CN116854663B - 阿朴菲类生物碱衍生物及其制备方法和应用 - Google Patents
阿朴菲类生物碱衍生物及其制备方法和应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—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
- 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
- C07D405/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明公开了结构如式I所示的阿朴菲类生物碱衍生物,R选自 n为2~10的整数;但不包括:R选自n为2、3。本发明阿朴菲类生物碱衍生物对皮质酮诱导的PC12细胞损伤具有较好的保护活性,且对皮质酮诱导的细胞损伤的保护活性优于母核阿朴菲,说明皮质酮诱导的PC12细胞损伤具有神经保护功能和抗抑郁效果;且阿朴菲类生物碱衍生物能够显著增加旷场实验中移动距离和移动速度,显著缩短悬尾实验与强迫游泳不动实验中不动时间,能够显著改善抑郁状态。本发明还公开了所述的阿朴菲类生物碱衍生物在制备抗抑郁药物中的应用。本发明还公开了所述的阿朴菲类生物碱衍生物在制备神经保护药物中的应用。
Description
技术领域
本发明属于药物化学领域,涉及一种阿朴菲生物碱衍生物及其制备方法和在制备抗抑郁药物中的应用。
技术背景
抑郁症(Depression)是一种典型的情绪情感障碍疾病,在临床上的核心症状表现为显著持久的情绪低落、快感缺乏、思维迟缓、意志活动减少。并可能同时伴有自杀自残观念以及躯体症状等,患者自杀死亡率高达15%~25%。在全球,抑郁障碍占精神障碍疾病首位,据统计,全球范围内有3.5亿存在或表现出抑郁症状的患者。不仅如此,抑郁症还具有高复发率的特点。抑郁症正逐步成为威胁人类心理和生理健康的第二大杀手疾病,仅次于癌症。抑郁症对患者的工作和生活、以至家庭与社会都会带来严重的负担和影响。抑郁症的患病率持续上升,据世界卫生组织报道,在2030年,抑郁症将跃居全球疾病负担首位。抑郁症的病因和发病机制至今尚未完全阐明。根据抑郁症的单胺假说,单胺能神经传递的增加可以有效缓解抑郁症状。
尽管抑郁症发病率越来越高,负担也越来越重,但对焦虑和抑郁的治疗效果却不尽人意。传统的一线治疗,包括心理治疗和药物治疗,只有50%的有效率,现有的抗抑郁药物具有一定的局限性,比如不良反应严重、起效缓慢、疗效有限等,不能充分的满足临床需求。因此,研发出快速起效、并具有增强认知和低毒副作用的抗抑郁药十分迫切。
发明内容
本发明的目的在于提供结构如通式I所示的阿朴菲类生物碱衍生物:
其中,R选自n为2~10的整数;但不包括:R选自/>n为2、3。
优选的,n为2~6的整数;但不包括:R选自n为2、3。
更优选的,R选自n为2、3、6。
具体的,所述的阿朴菲类生物碱衍生物选自下列化合物:
本发明的另一目的在于提供一种所述的阿朴菲类生物碱衍生物的制备方法,反应路线如下:
其中,R、n如前所述。
包括以下步骤:
步骤(1)、在缚酸剂存在的条件下,在催化剂作用下,式IV所示的阿朴菲与RCOOH发生酰胺缩合反应,得到中间体III;
步骤(2)、在催化剂作用下,中间体III与式所示的双取代溴烷反应,得到中间体II;
步骤(3)、在避光条件下,中间体II与硝酸银反应,得到式I所示的阿朴菲类生物碱衍生物。
步骤(1)中,所述的阿朴菲和RCOOH的摩尔比为1:1~1.1:1。
RCOOH选自N-甲基吲哚-2-甲酸、5-氟-苯并噻吩-2-甲酸、5-氟-苯并呋喃-2-甲酸。
所述的催化剂为EDCI、HoBt(1-羟基苯并三唑)。
所述的阿朴菲和EDCI的摩尔比为1:2~1:4;阿朴菲和HoBt的摩尔比为1:2~1:3.5。
所述的阿朴菲和缚酸剂的摩尔比为1:2~1:6。
所述的缚酸剂为三乙胺、DIEA、吡啶、醋酸钠、碳酸钠、碳酸钾等。
反应溶剂选自N,N-二甲基甲酰胺。
酰胺缩合反应的温度为-20~4℃。
反应结束后,减压干燥除去溶剂,以PE:EA=8:1~5:1(V:V)为洗脱剂,经硅胶柱层析纯化得到中间体III。
步骤(2)中,所述的中间体III和双取代溴烷的摩尔比为1:1.8~1:5。
所述的中间体III和催化剂的摩尔比为1:2~1:3.5。
所述的催化剂为碳酸铯。
反应溶剂选自乙腈。
反应温度为60℃~80℃。
反应结束后,减压干燥除去溶剂,以PE:EA=9:1~6:1(V:V)为洗脱剂,经硅胶柱层析纯化得到中间体II。
步骤(3)中,所述的中间体II与AgNO3的摩尔比为1:1.5~1:2.5。
反应溶剂选自乙腈。
反应温度为60℃~75℃。
反应结束后,减压干燥除去溶剂,以PE:EA=7:1~5:1(V:V)为洗脱剂,经硅胶柱层析纯化得到通式I所示的阿朴菲生物碱衍生物。
体外活性实验表明,本发明所述的阿朴菲类生物碱衍生物对皮质酮诱导的PC12细胞损伤具有较好的保护活性,且对皮质酮诱导的细胞损伤的保护活性优于母核阿朴菲,说明皮质酮诱导的PC12细胞损伤具有神经保护功能和抗抑郁效果;且体内抗抑郁药效评价表明,阿朴菲类生物碱衍生物能够显著增加旷场实验中移动距离和移动速度,显著缩短悬尾实验与强迫游泳不动实验中不动时间,说明能够显著改善抑郁状态。
因此,本发明的另一个目的是提供所述的阿朴菲类生物碱衍生物在制备抗抑郁药物中的应用。
本发明的另一个目的是提供所述的阿朴菲类生物碱衍生物在制备神经保护药物中的应用。
