CN104003987B - 他克林-β-咔啉异二连体类多功能胆碱酯酶抑制剂 - Google Patents
他克林-β-咔啉异二连体类多功能胆碱酯酶抑制剂 Download PDFInfo
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- 238000004148 unit process Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明涉及药物化学领域,具体涉及一类他克林-β-咔啉异二连体类化合物(I,II,III),药效学试验证明,本发明的这类化合物可作为多功能胆碱酯酶抑制剂,临床可用于治疗阿尔茨海默病。
Description
技术领域
本发明涉及药物化学领域,具体涉及一类他克林-β-咔啉异二连体类化合物,这类化合物可作为多功能胆碱酯酶抑制剂。
背景技术
阿尔茨海默病简称AD。AD是一种多病机异质性疾病,其成因除了同脑内胆碱水平的降低相关外还同Aβ的聚集、金属离子代谢的紊乱、钙平衡的失调、自由基的增多以及炎症的发生等因素密切相关。针对上述病因,AD的治疗靶点主要有:乙酰胆碱酯酶(AChE)、金属离子、β淀粉样蛋白肽(Aβ)、单胺氧化酶(MAO)、自由基、τ蛋白、N-甲基-D-天冬氨酸(NMDA)受体及其他相关靶点。目前临床上用于治疗AD的药物多属于针对单一靶点治疗药物,一类是以提高脑内胆碱水平为目的的乙酰胆碱酯酶抑制剂,有他克林(Tacrine)、多奈哌齐(Donepezil)、利伐司替明(Rivastigmine)和加兰他敏(Galanthamine)。另一类为NMDA受体拮抗剂美金刚(Memantine)。这些药物虽然能够提高患者的认知能力和日常行为能力,暂时缓解AD症状,但不能从根本上改善疾病状态或终止疾病的进程。
随着AD致病机理的不断阐明,发现AD的发生和发展是细胞内及生物体内复杂的调控网络和调控因子的多重作用结果,涉及多基因之间的关联。而针对单一靶点的单靶点药物往往只能调控其中的某一个生理途径不能从根本上抑制AD的病理进程。因此,寻求具有针对多个靶标的多靶点治疗药物成了AD治疗药物研发的新趋势。他克林是最早的经FDA批准上市的AD治疗药物,能有效的抑制胆碱酯酶,其体外活性达到纳摩尔级,但是由于其严重的肝脏毒副作用,近些年来退出了临床应用。但尽管如此,他克林作为一个曾经上市过的药物还是受到了广泛的关注,他克林能很好的结合于乙酰胆碱酯酶的CAS,通过连接一个具有另外活性的结构片段不但能很好的发挥补充的生物活性而且还能有效结合于乙酰胆碱酯酶的PAS位点从而达到双作用、多靶点作用目的。因此,研究开发具有他克林骨架的新型多功能胆碱酯酶抑制剂不仅符合抗阿尔茨海默病的要求,而且具有良好的市场前景。
发明内容
本发明公开了一类他克林-β-咔啉异二连体类化合物,药效学实验证明,本发明的化合物可作为多功能胆碱酯酶抑制剂。
本发明的化合物结构如I、II或III所示:
其中R1表示H、CH3、C2H5、C6H5、C6H5-p-F或C6H5-p-OCH3,n=2、4、6、8或10;
R2表示H或BOC;
R3表示H、COCH3或BOC。
最优选的化合物结构如下:
本发明化合物的药学上可接受的盐是通式I、II或III化合物的盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、萘磺酸盐、柠檬酸盐、酒石酸盐、乳酸盐、丙酮酸盐、乙酸盐、马来酸盐、琥珀酸盐、富马酸盐、水杨酸盐、苯基乙酸盐、杏仁酸盐、碱性金属阳离子盐、碱土金属阳离子盐或铵阳离子盐。最优选盐酸盐。
本发明通式I、II或III化合物的制备方法如下:
R1,R2,R3,n的定义同前。
本发明化合物都可以用上述或类似上述的制备方法制备得到,根据取代基的不同和取代基位置的不同选用相应的原料即可。
反应基本过程:本发明他克林-β-咔啉异二连体类化合物的制备方法包括Pictet-Spengler反应,酯化反应,氧化反应,酯水解反应,酰氯化反应,胺化反应、缩合反应以及后处理各单元过程:
中间体Ⅳ-6的合成优选:在适量的硫酸催化下,L-色氨酸与不同的醛发生Pictet-Spengler反应,室温反应8-10小时,监测反应结束后,调节反应液pH至4左右,有大量固体析出,抽滤,粗品用甲醇重结晶得中间体Ⅳ-2;Ⅳ-2在甲醇溶液中与过量的SOCl2回流2-4小时,酯化反应完全后,减压蒸去溶剂,萃取,浓缩,干燥得中间体Ⅳ-3;Ⅳ-3在甲苯中与硫回流12小时氧化得中间体Ⅳ-4;Ⅳ-4在NaOH溶液中水解4-6小时得中间体Ⅳ-5;Ⅳ-5与SOCl2回流发生酰氯化反应得中间体Ⅳ-6。
