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Oxidized isoaporphine alkaloid derivative as well as preparation method and anti-depression application thereof

An alkaloid derivative, the technology of isoapofil, which is applied in the field of medicinal chemistry, can solve the problems of poor patient compliance and no expected treatment response, and achieve the effects of improving depression, good protective activity, and low toxicity of reagents

Active Publication Date: 2022-04-15
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003]Currently, there are many kinds of antidepressant drugs available clinically, but there are still quite a few patients who are still resistant to some classic antidepressant drugs or even imipramine, fluoxetine, 'Blockbuster' drugs like citalopram, venlaxine don't have expected therapeutic response
In addition, the long treatment cycle of the drug often leads to poor patient compliance

Method used

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  • Oxidized isoaporphine alkaloid derivative as well as preparation method and anti-depression application thereof
  • Oxidized isoaporphine alkaloid derivative as well as preparation method and anti-depression application thereof
  • Oxidized isoaporphine alkaloid derivative as well as preparation method and anti-depression application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1: 5-[[1-(2-chlorophenyl) piperazine] ethoxy] -1- azabenzanthrone (compound I 1 )Synthesis

[0043] The reaction formula is as follows:

[0044]

[0045] Dissolve 5-hydroxyl-1-azabenzanthrone (247mg, 1mmol, 1eq) in 10ml acetone, add K 2 CO 3 (207mg, 1.5mmol, 1.5eq) and 1,2-dibromoethane (335mg, 1.8mmol, 1.8eq), stirred overnight at 50°C, stopped the reaction, dried under reduced pressure to remove the solvent, and subjected to silica gel column chromatography (eluent PE:EA=8:1V:V) purification to obtain intermediate 5-(2-bromoethoxy)-1-azabenzanthrone; then 5-(2-bromoethoxy)-1- Azabenzanthrone (141mg, 0.4mmol, 1eq) was added to the reaction flask, dissolved in 10ml of acetonitrile, and K 2 CO 3 (166mg, 1.2mmol, 3eq), KI (33mg, 0.2mmol, 0.5eq) and 1-(2-chlorophenyl)piperazine (157mg, 0.8mmol, 2eq), stirred overnight at 60°C, stopped the reaction, and reduced pressure The solvent was removed by drying, and purified by silica gel column chromatography (...

Embodiment 2

[0047] 1 H 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). Example 2: 5-[[1-(2-methoxyphenyl)piperazine]ethoxy] -1-azabenzoanthrone (compound I 2 )Synthesis

[0048] The reaction formula is as follows:

[0049]

[0050] Reference compound I 1 The preparation method, replace compound 1-(2-chlorophenyl) piperazine with 1-(2-methoxyphenyl) piperazine, other conditions are unchanged, through silica gel column chromatography (eluent is DCM:MeOH= 30:1V:V) obtain target compound I 2 , yellow solid, yield 61%.

[0051] ESI-MS: 466.2.[M+H] + .

[0052] 1 H 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...

Embodiment 3

[0053] Embodiment 3: 5-[[(2,3-dichlorophenyl) piperazine] ethoxy] -1- azabenzanthrone (compound I 3 )Synthesis

[0054] The reaction formula is as follows:

[0055]

[0056] Reference compound I 1 The preparation method, replace compound 1-(2-chlorophenyl) piperazine with 1-(2,3-dichlorophenyl) piperazine, other conditions are constant, through silica gel column chromatography (eluent is DCM: MeOH=25:1V:V) to obtain target compound I 3 , yellow solid, yield 58%.

[0057] ESI-MS: 504.1[M+H] + .

[0058] 1 H 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).

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Abstract

The invention discloses an oxidized isoaporphine alkaloid derivative with a structure as shown in a formula I, wherein R1 and R2 are independently selected from H, F, Cl and methoxyl respectively; and n is an integer of 2-6. An in-vitro activity experiment shows that the oxidized isoaporphine alkaloid derivative has relatively good protection activity on corticosterone-induced PC12 cell injury, which indicates that the corticosterone-induced PC12 cell injury has a neuroprotection function; in-vivo anti-depression drug effect evaluation shows that the oxidized isoaporphine alkaloid derivative can remarkably increase the moving distance and the moving speed in an open field experiment and remarkably shorten the immobility time in a tail suspension experiment and a forced swimming immobility experiment, which indicates that the oxidized isoaporphine alkaloid derivative can remarkably improve the depression state. The invention also discloses an application of the oxidized isoaporphine alkaloid derivative in preparation of an antidepressant drug. The invention also discloses an application of the oxidized isoaporphine alkaloid derivative in preparation of a neuroprotective drug.

Description

technical field [0001] 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. Background technique [0002] 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 , In severe cases, even suicidal ideation and behavior may occur. 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/18A61P25/00A61P25/24
CPCC07D221/18A61P25/00A61P25/24
Inventor 孙建博孙晓娜吴贤殊
Owner CHINA PHARM UNIV
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