CN115160227A - R-或s-2-(1-乙酰氧正戊基)苯甲酸与4-氟-依达拉奉的杂合物及其制备与应用 - Google Patents
R-或s-2-(1-乙酰氧正戊基)苯甲酸与4-氟-依达拉奉的杂合物及其制备与应用 Download PDFInfo
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Abstract
本发明公开了R‑或S‑2‑(1‑乙酰氧正戊基)苯甲酸与4‑氟‑依达拉奉的杂合物(R‑或S‑FMPB)的制备方法及其用途,本发明的优选化合物S‑FMPB具有前体药物的基本特征,在体内可快速代谢并释放出可协同作用的S‑丁苯酞和4‑氟‑依达拉奉两个活性片段,展示了较RS‑和R‑FMPB更显著的抗急性缺血性脑卒中活性。S‑FMPB的疗效不仅优于等摩尔的S‑2‑(1‑乙酰氧正戊基)苯甲酸和4‑氟‑依达拉奉单独或联合给药,而且优于临床常用的丁苯酞与依达拉奉联合用药的效果。此外,S‑FMPB具有较高的体外稳定性及良好的体内药代动力学性质。
Description
技术领域
本发明属于药物化学和药物治疗学领域,具体涉及一对具有光学活性的开环丁苯酞衍生物(R-或S-2-(1-乙酰氧正戊基)苯甲酸)与依达拉奉衍生物(4-氟-依达拉奉)的杂合物(R-和S-FMPB)的制备方法以及它们的医药用途,特别是在制备预防或治疗缺血性心脑血管疾病及改善心脑循环障碍药物中的应用。
背景技术
3-正丁基苯酞(3-N-butylphthalide,NBP),简称丁苯酞,化学名为消旋RS-3-正丁基-1(3H)-异苯并呋喃酮,是我国自主研发并上市的治疗轻、中度缺血性脑卒中药物,临床上常与其它药物联用以增强其疗效。NBP联合依达拉奉(Edaravone,Eda)是最常见的治疗急性缺血性脑卒中的给药组合(中国神经免疫学和神经病学杂志,2016,23(1):51-54.中国临床药理学杂志,2016,32(16):1453-1455.),二者可通过作用于多种神经血管单元组分,发挥广泛的神经保护作用,有效预防和治疗急性缺血性脑损伤(Mol Med Rep.,2021,24,850-863.)。
发明人前期研究发现,4-氟-依达拉奉(4-F-Eda)对H2O2介导神经元细胞(PC12)死亡的抑制作用优于NBP和Eda单独或联合给药,且4-F-Eda对羟基自由基(·OH)和超氧阴离子自由基(·O2 -)具有强效的清除作用(Bioorg Med Chem Lett.,2015,25,3535-3540.)。基于此,发明人设计、合成了NBP开环衍生物(RS-2-(1-乙酰氧正戊基)苯甲酸,RS-APB)与4-F-Eda的杂合物,即3-甲基-1-(对-氟苯基)-1H-吡唑-5-(RS)-2-(1-乙酰氧正戊基)苯甲酸酯(RS-FMPB)。研究表明,RS-FMPB对大鼠口服给药显示了良好的抗缺血性脑卒中活性(ActaPharmacol.Sin.,2015,36,917–927.)。
中国专利ZL98125618.x和ZL99109673.8公开了R-和S-NBP的制备工艺及其抗血小板聚集、抗血栓活性,其中S-NBP的活性优于R-NBP和RS-NBP。
RS-FMPB分子中存在一个手性中心,其光学异构体R-或S-FMPB抗急性缺血性脑卒中活性是否优于RS-FMPB需要探索。此外,静脉注射给药是否比口服给药更能有效地治疗急性缺血性脑损伤也值得进一步研究。
发明内容
