CN104529775A - α-细辛醇酯及其制备方法与应用 - Google Patents
α-细辛醇酯及其制备方法与应用 Download PDFInfo
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- CN104529775A CN104529775A CN201410699506.6A CN201410699506A CN104529775A CN 104529775 A CN104529775 A CN 104529775A CN 201410699506 A CN201410699506 A CN 201410699506A CN 104529775 A CN104529775 A CN 104529775A
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Abstract
本发明涉及α-细辛醇酯及其制备方法与应用。所涉及的α-细辛醇酯的化学结构通式如式I所示。所涉及的应用为上述化合物用于制备镇静、安神、抗老年痴呆、抗惊厥、抗癫痫、抗抑郁药物的应用。
Description
技术领域
本发明主要涉及α-细辛醇酯的制备方法及其用于镇静、安神、抗老年痴呆、抗惊厥、抗癫痫、抗抑郁的药物研究。
背景技术
石菖蒲,首次记录于《神农本草经》,为上品,来源于天南星科多年生草本植物石菖蒲Acorus tatarinowii Schott.的干燥根茎。性温,味辛、苦。入心、胃经,具有芳香之气,辛温行散之力,可以化湿和胃,又可化痰开窍,具有益智醒神等功效,常用于治疗中风、痰厥癫痫、神昏、健忘等。主要化学成分为挥发油、氨基酸和糖类等,挥发油主要含有β-细辛醚,α-细辛醚等。现代药理研究认为,石菖蒲具有抗痴呆、神经细胞保护、抗突变、抗癫痫等作用。
远志,首次收录于《神农本草经》,为上品,来源于远志科植物远志Polygalatenuifalia Willd.或卵叶远志Polygala sibirica L.的干燥根。远志味苦、辛,性温。具有益智安神、消痰驱肿之功效。远志中化学成分主要包含三萜皂苷类、糖酯类、酮类,也含有少量的生物碱、香豆素、木质素等。研究表明,远志在抗痴呆、脑保护、镇静、抗惊厥、抗抑郁、祛痰镇咳、保护心脑血管等方面具有良好活性。
王莎莎等通过给大鼠口服远志提取物后,在血和胆汁中发现了能延长小鼠戊巴比妥钠睡眠时间的活性物质3,4,5-三甲氧基肉桂酸(TMCA)、甲基3,4,5-三甲氧基肉桂酸(M-TMCA)和对甲氧基肉桂酸(PMCA),提示远志水提物中含有TMCA的天然前体药物。[Wang S.S.Wakan Iyakugaku Zasshi,1995,12(2),102]
凌仰之等对TMCA进行结构拼合,得到了3,4,5-三甲氧基肉桂酰胺类化合物,发现其具有很好的抗惊厥活性。[凌仰之,医药工业,1987,18(2):56]
基于远志中TMCA和石菖蒲中α-细辛醚在镇静、安神、抗惊厥、神经细胞保护等方面具有很好的药理活性,我们通过结构及药效团拼合设计了3,4,5-三甲氧基肉桂酸α-细辛醇酯及以α-细辛醇为核心的一系列酯类衍生物,以期在抗老年痴呆、脑保护、镇静、抗惊厥、抗抑郁等方面筛选得到更具疗效的化学新药。
发明内容
本发明提供了α-细辛醇酯,其结构通式如式I所示:
其中:
R为支链或直链C1-12烷基、烯基或炔基;C3-9的环烷基、取代环烷基;C3-9的环烯基、取代环烯基;芳基、单取代芳基或多取代芳基;杂环芳基、单取代杂环芳基或多取代杂环芳基;氨基酸基。
进一步可选的,所述的R为芳甲基、单取代芳甲基或多取代芳甲基;芳乙基、单取代或多取代芳乙基;芳乙烯基、单取代或多取代芳乙烯基;取代苯氧乙基。
更进一步可选的,所述的R为:
本发明还提供了上述α-细辛醇酯的制备方法,方法包括:将通式II化合物与通式III、催化剂按摩尔比1.0~2.0:1.0~2.0:0.1~1.0依次加入含有适当有机溶剂反应容器中,待完全溶解后,再加入脱水剂,脱水剂与通式II化合物的摩尔比为1~2:1,室温搅拌5-20小时,停止反应,乙酸乙酯/水分离,有机相用无水硫酸钠干燥,浓缩,柱色谱分离纯化;
所述催化剂为吡啶、2,4,6-三甲基吡啶、2,6-二甲基吡啶、2,6-二叔丁基-4-甲基吡啶和4-二甲氨基吡啶(DMAP)中的一种或其中任意组合;
所述有机溶剂为二氯甲烷、三氯甲烷、四氯甲烷、四氢呋喃、乙酸乙酯、甲基叔丁基醚、乙醚、1,4-二氧六环、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、N,N-二甲基乙酰胺和二甲基亚砜中一种或其中任意组合;