本发明的有益效果:
本发明制备阿朴菲生物碱衍生物的方法反应条件温和,所用试剂低毒,原料易得,后处理方便,产率较高。
本发明阿朴菲生物碱衍生物对皮质酮诱导的PC12细胞损伤具有较好的保护活性,表现出神经保护作用,且体内抗抑郁药效评价表明,能够显著改善抑郁状态,本发明阿朴菲衍生物有望成为具有研究前景的抗抑郁药物。
附图说明
图1为化合物(1μM)与皮质酮(200μM)共处理PC12细胞的存活率。
图2为化合物I15体内抗抑郁药效结果;其中,A:旷场实验中小鼠移动总路程;B:旷场实验中小鼠移动速度;C:强迫游泳不动实验中小鼠静止时间;D:悬尾实验中小鼠静止时间;###P<0.0001,#P<0.05指模型组与空白对照组间的显著性差异;****P<0.0001,***P<0.001,**P<0.01,*P<0.05指给药组与模型组间的显著性差异。
具体实施方式
下面列举一系列实施例进一步阐明本发明的技术方案。这些实施例是例证性的,不应当理解为对本发明的限制。
实施例1
2-((1,2,10-三甲氧基-6-(1-甲基-1H-吲哚-2-羰基)-5,6,6a,7-四氢-4H-苯并[de,g]喹啉-9-氧基)硝酸乙酯(化合物I1)的合成
以5mL DMF为反应溶剂,在温度-15℃下,先加入N-甲基吲哚-2-甲酸(1.2eq,42mg)和HoBt(2.5eq,63mg),搅拌1h后加入EDCI(2eq,84mg)、Et3N(2.5eq,75μL)以及式IV所示的阿朴菲(1eq,70mg),保持反应温度在4℃,反应3h,此时TLC监测反应结束;将10mL冰水加入反应液中,析出浅棕色固体,抽滤,干燥,粗品经硅胶柱色谱(洗脱剂为PE:EA=5:1V/V)纯化得中间体III 1。
在反应瓶中依次加入中间体III 1(1eq,30mg)、Cs2CO3(2eq,40)、乙腈(5mL)、1,2-二溴乙烷(5eq,26uL),70℃回流反应24h,此时TLC检测反应结束,减压浓缩,粗品经硅胶柱层析(PE:EA=6:1V:V)得中间体II 1。
在反应瓶中依次加入中间体II 1(1eq,50mg),AgNO3(2eq)、乙腈(5mL),60℃避光加热回流过夜,此时TLC检测反应结束,减压浓缩,粗品经硅胶柱层析(洗脱剂为PE:EA,V:V=5:1)得到化合物I1,白色固体,产率95%。
HRMS(ESI)calculated for C31H32N3O8[M+H]+:574.2189found 574.2184.
1H NMR(400MHz,CDCl3)δH 8.16(s,1H),7.79(dd,J=8.9,4.7Hz,1H),7.48(d,J=10.8Hz,2H),7.18(td,J=8.8,2.5Hz,1H),6.79(s,1H),6.65(s,1H),5.18(d,J=13.4Hz,1H),4.47(t,J=6.7Hz,2H),4.06(q,J=8.2,6.8Hz,2H),3.90(d,J=3.4Hz,6H),3.68(s,3H),3.38(d,J=13.3Hz,1H),3.17-2.85(m,4H),2.79-2.59(m,1H),1.89(t,J=7.0Hz,2H),1.78(t,J=7.1Hz,2H),1.57-1.48(m,4H).13C NMR(125MHz,CDCl3)δC 163.75,152.24,148.40,146.72,145.18,137.82,132.40,129.47,127.67,126.49,125.68,125.39,123.33,121.55,120.34,114.56,114.49,112.68,110.77,110.15,109.86,103.71,71.12,65.46,55.98,31.18.
实施例2
3-((1,2,10-三甲氧基-6-(1-甲基-1H-吲哚-2-羰基)-5,6,6a,7-四氢-4H-并苯基[de,g]喹啉-9-氧基)硝酸丙酯(化合物I2)的合成
参照实施例1化合物I1的制备方法,以等摩尔量的1,3-二溴丙烷替代1,2-二溴乙烷,其他条件不变,经硅胶柱层析(洗脱剂为PE:EA=5:1V/V)制得目标化合物I2,白色固体,产率93%。
HRMS(ESI)calculated for C32H34N3O8[M+H]+:588.2346,found 588.2340.
1H NMR(400MHz,CDCl3)δH 8.18(s,1H),7.65(d,J=7.9Hz,1H),7.39(d,J=8.3Hz,1H),7.30(d,J=8.2Hz,1H),7.21-7.12(m,1H),6.83(s,1H),6.67(d,J=8.9Hz,2H),5.24(d,J=9.7Hz,1H),4.72(td,J=6.3,2.0Hz,2H),4.59(d,J=12.2Hz,1H),4.21-4.11(m,2H),3.35(t,J=12.4Hz,1H),3.13(d,J=10.7Hz,1H),2.94(dt,J=26.5,12.5Hz,2H),2.70(d,J=15.5Hz,1H),2.27(q,J=7.3,6.2Hz,2H).13C NMR(125MHz,CDCl3)δC 148.10,147.27,145.11,137.81,132.45,129.48,129.29,127.80,126.51,125.37,124.85,123.32,121.54,120.33,113.54,112.37,110.63,109.86,102.81,70.09,64.76,55.98,31.18,27.00.
