CN117886797A - 一种他克林-查斯曼宁拼合物及其制备方法和用途 - Google Patents
一种他克林-查斯曼宁拼合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明提供了一种他克林‑查斯曼宁拼合物及其制备方法和用途,属于医药化学领域。该他克林‑查斯曼宁拼合物的结构如式I所示。本发明提供的他克林‑查斯曼宁拼合物兼具抑制胆碱酯酶和抑制Aβ聚集的作用,可以作为抑制胆碱酯酶的药物和抑制Aβ聚集的药物,在制备多靶点治疗阿尔兹海默病的药物中具有广阔的应用前景。
Description
技术领域
本发明属于医药化学领域,具体涉及一种他克林-查斯曼宁拼合物及其制备方法和用途。
技术背景
阿尔兹海默病(Alzheimer disease,AD)是一种进行性神经退行性疾病,多发于老年人,严重影响患者生活质量和身心健康。
目前,治疗AD的药物主要为胆碱酯酶抑制剂。乙酰胆碱(Ach)是突触传递过程中重要的神经递质,其含量减少可造成脑组织功能紊乱。研究表明胆碱能***与记忆的形成和储存具有重要关系,在AD患者大脑中发现胆碱能神经元明显减少,胆碱能活性降低,这可能与AD患者的认知功能下降有关。乙酰胆碱可被两种类型的胆碱酯酶(ChE)水解:乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BuChE)。AChE和BuChE抑制已被证明是有效治疗AD的关键靶点,用作胆碱酯酶抑制剂药物例如他克林、多奈哌齐、新斯的明,已显示出多种益处,包括改善大脑ACh水平,从而导致胆碱能传递增强,缓解与AD相关的认知和行为功能障碍。
他克林是美国FDA批准的第一个治疗AD药物,结构见(A)。它通过抑制乙酰胆碱酯酶(AChE)活性,阻断大脑皮层和海马中胆碱能神经的降解,增加胆碱能传递,达到减轻AD症状的目的。但是,一方面,较大的肝毒性严重限制了他克林广泛的临床药用;另一方面,他克林治疗AD的效果还有待进一步提高。
目前,AD的致病机理尚不清楚,对于AD的致病机理,科学家们提出了多种假说,其中淀粉样级联假说被广泛认可。淀粉样级联假说认为,β-淀粉样蛋白(amyloidβ-protein,Aβ)的聚集和沉积是导致阿尔兹海默病神经纤维缠结、细胞损伤以及痴呆的原因。研究表明,减少Aβ的产生、加速Aβ的清除和抑制Aβ的聚集均能防止Aβ对大脑产生的损伤,减缓AD病情进展。开发出一种能够同时抑制胆碱酯酶活性和抑制Aβ聚集的药物,对提高AD的治疗效果具有重要意义。
二萜生物碱是乌头属、翠雀属和Consolida(毛茛科)的特征成分。查斯曼宁(又称查斯马宁)是一种C19型二萜生物碱,结构见(B)。查斯曼宁对人乳腺癌细胞MCF-7、人肺腺癌细胞A549和人***癌细胞PC-3有不同程度的细胞毒活性,可用于制备抗肿瘤药物。但是,未见将他克林与查斯曼宁进行拼合用于治疗AD的报道。
发明内容
本发明的目的在于提供一种能够用于多靶点治疗阿尔兹海默病的新型他克林-查斯曼宁拼合物及其制备方法和用途。
为解决上述技术问题,本发明提供了如下技术方案:
本发明提供了一种化合物、其立体异构体或其药学上可接受的盐,所述化合物的结构如式I所示:
其中,n为1-15的整数。
进一步地,所述n为7-9的整数。
进一步地,所述化合物的结构选自以下结构之一:
本发明还提供了一种制备上述式I所示化合物的方法,所述方法包括以下步骤:化合物X与查斯曼宁反应,得到式I所示化合物;
其中,R1为卤素,n如前文所述。
进一步地,制备式I所示化合物的方法中,所述反应是在氢化钠的作用下进行的,所述化合物X、查斯曼宁、氢化钠的摩尔比为1:(0.8-1.5):(2-5),所述反应的温度为0℃-40℃,时间为2-6小时,溶剂为有机溶剂。
