CN100396665C - 吡咯烷衍生物，其制备方法及含有该化合物的药物组合物 - Google Patents
吡咯烷衍生物，其制备方法及含有该化合物的药物组合物 Download PDFInfo
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- CN100396665C CN100396665C CNB2004100971558A CN200410097155A CN100396665C CN 100396665 C CN100396665 C CN 100396665C CN B2004100971558 A CNB2004100971558 A CN B2004100971558A CN 200410097155 A CN200410097155 A CN 200410097155A CN 100396665 C CN100396665 C CN 100396665C
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Abstract
本发明公开了一种新颖的如通式(I)表示的吡咯烷衍生物，其中R表示氢或含1～8个碳原子的酰基，M-表示抗衡离子。适宜的抗衡离子M-包括由药物上可接受的酸提供的离子。本发明还涉及该化合物的制备方法及含有该化合物的药物组合物，以及它们在制备预防和治疗缺血性心脑血管疾病的药物中的应用。
Description
(一)技术领域
本发明涉及一种新颖的吡咯烷衍生物，其制备方法及含有该化合物的药物组合物，以及它们在制备预防和治疗缺血性心脑血管疾病的药物中的应用。
(二)背景技术
党参是一味传统中药材，味甘，性平。有补气、益血、生津的功能。近年来的临床及药理研究表明党参的水溶性提取物可以改善心肌能量代谢和左心室收缩功能，同时具有增加PGI2合成和抑制血小板活性的功能，临床上治疗冠心病心绞痛具有较好疗效。到目前为止，从党参中已分离出四十多种成分，大部分为糖、苷类，甾醇类和三萜类化合物，但其中的水溶性化合物未发现有很强的心血管药理活性。
CA(化学文摘)73：15050，1970；CA(化学文摘)71：13245，1969；CA(化学文摘)77：135091，1972报道了前苏联学者Matkhalikova S.F.等从新疆党参地上部分分得吡咯烷类生物碱党参碱(codonopsine)和党参次碱(codonopsinine)，结构式见附图1。这两个生物碱是叔胺碱，吡咯烷环上与氮原子相连的4位碳上是甲基取代；而本发明化合物是季铵碱，并且吡咯烷环上与氮原子相连的4位碳上有含氧取代基，本发明化合物的稳定性和生理活性都有特别的、令人惊讶的增强。
现有技术没有提供任何与本发明提供的新的吡咯烷衍生物有关的信息。既没有化合物及其结构确证的公开报道，也没有企图从动、植物中提取分离或化学合成制备该化合物的方法的报道，更没有任何与该化合物有关的生物活性的公开报道。
(三)发明内容
本发明的目的在于提供一种新的具有药用价值的吡咯烷衍生物。
本发明的另一目的在于提供一种从桔梗科党参属植物中提取R为氢的本发明化合物的方法。
本发明的进一步的目的是提供一种预防和治疗缺血性心脑血管疾病的药物组合物。
本发明的另一目的是提供上述化合物和组合物在制备预防和治疗缺血性心脑血管疾病的药物方面的用途。
发明人从桔梗科党参属植物(Codonopsis pilosula)的根中分离出一种新的吡咯烷衍生物，该衍生物具有多种有价值的药物活性，这些活性是现有党参属植物中分离到的化合物所不具备的。
本发明化合物用如下通式(I)表示：
其中R表示氢或含1～8个碳原子的酰基；M-表示抗衡离子。
上述含1～8个碳原子的酰基是指具有1～8个碳原子的直链或支链羧酸的酰基，例如甲酰基、乙酰基、丙酰基、异丙酰基、丁酰基、叔丁酰基、戊酰基、新戊酰基、己酰基、庚酰基和辛酰基等。
适宜的抗衡离子M-包括由药物上可接受的酸提供的离子。
优选的药物上可接受的酸包括盐酸、硫酸、磷酸、甲酸、乙酸、苯甲酸、柠檬酸、水杨酸、苹果酸、草酸、琥珀酸、酒石酸、乳酸、葡萄糖酸、马来酸、谷氨酸、天冬氨酸、苯磺酸、甲磺酸、乙磺酸、羟基甲磺酸或羟基乙磺酸。特别是盐酸、硫酸、乙酸、酒石酸、马来酸、谷氨酸和天冬氨酸。