中间体Ⅴ-1的合成优选:Ⅳ-2与BOC2O和催化量三乙胺在DMF中反应4小时,得中间体Ⅴ-1。
化合物Ⅰ的合成优选:中间体Ⅳ-6与Ⅳ-7在无水CH2Cl2中,室温下以三乙胺催化反应1小时得化合物Ⅰ。
化合物Ⅱ的合成优选:中间体Ⅴ-1与Ⅳ-7在无水THF中,室温下以N,N'-羰基二咪唑(CDI)为缩合剂反应12小时得化合物Ⅱ。
化合物Ⅲ的合成优选:中间体Ⅵ-1与Ⅳ-7在无水THF中,室温下以N,N'-羰基二咪唑(CDI)为缩合剂反应12小时得化合物Ⅲ。
下面是本发明化合物的部分药理学实验及数据:
一、乙酰胆碱酯酶和丁酰胆碱酯酶抑制活性
实验方法:AChE和BuChE抑制活性测试方法为Ellman法。将化合物溶解于DMSO中,依次用缓冲液A稀释至所需浓度,控制所配置溶液中的DMSO含量低于1%。往96空白中依次加入,160微升1.5毫摩尔DTNB,50微升AChE(0.22U/mL,用缓冲液B制得)和10微升不同浓度抑制剂。37度下孵化6分钟,然后快速加入30微升碘化乙酰胆碱(15mM)。在405纳米下测定0,60,120和180秒的吸光度变化。丁酰胆碱酯酶的测定方法同乙酰胆碱酯酶类似,将所用的乙酰胆碱酯酶换为丁酰胆碱酯酶(0.12U/mL,用缓冲液B制得)同时替换底物碘化乙酰胆碱为硫代碘化丁酰胆碱(15mM)。抑制率的计算为:[1-(实验组吸光度变化/空白组吸光度变化)]*100%。选择化合物的五至七个浓度测定酶的抑制率(0.001-100μM)并以该化合物摩尔浓度的负对数与酶抑制率进行线性回归,求得50%抑制时的摩尔浓度即为该化合物的IC50值.每个实验重复三次,实验结果表达为平均值±SEM。
表1本发明化合物乙酰、丁酰胆碱酯酶抑制活性和选择性指数
a选择性指数=IC50(丁酰胆碱酯酶)/IC50(乙酰胆碱酯酶)
从表1可知,本发明化合物对乙酰胆碱酯酶和丁酰胆碱酯酶均具有显著抑制作用:对乙酰胆碱酯酶抑制的IC50为21.6nM-783nM,对丁酰胆碱酯酶抑制的IC50为7.5nM-539nM;而优选的化合物Ⅱ-2对乙酰胆碱酯酶的抑制活性(IC50=21.6nM)是β-咔啉化合物哈尔满碱(IC50=63,000nM)的2916倍,是前体化合物他克林(IC50=260nM)的12倍;化合物Ⅲ-1对丁酰胆碱酯酶的抑制活性(IC50=4.3nM)是前体化合物他克林(IC50=50.5nM)的12倍。说明本发明所公开的化合物对胆碱酯酶具有好的抑制作用。
二、乙酰胆碱酯的动力学研究
用Ellman法对化合物Ⅳ-2进行酶动力学研究。化合物Ⅱ-2的三个不同浓度选作动力学研究分别为40,20和10nM。往96空板中依次加入,160微升1.5毫摩尔的DTNB,50微升AChE(0.22U/mL,用缓冲液B制得)和10微升40nM的化合物。37度下孵化6分钟,然后快速加入30微升不同浓度的碘化乙酰胆碱(终浓度为0.05-0.5mM)。在405纳米下测定0,60,120和180秒的吸光度变化。以浓度的倒数为X轴和吸光度变化速率为Y轴作图,做出第一条双倒数曲线。依此方法,加入20nM,10nM和0nM浓度的化合物,做出第二、三、四双倒数曲线,以双倒数曲线的的交点判断化合物同酶的作用模式。
结果见图1,图1表明:本发明所公开的化合物随着浓度的增加Lineweaver-Burk的双倒数曲线的斜率和截距也不断增加。这种模式显示,化合物为混合型抑制剂,说明化合物结合于酶的不同位点,即能同时的结合于PAS和CAS两个位点,为双位点抑制剂,更有利于阿尔茨海默病的治疗。
三、抗Aβ(1-42)聚集作用研究
将1mgAβ(1-42)用1,1,1,3,3,3-六氟-2-异丙醇(HFIP)溶解后,分装为10份,在通风橱中隔夜挥干,使其解聚,保存在-30℃待用。在准备实验之前,取其中一份加DMSO配成悬浮液,再加入磷酸缓冲液稀释至25μM,超声使其溶解,控制DMSO含量不高于10%。化合物用DMSO配制为浓度200μM。往黑色96孔板中依次加入,1μL测试化合物和9μLAβ(1-42)磷酸盐溶液,加入完毕后,轻拍使之混匀,用盖板膜将96空板盖好,防止溶液挥发,于室温下,黑暗处静置46-48小时。静置结束后,加入200μL用甘氨酸-氢氧化钠缓冲液制备的50mM硫代硫磺素T,于激发光波长446nm和吸收光波长为490nm下测定荧光吸收。其抑制率计算公式为:100-(IFi/IFo*100),IFi代表抑制剂存在下的荧光吸收;IFo代表无抑制存在下的荧光吸收。每个实验重复三次,结果表达为平均值±SD。结果见表2.
