CN101597294A - 3-胺基烷酰胺基-吴茱萸次碱与3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物 - Google Patents
3-胺基烷酰胺基-吴茱萸次碱与3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物 Download PDFInfo
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Abstract
本发明公开了3-胺基烷酰胺基-吴茱萸次碱与3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物及其合成方法与应用。实验证明,本发明的3-胺基烷酰胺基-吴茱萸次碱和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性能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活性高出500多倍。表明该类化合物具有发展成为治疗阿尔茨海默病(Alzheimer’sdisease)和脑血管痴呆等疾病药物的应用前景。
Description
技术领域
本发明涉及一种3-胺基烷酰胺基-吴茱萸次碱与3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物及其合成方法与应用。
背景技术
乙酰胆碱酯酶(AChE)是生物神经传导中的一种关键的酶,在胆碱能突触间,该酶降解乙酰胆碱,终止神经递质乙酰胆碱对突触后膜的兴奋作用,保证神经信号在生物体内的正常传递。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被称为真性或特异性胆碱酯酶,是维持体内胆碱能神经冲动最重要的水解酶。BuChE被称为假性或非特异性胆碱酯酶,属于丝氨酸酯酶家族,主要分布于血清及肝脏中,肌肉和脑组织中有少量存在。BuChE能与有机磷毒剂或杀虫剂结合,并能水解许多酯类、肽类及酰胺类化合物,参与某些药物的代谢过程,还有促进细胞生长的作用。
老年痴呆是60岁以上老人常见病之一,以阿尔茨默病(Alzheimer’s disease,AD)和脑血管痴呆为主,目前尚无特异性的有效治疗手段。研究表明,AD的主要临床症状是因为胆碱能的神经递质减少引起的,目前对AD患者主要通过药物来改善认知力、行为症状及维持日常生活,而乙酰胆碱酯酶抑制剂(AChEI)是目前治疗AD最常用的药物。AChEI可阻滞突触中Ach的水解,提高对胆碱能(毒覃碱和烟碱)受体的作用。也有间接证据表明,它可以通过改变APP的过程和增加神经元生长因子的产物来避免神经元的退还。同时,最新的研究发现,阿尔茨默病患者突触中的丁酰胆碱酯酶活性并无明显提高。
因此,在未来对乙酰胆碱酯酶抑制剂药物的开发过程中,抑制剂的选择性和专一性将是开发人员关心的重点问题,这对增强药效,降低副作用起着至关重要的作用。
发明内容
本发明的目的是提供3-胺基烷酰胺基-吴茱萸次碱与3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物。
本发明的3-胺基烷酰胺基-吴茱萸次碱与3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物化学结构通式为:
其中,n=1、2、3、4或5;
R代表-N(CH2CH3)2、
X代表-CH=CH-或-CH2-CH2-。
本发明的另一目的是提供上述化合物的合成方法,包括如下步骤:
(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DDQ脱氢后得到7,8-脱氢吴茱萸次碱的酰化产物;
(4)酰化产品与相应的胺反应得到3-胺基烷酰胺基-吴茱萸次碱与3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物。
合成3-氨基-吴茱萸次碱的方法优选按照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,合成流程如下所示:
Bergman,J.;Bergman,S.Studies of Rutaecarpine and RelatedQuinazolinocarboline Alkaloids.J.Org.Chem.,1985,50,1246
3-胺基烷酰胺基-吴茱萸次碱与3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物的合成流程如下所示:
上述步骤(2)所述酰化为利用氯代烷基酰氯酰化。
本发明的进一步目的是提供3-胺基烷酰胺基-吴茱萸次碱与3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物在制备乙酰胆碱酯酶抑制药物中的应用。优选治疗疾病为阿尔茨海默病、脑血管痴呆、青光眼或重症肌无力。
本发明的衍生物可在药物领域可接受的情况下制成各种剂型,如片剂、丸剂、胶囊、注射剂、悬浮剂或乳剂。
与现有技术相比,本发明具有如下有益效果:
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-吴茱萸次碱与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。
具体实施方式
实施例1 3-(2-氯乙酰胺基)-吴茱萸次碱的合成
在90mL二氯甲烷中加入1.5g 3-氨基-吴茱萸次碱和0.83gK2CO3,室温下滴加5mL含有0.48mL氯乙酰氯的二氯甲烷,滴加完后再加热回流4小时,冷却,过滤,依次用二氯甲烷和水洗涤,干燥后得到绿色固体1.5g,产率77%。mp 281.6-284.3℃;1H-NMR(400MHz,DMSO-d6):δ11.86(s,1H),10.67(s,1H),8.49(d,J=2.1,1H),7.98(dd,J=8.8,2.3,1H),7.67(dd,J=16.1,8.4,2H),7.48(d,J=8.3,1H),7.26(t,J=7.7,1H),7.09(t,J=7.5,1H),4.46(t,J=6.8,2H),4.32(s,2H),3.18(t,J=6.8,2H);ESI-MS:m/z 379[M+1]+.
