CN117586232A - 一种依达拉奉前药衍生物及其应用 - Google Patents
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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Abstract
本发明提供的一种依达拉奉前药衍生物及其在制备治疗和/或预防心脑血管病药物中的应用。本发明通过对依达拉奉进行结构修饰,修饰后的结构与现有技术相比在体内表现出更长的半衰期,更高的暴露量,可适于长效性医药组合物,有望通过延长药物作用时间,减少单日给药次数,提高临床使用便利性及病人顺应性;此外,本发明提供的依达拉奉前药衍生物药效活性较好,毒副作用小,水溶性较好,理化性质较优,适宜制备各种固体和液体制剂,尤其是开发成注射剂。
Description
技术领域
本发明属于制药领域,涉及一种依达拉奉前药衍生物,以及其在制备治疗和/或预防心脑血管病药物中的应用。
技术背景
心脑血管疾病是心血管疾病和脑血管疾病的统称,泛指由于高脂血症、血液黏稠、动脉粥样硬化、高血压等所导致的心脏、大脑及全身组织发生缺血性或出血性疾病的通称。
脑血管病(cerebrovascular disease,简称CVD)是指由于脑血管异常导致的脑部病变。脑血管病可简单分为两类,一类是由于血液流动的减少或断流造成的缺血性脑血管病,另一类是由于血管破裂造成出血性脑血管病。缺血性脑血管病主要是脑梗塞(包括脑血栓形成和脑栓塞),除了脑梗塞以外,还有一种在24小时内可以完全恢复,不留任何后遗症的缺血性脑血管病,被称为短暂性脑缺血发作或一过性脑缺血发作,医生习惯简称为TIA,也叫作小中风。出血性脑血管病也分为两类,一类是血管破裂,血液流入脑实质内,称为脑出血或脑溢血。另一类是血管破裂,血液流入人包饶脑周围的蛛网膜下腔,称为蛛网膜下腔出血,医生简称为SAH。
依达拉奉(Edaravone),化学名称为3-甲基-1-苯基-2-吡唑啉-5-酮,其结构式如下所示,具有清除自由基和抑制脂质过氧化的作用,可以抑制脑细胞的过氧化作用及延迟性神经细胞死亡,并且可以减轻脑缺血和脑缺血引起的脑水肿及组织损伤,在各种动物脑缺血模型中均显示出对脑缺血具有非常好的保护作用。
由于依达拉奉在体内的半衰期短、代谢速度快,为了快速起效并在脑内达到较高的药物浓度,依达拉奉的上市剂型仅有注射剂,且单日给药次数多,临床上用于缺血性脑卒中治疗,治疗剂量为30mg*2次/d。此外,依达拉奉的水溶性不佳,稳定性较差,特别是在溶液条件下的稳定性较差,需要添加抗氧化剂以减少依达拉奉的氧化,这不但增加了注射剂生产和储存过程中的质量控制难度,也增加了患者使用时发生不良反应的风险。
为克服现有技术存在的缺陷,本发明提供的一种依达拉奉前药衍生物,通过对依达拉奉进行结构修饰,修饰后的结构与现有技术相比在体内表现出更长的半衰期,更高的暴露量,可适于长效性医药组合物,有望通过延长药物作用时间,减少单日给药次数,提高临床使用便利性及病人顺应性;此外,本发明提供的依达拉奉前药衍生物药效活性较好,毒副作用小,水溶性较好,理化性质较优,适宜制备各种固体和液体制剂,尤其是开发成注射剂。
发明内容
本发明的目的在于提供一种依达拉奉前药衍生物及其在制备治疗和/或预防心脑血管病药物中的应用,以克服现有技术中依达拉奉或其衍生物存在的缺陷和不足。
本发明提供了一种依达拉奉前药衍生物,具有通式(Ⅰ)所示的化合物或其盐:
其中,R1选自
L选自键、-C1-6烷基、-CH2O(C=O)CH2CH2-;
R2选自
条件是当L选自键的时候,R1不选自在一些优选的实施例中,所述的R1选自/>所述L定义如前所述。在一些优选的实施例中,所述的R2选自/>在一些优选的实施例中,本发明提供的化合物选自以下任一化合物或其盐:
本发明的第二个方面是提供上述化合物或药物组合物在制备治疗和/或预防心脑血管病药物中的应用。优选的,将上述药物组合物用于制备预防和/或治疗脑血管病药物中的应用;更优选的,将上述药物组合物用于制备预防和/或治疗缺血性脑血管病或者脑梗塞药物中的应用。
与现有技术相比,本发明提供的一种依达拉奉前药衍生物,通过对依达拉奉进行结构修饰,修饰后的结构在体内表现出更长的半衰期,更高的暴露量,可适于长效性医药组合物,有望通过延长药物作用时间,减少单日给药次数,提高临床使用便利性及病人顺应性;此外,本发明提供的依达拉奉前药衍生物药效活性较好,毒副作用小,水溶性较好,理化性质较优,适宜制备各种固体和液体制剂,尤其是开发成注射剂。
具体实施例
实施例1
3-甲基-1-苯基-1H-吡唑-5-基-3,5,6-三甲基吡嗪-2-甲酸酯(化合物1)的合成
将化合物1-1(315mg,1.81mmol)、化合物1-2(300mg,1.81mmol)溶解于二氯甲烷(9mL)中,室温搅拌下依次加入二环己基碳二亚胺(DCC,448mg,2.17mmol)与4-二甲氨基吡啶(DMAP,44mg,0.36mmol),搅拌过夜后过滤除去白色固体,得到滤液依次用饱和氯化铵水溶液(10mL)、饱和食盐水(10mL)洗涤,无水硫酸钠干燥后过滤,真空下除去溶剂后柱层析分离(VPE:VEA=4:1)得到化合物1(501mg,产率:86%)。
1H NMR(400MHz,Chloroform-d)δ7.88-7.81(m,2H),7.40(dd,J=8.6,7.2Hz,2H),7.29-7.26(m,1H),6.33(s,1H),2.73(s,3H),2.61(d,J=6.0Hz,6H),2.37(s,3H)。
实施例2
1-(2-(((3-甲基-1-苯基-1H-吡唑-5-基)氧)羰基)苯基)戊基-3,5,6-三甲基吡嗪-2-甲酸酯(化合物2)的合成
步骤1:中间体2-3的合成
将化合物1-2(1.0g,6.0mmol)溶解于无水二氯甲烷(30mL)中,冷却至0℃后向其中滴加草酰氯(765mg,6.0mmol)再滴加一滴DMF,搅拌10min后移至室温继续反应2h。反应完全后真空下除去溶剂,向其中加入甲苯(20mL),继续真空浓缩除去甲苯后得到中间体2-3。
步骤2:中间体2-2的合成
将化合物2-1(760mg,4.00mmol)溶解于甲醇(5mL)和水(5mL)组成的混合溶剂中,室温搅拌下加入氢氧化钠(0.17g,4.4mmol)固体,随后升温至50℃反应1h。反应完成使之冷却至室温,向其中滴加1M盐酸溶液至pH=3-4,乙醚(15mL)萃取,有机相再用饱和食盐水(10mL)洗涤,无水硫酸钠干燥后过滤,得到中间体2-2的乙醚溶液立即用于下步反应。
步骤3:中间体2-4的合成
按步骤2得到的中间体2-2的乙醚溶液(4.00mmol,15mL)用无水二氯甲烷(25mL)稀释后,氮气保护下冷却至0℃,依次加入三乙胺(1.11mL,8.00mmol)与DMAP(49mg,0.40mmol),搅拌5min后向其中滴加中间体2-3(6.0mmol,20mL)的二氯甲烷溶液,室温下反应过夜。反应完全后,用饱和氯化铵水溶液(15mL)淬灭反应,二氯己烷萃取(30mL×2)水相,有机相合并用饱和食盐水(30mL)洗涤,无水硫酸钠干燥后过滤,真空除去溶剂后柱层析分离(VPE:VEA=4:1)浓缩得到中间体2-4(650mg,产率:46%)。
步骤4:化合物1-(2-(((3-甲基-1-苯基-1H-吡唑-5-基)氧)羰基)苯基)戊基-3,5,6-三甲基吡嗪-2-甲酸酯(2)的合成