其中R为氢的本发明化合物是从党参属植物中提取而得到的，该方法包括以下步骤：
a.取桔梗科植物党参(Codonopsis pilosula)的干燥根，用溶剂提取，回收提取液，得到浓缩液；
b.浓缩液用离子交换树脂柱或大孔树脂柱精制，得到精制液；
c.精制液经过正相或反相色谱层析分离，收集含有目标物的洗脱液；
d.洗脱液无需进一步纯化，即可用酸在溶液中处理得到所需产物。
提取溶剂可以是水、乙醇、甲醇、丙醇、丁醇或任意比例的醇、水混合溶剂，优选含水5％～100％的乙醇或甲醇。提取方法可以是煎煮、回流、浸渍、渗漉、微波提取或超声提取，优选回流和煎煮。
提取液浓缩后可通过极性或非极性大孔吸附树脂柱，用水洗去杂质，用含水低于80％的乙醇或甲醇洗脱，将含有目标物的洗脱液浓缩，得到精制液。也可以用各类离子交换树脂富集碱性成分，其中优选弱酸性离子交换树脂，交换后将树脂用酸溶液处理，然后用水或醇提取树脂，得到精制液。
浓缩后的精制液可在硅胶或氧化铝等正相吸附材料中进行色谱分离，也可在硅烷键合硅胶、含有氨基或氰基的硅烷键合硅胶等反相材料中进行色谱分离，收集含有目标物的洗脱液。
所得洗脱液无需进一步纯化，即可用药物上可接受的酸在溶液中处理得到不同酸根的本发明化合物。所用的酸可以是盐酸、硫酸、磷酸、甲酸、乙酸、苯甲酸、柠檬酸、水杨酸、苹果酸、草酸、琥珀酸、酒石酸、乳酸、葡萄糖酸、马来酸、谷氨酸、天冬氨酸、苯磺酸、甲磺酸、乙磺酸、羟基甲磺酸或羟基乙磺酸。
R表示含1～8个碳原子的酰基的本发明化合物可以上述R为氢的产品为原料，按照化学领域常规的方法酰化而制得。例如在溶剂如吡啶中用酸酐进行酰化。
发明人发现本发明化合物对缺血性心脑血管疾病具有预防和治疗的作用。发明人还发现本发明化合物的毒性很低。
本发明的药物组合物含有治疗有效量的通式(I)代表的化合物，以及一种或多种药学上可接受的载体。
本发明的化合物和药物组合物可以用于制备预防和治疗脑卒中、冠心病、心肌梗塞、心绞痛、心功能不全和动脉粥样硬化的药物。
上文所述药学上可接受的载体是指药学领域常规的药物载体，例如：固体制剂填充剂如淀粉、蔗糖、微晶纤维素、二氧化硅，粘合剂如羧甲基纤维素、藻酸盐、明胶和聚乙烯吡咯烷酮，湿润剂如十六烷醇、甘油，崩解剂如琼脂、碳酸钙、碳酸氢钠，吸附剂如高岭土，润滑剂如滑石粉、硬脂酸镁、聚乙二醇等；液体制剂溶剂如水、乙醇、丙二醇、聚乙二醇，防腐剂如苯甲酸、苯甲酸钠等。
本发明化合物可制成各种口服剂型，包括胶囊剂、片剂、颗粒剂、口服液、糖浆剂、软胶囊剂、微丸剂、微囊剂和各种缓释剂型；也可制成注射用的溶液或无菌粉剂。
本发明药物的各种剂型可以按药学领域的常规生产方法制备。例如使活性成分与一种或多种药学上可接受的载体混合，然后将其制成所需的剂型。
本发明化合物的施用量可根据用药途径、患者的年龄、体重、预防或治疗的疾病种类和严重程度等变化，其日剂量可以是0.01～10mg/kg体重，可以一次或多次给药。
(四)附图说明
图1是党参碱(codonopsine)和党参次碱(codonopsinine)的化学结构式。
图2是本发明化合物对结扎带迷走神经的颈总动脉所致小鼠急性脑缺血模型的影响。
图3，图4是本发明化合物对垂体后叶素所致心肌缺血大鼠心电图T波的影响(X±SD)(n＝10)。
图5，图6是本发明化合物对垂体后叶素所致心肌缺血大鼠心率的影响(X±SD)(n＝10)。
(五)具体实施方式
下列实施例可以使本专业技术人员更全面地理解本发明，但不以任何方式限制本发明。
实施例1：2-(4-甲氧基)-苯基-3，4-二羟基-5-羟甲基-N，N-二甲基-四氢吡咯的乙酸盐的制备
将10公斤党参(Codonopsis pilosula)的干燥根切片后，用100公斤70％乙醇分三次浸提，浸提液浓缩后通过苯乙烯系大孔吸附树脂，先水洗除杂，再用70％乙醇洗脱。70％乙醇洗脱浓缩至干，用1％乙酸水溶液溶解，过滤，滤液经过RP-18反相柱层析(MeOH-H2O-CH1COOH85∶14∶1)，收集流份，再经过RP-8反相柱层析(15％MeOH)得到目标产物，甲醇重结晶得到白色针状结晶，经高效液相色谱检测纯度达99.5％。