合成化合物1的结构式如下:
实施例2 3-(2-氯丙酰胺基)-吴茱萸次碱的合成
在90mL二氯甲烷中加入1.5g 1.5g 3-氨基-吴茱萸次碱和0.83gK2CO3,室温下滴加5mL含有0.53mL 3-氯丙酰氯的二氯甲烷,滴加完后再加热回流4小时,冷却,过滤,依次用二氯甲烷和水洗涤,干燥得1.8g绿色固体,产率90%。mp 275.4-277.0℃;1H-NMR(400MHz,DMSO-d6):δ11.84(s,1H),10.44(s,1H),8.51(d,J=2.3,1H),8.00(dd,J=8.8,2.4,1H),7.66(dd,J=14.1,8.4,2H),7.49(d,J=8.2,1H),7.26(t,J=7.5,1H),7.09(t,J=7.4,1H),4.46(t,J=6.8,2H),3.93(t,J=6.2,2H),3.17(t,J=6.8,2H),2.89(t,J=6.2,2H);ESI-MS:m/z 393[M+1]+.
合成化合物2的结构式如下:
实施例3 3-(2-乙酰氨基)-7,8-脱氢吴茱萸次碱的合成
在50mL的二氧六环中加入0.76g 3-(2-氯乙酰胺基)-吴茱萸次碱,加热搅拌;将0.54g DDQ溶于5mL二氧六环中,缓慢滴加到反应液中;滴加完后,加热回流4小时后,过滤收集沉淀,沉淀用KOH溶液(1.5gKOH溶于25mL水中)处理多次,直至DDQ-2H全部除去,得到的固体真空干燥,得到淡棕色固体0.39g,产率52%。mp299.6-302.4℃;1H-NMR(400MHz,DMSO-d6):δ12.68(s,1H),10.69(s,1H),8.71(s,1H),8.61(d,J=7.4,1H),8.16(d,J=7.9,1H),8.07(d,J=8.8,1H),7.84(dd,J=14.0,8.3,2H),7.69(d,J=8.2,1H),7.49(t,J=7.5,1H),7.29(t,J=7.4,1H),4.34(s,2H);ESI-MS:m/z 377[M+1]+.