将中间体2-4(109mg,0.31mmol)、化合物1-1(44mg,0.26mmol)溶解于二氯甲烷(1.5mL)中,室温搅拌下依次加入DCC(63mg,0.31mmol)与DMAP(6mg,0.05mmol),搅拌过夜后过滤除去白色固体,得到滤液依次用饱和氯化铵水溶液(2mL)、饱和食盐水(2mL)洗涤,无水硫酸钠干燥后过滤,真空下除去溶剂后柱层析分离(VPE:VEA=4:1)得到化合物2(102mg,产率:77%)。
1H NMR(400MHz,Chloroform-d)δ7.98(dd,J=7.9,1.4Hz,1H),7.75(dd,J=7.9,1.2Hz,1H),7.64-7.58(m,3H),7.47-7.40(m,2H),7.36(dd,J=7.6,1.4Hz,1H),7.34-7.28(m,1H),6.81(dd,J=8.4,4.4Hz,1H),6.30(s,1H),2.68(s,3H),2.56(d,J=4.8Hz,6H),2.38(s,3H),2.00-1.89(m,2H),1.51-1.41(m,2H),1.33(ddd,J=13.6,7.5,4.5Hz,2H),0.87(t,J=7.2Hz,3H)。
实施例3
3-甲基-1-苯基-1H-吡唑-5-基-4-((2-(4-(1-异吲哚啉-2-基)苯基)丁酰)氧基)丁酸盐(化合物3)的合成
步骤1:中间体3-3的合成
将化合物3-1(1.5g,5.08mmol)、化合物3-2(719mg,6.10mmol)溶解于二氯甲烷(25mL)中,室温搅拌下依次加入DCC(1.26g,6.10mmol)与DMAP(124mg,1.02mmol),搅拌过夜后过滤除去白色固体,得到滤液依次用饱和氯化铵水溶液(20mL)、饱和食盐水(20mL)洗涤,无水硫酸钠干燥后过滤,真空下除去溶剂后柱层析分离(VPE:VEA=10:1)得到中间体3-3(1.49g,产率:74%)。
步骤2:中间体3-4的合成
将中间体3-3(1.49g,3.77mmol)溶解于二氯甲烷(30mL)中,加入TFA(7.5mL)室温搅拌2h后旋干除去溶剂,得到中间体3-4粗产品直接用于下步反应。
步骤3:化合物3-甲基-1-苯基-1H-吡唑-5-基-4-((2-(4-(1-异吲哚啉-2-基)苯基)丁酰)氧基)丁酸盐(3)的合成
将中间体3-4(245mg,0.65mmol)、化合物1-1(100mg,0.59mmol)溶解于二氯甲烷(3.5mL)中,室温搅拌下依次加入DCC(133mg,0.65mmol)与DMAP(14mg,0.12mmol),搅拌过夜后过滤除去白色固体,得到滤液依次用饱和氯化铵水溶液(5mL)、饱和食盐水(5mL)洗涤,无水硫酸钠干燥后过滤,真空下除去溶剂后柱层析分离(VPE:VEA=2:1)得到化合物3(213mg,产率:68%)。
1H NMR(400MHz,Chloroform-d)δ7.93-7.89(m,1H),7.80(d,J=8.5Hz,2H),7.59(t,J=7.4Hz,1H),7.49(dd,J=16.0,8.1Hz,4H),7.39(t,J=7.8Hz,2H),7.32(d,J=8.4Hz,2H),7.29(d,J=7.4Hz,1H),6.08(s,1H),4.78(s,2H),4.09(t,J=6.1Hz,2H),3.43(t,J=7.8Hz,1H),2.48(t,J=7.3Hz,2H),2.29(s,3H),2.15-2.03(m,1H),1.94(p,J=6.8Hz,2H),1.80(dt,J=14.2,7.3Hz,1H),0.89(t,J=7.2Hz,3H)。
实施例4
2,2-二甲基-3-((3-甲基-1-苯基-1H-吡唑-5-基)氧基)-3-氧代丙基-2-(4-(1-氧代异吲哚啉-2-基)苯基)丁酸酯(化合物4)的合成
步骤1:中间体4-2的合成