发明目的:针对上述现有技术,本发明提供一种具有光学活性的NBP开环衍生物(R-或S-APB)与4-F-Eda的杂合物,即R-和S-FMPB(I),并提供上述新化合物I的制备方法及其制药用途。I在体内可快速代谢为相应的R-或S-APB和4-F-Eda,R-或S-APB又进一步代谢成R-或S-NBP,并与4-F-Eda协同发挥更强的抗急性缺血性脑卒中疗效。
技术方案:本申请所述的一种如通式I所示的化合物,
其中,星号*代表3-甲基-1-(对氟苯基)-1H-吡唑-5-(RS)-2-(1-乙酰氧正戊基)苯甲酸酯(RS-FMPB)的手性中心,可以是R-或S-构型。
进一步优选的,所述的通式I化合物选自以下化合物:
3-甲基-1-(对氟苯基)-1H-吡唑-5-(R)-2-(1-乙酰氧正戊基)苯甲酸酯(R-FMPB)(I1r)
3-甲基-1-(对氟苯基)-1H-吡唑-5-(S)-2-(1-乙酰氧正戊基)苯甲酸酯(S-FMPB)(I1s)
本发明还公开了通式I所述化合物的制备方法,包括如下步骤:
步骤a,4-氟苯肼盐酸盐1与乙酰乙酸乙酯在氮气下于冰醋酸中回流反应得到4-F-Eda(2);
步骤b和c,NBP在碱性条件下开环、酸化,得到不稳定羧酸化合物3后,直接与相应手性拆分剂R-或S-α-苯乙胺成盐得到4粗品,并经重结晶得到光学纯的4;
步骤d,在低温和有机碱存在下,向4的有机溶剂溶液中滴加乙酸酐或乙酰氯,反应结束后酸化,得到相应羧酸化合物5;
步骤e,5与酰氯反应,得氯化物6。步骤f,在有机碱存在下,将6的有机溶剂溶液滴入2中,得到化合物I。
进一步的,步骤b中,所述的碱性环境为氢氧化钠或氢氧化钾的水溶液,所述的酸化是用质量分数为5%稀盐酸调节pH至pH 3~4。
步骤c中,所述重结晶,其重结晶溶剂为丙酮,乙酸乙酯,异丙醇,四氢呋喃中的一种或两种组合物。
步骤d中,所述的低温,其反应温度为-30~-5℃,所述的有机碱为4-二甲氨基吡啶、二乙胺、三乙胺或吡啶,所述的有机溶剂为乙醚、四氢呋喃、二氯甲烷、三氯甲烷或丙酮中的一种或两种组合物,所述的酸化利用浓盐酸、稀盐酸、硫酸或硝酸酸化至pH 2~6。
步骤e中,所述的酰氯为草酰氯或氯化亚砜。
步骤f中,反应温度为-30~-5℃,所述的有机碱为三乙胺、二乙胺或吡啶,有所述的机溶剂为二氯甲烷、三氯甲烷或乙醚中的一种或两种组合物。
所述化合物I在制备预防或治疗缺血性心脑血管疾病及改善心脑循环障碍药物中的应用也在本发明的保护范围内。
本发明化合物I的各种剂型可以由本领域技术人员,按照药学领域的常规生产方法制备。例如,使活性成分与一种或多种载体(也称为辅料)混合,然后将其制成所需的剂型,包括片剂、胶囊、颗粒剂;还可以按照注射剂常规生产方法制成静脉注射剂或静脉注射冻干剂。
本发明的化合物I可用于制备预防和治疗缺血性心脑血管疾病及心脑循环障碍疾病的药物,所述疾病如心肌梗死、心绞痛、心律失常、冠心病、脑梗死及脑卒中。
有益效果:
本发明的化合物具有如下优异的性能:(1)具有前体药物的基本特征,在体内可快速代谢并释放出发挥协同作用的R-或S-NBP和4-F-Eda两个活性片段,显著增强了抗急性缺血性脑卒中的治疗效果;(2)强效的神经功能保护活性以及抗脑梗死、抗脑水肿活性;(3)较高的体外稳定性;(4)优良的体内药代动力学性质。具体阐述如下:
本发明化合物I为固体化合物,具有前体药物的基本特征,在体内可快速代谢并释放出相应的R-或S-APB和4-F-Eda。R-或S-APB在体内酯酶作用下进一步去乙酰化,生成R-或S-2-(1-羟基正戊基)苯甲酸,再快速环合成相应的R-或S-NBP,其与4-F-Eda协同发挥抗脑缺血活性。本发明的优选化合物S-FMPB(I1s)具有强效的抑制短暂性大脑中动脉闭塞(tMCAO)模型大鼠脑梗死和脑水肿的活性,并且能显著改善tMCAO大鼠神经功能学评分,效果分别优于RS-和R-FMPB,也分别优于等摩尔S-APB和4-F-Eda的单独或联合给药以及临床常用的NBP与Eda的联合给药。本发明的优选化合物S-FMPB(I1s)在体外大鼠血浆和肝微粒体中具有较高的稳定性。此外,本发明的优选化合物S-FMPB(I1s)具有优良的药代动力学性质,其活性代谢物S-NBP与S-NBP单独给药或S-NBP+4-F-Eda联合给药的代谢物S-NBP比较,具有更长的半衰期(t1/2)和平均驻留时间(MRT)以及更大的药时曲线下面积(AUC)。
附图说明
图1是化合物对tMCAO大鼠的脑梗塞体积、脑水肿、神经缺损和体重的影响;
图2是S-FMPB在大鼠血浆和肝微粒体中的稳定性情况;
图3是静注S-FMPB、S-NBP和S-NBP+4-F-Eda后大鼠血浆中S-NBP药时曲线药物浓度-时间图;
图4是静注S-FMPB、4-F-Eda和S-NBP+4-F-Eda后大鼠血浆中4-F-Eda药时曲线药物浓度-时间图。
具体实施方式
下面结合具体实施例对本发明作出详细说明。
实施例1:3-甲基-1-(对氟苯基)-1H-吡唑-5-(R)-2-(1-乙酰氧正戊基)苯甲酸酯(R-FMPB)(I1r)
将NBP(100mmol,19.0g)溶解在甲醇(120mL)和水(80mL)混合体系中,加入氢氧化钠(200mmol,8.0g)水(40mL)溶液,在50℃下搅拌0.5h。反应结束,反应液在真空下浓缩除去甲醇,降温至0~-10℃,用5%稀盐酸调pH至2~3,析出大量白色固体,无水乙醚(150mL*3)萃取,合并有机层,水洗,无水硫酸钠干燥。加入R-α-苯乙胺(100mmol,12.1g)继续搅拌1h,析出大量白色固体,过滤,干燥。用丙酮(100mL:15g,60℃)重结晶三次得白色针状晶体R-2-(1-羟基正戊基)苯甲酸R-α-苯乙胺盐。不经进一步处理直接用于下一步反应。
将R-2-(1-羟基正戊基)苯甲酸R-α-苯乙胺盐(15mmol,5.1g)溶于二氯甲烷中,加入三乙胺(45mmol,4.5g)和4-二甲氨基吡啶(1.5mmol,0.2g)。将反应体系降温至-10℃后,在氮气下滴加乙酰氯(30mmol,2.4g)的二氯甲烷(10mL)溶液。滴毕,移至室温继续反应4h。反应结束,加水(100mL)猝灭反应,用5%HCl调pH至2~3,乙酸乙酯萃取(80mL*3),合并有机层,水洗两次,盐水洗一次,无水硫酸钠干燥。经快速柱层析(PE:EA=10:1)纯化得无色油状物R-2-(1-乙酰氧正戊基)苯甲酸(R-APB)3.2g,收率19.1%。[α]2D0=+38.2°(c=1.00,MeOH);MS(m/z):249[M1–H]-;IR(KBr,ν):2929,1735,1579,1410,1250,757cm-1.1H NMR(300MHz,CDCl3):δ(ppm):0.97(3H,t,J=6.9Hz),1.38–1.52(m,4H),1.84–1.99(2H,m),2.17(3H,s),6.69(1H,dd,J1=8.1Hz,J2=4.5Hz),7.38–7.44(1H,m),7.56–7.65(2H,m),8.09–8.12(1H,m);13C NMR(75MHz,CDCl3):δ(ppm):174.4,131.2,128.8,128.3,127.2,74.9,61.1,54.4,40.5,27.6,27.2,23.9,21.7,13.3.