表2本发明化合物的Aβ(1-42)抑制率
表2表明,本发明所公开的化合物都表现出了中等到好(25.3~65.8%at20μM)的抑制活性(阳性对照药姜黄素:42.3%at20μM)。优选的化合物Ⅱ-2(68.5%at20μM)对Aβ(1-42)的抑制活性强于β-咔啉化合物哈尔满碱(22.1%at20μM)和他克林(6.5%at20μM)。四、金属离子螯合物作用
将氯化铜用甲醇溶解后,分别定量到不同浓度,其终浓度为5,10,15,20,30,40,50,60,70,80μM留待后用,化合物用甲醇配制后定容,终浓度为25μM。在固定量的化合物中依次加入增量的金属离子,测定其200到500nM的吸光度。将加入增加金属离子后的化合物紫外光谱减去相同浓度下的金属离子的吸光度和化合物本身的吸光度得到化合物由于加入金属离子后的吸光度增加的差谱。
图2为化合物Ⅱ-2与增加量的铜离子作用的紫外吸光谱图。其加增的吸收可以有图3看出,可以看出化合物Ⅱ-2吸光度的增加是由于化合物与金属离子作用引起的并不是金属离子本身造成的。这说明化合物能够螯合金属离子可以作为金属离子螯合剂,从而用于阿尔茨海默病的治疗。
本发明他克林-β-咔啉异二连体组合了对AD治疗有效的他克林及β-咔啉母核,并加以适当长度的连接基;计算化学的分子对接结果表明,异二连体可以同时与AChE的催化位点(CAS)和外周结合位点(PAS);而且他克林-(β-咔啉)异二连体在体外实验中显示出好的乙酰/丁酰胆碱酯酶抑制活性,抗Aβ(1-42)聚集活性,抗氧化活性和金属离子螯合活性,也可以减轻H2O2诱导的PC12细胞凋亡并且能够通过血脑屏障。故它们可以作为多功能胆碱酯酶抑制剂来控制AD病程的发展。
本发明还公开了一种药物组合物,含有通式I、II或III的化合物或其药学上可接受的盐及药学上可接受的载体。可以通过添加药学上可接受的载体制成各种制剂。在临床用于口服、注射等。
本发明的化合物临床所用剂量为0.01mg~1000mg/天,也可根据病情的轻重或剂型的不同偏离此范围。
附图说明
图1是化合物Ⅱ-2抑制乙酰胆碱酯酶的动力学研究
图2是化合物Ⅱ-2加入增加量铜离子的紫外谱图
图3是化合物Ⅱ-2同铜离子的差谱
具体实施方式
实施例1
中间体3S-1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸(Ⅳ-2-a)的制备
在250mL单颈瓶中加入L-色胺酸10.2g(50mmol)、氢氧化纳固体2.05g(55mmol)和水100mL,搅拌至固体全部溶解,室温下加入乙醛水溶液(6mL),该反应液先于室温搅拌3h,然后加热回流3h,TLC检测原料消失(展开剂:甲醇/氯仿=1:1)。将反应液倒入冰水(100mL)中,用冰乙酸调节pH到6,有大量白色固体析出,冷却,抽滤,滤饼用水洗涤,甲醇重结晶得淡白色固体9.0g,收率83.5%。1HNMR(500MHz,DMSO):δ11.92(s,1H),10.97(s,1H),9.17(s,1H),7.42(d,J=7.5Hz,1H),7.29(t,J=8.0Hz,1H),7.10(t,J=8.0Hz,1H),7.00(t,J=7.5Hz,1H),4.22(q,J=5.0Hz,1H),3.66(dd,J=10.5Hz,J=5.0Hz,1H),3.14(dd,J=10.5Hz,J=2.5Hz,1H),2.85(m,1H),1.56(d,J=5.0Hz,3H).