更进一步地,制备式I所示化合物的方法中,所述化合物X、查斯曼宁、氢化钠的摩尔比为1:(1-1.2):(3-4),所述反应的温度为0℃-室温,时间为4小时,溶剂为N,N-二甲基甲酰胺。
进一步地,所述化合物X的制备方法包括以下步骤:他克林与化合物Y反应,得到化合物X;
其中,R2为卤素。
进一步地,制备化合物X的方法中,所述反应是在氢化钠的作用下进行的,所述他克林、化合物Y、氢化钠的摩尔比为1:(0.8-1.5):(2-5),所述反应的温度为0℃-40℃,时间为2-6小时,溶剂为有机溶剂。
更进一步地,制备化合物X的方法中,所述他克林、化合物Y、氢化钠的摩尔比为1:(1-1.2):(3-4),所述反应的温度为0℃-室温,时间为4小时,溶剂为N,N-二甲基甲酰胺。
进一步地,所述卤素为溴。
本发明还提供了一种药物组合物,它是以式I所示化合物、其立体异构体或其药学上可接受的盐为活性成分,加上药学上可接受的辅料制备而成的制剂。
本发明还提供了式I所示化合物、其立体异构体或其药学上可接受的盐在制备抑制胆碱酯酶的药物和/或抑制β-淀粉样蛋白聚集的药物中的用途。
进一步地,所述胆碱酯酶为乙酰胆碱酯酶和/或丁酰胆碱酯酶。
进一步地,所述药物为预防和/或治疗阿尔兹海默病的药物。
本发明取得的有益效果是:
1.本发明提供的式I所示他克林-查斯曼宁拼合物兼具抑制胆碱酯酶和抑制Aβ聚集的作用,可以作为抑制胆碱酯酶的药物和抑制Aβ聚集的药物,在制备多靶点治疗阿尔兹海默病的药物中具有广阔的应用前景。
2.查斯曼宁无法有效抑制乙酰胆碱酯酶和丁酰胆碱酯酶的活性,他克林对乙酰胆碱酯酶和丁酰胆碱酯酶有一定的抑制活性,但是,本发明他克林-查斯曼宁拼合物对丁酰胆碱酯酶的抑制活性优于他克林,其中实施例2化合物(他克林-8C-查斯曼宁)的丁酰胆碱酯酶抑制活性明显高于他克林,他克林的IC50值是其10.4倍。本发明取得了预料不到的技术效果。
3.他克林、查斯曼宁抑制Aβ自身聚集活性都较低,而本发明他克林-查斯曼宁拼合物具有显著的抑制Aβ自身聚集活性。本发明取得了预料不到的技术效果。
4.本发明他克林-查斯曼宁拼合物的制备方法简单易行,适合产业化生产。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。
实施例合成他克林-查斯曼宁拼合物的路线如下所示:
实施例1
取他克林1g(5mmol)于两颈瓶中,用超干N,N-二甲基甲酰胺(DMF)溶解。在0℃下,加入氢化钠363mg(15mmol),边搅拌边滴加1.5g(6mmol)烷基二溴取代物(上述路线中n=7),搅拌约20分钟,移至室温。混合悬浮液在氩气保护下,搅拌4小时后得到黄色溶液,然后用水淬灭。反应液经二氯甲烷萃取,合并有机层,饱和食盐水洗涤,无水硫酸钠干燥。减压蒸除二氯甲烷,得到中间体7C-溴代他克林。
将中间体7C-溴代他克林300mg(0.8mmol)溶于超干DMF中,冰浴上冷却,0℃下加入NaH(59.8mg,2.5mmol),搅拌约5分钟后,加入查斯曼宁(360.7mg,0.8mmol),搅拌约20分钟,移至室温,继续反应4小时。反应终止,加入3毫升水,反应液经二氯甲烷萃取,饱和食盐水洗涤,无水硫酸钠干燥。减压蒸除二氯甲烷,残渣用硅胶柱层析纯化得他克林-7C-查斯曼宁。其结构及其表征如下:
