CN103059020A - 一种吴茱萸次碱衍生物及其制备方法和应用 - Google Patents
一种吴茱萸次碱衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及药物化学和药物治疗学领域,提供了一种3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物及其制备方法与应用。实验证明,本发明的3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物对乙酰胆碱酯酶具有很强的抑制活性及很好的抑制选择性,其对乙酰胆碱酯酶的抑制能力比对丁酰胆碱酯酶的抑制能力高出3000多倍。所述3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物的化学式如下所示,式中n=1或2,R=吡啶基、3-氟吡啶基或1-甲基咪唑基。
Description
技术领域
本发明涉及药物化学和药物治疗学领域,具体涉及3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物及其制备方法与应用。
背景技术
胆碱酯酶依其催化底物的特异性分为乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BuChE)。AChE是生物神经传导中的关键酶之一,能在胆碱能突触间降解神经递质乙酰胆碱,终止神经递质对突触后膜持续去极化,保证生物体内的神经信号正常传递。BuChE主要存在于神经系统以外的各种组织中,参与某些药物的代谢过程,并有促进细胞生长的作用。
胆碱能神经元损伤,脑内Ach水平减少,会导致多种老年性痴呆,如阿尔兹海默症(Alzheimer’sdisease,AD)、脑血管痴呆等。阿尔兹海默症是一种进行性发展的致死性神经退行性疾病,是威胁老人健康的“四大杀手”之一,目前尚无有效的治疗手段。AD的发病机制尚未完全阐明,其中能得到普遍认同的是胆碱能假说,该假说认为胆碱能水平的降低是AD发病的主要原因。目前,利用乙酰胆碱酯酶抑制剂(AChEI)来提高患者脑内Ach的水平是治疗初期AD的主要药物。另外,有研究发现,AD患者的突触中BChE的活性并无明显提高。因此,乙酰胆碱酯酶抑制剂的选择性和专一性成为研究人员关注的重点问题之一。
重症肌无力是一种神经-肌肉接头部位因乙酰胆碱受体减少而出现传递功能障碍的自身免疫性疾病,这种无力现象是可逆的,临床研究发现通过给予乙酰胆碱酯酶抑制剂药物即可恢复。
吴茱萸次碱(Rutaecarpine)是存在于芸香科植物吴茱萸中的一种吲哚喹唑啉类生物碱,具有抗胃黏膜损伤、抗炎镇痛、降血压、松弛血管等广泛的药理作用。专利申请200910040039.5已公开了一种3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物及其应用,但是,目前7,8-脱氢吴茱萸次碱衍生物的开发研究仍比较少。
发明内容
为实现上述目的,本发明提供一种3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物,结构式为:
结构式中,n=1或2,
所述的-R为吡啶基、3-氟吡啶基或1-甲基咪唑基。
另外提供一种制备如权利要求1所述的吴茱萸次碱衍生物的方法,包括,
(1)合成3-氨基-吴茱萸次碱;
(2)酰化3-氨基-吴茱萸次碱到相应的酰化产物;
(3)3-氨基-吴茱萸次碱的酰化产物经2,3-二氯-5,6-二氰对苯醌脱氢后得到7,8-氢吴茱萸次碱的酰化产物;
(4)酰化产品与相应的胺反应,纯化,得到3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物;
其所述的步骤(2)到(4)的反应式如下:
所述的步骤(1)是按照Bergman合成吴茱萸次碱的方法,以硝化靛红酸酐、三氟乙酸、色胺为起始原料,经关环、氢化、去三氟甲基反应得到3-氨基-吴茱萸次碱。反应式如下所示:
Bergman,J.;Bergman,S.StudiesofRutaecarpineand RelatedQuinazolinocarboline Alkaloids.J.Org.Chem.,1985,50,1246
步骤(2)所述酰化为利用氯代烷基酰氯酰化。
所述的纯化为柱层析或重结晶。
另外提供一种如权利要求1所述的吴茱萸次碱衍生物的应用,其特征在于,3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物作为制备乙酰胆碱酯酶抑制剂药物中的应用。
再提供一种如权利要求1所述的吴茱萸次碱衍生物的应用,其特征在于,3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物作为制备治疗阿尔兹海默症、脑血管痴呆或重症肌无力疾病的药物中的应用。
所述的药物为注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂。
与现有技术相比,本发明具有如下有益效果:
1.本发明通过体外乙酰胆碱酯酶和丁酰胆碱酯酶的抑制实验,证明本发明的3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物对乙酰胆碱酯酶具有较强的抑制活性和较高的选择性,可以作为乙酰胆碱酯酶抑制剂药物应用。表明本发明所述的衍生物可用于制备治疗AD、脑血管痴呆与类胆碱能神经递质减少引起的相关疾病药物。
2.发明人对专利申请号为200910040039.5中的3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱的结构基础上进行结构优化研究,发现了比专利申请200910040039.5的衍生物活性更好、选择性更高的3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物。本发明所涉及的3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物,与专利申请200910040039.5的衍生物相比,对乙酰胆碱酯酶抑制活性提高了100多倍,选择性提高了10倍左右,具有显著的创新性。
具体实施方式
实施例1:化合物1的合成
在250mL的二氧六环中加入0.0026mol3-(2-氯乙酰胺基)-吴茱萸次碱,60℃加热搅拌至固体溶解;将0.0052molDDQ溶于10mL二氧六环,缓慢滴加到反应液中;滴加完后,加热回流12小时后,蒸干溶剂,固体用500mLKOH溶液(1.5gKOH溶于25mL水中)处理多次,直至DDQ-2H全部除去(滤液洗至无色),水洗,干燥得墨绿色固体1。
产率:86%;1H-NMR(400MHz,DMSO)δ(ppm):12.68(s,1H),10.69(s,1H),8.72(d,J=0.8,1H),8.63(d,J=7.5,1H),8.18(d,J=7.9,1H),8.08(d,J=7.8,1H),7.85(dd,J=10.6,8.7,2H),7.69(d,J=8.1,1H),7.50(t,J=7.3,1H),7.30(t,J=7.3,1H),4.34(s,2H);ESI-MSm/z:377.1[M+H]+.
化合物1
实施例2:化合物2的合成
在300mL的二氧六环中加入0.0025mol3-(2-氯丙酰胺基)-吴茱萸次碱,60℃加热搅拌至固体溶解;将0.0052molDDQ溶于10mL二氧六环,缓慢滴加到反应液中;滴加完后,加热回流12小时后,蒸干溶剂,固体用500mLKOH溶液(1.5gKOH溶于25mL水中)处理多次,直至DDQ-2H全部除去(滤液洗至无色),水洗,干燥得墨绿色固体2。
产率:95%;1H-NMR(400MHz,DMSO)δ(ppm):12.78(s,1H),10.53(s,1H),8.77(d,J=1.8Hz,1H),8.66(d,J=7.5Hz,1H),8.21(d,J=7.9Hz,1H),8.11(dd,J=8.9,2.1Hz,1H),7.89(t,J=7.2Hz,2H),7.71(d,J=8.2Hz,1H),7.53(t,J=7.5Hz,1H),7.32(t,J=7.6Hz,1H),3.94(t,J=6.2Hz,2H),2.92(t,J=6.1Hz,2H);ESI-MSm/z:391.1[M+H]+.
化合物2
实施例3:化合物3的合成
将0.0015mol化合物1与12.5mL吡啶混合,110℃加热回流8h后,冷却,加入少量乙醚析出沉淀,滤取沉淀,沉淀用乙醇/DMF(v/v=5:1)重结晶后得到棕色固体3。
产率:64%;1H-NMR(400MHz,DMSO)δ(ppm):12.69(s,1H),11.45(s,1H),9.13(d,J=5.1Hz,2H),8.76(d,J=7.5Hz,1H),8.72(d,J=8.3Hz,1H),8.60(d,J=15.9,4.6Hz,1H),8.26(t,J=6.8Hz,2H),8.18(d,J=8.1Hz,1H),8.10(d,J=9.6Hz,1H),7.89(d,J=8.8Hz,1H),7.84(d,J=7.6Hz,1H),7.70(d,J=8.2Hz,1H),7.54–7.46(m,1H),7.30(t,J=7.2Hz,1H),5.79(s,2H);ESI-MSm/z:420.1[M]+.
化合物3
实施例4:化合物4的合成
将0.0015mol化合物1与14.2mL3-氟吡啶混合,110℃加热回流8h后,冷却,加入少量乙醚析出沉淀,滤取沉淀,沉淀用乙醇/DMF(v/v=5:1)重结晶后得到棕色固体4。
产率:89%;1H-NMR(400MHz,DMSO)δ(ppm):12.70(s,1H),11.66(s,1H),9.59(s,1H),9.12(d,J=5.6Hz,1H),8.80(d,J=13.2Hz,2H),8.61(d,J=8.1Hz,1H),8.39(d,J=7.4Hz,1H),8.18(d,J=7.3Hz,1H),8.12(d,J=10.1Hz,1H),7.89(d,J=9.7Hz,1H),7.84(d,J=8.3Hz,1H),7.70(d,J=9.1Hz,1H),7.53–7.47(m,1H),7.35–7.23(m,1H),5.85(s,2H);ESI-MSm/z:438.1[M]+.
