CN114349700A - Oxidized isoaporphine alkaloid derivative, preparation method and anti-depression application thereof - Google Patents
Oxidized isoaporphine alkaloid derivative, preparation method and anti-depression application thereof Download PDFInfo
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Abstract
The invention discloses an oxidized isoaporphine alkaloid derivative with a structure shown as a formula I, R1、R2Each independently selected from H, F, Cl, methoxy; n is an integer of 2 to 6. In vitro activity experiments show that the oxidized isoaporphine alkaloid derivative has better protective activity on PC12 cell injury induced by corticosterone, and the PC12 cell injury induced by corticosterone has a neuroprotective function; and the evaluation of the antidepressant effect in vivo shows that the oxidized isoaporphine alkaloid derivative can obviously increase the moving distance and the moving speed in an open-field experiment, obviously shorten the immobility time in a tail suspension experiment and a forced swimming immobility experiment, and obviously improve the depression state. The invention also discloses the application of the oxidized isoaporphine alkaloid derivative in the preparation of antidepressant drugsThe application is as follows. The invention also discloses application of the oxidized isoaporphine alkaloid derivative in preparing a neuroprotective medicament.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an oxidized isoaporphine alkaloid derivative, a preparation method thereof and application thereof in preparation of antidepressant drugs.
Background
Depression is a mental disorder with persistent depressed mood as the main clinical symptom, the clinical manifestations are mainly the symptoms of depressed mood, anxiety, retardation and various physical discomforts, the interest in pleasure is lost, there is guilt or worthless feeling, and even suicide concept and behavior can be generated in severe cases. Depression is sometimes accompanied by symptoms such as diminished energy, altered appetite, more or less sleep, anxiety, decreased attention, agitation, and the like. The etiology and pathogenesis of depression have not yet been fully elucidated. The hypofunction of monoamine neurotransmitters such as central norepinephrine, hydroxytryptamine and dopamine and the hypofunction of their receptors are considered to be the cause of depression.
Currently, there are a number of clinically available antidepressant drug categories, but there is still a significant fraction of patients who have no expected therapeutic response to some of the classical antidepressant drugs, even the "heavy bomb" drugs like imipramine, fluoxetine, citalopram, and venlafaxine. In addition, longer treatment periods with drugs often also lead to poor patient compliance. How to avoid or reduce the side effects of antidepressant drugs is also one of the main targets of current antidepressant drug research. Therefore, the development of antidepressant with a brand-new action mechanism is significant. The neuroprotective or reparative effect of antidepressant drugs has been widely reported in recent decades and is expected to become a novel mechanism of action for treating mental diseases[1-2]。
Reference documents:
[1] quercetin and its glycoside derivatives have been studied for their antidepressant action and mechanism [ 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.
Disclosure of Invention
The invention aims to provide an oxidized isoaporphine alkaloid derivative, a preparation method and medical application thereof.
The purpose of the invention is realized by the following technical scheme:
an oxoisoaporphine alkaloid derivative having the structure shown in the general formula I:
wherein R is1、R2Each independently selected from H, F, Cl, methoxy; n is an integer of 2 to 6.
Preferably, R1Selected from H, F, Cl, methoxy, R2Selected from H, Cl; n is an integer of 2 to 6.
More preferably, R1Selected from F, R2Is selected from H; n is an integer of 2 to 6.
Specifically, the oxidized isoaporphine alkaloid derivative is selected from the following compounds:
the invention also aims to provide a preparation method of the oxidized isoaporphine alkaloid derivative, which comprises the following reaction route:
wherein R is1、R2N is as defined above.
The method comprises the following steps:
step (1) reacting 5-hydroxy-1-azabenzanthrone with a compound of formula (II a) in the presence of a catalyst
Reacting the disubstituted bromoalkane to obtain an intermediate II;
step (2), under the action of catalyst, intermediate II and
reacting to obtain the oxidized isoaporphine alkaloid derivative shown in the general formula I.
In the 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-hydroxy-1-azabenzanthrone to the 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 50-75 ℃.
After the reaction is finished, the solvent is removed by drying under reduced pressure, and the intermediate II is obtained by silica gel column chromatography purification with PE: EA ═ 10: 1-8: 1(V: V) as an eluent.
In step (2), intermediate II is reacted with
The molar ratio of (a) to (b) is 1:1.5 to 1: 2.