实施例2
中间体3S-1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(Ⅳ-3-a)的制备
在1000mL三颈瓶中加入中间体Ⅳ-2-a(25g,116mmol)和无水甲醇580mL,室温搅拌下缓慢滴加二氯亚砜(23mL,315mmol)。滴加完毕后升温至回流,反应6h。冷却反应液至室温,减压蒸去溶剂,所得固体用甲醇-乙酸乙酯重结晶,得黄色固体29.6g,收率95.5%。
实施例3
中间体β-咔啉-3-羧酸甲酯(Ⅳ-4-a)的制备
将中间体Ⅳ-3-a(6.9g,30mmol)置于100ml的单颈瓶中,冰浴冷却条件下加入无水DMF并分批加入高锰酸钾(5.0g,32mmol),反应液过夜,将反应液过滤,滤液减压浓缩的红褐色固体,乙酸乙酯重结晶得浅黄色固体3.3g,收率67.4%。
实施例4
中间体1-甲基-β-咔啉-3-羧酸(Ⅳ-5-a)的制备
将中间体Ⅳ-4-a(2.3g,10mmol),氢氧化钠(40mmol),乙醇(50mL)和水(100mL)置于100mL的单颈瓶,回流1h,减压蒸去乙醇,用盐酸调节pH到5,有大量固体析出,冷却,抽滤,干燥得淡黄色固体,收率90.1%。
实施例5
中间体1-甲基-β-咔啉-3-甲酰氯(Ⅳ-6-a)的制备
将中间体Ⅳ-5-a(2.1g,10mmol),二氯亚砜(10mL)和无水氯仿(50mL)置于100mL的单颈瓶,回流1h,减压蒸去溶剂,未经纯化直接用于下一步。
实施例6
中间体N-BOC-3S-1,2,3,4-四氢-β-咔啉-3-羧酸的制备(Ⅴ-1-a)
BOC2O(1.7g,7.7mmol)缓慢加到盛有3S-1,2,3,4-四氢-β-咔啉-3-羧酸(1.1g,5.0mmol)和三乙胺的无水DMF(15mL)中,室温反应5h,加入20%柠檬酸(5mL),乙酸乙酯萃取,无水硫酸钠干燥,过滤,浓缩,氯仿重结晶得淡白色固体1.2g,收率76%。ESI/MSm/z:317.1[M+H]+;1HNMR(500MHz,DMSO):δ10.87(s,1H),9.86(s,1H),7.32(t,J=7.5Hz,1H),7.21(t,J=8.0Hz,1H),7.00(d,J=8.0Hz,1H),6.84(t,J=7.5Hz,1H),4.84(t,J=5.0Hz,1H),4.20(dd,J=10.0Hz,J=5.0Hz,1H),3.98(dd,J=10.0Hz,J=3.0Hz,1H),2.93(d,J=10.0Hz,2H),1.46(s,9H).
实施例7
1-甲基-N-(2-((1,2,3,4-四氢吖啶-9-基)氨基)乙基)-9H-吡啶[3,4-b]吲哚-3-甲酰胺(Ⅰ-1)的制备
将中间体Ⅳ-6-a(0.25mg,1mmol)溶于无水二氯甲烷(30mL),缓慢滴加到盛有三乙胺(0.28mL,2mmol)和中间体Ⅳ-7-a(N1-(四氢吖啶-9-基)乙基-1,2-二胺)(0.24mg,1mmol)的二氯甲烷(10mL)溶液中,反应2h,加水,二氯甲烷萃取,无水硫酸钠干燥,过滤,浓缩,柱层析(二氯甲烷:甲醇:三乙胺=100:4:0.5)得浅黄色固体(0.26mg,59.5%).m.p.139-141℃;ESI/MSm/z:405.3[M+H]+;1HNMR(500MHz,DMSO)δ12.08(s,1H),8.81(t,J=6.0Hz,1H),8.71(s,1H),8.39(d,J=8.0Hz,1H),8.24(d,J=8.5Hz,1H),7.74(d,J=8.0Hz,1H),7.68(d,J=8.0Hz,1H),7.61(t,J=7.5Hz,1H),7.55(t,J=7.5Hz,1H),7.37(t,J=7.0Hz,1H),7.32(t,J=7.5Hz,1H),3.74-3.69(m,2H),3.68-3.63(m,2H),2.87(d,J=6.0Hz,2H),2.84(s,3H),2.82(d,J=6.0Hz,2H),1.79(d,J=3.0Hz,4H).
实施例8
1-甲基-N-(2-((1,2,3,4-四氢吖啶-9-基)氨基)丁基)-9H-吡啶[3,4-b]吲哚-3-甲酰胺(Ⅰ-2)的制备
制备过程同Ⅰ-1,将中间体Ⅳ-7-a换为中间体Ⅳ-7-b(N1-(四氢吖啶-9-基)丁基-1,4-二胺),收率56.2%,m.p.145-147℃;ESI/MSm/z:478.3[M+H]+;1HNMR(500MHz,DMSO)δ12.04(s,1H),8.68(s,1H),8.62(t,J=6.0Hz,1H),8.36(m,2H),7.85(d,J=8.5Hz,1H),7.74(t,J=7.5Hz,1H),7.70(d,J=8.0Hz,1H),7.62(t,J=7.5Hz,1H),7.50(t,J=8.0Hz,1H),7.33(t,J=7.5Hz,1H),3.78(dd,J=13.0,6.5Hz,2H),3.43(dd,J=13.0,6.5Hz,2H),2.96(s,2H),2.87(s,3H),2.73(s,2H),1.84(s,4H),1.82-1.75(m,2H),1.75-1.66(m,2H).
实施例9
1-甲基-N-(2-((1,2,3,4-四氢吖啶-9-基)氨基)己基)-9H-吡啶[3,4-b]吲哚-3-甲酰胺(Ⅰ-3)的制备
制备过程同Ⅰ-1,将中间体Ⅳ-7-a换为中间体Ⅳ-7-c(N1-(四氢吖啶-9-基)己基-1,6-二胺),收率53.9%,m.p.136-139℃;ESI/MSm/z:506.3[M+H]+;1HNMR(500MHz,DMSO)δ11.94(s,1H),8.66(s,1H),8.54(t,J=6.0Hz,1H),8.34(d,J=8.0Hz,1H),8.18(d,J=8.5Hz,1H),7.74(d,J=8.5Hz,1H),7.66(d,J=8.0Hz,1H),7.59(dd,J=13.0,7.0Hz,2H),7.39(t,J=7.5Hz,1H),7.30(t,J=7.5Hz,1H),3.50(dd,J=13.5,6.5Hz,2H),3.35(m,2H),2.92(t,J=5.5Hz,2H),2.85(s,3H),2.71(t,J=5.5Hz,2H),1.81(d,J=5.0Hz,4H),1.66-1.59(m,2H),1.59-1.50(m,2H),1.36(s,4H).