化合物4
实施例5:化合物5的合成
将0.0015mol化合物1与13.2mL1-甲基咪唑混合,110℃加热回流8h后,冷却,加入少量乙醚析出沉淀,滤取沉淀,沉淀用乙醇/DMF(v/v=5:1)重结晶后得到棕色固体5。
产率:78%;1H-NMR(400MHz,DMSO)δ(ppm):12.69(s,1H),11.33(s,1H),9.21(s,1H),8.78(s,1H),8.62(d,J=7.2Hz,1H),8.18(d,J=7.5Hz,1H),8.10(d,J=8.6Hz,1H),7.86(dd,J=16.2,8.4Hz,3H),7.77(s,1H),7.70(d,J=8.2Hz,1H),7.50(t,J=7.0Hz,1H),7.30(t,J=6.9Hz,1H),5.35(s,2H),3.95(s,3H);ESI-MSm/z:423.1[M]+.
化合物5
实施例6:化合物6的合成
将0.0015mol化合物2与12.5mL吡啶混合,110℃加热回流8h后,冷却,加入少量乙醚析出沉淀,滤取沉淀,沉淀用乙醇/DMF(v/v=5:1)重结晶后得到棕色固体6。
产率:64%;1H-NMR(400MHz,DMSO)δ(ppm):12.70(s,1H),10.93(s,1H),9.23(d,J=4.5Hz,2H),8.74(s,1H),8.60(d,J=7.4Hz,2H),8.19(d,J=6.1Hz,3H),8.04(d,J=8.4Hz,1H),7.83(s,2H),7.68(d,J=7.8Hz,1H),7.49(t,J=6.5Hz,1H),7.29(t,J=6.7Hz,1H),4.98(m,2H),3.29(m,2H);ESI-MSm/z:434.2[M]+.
化合物6
实施例7:化合物7的合成
将0.0015mol化合物2与14.2mL3-氟吡啶混合,110℃加热回流8h后,冷却,加入少量乙醚析出沉淀,滤取沉淀,沉淀用乙醇/DMF(v/v=5:1)重结晶后得到棕色固体7。
产率:60%;1H-NMR(400MHz,DMSO)δ(ppm):12.70(s,1H),11.66(s,1H),9.59(s,1H),9.12(d,J=5.6Hz,1H),8.80(d,J=13.2Hz,2H),8.61(d,J=8.1Hz,1H),8.39(d,J=7.4Hz,1H),8.18(d,J=7.3Hz,1H),8.12(d,J=10.1Hz,1H),7.89(d,J=9.7Hz,1H),7.84(d,J=8.3Hz,1H),7.70(d,J=9.1Hz,1H),7.53–7.47(m,1H),7.35–7.23(m,1H),4.98(m,2H),3.29(m,2H);ESI-MSm/z:452.2[M]+.
化合物7
实施例8:化合物8的合成
将0.0015mol化合物2与13.2mL1-甲基咪唑混合,110℃加热回流8h后,冷却,加入少量乙醚析出沉淀,滤取沉淀,沉淀用乙醇/DMF(v/v=5:1)重结晶后得到棕色固体8。
产率:56%;1H-NMR(400MHz,DMSO)δ(ppm):12.69(s,1H),10.93(s,1H),9.27(s,1H),8.80(s,1H),8.61(d,J=7.5,1H),8.17(d,J=7.9,1H),8.08(d,J=8.0,1H),7.87–7.80(m,3H),7.74–7.66(m,2H),7.49(t,J=7.6,1H),7.30(t,J=7.4,1H),4.54(m,2H),3.88(s,3H),3.12 (m,2H);ESI-MSm/z:437.2[M]+.
