CN1088460C - 分离加兰他敏的方法 - Google Patents
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Abstract
本发明的目标是分离生物碱加兰他敏(结构式I)的方法，由所述方法生成的加兰他敏，由此生成的植物制剂形式的加兰他敏的用途，以及由此生成的加兰他敏在治疗闭角型青光眼、早老性痴呆(Alzheimer’s disease)和酒精及尼古丁依赖性方面的用途。
Description
本发明涉及分离生物碱加兰他敏的方法；由该方法生成的加兰他敏；由此制成的植物制剂(盖仑制剂)形式的加兰他敏的用途；以及由此生成的加兰他敏在治疗闭角型青光眼、早老性痴呆(Alzheimer’s disease)和酒精及尼古丁依赖性方面的用途。
加兰他敏(4a，5，9，10，11，12-六氢-3-甲氧基-11-甲基-6H-苯并呋喃并(3a，3，2-ef)-(2)并氮杂-6-醇)是一种四环生物碱，因其药理特性而属于具可逆作用的胆碱酯酶抑制剂。其作用类似于毒扁豆碱和新斯的明。但是，它还具有其独有的特性，例如可与吗啡相比的强镇痛作用。作为胆碱酯酶抑制剂，加兰他敏的治疗范围比毒扁豆碱和新斯的明宽3至6倍，因为它并不象它们那样有毒。该优点弥补了相对于剂量其胆碱酯酶抑制作用稍低的不足。加兰他敏被用于治疗脊髓灰质炎和各种神经系统疾病，但主要用于治疗闭角型青光眼和作为使用箭毒后的解毒药。使用加兰他敏治疗早老性痴呆尚在试验阶段。最近，还记述了将其用于治疗酒精及尼古丁依赖性(DE-OS4010079，DE-OS4301782)。
早老性痴呆、酒精及尼古丁依赖性以及闭角型青光眼的治疗需要适应具体情况的长效药物剂型。这可以是用于治疗闭角型青光眼的眼膏。在早老性痴呆和酒精或尼古丁依赖性的治疗中，显然，复杂治疗方案或长时间输注是不适当的。在这些疾病中，透皮治疗系统(TTS)是一种适宜的形式，例如DE-OS4301783中所述的。完整的皮肤或角膜都不能吸收活性成份的盐。因此，在治疗闭角型青光眼、早老性痴呆、或酒精及尼古丁依赖性时不能在软膏或TTS中使用氢溴酸加兰他敏或盐酸加兰他敏。所以，必须使用纯加兰他敏碱。
由于其具有有三个光学活性碳原子的复杂的四环结构，所以不可能经济有效地合成加兰他敏碱。因此，通常从石蒜科植物，例如雪花莲属，诸如snowdrop或夏雪片莲(Leucojum aestivum)中分离加兰他敏。这些植物的优点在于含有浓度高达0.3％的加兰他敏和少量的相伴生物碱，因此可使用DE-PS1193061中所述的萃取方法。但是，雪花莲属和夏雪片莲都是受保护的。另一方面，DE-PS1193061中所述的萃取方法最好使用含氯烃，但后者因其毒性而受到限制。因此，西方的药典提出含氯烃的残留量必须小于10ppm。所以，在药物的制备中应尽可能避免使用含氯烃。而且，在已知的方法中，必须由氧化铝吸附溶剂萃取液以确保树脂状物质与相伴生物碱分离。然后，从滤除了氧化铝的溶液中通过氢溴酸加兰他敏纯化加兰他敏；这就涉及到卤素盐的处理。为了用于软膏或TTS，然后必须从氢溴酸加兰他敏中游离出加兰他敏碱。
所以，本发明的目的之一是提供一种没有现有技术的缺点的分离和纯化加兰他敏的方法。具体地说，该方法方便了纯化，避免了使用含氯烃和利用加兰他敏盐进行的纯化。该目的是通过本发明中特征如权利要求1所述的方法达到的。从属权利要求对优选实施方式的特征进行了描述。
具体地说，本发明的主体是从生物材料中分离加兰他敏的方法，生物材料收获自农业栽培的石蒜科植物或那些通常被认作“杂草”的非保护植物，最好是自这些植物的球茎分离。这些石蒜科植物包括例如水仙或文殊兰(cirnum)。尤其适合的是黄水仙(Narcissus paseudonarcissus，“Carlton”)或苏门答腊文殊兰(Asian climber，Crinum amabile)。虽然这些植物中加兰他敏含量只有受保护植物的十分之一，而且具有多达12种的相伴生物碱，但令人惊奇的是本发明的方法能够从中分离出药用纯度的加兰他敏碱。
根据本发明，用毒理学上安全的有机溶剂萃取含有加兰他敏的生物材料，并利用液-液萃取从萃取液中提纯加兰他敏，最好将原料粉碎并与碱性粉末混合，碱粉末最好是氢氧化钠颗粒、碳酸钠、碳酸钾、或其它适合从生物材料中游离出碱并制备成药理活性物质的类似的盐。对成功实施本发明方法来说尤其重要的是在液-液萃取的第一阶段维持pH值。液-液萃取第一阶段的pH约为4，第二阶段约为9。除了浓氨之外，还可以使用其它碱的碳酸钠溶液来调节pH值。利用乙醚或特定沸点汽油作为毒理学上安全的有机溶剂。以使用特别沸点的汽油为佳，利用它可以达到一定程度的预纯化。将溶剂去除；从合适的溶剂，最好是异丙醇中重结晶加兰他敏。由此可获得熔点为129至130℃的白色加兰他敏碱。由此获得的加兰他敏的纯度显示在HPLC色谱(图2)中。