实施例10
1-甲基-N-(2-((1,2,3,4-四氢吖啶-9-基)氨基)辛基)-9H-吡啶[3,4-b]吲哚-3-甲酰胺(Ⅰ-4)的制备
制备过程同Ⅰ-1,将中间体Ⅳ-7-a换为中间体Ⅳ-7-d(N1-(四氢吖啶-9-基)辛基-1,8-二胺),收率54.2%,m.p.144-148℃;ESI/MSm/z:534.3[M+H]+;1HNMR(500MHz,DMSO)δ11.90(s,1H),8.64(s,1H),8.51(t,J=6.0Hz,1H),8.32(d,J=8.0Hz,1H),8.18(d,J=8.5Hz,1H),7.73(d,J=8.5Hz,1H),7.60(dt,J=15.0,8.0Hz,3H),7.39(t,J=7.5Hz,1H),7.28(t,J=7.5Hz,1H),3.52(d,J=4.0Hz,2H),3.32(d,J=4.0Hz,,2H),2.91(d,J=5.5Hz,2H),2.83(s,3H),2.69(d,J=5.5Hz,2H),1.80(d,J=5.0Hz,4H),1.65-1.57(m,2H),1.56-1.50(m,2H),1.28(s,8H).
实施例11
1-甲基-N-(2-((1,2,3,4-四氢吖啶-9-基)氨基)葵基)-9H-吡啶[3,4-b]吲哚-3-甲酰胺(Ⅰ-5)的制备
制备过程同Ⅰ-1,将中间体Ⅳ-7-a换为中间体Ⅳ-7-e(N1-(四氢吖啶-9-基)葵基-1,10-二胺),收率53.8%,m.p.105-107℃;ESI/MSm/z:562.3[M+H]+;1HNMR(500MHz,DMSO)δ11.91(s,1H),8.66(s,1H),8.55(t,J=6.0Hz,1H),8.33(d,J=8.0Hz,1H),8.19(d,J=8.5Hz,1H),7.74(d,J=8.5Hz,1H),7.61(m,3H),7.41(t,J=7.5Hz,1H),7.29(t,J=7.5Hz,1H),3.53(d,J=6.0Hz,2H),3.30(m,2H),2.92(t,J=6.0Hz,2H),2.85(s,3H),2.69(t,J=5.5Hz,2H),1.82(d,J=5.5Hz,4H),1.66-1.50(m,4H),1.29(s,6H),1.23(s,6H).
实施例12
N-(6-((1,2,3,4-四氢吖啶-9-基)氨基)己基)-9H-吡啶[3,4-b]吲哚-3-甲酰胺(Ⅰ-6)的制备
制备过程同Ⅰ-3,将中间体Ⅳ-6-a换为中间体Ⅳ-6-b(β-咔啉-3-甲酰氯),收率,58.5%;m.p.68-71℃;ESI/MSm/z:491.3[M+H]+;1HNMR(500MHz,DMSO)δ9.12(s,1H),8.85(s,1H),8.69(t,J=6.0Hz,1H),8.44(d,J=8.0Hz,1H),8.12(d,J=8.5Hz,1H),7.87(d,J=8.5Hz,1H),7.69(m,2H),7.57-7.48(m,1H),7.39(t,J=7.5Hz,1H),7.36-7.30(m,1H),3.42(dd,J=14.0,7.0Hz,4H),2.89(t,J=6.0Hz,2H),2.70(t,J=6.0Hz,2H),1.79(d,J=5.5Hz,4H),1.56(dt,J=14.5,7.0Hz,4H),1.38-1.27(m,4H).
实施例13
1-乙基-N-(6-((1,2,3,4-四氢吖啶-9-基)氨基)己基)-9H-吡啶[3,4-b]吲哚-3-甲酰胺(Ⅰ-7)的制备
制备过程同Ⅰ-3,将中间体Ⅳ-6-a换为中间体Ⅳ-6-c(1-乙基-β-咔啉-3-甲酰氯),收率,57.5%;m.p.119-122℃;ESI/MSm/z:520.3[M+H]+;1HNMR(500MHz,DMSO)δ11.93(s,1H),8.64(s,1H),8.53(t,J=6.0Hz,1H),8.32(d,J=8.0Hz,1H),8.27(d,J=8.5Hz,1H),7.78(d,J=8.5Hz,1H),7.69(t,J=7.5Hz,1H),7.64(d,J=8.0Hz,1H),7.57(t,J=7.5Hz,1H),7.46(t,J=7.5Hz,1H),7.28(t,J=7.5Hz,1H),3.65(dd,J=13.0,6.5Hz,2H),3.35(dd,J=13.5,6.5Hz,2H),3.17(q,J=7.5Hz,2H),2.93(s,2H),2.67(s,2H),1.81(s,4H),1.68(dt,J=14.0,7.0Hz,2H),1.57(dt,J=13.5,7.0Hz,2H),1.43-1.33(m,7H).