化合物8
以上所述的化合物1、2为中间产物,化合物3、4、5、6、7、8为目标3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物。
实施例9:应用Ellman(Biochemical Pharmacology 1961,7,88-95.)的方法测试化合物对乙酰胆碱酯酶和丁酰胆碱酯酶的抑制作用,结果用IC50值表示,以Tacrine以及专利申请200910040039.5的化合物10、11、12作为阳性对照。所有的测试均在PowerWaveXS2型全波长酶标仪上进行,在37℃的条件下测定。数据分析利用软件Origin进行处理。
实验步骤:
(1)药物溶液的配制:
称取一定量的各种待分析样品溶于二甲亚砜(DMSO,dimethylsulfoxide),配成10mM浓度,-20℃低温冰箱保存,临用时用磷酸盐缓冲液(0.1mol/L,pH8.0)稀释至所需浓度,使DMSO终浓度小于或等于0.5%(v/v)。
(2)酶储备液的配制:
乙酰胆碱酯酶(E.C.3.1.1.7,from electric ell.)和丁酰胆碱酯酶(E.C.3.1.1.8,from equine serum)从Sigma公司购买;称取一定量乙酰胆碱酯酶或丁酰胆碱酯酶,用去离子水稀释至合适活力范围。
(3)底物储备液的配制:
硫代乙酰胆碱(Acetylthiocholine,ATC)和硫代丁酰胆碱(Butylthiocholine,BTC)从Sigma公司购买;称取一定量ATC或BTC,用磷酸盐缓冲溶液(0.1mol/L,pH8.0)配制成0.01mol/L的溶液,
4℃遮光保存。
(4)显色剂储备液的配制:
显色剂5,5-二硫代双(2-硝基苯甲酸)(DTNB)从Sigma公司购买;称取一定量DTNB,用磷酸盐缓冲溶液(0.1mol/L,pH8.0)配制成0.01mol/L,4℃遮光保存。
(5)测试:
在96孔板中选取6个孔,分别加入10μL酶溶液,以及0,5,10,20,35,50μL待测化合物溶液,加入0.1mol/LpH8.0磷酸缓冲溶液使总体积为100μL,在37℃全波长酶标仪中孵育15min,立即加入10μLATC溶液(或BTC)、10μLDTNB溶液及80μL磷酸缓冲溶液的混合液共100μL,在λ=412nm扫描2min测定吸光度变化。
(6)结果判断:
以没有加入抑制剂时测得的吸光度变化(斜率)为100个活力单位(Acontrol),相对酶活力=(加入抑制剂的吸光度变化/没有加入抑制剂的吸光度变化)×100,当相对酶活力达到50时,即为抑制剂的IC50值。实验结果为三次独立实验的平均值。
实验结果:
表1化合物3-8,10-12及Tacrine对乙酰胆碱酯酶和丁酰胆碱酯酶抑制作用的IC50值及抑制选择性
a对乙酰胆碱酯酶的选择性=IC50(丁酰胆碱酯酶)/IC50(乙酰胆碱酯酶)
b化合物10、11、12对应专利申请200910040039.5的化合物10、11、12
结论:从表1发现所有的衍生物对乙酰胆碱酯酶均有较好的抑制活性,活性达到0.6~9.3nM,大大高于专利申请200910040039.5的化合物10、11、12(IC50均高于50nM);而对丁酰胆碱酯酶的抑制活性较弱,对乙酰胆碱酯酶的选择性较高,选择性范围达到755~3225,大大高于专利申请200910040039.5的化合物10、11、12(选择性均低于400)。化合物3和4在所测试的化合物中具有最高的乙酰胆碱酯酶抑制活性(IC50依次为0.76nM、0.60nM),同时具有最高的乙酰胆碱酯酶抑制选择性(依次为3225、3092),因此本发明的化合物具有显著创新性。
Claims (8)
2.一种制备如权利要求1所述的吴茱萸次碱衍生物的方法,其特征在于,包括,
(1) 合成3-氨基-吴茱萸次碱;
(2) 酰化3-氨基-吴茱萸次碱到相应的酰化产物;
(3) 3-氨基-吴茱萸次碱的酰化产物经2,3-二氯-5,6-二氰对苯醌脱氢后得到7,8-氢吴茱萸次碱的酰化产物;
(4) 酰化产品与相应的胺反应,纯化,得到3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物。
3.如权利要求2所述的制备方法,其特征在于步骤(1)是按照Bergman合成吴茱萸次碱的方法,以硝化靛红酸酐、三氟乙酸、色胺为起始原料,经关环、氢化、去三氟甲基反应得到3-氨基-吴茱萸次碱。
4.如权利要求2 所述的制备方法,其特征在于步骤(2) 所述酰化为利用氯代烷基酰氯酰化。
5.如权利要求2所述的吴茱萸次碱衍生物的制备方法,其特征在于,所述的纯化为柱层析或重结晶。
6.一种如权利要求1所述的吴茱萸次碱衍生物的应用,其特征在于,3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物作为制备乙酰胆碱酯酶抑制剂药物中的应用。
7.一种如权利要求1所述的吴茱萸次碱衍生物的应用,其特征在于,3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物作为制备治疗阿尔兹海默症、脑血管痴呆或重症肌无力疾病的药物中的应用。
8.如权利要求6或7所述的应用,所述的药物为注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂。
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