实施例3
4-((1,2,10-三甲氧基-6-(1-甲基-1H-吲哚-2-羰基)-5,6,6a,7-四氢-4H-并苯基[de,g]喹啉-9-氧基)硝酸丁酯(化合物I3)的合成
参照实施例1化合物I1的制备方法,以等摩尔量的1,4-二溴丙烷替代1,2-二溴乙烷,其他条件不变,经硅胶柱层析(洗脱剂为PE:EA=5:1V/V)制得目标化合物I3,白色固体,产率92%。
HRMS(ESI)calculated for C33H36N3O8[M+H]+:602.2502,found 602.2497.
1H NMR(400MHz,CDCl3)δH 8.17(s,1H),7.65(d,J=7.9Hz,1H),7.39(d,J=8.4Hz,1H),7.31(t,J=7.6Hz,1H),7.16(t,J=7.5Hz,1H),6.81(s,1H),6.67(d,J=11.2Hz,2H),5.23(d,J=13.6Hz,1H),4.59(d,J=5.0Hz,3H),4.16-4.04(m,2H),3.35(t,J=11.9Hz,1H),3.13(d,J=12.2Hz,1H),3.03-2.85(m,2H),2.70(d,J=15.4Hz,1H),1.99(q,J=3.1Hz,4H).13C NMR(125MHz,CDCl3)δC 152.24,147.98,145.08,137.81,132.48,129.42,127.88,126.51,125.33,123.31,121.54,120.32,112.99,112.22,110.54,109.86,102.82,73.07,68.00,60.06,55.97,31.19,25.48,23.97.
实施例4
5-((1,2,10-三甲氧基-6-(1-甲基-1H-吲哚-2-羰基)-5,6,6a,7-四氢-4H-并苯基[de,g]喹啉-9-氧基)硝酸戊酯(化合物I4)的合成
参照实施例1化合物I1的制备方法,以等摩尔量的1,5-二溴戊烷替代1,2-二溴乙烷,其他条件不变,经硅胶柱层析(洗脱剂为PE:EA=5:1V/V)制得目标化合物I4,白色固体,产率94%。
HRMS(ESI)calculated for C33H36N3O8[M+H]+:616.2659,found 616.2653.
1H NMR(400MHz,CDCl3)δH 8.17(s,1H),7.65(d,J=7.9Hz,1H),7.39(d,J=8.2Hz,1H),7.33-7.28(m,1H),7.16(t,J=7.5Hz,1H),6.81(s,1H),6.66(d,J=12.6Hz,2H),5.24(d,J=13.2Hz,1H),4.50(t,J=6.6Hz,2H),4.07(dd,J=12.7,6.4Hz,2H),3.91(d,J=3.3Hz,6H),3.86(s,3H),3.69(s,3H),3.35(t,J=12.4Hz,1H),3.13(d,J=13.3Hz,1H),2.98-2.85(m,2H),2.69(d,J=15.5Hz,1H),1.92(p,J=6.6Hz,3H),1.86-1.80(m,2H),1.64(d,J=7.3Hz,2H).13C NMR(125MHz,CDCl3)δC 152.23,147.90,147.76,137.80,132.49,129.42,127.93,126.51,125.69,125.33,124.17,123.31,121.53,120.32,112.82,112.18,110.47,109.85,102.81,73.21,68.32,55.97,31.45,31.18,28.72,26.57.
实施例5
6-((1,2,10-三甲氧基-6-(1-甲基-1H-吲哚-2-羰基)-5,6,6a,7-四氢-4H-并苯基[de,g]喹啉-9-氧基)硝酸己酯(化合物I5)的合成
参照实施例1化合物I1的制备方法,以等摩尔量的1,6-二溴己烷替代1,2-二溴乙烷,其他条件不变,经硅胶柱层析(洗脱剂为PE:EA=6:1V/V)制得目标化合物I5,白色固体,产率90%。
HRMS(ESI)calculated for C35H40N3O8[M+H]+:630.2815,found 630.2810.
1H NMR(400MHz,CDCl3)δH 8.18(s,1H),7.65(d,J=7.9Hz,1H),7.39(d,J=8.3Hz,1H),7.34-7.28(m,1H),7.19-7.11(m,1H),6.82(s,1H),6.67(d,J=13.7Hz,2H),5.25(d,J=13.7Hz,1H),4.47(t,J=6.7Hz,2H),4.15-4.01(m,2H),3.91(s,6H),3.86(s,3H),3.70(s,3H),3.39-3.31(m,1H),3.14(d,J=13.2Hz,1H),2.91(t,J=13.8Hz,2H),2.70(d,J=17.8Hz,1H),1.90(d,J=7.0Hz,2H),1.80-1.73(m,2H),1.57-1.49(m,4H).13C NMR(125MHz,CDCl3)δC163.74,152.24,147.87,145.05,137.83,137.80,132.51,129.43,129.25,127.96,126.52,125.32,124.08,124.04,123.30,121.53,120.32,112.73,112.16,110.45,109.86,102.81,73.33,68.50,60.04,56.03,55.97,31.17,28.98,26.71,25.67,25.47.
实施例6
2-((6-(5-氟)苯并呋喃基-2-羰基)-1,2,10-三甲氧基-5,6,6a,7-四氢-4H-并苯[de,g]喹啉-9-氧基)硝酸乙酯(化合物I6)的合成
参照实施例1化合物I1的制备方法,以等摩尔量的等摩尔量的5-氟-苯并呋喃-2-甲酸替代N-甲基吲哚-2-甲酸,其他条件不变,经硅胶柱层析(洗脱剂为PE:EA=7:1V:V)制得目标化合物I6,白色固体,产率90%。
HRMS(ESI)calculated for C30H28FN2O9[M+H]+:579.1779,found 579.1773.