将R-2-(1-乙酰氧正戊基)苯甲酸(1mmol,250mg)溶于二氯甲烷中(20mL),加入1滴N,N-二甲基甲酰胺。将反应体系降温至0℃后,滴加草酰氯(1.3mmol,250mg)。滴毕,移至室温继续反应8h。反应结束,将反应液减压浓缩至干,得R-2-(1-乙酰氧正戊基)苯甲酰氯,不经进一步纯化直接用于下一步反应。
将4-F-Eda(1.5mmol,288mg)溶于二氯甲烷(20mL)中,加入三乙胺(2mmol,202mg)后在室温搅拌10min。随后,将反应液降温至0℃,在氮气下滴加上述R-2-(1-乙酰氧正戊基)苯甲酰氯(1mmol,268mg)的二氯甲烷(10mL)溶液。滴毕,移至室温继续反应4h。反应结束,加水(20mL)猝灭反应,乙酸乙酯萃取(20mL*3)三次,合并有机层,水洗两次,盐水洗一次,无水硫酸钠干燥。经快速柱层析(PE:EA=10:1)纯化得白色固体3-甲基-1-(对氟苯基)-1H-吡唑-5-(R)-2-(1-乙酰氧正戊基)苯甲酸酯(R-FMPB)285mg,收率67.1%。mp 79.6~81.5℃;IR(KBr,ν):844.2,1228.6,1518.4,1726.7,1736.4,1752.2,2856.2,2958.4,3076.7,3176.3cm-1;1H NMR(500MHz,CDCl3):δ(ppm):0.87(3H,t,J=7.1Hz),1.28–1.37(4H,m),1.73–1.82(2H,m),2.07(3H,s),2.37(3H,s),6.26(1H,s),6.47(1H,t,J=6.4Hz),7.12(2H,t,J=8.6Hz),7.31–7.37(1H,m),7.53–7.61(4H,m),7.89(1H,d,J=8.0Hz);13C NMR(125MHz,CDCl3):δ(ppm):170.32,162.76,161.91,160.80,149.29,145.79,144.69,133.94,130.72,127.59,126.73,125.77,125.55,125.49,116.26,116.08,96.19,72.75,36.53,28.13,22.54,21.23,14.59,14.06;ESI-HRMS(m/z):calculated for C24H25FN2O4[M+Na]+447.16906,found 447.16838.
实施例2:3-甲基-1-(对氟苯基)-1H-吡唑-5-(S)-2-(1-乙酰氧正戊基)苯甲酸酯(S-FMPB)(I1s)
按类似实施例1制备3-甲基-1-(对氟苯基)-1H-吡唑-5-(R)-2-(1-乙酰氧正戊基)苯甲酸酯(R-FMPB)(I1r)的方法制得3-甲基-1-(对氟苯基)-1H-吡唑-5-(S)-2-(1-乙酰氧正戊基)苯甲酸酯(S-FMPB)(I1s)。
S-2-(1-乙酰氧正戊基)苯甲酸(S-APB):MS(m/z):249[M1–H]-;IR(KBr,ν):2929,1735,1579,1410,1250,757cm-1.1HNMR(300MHz,CDCl3):δ(ppm):0.97(3H,t,J=6.9Hz),1.38–1.52(4H,m),1.84–1.99(2H,m),2.17(3H,s),6.69(1H,dd,J1=8.1Hz,J2=4.5Hz),7.38–7.44(1H,m),7.56–7.65(2H,m),8.09–8.12(1H,m);13CNMR(75MHz,CDCl3):δ(ppm):174.4,131.2,128.8,128.3,127.2,74.9,61.1,54.4,40.5,27.6,27.2,23.9,21.7,13.3.