实施例14
1-苯基-N-(6-((1,2,3,4-四氢吖啶-9-基)氨基)己基)-9H-吡啶[3,4-b]吲哚-3-甲酰胺(Ⅰ-8)的制备
制备过程同Ⅰ-3,将中间体Ⅳ-6-a换为中间体Ⅳ-6-d(1-苯基-β-咔啉-3-甲酰氯),收率,56.5%;m.p.136-139℃;ESI/MSm/z:568.3[M+H]+;1HNMR(500MHz,DMSO)δ11.83(s,1H),8.80(s,1H),8.67(t,J=6.0Hz,1H),8.40(d,J=8.0Hz,1H),8.14(d,J=7.0Hz,3H),7.70(d,J=3.5Hz,1H),7.68(d,J=3.5Hz,1H),7.66-7.50(m,5H),7.35(t,J=7.5Hz,1H),7.31(t,J=7.5Hz,1H),3.47(dd,J=13.5,7.0Hz,4H),2.88(t,J=6.0Hz,2H),2.67(t,J=5.5Hz,2H),1.78(d,J=5.5Hz,4H),1.65-1.51(m,4H),1.34(d,J=3.0Hz,4H).
实施例15
1-(4-氟苯基)-N-(6-((1,2,3,4-四氢吖啶-9-基)氨基)己基)-9H-吡啶[3,4-b]吲哚-3-甲酰胺(Ⅰ-9)的制备
制备过程同Ⅰ-3,将中间体Ⅳ-6-a换为中间体Ⅳ-6-e(1-(4-氟苯基)-β-咔啉-3-甲酰氯),收率,55.8%;m.p.126-129℃;ESI/MSm/z:586.3[M+H]+;1HNMR(500MHz,DMSO)δ11.86(s,1H),8.83(s,1H),8.69(t,J=6.0Hz,1H),8.42(d,J=8.0Hz,1H),8.27-8.20(m,2H),8.13(d,J=8.5Hz,1H),7.71(d,J=8.0Hz,2H),7.62(t,J=7.5Hz,1H),7.52(t,J=7.5Hz,1H),7.47(t,J=8.5Hz,2H),7.34(t,J=7.5Hz,2H),3.47-3.40(m,2H),3.39-3.35(m,2H),2.90(t,J=6.0Hz,2H),2.71(t,J=6.0Hz,2H),1.91-1.70(m,4H),1.69-1.53(m,4H),1.44-1.30(m,4H).
实施例16
1-(4-甲氧基苯基)-N-(6-((1,2,3,4-四氢吖啶-9-基)氨基)己基)-9H-吡啶[3,4-b]吲哚-3-甲酰胺(Ⅰ-10)的制备
制备过程同Ⅰ-3,将中间体Ⅳ-6-a换为中间体Ⅳ-6-f(1-(4-甲氧基苯基)-β-咔啉-3-甲酰氯),收率,54.6%;m.p.161-164℃;ESI/MSm/z:598.3[M+H]+;1HNMR(500MHz,DMSO)δ11.82(s,1H),8.76(s,1H),8.68(t,J=6.0Hz,1H),8.42-8.36(m,2H),8.14(d,J=8.5Hz,2H),7.92(d,J=8.5Hz,1H),7.83(t,J=8.0Hz,1H),7.72(d,J=8.0Hz,1H),7.58(m,2H),7.32(t,J=7.5Hz,1H),7.19(d,J=8.5Hz,2H),3.90(s,3H),3.86(dd,J=13.5,6.5Hz,2H),3.43-3.39(m,2H),2.99(s,2H),2.66(s,2H),1.82(s,4H),1.80-1.72(m,2H),1.65-1.57(m,2H),1.42(s,4H).
实施例17
(S)-叔丁基-3-((6-((1,2,3,4-四氢吖啶-9-基)氨基)己基)氨基甲酰)-3,4-二氢-1H-吡啶[3,4-b]吲哚-2(9H)-甲酰胺(Ⅱ-1)的制备
中间体Ⅴ-1-a(0.63g,2mmol)和CDI(0.36g,2.2mmol)溶于无水THF(25mL),室温反应1h后,将中间体Ⅳ-7-c(0.60g,2mmol)溶于无水THF加入反应液中,继续反应过夜。加水,二氯甲烷萃取,无水硫酸钠干燥,过滤,浓缩,柱层析(二氯甲烷:甲醇:三乙胺=100:4:0.5)得淡白色固体0.6g,收率45.5%;m.p.134-137℃;ESI/MSm/z:596.3[M+H]+;1HNMR(500MHz,DMSO)δ10.83(s,1H),8.26(d,J=8.5Hz,1H),7.86(d,J=8.5Hz,1H),7.76(t,J=7.5Hz,1H),7.67(s,1H),7.50(t,J=7.5Hz,1H),7.32(d,J=7.5Hz,1H),7.21(d,J=7.0Hz,1H),6.95(s,1H),6.88(t,J=7.0Hz,1H),4.99(m,1H),4.73(d,J=16.0Hz,1H),4.53(m,1H),3.58(s,2H),3.24(d,J=16.0Hz,1H),2.97(s,3H),2.93(s,2H),2.63(s,2H),1.82(s,4H),1.47(s,2H),1.45(s,5H),1.40(s,4H),1.27(d,J=6.0Hz,2H),1.16(s,2H),1.06(d,J=15.0Hz,2H).