1H NMR(400MHz,CDCl3)δH 8.19(s,1H),7.41(s,1H),7.37-7.29(m,2H),7.12(t,J=7.7Hz,1H),6.84(s,1H),6.68(s,1H),5.21(d,J=13.5Hz,1H),4.89-4.79(m,2H),4.36(q,J=4.7Hz,2H),3.91(d,J=5.6Hz,6H),3.69(s,3H),3.40-3.22(m,1H),3.14-2.91(m,3H),2.76(d,J=15.4Hz,1H).13C NMR(125MHz,CDCl3)δC 159.95,152.29,151.16,150.89,147.11,146.78,145.25,129.60,129.57,127.77,127.56,125.20,124.60,124.01,119.11,115.18,114.57,112.80,112.70,112.63,110.92,107.68,107.48,92.39,71.15,65.71,60.10,56.01,31.46,30.22,29.35,27.24,22.72.
实施例7
3-((6-(5-氟)苯并呋喃基-2-羰基)-1,2,10-三甲氧基-5,6,6a,7-四氢-4H-并苯[de,g]喹啉-9-氧基)硝酸丙酯(化合物I7)的合成
参照实施例1化合物I1的制备方法,以等摩尔量的5-氟-苯并呋喃-2-甲酸替代N-甲基吲哚-2-甲酸,及等摩尔量的1,3-二溴丙烷替代1,2-二溴乙烷,其他条件不变,经硅胶柱层析(洗脱剂为PE:EA=6:1V/V)制得目标化合物I7,白色固体,产率89%。
HRMS(ESI)calculated for C31H30FN2O9[M+H]+:593.1935,found 593.1930.
1H NMR(400MHz,CDCl3)δH 8.17(s,1H),7.40(s,1H),7.34-7.28(m,2H),7.12(td,J=9.0,2.6Hz,1H),6.82(s,1H),6.67(s,1H),5.20(dd,J=13.5,4.1Hz,1H),4.73(t,J=6.2Hz,3H),4.19(d,J=4.7Hz,2H),3.90(d,J=6.5Hz,6H),3.69(s,3H),3.26(s,1H),3.14-2.88(m,3H),2.76(d,J=15.5Hz,1H),2.29(t,J=6.1Hz,2H).13C NMR(125MHz,CDCl3)δC160.47,159.94,158.56,152.29,151.19,150.89,148.20,147.33,145.10,129.56,129.45,127.82,127.72,125.20,124.97,114.75,114.54,112.69,112.62,112.45,110.73,107.67,107.47,70.05,64.87,60.09,56.00,31.75,29.73,29.39,27.07,21.08.
实施例8
4-((6-(5-氟)苯并呋喃基-2-羰基)-1,2,10-三甲氧基-5,6,6a,7-四氢-4H-并苯[de,g]喹啉-9-氧基)硝酸丁酯(化合物I8)的合成
参照实施例1化合物I1的制备方法,以等摩尔量的5-氟-苯并呋喃-2甲酸替代N-甲基吲哚-2-甲酸、等摩尔量的1,4-二溴丁烷替代1,2-二溴乙烷,其他条件不变,经硅胶柱层析(洗脱剂为PE:EA=6:1V:V)制得目标化合物I8,白色固体,产率90%。
HRMS(ESI)calculated for C32H32FN2NaO9 +[M+Na]+:629.1906,found 629.1906.
1H NMR(400MHz,CDCl3)δH 8.19(s,1H),7.43(s,1H),7.37-7.31(m,2H),7.14(td,J=9.0,2.6Hz,1H),6.83(s,1H),6.69(s,1H),5.24(dd,J=13.6,4.2Hz,1H),4.62(d,J=3.7Hz,2H),4.13(d,J=5.4Hz,2H),3.93(d,J=7.0Hz,6H),3.71(s,3H),3.33(d,J=19.3Hz,1H),3.17-2.91(m,3H),2.79(d,J=15.6Hz,1H),2.07-1.95(m,4H).13C NMR(125MHz,CDCl3)δC160.47,159.94,158.56,152.29,151.21,150.88,147.62,145.09,129.50,129.41,127.84,127.75,125.17,124.53,114.70,114.49,112.70,112.63,112.31,110.63,107.67,107.47,73.05,68.14,60.08,55.96,31.46,29.73,25.53,24.02.
实施例9
5-((6-(5-氟)苯并呋喃基-2-羰基)-1,2,10-三甲氧基-5,6,6a,7-四氢-4H-并苯[de,g]喹啉-9-氧基)硝酸戊酯(化合物I9)的合成
参照实施例1化合物I1的制备方法,以等摩尔量的5-氟-苯并呋喃-2-甲酸替代N-甲基吲哚-2-甲酸、等摩尔量的1,5-二溴戊烷替代1,2-二溴乙烷,其他条件不变,经硅胶柱层析(洗脱剂为PE:EA=6:1V/V)制得目标化合物I9,白色固体,产率91%。
HRMS(ESI)calculated for C33H33FN2NaO9 +[M+Na]+:643.2062,found 643.2062.
