究发现,多数精神疾病患者存在褪黑素分泌异常或褪黑素受体功能失调的状况,通过补充外源性的褪黑素或褪黑素受体激动剂可改善或缓解病情。褪黑素对人体生理功能影响十分广泛,但褪黑素直接作为药用,效果并不是特别显著。当褪黑素进入人体后,在体内代谢非常快,半衰期介于20至30分钟之间,因此开发作用时间更持久的褪黑素衍生物成为当今的研究热点。现有褪黑素受体激动剂主要包括:1)简单吲哚型:保留了吲哚环的褪黑素类似物,通过在吲哚环上引入不同的取代基可改变其与受体的结合力及其活性;2)吲哚生物电子等排体型:主要是将吲哚替换为萘环或其他6+5体系,诸如茚满、苯并呋喃、吲哚啉等结构;3)苯类衍生物:母核仅保留苯环;4)二聚体型:分子中含有两个相同或相似的芳香体系。已上市的褪黑素受体类药物包括:用于治疗难以入睡型失眠症的雷美替胺(ramelteon);用于治疗成人抑郁症的阿戈美拉汀(agomelatine);首个用于治疗盲人非24小时睡眠紊乱的药物他司美琼(tasimelteon)。
本发明研究发现在川赤芍中得到的化合物paeoveitol D对MT1和MT2受体具有一定的激动活性,以褪黑素为阳性对照药物,在浓度约为1mM时,其对MT1和MT2受体激动率的分别为57.52%和51.67%。
对paeoveitol D进行结构修饰合成新衍生物,本发明提供了新的褪黑素受体激动剂。现有技术无paeoveitol D衍生物1-27的报道,无化合物1-27合成方法的报道,没有化合物1-27在制备褪黑素受体激动剂和抗抑郁活性的报道,也没有其作为有效成分的药物组合物的报道。
发明内容
本发明的目的在于提供新的paeoveitol D衍生物1-27(化合物1-27),其制备合成方法,以及其作为有效成分的药物组合物,其作为褪黑素受体激动剂,及其在治疗或预防与褪黑素受体相关的中枢神经系统疾病中的应用。
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(I)所示的paeoveitol D衍生物1-27(化合物1-27)及其药用盐,
结构式(I)所示的paeoveitol D衍生物1-27在制备褪黑素受体激动剂中的应用。
结构式(I)所示的化合物1-27在制备治疗或改善中枢神经系统疾病的药物中的应用。
本发明同时还提供了含有治疗有效量的式(I)化合物1-27和药学上可接受的载体的药物组合物。
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预防中枢神经系统疾病的药物中的应用。
如所述的应用,其中所述的疾病是与褪黑素受体相关的中枢神经系统疾病。
本发明此外还提供了所述的式(I)paeoveitol D衍生物1-27(化合物1-27)的制备方法,该方法包括以下步骤:
化合物1-7的制备:
5-甲氧基-6-甲基苯并呋喃-3-羧酸乙酯在还原剂作用下制备得到化合物1;化合物1在碱作用下与环丙基甲酰氯反应制备得到化合物2;化合物1与邻苯二甲酰亚胺在三苯基膦、偶氮试剂的作用下经Mitsunobu反应制备化合物得到化合物3;化合物3经水合肼水解制备得到化合物4;化合物4在碱作用下与乙酰氯或环丙基甲酰氯反应制备得到化合物5-6;化合物1经氧化制备化合物7。
化合物8-27的制备:
苯并呋喃-3-醛类化合物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,经还原胺化得到化合物8-17,19-27,所述苯并呋喃-3-醛类化合物包括6-甲基-5-甲氧基-3-苯并呋喃醛或5-甲氧基-3-苯并呋喃醛或5-甲氧基-2-甲基-3-苯并呋喃醛或5-甲氧基-2-苯基-3-苯并呋喃醛,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。化合物17在适当的酸作用下脱除叔丁氧羰基后制备得到化合物18,所述适当的酸为三氟乙酸、对甲苯磺酸等。
同时提供了本发明药物组合物的制备方法,该方法包括下述步骤:先制得paeoveitol D衍生物1-27,然后加入药学上可接受的载体。
所述药物组合物包括上述的式(I)所示的化合物1-27任其一种或任其组合和至少一种药学上可接受的载体或赋型剂。
本发明提供的药物组合物,包括上述化合物1-27中的至少一种或其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1-27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1-27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1-27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 D衍生物,其作为有效成分的药物组合物,同时提供了paeoveitol D衍生物及其药物组合物在制备与褪黑素受体相关的中枢神经系统疾病的药物中的应用,提供了化合物13的抗抑郁活性,并提供paeoveitol D衍生物的制备方法。该方法原料易得,易于操作,收率较高,适于工业化生产。
附图说明:
图1为本发明paeoveitolD衍生物1-27(化合物1-27)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
5-甲氧基苯并呋喃-3-甲醇(化合物1)的制备:
氮气保护下,将5-甲氧基-6-甲基苯并呋喃-3-羧酸乙酯(2.34g,10mmol)溶于25mL干燥的二氯甲烷,冷却到-78℃,缓慢加入DIBAL-H的甲苯溶液(25mL,1.2M,30mmo),滴加结束后缓慢升温至0℃反应1h后使用50mL饱和NH4Cl溶液淬灭反应,用乙酸乙酯萃取(3×50mL),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(丙酮-石油醚,15:85)分离得到1.75g目标化合物,收率为91%。
化合物1的结构数据:
性状:白色固体
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ7.50(s,1H,H-2),7.25(s,1H,H-7),7.03(s,1H,H-4),4.79(s,3H,-OMe),3.87(s,2H,H-1′),2.31(s,3H,H-2′);13C NMR(100MHz,CDCl3)δ154.6(C-5),150.4(C-8),142.1(C-2),125.1(C-9),124.8(C-6),120.6(C-3),113.1(C-7),99.9(C-4),56.2(C-1′),56.0(-OMe),17.2(C-2′).