将化合物3-1(200mg,0.68mmol)、化合物4-1(72mg,0.61mmol)溶解于二氯甲烷(3.5mL)中,室温搅拌下依次加入DCC(140mg,0.68mmol)与DMAP(16mg,0.14mmol),搅拌过夜后过滤除去白色固体,得到滤液依次用饱和氯化铵水溶液(5mL)、饱和食盐水(5mL)洗涤,无水硫酸钠干燥后过滤,真空下除去溶剂后柱层析分离(VDCM:VMeOH=15:1)得到中间体4-2(202mg,产率:84%)。
步骤2:化合物2,2-二甲基-3-((3-甲基-1-苯基-1H-吡唑-5-基)氧基)-3-氧代丙基2-(4-(1-氧代异吲哚啉-2-基)苯基)丁酸酯(4)的合成
将中间体4-2(167mg,0.42mmol)、化合物1-1(65mg,0.38mmol)溶解于二氯甲烷(2.5mL)中,室温搅拌下依次加入DCC(87mg,0.42mmol)与DMAP(9mg,0.08mmol),搅拌过夜后过滤除去白色固体,得到滤液依次用饱和氯化铵水溶液(3mL)、饱和食盐水(3mL)洗涤,无水硫酸钠干燥后过滤,真空下除去溶剂后柱层析分离(VPE:VEA=6:1)得到化合物4(162mg,产率:78%)。
1H NMR(400MHz,Chloroform-d)δ7.88(d,J=7.9Hz,1H),7.75-7.69(m,2H),7.56(dd,J=7.9,6.5Hz,1H),7.47(dt,J=7.5,3.5Hz,2H),7.34(d,J=4.3Hz,4H),7.23(d,J=3.1Hz,3H),6.02(s,1H),4.74(s,2H),4.08(s,2H),3.38(t,J=7.7Hz,1H),2.25(s,3H),2.06-1.95(m,1H),1.80-1.71(m,1H),1.18(s,3H),1.15(s,3H),0.84(t,J=7.3Hz,3H)。
实施例5
3-甲基-1-苯基-1H-吡唑-5-基-((3,5,6-三甲基吡嗪-2-基)甲基)琥珀酸酯(化合物5)的合成
步骤1:中间体5-3的合成
将化合物5-1(200mg,1.32mmol)溶解于二氯甲烷(5mL)中,室温搅拌下依次加入化合物5-2(197mg,1.97mmol)与DMAP(240mg,1.97mmol),搅拌6h后用水(1mL)淬灭反应,加入二氯甲烷(10mL)稀释反应液,再依次用饱和碳酸氢钠水溶液(10mL)洗涤,水相用盐酸(3M)调节pH=4-5,EA(20mL)萃取水相后用饱和食盐水(10mL)洗涤,无水硫酸钠干燥后过滤,真空下除去溶剂后柱层析分离(VPE:VEA=6:1)得到中间体5-3(159mg,产率:48%)。
步骤2:3-甲基-1-苯基-1H-吡唑-5-基-((3,5,6-三甲基吡嗪-2-基)甲基)琥珀酸酯(5)的合成
将中间体5-3(159mg,0.63mmol)、化合物1-1(100mg,0.57mmol)溶解于二氯甲烷(3mL)中,室温搅拌下依次加入DCC(130mg,0.63mmol)与DMAP(7mg,0.06mmol),搅拌过夜后过滤除去白色固体,得到滤液依次用饱和氯化铵水溶液(3mL)、饱和食盐水(3mL)洗涤,无水硫酸钠干燥后过滤,真空下除去溶剂后柱层析分离(VDCM:VMeOH=10:1)得到化合物5(190mg,产率:81%)。
1H NMR(400MHz,Chloroform-d)δ7.53-7.45(m,2H),7.40(t,J=7.8Hz,2H),7.32-7.27(m,1H),6.07(d,J=1.0Hz,1H),5.19(s,2H),2.88-2.79(m,2H),2.79-2.71(m,2H),2.48(d,J=3.2Hz,6H),2.46(s,3H),2.30(d,J=1.1Hz,3H)。
实施例6
3-甲基-1-苯基-1H-吡唑-5-基-(2E)-3-(4-((1-H-咪唑-1-基)甲基)苯基)-2-丙烯酸(化合物6)的合成
