WO2023137962A1 - 一种氧化异阿朴菲生物碱衍生物及其制备方法和抗抑郁用途 - Google Patents

一种氧化异阿朴菲生物碱衍生物及其制备方法和抗抑郁用途 Download PDF

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WO2023137962A1
WO2023137962A1 PCT/CN2022/099301 CN2022099301W WO2023137962A1 WO 2023137962 A1 WO2023137962 A1 WO 2023137962A1 CN 2022099301 W CN2022099301 W CN 2022099301W WO 2023137962 A1 WO2023137962 A1 WO 2023137962A1
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oxidized
preparation
alkaloid
alkaloid derivative
isoaporphine
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孙建博
孙晓娜
吴贤殊
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中国药科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/18—Ring systems of four or more rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

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  • the invention belongs to the field of medicinal chemistry, and in particular relates to an oxidized isoaporphine derivative, a preparation method thereof and an application in the preparation of antidepressant drugs.
  • Depression is a mental disorder with persistent depressed mood as the main clinical symptom.
  • the main clinical manifestations are depression, anxiety, hysteresis and various physical discomfort symptoms, loss of interest in pleasant things, guilt or worthlessness, and even suicidal ideation and behavior in severe cases.
  • Depression is sometimes accompanied by symptoms such as decreased energy, changes in appetite, more or less sleep, anxiety, decreased concentration, and restlessness.
  • the etiology and pathogenesis of depression have not yet been fully elucidated. Low content of central norepinephrine, serotonin, dopamine and other monoamine neurotransmitters and low receptor function are considered to be the cause of depression.
  • antidepressant drugs available clinically, but there are still quite a few patients who do not have the expected therapeutic response to some classic antidepressant drugs or even "blockbuster” drugs such as imipramine, fluoxetine, citalopram, and venlaxine. In addition, longer treatment cycles of drugs often lead to poorer patient compliance. How to avoid or reduce the side effects of antidepressant drugs is also one of the main goals of current antidepressant drug research. Therefore, it is of great significance to develop antidepressant drugs with a new mechanism of action. In recent decades, the neuroprotective or restorative effects of antidepressants have been widely reported, and this neuroprotective or restorative effect is expected to become a new mechanism of action for the treatment of mental disorders [1-2] .
  • the object of the present invention is to provide a kind of oxidized isoapomorphine alkaloid derivative and its preparation method and medical application.
  • R 1 and R 2 are independently selected from H, F, Cl, and methoxy; n is an integer of 2-6.
  • R 1 is selected from H, F, Cl, and methoxy
  • R 2 is selected from H, Cl
  • n is an integer of 2-6.
  • R 1 is selected from F
  • R 2 is selected from H
  • n is an integer of 2-6.
  • oxidized isoaporphine alkaloid derivative is selected from the following compounds:
  • Another object of the present invention is to provide a kind of preparation method of described oxidized isoapomorphyl alkaloid derivatives, the reaction scheme is as follows:
  • R 1 , R 2 , and n are as described above.
  • Step (2) under catalyst action, intermediate II and Reaction, obtains the oxidized isoaporphyl alkaloid derivative shown in general formula I.
  • step (1) the molar ratio of the 5-hydroxy-1-azabenzanthrone to the disubstituted bromoalkane is 1:1.8 ⁇ 1:5.
  • the molar ratio of the 5-hydroxyl-1-azabenzanthrone to potassium carbonate is 1:1.5 ⁇ 1:3.5; the catalyst is potassium carbonate.
  • the reaction solvent is selected from acetone and acetonitrile.
  • the reaction temperature is 50°C to 75°C.
  • step (2) intermediate II and The molar ratio is 1:1.5 ⁇ 1:2.
  • the catalyst is selected from the combination of potassium carbonate and potassium iodide, the molar ratio of potassium carbonate and potassium iodide is 6:1; the molar ratio of the catalyst and intermediate II is 1:1.5-1:3.5.
  • the reaction solvent is selected from acetone or acetonitrile.
  • the reaction temperature is 50°C to 75°C.
  • N-phenylpiperazine 1-(2,3-dichlorophenyl)piperazine, 1-(2-methoxyphenyl)piperazine, 1-(2-fluorophenyl)piperazine, 1-(2-chlorophenyl)piperazine.
  • the in vitro activity experiment shows that the oxidized isoapophyl alkaloid derivatives of the present invention have good protective activity against corticosterone-induced PC12 cell damage, indicating that corticosterone-induced PC12 cell damage has a neuroprotective function; and in vivo antidepressant drug efficacy evaluation shows that the oxidized isoapophyl alkaloid derivatives can significantly increase the moving distance and moving speed in the open field test, and significantly shorten the immobility time in the tail suspension test and forced swimming immobility test, indicating that it can significantly improve the depression state.
  • Another object of the present invention is to provide the application of the oxidized isoaphil alkaloid derivatives in the preparation of antidepressants.
  • Another object of the present invention is to provide the application of the oxidized isoapomorphine alkaloid derivatives in the preparation of neuroprotective drugs.
  • the method of the invention for preparing the oxidized isoaportalkaloid derivative has mild reaction conditions, the reagents used are low-toxic, the raw materials are easy to obtain, the post-treatment is convenient, and the yield is high.
  • the oxidized isoapomorphine alkaloid derivative of the present invention has good protective activity against corticosterone-induced PC12 cell damage, and the in vivo antidepressant drug efficacy evaluation shows that it can significantly improve the depression state, and the oxidized isoapofil derivative of the present invention is expected to become an antidepressant drug with research prospects.
  • Figure 1 is the survival rate of PC12 cells co-treated with compound (0.5 ⁇ M/mL) and corticosterone (500 ⁇ M/mL).
