CN102617533A - 一种从红曲中分离的化合物、其制备方法及用途 - Google Patents
一种从红曲中分离的化合物、其制备方法及用途 Download PDFInfo
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- CN102617533A CN102617533A CN2011100339248A CN201110033924A CN102617533A CN 102617533 A CN102617533 A CN 102617533A CN 2011100339248 A CN2011100339248 A CN 2011100339248A CN 201110033924 A CN201110033924 A CN 201110033924A CN 102617533 A CN102617533 A CN 102617533A
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Abstract
本发明属于医药化工领域,涉及一种从红曲中分离的化合物、其制备方法及用途。具体地,式I所示的化合物,或其药学上可接受的盐,其中,R1选自氢、羟基、C1-6直链或支链烷氧基、 和R2为氢或C1-6烷基;R3选自氢、羟基、和C1-6直链或支链烷氧基。本发明还涉及含有该化合物的药物组合物。本发明的化合物具有HMG-CoA还原酶抑制作用。
Description
技术领域
本发明属于医药化工领域,涉及一种从红曲中分离的化合物、其制备方法及用途。本发明还涉及含有该化合物的药物组合物。
背景技术
红曲(Monascus-fermented rice)是以大米为原料,经红曲霉(Monascus)发酵制成的一种***米曲。红曲古代称丹曲,是将红曲霉为主的曲母或酒曲接种于米饭上发酵而成,其色赤红,故又名赤曲、红米、红大米、红糟,又因主产于福建等地,故又名福曲、福米等。
我国利用红曲菌的历史悠久,从汉代起就用它制曲。红曲是一味食疗兼备的传统中药。早在古代它已被广泛应用于食品着色、酿酒、发酵、中医中药方面。《饮膳正要》有红曲“味甘、平、无毒”“健脾、益气、温中”;《本草纲目》有“甘、温、无毒”,“治女人血痛及产后恶血不净,擂酒饮之良”;《本草衍义补遗》有“活血、消食、健脾暖胃、治赤白下痢、跌打损伤”等记载。
上世纪70年代,日本Endo教授首次从红色红曲霉(Monascusruber)中分离出生理活性物质莫纳克林K(monacolin K)以来,众多国内外学者在红曲霉代谢产物中不断发现生理活性物质,包括monacolins类化合物,红曲色素,降压成分GABA及抗氧化成分dimerumic acid及最近分离的一些萜类化合物等等。随着现代生物化学与药理学的发展,红曲的降血脂、降压、降糖、抗肥胖、抗癌、防治老年痴呆和骨质疏松等功效不断被挖掘。从而使传统的红曲增添了新的内涵。
血脂康胶囊是红曲的醇提取物,它富含一系列天然他汀类化合物,monacolin K,dehydromonacolin K,monacolin L,dihydromonacolinK及其他monacolin类似物。此外,血脂康胶囊中还含有色素类化合物、异黄酮类化合物、甾醇类化合物、20种氨基酸、不饱和脂肪酸、以及多种微量元素。异黄酮类化合物主要包括染料木素、大豆苷元、和黄豆黄素等,其含量约为0.045%;甾醇类化合物含量约为0.3%,主要包括麦角甾醇、豆甾醇、和谷甾醇等。
发明内容
本发明人经过大量的试验和创造性的劳动,从红曲或其醇提取物(例如血脂康胶囊内容物干粉)中得到了一种新的化合物,并且惊奇地发现,这种化合物具有有效的HMG-CoA还原酶抑制活性。由此提供了下述发明:
本发明的一个方面涉及式I所示的化合物,或其药学上可接受的盐,
其中,
R2为氢或C1-6烷基;
R3为一个或多个选自氢、羟基、和C1-6直链或支链烷氧基相同或不同的基团。