将化合物6-1(241mg,1.06mmol)、化合物1-1(150mg,0.88mmol)溶解于二氯甲烷(5mL)中,室温搅拌下依次加入DCC(218mg,1.06mmol)与DMAP(11mg,0.09mmol),搅拌过夜后过滤除去白色固体,得到滤液依次用饱和氯化铵水溶液(5mL)、饱和食盐水(5mL)洗涤,无水硫酸钠干燥后过滤,真空下除去溶剂后柱层析分离(VDCM:VMeOH=10:1)得到化合物6(264mg,产率:79%)。
1H NMR(400MHz,Methanol-d4)δ9.11(d,J=1.6Hz,1H),7.91(d,J=15.8Hz,1H),7.81-7.75(m,3H),7.75-7.58(m,5H),7.50(q,J=7.9Hz,4H),7.36(t,J=7.4Hz,1H),5.51(s,2H),2.60(s,3H)。
实施例7
药代动力学实验
对本发明被研究化合物单次静脉给药(溶媒5%DMSO+10%Solutol(HS-15)+85%saline)于动物(例如小鼠、大鼠、犬或者猴子),在固定的时间点取血。血样采集后,立即温和地颠倒试管至少5次,保证混合充分后放置于冰上。血液用肝素抗凝,然后8000rpm离心5分钟,将血清与红细胞分离。用移液器吸岀血清转移至2mL的聚丙烯管,标明化合物的名称和时间点,在进行LC-MS分析前保存在-40℃冰箱,待测。髙浓度样品用空白血浆稀释测定时。样品处理后,用LCMS/MS对血浆中的物质进行定量分析。通过进行了验证的药动学计算机程序,用以这种方式获得的血浆浓度/时曲线来计算药动学参数。实验发现本发明化合物均具有较好的药代动力学性质。
SD雄性大鼠以表1组别剂量静脉给药后(各组为等摩尔剂量给药,溶媒为5%DMSO+10%Solutol(HS-15)+85%saline,每组3只),在固定的时间点取血检测,对照组的设置有:依达拉奉组、以及现有技术文献《Novel hybrids of 3-n-butylphthalide andedaravone:Design,synthesis and evaluations as potential anti-ischemic strokeagents》Xiao Sheng等报道的如下结构作为对照组1(CAS:1802341-60-1),以文献《吲哚布芬酯类化合物的设计与合成》李丰等报道的如下结构式作为对照组2。本发明的部分化合物以及对照组化合物在大鼠血浆中的依达拉奉药代动力学参数如下表1;
表1:
实验发现本发明化合物能在体内转化成依达拉奉,大鼠血浆中的依达拉奉的AUC相比对照组依达拉奉的AUC无显著降低,但半衰期均有所延长,尤其是化合物2半衰期相比依达拉奉以及其它对照组均显著延长,且AUC也表现出显著增加,体现出具有良好的药代动力学性质。
Claims (7)
1.一种依达拉奉前药衍生物,其特征在于,具有通式(Ⅰ)所示的化合物或其盐:
其中,R1选自
L选自键、-C1-6烷基、-CH2O(C=O)CH2CH2-;
R2选自
条件是当L选自键的时候,R1不选自
2.根据权利要求1所述的依达拉奉前药衍生物,其特征在于,R1选自
3.根据权利要求2所述的依达拉奉前药衍生物,其特征在于,R2选自
4.根据权利要求1所述的依达拉奉前药衍生物,其特征在于,选自以下任一化合物或其盐:
5.一种药物组合物,其特征在于,所述药物组合物包含权利要求1至4任一项所述的依达拉奉前药衍生物和药物上可接受的载体。
6.根据权利要求1至4任一项所述的依达拉奉前药衍生物或权利要求5所述的药物组合物在制备治疗和/或预防心脑血管病药物中的应用。
7.根据权利要求6所述的应用,所述应用为用于制备治疗和/或预防缺血性脑血管病或者脑梗塞药物中的应用。
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