  • Figure 2 shows the antidepressant efficacy results of compound I 14 in vivo; where, A: the total distance moved by the mice in the open field test; B: the moving speed of the mice in the open field test; C: the immobility time of the mice in the forced swimming test; D: the immobile time of the mice in the tail suspension test.
  • A the total distance moved by the mice in the open field test
  • B the moving speed of the mice in the open field test
  • C the immobility time of the mice in the forced swimming test
  • D the immobile time of the mice in the tail suspension test.
  • P ⁇ 0.001 refers to the significant difference between the model group and the blank group
  • ** P ⁇ 0.001 refers to the significant difference between the drug treatment group and the model group.
  • the toxicity and nerve cell protection activity of compounds I 1 to I 15 were tested by the tetramethylazolium blue colorimetric method (MTT method).
  • MTT method tetramethylazolium blue colorimetric method
  • DMEM incomplete (high glucose) medium with double antibodies, KGI
  • DMEM-F12 incomplete medium with double antibodies, KGI
  • RPMI-1640 incomplete medium with double antibodies, KGI
  • BI fetal bovine serum
  • KGI trypsin-EDTA digestion solution
  • MI trypsin digestion solution
  • MTT tetramethylthio Zolidine Blue
  • Cytotoxicity evaluation Resuscitate the cell lines frozen in liquid nitrogen, thaw quickly in a water bath at 37°C, inoculate in a culture bottle, and place in CO 2 Culture in an incubator at a constant temperature of 37°C, replace the medium every other day (LO2 cells use DMEM complete medium containing 10% fetal bovine serum, SH-SY5Y cells use DMEM-F12 complete medium containing 10% fetal bovine serum, PC12 cells use RPMI-1640 complete medium containing 10% fetal bovine serum), take the cells in the exponential growth phase and in good condition to plate, discard the old medium, gently wash once with PBS, add 1 mL of trypsin-EDTA digestion solution to digest the cells, and observe under the microscope When the cells just become round, add 1mL of the corresponding complete medium to stop, gently pipette and suspend the cells, move them to a centrifuge tube, centrifuge at 1000rpm for 5min, discard the supernatant, add fresh complete medium to suspend the cells, count,
  • the corresponding complete medium was used to prepare different concentrations of drug-containing medium containing positive control drugs and the compounds to be tested.
  • the complete medium added with the same amount of DMSO was used as the blank control group, and the old medium in the 96-well plate was replaced with fresh drug-containing complete medium.
  • Three replicate wells were set and the culture continued for 24 hours. Under dark conditions, MTT reagent (10 ⁇ L/well) was added to the 96-well plate, and culture was continued for 4 h. Discard the MTT-containing medium, add DMSO (150 ⁇ L/well) and shake gently to dissolve the crystals, measure the absorbance (OD value) at 570 nm, and calculate the cell inhibition rate.
  • the formula for calculating the cell inhibition rate is:
  • Cell inhibition rate% [(OD value of blank control – OD value of administration group)/OD value of blank control group] ⁇ 100%
  • ⁇ CORT ⁇ PC12 ⁇ ⁇ PC12 ⁇ 96 ⁇ (5 ⁇ 10 4 /mL,100 ⁇ L/ ⁇ ) ⁇ CO 2 ⁇ 24h, ⁇ , ⁇ ( ⁇ 500 ⁇ M/mL) ⁇ ( ⁇ 0.5 ⁇ M/mL) ⁇ RPMI-1640- ⁇ 24h, ⁇ DMSO ⁇ , ⁇ ( ⁇ 500 ⁇ M/mL) ⁇ DMSO ⁇
  • MTT method was used to measure cell viability, and the formula for calculating cell viability was:
  • Protection rate% cell survival rate of administration group - cell survival rate of model group
  • oxidized isoaportalkaloid derivatives of the present invention have less toxic and side effects, have better neuroprotective activity, and have good development prospects.
  • compound Protection rate (%) compound Protection rate (%) I 1 12.13 ⁇ 0.37 i 9 19.64 ⁇ 0.60 I 2 8.33 ⁇ 0.80 I 10 8.56 ⁇ 0.85 I 3 14.46 ⁇ 0.94 I 11 5.55 ⁇ 0.43 I 4 21.24 ⁇ 0.63 I 12 11.05 ⁇ 0.46 I 5 15.70 ⁇ 0.75 I 13 12.30 ⁇ 0.74 I 6 11.30 ⁇ 0.85 I 14 27.40 ⁇ 0.75 I 7 10.96 ⁇ 0.16 I 15 8.57 ⁇ 0.91
  • Open-field test OFT
  • tail suspension test TST
  • forced swimming test Force swimming test
  • mice 32 ICR mice, male, weighing 18-20 g, purchased from Nanjing Qinglongshan Animal Farm.
  • Test drugs Sodium chloride injection was purchased from Anhui Shuanghe Pharmaceutical, fluoxetine hydrochloride and reserpine were purchased from sigma, compound I 14 .
  • mice were subjected to 12 hours of alternating light and dark light (turn on the light at 6:00 and turn off the light at 18:00), rearing temperature (25 ⁇ 2)°C, humidity 50% ⁇ 20%, water and litter regularly changed every 2 days, free to eat and drink, 5 animals per cage.
  • the mice were divided into a blank control group (8 mice) and a reserpine group (24 mice).
  • the reserpine group was injected intraperitoneally with reserpine (0.2 mg/kg) for 3 consecutive days to create a depression model, and the blank control group was injected with normal saline intraperitoneally.
  • mice in the reserpine group were randomly divided into 3 groups, namely the model group (8 mice), the positive drug group (8 mice, fluoxetine 20 mg/kg), and the compound I 14 group (8 mice, 20 mg/kg). Each group was administered intraperitoneally at 10 mL/kg, once a day, for one week continuously.