高分辨质谱(ESI)计算值C11H12O3Na[M+Na]+:215.0684,测定值为215.0686.
实施例2
化合物2的制备:
10mL圆底烧瓶中,将76.9mg化合物1(0.4mmol)溶于3mL二氯甲烷,再依次加入DMAP(2.4mg,0.02mmol),48.2μL吡啶(0.6mmol),冰水浴冷却到0℃后缓慢加入环丙基甲酰氯(0.6mmol),自然升至室温反应5h。待反应结束后,加入5mL饱和碳酸氢钠猝灭反应,二氯甲烷萃取(3×5mL),合并有机相,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90.5mg目标化合物,收率为87%。
化合物2的结构数据:
性状:白色粉末
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.59(s,1H,H-2),7.27(s,1H,H-7),7.00(s,1H,H-4),5.25(s,2H,H-1′),3.89(s,3H,-OMe),2.33(s,3H,H-2′),1.68-1.63(m,1H,H-4′),1.06-1.03(m,2H,H-5′),0.90-0.86(m,2H,H-5′);13C NMR(125MHz,CDCl3)δ175.0(C-3′),154.7(C-5),150.2(C-8),143.8(C-2),125.1(C-9),124.8(C-6),116.2(C-2),113.0(C-7),99.7(C-4),56.8(-OMe),55.8(C-1′),17.1(C-2′),13.0(C-4′),8.7(C-5′)
高分辨质谱(ESI)计算值C15H17O4[M+H]+:261.1127,测定值为261.2234.
实施例3
化合物3的制备:
氮气保护下,向100mL三口烧瓶中依次加入0.77g醇(4mmol),40mL干燥的四氢呋喃,0.77g邻苯二甲酰亚胺(5.2mmol),1.36g三苯基膦(5.2mmol),搅拌下缓慢向上述溶液中滴加DIAD(1.05g,5.2mmol)的5mL四氢呋喃溶液,室温反应过夜。待反应结束后,向反应液中加入50mL水,乙酸乙酯萃取(3×50mL),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(乙酸乙酯-石油醚,25:75)分离得到1.01g目标化合物,收率79%。
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)δ7.83-7.80(m,2H,H-5′),7.70(s,1H,H-2),7.69-7.65(m,2H,H-6′),7.27(s,1H,H-7),7.20(s,1H,H-4),4.91(s,3H,-OMe),3.92(s,2H,H-1′),2.28(s,3H,H-2′);13C NMR(125MHz,CDCl3)δ168.1(C-3′),154.6(C-5),150.0(C-8),144.5(C-2),134.1(C-6′),132.2(C-4′),124.9(C-9),124.7(C-6),123.4(C-5′),115.9(C-3),112.9(C-7),100.2(C-4),55.9(-OMe),31.1(C-1′),17.1(C-2′).
高分辨质谱(ESI)计算值C19H16NO4[M+H]+:322.1079,测定值为322.1085
实施例4
化合物4的制备:
室温下,将0.64g酰胺(2mmol)溶于20mL甲醇,搅拌下向其中滴加296μL水合肼(6mmol),室温搅拌30min,再加入5%盐酸溶液(20mL)搅拌过夜。待反应结束后,过滤除去不溶性固体,加入40mL水稀释滤液,并用盐酸调节溶液pH至2,乙醚洗涤,收集水相,用氢氧化钾调节溶液pH值至11,乙醚萃取(3×30mL),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(甲醇-氯仿,10:90)分离得到356mg目标化合物,收率为93%。
性状:淡黄色固体
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.46(s,1H,H-2),7.23(s,1H,H-7),6.95(s,1H,H-4),3.96(s,2H,H-1′),3.87(s,3H,-OMe),2.53(brs,2H,-NH2),2.30(s,3H,H-2′);13C NMR(125MHz,CDCl3)δ154.5(C-5),150.3(C-8),141.4(C-2),124.9(C-9),124.8(C-6),121.6(C-3),113.1(C-7),99.6(C-4),56.0(-OMe),36.1(C-1′),17.2(C-2′).