3-甲基-1-(对氟苯基)-1H-吡唑-5-(S)-2-(1-乙酰氧正戊基)苯甲酸酯(S-FMPB)(I1s):mp 80.5~82.9℃;IR(KBr,ν):844.4,1228.9,1518.5,1726.9,1736.6,1752.1,2856.3,2958.5,3076.9,3176.2cm-1;1HNMR(500MHz,CDCl3):δ(ppm):0.87(3H,t,J=7.1Hz),1.28–1.38(4H,m),1.73–1.82(2H,m),2.07(3H,s),2.37(3H,s),6.26(1H,s),6.47(1H,t,J=6.4Hz),7.12(2H,t,J=8.6Hz),7.31–7.31(1H,m),7.53–7.61(4H,m),7.89(1H,d,J=8.0Hz);13C NMR(125MHz,CDCl3):δ(ppm):170.32,162.76,161.92,160.79,149.30,145.79,144.68,133.94,130.72,127.59,126.73,125.78,125.55,125.48,116.26,116.07,96.19,72.75,36.53,28.13,22.54,21.23,14.59,14.06;ESI-HRMS(m/z):calculated for C24H25FN2O4[M+Na]+447.16906,found 447.16849.
实施例3:化合物I对局部脑缺血大鼠脑梗死、脑水肿及神经功能的影响试验动物:
SPF级SD大鼠,雄性,体重均值250~300g,购自北京维通利华实验动物技术有限公司,饲养于SPF级饲养环境中,室内温度控制在23±2℃,自由饮水和摄食。动物总数100只,实验使用81只。
试验分组:
假手术组:只暴露并分离颈动脉,按5mL/kg给药体积尾静脉注射生理盐水(含5%Solutol)(n=9);
模型组:tMCAO再灌注线栓法栓塞大鼠大脑中动脉,缺血2h后,取出线栓实现再灌注,再灌注后立刻尾静脉注射生理盐水(含5%Solutol),给药体积为5mL/kg(n=9);
RS-FMPB组,R-FMPB组和S-FMPB组:10mg/kg,tMCAO再灌注线栓法栓塞大鼠大脑中动脉,缺血2h后,取出线栓实现再灌注,再灌注后立刻尾静脉注射相应受试物生理盐水溶液(含5%Solutol),给药体积为5mL/kg(n=9);
等摩尔的S-APB(5.90mg/kg)组:tMCAO再灌注线栓法栓塞大鼠大脑中动脉,缺血2h后,取出线栓实现再灌注,再灌注后立刻尾静脉注射S-APB生理盐水溶液(含5%Solutol),给药体积为5mL/kg(n=9);
等摩尔的4-F-Eda(4.53mg/kg)组:tMCAO再灌注线栓法栓塞大鼠大脑中动脉,缺血2h后,取出线栓实现再灌注,再灌注后立刻尾静脉注射4-F-Eda生理盐水溶液(含5%Solutol),给药体积为5mL/kg(n=9);
等摩尔的S-APB(5.90mg/kg)+4-F-Eda(4.53mg/kg)组:tMCAO再灌注线栓法栓塞大鼠大脑中动脉,缺血2h后,取出线栓实现再灌注,再灌注后立刻尾静脉注射S-APB和4-F-Eda生理盐水溶液(含5%Solutol),给药体积为5mL/kg(n=9);
等摩尔的NBP(4.48mg/kg)+Eda(4.10mg/kg)组:tMCAO再灌注线栓法栓塞大鼠大脑中动脉,缺血2h后,取出线栓实现再灌注,再灌注后立刻尾静脉注射NBP和Eda生理盐水溶液(含5%Solutol),给药体积为5mL/kg(n=9)。