  • Reserpine was dissolved in normal saline containing 0.2% acetic acid, compound I 14 was dissolved in normal saline containing 0.01% DMSO, fluoxetine was dissolved in normal saline, and the prepared concentration met the final administration volume of 10 mL/kg for mice.
  • A. Open field test 1 hour after the last administration, the mouse OFT was performed to detect the autonomous activities of the animals.
  • the mouse open-field detection system was used. Before the test, the animals were first acclimatized in the test room for 1 hour, and then put into a closed autonomous activity box (length 50cm, width 50cm, height 50cm) one by one, first adapted for 1 minute, and then recorded the total distance, movement time, movement speed and other indicators of their voluntary activities within 5 minutes. After the test of each animal, the empty field box needs to be cleaned (wiped with 70% ethanol and evaporated), so as to avoid being disturbed by the breath of the previous animal.
  • mice were put into a cylindrical forced swimming container (diameter 10 cm, height 20 cm, water depth 15 cm), and the water temperature was kept at 25°C. After the animals adapted for 1 min, the computer image real-time detection and analysis processing system automatically recorded the cumulative immobility time of the animals within the next 4 min (the mice stopped struggling or floated on the water, and only slight movements to keep the head above the water surface were considered as immobile).
  • the immobility time of the mice in the model group was significantly increased, suggesting that the modeling was successful; compared with the model group, the immobility time of the compound I 14 group and the positive drug group were significantly reduced, suggesting that the drug was effective, and the drug effect of the compound I 14 was slightly better than that of the positive drug fluoxetine.

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Abstract

本发明公开了结构如式I所示的氧化异阿朴菲生物碱衍生物，R 1、R 2分别独立的选自H、F、Cl、甲氧基；n为2～6的整数。体外活性实验表明，所述的氧化异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，说明皮质酮诱导的PC12细胞损伤具有神经保护功能；且体内抗抑郁药效评价表明，氧化异阿朴菲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。本发明还公开了供所述的氧化异阿朴菲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氧化异阿朴菲生物碱衍生物在制备神经保护药物中的应用。

Description

一种氧化异阿朴菲生物碱衍生物及其制备方法和抗抑郁用途 技术领域
本发明属于药物化学领域，具体涉及一种氧化异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。
背景技术
抑郁症是一种以持久的抑郁心境为主要临床症状的精神障碍，临床表现以情绪低落、焦虑、迟滞和繁多的躯体不适症状为主，对愉快事物的兴趣丢失，有罪恶感或无价值感，严重时甚至会产生自杀观念和行为。抑郁症有时还有一些伴随症状，如精力减退、食欲改变、睡眠更多或更少、焦虑、注意力下降、躁动等。抑郁症的病因和发病机制至今尚未完全阐明。中枢去甲肾上腺素、羟色胺、多巴胺等单胺类神经递质含量过低及其受体功能低下等都被认为是引起抑郁症的原因。
当前，临床可用的抗抑郁药物品种不少，但是仍然有相当一部分患者对一些经典的抗抑郁药物甚至是丙咪嗪、氟西汀、西酞普兰、文法拉辛这样的“重磅炸弹”药物没有预期的治疗反应。此外，药物较长的治疗周期往往也会导致患者较差的顺应性。如何避免或减轻抗抑郁药物的副作用也是当前抗抑郁药物研究的主要目标之一。因此，开发具有全新作用机制的抗抑郁药物意义重大。近几十年以来，抗抑郁药物的神经保护或修复作用被广泛报道，这种神经保护或修复作用有望成为全新的治疗精神疾病的作用机制 [1-2]。
参考文献：
[1]王叶情等.槲皮素及其糖苷衍生物抗抑郁作用及其机制的研究进展[J].Chinese Traditional and Herbal Drugs.2021(52):1-10.
[2]Zhong-Xuan Ma,etal.Quercetin alleviates chronic unpredictable mild stress-induced depressive-like behaviors by promoting adulthippocampal neurogenesis via FoxG1/CREB/BDNF signaling pathway[J].Behavioural BrainResearch.2021(406):113245.
发明内容
本发明的目的在于提供一种氧化异阿朴菲生物碱衍生物及其制备方法与医药用途。
本发明的目的是通过以下技术方案实现的：
结构如通式I所示的氧化异阿朴菲生物碱衍生物：
Figure PCTCN2022099301-appb-000001