元素分析：C16H25NO6
计算值(％) 实测值(％)
C 58.70 58.74
H 7.70 7.88
N 4.28 4.36
电喷雾质谱(ESI-MS)：268(m/z)
紫外吸收光谱(UV)：λmax(MeOH) 232.3nm
红外吸收光谱(IR)：3270cm-1(O-H伸缩振动)，2919cm-1(C-H伸缩振动)，1557cm-1(C＝O伸缩振动)，1404cm-1(C-O伸缩振动)，1254cm-1(C-O-C伸缩振动)，1084cm-1(C-O-H伸缩振动)，850cm-1(苯环面外弯曲振动)。
氢谱(1H-NMR)：(溶剂DMSO-D6)δ，ppm
2.67(s，3H，C7-H)，3.09(s，3H，C6-H)，3.59(m，1H，C5-H)，3.79(s，3H，C7′-H)，3.97(m，2H，C8-H)，4.16(m，1H，C4-H)，4.59(m，2H，C3、C2-H)，7.04(d，2H，C3′、C5′-H)，7.56(d，2H，C2′、C6′-H)，1.68(s，3H，C2″-H)。
碳谱(13C-NMR)和DEPT谱：(溶剂DMSO-D6)δ，ppm
48.30(伯碳，C6)，51.11(伯碳，C7)，55.48(伯碳，C7′)，57.56(仲碳，C8)，74.67(叔碳，C4)，76.21(叔碳，C3)，80.06(叔碳，C5)，80.77(叔碳，C2)，114.47(叔碳，C3′、C5′)，121.21(季碳，C1′)，133.34(叔碳，C2′、C6′)，160.94(季碳，C4′)，25.07(伯碳，C2″)，175.44(季碳，C1″)。
实施例2：片剂
处方：(1000片)
活性成分 10g
乳糖 144g
预胶化淀粉 45g
硬脂酸镁 1g
制备工艺：将活性成分、乳糖和预胶化淀粉混合均匀，用30％乙醇均匀湿润，14目筛制粒，70℃干燥，14目筛整粒，加入硬脂酸镁，混匀，压片，每片重200mg，活性成分含量为10mg。
实施例3：胶囊剂
处方：(1000粒)
活性成分 10g
微晶纤维素 114g
硬脂酸镁 1g
制备工艺：将活性成分和微晶纤维素混合均匀，用30％乙醇均匀湿润，30目筛制粒，70℃干燥，30目筛整粒，加入硬脂酸镁，混匀，装入明胶硬胶囊，每粒内容物重125mg，活性成分含量为10mg。
实施例4：注射液
处方：(1000支)
活性成分 2g
注射用氯化钠 88.7g
制备工艺：将活性成分和注射用氯化钠，加入全量的70％的注射用水，搅拌使溶解，再加注射用水至全量2000毫升，过滤，调pH值为3.0～5.0，灌封，灭菌。每支2毫升含活性成分2mg。
实施例5：注射用无菌粉针
处方：(1000支)
活性成分 2g
注射用氯化钠 88.7g
制备工艺：将活性成分和注射用氯化钠，于100℃真空干燥6小时，放冷，送入无菌室分装。每支无菌粉针含活性成分2mg。
实施例6：本发明化合物对结扎小鼠带迷走神经的颈总动脉所致小鼠急性脑缺血模型的影响
实验方法：
选用昆明种小鼠70只，雌雄各半，体重18-22g，随机分为7组，分别为正常组，模型组，试验化合物p.o I组(12mg/kg)、p.o II组(24mg/kg)、i.p I组(2mg/kg)、i.p II组(4mg/kg)和阳性对照尼莫地平i.p组(2mg/kg)，每组10只。p.o组动物分别一日一次灌胃给药，连续5天，模型组和正常组给予生理盐水，手术当天各组动物分别灌胃或腹腔注射给药后1小时，各组动物乙醚麻醉，除正常组分离双侧颈总动脉及迷走神经不进行结扎外，其余均结扎，观察存活时间，实验结果进行t检验，以x±sd表示。
实验结果：
各给药组均可显著延长小鼠急性脑缺血的存活时间。
结论：本发明化合物i.p和p.o两种给药途径均具有显著的抗小鼠急性脑缺血作用。
注：**与模型组比较P＜0.01；*与模型组比较P＜005。
实验结果详见附图2。
实施例7：本发明化合物对垂体后叶素(Pit)所致大鼠急性心肌缺血的作用
实验方法：