白色固体(150mg),收率40%。1H NMR(600MHz,CDCl3)δ8.29(d,J=8.4Hz,1H),8.16(d,J=8.6Hz,1H),7.59(t,J=7.4Hz,1H),7.37(t,J=8.4Hz,1H),4.17(d,J=6.6Hz,1H),3.79(t,J=7.2Hz,2H),3.74(t,J=4.6Hz,1H),3.63(t,J=8.2Hz,2H),3.51-3.41(m,1H),3.31(s,3H),3.27(s,3H),3.26(s,3H),3.25(s,3H),3.22-3.10(m,5H),2.99(s,2H),2.92-2.68(m,2H),2.66(t,J=6.0Hz,2H),2.30(s,1H),2.27-2.12(m,3H),2.10-1.98(m,3H),1.98-1.61(m,11H),1.57(d,J=8.6Hz,1H),1.54-1.44(m,2H),1.43-1.25(m,7H),1.22(d,J=5.6Hz,4H).13C NMR(150MHz,CDCl3)δ154.6,152.8,141.0,131.2,124.6,124.2,122.6,116.9,112.1,82.6,82.3,82.2,79.6,,77.4,74.2,69.6,61.7,59.3×2,58.0,56.1,56.0,52.7,50.4,49.3,48.6,47.6,44.5,42.0,38.7,37.4,31.9,31.2,30.2,29.8,29.7,29.0,26.7,26.2,24.3,22.7,22.3,21.3,14.2,12.1.HRESIMS m/z 746.5096[M+H]+,calcd forC45H67N3O6,746.5108.
实施例2
参照实施例1制备中间体7C-溴代他克林的方法,将原料替换为上述路线中n=8的烷基二溴取代物,制备得到中间体8C-溴代他克林。
将中间体8C-溴代他克林300mg(0.77mmol)溶于超干DMF中,冰浴上冷却,0℃下加入NaH(59.8mg,2.5mmol),搅拌约5分钟后,加入查斯曼宁(347.5mg,0.77mmol),搅拌约20分钟,移至室温,继续反应4小时。反应终止,加入3毫升水,反应液经二氯甲烷萃取,饱和食盐水洗涤,无水硫酸钠干燥。减压蒸除二氯甲烷,残渣用硅胶柱层析纯化得他克林-8C-查斯曼宁。其结构及其表征如下:
白色固体(150mg),收率40%。1H NMR(600MHz,CDCl3)δ7.95(d,J=8.4,Hz,1H),7.89(dd,J=8.4,1H),7.54(t,J=6.8Hz,1H),7.34(t,J=7.0Hz,1H),4.15(d,J=6.8Hz,1H),3.75-3.68(m,3H),3.49-3.45(m,3H),3.31(s,3H),3.30(s,3H),3.27(s,3H),3.23(s,3H),3.21-3.17(m,1H),3.05(d,J=6.0Hz,3H),2.99(dd,J=10.2,6.4Hz,1H),2.84(s,1H),2.71(d,J=4.8Hz,2H),2.62-2.36(m,5H),2.32-2.23(m,2H),2.22-2.16(m,1H),2.04-1.89(m,8H),1.79(dd,J=6.8,4.0Hz,2H),1.66(q,J=7.2Hz,3H),1.59-1.49(m,2H),1.41-1.35(m,3H),1.36-1.21(m,7H),1.06(t,J=7.2Hz,3H).3C NMR(150MHz,CDCl3)δ158.6,150.9,147.7,128.9,128.4,123.7,123.0,120.4,116.0,85.4,83.0,82.9,82.6,81.0,74.2,69.6,62.1,59.3,57.6,56.1,56.0,54.1,52.5,50.3,50.2,49.7,49.2,48.8,45.4,42.1,39.3,37.7,35.1,34.2,31.9,30.3,30.1,29.5,29.5,27.1,26.6,26.4,24.9,23.2,23.0,13.7.HRESIMS m/z 760.5254[M+H]+,calcd for C46H69N3O63,760.5265.
