3-(3,4-二氯苯基)-N,N-二甲基-3-吗啉-1-丙胺的立体异构体的合成、抗抑郁活性和毒性评价（英文）
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摘要
合成制备5-HT/NE/DA三重再摄取抑制剂3-(3,4-二氯苯基)-N,N-二甲基-3-吗啉-1-丙胺(SIPI6116)的2个立体异构体,并分别评价其抗抑郁活性、初步安全性及药代动力学特征。研究表明,左旋异构体(-)-SIPI6116显示出更好的体内外抑制活性和更高的安全性,药代特征理想,有望作为新型抗抑郁候选药物进行深入开发。
Two stereo-isomers of 3-(3,4-dichlorophenyl)-N,N-dimethyl-3-morpholinopropan-1-amine(SIPI6116) were synthesized and evaluated for their antidepressant activities, toxicities, and pharmacokinetics as novel triple reuptake inhibitors of monoamine transmitters. Pharmacological data indicated that the levo-isomer(-)-SIPI6116 showed better inhibitory activity and lower toxicity, which could act as a potential antidepressant candidate for further evaluation.
Two stereo-isomers of 3-(3,4-dichlorophenyl)-N,N-dimethyl-3-morpholinopropan-1-amine(SIPI6116) were synthesized and evaluated for their antidepressant activities, toxicities, and pharmacokinetics as novel triple reuptake inhibitors of monoamine transmitters. Pharmacological data indicated that the levo-isomer(-)-SIPI6116 showed better inhibitory activity and lower toxicity, which could act as a potential antidepressant candidate for further evaluation.
引文
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[3] SHELTON R C. The dual-action hypothesis:Does pharmacology matter?[J] J Clin Psychiatry, 2004, 65:5-10.
[4] WALTER M W. Monoamine re uptake inhibitors:Highlights of recent research developments[J]. Drug Develop Res,2005, 65(3):97-118.
[5] LIU S, MOLINO B F. Recent developments in monoamine reuptake inhibitors[J]. Annu Rep Med Chem, 2007, 42:13-26.
[6] NELSON J C. Are the SSRIs really better tolerated than the TCAs for treatment of major depression[J].Psychiat Ann,1994, 24(12):628-631.
[7] MICHELI F, CAVANNI P, ARBAN R, et al. 1-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes:A new series of potent and selective triple reuptake inhibitors[J]. J Med Chem, 2010, 53(6):2534-2551.
[8] D'AQUILA P S,COLLU M, CESSA G L,et al. The role of dopamine in the mechanism of action of antidepressant drugs[J]. Eur J Pharmacol, 2000, 405(1-3):365-373.
[9] SUBBAIAH M A M. Triple reuptake inhibitors as potential therapeutics for depression and other disorders:design paradigm and developmental challenges[J].J Med Chem,2018, 61(6):2133-2165.
[10] SHAO L M, LI W, XIE Q, et al. Triple reuptake inhibitors:a patent review(2006-2012)[J]. Expert Opin Ther Pat,2014,24(2):131-154.
[11] WENG Z J, LI J Q. Synthesis and antidepressant activity of optical isomers of 2-(4-benzylpiperazin-l-yl)-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-l-ol(SIPI5056)[J].Bioorg Med Chem Lett, 2010, 20(3):1256-1259.
[12] WENG Z J, ZHENG Y Y, LI J Q. Synthesis, antidepressant activity, and toxicity of the erythro/threo racemates and optical isomers of 2-(4-benzylpiperazin-l-yl)-1-(5-chloro-6-methoxynaplitlialen-2-yl)hexan-1-ol[J].Chem Biol Drug Des, 2015, 85(4):454-460.
[13] ZHENG Y Y, GUO L, ZHEN X C, et al. Synthesis and antidepressant activity of arylalkanol-piperi dine derivatives as triple reuptake inhibitors[J]. Eur J Med Chem, 2012, 54:123-136.
[14] ZHENG Y Y, XIE P, XING L X, et al. Development and practical synthesis of a triple reuptake inhibitor,(1R,2S)-SIPI 5357[J]. Org Process Res Dev, 2012, 16(12):1921-1926.
[15] GU Z S, XIAO Y, ZHANG Q W, et al. Synthesis and antidepressant activity of a series of arylalkanol and aralkyl piperazine derivatives targeting SSRI/5-HT1A/5-HT7[J].Bioorg Med Chem Lett,2017, 27(24):5420-5423.
[16] HE X D, JIANG D, CHEN C, et al. Non-covalent complexes of the antidepressant compound SIPI5358 with cyclodextrins[J]. Acta Phys-Chim Sin, 2010, 26(10):2604-2612.
[17] GU Z S, ZHOU A N, XIAO Y, et al. Synthesis and antidepressant-like activity of novel aralkyl piperazine derivatives targeting SSRI/5-HT1A/5-HT7[J]. Eur J Med Chem,2018,144:701-715.
[18] PAN T T, CHU Y Q, ZHOU M F, et al. Non-covalent complexes of cyclodextrins with antidepressant compound SIPI5838[J]. Acta Chim Sinica,2008, 66(22):2462-2468.
[19] ZHENG Y Y, WENG Z J, XIE P, et al. Synthesis and pharmacological investigation of aralkyl diamine derivatives as potential triple re uptake inhibitors[J]. Eur J Med Chem,2014,86:219-234.
[20] FUJIMA Y,IKUNAKA M, INOUE T,et al. Synthesis of(S)-3-(N-methylamino)-1-(2-thienyl)propan-1-of:Revisiting Eli Lilly's resolution-racemization-recycle synthesis of duloxetine for its robust processes[J]. Org Process Res Dev,2006, 10(5):905-913.
[21]SUTHRAPU S,SRIPATHI S,VEERAMALLA R,et al.An investigation on key parameters that influence the synthesis of(S)-(+)-N,N-dimethyl-3-(I-naphthalenyloxy)-3-(2-thienyl)propylamine:A key intermediate for duloxetine[J]. Org Process Res Dev, 2009,13(5):854-856.