高分辨质谱(ESI)计算值C11H13NO2Na[M+Na]+:214.0844,测定值为214.0853.
实施例5
化合物5的制备:
10mL圆底烧瓶中,将28.7mg伯胺(0.15mmol)溶液1mL干燥的二氯甲烷,再加入31μL三乙胺(2.25mmol),将反应液冷却到0℃后向其中加入乙酰氯(11.7μL,0.165mmol),继续在0℃反应30min后升至室温反应过夜。减压浓缩除去溶剂,粗产品经硅胶柱层析(乙酸乙酯-石油醚,20:80)分离得到34mg目标化合物,收率为96%。
性状:白色粉末
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.45(s,1H,H-2),7.23(s,1H,H-7),6.96(s,1H,H-4),5.81(brs,1H,NH),4.49(d,J=5.5Hz,2H,H-1′),3.85(s,3H,-OMe),2.30(s,3H,H-2′),1.99(s,3H,H-4′);13C NMR(125MHz,CDCl3)δ170.2(C-3′),154.6(C-5),150.2(C-8),142.4(C-2),125.2(C-9),124.7(C-6),117.8(C-3),113.1(C-7),99.8(C-4),55.9(-OMe),33.5(C-1′),23.3(C-4′),17.2(C-2′).
高分辨质谱(ESI)计算值C13H15NO3Na[M+Na]+:256.0950,测定值为256.0971.
实施例6
化合物6的制备:
除了将乙酰氯换成环丙基甲酰氯外,其余所需原料、试剂及制备方法同实施例5,得36mg目标化合物,收率为94%。
性状:白色粉末
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.47(s,1H,H-2),7.25(s,1H,H-7),6.97(s,1H,H-4),4.55(d,J=5.5Hz,2H,H-1′),3.86(s,3H,-OMe),2.31(s,3H,H-2′),1.35-1.30(m,1H,H-4′),1.04-1.01(m,2H,H-5′),0.76-0.74(m,2H,H-5′);13C NMR(125MHz,CDCl3)δ173.7(C-3′),154.6(C-5),150.3(C-8),142.3(C-2),125.1(C-9),124.8(C-6),118.1(C-3),113.1(C-7),100.0(C-4),55.9(-OMe),33.7(C-1′),17.2(C-2′),14.7(C-4′),7.4(C-5′).
高分辨质谱(ESI)计算值C15H18NO3[M+H]+:260.1287,测定值为260.1295.
实施例7
化合物7的制备:
室温下,将0.96g醇(5mmol)溶于10mL二氯甲烷,搅拌下向其中加入3.18g Dess-Martin试剂(7.5mmol),室温反应2h。待反应结束后,加入20mL二氯甲烷稀释反应液,依次用饱和硫代硫酸钠(20mL)、饱和碳酸氢钠(20mL)和饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩除去溶剂,粗产品经硅胶柱层析(乙酸乙酯-石油醚,10:90)分离得到0.85g目标化合物,收率为89%
性状:淡黄色固体
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ10.11(s,1H,-CHO),8.16(s,1H,H-2),7.53(s,1H,H-7),7.30(s,1H,H-4),3.90(s,3H,-OMe),2.32(s,3H,H-2′);13C NMR(125MHz,CDCl3)δ185.2(C-1′),156.0(C-5),155.3(C-6),150.7(C-8),126.9(C-1),124.1(C-8),121.1(C-6),113.0(C-7),102.0(C-4),56.0(OMe),17.3(C-2′)。
高分辨质谱(ESI)计算值C11H10O3Na[M+Na]+:213.0528,测定值为213.0536.
实施例8
化合物8的制备:
氮气保护下,将化合物7(57.1mg,0.3mmol)溶于4mL二氯甲烷,搅拌下,依次向其中加入0.45mmol二甲胺、95.4mg三乙酰基硼氢化钠(0.45mmol)及3.4μL乙酸(0.06mmol),室温反应24h,待反应结束后,加入1M氢氧化钠溶液(5mL)猝灭反应,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(乙酸乙酯-石油醚,20:80)分离得到48mg目标化合物,收率为73%。
性状:白色粉末
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.47(s,1H,H-2),7.24(s,1H,H-7),7.04(s,1H,H-4),3.89(s,3H,-OMe),3.56(s,2H,H-1′),2.31(overlap,9H,H-2′,-NMe2);13CNMR(125MHz,CDCl3)δ154.5(C-5),150.2(C-8),143.1(C-2),126.0(C-9),124.7(C-6),117.4(C-1),112.9(C-7),100.3(C-4),56.0(OMe),53.2(C-1′),45.4(-NMe2),17.2(C-2′).
高分辨质谱(ESI)计算值C13H18NO2[M+H]+:220.1332,测定值为220.1324.