试验方法:
采用线栓法首先阻塞大鼠大脑中动脉,2h后再灌注。再灌注后,立刻对大鼠尾静脉分别注射上述配制的药物(RS-FMPB,R-FMPB,S-FMPB,S-APB,4-F-Eda,S-APB+4-F-Eda联合给药,NBP+Eda联合给药)溶液以及等体积的生理盐水(含5%Solutol)溶液。所有受试物给药持续时间大约控制在1min。于缺血后4h和26h,分别进行神经功能学评分。并在分组前和缺血后26h称量各组大鼠的体重。然后处死各组大鼠,取出全脑后进行称重(湿重)、TTC染色、烘干,测定化合物对脑梗死、脑水肿的影响。
神经功能学评分
缺血后4h和26h,采用Longa’s方法对动物的神经功能缺陷进行分级评分,标准如下:0分:神经功能正常;1分:轻度神经功能缺损:提尾时,动物的左前肢屈曲;2分:中度神经功能缺损:将动物置于光滑平面上行走,行走时向左侧转圈;3分:中度神经缺损:静止状态下,向左侧倾斜;4分:意识减退,肢体无自发活动;5分:对刺激无应答或死亡。
TTC染色
神经行为学检测完毕后,在大鼠全脑视交叉及其前后各2mm处,做冠状切四刀,切成五片后迅速将脑片置5mL含有2%TTC的磷酸缓冲溶液中,37℃避光温孵,在温孵过程中每隔7~8min翻动一次,温孵10min后取出脑片,用数码相机(Canon EOS550D,Japan)拍照,之后用眼科镊分离苍白区(梗塞区)和非苍白区(正常区),通过Image pro-plus 6.0计算梗塞百分比如下:
梗塞百分比(%)=苍白区重量/(苍白区重量+非苍白区重量)×100%;
梗死面积抑制率(%)=(模型组梗塞百分比(%)–给药组梗塞百分比(%))/模型组梗塞百分比(%)×100%。
将染色后的脑组织置于105℃烘箱烘干,24h后称重(干重)。脑含水量计算公式如下:
脑组织含水量(%)=(1–脑组织干重/脑组织湿重)×100%;
脑水肿率(%)=各组脑组织含水量(%)–假手术组脑组织含水量(%)/假手术组脑组织含水量(%)×100%;
脑水肿抑制率(%)=给药组脑水肿率(%)–模型组脑水肿率(%)/模型组脑水肿率(%)×100%。
试验结果:
化合物对tMCAO大鼠的梗塞体积、脑水肿和神经缺损的影响见图1,表1和表2。图1中:(A)TTC染色和脑成像分析;(B)脑梗死体积数据;(C)脑含水量数据;(D)缺血后4h神经功能学评分;(E)缺血后26h神经功能学评分;(F)体重数据。所有数据均表示为平均值±SD(n=9)。*P<0.05,**P<0.01vs模型组,#P<0.05,##P<0.01vs S-FMPB组。
表1.化合物对脑梗死体积的影响。*P<0.05,**P<0.01vs模型组。
由图1A、1B和表1可知,S-FMPB组对tMCAO大鼠的脑梗死面积改善最为明显,脑梗死面积在给药后减少至10.53±1.31%,梗死面积抑制百分率达到77.85%。
表2.化合物对脑水肿的影响。*P<0.05,**P<0.01vs模型组。
由图1C和表2可知,S-FMPB对tMCAO大鼠的脑水肿率改善最为明显,脑水肿在给药后减少至74.01±6.57%,脑水肿抑制百分率达到13.96%。
由图1D和1E可知,S-FMPB对tMCAO大鼠神经功能改善最为明显(P<0.01vs模型组),显著优于RS-和R-FMPB、等摩尔的S-APB和4-F-Eda单独或联合给药(P<0.05vs模型组)以及临床常用的NBP与Eda的联合给药组合(P<0.05vs模型组)。此外,缺血后26h各组大鼠体重没有显著性变化(图1F)。这些结果表明,S-FMPB可显著增强tMCAO大鼠的神经功能恢复。