其中，R 1、R 2分别独立的选自H、F、Cl、甲氧基；n为2～6的整数。
优选的，R 1选自H、F、Cl、甲氧基，R 2选自H、Cl；n为2～6的整数。
更优选的，R 1选自F，R 2选自H；n为2～6的整数。
具体的，所述的氧化异阿朴菲生物碱衍生物选自下列化合物：
Figure PCTCN2022099301-appb-000002
本发明的另一目的在于提供一种所述的氧化异阿朴菲生物碱衍生物的制备方法，反应路线如下：
Figure PCTCN2022099301-appb-000003
其中，R 1、R 2、n如前所述。
包括：
步骤(1)、在催化剂作用下，5-羟基-1-氮杂苯并蒽酮与式
Figure PCTCN2022099301-appb-000004
所示的双取代溴烷反应，得到中间体Ⅱ；
步骤(2)、在催化剂作用下，中间体Ⅱ与
Figure PCTCN2022099301-appb-000005
反应，得到通式I所示的氧化异阿朴菲生物碱衍生物。
步骤(1)中，所述的5-羟基-1-氮杂苯并蒽酮和双取代溴烷的摩尔比为1:1.8～1:5。
所述的5-羟基-1-氮杂苯并蒽酮和碳酸钾的摩尔比为1:1.5～1:3.5；所述的催化剂为碳酸钾。
反应溶剂选自丙酮、乙腈。
反应温度为50℃～75℃。
反应结束后，减压干燥除去溶剂，以PE:EA＝10:1～8:1(V:V)为洗脱剂，经硅胶柱层析纯化得到中间体Ⅱ。
步骤(2)中，中间体Ⅱ与
Figure PCTCN2022099301-appb-000006
的摩尔比为1:1.5～1:2。
所述的催化剂选自碳酸钾和碘化钾的组合，碳酸钾和碘化钾的摩尔比为6:1；所述的催化剂和中间体Ⅱ的摩尔比为1:1.5～1:3.5。
反应溶剂选自丙酮或乙腈。
反应温度为50℃～75℃。
反应结束后，减压干燥除去溶剂，以DCM:MeOH＝50:1～10:1(V:V)为洗脱剂，经硅胶柱层析纯化得到通式I所示的氧化异阿朴菲生物碱衍生物。
具体的，
Figure PCTCN2022099301-appb-000007
选自N-苯基哌嗪，1-(2,3-二氯苯基)哌嗪，1-(2-甲氧苯基)哌嗪，1-(2-氟苯基)哌嗪，1-(2-氯苯基)哌嗪。
体外活性实验表明，本发明所述的氧化异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，说明皮质酮诱导的PC12细胞损伤具有神经保护功能；且体内抗抑郁药效评价表明，氧化异阿朴菲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氧化异阿朴菲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氧化异阿朴菲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：
本发明制备氧化异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。
本发明氧化异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，且体内抗抑郁药效评价表明，能够显著改善抑郁状态，本发明氧化异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(0.5μM/mL)与皮质酮(500μM/mL)共处理PC12细胞的存活率。
图2为化合物I 14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＜0.001指模型组与空白组间的显著性差异， **P＜0.001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1：5-[[1-(2-氯苯基)哌嗪]乙氧基]-1-氮杂苯并蒽酮(化合物I 1)的合成
反应式如下：
Figure PCTCN2022099301-appb-000008
将5-羟基-1-氮杂苯并蒽酮(247mg,1mmol,1eq)溶于10ml丙酮，加入K 2CO 3(207mg,1.5mmol，1.5eq)和1,2-二溴乙烷(335mg,1.8mmol,1.8eq)，50℃搅拌过夜，停止反应，减压干燥除去溶剂，经硅胶柱色谱(洗脱剂为PE:EA＝8:1V:V)纯化得到中间体5-(2-溴乙氧基)-1-氮杂苯并蒽酮；再将5-(2-溴乙氧基)-1-氮杂苯并蒽酮(141mg,0.4mmol,1eq)加入反应瓶，用10ml乙腈溶解，加入K 2CO 3(166mg,1.2mmol,3eq)、KI(33mg,0.2mmol,0.5eq)及1-(2-氯苯基)哌嗪(157mg,0.8mmol,2eq)，60℃搅拌过夜，停止反应，减压干燥除去溶剂，经硅胶柱色谱(洗脱剂为DCM:MeOH＝20:1V:V)纯化得到化合物I 1，黄色固体，产率70％。
ESI-MS：470.2.[M+H] +。
1H NMR(500MHz,CDCl 3)δ8.88(d,J＝7.8Hz,1H),8.68(d,J＝5.4Hz,1H),8.40(d,J＝7.7Hz,1H),8.29(d,J＝1.9Hz,1H),7.80(t,J＝7.3Hz,1H),7.63(dd,J＝13.3,6.4Hz,2H),7.43(d,J＝1.7Hz,1H),7.36(d,J＝7.8Hz,1H),7.22(t,J＝7.2Hz,1H),7.06(d,J＝7.8Hz,1H),6.97(t,J＝7.2Hz,1H),4.38(t,J＝4.7Hz,2H),3.14(s,4H),3.03(t,J＝4.5Hz,2H),2.86(s,4H).
实施例2：5-[[1-(2-甲氧苯基)哌嗪]乙氧基]-1-氮杂苯并蒽酮(化合物I 2)的合成
反应式如下：
Figure PCTCN2022099301-appb-000009
参照化合物I 1的制备方法，以1-(2-甲氧苯基)哌嗪替换化合物1-(2-氯苯基)哌嗪，其他条件不变，经硅胶柱层析(洗脱剂为DCM:MeOH＝30:1V:V)制得目标化合物I 2，黄色固体，产率61％。
ESI-MS：466.2.[M+H] +。
1H NMR(500MHz,CDCl 3)δ8.88(d,J＝7.7Hz,1H),8.68(d,J＝5.6Hz,1H),8.40(d,J＝7.2Hz,1H),8.29(d,J＝2.2Hz,1H),7.80(t,J＝7.0Hz,1H),7.63(dd,J＝12.8,6.3Hz,2H),7.43(d,J＝2.0Hz,1H),7.01(t,J＝7.4Hz,1H),6.97-6.91(m,2H),6.87(d,J＝7.6Hz,1H),4.40(t,J＝5.0Hz,2H),3.88(s,3H),3.17(s,4H),3.04(t,J＝5.0Hz,2H),2.89(s,4H).
实施例3：5-[[(2,3-二氯苯基)哌嗪]乙氧基]-1-氮杂苯并蒽酮(化合物I 3)的合成
反应式如下：
Figure PCTCN2022099301-appb-000010
参照化合物I 1的制备方法，以1-(2,3-二氯苯基)哌嗪替换化合物1-(2-氯苯基)哌嗪，其他条件不变，经硅胶柱层析(洗脱剂为DCM:MeOH＝25:1V:V)制得目标化合物I 3，黄色固体，产率58％。
ESI-MS：504.1[M+H] +。
1H NMR(500MHz,CDCl 3)δ8.88(d,J＝7.7Hz,1H),8.68(d,J＝5.5Hz,1H),8.40(d,J＝7.6Hz,1H),8.29(s,1H),7.81(t,J＝7.2Hz,1H),7.63(dd,J＝13.3,6.4Hz,2H),7.43(s,1H),7.15(d,J＝7.2Hz,2H),6.97(d,J＝5.3Hz,1H),4.38(s,2H),3.13(s,4H),3.03(s,2H),2.87(s,4H).
