CN85109441A - 新的烯丙基胺类的制备方法 - Google Patents

新的烯丙基胺类的制备方法 Download PDF

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CN85109441A
CN85109441A CN85109441.4A CN85109441A CN85109441A CN 85109441 A CN85109441 A CN 85109441A CN 85109441 A CN85109441 A CN 85109441A CN 85109441 A CN85109441 A CN 85109441A
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巴格·索马斯·M
布罗里斯马·罗伯特
麦克卡思·詹姆斯·R
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Abstract

本文叙述了新的β-亚甲基呋喃乙胺类化合物，该类化合物基本的作用机制是抑制多巴胺β-羟基化酶，因此，本发明化合物可用作抗高压药物。

Description

本发明是关于新的烯丙基胺类和其中间体的制备方法，本发明还涉及药物组合物以及用该组合物治疗高血压的方法。
本发明尤其涉及到具有下式的烯丙基胺类
Figure 85109441_IMG3
和它的药学上可以接受的无毒的酸加成盐。特别是，本发明的化合物涉及到β-亚甲基-2-呋喃乙胺、β-亚甲基-3-呋喃乙胺以及它们在药学上可以接受的无毒的酸加成盐。
典型的盐是与无毒有机酸或无机酸形成的盐，例如与下列酸所形成的盐：盐酸、氢溴酸、磺酸、硫酸、磷酸、硝酸、马来酸、富马酸、苯甲酸、抗坏血酸、琥珀酸、甲磺酸、醋酸、丙酸、酒石酸、柠檬酸、乳酸、苹果酸、扁桃酸、肉桂酸、棕榈酸、衣康酸和苯磺酸。
本发明的烯丙基胺类（Ⅰ），按下列反应路线，通过所示的一系列反应，可以很容易地制得：
Figure 85109441_IMG4
Figure 85109441_IMG5
上述反应路线实质上叙述了按照标准的格利雅反应条件，用甲基溴化镁反应，接着进行脱水，由2-或3-乙酰基呋喃衍生物转变为相应的2-或3-异亚丙基呋喃衍生物的方法。按照标准的条件，将该异亚丙基衍生物（Ⅳ）进行烯丙基氯化，得到粗产品（Ⅴ），用著名的加布里埃耳合成法，经过邻苯二甲酰亚胺衍生物（Ⅵ）得到所需的烯丙基胺类（Ⅰ）。用常规的化学方法，可以将游离碱转变为它的酸加成盐，或者将酸加成盐转变为游离碱。
上述反应路线用下述具体的实例进一步例叙述。
实例1
β-亚甲基-2-呋喃乙胺盐酸盐
A步：2-（1-甲基）乙烯基呋喃：
将55.06克（0.5摩尔）2-乙酰基呋喃溶于100毫升无水乙醚的溶液在氮气下滴加到211毫升2.85摩尔甲基溴化镁/乙醚（0.6摩尔）中，滴加的时间为1.5小时，并且滴加时反应混合物需在冰浴上冷却和不断地搅拌。控制滴加的速度，使反应温度保持低于30℃，得到灰色的沉淀。混合物于25℃温热1小时，然后再在冰浴上冷却，同时小心地加入100毫升饱和碳酸氢钠（Na HCO3）溶液。得到的块状物溶于约1升水中，水相用乙醚萃取二次。合并的醚溶液用饱和氯化钠（Na Cl）溶液萃取，以碳酸钾（K2CO3）干燥，过滤，并且在常压下浓缩，得到黄色油状物（粗醇）。将5.0克硫酸氢钾（KHSO4）和约0.1克4-叔-丁基邻苯二酚（抑制剂）加到粗醇中，混合物在1大气压下蒸馏。所需产品和水在约90℃蒸出。分出水，产物以碳酸钾（K2CO3）干燥，然后过滤，得8.5克无色油状物。同样，可以制备3-（1-甲基）乙烯基呋喃。
B步：N-2-（2-呋喃基）丙烯基邻苯二甲酰亚胺：
将12.37克（0.093摩尔）N-氯代琥珀酰亚胺和1.46克（0.0047摩尔）二苯基联硒化物加到8.35克（0.077摩尔）由A步得到的烯烃溶于310毫升二甲基甲酰胺（DMF）的溶液中。3小时后，于室温将化合物在500毫升己烷和1000毫升5%硫代硫酸钠（Na2S2O3）二个液相组分之间进行分配。在常压下蒸出己烷，残余物溶于200毫升DMF中，加入9.49克（0.051摩尔）邻苯二甲酰亚胺钾，并且在氮气下将混合物加热到90℃。45分钟后，冷却的反应混合物注入水中，过滤收集沉淀，并用醋酸乙酯-2-丙醇重结晶，得到3.57克无色结晶，熔点136～137℃。
元素分析：C15H11NO2S：
计算值（%）C，66.90;H，4.12;N，5.20，
测定值（%）C，66.82;H，4.30;N，4.97，
同样，可以制得N-2-（3-呋喃基）丙烯基邻苯二甲酰亚胺。
C步：β-亚甲基-2-呋喃乙胺盐酸盐：
将3.50克（13.83毫摩尔）由B步得到的邻苯二甲酰亚胺的悬浮液用磁力搅拌器搅拌，加入1.34毫升（27.64毫摩尔）溶于400毫升乙醇中的水合肼，并且在氮气下将混合物加热回流1小时，在此期间，生成粘稠的沉淀。加入1摩尔氢氧化钾（KOH）以溶解沉淀，然后将冷却的混合物蒸馏，并用乙醚萃取。醚层用1摩尔氢氧化钾（KOH）洗涤，然后用1摩尔盐酸萃取。酸层用5N氢氧化钠（NaOH）碱化，然后用氯化钠饱和，并用乙醚萃取。醚相以碳酸钾（K2CO3）干燥，浓缩，得黄色油状物。蒸馏得1.23克无色液体，沸点为40℃/0.5托。胺溶于乙醚中，在冰浴上冷却，滴入用干燥氯化氢（HCl）饱和的乙醚溶液，直到不再有沉淀生成。减压除去挥发性物质，残余物用乙醇-醋酸乙酯重结晶，得到1.2克无色结晶，熔点150～151℃。
元素分析：C7H9NO·Cl：
计算值（%）C，52.68;H，6.31;N，8.78，
测定值（%）C，52.48;H，6.43;N，8.61，
同样，可以制得β-亚甲基-3-呋喃乙胺盐酸盐。
在作用机制中，本发明的烯丙基胺类（Ⅰ）是多巴胺Ω-羟基化酶（DBH）的抑制剂，DBH的失效与作用时间和药物浓度有关。因此，发明者予计式Ⅰ混合物是有价值的治疗高血压的药物。
用已知的标准方法，如美国专利4，415，191中陈述的方法，可以容易地测定本发明化合物对多巴胺β-羟基化酶的抑制性质。例如欲测定对DBH的抑制程度是否和作用时间相关的动力学问题，所用方法可举例如下，在含有分子氧、供电子体（如抗坏血酸）以及DBH所需辅助因子的水溶液中测定DBH氧化作用，水溶液的PH为5，温度为20℃～40℃（最好为37℃）。按需要的浓度加入受试化合物，将上述水溶液孵育。间隔不同的时间吸取水溶液的等分试样，用酪胺作为底物，用极谱电极和氧监测仪，按S.May等[J.Biol.chem.256 2258（1981）]的方法测量所吸收的氧，以表示DBH的活性。各化合物使DBH失败的抑制常数可用Kitz和Wilson等[J.Biol.chem.273，3245（1962）]所提供的简便方法进行测定。按上述方法，用表Ⅰ中的混合物试验时，对DBH的抑制作用随孵育时间而增加。活性降低的初始速度随抑制剂浓度的增加而增加。表Ⅰ的结果表明，失败的速率（Kinact）很快，而抑制常数（K1）低，因此β-亚甲基-2-呋喃乙胺是很有效的。
表Ⅰ
化合物在体外对DBH的抑制作用
化合物 K1（毫摩尔） Kinact（分-1）
β-亚甲基-2-呋喃乙胺    8    0.004
表Ⅱ
化合物在体内的抗高血压作用
化合物    剂量（毫克/公斤）    平均血压
（变化最大的百分数）
β-亚甲基-2-呋喃乙胺    10（腹膜内注射）    18
30（腹膜内注射）    32
应用高血压的大白鼠，按照已知的标准方法，可以测定本发明的混合物在体内低血压的能力。试验混合物通过腹膜内注射（ip）或口服给于大白鼠，并连续监测血压。由于DBH是合成儿茶酚胺类主要的酶，希望抑制剂能减少儿茶酚类生成的数量，从而产生抗高血压的作用。抗高血压作用的试验结果见表Ⅱ。
因此，根据上述情况以及其它已知的评价多巴胺β-羟基化酶抑制剂的标准试验室方法，用标准的毒性试验和测定哺乳类动物抗高血压作用的药理学试验。并将本试验结果与已知的抗高血压药物的试验结果进行比较，可以容易地确定本发明化合物抗高血压的有效剂量。一般来讲，每天每公斤体重按5毫克～100毫克剂量给药，可以获得抗高血压的有效结果。当然，按照负责诊断医师确定的高血压的类别和严重程度，每个病人具体的开始剂量和连续剂量会不相同。
用治疗上有效的本发明混合物，和药学上可以接受的载体组成的混合物给于宿主动物是有利的，该载体适用于肠内或肠胃外方式给药，并且它构成了混合物的主要部分。该制剂可以为这些形式，如片剂、胶囊剂和栓剂，或者为液体形式，如驰剂、乳剂、喷雾剂和注射剂。在配制药用制剂中，应用的物质应该不与有效成分发生反应，例如可以用水、明胶、乳糖、淀粉类、硬脂酸镁、滑石、植物油类、苄醇类、树胶类、聚亚烷基二醇类、凡士林等。该药用制剂中的有效成分按重量计最好占0.1%～50%。