The catalyst is selected from the combination of potassium carbonate and potassium iodide, and the molar ratio of the potassium carbonate to the potassium iodide is 6: 1; the molar ratio of the catalyst to the intermediate II is 1: 1.5-1: 3.5.
The reaction solvent is selected from acetone or acetonitrile.
The reaction temperature is 50-75 ℃.
And after the reaction is finished, drying under reduced pressure to remove the solvent, and purifying by silica gel column chromatography with DCM (DCM): MeOH) ═ 50: 1-10: 1(V: V) as an eluent to obtain the oxidized isoaporphine alkaloid derivative shown in the general formula I.
In particular, the method comprises the following steps of,
selected from N-phenylpiperazine, 1- (2, 3-dichloro)Phenyl) piperazine, 1- (2-methoxyphenyl) piperazine, 1- (2-fluorophenyl) piperazine, 1- (2-chlorophenyl) piperazine.
In vitro activity experiments show that the oxidized isoaporphine alkaloid derivative has better protective activity on PC12 cell injury induced by corticosterone, and the PC12 cell injury induced by corticosterone has a neuroprotective function; and the evaluation of the antidepressant effect in vivo shows that the oxidized isoaporphine alkaloid derivative can obviously increase the moving distance and the moving speed in an open-field experiment, obviously shorten the immobility time in a tail suspension experiment and a forced swimming immobility experiment, and obviously improve the depression state.
Therefore, the invention also aims to provide the application of the oxidized isopaporphine alkaloid derivative in the preparation of antidepressant medicaments.
The invention also aims to provide the application of the oxidized isoaporphine alkaloid derivative in the preparation of neuroprotective drugs.
The invention has the beneficial effects that:
the method for preparing the oxidized isoaporphine alkaloid derivative has the advantages of mild reaction conditions, low toxicity of the used reagent, easily obtained raw materials, convenient post-treatment and higher yield.
The oxidized isoaporphine alkaloid derivative has better protective activity on PC12 cell injury induced by corticosterone, and the evaluation of the antidepressant effect in vivo shows that the oxidized isoaporphine alkaloid derivative can obviously improve the depression state, and is expected to become an antidepressant medicament with research prospect.
Drawings
FIG. 1 shows the viability of PC12 cells co-treated with compound (0.5. mu.M/mL) and corticosterone (500. mu.M/mL).
FIG. 2 shows Compound I14In vivo anti-depressant efficacy outcomes; wherein, A: the total moving distance of the mouse in the open field experiment; b: the moving speed of the mouse in an open field experiment; c: standing time of a mouse in a forced swimming immobility experiment; d: mice resting time in tail suspension experiments.##P < 0.001 indicates a significant difference between the model group and the blank group,**p < 0.001 means significant difference between the group of drugs and the model group。
Detailed Description
The following examples are provided to further illustrate the technical solution of the present invention. These examples are illustrative and should not be construed as limiting the invention.
Example 1: 5- [ [1- (2-chlorophenyl) piperazine]Ethoxy radical]-1-azabenzanthrone (Compound I)1) Synthesis of (2)
The reaction formula is as follows:
5-hydroxy-1-azabenzanthrone (247mg,1mmol,1eq) was dissolved in 10ml acetone and K was added2CO3(207mg,1.5mmol, 1.5eq) and 1, 2-dibromoethane (335mg,1.8mmol,1.8eq), stirred at 50 ℃ overnight to stop the reaction, dried under reduced pressure to remove the solvent, and purified by silica gel column chromatography (eluent PE: EA ═ 8:1V: V) to give intermediate 5- (2-bromoethoxy) -1-azabenzanthrone; 5- (2-Bromoethoxy) -1-azabenzanthrone (141mg,0.4mmol,1eq) was added to the reaction flask, dissolved in 10ml acetonitrile and K was added2CO3(166mg,1.2mmol,3eq), KI (33mg,0.2mmol,0.5eq) and 1- (2-chlorophenyl) piperazine (157mg,0.8mmol,2eq) were stirred at 60 ℃ overnight, the reaction was stopped, the solvent was removed by drying under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent DCM: MeOH ═ 20:1V: V) to give compound I1Yellow solid, yield 70%.