实施例9
化合物9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8,得60mg目标化合物,收率为81%。
性状:白色粉末
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.44(s,1H,H-2),7.24(s,1H,H-7),7.10(s,1H,H-4),3.88(s,3H,-OMe),3.68(s,2H,H-1′),2.56(q,J=7.0Hz,4H,H-3′),2.32(s,3H,H-2′),1.09(t,J=7.0Hz,6H,H-4′);13C NMR(125MHz,CDCl3):δ154.2(C-5),150.2(C-8),142.6(C-2),126.4(C-9),124.4(C-6),118.4(C-1),112.8(C-7),100.7(C-4),55.9(OMe),47.0(C-1′),46.9(C-3′),17.1(C-2′),12.2(C-4′).
高分辨质谱(ESI)计算值C15H22NO2[M+H]+:248.1645,测定值为248.1640.
实施例10
化合物10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8,得63mg目标化合物,收率为77%。
性状:白色粉末
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.42(s,1H,H-2),7.23(s,1H,H-7),7.13(s,1H,H-4),3.87(s,3H,OMe),3.64(s,2H,H-1′),2.41(t,J=7.5Hz,4H,H-4′),2.32(s,3H,H-2′),1.56-1.49(m,4H,H-4′),0.88(t,J=7.5Hz,6H,H-5′);13C NMR(125MHz,CDCl3)δ154.2(C-5),150.3(C-8),142.5(C-2),126.4(C-9),124.3(C-6),118.8(C-1),112.7(C-7),101.0(C-4),56.0(C-3′),55.9(OMe),48.5(C-1′),20.5(C-4′),17.2(C-2′),12.1(C-5′).
高分辨质谱(ESI)计算值C17H26NO2[M+H]+:276.1964,测定值为276.1955.
实施例11
化合物11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8,得64mg目标化合物,收率为70%。
性状:白色粉末
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.41(s,1H,H-2),7.22(s,1H,H-7),7.11(s,1H,H-4),3.86(s,3H,OMe),3.64(s,2H,H-1′),2.44(t,J=7.5Hz,4H,H-3′),2.32(s,3H,H-2′),1.51-1.46(m,4H,H-4′),1.35-1.28(m,4H,H-5′),0.88(t,J=7.5Hz,6H,H-6′);13C NMR(125MHz,CDCl3)δ154.2(C-5),150.3(C-8),142.5(C-2),126.4(C-9),124.3(C-2),118.4(C-1),112.7(C-7),101.0(C-4),55.8(OMe),53.7(C-3′),48.4(C-1′),29.5(C-4′),20.8(C-5′),17.2(C-2′),14.2(C-6′).
高分辨质谱(ESI)计算值C19H31NO2[M+H]+:304.2271,测定值为304.2262.
实施例12
化合物12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8,得73mg目标化合物12,收率为85%。
化合物12
性状:淡黄色粘稠状液体
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.42(s,1H,H-2),7.22(s,1H,H-7),7.13(s,1H,H-4),3.88(s,3H,OMe),3.70(s,2H,H-1′),2.76(t,J=6.0Hz,2H,H-3′),2.75-2.73(m,2H,H-3′,H-7′),2.69(t,J=6.0Hz,2H,H-5′),2.63-2.61(m,2H,H-6′),2.36(s,3H,H-8′),2.31(s,3H,H-2′),1.86-1.82(m,2H,H-4′);13C NMR(125MHz,CDCl3)δ154.2(C-5),150.3(C-8),142.5(C-2),126.1(C-9),124.5(C-6),118.6(C-1),112.8(C-7),100.9(C-4),58.6(C-6′),56.5(C-7′),55.9(OMe),54.4(C-5′),54.2(C-3′),52.6(C-1′),47.0(C-8′),27.4(C-4′),17.1(C-2′).
高分辨质谱(ESI)计算值C17H25N2O2[M+H]+:289.1911,测定值为289.1909.
实施例13
化合物13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8,得66mg目标化合物13,收率为81%。
性状:淡黄色粉末
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.43(s,1H,H-2),7.22(s,1H,H-7),7.08(s,1H,H-4),3.87(s,3H,OMe),3.60-3.59(m,2H,H-1′),2.57-2.40(m,8H,H-3′,H-4′),2.30(s,3H,H-2′),2.30(s,3H,H-2′),2.27(s,3H,H-5′);13C NMR(125MHz,CDCl3)δ154.3(C-5),150.1(C-8),142.8(C-1),126.1(C-9),124.5(C-6),117.2(C-1),112.8(C-7),100.6(C-4),55.9(OMe),55.3(C-4′),53.1(C-3′),52.2(C-1′),46.1(C-5′),17.1(C-2′).
高分辨质谱(ESI)计算值C16H23N2O2[M+H]+:275.1754,测定值为275.1745.