1H NMR(400MHz,CDCl3)δH 8.19(s,1H),7.43(s,1H),7.38-7.30(m,2H),7.28(s,1H),7.15(d,J=8.7Hz,1H),6.83(s,1H),6.69(s,1H),5.28-5.20(m,1H),4.53(t,J=6.6Hz,2H),4.11(t,J=6.9Hz,2H),3.93(d,J=3.7Hz,6H),3.71(s,3H),3.36(s,1H),3.16-2.92(m,3H),2.79(d,J=15.6Hz,1H),1.95(p,J=6.6Hz,2H),1.91-1.82(m,3H),1.70-1.62(m,3H).13CNMR(125MHz,CDCl3)δC 160.47,159.93,158.56,152.29,151.22,150.88,148.01,147.82,145.07,129.50,129.40,127.84,127.75,125.16,124.30,114.69,114.48,112.71,112.63,112.27,110.58,107.67,107.47,73.19,68.46,60.06,55.99,31.95,31.46,30.22,29.72,28.78,26.61,22.50.实施例10
6-((6-(5-氟)苯并呋喃基-2-羰基)-1,2,10-三甲氧基-5,6,6a,7-四氢-4H-并苯[de,g]喹啉-9-氧基)硝酸己酯(化合物I10)的合成
参照实施例1化合物I1的制备方法,以等摩尔量的5-氟-苯并呋喃-2-甲酸替代N-甲基吲哚-2-甲酸、等摩尔量的1,6-二溴己烷替代1,2-二溴乙烷,其他条件不变,经硅胶柱层析(洗脱剂为PE:EA=6:1V/V)制得目标化合物I10,白色固体,产率89%。
HRMS(ESI)calculated for C34H35FN2NaO9 +[M+Na]+:657.2219,found 657.2219.
1H NMR(400MHz,CDCl3)δH 8.19(s,1H),7.43(s,1H),7.36-7.30(m,2H),7.16-7.09(m,1H),6.83(s,1H),6.68(s,1H),5.24(dd,J=13.3,4.0Hz,1H),4.49(t,J=6.6Hz,2H),4.09(q,J=6.6Hz,2H),3.93(d,J=2.4Hz,6H),3.71(s,3H),3.35(s,1H),3.08(d,J=46.1Hz,3H),2.79(d,J=15.4Hz,1H),1.92(p,J=6.8Hz,2H),1.80(p,J=6.8Hz,2H),1.63-1.48(m,5H).13C NMR(125MHz,CDCl3)δC 160.46,159.92,158.55,152.29,151.22,150.88,147.97,147.92,145.05,129.50,129.39,127.85,127.75,125.15,124.15,114.68,114.47,112.71,112.64,112.25,110.56,107.66,107.46,73.31,68.63,60.06,55.99,32.59,31.95,31.46,30.22,29.72,29.03,26.74,25.71,25.51.
实施例11
2-((6-(5-氟)苯并噻吩基-2-羰基)-1,2,10-三甲氧基-5,6,6a,7-四氢-4H-并苯[de,g]喹啉-9-氧基)硝酸乙酯(化合物I11)的合成
参照实施例1化合物I1的制备方法,以等摩尔量的5-氟-苯并噻吩-2-甲酸替代N-甲基吲哚-2-甲酸,其他条件不变,经硅胶柱层析(洗脱剂为PE:EA=6:1V/V)制得目标化合物I11,白色固体,产率91%。
HRMS(ESI)calculated for C30H28FN2O8S[M+H]+:595.1550,found 595.1545.
1H NMR(400MHz,CDCl3)δH 8.18(s,1H),7.79(dd,J=8.9,4.7Hz,1H),7.53-7.43(m,2H),7.18(t,J=7.6Hz,1H),6.82(s,1H),6.67(s,1H),5.16(d,J=16.8Hz,1H),4.90-4.81(m,2H),4.55(d,J=9.9Hz,1H),4.35(q,J=3.9Hz,2H),3.91(d,J=5.8Hz,6H),3.69(s,3H),3.35(t,J=12.8Hz,1H),3.17-2.97(m,2H),2.91(t,J=13.6Hz,2H),2.73(dt,J=15.6,2.4Hz,1H).13CNMR(125MHz,CDCl3)δC 163.82,162.00,160.07,152.33,148.49,146.80,145.24,139.90,139.70,139.62,135.55,129.35,129.23,127.63,125.72,125.20,124.44,123.74,123.66,115.03,114.83,114.51,112.75,110.85,110.00,109.81,71.53,65.54,56.04,56.01,31.52,30.71,30.22,29.73.
实施例12
3-((6-(5-氟)苯并噻吩基-2-羰基)-1,2,10-三甲氧基-5,6,6a,7-四氢-4H-并苯[de,g]喹啉-9-氧基)硝酸丙酯(化合物I12)的合成
参照实施例1化合物I1的制备方法,以等摩尔量的5-氟-苯并噻吩-2-甲酸替代N-甲基吲哚-2-甲酸,及等摩尔量的1,3-二溴丙烷替代1,2-二溴乙烷,其他条件不变,经硅胶柱层析(洗脱剂为PE:EA=6:1V/V)制得目标化合物I12,白色固体,产率93%。
HRMS(ESI)calculated for C31H29FN2NaO8S+[M+Na]+:631.1521,found 631.1521.
1H NMR(400MHz,CDCl3)δH 8.20(s,1H),7.82(dd,J=8.9,4.7Hz,1H),7.50(d,J=12.5Hz,2H),7.20(td,J=8.8,2.5Hz,1H),6.83(s,1H),6.69(s,1H),5.19(d,J=9.8Hz,1H),4.74(t,J=5.3Hz,2H),4.19(h,J=3.8Hz,2H),3.93(d,J=7.6Hz,6H),3.71(s,3H),3.38(t,J=12.5Hz,1H),3.17-2.88(m,4H),2.75(d,J=15.5Hz,1H),2.30(pd,J=6.1,1.8Hz,2H).13C NMR(125MHz,CDCl3)δC 163.81,162.32,160.24,152.32,148.19,147.33,145.17,139.93,139.70,135.58,129.34,129.20,127.77,125.19,124.87,124.44,123.74,123.66,115.02,114.82,113.51,112.43,110.69,109.99,109.80,70.09,65.20,60.55,56.01,55.99,31.53,30.71,30.22,29.73,27.03.