ESI-MS：470.2.[M+H]+。
1H NMR(500MHz,CDCl3) δ 8.88(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 ═ 4.7, 2H), 3.3, 4.86 (t, 3.3, 4.2 Hz, 4H), 5.86 (t, 2H, 4.6.6: 5- [ [1- (2-methoxyphenyl) piperazine]Ethoxy radical]-1-azabenzanthrone (Compound I)2) Synthesis of (2)
The reaction formula is as follows:
reference Compound I1The preparation method of (1) is that 1- (2-methoxyphenyl) piperazine is used for replacing 1- (2-chlorophenyl) piperazine, other conditions are not changed, and the target compound I is prepared by silica gel column chromatography (eluent is DCM: MeOH ═ 30:1V: V)2Yellow solid, yield 61%.
ESI-MS：466.2.[M+H]+。
1H NMR(500MHz,CDCl3)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).
Example 3: 5- [ [ (2, 3-dichlorophenyl) piperazine]Ethoxy radical]-1-azabenzanthrone (Compound I)3) Synthesis of (2)
The reaction formula is as follows:
reference Compound I1The preparation method of (1) is that 1- (2, 3-dichlorophenyl) piperazine is used for replacing 1- (2-chlorophenyl) piperazine, other conditions are not changed, and the target compound I is prepared by silica gel column chromatography (eluent is DCM: MeOH ═ 25:1V: V)3Yellow solid, 58% yield.
ESI-MS：504.1[M+H]+。
1H NMR(500MHz,CDCl3)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).
Example 4: 5- [ [1- (2-fluorophenyl) piperazine]Ethoxy radical]-1-azabenzanthrone(Compound I)4) Synthesis of (2)
The reaction formula is as follows:
reference Compound I1The preparation method of (1) is that 1- (2-fluorophenyl) piperazine is used for replacing 1- (2-chlorophenyl) piperazine, other conditions are not changed, and silica gel column chromatography is carried out (eluent is DCM: MeOH ═ 30:1V: V) to prepare the target compound I4Yellow solid, yield 51%.
ESI-MS：454.2[M+H]+。
1H NMR(500MHz,CDCl3)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).
Example 5: 5- [ (N-phenylpiperazine) ethoxy group]-1-azabenzanthrone (Compound I)5) Synthesis of (2)
The reaction formula is as follows:
reference Compound I1The preparation method comprises the steps of replacing 1- (2-chlorphenyl) piperazine with N-phenylpiperazine, carrying out silica gel column chromatography (eluent is DCM: MeOH ═ 20:1V: V) under the same conditions to obtain a target compound I5Yellow solid, yield 55%.
ESI-MS：436.2[M+H]+。
1H NMR(500MHz,CDCl3)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).
Example 6: 5- [ [1- (2-chlorophenyl) piperazine]Propoxy group]-1-azabenzanthrone (Compound I)6) Synthesis of (2)
The reaction formula is as follows:
reference Compound I1The preparation method of (1) is to replace 1, 2-dibromoethane with 1, 3-dibromopropane, the other conditions are not changed, and the target compound I is prepared by silica gel column chromatography (eluent is DCM: MeOH: 25:1V: V)6Yellow solid, yield 63%.
ESI-MS：484.2[M+H]+。
1H NMR(400MHz,CDCl3)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).
Example 7: 5- [ [1- (2-fluorophenyl) piperazine]Propoxy group]-1-azabenzanthrone (Compound I)7) Synthesis of (2)
The reaction formula is as follows:
reference Compound I1The preparation method comprises the steps of replacing 1- (2-chlorphenyl) piperazine with 1- (2-methoxyphenyl) piperazine, replacing 1, 2-dibromoethane with 1, 3-dibromopropane, and carrying out silica gel column chromatography (eluent is DCM: MeOH ═ 35:1V: V) to obtain a target compound I7Yellow solid, yield 46%.
ESI-MS：494.2[M+H]+。
1H NMR(500MHz,CDCl3)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).
Example 8: 5- [ [ (2, 3-dichlorophenyl) piperazine]Propoxy group]-1-azabenzanthrone (Compound I)8) Synthesis of (2)
The reaction formula is as follows:
reference Compound I1The preparation method comprises the steps of replacing 1- (2-chlorphenyl) piperazine with 1- (2, 3-dichlorophenyl) piperazine, replacing 1, 2-dibromoethane with 1, 3-dibromopropane, and carrying out silica gel column chromatography (eluent is DCM: MeOH-40: 1V: V) to obtain a target compound I8Yellow solid, yield 49%.