实施例14
化合物14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8,得63mg目标化合物14,收率为73%。
性状:淡黄色粉末
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.44(s,1H,H-2),7.22(s,1H,H-7),7.09(s,1H,H-4),3.87(s,3H,OMe),3.61(s,2H,H-1′),2.59-2.26(m,8H,H-3′,H-4′),2.39(q,J=7.2Hz,2H,H-5′),2.30(s,3H,H-2′),1.07(t,J=7.0Hz,1H,H-6′);13C NMR(125MHz,CDCl3)δ154.3(C-5),150.2(C-8),142.8(C-2),126.2(C-9),124.5(C-6),117.3(C-1),112.8(C-7),100.7(C-4),55.9(OMe),53.2(C-4′),53.1(C-3′),52.4(C-1′),52.2(C-5′),17.1(C-2′),12.1(C-6′).
高分辨质谱(ESI)计算值C17H26N2O2[M+H]+:289.1911,测定值为289.1901.
实施例15
化合物15的制备:
除了将二甲胺换成1-(2-吡嗪)哌嗪外,其余所需原料、试剂及制备方法同实施例8,得68mg目标化合物15,收率为67%
性状:淡黄色粉末
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ8.11(d,J=1.5Hz,1H,H-6′),8.05-8.04(m,1H,H-7′),7.83(d,J=2.5Hz,1H,H-8′),7.46(s,1H,H-2),7.25(s,1H,H-7),7.12(s,1H,H-4),3.87(s,3H,OMe),3.66(s,2H,H-1′),3.60(t,J=5.5Hz,4H,H-4′),2.61(t,J=5.0Hz,4H,H-3′),2.32(s,3H,H-2′);13C NMR(125MHz,CDCl3)δ155.1(C-5′),154.4(C-5),150.3(C-8),142.9(C-2),141.8(C-8′),133.0(C-7′),131.1(C-6′),125.9(C-9),124.7(C-6),116.9(C-3),112.9(C-7),100.6(C-4),55.9(OMe),52.7(C-3′),52.4(C-1′),44.7(C-4′),17.1(C-2′).
高分辨质谱(ESI)计算值C19H23N4O2[M+H]+:339.1816,测定值为339.1793.
实施例16
化合物16的制备:
除了将二甲胺换成乙酰哌嗪外,其余所需原料、试剂及制备方法同实施例8,得67mg目标化合物16,收率为74%
性状:淡黄色粉末
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.41(s,1H,H-3),7.22(s,1H,H-7),7.06(s,1H,H-4),3.85(s,3H,OMe),3.61(t,J=5.0Hz,2H,H-4′),3.59(s,2H,H-1′),3.42(t,J=5.0Hz,2H,H-6′),2.46-2.43(m,4H,H-3′,H-5′),2.29(s,3H,H-2′),2.05(s,3H,H-8′);13C NMR(125MHz,CDCl3)δ168.9(C-8′),154.3(C-5),150.1(C-8),142.8(C-2),125.8(C-9),124.7(C-6),116.8(C-3),112.8(C-7),100.4(C-4),55.8(OMe),52.9(C-3′),52.8(C-5′),52.1(C-1′),46.4(C-4′),41.5(C-6′),21.3(C-8′),17.0(C-2′).
高分辨质谱(ESI)计算值C17H23N2O3[M+H]+:303.1703,测定值为303.1689.
实施例17
化合物17的制备:
除了将二甲胺换成1-Boc-哌嗪外,其余所需原料、试剂及制备方法同实施例8,得63mg目标化合物17,收率为58%
性状:淡黄色粉末
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.43(s,1H,H-2),7.24(s,1H,H-7),7.09(s,1H,H-4),3.88(s,3H,OMe),3.61(s,2H,H-1′),3.43(d,J=5.0Hz,4H,H-4′),2.44(d,J=5.0Hz,4H,H-3′),2.31(s,3H,H-2′),1.45(s,9H,H-7′);13C NMR(125MHz,CDCl3)δ154.9(C-5′),154.4(C-5),150.3(C-8),142.9(C-2),126.0(C-9),124.7(C-6),117.1(C-1),112.9(C-7),100.7(C-4),79.7(C-6′),56.0(OMe),53.0(C-3′),53.0(C-4′),52.4(C-1′),28.6(C-7′),17.2(C-2′).
实施例18
化合物18的制备:
将36mg化合物17(0.1mmol)溶于3mL二氯甲烷,搅拌下向其中加入0.2mL三氟乙酸,室温反应6h后加入10mL饱和碳酸氢钠溶液淬灭反应,二氯甲烷萃取(3×5mL),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(甲醇-氯仿,5:95)分离得到25mg目标化合物,收率为98%。
性状:淡黄色粉末
1H-NMR和13C-NMR数据:1H NMR(500MHz,CD3OD)δ7.55(s,1H,H-2),7.19(s,1H,H-7),7.13(s,1H,H-4),3.85(s,3H,OMe),3.61(s,2H,H-1′),2.88(t,J=5.0Hz,4H,H-4′)2.52(brs,4H,H-3′),2.25(s,3H,H-2′);13C NMR(125MHz,CD3OD)δ155.8(C-5),151.5(C-9),144.9(C-2),127.3(C-8),125.6(C-6),117.4(C-3),113.5(C-7),101.3(C-4),56.2(OMe),53.9(C-3′),52.8(C-1′),46.0(C-4′),17.1(C-2′).