结论:S-FMPB(I1s)对tMCAO大鼠脑梗死、脑水肿的抑制作用及神经功能改善作用最为显著,效果优于RS-和R-FMPB以及等摩尔的S-APB与4-F-Eda的单独或联合给药。更重要的是,S-FMPB的抗脑缺血效果优于临床常用的NBP与Eda的联合给药组合。
实施例4:化合物S-FMPB(I1s)在体外大鼠血浆和肝微粒体中的稳定性。试验物质来源:
SD大鼠血浆,购自南京森贝伽生物科技有限公司,货号:SBJ-P-RAT002SD-100m。
I相代谢稳定性检测试剂盒(SD大鼠,雄性),购自北京汇智和源生物技术有限公司,货号0111D1.01-0111041。
试验方法:
S-FMPB溶于含5%Solutol的大鼠血浆中(化合物终浓度200μM),在37℃下共孵育。0,0.5,1,1.5,2,3,4,6,8,12和24h后,取出少量样品加入终止液中止反应,样品通过HPLC分析计算S-FMPB保留含量,并计算半衰期。
S-FMPB溶于含1%DMSO的生理盐水中,加入大鼠肝微粒体和NADPH(化合物终浓度20mM),在37℃下共孵育。0,10,30,60和120min后,加入终止液中止反应,样品通过HPLC分析计算S-FMPB保留含量,并计算半衰期。
试验结果:
由图2可知,S-FMPB在大鼠血浆中的半衰期约为17h,在大鼠肝微粒体中的半衰期约为50min。
结论:S-FMPB(I1s)在体外大鼠血浆和肝微粒体中具有较高的稳定性。
实施例5:药代动力学
试验动物:
SPF级SD雄性大鼠12只,购自上海杰思捷实验动物优先公司,动物合格证号:SCXK(沪)2018-0004/20180004063439。体重范围200~220g,购入后在实验动物中心实验室适应环境3天后使用,给药前1天禁食12~14h,给药后4h给食,试验期间自由饮水。
试验方法:
12只SD雄性大鼠被随机分为4组,每组3只。各组大鼠分别尾静脉注射S-FMPB(10mg/kg),S-NBP(4.48mg/kg),4-F-Eda(4.53mg/kg)和S-NBP(4.48mg/kg)+4-F-Eda(4.53mg/kg),给药5,15,30min,1,2,3,6,8,24h后于大鼠眼底静脉丛取血,用LC-MS/MS测定大鼠血中活性代谢物(S-NBP和4-F-Eda)的浓度,利用WinNonlin Professional v6.3(Pharsight,USA)非房室模型分析计算药代动力学参数。实验数据用“平均值±标准差”(Mean±SD,n≥3)表示。
试验结果:
1.化合物S-FMPB在体内迅速代谢成相应的S-NBP和4-F-Eda。给药5min后血浆中即检测到较高浓度的活性代谢物S-NBP和4-F-Eda。随时间延长,S-NBP和4-F-Eda血药浓度首先迅速下降,这可能与药物在体内发生迅速分布有关,随后血药浓度下降相对缓慢进入消除相,再结合血药浓度-时间曲线可知,该药物代谢基本符合二房室模型特点(见图3~4)。
2.由药代血药浓度-时间曲线可知,静脉注射给药2,4,6,8h后,S-FMPB组中活性代谢物S-NBP的血药浓度显著高于S-NBP组或S-NBP+4-F-Eda联合给药组,且平均滞留时间更长,符合S-FMPB作为前药的基本特征。各组化合物中活性代谢物4-F-Eda的血药浓度相当(见图3~4)。