实施例3
参照实施例1制备中间体7C-溴代他克林的方法,将原料替换为上述路线中n=9的烷基二溴取代物,制备得到中间体9C-溴代他克林。
将中间体9C-溴代他克林300mg(0.74mmol)溶于超干DMF中,冰浴上冷却,0℃下加入NaH(59.8mg,2.5mmol),搅拌约5分钟后,加入查斯曼宁(335.6mg,0.74mmol),搅拌约20分钟,移至室温,继续反应4小时。反应终止,加入3毫升水,反应液经二氯甲烷萃取,饱和食盐水洗涤,无水硫酸钠干燥。减压蒸除二氯甲烷,残渣用硅胶柱层析纯化得他克林-8C-查斯曼宁。其结构及其表征如下:
白色固体(150mg),收率40%。1H NMR(600MHz,CDCl3)δ8.37(d,J=8.4Hz,1H),8.22(d,J=8.8Hz,1H),7.62(t,J=7.6Hz,1H),7.39(t,J=7.8Hz,1H),4.22(dd,J=15.6,6.8Hz,1H),3.94-3.80(m,3H),3.80-3.71(m,1H),3.69-3.54(m,2H),3.46-3.37(m,1H),3.34(s,3H),3.31(s,3H),3.27(s,3H),3.26(s,3H),3.26-3.25(m,1H),3.23-3.07(m,8H),3.07-2.72(m,1H),2.66(t,J=6.3Hz,2H),2.35(t,J=5.6Hz,1H),2.29-2.03(m,3H),2.03-1.74(m,8H),1.48(dd,J=12.0,5.8Hz,1H),1.42-1.29(m,1H),1.29-1.22(m,17H),1.22-1.10(m,2H).3C NMR(150MHz,CDCl3)δ155.3,151.8,139.8,131.8,124.9,124.5,121.6,116.3,111.4,82.5,82.2,81.9,79.0,77.4,74.3,69.8,61.5,59.4,59.3,58.2,56.3,56.2,55.9,52.9,50.5,49.4,48.4,47.4,44.1,42.1,38.4,37.4,31.1,30.2,30.0,29.8,29.4,29.3,29.2,29.1,29.0,26.8,26.3,24.2,22.2,21.0.11.3.HRESIMS m/z 774.5402[M+H]+,calcd for C47H71N3O6,774.5421
以下通过试验例证明本发明的有益效果。
试验例1:抗乙酰胆碱酯酶及抗丁酰胆碱酯酶活性测定
1.实验方法
采用改良Ellmann法测定化合物抗乙酰胆碱酯酶(AChE)及抗丁酰胆碱酯酶(BuChE)的活性。
将2.5mg(0.5U/mL)乙酰胆碱酯酶溶解在1mL pH 8.0磷酸盐缓冲液中制备酶液。待测化合物原液用DMSO配置,并用磷酸盐缓冲液稀释至最终浓度。在96孔板中,加入140μL磷酸盐缓冲液、10μL酶液和10μL不同浓度的待测化合物,于37℃下孵育20分钟。然后,加入10μL 5,5'-二硫代双(2-硝基苯甲酸)(0.75mM)和10μL碘化硫代乙酰胆碱(1.5mM),在37℃孵育20min。使用酶标仪在405nm波长下测定吸光度。每组至少重复测定三次。
将1.0mg(0.5U/mL)乙酰胆碱酯酶溶解在20mL pH 8.0磷酸盐缓冲液中制备酶液。待测化合物原液用DMSO配置,并用磷酸盐缓冲液稀释至最终浓度。在96孔板中,加入140μL磷酸盐缓冲液、10μL酶液和10μL不同浓度的待测化合物,于37℃下孵育20分钟。然后,加入10μL 5,5'-二硫代双(2-硝基苯甲酸)(0.75mM)和10μL碘化硫代乙酰胆碱(1.5mM),在37℃孵育20min。使用酶标仪在405nm波长下测定吸光度。每组至少重复测定三次。
根据吸光值,计算不同浓度化合物对乙酰胆碱酯酶和丁酰胆碱酯酶的抑制率,使用软件计算化合物的IC50值。以查斯曼宁作为对照,以他克林作为阳性对照。
2.实验结果