Claims (5)

1、制备烯丙基胺和它的药学上可以接受的无毒的酸加成盐的方法，其特征在于具有式(Ⅰ)的胺
是水解式(Ⅵ)化合物或它的功能同等物得到的。
Figure 85109441_IMG2
2、按照权利要求1所述方法，该烯丙基胺是β-亚甲基-2-呋喃乙胺。
3、按照权利要求1所述方法，该烯丙基胺是β-亚甲基-3-呋喃乙胺。
4、按照权利要求1所述方法，其中水解是在醇存在下，将式Ⅵ化合物的肼一起加热而完成的。
5、制备药用制剂的方法，其特点在于将烯丙基胺化合物（Ⅰ）和/或它的药学上可以接受的盐与药学上可以接受的载体相混合。
CN85109441A 1984-12-31 1985-12-30 新的呋喃取代的烯丙基胺类的制备方法 Expired CN1007247B (zh)

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CN112441934A (zh) * 2020-11-25 2021-03-05 华南理工大学 一种卤代氧杂烯丙基胺类化合物及其制备方法和应用

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CA1293511C (en) * 1986-12-23 1991-12-24 James R. Mccarthy Allenyl amines
US4847288A (en) * 1986-12-23 1989-07-11 Merrell Dow Pharmaceuticals Inc. Allenyl amines
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