合成化合物3的结构式如下:
实施例4 3-(2-二乙胺基-乙酰胺基)-吴茱萸次碱的合成
在15mL乙醇中加入0.19g 3-(2-氯乙酰胺基)-吴茱萸次碱,0.03gKI和0.5mL二乙胺,加热回流6小时,冷却析出固体,过滤,干燥得到0.15g浅褐色固体,产率70%。mp 271.6-272.8℃;1H-NMR(400MHz,DMSO-d6):δ11.83(s,1H),10.02(s,1H),8.54(d,J=2.4,1H),8.06(dd,J=8.8,2.4,1H),7.65(dd,J=8.4,3.1,2H),7.49(d,J=8.3,1H),7.26(t,J=7.6,1H),7.09(t,J=7.4,1H),4.46(t,J=6.8,2H),3.19(dd,J=15.4,8.6,4H),2.63(q,J=7.1,4H),1.04(t,J=7.1,6H);ESI-MS:m/z 416[M+1]+.。
合成化合物4的结构式如下:
实施例5 3-(2-N-吡咯烷基-乙酰胺基)-吴茱萸次碱的合成
在15mL乙醇中加入0.19g 3-(2-氯乙酰胺基)-吴茱萸次碱,0.03gKI和0.5mL吡咯烷,加热回流6小时,冷却,过滤,干燥得到0.13g浅褐色固体,产率58%。mp 268.8-271.2℃;1H-NMR(400MHz,DMSO-d6):δ11.84(s,1H),10.10(s,1H),8.55(d,J=2.4,1H),8.06(dd,J=8.8,2.5,1H),7.65(d,J=8.7,2H),7.48(d,J=8.3,1H),7.26(t,J=7.5,1H),7.09(t,J=7.4,1H),4.46(t,J=6.8,2H),3.30(s,2H),3.18(t,J=6.8,2H),2.62(m,4H),1.76(dt,J=6.2,3.1,4H);ESI-MS:m/z414[M+1]+.。
合成化合物5的结构式如下:
实施例6 3-(2-N-哌啶基-乙酰胺基)-吴茱萸次碱的合成
在15mL乙醇中加入0.19g 3-(2-氯乙酰胺基)-吴茱萸次碱,0.03gKI和0.5mL哌啶,加热回流6小时,冷却,过滤,干燥得到0.19g浅褐色固体,产率89%。mp 266.8-269.7℃;1H-NMR(400MHz,DMSO-d6):δ11.85(s,1H),10.07(s,1H),8.53(d,J=2.4,1H),8.05(dd,J=8.8,2.4,1H),7.66(dd,J=8.0,5.7,2H),7.48(d,J=8.2,1H),7.26(t,J=7.5,1H),7.09(t,J=7.5,1H),4.46(t,J=6.8,2H),3.34(s,2H),3.18(t,J=6.8,4H),3.13(s,2H),1.59(m,4H),1.42(d,J=4.2,2H);ESI-MS:m/z 428[M+1]+。
合成化合物6的结构式如下:
实施例7 3-(2-二乙胺基-丙酰胺基)-吴茱萸次碱的合成
在15mL乙醇中加入0.20g 3-(2-氯丙酰胺基)-吴茱萸次碱,0.03gKI和0.5mL二乙胺,加热回流6小时,冷却析出固体,过滤,干燥得到0.17g粉白色固体,产率70%。mp 315.1-316.9℃;1H-NMR(400MHz,DMSO-d6):δ11.84(s,1H),10.55(s,1H),8.50(d,J=2.2,1H),8.00(dd,J=8.8,1.9,1H),7.64(dd,J=8.1,5.6,2H),7.48(d,J=8.2,1H),7.26(t,J=7.6,1H),7.09(t,J=7.5,1H),4.45(t,J=6.7,2H),3.17(t,J=6.7,2H),2.77(t,J=6.9,2H),2.51(dd,J=10.6,3.6,4H),2.47(d,J=7.2,2H),0.99(t,J=7.1,6H);ESI-MS:m/z 4[M+1]+.。
合成化合物7的结构式如下:
实施例8 3-(2-N-吡咯烷基-丙酰胺基)-吴茱萸次碱的合成
在15mL乙醇中加入0.20g 3-(2-氯丙酰胺基)-吴茱萸次碱,0.03gKI和0.5mL吡咯烷,加热回流6小时,冷却,过滤,干燥得到0.14g浅褐色固体,产率66%。mp 255.8-256.8℃;1H-NMR(400MHz,DMSO-d6):δ11.84(s,1H),10.50(s,1H),8.52(d,J=2.2,1H),7.99(dd,J=8.8,2.3,1H),7.64(dd,J=8.3,4.9,2H),7.48(d,J=8.3,1H),7.26(t,J=7.6,1H),7.09(t,J=7.5,1H),4.46(t,J=6.8,2H),3.17(t,J=6.8,2H),2.76(t,J=7.0,2H),2.55(t,J=7.1,2H),2.50(m,4H),1.69(m,4H);ESI-MS:m/z 428[M+1]+.。
合成化合物8的结构式如下:
实施例9 3-(2-N-哌啶基-丙酰胺基)-吴茱萸次碱的合成
在15mL乙醇中加入0.20g 3-(2-氯丙酰胺基)-吴茱萸次碱,0.03gKI和0.5mL哌啶,加热回流6小时,冷却,过滤,干燥得到0.16g白色固体,产率74%。mp 260-262℃;1H-NMR(400MHz,DMSO-d6):δ11.84(s,1H),10.59(s,1H),8.50(d,J=2.2,1H),7.98(dd,J=8.8,2.4,1H),7.65(dd,J=8.2,6.1,2H),7.48(d,J=8.3,1H),7.26(t,J=7.6,1H),7.09(t,J=7.5,1H),4.45(t,J=6.8,2H),3.17(t,J=6.8,2H),2.63(d,J=6.5,2H),2.53(d,J=6.7,2H),2.41(s,4H),1.52(m,4H),1.40(d,J=4.8,2H);ESI-MS:m/z 414[M+1]+.