所述脱水剂为二环己基碳二亚胺(DCC)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、或二异丙基碳二亚胺(DIC)。
本发明同时还提供可上述α-细辛醇酯的另一种制备方法,方法包括:
α-细辛醇与通式III化合物在Mitsunobu反应条件下生成α-细辛醇酯:
进一步,方法包括:将α-细辛醇、通式III化合物、偶氮化合物、有机磷化合物按摩尔比为1~1.5:1~1.5:1~1.5:1~1.5溶于干燥的四氢呋喃中,室温反应10-48小时,乙酸乙酯/水分离,有机相用无水硫酸钠干燥,浓缩,柱色谱分离纯化。
可选的,所述偶氮化合物为偶氮二甲酸二乙酯(DEAD)、偶氮二甲酸二异丙酯(DIAD)、偶氮二甲酰二哌啶(ADDP)、N,N,N’,N’-四甲基偶氮二羧酰胺(TMAD)、N,N,N’,N’-四异丙基偶氮二羧酰胺(TIPA)或4,7-二甲基-3,4,5,6,7,8-六氢-1,2,4,7-四氮杂辛因-3,8-二酮(DHTD)。
可选的,有机磷化合物为三苯基膦、三丁基膦或三甲基磷。
本发明又提供了上述化合物的立体异构或其不同立体异构化合物的混合物。
本发明同时提供可上述化合物用于制备镇静、安神、抗老年痴呆、抗惊厥、抗癫痫、抗抑郁药物的应用。
具体实施方式
本发明提供了一类α-细辛醇酯,其结构式如通式I所示:
其中,通式I中,R为支链或直链C1-12烷基、烯基或炔基;C3-9的环烷基、取代环烷基或环烯基、取代环烯基;芳基,单取代或多取代芳基;杂环芳基,单取代杂环芳基或多取代杂环芳基;芳甲基,单取代芳甲基或多取代芳甲基;芳乙基,单取代或多取代芳乙基;芳乙烯基,单取代或多取代芳乙烯基;取代苯氧乙基;氨基酸基。
本发明的化合物的制备方法为:
可选的,方法(1):通式II化合物与通式III化合物在脱水剂/催化剂的作用下得到相应的α-细辛醇酯(通式I化合物);
其中,将通式II化合物与通式III、催化剂按摩尔比1.0~2.0:1.0~2.0:0.1~1.0依次加入含有适当有机溶剂反应容器中,待完全溶解后,再加入脱水剂(脱水剂与通式II化合物的摩尔比为1~2:1),室温搅拌5-20小时,停止反应,乙酸乙酯/水分离,有机相用无水硫酸钠干燥,浓缩,柱色谱分离纯化。其中,优选通式II化合物与通式III、催化剂摩尔比为1.0:1.0~1.2:0.1~0.3。
所用催化剂包含:吡啶、2,4,6-三甲基吡啶、2,6-二甲基吡啶、2,6-二叔丁基-4-甲基吡啶、4-二甲氨基吡啶或其中任意组合,优选4-二甲氨基吡啶作为催化剂;
所用有机溶剂包含:二氯甲烷、三氯甲烷、四氯甲烷、四氢呋喃、乙酸乙酯、甲基叔丁基醚、乙醚、1,4-二氧六环、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、N,N-二甲基乙酰胺、二甲基亚砜或其中任意组合,优选N,N-二甲基甲酰胺、二氯甲烷、四氢呋喃作为溶剂;
所用脱水剂为:二环己基碳二亚胺(DCC)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、二异丙基碳二亚胺(DIC),优选EDCI作为脱水剂;
可选的,方法(2),通式III化合物先生成酰氯化合物再与通式II化合物反应,得到相应的α-细辛醇酯(通式I化合物),具体如下:在冰浴条件下,向通式III化合物中加入氯化亚砜,回流2-5小时,冷却,减压蒸馏过量的氯化亚砜,剩余物中加入四氢呋喃充分搅拌,得到通式III化合物的酰氯四氢呋喃溶液,在冰浴条件下,将上述通式III化合物的酰氯四氢呋喃溶液加入到含有和通式II化合物和吡啶的四氢呋喃的溶液中,搅拌10-20分钟,再升温回流3-4小时,反应完全后,冷却,过滤除去吡啶盐酸盐,滤液减压蒸除四氢呋喃,乙酸乙酯/水分离,有机相用无水硫酸钠干燥,浓缩,柱色谱分离纯化。
其中,通式III化合物与氯化亚砜的摩尔比为1:10至1:100,优选通式III化合物与氯化亚砜的摩尔比为1:50。
可选的,方法(3),通式II化合物与通式III化合物在Mitsunobu反应条件下生成通式化合物I。具体方式为:
将通式II化合物、通式III化合物、偶氮化合物、有机磷化合物按摩尔比为1~1.5:1~1.5:1~1.5:1~1.5溶于干燥的四氢呋喃中,室温反应10-48小时,乙酸乙酯/水分离,有机相用无水硫酸钠干燥,浓缩,柱色谱分离纯化,优选通式II化合物、通式III化合物、偶氮化合物、有机磷化合物摩尔比为1:1~1.1:1~1.2:1~1.2。