表1所测化合物的IC50值
由表1可知,查斯曼宁无法有效抑制乙酰胆碱酯酶和丁酰胆碱酯酶的活性,本发明实施例1-3化合物能够有效抑制乙酰胆碱酯酶和丁酰胆碱酯酶的活性。其中,实施例1-3化合物对乙酰胆碱酯酶的抑制活性与他克林相当;实施例1-3化合物对丁酰胆碱酯酶的抑制活性优于他克林,其中实施例2化合物(他克林-8C-查斯曼宁)的丁酰胆碱酯酶抑制活性明显高于他克林,他克林的IC50值是其10.4倍。
试验例2:抑制Aβ自身聚集活性测定
1.实验方法
将Aβ1-42冻干粉和六氟异丙醇(HFIP)在20℃下冷冻,随后将Aβ1-42冻干粉与HFIP(222μL)注入。密封后,涡旋混合,在室温下60分钟,得到Aβ-HFIP溶液(1mM)。然后用N2挥发HFIP,得到Aβ肽膜,可在20℃的冰箱中保存。就在使用前,向肽膜中加入44μLDMSO,在水浴中用超声波处理10分钟,得到Aβ-DMSO溶液(5mM)。将预冷的2156μL PBS溶液(100uM)加入到Aβ-DMSO溶液中,并通过涡旋进行混合。将得到的溶液在4℃的冰箱中培养1天。用无血清DMEM培养基稀释到目标浓度。取黑色96孔板,依次加入20μLAβ1-42溶液+20μL复合物溶液,20μLAβ1-42溶液+20μL缓冲液,20μL缓冲液+20μL缓冲液。复合物溶液和Aβ1-42的最终浓度为25μM。在37℃下孵育24小时。孵化后,加入160μL含5μM硫黄素T的缓冲液,然后立即用EnSpire多功能微孔板酶标仪(PerkinElmer)在激发波长446nm和发射波长490nm处测量荧光值。以他克林、查斯曼宁作为对照,以姜黄素为阳性对照。
2.实验结果
表2所测化合物抑制Aβ自身聚集的抑制率
化合物 | 名称 | 抑制率(%)(I=25μM) |
实施例2 | 他克林-8C-查斯曼宁 | 54.60 |
实施例3 | 他克林-9C-查斯曼宁 | 51.21 |
对照 | 他克林 | 12.90 |
对照 | 查斯曼宁 | 27.88 |
阳性对照 | 姜黄素 | 47.93 |
由表2可知,他克林、查斯曼宁抑制Aβ自身聚集活性都较低,而本发明化合物具有显著的抑制Aβ自身聚集活性。
综上,上述实验结果表明,本发明提供的他克林-查斯曼宁拼合物兼具抑制胆碱酯酶和抑制Aβ聚集的作用,可以作为抑制胆碱酯酶的药物和抑制Aβ聚集的药物,在制备多靶点治疗阿尔兹海默病的药物中具有广阔的应用前景。
Claims (10)
1.一种化合物、其立体异构体或其药学上可接受的盐,其特征在于,所述化合物的结构如式I所示:
其中,n为1-15的整数。
2.如权利要求1所述的化合物、其立体异构体或其药学上可接受的盐,其特征在于,所述n为7-9的整数。
3.如权利要求1或2所述的化合物、其立体异构体或其药学上可接受的盐,其特征在于,所述化合物的结构选自以下结构之一:
4.一种制备权利要求1-3任一项所述化合物的方法,其特征在于,所述方法包括以下步骤:化合物X与查斯曼宁反应,得到式I所示化合物;
其中,R1为卤素,n如权利要求1-3任一项中所述。
5.如权利要求4所述的方法,其特征在于,所述化合物X的制备方法包括以下步骤:他克林与化合物Y反应,得到化合物X;
其中,R2为卤素。
6.如权利要求4或5所述的方法,其特征在于,所述卤素为溴。
7.一种药物组合物,其特征在于,它是以权利要求1-3任一项所述化合物、其立体异构体或其药学上可接受的盐为活性成分,加上药学上可接受的辅料制备而成的制剂。
8.权利要求1-3任一项所述化合物、其立体异构体或其药学上可接受的盐在制备抑制胆碱酯酶的药物和/或抑制β-淀粉样蛋白聚集的药物中的用途。
9.如权利要求8所述的用途,其特征在于,所述胆碱酯酶为乙酰胆碱酯酶和/或丁酰胆碱酯酶。
10.根据权利要求8所述的用途,其特征在于,所述药物为预防和/或治疗阿尔兹海默病的药物。
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