该结果是令人震惊的，因为使用至今的DE-PS1193061所述的方法被发现是不适用于从含有少量加兰他敏而且含有多达12种相伴生物碱的生物材料中分离加兰他敏的。DE-PS1193061所述的方法会形成难以破乳的乳状液，使得萃取无法进行。略加改进后的该方法生成油状残留物，根据HPLC色谱(图1)所示，至少被4种物质所污染。
所以，必须将此认为是一项惊人的特殊发现，即无需另外的氧化铝吸附步骤，利用本发明的简单方法可从除大量相伴生物碱之外含有少量加兰他敏的生物材料中高产率地分离出纯的游离加兰他敏碱。
由本发明方法制备的加兰他敏碱可用于治疗闭角型青光眼、早老性痴呆或酒精及尼古丁依赖性。此外，本发明方法制备的加兰他敏碱还可用于同样可治疗上述疾病的植物制剂，例如眼膏或透皮治疗系统。
以下实施例更具体地说明了本发明，它们只用于说明本发明而并不限定本发明。
实施例1(比较实施例)：
根据DE-PS1193061所述的方法，小心地将10kg晾干并粉碎的黄水仙(Narcissus pseudonarcissus，“Carlton”)球茎与2.5L 8％的氨水溶液混合。原料发生溶胀；整批原料成为膏状。为了萃取而加入23L二氯乙烷，结果生成无法破乳的乳状液。
实施例2(比较实施例)：
对本领域已知的分离加兰他敏的方法(DE-PS1193061)进行改良。小心地将10kg晾干并粉碎的黄水仙(Narcissus pseudonarcissus，“Carlton”)球茎与400g碳酸钠混合。加入23L二氯乙烷。将混合物静置10小时；然后倾去溶剂。再一次用23L二氯乙烷浸泡球茎，2至3小时后倾去溶剂。然后，在球茎中第三次加入17L二氯乙烷；但是，这次立即倾去溶剂。用10％的硫酸(2×600ml；2×300ml)萃取混合后的二氯乙烷萃取液。混合酸萃取液，加入乙醚振荡以去除微量二氯乙烷进行纯化。边搅拌边冷却至15至20℃，然后加入25％的氨水溶液约200ml，直至石蕊反应呈碱性。pH范围为7至8。与现有技术中所说的不同，相伴生物碱没有沉淀。用盐使碱性溶液饱和并用乙醚萃取。蒸发去除乙醚后，留下微量残留物，这也与现有技术中所说的不同。用碳酸钾使水相饱和，将其pH调节至约14。用乙醚重复萃取水相。将混合后的乙醚萃取液蒸干，将留下的含加兰他敏的残留物溶解在丙酮(50ml)中。与现有技术相反，其中没有沉淀。再加入350ml丙酮，加入200g氧化铝，搅拌45分钟。滤出氧化铝，各用100ml丙酮洗涤两次。将合并后的丙酮溶液蒸干，获得1.3g油状残留物，用HPLC进行检测。其色谱如图1所述。对主峰，即加兰他敏作了标明。显然，由此获得的加兰他敏至少被4种物质所污染。
实施例3
小心地将100kg晾干的并经粉碎的黄水仙(Narcissus pseudonarcissus，“Carlton”)球茎与4kg碳酸钠混合。将混合物分成3等份，每份用15L特定沸点汽油80/110浸渍。将混合物静置24小时。分别更换两次溶剂，收集溶剂，在真空下蒸发至干。将萃取液加入2％硫酸水溶液，用浓氨水溶液调节pH至4。然后用乙醚萃取5次。用浓氨水将水相的pH调节至9，用乙醚萃取5次。汇集各份醚萃取液后用硫酸钠干燥，然后蒸发。由此获得20g浅黄色油状残留物，然后在热异丙醇中重结晶。由此获得10g熔点为129至130℃的白色加兰他敏碱。在HPLC色谱(图2)中只看见一个峰。
Claims (7)
1.一种分离如下加兰他敏的方法，
包括以下步骤：
a.将石蒜科植物植株或其部分粉碎，并与碱粉末混合；
b.用毒理学上安全的有机溶剂来萃取所得的混合物；
c.利用pH4的第一阶段液-液萃取纯化所得萃取液中的加兰他敏；
d.利用pH9的第二阶段液-液萃取进一步纯化所得萃取液中的加兰他敏；
e.用适宜的溶剂重结晶加兰他敏。
2.根据权利要求1所述的方法，其中使用的石蒜科植物是水仙或文殊兰(crinum)。
3.根据权利要求2所述的方法，其中使用的水仙是黄水仙(Narcissuspseudonarcissus，“Carlton”)，使用的文殊兰是苏门答腊文殊兰(Crinumamabile).
4.根据权利要求1所述的方法，其中所用的植物部分是球茎。
5.根据权利要求1所述的方法，其中所用的碱粉末是碳酸钠。
6.根据权利要求1所述的方法，其中所用的毒理学上安全的有机溶剂是乙醚或特定沸点汽油。
7.根据权利要求1所述的方法，其中用来重结晶加兰他敏的适宜溶剂是异丙醇。
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