其中,偶氮化合物包括偶氮二甲酸二乙酯(DEAD)、偶氮二甲酸二异丙酯(DIAD)、偶氮二甲酰二哌啶(ADDP)、N,N,N’,N’-四甲基偶氮二羧酰胺(TMAD)、N,N,N’,N’-四异丙基偶氮二羧酰胺(TIPA)、4,7-二甲基-3,4,5,6,7,8-六氢-1,2,4,7-四氮杂辛因-3,8-二酮(DHTD),优选DIAD、DEAD。
有机磷化合物包括三苯基膦、三丁基膦、三甲基磷,优选三苯基膦。
本发明通式I化合物中可以存在一个或多个不对称碳原子,其任何立体异构或其立体异构的任何混合物均为本发明的一部分。
本发明通式I化合物用于镇静、安神、抗老年痴呆、抗惊厥、抗癫痫、抗抑郁的药物研究。
本发明中所涉及的α-细辛醇制备方法包括:
(1)化合物IV与化合物V在脂肪醇的存在下经催化剂催化反应得到化合物VI:
其中R1选自C1-C5的直链或支链烷基;
(2)还原化合物VI得到化合物II:
步骤(1)是将化合物V与脂肪醇先在二甲苯、甲苯或苯中回流反应3-12小时,进一步可选4-10个小时,冷却至室温后,加入2,4,5-三甲氧基苯甲醛(化合物IV)与催化剂,再回流反应5-24小时,进一步可选8-14小时,得到化合物VI;步骤(1)中所使用的脂肪醇为甲醇、乙醇、丙醇、异丙醇、丁醇、异丁醇、正戊醇和异戊醇中的一种或其中任意组合,进一步可选甲醇和乙醇;中的一种或其中任意组合脂肪醇与化合物V的摩尔比率在1:1~1:10,进一步可选脂肪醇与化合物V的摩尔比率为1:1~1:4;所用的催化剂为吡啶、2,4,6-三甲基吡啶、2,6-二甲基吡啶、2,6-二叔丁基-4-甲基吡啶、4-二甲氨基吡啶、哌啶和四氢吡咯中的一种或其中任意组合;催化剂与2,4,5-三甲氧基苯甲醛的摩尔比率在0.1:1~2:1。
步骤(2)所用还原剂为硼氢化钠、二氢双(2-甲氧乙氧基)铝酸钠、氢化铝锂或二异丁基氢化铝;还原剂与化合物VI的比率为1:1~10:1;所用溶剂为四氢呋喃、1,4二氧六环、二甲基乙二醚、甲苯、苯、二甲苯、乙醚、甲基叔丁基醚、二氯甲烷、二氯乙烷、三氯甲烷、四氯甲烷和正己烷中的一种或其中任意组合;反应温度在-78℃~25℃;反应时间在0.5~24小时之间。
通过以下描述将更好的理解本发明,这些实施例仅为说明,本发明的有利实施方案不限于此。
以下实施例中所用的α-细辛醇采取以下方法合成:
2,4,5-三甲氧基肉桂酸甲酯的制备
3L三口烧瓶,带温度计,冷凝管,分别加入麦氏酸195.5g(1.35mol)、甲醇(50mL)、甲苯(750mL),110℃下加热回流4小时后,冷却至室温,再加入2,4,5-三甲氧基苯甲醛196.2g(1.0mol)、吡啶134.5g(1.7mol)、哌啶14.5g(0.17mol),加热回流18小时,减压浓缩后,加入乙酸乙酯(200mL),水(200mL),萃取分离3次,合并有机相,减压浓缩后,加入乙醇(1000mL),放入冰箱冷藏过夜,待沉淀析出后,抽滤,500mL冰乙醇洗涤3次,得淡黄色固体166.3g,产率66%。
3L三口烧瓶,带恒压漏斗,加入LiAlH4 28.5g(0.75mol)(溶解于250mL四氢呋喃中),冰浴下搅拌20分钟,加入AlCl3 42.6g(0.32mol)(溶解于150mL四氢呋喃中),搅拌30分钟后,0℃下,缓慢滴加2,4,5-三甲氧基肉桂酸甲酯63.1g(0.25moL)(溶解于200mL四氢呋喃中),缓慢升温,室温下搅拌1小时。缓慢加入水(23g)、10%的氢氧化钠(23mL)、水(69mL),待沉淀析出后,抽滤,减压浓缩后,加入乙酸乙酯(50mL),水(100mL),萃取分离3次,合并有机相,无水硫酸钠干燥,抽滤,减压浓缩,所得粗品经硅胶色谱柱分离得到浅黄色固体28.0g,产率50%。
实施例1:
3,4,5-三甲氧基肉桂酸α-细辛醇酯
250mL单口烧瓶,分别加入α-细辛醇11.20g(50.0mmol)、3,4,5-三甲氧基肉桂酸17.85g(75.0mmol)、DMAP 1.83g(15.0mmol)、二氯甲烷(120mL),室温下搅拌30分钟后,加入EDCI 14.38g(75.0mmol),室温下反应6小时,TLC监控反应,待原料反应结束后,加入饱和碳酸氢钠溶液,调节pH=7-8,用乙酸乙酯/水体系萃取、洗涤3次,合并有机相,无水硫酸钠干燥,抽滤,减压浓缩,所得粗品经硅胶色谱柱分离得到黄色固体17.76g,产率80%。
m/z=[M+Na]467.1684
1H NMR(600MHz,cdcl3)δ7.64(d,J=15.9Hz,1H),7.00(t,J=7.9Hz,2H),6.76(s,2H),6.51(s,1H),6.39(d,J=15.9Hz,1H),6.26(dt,J=13.8,6.7Hz,1H),4.87(d,J=6.7Hz,2H),3.90(s,3H),3.88(s,9H),3.87(s,3H),3.84(s,3H).