实施例4：5-[[1-(2-氟苯基)哌嗪]乙氧基]-1-氮杂苯并蒽酮(化合物I 4)的合成
反应式如下：
Figure PCTCN2022099301-appb-000011
参照化合物I 1的制备方法，以1-(2-氟苯基)哌嗪替换化合物1-(2-氯苯基)哌嗪，其他条件不变，经硅胶柱层析(洗脱剂为DCM:MeOH＝30:1V:V)制得目标化合物I 4，黄色固体，产率51％。
ESI-MS：454.2[M+H] +。
1H NMR(500MHz,CDCl 3)δ8.88(d,J＝7.7Hz,1H),8.68(d,J＝5.5Hz,1H),8.40(d,J＝7.6Hz,1H),8.29(s,1H),7.81(t,J＝7.2Hz,1H),7.63(dd,J＝13.3,6.4Hz,2H),7.43(s,1H),7.15(d,J＝7.2Hz,2H),6.97(d,J＝5.3Hz,1H),4.38(s,2H),3.13(s,4H),3.03(s,2H),2.87(s,4H).
实施例5：5-[(N-苯基哌嗪)乙氧基]-1-氮杂苯并蒽酮(化合物I 5)的合成
反应式如下：
Figure PCTCN2022099301-appb-000012
参照化合物I 1的制备方法，以N-苯基哌嗪替换化合物1-(2-氯苯基)哌嗪，其他条件不变，经硅胶柱层析(洗脱剂为DCM:MeOH＝20:1V:V)制得目标化合物I 5，黄色固体，产率55％。
ESI-MS：436.2[M+H] +。
1H NMR(500MHz,CDCl 3)δ8.89(d,J＝7.7Hz,1H),8.68(d,J＝5.6Hz,1H),8.40(d,J＝7.4Hz,1H),8.29(d,J＝2.2Hz,1H),7.81(t,J＝7.1Hz,1H),7.63(dd,J＝12.0,6.4Hz,2H),7.44(d,J＝2.0Hz,1H),7.28(d,J＝8.2Hz,2H),6.95(d,J＝7.9Hz,2H),6.87(t,J＝7.1Hz,1H),4.39(t,J＝5.2Hz,2H),3.27(s,4H),3.01(t,J＝5.2Hz,2H),2.83(s,4H).
实施例6：5-[[1-(2-氯苯基)哌嗪]丙氧基]-1-氮杂苯并蒽酮(化合物I 6)的合成
反应式如下：
Figure PCTCN2022099301-appb-000013
参照化合物I 1的制备方法，以1,3-二溴丙烷替换1,2-二溴乙烷，其他条件不变，经硅胶柱层析(洗脱剂为DCM:MeOH＝25:1V:V)制得目标化合物I 6，黄色固体，产率63％。
ESI-MS：484.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.86(1H,d,J＝8.0Hz),8.65(1H,d,J＝5.6Hz),8.39(1H,d,J＝7.9Hz),8.24(1H,d,J＝2.5Hz),7.83-7.77(m,1H),7.66-7.58(m,2H),7.39(d,J＝2.5Hz,1H),7.36(dd,J＝7.9,1.5Hz,1H),7.24-7.19(m,1H),7.06(dd,J＝8.1,1.5Hz,1H),7.00-6.94(m,1H),4.26(t,J＝6.3Hz,2H),3.12(s,4H),2.84-2.60(m,6H),2.17-2.10(m,2H).
实施例7：5-[[1-(2-氟苯基)哌嗪]丙氧基]-1-氮杂苯并蒽酮(化合物I 7)的合成
反应式如下：
Figure PCTCN2022099301-appb-000014
参照化合物I 1的制备方法，以1-(2-甲氧苯基)哌嗪替换1-(2-氯苯基)哌嗪，1,3-二溴丙烷替换1,2-二溴乙烷，其他条件不变，经硅胶柱层析(洗脱剂为DCM:MeOH＝35:1V:V)制得目标化合物I 7，黄色固体，产率46％。
ESI-MS：494.2[M+H] +。
1H NMR(500MHz,CDCl 3)δ8.89(d,J＝7.7Hz,1H),8.68(d,J＝5.6Hz,1H),8.40(d,J＝7.4Hz,1H),8.29(d,J＝2.2Hz,1H),7.81(t,J＝7.1Hz,1H),7.63(dd,J＝12.0,6.4Hz,2H),7.44(d,J＝2.0Hz,1H),7.28(d,J＝8.2Hz,2H),6.95(d,J＝7.9Hz,2H),6.87(t,J＝7.1Hz,1H),4.39(t,J＝5.2Hz,2H),3.27(s,4H),3.01(t,J＝5.2Hz,2H),2.83(s,4H).
实施例8：5-[[(2,3-二氯苯基)哌嗪]丙氧基]-1-氮杂苯并蒽酮(化合物I 8)的合成
反应式如下：
Figure PCTCN2022099301-appb-000015
参照化合物I 1的制备方法，以1-(2,3-二氯苯基)哌嗪替换1-(2-氯苯基)哌嗪，以1,3-二溴丙烷替换1,2-二溴乙烷，其他条件不变，经硅胶柱层析(洗脱剂为DCM:MeOH＝40:1V:V)制得目标化合物I 8，黄色固体，产率49％。
ESI-MS：518.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.88(d,J＝8.0Hz,1H),8.67(d,J＝5.6Hz,1H),8.40(d,J＝7.8Hz,1H),8.26(s,1H),7.84-7.78(m,1H),7.66-7.60(m,2H),7.42(d,J＝2.5Hz,1H),7.18-7.11(m,2H),6.97(dd,J＝6.8,2.8Hz,1H),4.28(t,J＝6.3Hz,2H),3.11(s,4H),2.83-2.60(m,6H),2.19-2.10(m,2H).