ESI-MS：518.1[M+H]+。
1H NMR(400MHz,CDCl3)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).
Example 9: 5- [ [1- (2-fluorophenyl) piperazine]Propoxy group]-1-azabenzanthrone (Compound I)9) Synthesis of (2)
The reaction formula is as follows:
reference Compound I1The preparation method comprises the steps of replacing 1- (2-chlorphenyl) piperazine with 1- (2-fluorophenyl) piperazine, replacing 1, 2-dibromoethane with 1, 3-dibromopropane, and carrying out silica gel column chromatography (eluent is DCM: MeOH ═ 35:1V: V) to obtain a target compound I9Yellow solid, yield 52%.
ESI-MS：468.2[M+H]+。
1H NMR(400MHz,CDCl3)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).
Example 10: 5- [ (N-phenylpiperazine) propoxy group]-1-azabenzanthrone (Compound I)10) Synthesis of (2)
The reaction formula is as follows:
reference Compound I1The preparation method comprises the steps of replacing 1- (2-chlorphenyl) piperazine with N-phenylpiperazine and replacing 1, 2-dibromoethane with 1, 3-dibromopropane, carrying out silica gel column chromatography (eluent is DCM: MeOH ═ 25:1V: V) to obtain a target compound I10Yellow solid, yield 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).
Example 11: 5- [ [1- (2-chlorophenyl) piperazine]Butoxy radical]-1-azabenzanthrone (Compound I)11) Synthesis of (2)
The reaction formula is as follows:
reference Compound I1The preparation method of (1, 4-dibromobutane is used for replacing 1, 2-dibromoethane, other conditions are not changed, and the target compound I is prepared by silica gel column chromatography (eluent is DCM: MeOH: 30:1V: V)11Yellow solid, yield 55%.
ESI-MS：498.2[M+H]+。
1H NMR(400MHz,CDCl3)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).
Example 12: 5- [ [1- (2-methoxyphenyl) piperazine]Butoxy radical]-1-azabenzanthrone (Compound I)12) Synthesis of (2)
The reaction formula is as follows:
reference Compound I1The preparation method comprises the steps of replacing 1- (2-chlorphenyl) piperazine with 1- (2-methoxyphenyl) piperazine, replacing 1, 2-dibromoethane with 1, 4-dibromobutane, and carrying out silica gel column chromatography (eluent is DCM: MeOH: 40:1V: V) to obtain a target compound I12Yellow solid, yield 47%.
ESI-MS：466.2[M+H]+。
1H NMR(400MHz,CDCl3)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).
Example 13: 5- [ [ (2, 3-dichlorophenyl) piperazine]Butoxy radical]-1-azabenzanthrone (Compound I)13) Synthesis of (2)
The reaction formula is as follows:
reference Compound I1The preparation method comprises the steps of replacing 1- (2-chlorphenyl) piperazine with 1- (2, 3-dichlorophenyl) piperazine and replacing 1, 2-dibromoethane with 1, 4-dibromobutane under the same conditions, and performing silica gel column chromatography (eluent is DCM: MeOH ═ 35:1V: V) to obtain a target compound I13Yellow solid, yield 50%.
ESI-MS：532.2[M+H]+。
1H NMR(400MHz,CDCl3)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).
Example 14: 5- [ [1- (2-fluorophenyl) piperazine]Butoxy radical]-1-azabenzanthrone (Compound I)14) Synthesis of (2)
The reaction formula is as follows:
reference Compound I1The preparation method comprises the steps of replacing 1- (2-chlorphenyl) piperazine with 1- (2-fluorophenyl) piperazine and replacing 1, 2-dibromoethane with 1, 4-dibromobutane under the same conditions, and performing silica gel column chromatography (eluent is DCM: MeOH: 40:1V: V) to obtain a target compound I14Yellow solid, yield 60%.
ESI-MS：482.2[M+H]+。
1H NMR(400MHz,CDCl3)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).
Example 15: 5- [ (N-phenylpiperazine) butoxy group]-1-azabenzanthrone (Compound I)15) Synthesis of (2)
The reaction formula is as follows:
reference Compound I1The preparation method comprises the steps of replacing 1- (2-chlorphenyl) piperazine with N-phenylpiperazine and replacing 1, 2-dibromoethane with 1, 4-dibromobutane under the same conditions, and performing silica gel column chromatography (eluent is DCM: MeOH ═ 30:1V: V) to obtain a target compound I15Yellow solid, yield 62%.