13C NMR(600MHz,cdcl3)δ166.78(s),153.41(s),151.70(s),149.95(s),144.87(s),143.29(s),140.07(s),129.92(s),129.23(s),128.84(s),125.93(s),121.30(s),117.34(s),116.86(s),110.01(s),105.18(s),97.46(s),65.97(s),60.97(s),56.58(s),56.50(s),56.13(s),56.06(s).
实施例2:
烟酸α-细辛醇酯
100mL单口烧瓶,分别加入α-细辛醇1.12g(5.0mmol)、烟酸0.92g(7.5mmol)、DMAP 0.18g(1.5mmol)、N,N-二甲基甲酰胺(20mL),室温下搅拌35分钟后,加入EDCI 1.44g(7.5mmol),室温下反应8小时,TLC监控反应,待原料反应结束后,加入饱和碳酸氢钠溶液,调节pH=7-8,用乙酸乙酯/水体系萃取、洗涤3次,合并有机相,无水硫酸钠干燥,抽滤,减压浓缩,所得粗品经硅胶色谱柱分离得到黄色固体0.82g,产率50%。
实施例3:
异烟酸α-细辛醇酯
100mL单口烧瓶,分别加入α-细辛醇0.90g(4.0mmol)、异烟酸0.74g(6.0mmol)、DMAP 0.15g(1.2mmol)、三氯甲烷(20mL),室温下搅拌30分钟后,加入EDCI 1.15g(6.0mmol),室温下反应6小时,TLC监控反应,待原料反应结束后,加入饱和碳酸氢钠溶液,调节pH=7-8,用乙酸乙酯/水体系萃取、洗涤3次,合并有机相,无水硫酸钠干燥,抽滤,减压浓缩,所得粗品经硅胶色谱柱分离得到黄色固体0.59g,产率45%。
实施例4:
3,4,5-三甲氧基苯乙酸α-细辛醇酯
100mL单口烧瓶,分别加入α-细辛醇1.34g(6.0mmol)、3,4,5-三甲氧基苯乙酸2.03g(9.0mmol)、DMAP 0.22g(1.8mmol)、N,N-二甲基甲酰胺(30mL),室温下搅拌30分钟后,加入EDCI 1.73g(9.0mmol),室温下反应6小时,TLC监控反应,待原料反应结束后,加入饱和碳酸氢钠溶液,调节pH=7-8,用乙酸乙酯/水体系萃取、洗涤3次,合并有机相,无水硫酸钠干燥,抽滤,减压浓缩,所得粗品经硅胶色谱柱分离得到黄色固体1.68g,产率65%。
实施例5:
L-脯氨酸α-细辛醇酯
(i)100mL三口烧瓶,带温度计,分别加入L-脯氨酸2.30g,(20.0mmol)、1,4-二氧六环(10mL)、2mol/L氢氧化钠水溶液(30mL),冷却至0℃,搅拌10分钟,再滴加二碳酸二叔丁酯6.55g,(30.0mmol)(60分钟内滴完),缓慢升温,室温下搅拌6小时或过夜。反应液用2mol/L稀盐酸调节pH=4,用乙酸乙酯/水体系萃取、洗涤3次,合并有机相,无水硫酸钠干燥,得白色固体boc-L-脯氨酸3.78g,产率88%。
(ii)100mL单口烧瓶,分别加入(i)中boc-L-脯氨酸1.46g(6.8mmol)、α-细辛醇1.01g(4.5mmol)、DMAP 0.22g(1.8mmol)、二氯甲烷(30mL),室温下搅拌30分钟后,加入EDCI 1.73g(9.0mmol),室温下反应6小时,TLC监控反应,待原料反应结束后,加入饱和碳酸氢钠溶液,调节pH=7-8,乙酸乙酯萃取,分离3次,合并有机相,无水硫酸钠干燥,抽滤,减压浓缩,所得粗品经硅胶色谱柱分离得到黄色固体boc-L-脯氨酸α-细辛醇1.10g,产率58%。
(iii)100mL单口烧瓶,分别加入(ii)中boc-L-脯氨酸α-细辛醇0.97g(2.3mmol)、二氯甲烷(10mL),滴加三氟乙酸(3mL)氮气保护下,室温搅拌5小时,减压浓缩后,加入乙酸乙酯(20mL),水(20mL),饱和碳酸氢钠水溶液(50mL),萃取分离3次,合并有机相,无水硫酸钠干燥,抽滤,减压浓缩,得到浅黄色固体L-脯氨酸α-细辛醇0.69g,产率93%。
实施例6:
3,4,-二羟基肉桂酸α-细辛醇酯
100mL单口烧瓶,0℃加入α-细辛醇1.79g(8.0mmol)、3,4-二羟基肉桂酸2.16g(12.0mmol)、四氢呋喃(30mL)、三苯基磷2.10g(8.0mmol)、偶氮二甲酸二异丙酯1.62g(8.0mmol),室温下搅拌36小时,TLC监控反应,待原料反应结束后,用乙酸乙酯/水体系萃取、洗涤3次,合并有机相,无水硫酸钠干燥,抽滤,减压浓缩,所得粗品经硅胶色谱柱分离得到黄色固体1.24g,产率40%。
实施例7:
3,4,-二羟基苯乙酸α-细辛醇酯
100mL单口烧瓶,0℃加入α-细辛醇1.68g(7.5mmol)、3,4-二羟基苯乙酸1.90g(11.3mmol)、四氢呋喃(30mL)、三苯基磷1.97g(7.5mmol)、偶氮二甲酸二异丙酯1.52g(7.5mmol),室温下搅拌40小时,TLC监控反应,待原料反应结束后,用乙酸乙酯/水体系萃取、洗涤3次,合并有机相,无水硫酸钠干燥,抽滤,减压浓缩,所得粗品经硅胶色谱柱分离得到黄色固体1.23g,产率44%。
实施例8:
3-硝基苯乙酸α-细辛醇酯
100mL单口烧瓶,分别加入α-细辛醇1.57g(7.0mmol)、3-硝基苯乙酸1.90g(10.5mmol)、DMAP 0.26g(2.1mmol)、N,N-二甲基甲酰胺(30mL),室温下搅拌30分钟后,加入EDCI 2.01g(10.5mmol),室温下反应6小时,TLC监控反应,待原料反应结束后,加入饱和碳酸氢钠溶液,调节pH=7-8,用乙酸乙酯/水体系萃取、洗涤3次,合并有机相,无水硫酸钠干燥,抽滤,减压浓缩,所得粗品经硅胶色谱柱分离得到黄色固体0.81g,产率30%。
实施例9:
2,5-甲氧基肉桂酸α-细辛醇酯
100mL单口烧瓶,分别加入α-细辛醇0.90g(4.0mmol)、2,5-甲氧基肉桂酸1.25g(6.0mmol)、DMAP 0.15g(1.2mmol)、二氯甲烷(20mL),室温下搅拌30分钟后,加入EDCI 1.15g(6.0mmol),室温下反应9小时,TLC监控反应,待原料反应结束后,加入饱和碳酸氢钠溶液,调节pH=7-8,用乙酸乙酯/水体系萃取、洗涤3次,合并有机相,无水硫酸钠干燥,抽滤,减压浓缩,所得粗品经硅胶色谱柱分离得到黄色固体1.03g,产率62%。
实施例10:
对甲氧基肉桂酸α-细辛醇酯
100mL单口烧瓶,分别加入α-细辛醇0.67g(3.0mmol)、对甲氧基肉桂酸0.80g(4.5mmol)、DMAP 0.11g(0.9mmol)、二氯甲烷(20mL),室温下搅拌30分钟后,加入EDCI 0.86g(4.5mmol),室温下反应6小时,TLC监控反应,待原料反应结束后,加入饱和碳酸氢钠溶液,调节pH=7-8,用乙酸乙酯/水体系萃取、洗涤3次,合并有机相,无水硫酸钠干燥,抽滤,减压浓缩,所得粗品经硅胶色谱柱分离得到黄色固体0.69g,产率60%。
实施例11:
对氯苯甲酸α-细辛醇酯
100mL单口烧瓶,分别加入α-细辛醇0.45g(2.0mmol)、对氯苯甲酸0.47g(3.0mmol)、DMAP 0.07g(0.6mmol)、二氯甲烷(20mL),室温下搅拌30分钟后,加入EDCI 0.58g(3.0mmol),室温下反应6小时,TLC监控反应,待原料反应结束后,加入饱和碳酸氢钠溶液,调节pH=7-8,用乙酸乙酯/水体系萃取、洗涤3次,合并有机相,无水硫酸钠干燥,抽滤,减压浓缩,所得粗品经硅胶色谱柱分离得到黄色固体0.35g,产率48%。
实施例12:
丙酸α-细辛醇酯
100mL单口烧瓶,加入丙酸0.28g(3.8mmol),在冰浴条件下,加入氯化亚砜(12mL),回流3小时,冷却至室温,减压蒸馏过量的氯化亚砜,剩余物中加入四氢呋喃充分搅拌,得到丙酰氯四氢呋喃溶液;在冰浴条件下,分别加入α-细辛醇0.56g(2.5mmol)、吡啶0.60g(7.6mmol)、丙酰氯呋喃溶液,搅拌15分钟,再升温回流3小时,反应完全后,冷却,过滤除去吡啶盐酸盐,滤液减压蒸除四氢呋喃,乙酸乙酯/水分离,合并有机相,无水硫酸钠干燥,抽滤,减压浓缩,所得粗品经硅胶色谱柱分离得到黄色固体0.44g,产率65%。
3,4,5-三甲氧基肉桂酸α-细辛醇酯的活性研究
3,4,5-三甲氧基肉桂酸α-细辛醇酯用于治疗惊厥与癫痫。所使用抗癫痫药理实验釆用美国国立卫生研究院(NIH)实施的抗癫痫药开发程序。包括评价抗癲痫活性的最大电惊厥实验法(MES)及考察神经毒性的旋转法(Rotarodtest)。为了进一步研究并评价药物在不同化学模型中的抗惊厥药理机制,采用戊四唑、3-巯基丙酸等2种经典化学模型予以评价。
(1)最大电惊厥实验(MES)
MES是癫痫大发作的常用实验模型,受试化合物若能显著对抗MES,则该化合物有可能开发成临床上治疗癫痫大发作有效的药物。