高分辨质谱(ESI)计算值C15H21N2O2[M+H]+:261.1598,测定值为261.1605.
实施例19
化合物19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8,得55mg目标化合物19,收率为75%.
性状:淡黄色油状物
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.49(s,1H,H-2),7.24(s,1H,H-7),7.05(s,1H,H-4),3.88(s,3H,OMe),3.77(s,2H,H-1′),2.65-2.62(m,4H,H-3′),2.31(s,3H,H-2′),1.83-1.80(m,4H,H-4′);13C NMR(125MHz,CDCl3)δ154.5(C-5),150.1(C-8),142.9(C-2),126.0(C-9),124.6(C-2),117.7(C-1),112.9(C-7),100.3(C-4),56.0(OMe),54.2(C-3′),49.1(C-1′),23.7(C-4′),17.1(C-2′).
高分辨质谱(ESI)计算值C15H20NO2[M+H]+:246.1489,测定值为246.1480.
实施例20
化合物20的制备:
除了将化合物7换成5-甲氧基-3-苯并呋喃醛,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8,得54mg目标化合物20,收率为79%。
性状:淡黄色油状物
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ7.50(s,1H,H-2),7.28(d,J=8.8Hz,1H,H-7),7.05(d,J=2.4Hz,1H,H-4),6.82(dd,J=8.8,2.4Hz,1H,H-6),3.78(s,3H,OMe),3.72(s,2H,H-1′),2.59(t,J=6.0Hz,4H,H-2′),1.76-1.73(m,4H,H-3′);13C NMR(100MHz,CDCl3)δ156.0(C-5),150.4(C-8),144.3(C-2),128.6(C-9),117.3(C-3),113.1(C-6),112.0(C-7),102.7(C-4),56.1(OMe),53.9(C-2′),48.7(C-1′),23.6(C-3′).
高分辨质谱(ESI)计算值C14H18NO2C[M+H]+:232.1332,测定值为232.1316.
实施例21
化合物21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8,得69mg目标化合物21,收率为88%
性状:淡黄色油状物
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.45(s,1H,H-2),7.25(s,1H,H-7),7.12(s,1H,H-4),3.89(s,3H,-OMe),3.72(t,J=5.0Hz,4H,H-4′),3.60(s,2H,H-1′),2.50(t,J=4.5Hz,4H,H-3′),2.34(s,3H,H-2′);13C NMR(125MHz,CDCl3)δ154.3(C-5),150.2(C-8),142.8(C-2),126.0(C-9),124.7(C-6),116.9(C-1),112.8(C-7),100.6(C-4),67.2(C-4′),55.9(OMe),53.7(C-3′),52.7(C-1′),17.1(C-2′).
高分辨质谱(ESI)计算值C15H20NO3[M+H]+:262.1438,测定值为262.1436.
实施例22
化合物22的制备:
除了将化合物7换成5-甲氧基-3-苯并呋喃醛,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8,得67mg目标化合物22,收率为90%。
性状:淡黄色油粉末
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ7.40(s,1H,H-2),7.24(d,J=8.8Hz,1H,H-7),7.09(d,J=2.4Hz,1H,H-4),6.80(dd,J=8.8,2.4Hz,1H,H-6),3.75(s,3H,OMe),3.60(t,J=4.4Hz,4H,H-3′),3.48(s,2H,H-1′),2.38(t,J=4.4Hz,4H,H-3′);13C NMR(125MHz,CDCl3)δ155.8(C-5),150.5(C-8),144.0(C-2),128.5(C-9),116.9(C-3),112.9(C-6),111.8(C-7),103.2(C-4),67.1(C-3′),55.9(OMe),53.6(C-2′),52.5(C-1′).
高分辨质谱(ESI)计算值C14H18NO3[M+H]+:248.1281,测定值为248.1277.
实施例23
化合物23的制备:
除了将化合物7换成5-甲氧基-3-苯并呋喃醛,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8,得67mg目标化合物22,收率为86%。
性状:淡黄色粉末
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ7.50(s,1H,H-2),7.32(d,J=8.8Hz,1H,H-7),7.09(d,J=2.4Hz,1H,H-4),6.86(dd,J=8.8,2.4Hz,1H,H-5),3.82(s,3H,OMe),3.64(s,2H,H-1′),2.85-2.73(m,8H,H-2′,H-3′),2.51(s,3H,H-4′);13C NMR(100MHz,CDCl3)155.9(C-5),150.5(C-8),144.5(C-2),128.3(C-9),116.2(C-1),113.0(C-6),112.0(C-7),103.1(C-4),56.1(OMe),54.0(C-3′),51.4(C-1′),50.7(C-2′),44.2(C-4′).
高分辨质谱(ESI)计算值C15H21N2O2[M+H]+:261.1598,测定值为261.1598.