合成化合物9的结构式如下:
实施例10 3-(2-二乙胺基-乙酰胺基)-7,8-脱氢吴茱萸次碱的合成
在15mL乙醇中加入0.20g 3-乙酰氨基-7,8-脱氢吴茱萸次碱,0.03g KI和0.5mL二乙胺,加热回流6小时,冷却,过滤,干燥得到0.14g浅褐色固体,产率79%。mp 297.6-299.9℃;1H-NMR(400MHz,DMSO-d6):δ12.71(s,1H),10.12(s,1H),8.77(d,J=10.8,1H),8.62(d,J=7.4,1H),8.18(d,J=8.1,2H),7.85(t,J=10.8,2H),7.69(d,J=8.1,1H),7.50(t,J=7.4,1H),7.30(t,J=7.3,1H),3.26(s,2H),2.68(t,J=18.0,4H),1.06(t,J=6.9,6H);ESI-MS:m/z 414[M+1]+.
合成化合物10的结构式如下:
实施例11 3-(2-N-吡咯烷基-乙酰胺基)-7,8-脱氢吴茱萸次碱的合成
在15mL乙醇中加入0.20g 3-乙酰氨基-7,8-脱氢吴茱萸次碱,0.03g KI和0.5mL吡咯烷,加热回流6小时,冷却,过滤,干燥得到0.14g褐色固体,产率70%。mp 261.4-263.2℃;1H-NMR(400MHz,DMSO-d6):δ12.70(s,1H),10.20(s,1H),8.78(s,1H),8.62(d,J=7.4,1H),8.16(m,2H),7.83(d,J=6.6,2H),7.69(d,J=8.0,1H),7.50(t,J=7.2,1H),7.30(t,J=7.2,1H),3.34(s,2H),2.64(m,4H),1.78(m,4H);ESI-MS:m/z 412[M+1]+.
合成化合物11的结构式如下:
实施例12 3-(2-N-哌啶基-乙酰胺基)-7,8-脱氢吴茱萸次碱的合成
在15mL乙醇中加入0.20g 3-乙酰氨基-7,8-脱氢吴茱萸次碱,0.03g KI和0.5mL哌啶,加热回流6小时,冷却,过滤,干燥得到0.14g褐色固体,产率82%。mp 280.4-283.0℃;1H-NMR(400MHz,DMSO-d6):δ12.71(s,1H),10.16(s,1H),8.77(s,2H),8.62(d,J=7.4,1H),8.17(m,2H),7.84(d,J=6.3,2H),7.68(d,J=8.1,1H),7.50(t,J=7.4,1H),7.30(t,J=7.2,1H),3.16(s,2H),2.44(m,2H),1.51(d,J=70.1,6H);ESI-MS:m/z 426[M+1]+.