选用SD大鼠70只，雄性，体重200-250g，分别为正常组，模型组，试验化合物p.oI组(6mg/kg)、p.oII组(12mg/kg)、i.pI组(1mg/kg)、i.pII组(2mg/kg)和阳性对照普萘洛尔组p.o(10mg/kg)，每组10只。p.o组动物分别一日一次灌胃给药，连续5天，模型组和正常组给予生理盐水，手术大鼠禁食不禁水12h，手术当天各组动物分别灌胃或腹腔注射给药后1小时，腹腔注射乌拉坦1g/kg麻醉，取仰卧位，针状电极小心刺入四肢皮下，测定II导联心电图，稳定30min，并记录正常心电图。45min迅速经舌下静脉注射垂体后叶素1.5u/kg，给垂体后叶素的时间不超过10s，记录注射垂体后叶素后15s、30s、1、2、3、5、7、10、15min的心电图。
实验结果：
1)试验化合物各组均能明显对抗垂体后叶素引起的T波变化，四个给药组在15s时，就开始起作用，与模型组比较T波的变化率有显著性差异(P＜0.05；P＜0.01)。其中i.pII(2mg/kg)组作用持续至10min。
2)试验化合物i.pII(2mg/kg)组自造模30s后就可使心率恢复，其它各组在1min以后也产生作用与模型组比较显著性差异(P＜0.05或P＜0.01)。
结论：实验结果表明本发明化合物具有一定的抗Pit所致心肌缺血的作用。
附图3，图4对垂体后叶素所致心肌缺血大鼠心电图T波的影响(X±SD)(n＝10)
附图5，图6对垂体后叶素所致心肌缺血大鼠心率的影响(X±SD)(n＝10)
注：**与模型组相比P＜0.01，*与模型组相比P＜0.05。
Claims (9)
1.下述通式(I)化合物：
其中R表示氢；M-表示由药物上可接受的酸提供的离子。
2.根据权利要求1所述的药物上可接受的酸，其特征在于：所述的酸可以选自盐酸、硫酸、磷酸、甲酸、乙酸、苯甲酸、柠檬酸、水杨酸、苹果酸、草酸、琥珀酸、酒石酸、乳酸、葡萄糖酸、马来酸、谷氨酸、天冬氨酸、苯磺酸、甲磺酸、乙磺酸、羟基甲磺酸或羟基乙磺酸。
3.权利要求1化合物的制备方法，该方法包括以下步骤：
a.取桔梗科植物党参的干燥根，用溶剂提取，回收提取液，得到浓缩液；
b.浓缩液用离子交换树脂柱或大孔树脂柱精制，得到精制液；
c.精制液经过正相或反相色谱层析分离，收集含有目标物的洗脱液；
d.洗脱液无需进一步纯化，即可用酸在溶液中处理得到所需产物。
4.根据权利要求3所述的制备方法，其特征在于：提取溶剂可以是水、乙醇、甲醇、丙醇、丁醇或所述任意比例的醇、水混合溶剂。
5.根据权利要求3所述的制备方法，其特征在于：用于色谱层析分离的材料可以是硅胶、氧化铝、硅烷键合硅胶、含有氨基或氰基的硅烷键合硅胶。
6.根据权利要求3所述的制备方法，其特征在于：所用的酸可以是盐酸、硫酸、磷酸、甲酸、乙酸、苯甲酸、柠檬酸、水杨酸、苹果酸、草酸、琥珀酸、酒石酸、乳酸、葡萄糖酸、马来酸、谷氨酸、天冬氨酸、苯磺酸、甲磺酸、乙磺酸、羟基甲磺酸或羟基乙磺酸。
7.用于预防和治疗缺血性心脑血管疾病的药物组合物，其中含有治疗有效量的权利要求1化合物和药学上可接受的载体。
8.权利要求1中化合物在制备预防和治疗缺血性心脑血管疾病的药物中的应用。
9.根据权利要求8所述的应用，其特征在于，所述的缺血性心脑血管疾病是：脑卒中、冠心病、心肌梗塞、心绞痛、心功能不全、动脉粥样硬化。
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| 党参化学成分的研究. 贺庆，朱恩圆，王峥涛，侴桂新，徐珞珊，胡之璧.中国药学杂志，第41卷第1期. 2006 |
| 党参化学成分的研究. 贺庆，朱恩圆，王峥涛，侴桂新，徐珞珊，胡之璧.中国药学杂志，第41卷第1期. 2006 * |
| 党参化学成分系统研究进展. 刘玉兰，姚丽，张吉平，林伯群，胡晓蓓.山东医药工业，第18卷第1期. 1999 |
| 党参化学成分系统研究进展. 刘玉兰，姚丽，张吉平，林伯群，胡晓蓓.山东医药工业，第18卷第1期. 1999 * |
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