实施例13
4-((6-(5-氟)苯并噻吩基-2-羰基)-1,2,10-三甲氧基-5,6,6a,7-四氢-4H-并苯[de,g]喹啉-9-氧基)硝酸丁酯(化合物I13)的合成
参照实施例1化合物I1的制备方法,以等摩尔量的5-氟-苯并噻吩-2-甲酸替代N-甲基吲哚-2-甲酸\等摩尔量的1,4-二溴丁烷替代1,2-二溴乙烷,其他条件不变,经硅胶柱层析(洗脱剂为PE:EA=6:1V/V)制得目标化合物I13,白色固体,产率92%。
HRMS(ESI)calculated for C32H32FN2O8S[M+H]+:623.1863,found 623.1858.
1H NMR(400MHz,CDCl3)δH 8.19(s,1H),7.81(dd,J=8.8,4.7Hz,1H),7.53-7.48(m,2H),7.20(td,J=8.8,2.5Hz,1H),6.81(s,1H),6.68(s,1H),5.19(dd,J=13.8,4.1Hz,1H),4.61(t,J=6.1Hz,3H),4.19-4.06(m,2H),3.92(d,J=6.8Hz,6H),3.71(s,3H),3.43-3.31(m,1H),3.21-2.99(m,2H),3.02-2.75(m,2H),2.75(dt,J=15.6,2.3Hz,1H),2.05-1.97(m,4H).13CNMR(125MHz,CDCl3δC 163.79,161.99,160.49,152.32,148.06,147.63,145.14,140.00,139.72,139.64,129.30,129.17,127.84,125.15,124.43,123.73,123.66,115.00,114.80,112.94,112.29,110.60,109.98,109.80,73.06,68.06,60.06,56.00,55.97,31.46,30.73,30.22,29.72,25.50,24.00.实施例14
5-((6-(5-氟)苯并噻吩基-2-羰基)-1,2,10-三甲氧基-5,6,6a,7-四氢-4H-并苯[de,g]喹啉-9-氧基)硝酸戊酯(化合物I14)的合成
参照实施例1化合物I1的制备方法,以等摩尔量的5-氟-苯并噻吩-2-甲酸替代N-甲基吲哚-2-甲酸、等摩尔量的1,5-二溴戊烷替代1,2-二溴乙烷,其他条件不变,经硅胶柱层析(洗脱剂为PE:EA=6:1V/V)制得目标化合物I14,白色固体,产率93%。
HRMS(ESI)calculated for C33H34FN2O8S[M+H]+:637.2020,found 637.2015.
1H NMR(400MHz,CDCl3)δH 8.19(s,1H),7.81(dd,J=8.9,4.7Hz,1H),7.53-7.47(m,2H),7.20(td,J=8.8,2.5Hz,1H),6.81(s,1H),6.68(s,1H),5.19(dd,J=13.7,4.0Hz,1H),4.52(t,J=6.6Hz,2H),4.15-3.99(m,2H),3.93(d,J=3.8Hz,6H),3.71(s,3H),3.38(t,J=12.3Hz,1H),3.16-2.88(m,3H),2.80-2.71(m,1H),1.94(dt,J=14.6,6.6Hz,2H),1.85(dd,J=15.1,6.8Hz,2H),1.68-1.62(m,2H).13C NMR(125MHz,Chloroform-d)δC163.79,160.06,152.32,147.83,140.03,139.72,139.64,135.57,129.30,129.15,127.89,125.15,124.36,124.20,123.74,123.66,115.01,114.80,112.77,112.26,110.55,109.98,109.80,73.21,68.39,60.06,56.03,56.00,31.46,30.73,30.22,29.73,28.74,26.60,22.48.
实施例15
6-((6-(5-氟)苯并噻吩基-2-羰基)-1,2,10-三甲氧基-5,6,6a,7-四氢-4H-并苯[de,g]喹啉-9-氧基)硝酸己酯(化合物I15)的合成
参照实施例1化合物I1的制备方法,以等摩尔量的5-氟-苯并噻吩-2-甲酸替代N-甲基吲哚-2-甲酸、等摩尔量的1,6-二溴己烷替代1,2-二溴乙烷,其他条件不变,经硅胶柱层析(洗脱剂为PE:EA=6:1V/V)制得目标化合物I15,白色固体,产率93%。
HRMS(ESI)calculated for C34H36FN2O8S[M+H]+:651.2176,found 651.2171.
1H NMR(400MHz,CDCl3)δH 8.16(s,1H),7.79(dd,J=8.9,4.7Hz,1H),7.48(d,J=10.8Hz,2H),7.18(td,J=8.8,2.5Hz,1H),6.79(s,1H),6.65(s,1H),5.18(d,J=13.4Hz,1H),4.47(t,J=6.7Hz,2H),4.06(q,J=8.2,6.8Hz,2H),3.90(d,J=3.4Hz,6H),3.68(s,3H),3.38(d,J=13.3Hz,1H),3.17-2.85(m,4H),2.79-2.59(m,1H),1.89(t,J=7.0Hz,2H),1.78(t,J=7.1Hz,2H),1.57-1.48(m,4H).13C NMR(125MHz,CDCl3)δC 163.78,159.20,152.32,147.96,147.93,140.05,139.72,139.65,135.57,129.29,129.15,127.92,125.15,124.35,124.06,123.74,123.66,115.01,114.80,112.67,112.23,110.52,109.98,109.80,73.32,68.56,60.05,56.03,56.00,31.46,30.73,30.22,29.72,28.99,26.74,25.69,25.49.