ESI-MS：464.2[M+H]+。
1H NMR(400MHz,CDCl3)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).
Example 16: test for toxicity and neuronal protection Activity of Compounds
The compound I is treated by adopting a tetramethyl azole blue colorimetric method (MTT method)1～I15Performing toxicity and nerve cell protection activity test, and firstly evaluating the cytotoxicity of the compound on a neuroblastoma cell SH-SY5Y, a human normal liver cell L02 and a rat adrenal pheochromocytoma cell PC 12; detecting compound I by taking fluoxetine as a positive control drug1～I15Protection rate against corticosterone CORT-induced PC12 cell damage.
The instrument comprises the following steps: Direct-Q with pump ultra-pure water meter (Millopore), POLARstar multifunctional microplate reader (Omega), Heracell VIOS 160i constant temperature CO2Incubator (Thermo), MiniSpin centrifuge (Thermo).
Reagent: DMEM incomplete (high glucose) medium (containing diabase, keji bio), DMEM-F12 incomplete medium (containing diabase, keji bio), RPMI-1640 incomplete medium (containing diabase, keji bio), fetal bovine serum (BI), lxpbs (0.01M, pH 7.4, keji bio), trypsin-EDTA digest (keji bio), trypsin digest (without EDTA, keji bio), tetramethylthiazole blue (MTT, keji bio).
Cell lines: human normal liver cell LO2, human neuroblastoma cell SH-SY5Y, rat adrenal pheochromocytoma cell PC 12.
Evaluation of cytotoxicity: recovering the frozen cell strain in liquid nitrogen, rapidly thawing in water bath at 37 deg.C, inoculating in culture flask, and placing in CO2Culturing at 37 deg.C in incubator, replacing culture medium every other day (LO2 cell using DMEM complete culture medium containing 10% fetal calf serum, SH-SY5Y cell using DMEM-F12 complete culture medium containing 10% fetal calf serum, PC12 cell using RPMI-1640 complete culture medium containing 10% fetal calf serum), spreading the cells in exponential growth phase and in good state, discarding old culture medium, washing PBS once, adding 1mL trypsin-EDTA digestive juice to digest the cells, observing under microscope when the cells just become round, adding 1mL corresponding complete culture medium to stop, blowing gently and beating the suspended cells to transfer to centrifuge tube, centrifuging at 1000rpm for 5min, discarding supernatant, adding fresh suspended cells of complete culture medium, counting, adjusting cell density to 5 × 104Perml, seeded on a 96-well plate (100. mu.L/well) and placed in a thermostated CO2Culturing in an incubator for 24 h.
Preparing a drug-containing culture medium containing a positive control drug and a compound to be tested with different concentrations by using a corresponding complete culture medium, taking the complete culture medium added with the same amount of DMSO as a blank control group, replacing the old culture medium in a 96-well plate with a fresh drug-containing complete culture medium, setting 3 multiple wells, and continuing to culture for 24 hours. MTT reagent (10. mu.L/well) was added to a 96-well plate in the dark, and the culture was continued for 4 hours. MTT-containing medium was discarded, DMSO (150. mu.L/well) was added and the crystals were dissolved by gentle shaking, and the cell inhibition ratio was calculated by measuring the absorbance (OD value) at 570nm according to the formula:
percent cell inhibition [ (% OD value of blank control-OD value of administered group)/OD value of blank control ]. times.100%
As shown in Table 1, all compounds showed no significant cytotoxicity (IC) against LO2, SH-SY5Y and PC12 cells50>10μM)。
Cortone CORT induced PC12 cell injury by compoundProtection ratio of (2): PC12 cells were seeded in 96-well plates (5X 10) as described above4mL, 100. mu.L/well) in a constant temperature CO2The culture was carried out in an incubator for 24 hours, the old complete medium was discarded, the administration group was added with fresh incomplete RPMI-1640 medium containing corticosterone (final concentration 500. mu.M/mL) and compound (final concentration 0.5. mu.M/mL) for 24 hours, the blank control group was added with incomplete medium containing DMSO in an amount equivalent to that of corticosterone and compound, and the model group was added with incomplete medium containing corticosterone (final concentration 500. mu.M/mL) and DMSO in an amount equivalent to that of compound in place of the compound. The MTT method is adopted to determine the cell activity, and the cell activity calculation formula is as follows:
percent cell viability ═ 100% (OD value of administered group/OD value of blank control group) ×
The protection rate%
The results are shown in FIG. 1 and Table 2, and most of the compounds have better protective activity on corticosterone-induced cell damage, wherein the compound I is used4、I9、I14Preferably, and when R is1When substituted by fluorine, the activity of the compounds increases with increasing chain length, especially with I14The activity is optimal, the protection rate is 27.40 percent and is better than 22.03 percent of that of the positive fluoxetine.