实施例24
化合物24的制备:
除了将化合物7换成2-甲基-5-甲氧基-3-苯并呋喃醛,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8,得47mg目标化合物24,收率为57%。
性状:淡黄色粉末
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ7.26-7.24(m,1H,H-7),7.12-7.11(m,1H,H-4),6.81-6.78(m,1H,H-6),3.84(s,3H,OMe),3.53(s,2H,H-1′),2.55-2.45(m,8H,H-3′,H-4′),2.40(s,3H,H-5′),2.28(s,3H,H-2′);13C NMR(100MHz,CDCl3)δ155.7(C-5),153.8(C-2),149.0(C-8),130.5(C-9),111.5(C-1),111.2(C-6),110.8(C-7),103.2(C-4),56.1(OMe),55.4(C-4′),53.1(C-3′),52.2(C-1′),46.1(C-5′),12.5(C-2′).
实施例25
化合物25的制备:
除了将化合物7换成2-甲基-5-甲氧基-3-苯并呋喃醛,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8,得45mg目标化合物25,收率为45%。
性状:淡黄色粉末
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ7.88(d,J=7.2Hz,2H,H-6′),7.41-7.37(m,2H,H-7′),7.32-7.28(m,2H,H-7,H-8′),7.14(d,J=2.8Hz,1H,H-4),6.83(dd,J=8.8,2.8Hz,1H,H-6),3.80(s,3H,OMe),3.63(s,2H,H-1′),2.55-2.38(m,8H,H-2′,H-3′),2.22(s,3H,H-4′);13C NMR(100MHz,CDCl3)δ155.9(C-2),154.3(C-5),148.9(C-8),131.5(C-5′),131.1(C-8),128.7(C-7′),128.5(C-8′),127.7(C-5′),113.0(C-3),112.9(C-6),111.5(C-7),103.0(C-4),56.0(OMe),55.4(C-3′),53.1(C-2′),52.3(C-4′),46.1(C-1′).
高分辨质谱(ESI)计算值C21H25N2O2[M+H]+:337.1911,测定值为337.1896.
实施例26
化合物26的制备:
除了将二甲胺换成哌嗪外,其余所需原料、试剂及制备方法同实施例8,得41mg目标化合物26,收率为63%。
性状:淡黄色粉末
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.44(s,2H,H-2),7.23(s,2H,H-7),7.08(s,2H,H-4),3.87(s,6H,OMe),3.62(s,4H,H-1′),2.58(brs,8H,H-3′),2.31(s,6H,H-2′);13C NMR(125MHz,CDCl3)δ154.3(C-5),150.2(C-8),142.8(C-2),126.2(C-9),124.6(C-2),117.3(C-1),112.8(C-7),100.7(C-4),56.0(OMe),53.3(C-1′),52.2(C-3′),17.1(C-2′).
高分辨质谱(ESI)计算值C26H30N2O4[M+H]+:435.2278,测定值为435.2238.
实施例27
化合物27的制备:
除了将二甲胺换成哌嗪外,其余所需原料、试剂及制备方法同实施例8,得31mg目标化合物26,收率为46%。
性状:淡黄色粉末
1H-NMR和13C-NMR数据:1H NMR(500MHz,CDCl3)δ7.42(s,2H,H-2),7.23(s,2H,H-7),7.10(s,2H,H-4),3.83(s,6H,OMe),3.74(s,4H,H-1′),2.80(t,J=6.0Hz,4H,H-3′),2.74(s,4H,H-5′),2.32(s,6H,H-2′),1.88-1.84(m,2H,H-4′);13C NMR(125MHz,CDCl3)δ154.3(C-5),150.3(C-8),142.6(C-2),126.1(C-9),124.6(C-6),118.2(C-1),112.8(C-7),100.9(C-4),55.9(OMe),55.4(C-5′),54.1(C-3′),52.4(C-1′),27.8(C-4′),17.2(C-2′).
高分辨质谱(ESI)计算值C27H33N2O4[M+H]+:449.2435,测定值为449.2411.