实施例9：5-[[1-(2-氟苯基)哌嗪]丙氧基]-1-氮杂苯并蒽酮(化合物I 9)的合成
反应式如下：
Figure PCTCN2022099301-appb-000016
参照化合物I 1的制备方法，以1-(2-氟苯基)哌嗪替换1-(2-氯苯基)哌嗪，1,3-二溴丙烷替换1,2-二溴乙烷，其他条件不变，经硅胶柱层析(洗脱剂为DCM:MeOH＝35:1V:V)制得目 标化合物I 9，黄色固体,产率52％。
ESI-MS：468.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.86(d,J＝7.9Hz,1H),8.65(d,J＝5.6Hz,1H),8.39(d,J＝7.8Hz,1H),8.24(d,J＝2.5Hz,1H),7.80(t,J＝7.6Hz,1H),7.66-7.58(m,2H),7.39(d,J＝2.5Hz,1H),7.09-6.92(m,4H),4.27(t,J＝6.3Hz,2H),3.21-3.11(m,4H),2.69(dd,J＝14.1,6.6Hz,6H),2.17-2.10(m,2H).
实施例10：5-[(N-苯基哌嗪)丙氧基]-1-氮杂苯并蒽酮(化合物I 10)的合成
反应式如下：
Figure PCTCN2022099301-appb-000017
参照化合物I 1的制备方法，以N-苯基哌嗪替换1-(2-氯苯基)哌嗪，1,3-二溴丙烷替换1,2-二溴乙烷，其他条件不变，经硅胶柱层析(洗脱剂为DCM:MeOH＝25:1V:V)制得目标化合物I 10，黄色固体，产率62％。
ESI-MS：450.2[M+H] +。
1H NMR(400MHz,CDCl3)δ8.88(d,J＝7.9Hz,1H),8.67(d,J＝5.6Hz,1H),8.40(d,J＝7.8Hz,1H),8.26(d,J＝2.5Hz,1H),7.86-7.77(m,1H),7.70-7.60(m,2H),7.42(d,J＝2.4Hz,1H),7.32-7.27(m,2H),6.99-6.84(m,3H),4.28(t,J＝6.1Hz,2H),3.26(d,J＝4.0Hz,4H),2.70(dd,J＝11.8,6.5Hz,6H),2.22-2.12(m,2H).
实施例11：5-[[1-(2-氯苯基)哌嗪]丁氧基]-1-氮杂苯并蒽酮(化合物I 11)的合成
反应式如下：
Figure PCTCN2022099301-appb-000018
参照化合物I 1的制备方法，1,4-二溴丁烷替换1,2-二溴乙烷，其他条件不变，经硅胶柱层析(洗脱剂为DCM:MeOH＝30:1V:V)制得目标化合物I 11，黄色固体，产率55％。
ESI-MS：498.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.86(d,J＝7.8Hz,1H),8.64(d,J＝5.6Hz,1H),8.38(d,J＝7.8Hz,1H),8.22(d,J＝2.5Hz,1H),7.79(t,J＝7.0Hz,1H),7.62(t,J＝7.1Hz,1H),7.58(d,J＝ 5.7Hz,1H),7.35(dd,J＝8.1,1.5Hz,2H),7.21(t,J＝7.7Hz,1H),7.04(d,J＝8.0Hz,1H),6.96(t,J＝7.6Hz,1H),4.21(t,J＝6.2Hz,2H),3.11(s,4H),2.70(s,4H),2.58-2.53(m,2H),1.99-1.92(m,2H),1.81(dd,J＝14.9,8.0Hz,2H).
实施例12：5-[[1-(2-甲氧苯基)哌嗪]丁氧基]-1-氮杂苯并蒽酮(化合物I 12)的合成
反应式如下：
Figure PCTCN2022099301-appb-000019
参照化合物I 1的制备方法，以1-(2-甲氧苯基)哌嗪替换1-(2-氯苯基)哌嗪，1,4-二溴丁烷替换1,2-二溴乙烷，其他条件不变，经硅胶柱层析(洗脱剂为DCM:MeOH＝40:1V:V)制得目标化合物I 12，黄色固体，产率47％。
ESI-MS：466.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.85(d,J＝7.9Hz,1H),8.63(d,J＝5.6Hz,1H),8.37(dd,J＝7.8,1.0Hz,1H),8.20(d,J＝2.5Hz,1H),7.82-7.76(m,1H),7.65-7.59(m,1H),7.56(d,J＝5.7Hz,1H),7.34(d,J＝2.5Hz,1H),7.02-6.84(m,4H),4.19(t,J＝6.3Hz,2H),3.86(s,3H),3.12(s,4H),2.70(s,4H),2.56-2.50(m,2H),1.99-1.91(m,2H),1.84-1.75(m,2H).
实施例13：5-[[(2,3-二氯苯基)哌嗪]丁氧基]-1-氮杂苯并蒽酮(化合物I 13)的合成
反应式如下：
Figure PCTCN2022099301-appb-000020
参照化合物I 1的制备方法，以1-(2,3-二氯苯基)哌嗪替换1-(2-氯苯基)哌嗪，1,4-二溴丁烷替换1,2-二溴乙烷，其他条件不变，经硅胶柱层析(洗脱剂为DCM:MeOH＝35:1V:V)制得目标化合物I 13，黄色固体，产率50％。
ESI-MS：532.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.86(d,J＝7.9Hz,1H),8.65(d,J＝5.6Hz,1H),8.38(d,J＝7.8Hz,1H),8.22(d,J＝2.5Hz,1H),7.79(t,J＝7.6Hz,1H),7.65-7.57(m,2H),7.36(d,J＝2.5Hz,1H),7.14(t,J＝6.7Hz,2H),6.94(dd,J＝7.1,2.5Hz,1H),4.21(t,J＝6.2Hz,2H),3.09(s,4H),2.70(s,4H),2.58-2.53(m,2H),1.99-1.92(m,2H),1.81(dd,J＝14.9,7.9Hz,2H).