实施例18
(S)-N-(6-((1,2,3,4-四氢吖啶-9-基)氨基)己基)2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-3-甲酰胺(Ⅱ-2)的制备
将化合物Ⅱ-1(1g,1.85mmol)加入4mol/L盐酸/乙酸乙酯(20mL)溶液中,室温搅拌1h,减压蒸干溶剂,乙酸乙酯萃取,无水硫酸钠干燥,过滤,浓缩,柱层析(二氯甲烷:甲醇:三乙胺=100:5:0.5)得淡黄色固体0.72g,收率86.1%;m.p.117-120℃;ESI/MSm/z:496.3[M+H]+;1HNMR(500MHz,DMSO)δ10.68(s,1H),8.16(d,J=8.5Hz,1H),7.87(t,J=5.5Hz,1H),7.72(d,J=8.5Hz,1H),7.56(t,J=7.5Hz,1H),7.37(m,2H),7.26(d,J=8.0Hz,1H),7.00(t,J=7.5Hz,1H),6.92(t,J=7.5Hz,1H),3.93(q,J=16.5Hz,2H),3.47(d,J=6.0Hz,2H),3.44-3.40(m,1H),3.09(dd,J=13.0,6.5Hz,2H),2.91(t,J=6.0Hz,2H),2.87(dd,J=15.0,4.5Hz,1H),2.70(t,J=6.0Hz,2H),2.63(dd,J=15.0,10.0Hz,1H),1.81(m,4H),1.58(dt,J=14.0,7.0Hz,2H),1.41(dt,J=14.0,7.0Hz,2H),1.34-1.24(m,4H)
实施例19
(3S)-叔丁基-1-甲基-3-((6-((1,2,3,4-四氢吖啶-9-基)氨基)己基)氨基甲酰)-3,4-二氢-1H-吡啶[3,4-b]吲哚-2(9H)-甲酰胺(Ⅱ-3)的制备
制备过程同Ⅱ-1,将中间体Ⅴ-1-a换为中间体Ⅴ-1-b(N-BOC-3S-1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸),收率42.5%;m.p.77-81℃;ESI/MSm/z:610.3[M+H]+;1HNMR(500MHz,DMSO)δ10.85(s,1H),8.18(d,J=8.5Hz,1H),7.76(d,J=8.5Hz,1H),7.67(s,1H),7.63(t,J=7.5Hz,1H),7.51(s,1H),7.42(d,J=7.5Hz,1H),7.38(d,J=8.0Hz,1H),7.29(d,J=8.0Hz,1H),6.95(t,J=7.5Hz,1H),5.10(d,J=6.0Hz,2H),3.53(d,J=6.5Hz,1H),3.48(d,J=6.5Hz,2H),3.22(d,J=15.5Hz,1H),3.04-2.99(m,1H),2.94(s,2H),2.91-2.86(m,1H),2.69(t,J=5.5Hz,2H),1.83(d,J=5.0Hz,4H),1.57(d,J=6.5Hz,2H),1.54-1.50(m,2H),1.46(s,9H),1.37(s,3H),1.34-1.30(m,2H),1.26-1.21(m,2H).
实施例20
(S)-1-甲基-N-(6-((1,2,3,4-四氢吖啶-9-基)氨基)己基)2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-3-甲酰胺(Ⅱ-4)的制备
制备过程同Ⅱ-2,收率87.5%;m.p.84-87℃;ESI/MSm/z:510.3[M+H]+;1HNMR(500MHz,DMSO)δ10.76(s,1H),8.14(d,J=8.5Hz,1H),7.82(t,J=5.5Hz,1H),7.71(d,J=8.0Hz,1H),7.53(t,J=7.5Hz,1H),7.36(m,2H),7.28(d,J=8.0Hz,1H),7.02(t,J=7.5Hz,1H),6.93(t,J=7.5Hz,1H),4.18-4.00(m,2H),3.42(m,4H),3.10(dd,J=13.0,6.0Hz,2H),2.91(t,J=6.0Hz,2H),2.72(t,J=5.5Hz,2H),1.81(d,J=5.5Hz,4H),1.58(dt,J=14.5,7.0Hz,2H),1.43(m,5H),1.36-1.20(m,4H).
