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二甲啡烷磷酸盐 |
| CAS No.: |
36304-84-4 |
| 分子式： |
C18H25N.H3O4P |
| 分子量： |
353.396 |
| 备注： |
中文名称二甲啡烷磷酸盐中文同义词磷酸二甲啡烷杂质;二甲啡烷磷酸盐;磷酸二甲啡烷;(9S,13S,14S)-3,17-二甲基吗喃磷酸盐英文名称Dimemorfanphosphate英文同义词DIMEMORFANPHOSPHATE;(9alpha,13alpha,14alpha)-3,17-dimethylmorphinandihydrogenphosphate;Astomin;dimemorphanphosphate;Morphinan,3,17-dimethyl-,(9α,13α,14α)-,phosphate(1:1);Dimemomin;Hofvan;DimemorfanphosphateUSP/EP/BPCAS号36304-84-4分子式C18H25N.H3O4P分子量353.396EINECS号252-958-6相关类别原料药及中间体Mol文件36304-84-4.mol结构式二甲啡烷磷酸盐性质熔点267-269°比旋光度D23+25.7°(c=0.5inmethanol)储存条件Storeat-20°C溶解度水：20mg/mL(56.59mM)；DMSO：1mg/mL(2.83mM)形态固体颜色白色至米白色二甲啡烷磷酸盐用途与合成方法概述磷酸二甲啡烷抑制延脑咳嗽中枢，为非成瘾性中枢镇咳药。效果略优于右美沙芬，约为可待因的2倍，但毒性更低，反复应用不会成瘾，安全性较大。服用后迅速见效，且持续时间长，亦不会引起便秘，且国内尚无厂家批准上市，具有非常大的市场潜力，在国内开发本品具有广阔的市场前景。制备氮气保护下，将起始原料3-甲氧基-17-甲基右吗喃(5.71g，20mmol)和双(三环己基膦)二氯化镍(0.70g，1mmol)加入100ml甲苯中搅拌溶解，升温至65℃，滴加甲基溴化镁(四氢呋喃溶液)(1mol/L，20ml，20mmol)，滴加完毕保温反应，TLC检测原料反应完毕后降至室温，滴加少量饱和氯化铵溶液淬灭反应，加水洗涤分层，分取有机层；有机层饱和食盐水洗涤，再经干燥后，减压蒸馏除去甲苯得到二甲啡烷；不经纯化直接加入25ml95％乙醇室温搅拌溶解，然后加入85％磷酸(2.3g，20mmol)反应后析出白色固体，经过滤、洗涤、干燥得到磷酸二甲啡烷5.46g，收率77.4％，纯度96.2％。生物活性Dimemorfanphosphate是sigma1receptor的有效激动剂，能够有效止咳。靶点TargetValueσ1receptor(onratbrainmembranes)150nM(Ki)体外研究Dimemorfan(5-20μM)inhibitsbothfMLP-andPMA-inducedROSproductioninaconcentration-dependentmannerandisrelativelymorepotentininhibitingfMLP-inducedROSproductionwithanIC50valueof7.0μM.DimemoChemicalbookrfan(10-50μM)doesnotdisplaysignificantactivityinscavengingfreeradicalsbyxanthine/xanthineoxidasesystem.DimemorfansignificantlysuppressedMac-1upregulationbothinPMA-andfMLP-activatedgroups.Dimemorfan(10-20μM)significantlysuppressesLPS-inducedROSandNOproduction,andsuppressesLPS-inducediNOSproteinexpression,andboththepercentageofthepositivelystainedpopulationandtheMCFintensitiesofMCP-1andTNF-αinBV2cytosol.Dimemorfan(20μM)significantlyblocksthedegradationofcytosolicIκ-BαandnucleartranslocationofNF-κBp65,aswellasthetranscriptionalactivityofNF-κB.体内研究Dimemorfan(6.25or12.5mg/kg,s.c.)significantlyattenuatestheBAYk-8644-inducedconvulsivebehaviors,inadose-relatedmanner(6.25mg/kgdimemorfan+BAYk-8644or12.5mg/kgdimemorfan+BAYk-8644versusSaline+BAYk-8644,P<0.05andP<0.01,respectively).DimemorfansignificantlyattenuatesBAYk-8644-inducedincreasesinthec-fosandc-junproteinexpressioninadose-dependentmanner.Dimemorfandoesnotsignificantlyaffectlocomotoractivityorproducesignificantcirclingbehaviorinanylocomotorpatterninmice.Dimemorfan(1and5mg/kg,i.p.)surpressestheincareaseoftheplasmalevelsofTNF-αinmice.Theinfiltrationofneutrophilsintolungandliveraswellastheproductionofoxidativestress(EBstaining)inthesetissuesinducedbyLPSismarkedlyinhibitedbythetreatmentwithdimemorfan. |
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