实施例16
化合物毒性及神经细胞保护活性测试
采用四甲基氮唑蓝比色法(MTT法)对化合物I1-化合物I15进行毒性及神经细胞保护活性测试,首先评价化合物对大鼠肾上腺嗜铬细胞瘤细胞PC12的细胞毒性;然后检测化合物I1~I15对皮质酮(corticosterone,CORT)诱导的PC12细胞损伤的存活率。
仪器:Direct-Q with pump超纯水仪(Millopore),POLARstar多功能酶标仪(Omega),Heracell VIOS160i恒温CO2培养箱(Thermo),MiniSpin离心机(Thermo)。
试剂:DMEM不完全(高糖)培养基(含双抗,凯基生物),胎牛血清(BI),l×PBS(0.01M,pH=7.4,凯基生物),胰蛋白酶-EDTA消化液(凯基生物),胰蛋白酶消化液(不含EDTA,凯基生物),四甲基噻唑蓝(MTT,凯基生物),Cell Counting Kit-8(CCK-8,碧云天生物)。
细胞株:大鼠肾上腺嗜铬细胞瘤细胞PC12。
细胞毒性评价:取复苏液氮中冻存的细胞株,水浴37℃快速融化,接种于培养瓶中,置于CO2培养箱中37℃恒温培养,隔天更换培养基(含10%胎牛血清的DMEM完全培养基),待细胞生长至80%后传代,细胞稳定培养三代后,取指数生长期且状态良好的细胞铺板,弃去旧培养基,PBS轻轻洗涤一次,加入1mL胰蛋白酶-EDTA消化液消化细胞,显微镜下观察细胞刚变圆时,加入1mL对应的完全培养基中止,轻轻吹打并悬浮细胞移至离心管,1000rpm离心5min,弃去上清,加入新鲜的完全培养基悬浮细胞,计数,调整细胞密度为5×104/mL,接种于96孔板上(100μL/孔),置于恒温CO2培养箱中培养24h。
用对应的完全培养基配制不同浓度含有阳性对照药、待测化合物的含药培养基,用新鲜含药完全培养基替换96孔板中的旧培养基,每个浓度设置3个复孔,继续培养24h,以加入等量DMSO的完全培养基为空白对照组。避光条件下,在96孔板中加入MTT试剂(10μL/孔),继续培养4h。弃去含MTT培养基,加入DMSO(150μL/孔)并轻轻振摇溶解结晶,570nm处测吸光度(OD值),计算细胞抑制率。
细胞抑制率%=[(空白对照OD值-给药组OD值)/空白对照组OD值]×100%
结果如表1所示,所有化合物对PC12细胞均没有表现出明显细胞毒性(IC50>10μM)。
表1.化合物对PC12细胞的IC50
采用皮质酮诱导PC12细胞损伤,进行抗抑郁药物筛选,该方法是目前学术界常用的抗抑郁药物筛选及研究的细胞模型。
按“细胞毒性评价”方法将PC12细胞接种于96孔板(5×104/mL,100μL/孔),置于恒温CO2培养箱中培养24h,设立空白组(含不完全培养基,无细胞),对照组(含不完全培养基),模型组(含皮质酮的不完全培养基,皮质酮终浓度200μM),给药组(同时含皮质酮、化合物I1-I15的不完全培养基,皮质酮终浓度200μM,化合物I1-化合物I15终浓度1μM),按照分组进行不同处理:空白组与对照组更换新鲜不完全培养基;模型组加入200μM含皮质酮的不完全培养基;给药组给予含有不同药物与皮质酮的不完全培养基,继续孵育24h。24h后加入10%体积(10μL/孔)CCK-8试剂共孵育1h,450nm处测定吸光度(OD值),计算细胞活力。
细胞存活率%=(给药组OD值/空白对照组OD值)×100%
结果见图1,除化合物I2、I3外,其余化合物对皮质酮诱导的细胞损伤都有较好的保护活性,且化合物对皮质酮诱导的细胞损伤的保护活性优于阿朴菲(式IV);其中以化合物I11-I15整体活性较佳。化合物I2、I3与模型组相比没有统计学上的显著性差异,说明不能改善抑郁症,但并非加重抑郁症。
综上,说明本发明阿朴菲生物碱衍生物毒副作用小,且有较好的神经保护活性,提示本发明阿朴菲衍生物有潜在的抗抑郁药效,有良好的开发前景。
实施例17
化合物的小鼠体内抗抑郁药效评价
采用慢性不可预见性温和应激(Chronic Unpredictable Mild Stress,CUMS)抑郁模型对药物抗抑郁活性进行体内验证,CUMS是将动物连续暴露于一系列不可预知的温和的压力来模拟一系列生活应激事件,其模拟的是人们每天生活中遇到的众多不可预测的温和刺激,主要以躯体应激为主。研究报道CUMS所引起的动物抑郁样症状与人类抑郁症患者所表现出的症状相类似。其诱导的行为和神经生化改变具有较好的稳定性,是目前最有效和使用最广泛的抑郁症动物模型之一,常用来筛选抗抑郁药物。
采用旷场试验(Open-field test,OFT)、悬尾实验(Tail suspension test,TST)、强迫游泳实验(Forced swimming test,FST),在慢性不可预见性温和应激诱导抑郁模型小鼠上进行化合物I15体内抗抑郁活性测试,选取氟西汀作为阳性药。
实验动物:C57小鼠40只,雄性,体重18-20g,购自南京青龙山动物场。
受试药物:氯化钠注射液购自安徽双鹤药业,盐酸氟西汀、化合物I15。
实验器材:自主活动箱(长50cm,宽50cm,高50cm)、圆柱形强迫游泳容器(直径10cm、高20cm)北京众实迪创科技有限公司ZS行为学分析仪器。