In conclusion, the oxidized isoaporphine alkaloid derivative has small toxic and side effects, better neuroprotective activity and good development prospect.
TABLE 1 IC of compounds on LO2, SH-SY5Y and PC12 cells50
| Compound (I) | LO2(μM) | SH-SY5Y(μM) | PC12(μM) |
| I1 | ＞100 | ＞100 | ＞100 |
| I2 | ＞100 | ＞20 | ＞10 |
| I3 | ＞100 | ＞100 | ＞100 |
| I4 | ＞100 | ＞100 | ＞50 |
| I5 | ＞100 | ＞20 | ＞10 |
| I6 | ＞100 | ＞20 | ＞50 |
| I7 | ＞100 | ＞100 | ＞50 |
| I8 | ＞100 | ＞100 | ＞100 |
| I9 | ＞100 | ＞20 | ＞10 |
| I10 | ＞100 | ＞20 | ＞10 |
| I11 | ＞100 | ＞20 | ＞100 |
| I12 | ＞100 | ＞20 | ＞10 |
| I13 | ＞100 | ＞100 | ＞100 |
| I14 | ＞100 | ＞20 | ＞10 |
| I15 | ＞100 | ＞20 | ＞10 |
TABLE 2 protection rates of Compounds on corticosterone-damaged PC12 cells
Example 17: evaluation of antidepressant efficacy of Compounds in mice
The compound I is carried out on reserpine induced depression model mice by adopting Open-field test (OFT), Tail Suspension Test (TST) and Forced Swimming Test (FST)14And (3) testing the in vivo antidepressant activity, and selecting fluoxetine as a positive drug.
Experimental animals: ICR mice 32, male, weighing 18-20g, were purchased from Nanjing Qinglong mountain animal farm.
The tested drugs are: sodium chloride injection is purchased from Anhui-Shuanghe pharmaceutical industry, fluoxetine hydrochloride and reserpine are purchased from sigma, compound I14。
Experimental equipment: autonomous activity box (length 50cm, width 50cm, height 50cm), cylindrical forced swimming container (diameter 10cm, height 20cm) ZS behavioristics analyzer of Beijing Zhongcheng Dichu science and technology Limited
The experimental method comprises the following steps: the tested animals are irradiated with 12h light and shade alternately (6:00 lights on and 18:00 lights off), the raising temperature is 25 +/-2 ℃, the humidity is 50 +/-20%, water and padding are replaced regularly every 2 days, drinking water is freely taken, and 5 animals are fed in each cage. After adaptive feeding for 5 days, the mice are divided into a blank control group (8 mice) and a reserpine group (24 mice), the reserpine group is injected into the abdominal cavity of the reserpine (0.2mg/kg) for 3 days continuously to make a depression model, and the blank control group is injected into the abdominal cavity of the reserpine (0.2 mg/kg).
After the model building is finished, mice in the reserpine group are randomly divided into 3 groups, namely a model group (8 mice), a positive drug group (8 mice, 20mg/kg of fluoxetine) and a compound I14Groups (8, 20mg/kg) were administered by intraperitoneal injection at 10mL/kg once a day for one week.
Reserpine is dissolved in physiological saline containing 0.2% acetic acid, and compound I14The solution is dissolved by physiological saline containing 0.01 percent DMSO, and fluoxetine is dissolved by physiological saline, and the preparation concentration meets the final administration volume of 10mL/kg of mice.