具体地,所述C1-6直链或支链烷氧基为甲氧基、乙氧基、C3直链或支链烷氧基、C4直链或支链烷氧基、C5直链或支链烷氧基、或者C6直链或支链烷氧基。
具体地,所述C1-6烷基为甲基、乙基、丙基、异丙基、C4直链或支链烷基、C5直链或支链烷基、或者C6直链或支链烷基。
在本发明的一个实施方案中,R1为氢,R2为氢,R3为2个氢,即该化合物如下面的式II所示:
本发明的另一方面涉及一种药物组合物,其含有本发明的化合物或其药学上可接受的盐,以及药学上可接受的载体或辅料。
在本发明的一个实施方案中,所述的药物组合物,其为片剂、颗粒剂、胶囊剂、丸剂、栓剂、散剂、膏剂、滴剂、气雾剂、粉雾剂、溶液剂、混悬剂、***片、冻干粉针剂、或乳剂。可以是普通制剂、缓释制剂、控释制剂及各种微粒给药***。
运用本领域技术人员熟悉的药物载体可以制备成含有效剂量的本发明化合物的药物组合物。例如,口服制剂(如片剂、胶囊剂、溶液或混悬液);可注射的制剂(如可注射的溶液或混悬液,或者是可注射的干燥粉末,在注射前加入注射水可立即使用)。所述的药物组合物中载体包括:口服制剂使用的粘合剂(如淀粉,通常是玉米、小麦或米淀粉、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮),稀释剂(如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素,和/或甘油),润滑剂(如二氧化硅、滑石、硬脂酸或其盐,通常是硬脂酸镁或硬脂酸钙,和/或聚乙二醇),以及如果需要,还含有崩解剂,如淀粉、琼脂、海藻酸或其盐,通常是藻酸钠,和/或泡腾混合物,助溶剂、稳定剂、悬浮剂、无色素、矫味剂等,可注射的制剂使用的防腐剂、加溶剂、稳定剂等;局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下是不稳定的,可以将其配制成肠衣片剂。
本发明的还一方面涉及本发明的化合物的制备方法,包括如下步骤:
1)将红曲或其醇提取物加入1-10倍体积的有机溶剂,超声提取至少一次,每次10-60分钟,合并提取液,减压浓缩,得到浓缩液;
2)将浓缩液上硅胶柱分离,用选自石油醚、乙酸乙酯、和甲醇中的一种或多种进行梯度洗脱;
3)将步骤2)洗脱得到的含有式I或式II化合物的部分进行硅胶柱层析、sephadex LH-20柱层析、和高效液相纯化,得到该化合物。
本领域技术人员能够确定含有式I或式II化合物的部分(低极性部分),例如初始(洗脱)溶剂为体积比为75∶25石油醚∶乙酸乙酯时,含有式I或式II化合物的部分为第二柱体积。如果初始溶剂50∶50石油醚∶乙酸乙酯或者极性更高时,所述含有式I或式II化合物的部分为第一柱体积。
根据本发明的任一项所述的制备方法,其中,步骤1)中,所述有机溶剂选自正己烷、二氯甲烷、乙酸乙酯、正丁醇、甲醇、50%-95%(v/v)的甲醇水溶液、乙醇、以及50%-95%(v/v)的乙醇水溶液中的一种或多种。具体地,所述甲醇水溶液为70%(v/v)的甲醇水溶液。具体地,所述乙醇水溶液为70%(v/v)的乙醇水溶液。
根据本发明的任一项所述的制备方法,其中,步骤1)中,加入2-6倍体积的有机溶剂,例如,加入2、3、4、5、或者6倍体积的有机溶剂。
根据本发明的任一项所述的制备方法,其中,步骤1)中,超声提取为3-5次,每次20-40分钟;具体地,超声提取3次、4次、或者5次,每次20-40分钟。
根据本发明的任一项所述的制备方法,其中,步骤1)中,所述红曲或其醇提取物为血脂康胶囊内容物干粉。
根据本发明的任一项所述的制备方法,其中,步骤2)中,依次使用体积比为75∶25、50∶50、和0∶100的石油醚和乙酸乙酯,和或依次使用体积比为100∶0、95∶5、70∶30、和50∶50的乙酸乙酯和甲醇,进行梯度洗脱。所用硅胶柱的目数并不特别限定,在本发明的一个实施方案中,使用200-300目的硅胶柱。
本发明的式II化合物可以由monacolin L脱水制备:
其中,monacolin L可以商购获得,也可以采用下面的方法制备:
a.取红曲或其醇提取物(例如血脂康胶囊内容物干粉),依次以2-6倍体积的正己烷溶剂超声提取3次,每次20-40分钟,合并提取液,减压浓缩,得到浓缩液;
b.取步骤a.中得到的浓缩液,上硅胶柱色谱分离,用石油醚-乙酸乙酯梯度洗脱,收集25∶75石油醚-乙酸乙酯部分H-5;
c.将H-5部分进行sephadex LH-20柱层析、C-18反向硅胶柱层析、和高效液相纯化,得到monacolin L。
本发明的还一方面涉及红曲有机溶剂提取物或柱层析组分,其特征在于,所述提取物或柱层析组分含有本发明的式I或式II化合物或其药学上可接受的盐;具体地,有机溶剂为正己烷、二氯甲烷、乙酸乙酯、正丁醇、甲醇、50%-95%(v/v)的甲醇水溶液、乙醇、以及50%-95%(v/v)的乙醇水溶液;具体地,所述柱层析为硅胶柱层析和/或sephadex LH-20柱层析。本发明的红曲有机溶剂提取物可以参照上述本发明的化合物的任一项制备方法的步骤制得,例如上述步骤1)制得的浓缩液也是本发明的有机溶剂提取物。
本发明的还一方面涉及本发明的化合物或其药学上可接受的盐在制备HMG-CoA还原酶抑制剂中的用途。
本发明的还一方面涉及本发明的化合物或其药学上可接受的盐或者红曲有机溶剂提取物或柱层析组分在制备治疗或预防血脂异常、高血脂症、高胆固醇血症、或动脉粥样硬化,或者辅助治疗高脂血症及动脉粥样硬化引起的心脑血管疾病的药物中用途。
本发明的还一方面涉及本发明的化合物或其药学上可接受的盐或者红曲有机溶剂提取物或柱层析组分在制备调节血脂或者降血脂的药物中的用途。
本发明的还一方面涉及本发明的化合物或其药学上可接受的盐或者红曲有机溶剂提取物或柱层析组分在制备调节胆固醇或者降低胆固醇的药物中的用途。
本发明的还一方面涉及本发明的化合物或其药学上可接受的盐或者红曲有机溶剂提取物或柱层析组分在制备除湿祛痰、活血化瘀、或者健脾消食的药物中的用途。
本发明的还一方面涉及一种治疗或预防哺乳动物的血脂异常、高血脂症、高胆固醇血症、或动脉粥样硬化,或者辅助治疗高脂血症及动脉粥样硬化引起的心脑血管疾病的方法,包括给予有效量的本发明的化合物或者药物组合物或者红曲有机溶剂提取物或柱层析组分的步骤。
本发明的还一方面一种涉及以哺乳动物为对象的哺乳动物的调节血脂或者降血脂的方法,包括给予有效量的本发明的化合物或者药物组合物或者红曲有机溶剂提取物或柱层析组分的步骤。
本发明的还一方面涉及一种以哺乳动物为对象的调节胆固醇或者降低胆固醇的方法,包括给予有效量的本发明的化合物或者药物组合物或者红曲有机溶剂提取物或柱层析组分的步骤。
本发明的还一方面涉及一种以哺乳动物为对象的除湿祛痰、活血化瘀、或者健脾消食的方法,包括给予有效量的本发明的化合物或者药物组合物或者红曲有机溶剂提取物或柱层析组分的步骤。
当用于上述治疗和/或预防或其他治疗和/或预防时,治疗和/或预防有效量的一种本发明化合物可以以纯形式应用,或者以药学可接受的酯或前药形式(在存在这些形式的情况下)应用。或者,所述化合物可以以含有该目的化合物与一种或多种药物可接受赋形剂的药物组合物给药。词语“有效量”的本发明化合物指以适用于任何医学治疗和/或预防的合理效果/风险比治疗障碍的足够量的化合物。但应认识到,本发明化合物和组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者,具体的治疗有效剂量水平须根据多种因素而定,所述因素包括所治疗的障碍和该障碍的严重程度;所采用的具体化合物的活性;所采用的具体组合物;患者的年龄、体重、一般健康状况、性别和饮食;所采用的具体化合物的给药时间、给药途径和***率;治疗持续时间;与所采用的具体化合物组合使用或同时使用的药物;及医疗领域公知的类似因素。例如,本领域的做法是,化合物的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。一般说来,本发明式I化合物用于哺乳动物特别是人的剂量可以介于0.001-1000mg/kg体重/天,例如介于0.01-100mg/kg体重/天,例如介于0.01-10mg/kg体重/天。