方法:KM小鼠在试验前进行初步筛选,合格后方能用于下一步实验。筛选方法如下:实验前一天,对实验小鼠采用15V,60Hz的电刺激,两电极夹于小鼠双耳,通电剌激0.45s,出现后肢强直的小鼠属于试验备用小鼠,用于后期实验。抗最大电惊厥实验测定方法为:受试化合物溶解后,灌胃给药,分别在给药后0.25h、0.5h、1h、2h、3h、4h使用0.45s,15V,60Hz的耳电极刺激,如果小鼠不出现后肢强直,则表明该受试化合物在该剂量下具有抗惊厥活性。按照一定的给药规律,设计出梯度浓度,分别给予不同梯度浓度的受试化合物,观察记录其抗惊厥活性,最后计算出受试化合物抗最大惊厥活性的半数有效量(ED50)。依照下面的公式进行计算:
ED50=lg-1[Xm-i(∑P-0.5)]
SX50=i(∑P-∑P2/n-1)1/2
ED50的95%可信限=lg-1(lgED50±1.96SX50)
公式中符号的意义如下:
Xm 最大剂量的常用对数;
i 剂量间比例值的常用对数;
P 每组的阳性率,以小数表示;
n 每组的动物数;
SX50 lgED50的标准误;
表1.3,4,5-三甲氧基肉桂酸α-细辛醇酯的小鼠初期抗惊厥实验结果(i.g)a
a受试化合物加吐温用水溶解;
b在灌胃给药后0.25h、0.5h、1h、2h、3h、4h进行最大电惊厥实验;
c测试小鼠数量为6只;
d ED50为半数有效量;
e在括号中给出的95%置信限;
(2)神经毒性实验(Neurotoxicity)
方法:实验小鼠灌胃给药,分别在给药后0.25h、0.5h、1h、2h将小鼠放置在转棒式疲劳仪上,以16转/分旋转。在3min内试验小鼠不落下或者落下3次以内,就表明该化合物在该剂量下没有神经毒性;落下3次以上则认为该化合物在该剂量下有神经毒性。按照给药规律设计梯度浓度,分别给予不同梯度剂量旳受试化合物,计算半数中毒量(TD50)。依照下面的公式进行计算:
TD50=lg-1[Xm-i(∑P-0.5)]
SX50=i(∑P-∑P2/n-1)1/2
TD50的95%可信限=lg-1(lgTD50±1.96SX50)
公式中符号的意义如下:
Xm 最大剂量的常用对数;
i 剂量间比例值的常用对数;
P 每组的阳性率,以小数表示;
n 每组的动物数;
SX50 lgTD50的标准误;
表2.3,4,5-三甲氧基肉桂酸α-细辛醇酯的小鼠神经毒性实验与抗惊厥活性数据分析(i.g)a
a受试化合物加吐温用水溶解;
b在灌胃给药后0.25h、0.5h、1h、2h进行神经毒性实验;
c测试小鼠数量为4只;
d TD50为半数中毒量;
e ED50为半数有效量;
f PI为保护指数(TD50/ED50);
g在括号中给出的95%置信限;
通过测定后的实验数据计算得出,3,4,5-三甲氧基肉桂酸α-细辛醇酯在灌胃给药下对抗最大电惊厥实验的ED50=90.3mg/kg,TD50=939.7mg/kg,保护指数PI为10.4,显示出很好的抗惊厥活性,且未显示出明显毒性。
为了推断出3,4,5-三甲氧基肉桂酸α-细辛醇酯可能的抗惊厥机制,本研究采用戊四唑、3-巯基丙酸等化学试验模型对受试化合物(i.g:160mg/kg、80mg/kg、40mg/kg)的初步抗惊厥活性进行了评价。
(3)戊四唑诱发的实验性癫痫模型
方法:实验小鼠随机分成5组,分别为给药组(i.g:160mg/kg、80mg/kg、40mg/kg)、对照组和空白组,每组6只,给药组灌胃受试化合物,对照组灌胃阳性药卡马西平,空白组灌胃生理盐水,30分钟后,给予灌胃戊四唑200mg/kg,受试动物单独放置于一个鼠笼中观察60分钟,记录下每组小鼠阵挛性发作的潜伏时间、阵挛性发作个数、强直性发作个数及死亡个数。
表3.3,4,5-三甲氧基肉桂酸α-细辛醇酯对抗戊四唑引起的小鼠抗惊厥活性结果
**与生理盐水组比较p<0.01;*与生理盐水组比较p<0.05
在对抗戊四唑化学药物诱导的惊厥模型试验中,与生理盐水组相比,试验剂量下(160mg/kg、80mg/kg、40mg/kg)的3,4,5-三甲氧基肉桂酸α-细辛醇酯均能显著延长小鼠阵挛性发作的时间(p<0.05),且能抑制小鼠强直性发作,降低小鼠死亡率;与卡马西平相比,同等剂量下3,4,5-三甲氧基肉桂酸α-细辛醇酯对试验小鼠抑制强直性发作和减少死亡率效果相当。戊四唑是通过抑制γ-氨基丁酸(GABA)神经递质引起惊厥,GABA是存在于大脑中的主要抑制性神经递质,与癫痫有着密不可分的关系。根据表3,3,4,5-三甲氧基肉桂酸α-细辛醇酯可能是通过增加GABA神经递质,来抑制或减少戊四唑诱导的小鼠发生惊厥。
(4)3-巯基丙酸诱发的实验性癫痫模型
方法:实验小鼠随机分成5组,分别为给药组(i.g:160mg/kg、80mg/kg、40mg/kg)、对照组和空白组,每组6只,给药组灌胃受试化合物,对照组灌胃阳性药卡马西平,空白组灌胃生理盐水,30分钟后,给予灌胃3-巯基丙酸60mg/kg,受试动物单独放置于一个鼠笼中观察60分钟,记录下每组小鼠阵挛性发作的潜伏时间、阵挛性发作个数、强直性发作个数及死亡个数。