Observation indexes are as follows:
A. open field experiment: mice were OFT 1h after the last dose to test the animals for autonomic activity. The experiment adopts a mouse open field detection system, the animals are adapted for 1h in a test room before testing, then are put into a closed autonomous activity box (with the length of 50cm, the width of 50cm and the height of 50cm) one by one, are adapted for 1min, and then the indexes of the total distance of autonomous activity, the movement time, the movement speed and the like in 5min are recorded. Each animal was terminated and the empty chamber (wiped with 70% ethanol and evaporated) was cleaned to avoid interference from the previous animal breath.
B. Forced swimming immobility experiment: after 1 hour of the administration, the mice were placed in a cylindrical forced swimming vessel (diameter 10cm, height 20cm, water depth 15cm) and kept at a water temperature of 25 ℃. After the animal acclimated for 1min, the computer image real-time detection, analysis and processing system automatically recorded the cumulative immobility time of the animal for the next 4min (the mouse stopped struggling or floating on water, only fine movements to keep the head above the water surface were considered immobile).
C. Tail suspension experiment: the mice were subjected to TST 1h after the last administration, and the adhesive tape was fixed about 1cm from the mouse tail tip and suspended from the upper support of the instrument, so that the mice were suspended upside down in the tail suspension box. The test duration is totally 6min, after 2min adaptation, the cumulative animal immobility time (immobility, i.e. the mouse stops struggling and is still) within 4min is counted.
The results are shown in FIG. 2: in open field experiments, the total distance and the moving speed reflect the autonomous activity state of the mouse. Compared with blank control, the total moving distance and the moving speed of the mice in the model group are obviously reduced,prompting the success of molding; in comparison with the model group, Compound I14The total moving distance and the moving speed of the group and the positive medicine group are obviously increased, and the prompt of the compound I14Is effective. In Tail Suspension (TST) and forced swim immobility (FST) experiments, the immobility time of mice reflects their depressed state. Compared with blank control, the standing time of the mice in the model group is obviously improved, and the success of model building is prompted; in comparison with the model group, Compound I14The immobility time of the group and the positive medicine group is obviously reduced, the medicine is prompted to be effective, and the compound I14The drug effect is slightly better than that of the positive drug fluoxetine.
Claims (10)
1. An oxidized isoaporphine alkaloid derivative having the structure shown in formula I:
wherein R is1、R2Each independently selected from H, F, Cl, methoxy; n is an integer of 2 to 6.
2. Oxidized isoaporphine alkaloid derivative according to claim 1, characterized in that: r1Selected from H, F, Cl, methoxy, R2Selected from H, Cl; n is an integer of 2 to 6.
3. Oxidized isoaporphine alkaloid derivative according to claim 2, characterized in that: r1Selected from F, R2Is selected from H; n is an integer of 2 to 6.
4. Oxidized isoaporphine alkaloid derivatives, characterized in that: selected from the following compounds:
5. a method for preparing oxidized isoaporphine alkaloid derivatives according to claim 1, characterized in that: the reaction route is as follows:
6. the process for the preparation of oxidized isoaporphine alkaloid derivatives according to claim 5, wherein: the method comprises the following steps:
step (1) reacting 5-hydroxy-1-azabenzanthrone with a compound of formula (II a) in the presence of a catalyst
Reacting the disubstituted bromoalkane to obtain an intermediate II;
step (2), under the action of catalyst, intermediate II and
reacting to obtain the oxidized isoaporphine alkaloid derivative shown in the formula I.
7. The process for the preparation of oxidized isoaporphine alkaloid derivatives according to claim 5 or 6, characterized in that: in the 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-hydroxy-1-azabenzanthrone to the 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 50-75 ℃.
8. The process for the preparation of oxidized isoaporphine alkaloid derivatives according to claim 5 or 6, characterized in thatIn the following steps: in step (2), intermediate II is reacted with
The molar ratio of (A) to (B) is 1: 1.5-1: 2;
the catalyst is selected from the combination of potassium carbonate and potassium iodide, and the molar ratio of the potassium carbonate to the potassium iodide is 6: 1; the molar ratio of the catalyst to the intermediate II is 1: 1.5-1: 3.5;
the reaction solvent is selected from acetone or acetonitrile;
the reaction temperature is 50-75 ℃.
9. Use of the oxidized isoaporphine alkaloid derivative according to any of claims 1 to 4 for the preparation of an antidepressant medicament.
10. Use of the oxidized isoaporphine alkaloid derivative according to any of the claims 1-4 for the preparation of a neuroprotective medicament.
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