实施例14：5-[[1-(2-氟苯基)哌嗪]丁氧基]-1-氮杂苯并蒽酮(化合物I 14)的合成
反应式如下：
Figure PCTCN2022099301-appb-000021
参照化合物I 1的制备方法，以1-(2-氟苯基)哌嗪替换1-(2-氯苯基)哌嗪，1,4-二溴丁烷替换1,2-二溴乙烷，其他条件不变，经硅胶柱层析(洗脱剂为DCM:MeOH＝40:1V:V)制得目标化合物I 14，黄色固体，产率60％。
ESI-MS：482.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.86(d,J＝7.9Hz,1H),8.65(d,J＝5.6Hz,1H),8.38(d,J＝7.7Hz,1H),8.22(s,1H),7.80(t,J＝7.4Hz,1H),7.66-7.57(m,2H),7.36(s,1H),7.08-6.91(m,4H),4.21(t,J＝6.1Hz,2H),3.15(s,4H),2.72(s,4H),2.60-2.54(m,2H),2.00-1.92(m,2H),1.82(d,J＝6.8Hz,2H).
实施例15：5-[(N-苯基哌嗪)丁氧基]-1-氮杂苯并蒽酮(化合物I 15)的合成
反应式如下：
Figure PCTCN2022099301-appb-000022
参照化合物I 1的制备方法，以N-苯基哌嗪替换1-(2-氯苯基)哌嗪，1,4-二溴丁烷替换1,2-二溴乙烷，其他条件不变，经硅胶柱层析(洗脱剂为DCM:MeOH＝30:1V:V)制得目标化合物I 15，黄色固体，产率62％。
ESI-MS：464.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.88(d,J＝8.0,0.7Hz,1H),8.67(d,J＝5.6Hz,1H),8.40(d,J＝7.8,1.0Hz,1H),8.26(d,J＝2.5Hz,1H),7.84-7.78(m,1H),7.66-7.60(m,2H),7.40(d,J＝2.5Hz,1H),7.29-7.27(m,1H),7.25(d,J＝2.0Hz,1H),6.94(d,J＝7.9Hz,2H),6.86(t,J＝7.3Hz,1H),4.23(t,J＝6.2Hz,2H),3.24(t,J＝4.8Hz,4H),2.68(t,J＝4.8Hz,4H),2.55(t,J＝7.5Hz,2H),2.00-1.94(m,2H),1.86-1.78(m,2H).
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I 1～I 15进行毒性及神经细胞保护活性测试，首先评价化合物对神经母细胞瘤细胞SH-SY5Y、人正常肝细胞L02和大鼠肾上腺嗜铬 细胞瘤细胞PC12的细胞毒性；以氟西汀为阳性对照药，检测化合物I 1～I 15对皮质酮CORT诱导的PC12细胞损伤的保护率。
仪器：Direct-Q with pump超纯水仪(Millopore)，POLARstar多功能酶标仪(Omega)，Heracell VIOS 160i恒温CO 2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)，DMEM-F12不完全培养基(含双抗，凯基生物)，RPMI-1640不完全培养基(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)。
细胞株：人正常肝细胞LO2，人神经母细胞瘤细胞SH-SY5Y，大鼠肾上腺嗜铬细胞瘤细胞PC12。
细胞毒性评价：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CO 2培养箱中37℃恒温培养，隔天更换培养基(LO2细胞用含10％胎牛血清的DMEM完全培养基，SH-SY5Y细胞用含10％胎牛血清的DMEM-F12完全培养基，PC12细胞用含10％胎牛血清的RPMI-1640完全培养基)，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5×10 4/mL，接种于96孔板上(100μL/孔)，置于恒温CO 2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，以加入等量DMSO的完全培养基为空白对照组，用新鲜含药完全培养基替换96孔板中的旧培养基，设置3个复孔，继续培养24h。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，细胞抑制率计算公式为：
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LO2、SH-SY5Y和PC12细胞均没有表现出明显细胞毒性(IC 50>10μM)。
化合物对皮质酮CORT诱导的PC12细胞损伤的保护率：按照上述方法将PC12细胞接种于96孔板(5×10 4/mL，100μL/孔)置于恒温CO 2培养箱中培养24h，弃去旧的完全培养基，给药组加入含皮质酮(终浓度500μM/mL)、化合物(终浓度0.5μM/mL)的新鲜不完全RPMI-1640-培养基培养24h，空白对照组加入和皮质酮和化合物等量DMSO的不完全培 养基，模型组加入含皮质酮(终浓度500μM/mL)以及和化合物等量的DMSO的不完全培养基代替化合物。采用上述MTT法测定细胞活力，细胞活力计算公式为：
细胞存活率％＝(给药组OD值/空白对照组OD值)×100％
保护率％＝给药组细胞存活率-模型组细胞存活率
结果见图1和表2，大部分化合物对皮质酮诱导的细胞损伤都有较好的保护活性，其中以化合物I 4、I 9、I 14较佳，且当R 1被氟取代时，随着链长增加，化合物的活性增强，尤其以I 14活性最佳，保护率为27.40％，且优于阳性药氟西汀的22.03％。
综上，说明本发明氧化异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，有良好的开发前景。
表1.化合物对LO2、SH-SY5Y及PC12细胞的IC 50
化合物 LO2(μM) SH-SY5Y(μM) PC12(μM)
I 1 ＞100 ＞100 ＞100
I 2 ＞100 ＞20 ＞10
I 3 ＞100 ＞100 ＞100
I 4 ＞100 ＞100 ＞50