实验方法:受试动物12h明暗交替光照(6:00开灯,18:00关灯),饲养温度(25±2)℃,湿度50±20%,水和垫料每2d定期更换,自由摄食饮水,每笼5只。适应性饲养5d后,将小鼠分为空白对照组(Control,8只)和CUMS组(32只),CUMS组造模5周,造模方式和造模日程如表2和表3所示,空白对照组自主活动。
表2.造模方式
表3.造模日程
造模结束后,将CUMS组小鼠随机分为4组,即模型组(Model,8只)、阳性药组(8只,氟西汀10mg/kg)、化合物I15低剂量组(8只,5mg/kg),化合物I15高剂量组(8只,10mg/kg),阳性药组、化合物I15低剂量组、化合物I15高剂量组小鼠按照10mL/kg灌胃给药,每日一次,连续给药两周,模型组和空白对照组小鼠灌胃给予等体积氯化钠注射液。
化合物I15用含0.01% DMSO的氯化钠注射液溶解,氟西汀用氯化钠注射液溶解,配制浓度满足小鼠最终给药体积10mL/kg。
观察指标:
A.旷场实验:末次给药1h后进行小鼠旷场试验以检测动物的自主活动情况。本实验采用小鼠旷场检测系统,测试前动物先于测试房间内适应1h,随后逐只被放入封闭的自主活动箱(长50cm,宽50cm,高50cm)内,先适应1min,然后记录其5min内自主活动的总路程、运动时间、运动速度等指标。实验过程尽量保持安静,防止外界噪音对小鼠造成惊吓,扰乱运动轨迹。每只动物测试结束后需记录每只小鼠粪便数,然后用70%乙醇擦拭自主活动箱,挥发完全以后再放入下一只待测试小鼠,以避免其受前一只小鼠气味的干扰。测定全部完成后,使用诺达思EthoVision XT 11.5动物运动轨迹跟踪系统分析小鼠移动距离、移动速度、直立数等参数。
B.强迫游泳不动实验:次给药1h后,将小鼠放入圆柱形强迫游泳容器(直径10cm,高20cm,水深15cm)中,保持水温25℃。动物适应1min后,计算机图像实时检测分析处理系统自动记录动物随后4min内的累积不动时间(小鼠停止挣扎或漂浮在水上,仅有细微的动作以保持头部在水面以上被认定为不动)。
C.悬尾实验:末次给药1h后进行小鼠悬尾实验,将胶布固定于距小鼠尾尖约1cm处,并悬挂于仪器上部支架,使小鼠倒悬于悬尾箱中。测试时长总共6min,适应2min后,以诺达思EthoVision XT 11.5动物运动轨迹跟踪系统记录小鼠后4min的不动时间。
结果见图2。旷场实验(OFT)中,总路程及移动速度反映小鼠自主活动状态。与空白对照组小鼠比,模型组小鼠移动总路程和移动速度都显著降低,提示造模成功;与模型组小鼠比,化合物I15组和阳性药组小鼠移动总路程和移动速度都显著增加,提示化合物I15有效,且高剂量化合物I15抗抑郁药效优于等剂量的氟西汀。悬尾实验(TST)与强迫游泳不动(FST)实验中,小鼠不动时间反映其抑郁状态。与空白对照比,模型组小鼠静止时间都显著提高,提示造模成功;与模型组小鼠比,化合物I15组和阳性药组小鼠不动时间都显著减少,提示化合物I15有效,且化合物I15药效优于阳性药氟西汀。
Claims (10)
1.结构如式I所示的阿朴菲类生物碱衍生物:
其中,R选自n为2~10的整数;但不包括:R选自/>n为2、3。
2.根据权利要求1所述的阿朴菲类生物碱衍生物,其特征在于:n为2~6的整数;但不包括:R选自n为2、3。
3.根据权利要求2所述的阿朴菲类生物碱衍生物,其特征在于:R选自n为2、3、6。
4.结构如下所示的阿朴菲类生物碱衍生物:
5.一种权利要求1所述的阿朴菲类生物碱衍生物的制备方法,其特征在于:反应路线如下:
其中,R、n如权利要求1所述;
包括以下步骤:
步骤(1)、反应溶剂选自N,N-二甲基甲酰胺,在缚酸剂存在的条件下,在催化剂作用下,式IV所示的阿朴菲与RCOOH发生酰胺缩合反应,得到中间体III;所述的催化剂为EDCI、HoBt;所述的缚酸剂为三乙胺、DIEA、吡啶、醋酸钠、碳酸钠、碳酸钾;
步骤(2)、反应溶剂选自乙腈,在催化剂作用下,中间体III与式所示的双取代溴烷反应,得到中间体II;所述的催化剂为碳酸铯;
步骤(3)、反应溶剂选自乙腈,在避光条件下,中间体II与硝酸银反应,得到式I所示的阿朴菲类生物碱衍生物。
6.根据权利要求5所述的阿朴菲类生物碱衍生物的制备方法,其特征在于:步骤(1)中,所述的阿朴菲和RCOOH的摩尔比为1:1~1.1:1;
所述的阿朴菲和EDCI的摩尔比为1:2~1:4;阿朴菲和HoBt的摩尔比为1:2~1:3.5;
所述的阿朴菲和缚酸剂的摩尔比为1:2~1:6;
酰胺缩合反应的温度为-20~4℃。
7.根据权利要求5所述的阿朴菲类生物碱衍生物的制备方法,其特征在于:步骤(2)中,所述的中间体III和双取代溴烷的摩尔比为1:1.8~1:5;
所述的中间体III和催化剂的摩尔比为1:2~1:3.5;
反应温度为60℃~80℃。
8.根据权利要求5所述的阿朴菲类生物碱衍生物的制备方法,其特征在于:步骤(3)中,所述的中间体II与AgNO3的摩尔比为1:1.5~1:2.5;
反应温度为60℃~75℃。
9.权利要求1-4任一项所述的阿朴菲类生物碱衍生物在制备抗抑郁药物中的应用。
10.权利要求1-4任一项所述的阿朴菲类物生碱衍生物在制备神经保护药物中的应用。
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