在本发明中,所述甲醇水溶液或者乙醇水溶液的浓度为体积浓度(v/v)。
发明的有益效果
本发明的化合物具有有效的HMG-CoA还原酶抑制活性,可用于制备降血脂或者降低胆固醇的药物。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1:本发明的化合物的制备
1)取血脂康胶囊内容物干粉约1kg,依次以2-6倍体积的正己烷溶剂超声提取3次,每次20-40分钟,合并提取液,减压浓缩,得到浓缩液;
2)取步骤1)中得到的浓缩液50g,上硅胶柱色谱分离,用石油醚和乙酸乙酯及甲醇进行梯度洗脱。石油醚-乙酸乙酯的初始体积比为75∶25;
3)将75∶25石油醚-乙酸乙酯洗脱部分分为3部分,第一柱体积部分为H-1,第二柱体积部分为H-2,第三柱体积部分为H-3;
4)取H-2部分5.2g进行硅胶柱层析、sephadex LH-20柱层析、以及半制备高效液相纯化,得化合物10mg。
实施例2:实施例1的化合物的结构式的确定和验证
1.化合物的理化数据
无色油状物,旋光度:[α]25 D+36.63(c 0.636,CH2Cl2);
UV光谱中有三个最大吸收峰,分别为λmax(CH2Cl2)=232.6nm,240.20nm,249.0nm。
FT-IR光谱显示,有饱和碳上的氢(2926cm-1)和酯羰基(1717cm-1)。
2.分子式的确定
HR-ESI-MS给出的m/z 287.1985[M+H]+(calcd.287.2006,err2.1),推断为该化合物的分子量为286.19。在1H-NMR和13C-NMR显示,共有26个氢信号和19个碳信号。从DEPT显示,136.6ppm和164.6ppm处有2个季碳,164.6ppm处的季碳为一个酯羰基。在13C-NMR中,78.3ppm处有一个连氧碳信号。所以该分子中有19个碳原子,26个氢原子,2个氧原子,分子式为C19H26O2。具体数据如表1所示。
表1:实施例1制备的化合物的核磁共振数据
3.结构式的确定
分析该化合物的碳谱(C-NMR及DEPT),有19个碳原子,发现与monacolin L的数据相似。比较两个化合物的碳谱,发现该化合物在烯碳区比monacolin L多两个信号(121.5ppm和145.0ppm),而比monacolin L少一个氧连碳。通过两个化合物氢谱的比较,发现低场区多两个氢(6.06ppm和6.93ppm)。
并且Monacolin L有一个羟基3’-OH,所以可以推断该化合物可能是monacolin L(结构如式III所示)的脱水产物。
进一步分析该化合物的HMBC图(如式IV所示),证实了上述分析,而且说明多出的两个烯碳是羰基的邻位。
综合上述分析可推测为:
6-(2-(2,6-二甲基-1,2,6,7,8,8a-六氢萘)乙基)-5,6-二氢吡喃二酮,(6-(2-(2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)ethyl)-5,6-dihydropyran-2-one)。结构式如下面的式II所示:
实施例3:HMG-CoA还原酶活性抑制试验
1.实验材料
按照实施例1制备的IV化合物
monacolin L(商购或者参照发明内容中的方法制备)
洛伐他汀标准品(购自Sigma)
大鼠肝脏微粒体(HMG-CoA还原酶)商购,或者参照下述方法制备:取出雄性大鼠的肝脏,用KESD缓冲液冲洗之后,1,200g离心15min,取上清液。再用105,000g离心90min两次之后,收集离心沉淀。离心沉淀里加入8.3%甘油,用37℃温浴加热1h。大鼠肝脏微粒体粗体物用饱和硫酸铵纯化并收集35-50%纯化部分即得。得到的大鼠肝脏微粒体存放在-80℃冰箱中。
氯化钾、磷酸二氢钾、乙二胺四乙酸、二硫苏糖醇(均购自北京化学试剂公司)
烟酰胺腺嘌呤二核苷酸(NADPH)(购自Merk)