表4.3,4,5-三甲氧基肉桂酸α-细辛醇酯对抗3-巯基丙酸引起的小鼠抗惊厥活性结果
*与生理盐水组比较p<0.05
在对抗3-巯基丙酸化学药物诱导的惊厥模型试验中,与生理盐水组相比,160mg/kg、80mg/kg的3,4,5-三甲氧基肉桂酸α-细辛醇酯均能显著延长小鼠阵挛性发作的时间(p<0.05),且能抑制小鼠阵挛性发作和强直性发作,降低小鼠死亡率;与卡马西平相比,160mg/kg、80mg/kg的3,4,5-三甲氧基肉桂酸α-细辛醇酯对试验小鼠抑制强直性发作和减少死亡率效果相当。3-巯基丙酸是GABA合成酶谷氨酸脱羧酶竞争性抑制剂,会抑制GABA的合成导致GABA脑内水平减少。3,4,5-三甲氧基肉桂酸α-细辛醇酯能适度对抗3-巯基丙酸诱导的惊厥,说明3,4,5-三甲氧基肉桂酸α-细辛醇酯可能活化GABA合成酶谷氨酸脱羧酶或抑制脑内GABA。
Claims (10)
1.α-细辛醇酯,其特征在于,其结构通式如式I所示:
其中:
R为支链或直链C1-12烷基、烯基或炔基;C3-9的环烷基、取代环烷基;C3-9的环烯基、取代环烯基;芳基、单取代芳基或多取代芳基;杂环芳基、单取代杂环芳基或多取代杂环芳基;氨基酸基。
2.如权利要求1所述的α-细辛醇酯,其特征在于,所述的R为芳甲基、单取代芳甲基或多取代芳甲基;芳乙基、单取代或多取代芳乙基;芳乙烯基、单取代或多取代芳乙烯基;取代苯氧乙基。
3.如权利要求1所述的α-细辛醇酯,其特征在于,所述的R为:
4.如权利要求1所述α-细辛醇的制备方法,其特征在于,方法包括:将通式II化合物与通式III化合物、催化剂按摩尔比1.0~2.0:1.0~2.0:0.1~1.0依次加入含有适当有机溶剂反应容器中,待完全溶解后,再加入脱水剂,脱水剂与通式II化合物的摩尔比为1~2:1,室温搅拌5-20小时,停止反应,乙酸乙酯/水分离,有机相用无水硫酸钠干燥,浓缩,柱色谱分离纯化;
所述催化剂为吡啶、2,4,6-三甲基吡啶、2,6-二甲基吡啶、2,6-二叔丁基-4-甲基吡啶和4-二甲氨基吡啶中的一种或其中任意组合;
所述有机溶剂为二氯甲烷、三氯甲烷、四氯甲烷、四氢呋喃、乙酸乙酯、甲基叔丁基醚、乙醚、1,4-二氧六环、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、N,N-二甲基乙酰胺和二甲基亚砜中一种或其中任意组合;
所述脱水剂为二环己基碳二亚胺、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐、或二异丙基碳二亚胺。
5.权利要求1所述α-细辛醇酯的制备方法,其特征在于,方法包括:
α-细辛醇与通式III化合物在Mitsunobu反应条件下生成α-细辛醇酯:
6.如权利要求5所述的制备方法,其特征在于,方法包括:将α-细辛醇、通式化合物、偶氮化合物、有机磷化合物按摩尔比为1~1.5:1~1.5:1~1.5:1~1.5溶于干燥的四氢呋喃中,室温反应10-48小时,乙酸乙酯/水分离,有机相用无水硫酸钠干燥,浓缩,柱色谱分离纯化。
7.如权利要求6所述的制备方法,其特征在于,所述偶氮化合物为偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯、偶氮二甲酰二哌啶、N,N,N’,N’-四甲基偶氮二羧酰胺、N,N,N’,N’-四异丙基偶氮二羧酰胺或4,7-二甲基-3,4,5,6,7,8-六氢-1,2,4,7-四氮杂辛因-3,8-二酮。
8.如权利要求6的制备方法,其特征在于,所述有机磷化合物为三苯基膦、三丁基膦或三甲基磷。
9.权利要求1所述化合物的立体异构或其不同立体异构化合物的混合物。
10.权利要求1或9所述化合物用于制备镇静、安神、抗老年痴呆、抗惊厥、抗癫痫、抗抑郁药物的应用。
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Cited By (4)
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WO2016082780A1 (zh) * | 2014-11-26 | 2016-06-02 | 西北大学 | α-细辛醇酯及其制备方法与应用 |
CN109803948A (zh) * | 2016-08-04 | 2019-05-24 | 高砂香料工业株式会社 | 加温感觉化合物 |