I 5 ＞100 ＞20 ＞10
I 6 ＞100 ＞20 ＞50
I 7 ＞100 ＞100 ＞50
I 8 ＞100 ＞100 ＞100
I 9 ＞100 ＞20 ＞10
I 10 ＞100 ＞20 ＞10
I 11 ＞100 ＞20 ＞100
I 12 ＞100 ＞20 ＞10
I 13 ＞100 ＞100 ＞100
I 14 ＞100 ＞20 ＞10
I 15 ＞100 ＞20 ＞10
表2.化合物对皮质酮损伤的PC12细胞的保护率
化合物 保护率(％) 化合物 保护率(％)
I 1 12.13±0.37 I 9 19.64±0.60
I 2 8.33±0.80 I 10 8.56±0.85
I 3 14.46±0.94 I 11 5.55±0.43
I 4 21.24±0.63 I 12 11.05±0.46
I 5 15.70±0.75 I 13 12.30±0.74
I 6 11.30±0.85 I 14 27.40±0.75
I 7 10.96±0.16 I 15 8.57±0.91
I 8 13.64±0.96 氟西汀 22.03±0.17
实施例17：化合物的小鼠体内抗抑郁药效评价
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)，在利血平诱导抑郁模型小鼠上进行化合物I 14体内抗抑郁活性测试，选取氟西汀作为阳性药。
实验动物：ICR小鼠32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、利血平购自sigma，化合物I 14。
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(8只)和利血平组(24只)，利血平组连续3天腹腔注射利血平(0.2mg/kg)造抑郁模型，空白对照组腹腔注射生理盐水。
造模结束后将利血平组小鼠随机分为3组，即模型组(8只)、阳性药组(8只，氟西汀20mg/kg)、化合物I 14组(8只，20mg/kg)，各组按照10mL/kg腹腔注射给药，每日一次，连续给药一周。
利血平用含0.2％乙酸的生理盐水溶解，化合物I 14用含0.01％DMSO的生理盐水溶解，氟西汀用生理盐水溶解，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OFT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。每只动物测试结束后需要清理空场箱(以70％乙醇擦拭并挥干)，以避免受前一只动物气息的干扰。
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TST，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，统计后4min内动物累计不动时间(不动即小鼠停止挣扎，静止不动)。
结果见图2：旷场实验中，总路程及移动速度反映小鼠自主活动状态。与空白对照比，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；与模型组比，化合物I 14组和阳性药组移动总路程和移动速度都显著增加，提示化合物I 14有效。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；与模型组比，化合物I 14组和阳性药组不动时间都显著减少，提示药物有效，且化合物I 14药效略优于阳性药氟西汀。

Claims (10)

  1. 结构如式I所示的氧化异阿朴菲生物碱衍生物：
    Figure PCTCN2022099301-appb-100001
    其中，R 1、R 2分别独立的选自H、F、Cl、甲氧基；n为2～6的整数。
  2. 根据权利要求1所述的氧化异阿朴菲生物碱衍生物，其特征在于：R 1选自H、F、Cl、甲氧基，R 2选自H、Cl；n为2～6的整数。
  3. 根据权利要求2所述的氧化异阿朴菲生物碱衍生物，其特征在于：R 1选自F，R 2选自H；n为2～6的整数。
  4. 氧化异阿朴菲生物碱衍生物，其特征在于：选自下列化合物：
    Figure PCTCN2022099301-appb-100002
    Figure PCTCN2022099301-appb-100003
  5. 一种权利要求1所述的氧化异阿朴菲生物碱衍生物的制备方法，其特征在于：反应路线如下：
    Figure PCTCN2022099301-appb-100004
  6. 根据权利要求5所述的氧化异阿朴菲生物碱衍生物的制备方法，其特征在于：包括：
    步骤(1)、在催化剂作用下，5-羟基-1-氮杂苯并蒽酮与式
    Figure PCTCN2022099301-appb-100005
    所示的双取代溴烷反应，得到中间体Ⅱ；
    步骤(2)、在催化剂作用下，中间体Ⅱ与
    Figure PCTCN2022099301-appb-100006
    反应，得到式I所示的氧化异阿朴菲生物碱衍生物。
  7. 根据权利要求5或6所述的氧化异阿朴菲生物碱衍生物的制备方法，其特征在于：步骤(1)中，所述的5-羟基-1-氮杂苯并蒽酮和双取代溴烷的摩尔比为1:1.8～1:5；
    所述的5-羟基-1-氮杂苯并蒽酮和碳酸钾的摩尔比为1:1.5～1:3.5；所述的催化剂为碳酸钾；
    反应溶剂选自丙酮、乙腈；
    反应温度为50℃～75℃。
  8. 根据权利要求5或6所述的氧化异阿朴菲生物碱衍生物的制备方法，其特征在于：步骤(2)中，中间体Ⅱ与
    Figure PCTCN2022099301-appb-100007
    的摩尔比为1:1.5～1:2；
    所述的催化剂选自碳酸钾和碘化钾的组合，碳酸钾和碘化钾的摩尔比为6:1；所述的催化剂和中间体Ⅱ的摩尔比为1:1.5～1:3.5；
    反应溶剂选自丙酮或乙腈；
    反应温度为50℃～75℃。
  9. 权利要求1-4任一项所述的氧化异阿朴菲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任一项所述的氧化异阿朴菲生物碱衍生物在制备神经保护药物中的应用。
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