3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)和cremophore EL(购自Sigma)
2.实验方法
将按照实施例1制备的化合物用50%cremophore EL的乙醇溶液溶解,浓度为2mg/mL;测定体系中总体积为250μL,各成分的浓度为:氯化钾200mM,磷酸二氢钾160mM,乙二胺四乙酸4mM,二硫苏糖醇10mM,两个底物烟酰胺腺嘌呤二核苷酸和3-羟基-3-甲基戊二酰辅酶A的浓度分别为200μM和50μM,pH6.8,酶加30μL,酶抑制剂加5μL,空白对照组加5μL(溶解样品溶剂),在Versamax酶标仪上37℃条件下检测OD340的动态变化。通过检测OD340在5分钟内下降的快慢(以斜率值表示),来评价HMG-CoA还原酶活性的强弱,进而评价酶抑制剂活性的强弱。
3.试验结果
试验结果如下面的表2所示。
表2:酶抑制剂活性检测结果
*空白对照为溶剂
洛伐他汀及monacolin L是阳性对照。
从表2可见,按照实施例1制备的式IV化合物对HMG-CoA还原酶具有有效的抑制活性。
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解。根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (10)
3.一种药物组合物,其含有权利要求1或2所述的化合物或其药学上可接受的盐,以及药学上可接受的辅料。
4.根据权利要求3所述的药物组合物,其为片剂、颗粒剂、胶囊剂、丸剂、栓剂、散剂、膏剂、滴剂、气雾剂、粉雾剂、溶液剂、混悬剂、***片、冻干粉针剂、或乳剂。
5.权利要求1或2所述的化合物的制备方法,包括如下步骤:
1)将红曲或其醇提取物加入1-10倍体积的有机溶剂,超声提取至少一次,每次10-60分钟,合并提取液,减压浓缩,得到浓缩液;
2)将浓缩液上硅胶柱分离,用选自石油醚、乙酸乙酯、和甲醇中的一种或多种进行梯度洗脱;
3)将步骤2)洗脱得到的含有式I或式II化合物的部分进行硅胶柱层析、sephadex LH-20柱层析、和高效液相纯化,得到该化合物。
6.根据权利要求5所述的制备方法,其满足如下的(1)-(5)项中的任一项:
(1)步骤1)中,所述有机溶剂选自正己烷、二氯甲烷、乙酸乙酯、正丁醇、甲醇、50%-95%(v/v)的甲醇水溶液、乙醇、以及50%-95%(v/v)的乙醇水溶液中的一种或多种;
(2)步骤1)中,加入2-6倍体积的有机溶剂;
(3)步骤1)中,超声提取为3-5次,每次20-40分钟;优选超声提取3次,每次20-40分钟;
(4)步骤1)中,所述红曲醇提取物为血脂康胶囊内容物干粉;
(5)步骤2)中,依次使用体积比为75∶25、50∶50、和0∶100的石油醚和乙酸乙酯,和/依次使用体积比为100∶0、95∶5、70∶30、和50∶50的乙酸乙酯和甲醇,进行梯度洗脱。
7.红曲有机溶剂提取物或柱层析组分,其特征在于,所述提取物或柱层析组分含有权利要求1或2所述的化合物或其药学上可接受的盐;具体地,有机溶剂为正己烷、二氯甲烷、乙酸乙酯、正丁醇、甲醇、50%-95%(v/v)的甲醇水溶液、乙醇、以及50%-95%(v/v)的乙醇水溶液;具体地,所述柱层析为硅胶柱层析和/或sephadex LH-20柱层析。
8.权利要求1或2所述的化合物或其药学上可接受的盐或者权利要求7所述的红曲有机溶剂提取物或柱层析组分在制备HMG-CoA还原酶抑制剂中的用途。
9.权利要求1或2所述的化合物或其药学上可接受的盐或者权利要求7所述的红曲有机溶剂提取物或柱层析组分在制备治疗或预防血脂异常、高血脂症、高胆固醇血症、或动脉粥样硬化,或者辅助治疗高脂血症及动脉粥样硬化引起的心脑血管疾病的药物中用途。
10.权利要求1或2所述的化合物或其药学上可接受的盐或者权利要求7所述的红曲有机溶剂提取物或柱层析组分在制备除湿祛痰、活血化瘀、或者健脾消食的药物中的用途。
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