CN113248380A (zh) * | 2020-11-23 | 2021-08-13 | 西北大学 | 一种乙酸α-细辛醇酯与α-细辛醇的合成方法 |
CN113387804A (zh) * | 2021-06-04 | 2021-09-14 | 西安石油大学 | 乙酸α-细辛醇酯与α-细辛醇的合成方法 |
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WO2016082780A1 (zh) * | 2014-11-26 | 2016-06-02 | 西北大学 | α-细辛醇酯及其制备方法与应用 |
US10131619B2 (en) | 2014-11-26 | 2018-11-20 | Northwest University | α-Asary-laldehyde ester, preparation method therefor, and application thereof |
CN109803948A (zh) * | 2016-08-04 | 2019-05-24 | 高砂香料工业株式会社 | 加温感觉化合物 |
CN109803948B (zh) * | 2016-08-04 | 2022-03-01 | 高砂香料工业株式会社 | 加温感觉化合物 |
KR20220050245A (ko) * | 2016-08-04 | 2022-04-22 | 다카사고 고료 고교 가부시키가이샤 | 온감 화합물 |
KR102473931B1 (ko) | 2016-08-04 | 2022-12-02 | 다카사고 고료 고교 가부시키가이샤 | 온감 화합물 |
CN113248380A (zh) * | 2020-11-23 | 2021-08-13 | 西北大学 | 一种乙酸α-细辛醇酯与α-细辛醇的合成方法 |
CN113387804A (zh) * | 2021-06-04 | 2021-09-14 | 西安石油大学 | 乙酸α-细辛醇酯与α-细辛醇的合成方法 |
CN113387804B (zh) * | 2021-06-04 | 2023-05-02 | 西安石油大学 | 乙酸α-细辛醇酯与α-细辛醇的合成方法 |
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CA2968652A1 (en) | 2016-06-02 |
KR102029898B1 (ko) | 2019-10-08 |
PL3225616T3 (pl) | 2020-07-27 |
RU2673887C1 (ru) | 2018-12-03 |
HK1243995A1 (zh) | 2018-07-27 |
US20170260122A1 (en) | 2017-09-14 |
AU2015353112B2 (en) | 2018-07-05 |
EP3225616A1 (en) | 2017-10-04 |
IL252461A0 (en) | 2017-07-31 |
JP6506841B2 (ja) | 2019-04-24 |
EP3225616B1 (en) | 2020-03-04 |
MY175619A (en) | 2020-07-02 |
WO2016082780A1 (zh) | 2016-06-02 |
EP3225616A4 (en) | 2018-07-11 |
IL252461B (en) | 2020-07-30 |
CY1123193T1 (el) | 2021-10-29 |
KR20170086636A (ko) | 2017-07-26 |
AU2015353112A1 (en) | 2017-06-22 |
DK3225616T3 (da) | 2020-06-02 |
US10131619B2 (en) | 2018-11-20 |
CN104529775B (zh) | 2017-07-14 |
SI3225616T1 (sl) | 2020-07-31 |
JP2018503602A (ja) | 2018-02-08 |
HUE049249T2 (hu) | 2020-09-28 |
SG11201704239PA (en) | 2017-06-29 |
CA2968652C (en) | 2020-07-07 |
NZ732395A (en) | 2018-06-29 |
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