实施例28
本发明提供的paeoveitol D衍生物对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’sModified 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7,17和25对MT1受体具有一定的激动活性;化合物11,16,21和22对MT1受体具有较好的激动作用,化合物1,15和27对MT1受体具有好的激动作用,化合物4,8-10,12-14,18-19,23和26对MT1具有强的激动活性,激动率较paeoveitol D显著提高。
化合物7和16对MT2受体具有一定的激动活性;化合物10,17,22和25对MT2受体具有与paeoveitol D相当的激动作用,化合物15,21,23和27对MT2受体具有好的激动作用,激动活性强于paeoveitol D。化合物1,4,8-9,12-14,18-20和26对MT2具有强的激动活性,激动率较paeoveitol D显著提高。
化合物4,8-10,18-19和26对MT1和MT2受体均具有显著左右,激动率是原化合物的2-3倍(见表1)。
3结论
实验结果显示,化合物1,15和27对MT1受体具有好的激动作用,化合物4,8-10,12-14,18-19,23和26对MT1具有强的激动活性,化合物15,21,23和27对MT2受体具有好的激动作用,化合物1,4,8-9,12-14,18-20和26对MT2具有强的激动活性。以上结果表明这些化合物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系统疾病。
表1化合物1-27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29:
化合物13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13)由实施例13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13剂量组1(10mg/kg),化合物12剂量组2(20mg/kg),化合物13剂量组3(40mg/kg),化合物13剂量组4(80mg/kg),化合物13剂量组5(160mg/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
给药2天后,20,40,80 160mg/kg化合物13和氟西汀(20mg/kg)均可显著缩短小鼠强迫游泳不动时间(P<0.05或P<0.01),而低剂量组对此仅有缩短趋势而无统计差异(P>0.05)。高剂量(160mg/kg)活性与阳性药物氟西汀(20mg/kg)相当,提示化合物具有显著抗抑郁活性。
表2化合物13小鼠强迫游泳实验数据结果
实施例30:
制剂实施例
1.取化合物1-27任其一或任意组合,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.取化合物1-27任其一或任意组合,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.取化合物1-27任其一或任意组合,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.取化合物1-27任其一或任意组合,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.取化合物1-27任其一或任意组合,按常规口服液制法制成口服液。
6.取化合物1-27任其一或任意组合,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.取化合物1-27任其一或任意组合,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.取化合物1-27任其一或任意组合,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 D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 D衍生物对MT1和MT2受体具有细胞毒活性,能够与可药用载体或赋型剂组成药物组合物,能够用于治疗或改善与褪黑素受体相关的中枢神经系统疾病。
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)
2.权利要求1所述的式(I)所示的paeoveitol D衍生物1-27或其药用盐在制备褪黑素受体激动剂中的应用。
3.权利要求1所述的式(I)所示的paeoveitol D衍生物1-27或其药用盐在制备治疗或预防中枢神经系统疾病的药物中的应用。
4.权利要求1所述的式(I)所示的paeoveitol D衍生物1-27或其药用盐在制备与褪黑素受体相关的中枢神经系统疾病的药物中的应用。
5.权利要求1所述的式(I)所示的paeoveitol D衍生物1-27(化合物1-27)的制备方法,其特征在于,该方法包括下述步骤:
化合物1-7的制备:
5-甲氧基-6-甲基苯并呋喃-3-羧酸乙酯在还原剂作用下制备得到化合物1;化合物1在碱作用下与环丙基甲酰氯反应制备得到化合物2;化合物1与邻苯二甲酰亚胺在三苯基膦、偶氮试剂的作用下经Mitsunobu反应制备化合物得到化合物3;化合物3经水合肼水解制备得到化合物4;化合物4在碱作用下与乙酰氯或环丙基甲酰氯反应制备得到化合物5-6;化合物1经氧化制备化合物7;
化合物8-27的制备:
苯并呋喃-3-醛类化合物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,经还原胺化得到化合物8-17,19-27,所述苯并呋喃-3-醛类化合物包括6-甲基-5-甲氧基-3-苯并呋喃醛或5-甲氧基-3-苯并呋喃醛或5-甲氧基-2-甲基-3-苯并呋喃醛或5-甲氧基-2-苯基-3-苯并呋喃醛,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。化合物17在适当的酸作用下脱除叔丁氧羰基后制备得到化合物18,所述适当的酸为三氟乙酸、对甲苯磺酸。
6.含有治疗有效量的权利要求1所述的式(I)所示的paeoveitol D衍生物1-27任其一种或任其组合,或其药用盐,和药学上可接受的载体的药物组合物。
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预防中枢神经系统疾病的药物中的应用。
9.权利要求5所述的药物组合物在制备治疗或预防与褪黑素受体相关的中枢神经系统疾病的药物中的应用。
10.权利要求5所述的式(I)药物组合物的制备方法,其特征在于,该方法包括下述步骤:先制得paeoveitol D衍生物1-27,然后加入药学上可接受的载体,所述的paeoveitol D衍生物1-27(化合物1-27)由下述步骤制备而得:
化合物1-7的制备:
5-甲氧基-6-甲基苯并呋喃-3-羧酸乙酯在还原剂作用下制备得到化合物1;化合物1在碱作用下与环丙基甲酰氯反应制备得到化合物2;化合物1与邻苯二甲酰亚胺在三苯基膦、偶氮试剂的作用下经Mitsunobu反应制备化合物得到化合物3;化合物3经水合肼水解制备得到化合物4;化合物4在碱作用下与乙酰氯或环丙基甲酰氯反应制备得到化合物5-6;化合物1经氧化制备化合物7;
化合物8-27的制备:
苯并呋喃-3-醛类化合物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,经还原胺化得到化合物8-17,19-27,所述苯并呋喃-3-醛类化合物包括6-甲基-5-甲氧基-3-苯并呋喃醛或5-甲氧基-3-苯并呋喃醛或5-甲氧基-2-甲基-3-苯并呋喃醛或5-甲氧基-2-苯基-3-苯并呋喃醛,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。化合物17在适当的酸作用下脱除叔丁氧羰基后制备得到化合物18,所述适当的酸为三氟乙酸、对甲苯磺酸。
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