实施例21
S-叔丁基-(3-(1H-吲哚-3-基)-1-氧-1-((6-((1,2,3,4,-四氢吖啶-9-基)氨基)己基)氨基)丙烷-2-基)甲酰胺(Ⅲ-1)的制备
制备过程同Ⅱ-1,将中间体Ⅴ-1-a换为中间体Ⅵ-1-a(N-boc-L-色氨酸),收率53.5%;m.p.92-96℃;ESI/MSm/z:584.3[M+H]+;1HNMR(500MHz,DMSO)δ10.78(s,1H),8.12(d,J=8.0Hz,1H),7.76(t,J=5.0Hz,1H),7.70(d,J=7.5Hz,1H),7.55(d,J=8.0Hz,1H),7.52(t,J=7.5Hz,1H),7.37-7.32(m,1H),7.30(d,J=8.0Hz,1H),7.10(s,1H),7.06-6.99(m,1H),6.95(t,J=7.5Hz,1H),6.66(d,J=8.0Hz,1H),4.13(dd,J=13.5,8.5Hz,1H),3.40(dd,J=13.5,6.7Hz,4H),3.01(dd,J=9.5,4.0Hz,2H),2.90(t,J=6.0Hz,2H),2.70(t,J=6.0Hz,2H),1.88-1.73(m,4H),1.52(dt,J=14.0,7.0Hz,2H),1.36-1.22(m,13H),1.19(dd,J=14.0,7.0Hz,2H).
实施例22
S-2-氨基-3-(1H-吲哚-3-基)-N-(6-((1,2,3,4,-四氢吖啶-9-基)氨基)己基)甲酰胺(Ⅲ-2)的制备
制备过程同Ⅱ-2,收率85.5%;ESI/MSm/z:484.3[M+H]+;1HNMR(500MHz,DMSO)δ10.84(s,1H),8.12(d,J=8.0Hz,1H),7.81(t,J=5.5Hz,1H),7.71(d,J=8.0Hz,1H),7.53(m,2H),7.33(m,2H),7.14(d,J=2.0Hz,1H),7.03(dd,J=11.0,4.0Hz,1H),6.95(t,J=7.0Hz,1H),5.41(t,J=6.5Hz,1H),3.44(dd,J=8.0,5.0Hz,1H),3.39(m,2H),3.02(m,3H),2.91(t,J=6.2Hz,2H),2.76(dd,J=14.0,8.0Hz,1H),2.71(t,J=6.0Hz,2H),1.82(m,J=12.5,8.0Hz,4H),1.52(dt,J=14.5,7.5Hz,2H),1.31(dd,J=14.5,7.5Hz,2H),1.24(dd,J=14.0,8.5Hz,2H),1.20-1.11(m,2H).
实施例23
S-2-乙酰胺基-3-(1H-吲哚-3-基)-N-(6-((1,2,3,4,-四氢吖啶-9-基)氨基)己基)丙酰胺(Ⅲ-3)的制备
制备过程同Ⅱ-1,将中间体Ⅴ-1-a换为中间体Ⅵ-1-b(N-乙酰基-L色氨酸),收率52.5%;m.p.105-108℃;ESI/MSm/z:526.3[M+H]+;1HNMR(500MHz,DMSO)δ10.76(s,1H),8.11(d,J=8.5Hz,1H),7.98(d,J=8.0Hz,1H),7.86(t,J=5.5Hz,1H),7.70(d,J=8.5Hz,1H),7.56(d,J=8.0Hz,1H),7.52(t,J=7.5Hz,1H),7.34(t,J=7.5Hz,1H),7.29(d,J=8.0Hz,1H),7.09(d,J=2.0Hz,1H),7.02(t,J=7.5Hz,1H),6.94(t,J=7.5Hz,1H),4.45(td,J=8.5,6.0Hz,1H),3.39(dd,J=14.0,7.0Hz,4H),3.04(dd,J=14.5,5.5Hz,1H),2.97(dt,J=14.5,7.0Hz,1H),2.89(dd,J=12.0,6.0Hz,2H),2.70(t,J=6.0Hz,2H),1.86-1.77(m,4H),1.77(s,3H),1.52(dt,J=14.5,7.5Hz,2H),1.29(dd,J=14.5,7.5Hz,2H),1.23(dd,J=14.0,8.0Hz,2H),1.15(dd,J=12.5,6.0Hz,2H).
Claims (6)
1.一种通式I、II或III的他克林-β-咔啉异二连体类化合物或其药学上可接受的盐:
其中R1表示H、CH3、C2H5、C6H5、C6H4-p-F或C6H4-p-OCH3,n=2、4、6、8或10;
R2表示H或BOC;
R3表示H、COCH3或BOC。
2.权利要求1的化合物或其药学上可接受的盐,其中化合物是:
3.权利要求1的化合物或其药学上可接受的盐,其中药学上可接受的盐是通式I、II或III化合物的盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、萘磺酸盐、柠檬酸盐、酒石酸盐、乳酸盐、丙酮酸盐、乙酸盐、马来酸盐、琥珀酸盐、富马酸盐、水杨酸盐、苯基乙酸盐或杏仁酸盐。
4.一种药物组合物,含有权利要求1的通式I、II或III的化合物或其药学上可接受的盐及药学上可接受的载体。
5.权利要求1的通式I、II或III的化合物或其药学上可接受的盐用于制备治疗与多功能胆碱酯酶抑制剂相关疾病的药物的用途。
6.权利要求5的用途,其中与多功能胆碱酯酶抑制剂相关疾病是阿尔茨海默病。
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