3.由药代动力学参数可知,S-FMPB中活性代谢物S-NBP的半衰期(t1/2)为5.69h,显著长于S-NBP(1.14h)或S-NBP+4-F-Eda联合给药中S-NBP的t1/2(0.97h)。S-FMPB中活性代谢物4-F-Eda的t1/2为5.11h,与4-F-Eda(5.16h)和联合给药中4-F-Eda的t1/2(5.05h)相当(见表3~6)。
4.由药代动力学参数可知,S-FMPB中活性代谢物S-NBP的药时曲线下面积AUC0-t为2740hr*ng/mL,显著大于S-NBP(1351hr*ng/mL)或S-NBP+4-F-Eda联合给药中S-NBP的AUC0-t(1468hr*ng/mL)。S-FMPB中活性代谢物4-F-Eda的AUC0-t为2958hr*ng/mL,与4-F-Eda(2746hr*ng/mL)以及S-NBP+4-F-Eda联合给药中4-F-Eda的AUC0-t(2837hr*ng/mL)相当(见表3~6)。
表3. S-FMPB(10mg/kg)给药后活性代谢物(S-NBP和4-F-Eda)在大鼠体内的药代动力学参数。所有数据均以平均值±标准差表示(n=3)。
表4. S-NBP(4.48mg/kg)给药后活性代谢物(S-NBP)在大鼠体内的药代动力学参数。所有数据均以平均值±标准差表示(n=3)。
表5. 4-F-Eda(4.53mg/kg)给药后活性代谢物(4-F-Eda)在大鼠体内的药代动力学参数。
所有数据均以平均值±标准差表示(n=3)。
表6. S-NBP(4.48mg/kg)+4-F-Eda(4.53mg/kg)联合给药后活性代谢物(S-NBP和4-F-Eda)
在大鼠体内的药代动力学参数。所有数据均以平均值±标准差表示(n=3)。
结论:化合物S-FMPB具有前体药物的基本特征,且比S-NBP、4-F-Eda以及S-NBP+4-F-Eda联合给药具有更优良的药代动力学性质。
Claims (10)
4.根据权利要求3所述通式I化合物的制备方法,其特征在于,步骤b中,所述的碱性环境为氢氧化钠或氢氧化钾的水溶液,所述的酸化是用质量分数5%稀盐酸调pH至3~4。
5.根据权利要求3所述通式I化合物的制备方法,其特征在于,步骤c中,所述重结晶,其重结晶溶剂为丙酮,乙酸乙酯,异丙醇,四氢呋喃中的一种或两种组合物。
6.根据权利要求3所述通式I化合物的制备方法,其特征在于,步骤d中,所述的低温,其反应温度为-30~-5℃,所述的有机碱为4-二甲氨基吡啶、二乙胺、三乙胺或吡啶,所述的有机溶剂为乙醚、四氢呋喃、二氯甲烷、三氯甲烷或丙酮中的一种或两种组合物,所述的酸化为利用浓盐酸、稀盐酸、硫酸或硝酸酸化至pH 2~6。
7.根据权利要求3所述通式I化合物的制备方法,其特征在于,步骤e中,所述的酰氯为草酰氯或氯化亚砜。
8.根据权利要求3所述通式I化合物的制备方法,其特征在于,步骤f中,反应温度为-30~-5℃,所述的有机碱为三乙胺、二乙胺或吡啶,所述的有机溶剂为二氯甲烷、三氯甲烷或乙醚中的一种或两种组合物。
9.一种药物组合物,其特征在于,包含权利要求1或2所述的化合物I及其药学上可接受的载体。
10.权利要求1或2所述化合物I在制备预防或治疗缺血性心脑血管疾病及改善心脑循环障碍药物中的应用。
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