合成化合物12的结构式如下:
实施例13
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值来表示,以Tacrine作为阳性对照。所有的测试都是在岛津UV-2540型紫外可见分光光度计上,在37℃的条件下测定。数据分析软件用Origin软件进行数据处理。
1.10.0mM样品溶液的配制:称取一定量各种待分析样品用DMSO溶剂定容。
2.酶储备液的配制:乙酰胆碱酯酶(从电鳗中提取)和丁酰胆碱酯酶(从马的血浆中提取)从Sigma公司购买;乙酰胆碱酯酶储备液浓度为0.1mg/ml,丁酰胆碱酯酶的浓度为2mg/ml水溶液。
3.底物储备液的配制:乙酰巯基胆碱(乙酰胆碱酯酶的底物)和丁酰巯基胆碱(丁酰胆碱酯酶的底物)从Sigma公司购买。其中乙酰巯基胆碱溶液和丁酰巯基胆碱溶液浓度都为2mg/ml的磷酸钾(pH8.0)缓冲溶液。
4.显色剂储备液的配制:显色剂DTNB从Sigma公司购买,配成4mg/ml的磷酸钾缓冲液(pH8.0)。
5.测试:每次测试的体积都为1ml的磷酸钾缓冲液(pH8.0),其中包含酶储备液10μl、底物储备液50,显色剂储备液50和10相应的抑制剂,最后由缓冲液补齐至1ml的体积。测试时,先将酶、显色剂和抑制剂在37℃孵育15分钟,最后加入底物,活性是在检测溶液在412nm处在60秒的间隔中吸光度的变化。
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时的抑制剂浓度,即为抑制剂的IC50值。
表1化合物4-12及Tacrin对乙酰胆碱酯酶和丁酰胆碱酯酶的抑制作用的IC50和抑制的选择性
a对乙酰胆碱酯酶选择性=IC50(丁酰胆碱酯酶)/IC50(乙酰胆碱酯酶)
结论:从表1发现所有的衍生物都有对乙酰胆碱酯酶的抑制活性,而对丁酰胆碱酯酶的抑制活性相对较弱,选择性较高。化合物12在所有测试的化合物中具有最高的对乙酰胆碱酯酶的抑制活性(IC50=10.07nm),同时其选择性也最高(539)。
Claims (7)
2、一种3-胺基烷酰胺基-吴茱萸次碱与3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物的合成方法,其特征在于包括如下步骤:
(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DDQ脱氢后得到7,8-脱氢吴茱萸次碱的酰化产物;
(4)酰化产品与相应的胺反应得到3-胺基烷酰胺基-吴茱萸次碱与3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物。
3、根据权利要求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、根据权利要求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、权利要求1所述的3-胺基烷酰胺基-吴茱萸次碱与3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物在制备乙酰胆碱酯酶抑制药物中的应用。
6、根据权利要求4所述的应用,其特征是所述3-胺基烷酰胺基-吴茱萸次碱与3-胺基烷酰胺基-7,8-脱氢吴茱萸次碱衍生物在制备治疗阿尔茨海默病、脑血管痴呆、青光眼或重症肌无力疾病药物中的应用。
7、根据权利要求5或6所述的应用,其特征在于所述药物的剂型为片剂、丸剂、胶囊、注射剂、悬浮剂或乳剂。
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CN103059020A (zh) * | 2012-12-10 | 2013-04-24 | 中山大学 | 一种吴茱萸次碱衍生物及其制备方法和应用 |
CN109761980A (zh) * | 2019-02-19 | 2019-05-17 | 安徽医科大学 | 一种3-胺基磺酰胺基取代的吴茱萸次碱类衍生物及其制备方法和应用 |
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WO2014029360A1 (zh) * | 2012-08-23 | 2014-02-27 | 中山大学 | 氨基取代吴茱萸次碱类似物及其合成方法与在制备抗肥胖症药物中的应用 |
CN102775413B (zh) * | 2012-08-23 | 2014-07-16 | 中山大学 | 氨基取代吴茱萸次碱类似物及其合成方法与在制备抗肥胖症药物中的应用 |
CN103059020A (zh) * | 2012-12-10 | 2013-04-24 | 中山大学 | 一种吴茱萸次碱衍生物及其制备方法和应用 |
CN109761980A (zh) * | 2019-02-19 | 2019-05-17 | 安徽医科大学 | 一种3-胺基磺酰胺基取代的吴茱萸次碱类衍生物及其制备方法和应用 |
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