CN1304397A - 贯叶金丝桃素衍生物,其用途及含有它们的组合物 - Google Patents
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Abstract
式(Ⅰ)贯叶金丝桃素衍生物(其中R为酰基或糖苷基团)具有优越的药理学性质和良好的稳定性。
Description
本发明涉及新的贯叶金丝桃素衍生物,其治疗抑郁和焦虑的用途及含有它们的组合物。
贯叶连翘的花顶部含有许多结构类型不同的物质,它们可以直接或间接地作用于中枢神经系统。
更具体地,所述的化合物包括金丝桃素、贯叶金丝桃素以及二聚黄酮,它们在动物和人体身上具有抗抑郁和抗焦虑活性。
这些化合物的作用机制是不同的:抗MAO作用,对5-羟色胺释放的作用以及苯二氮杂样作用,
贯叶金丝桃素是贯叶连翘花顶部的主要亲脂性成分,近来许多研究将其作为目标,使得其有可能以抗抑郁剂的身份扮演重要角色;由申请者进行的研究表明该分子具有5-羟色胺模拟活性。
在通常的提取和保存条件下贯叶金丝桃素不十分稳定;根据WO97/13489(Schwabe)的报道,几周后,St.-John’s-wort水-醇提取物中贯叶金丝桃素的含量已经接近零。
另根据WO 97/13489,为了获得含有恒定浓度贯叶金丝桃素的稳定提取物,提取、纯化、保存均应在有抗氧剂(例如维生素C及其酯类,硫酸化氨基酸等)存在下进行。
由于贯叶金丝桃素的高度不稳定性,使其组合物的制备非常困难。
其中R为:
-饱和或不饱和的直链或支链C1-C22酰基,其选择性具有一或多个取代基,取代基可以相同也可不同且选自卤原子,硝基,氨基,-C1-C6-烷基氨基,二-C1-C6-烷基氨基,-C1-C6-酰基氨基;
-环脂肪族基或芳香酰基,其中的芳香基团任意地带有一或多个取代基,它们可以相同也可不同且选自卤原子,羟基,甲氧基,氨基;
-缩水甘油基,其中的一或多个羟基基团任意地被烷基化或酰基化。
“芳香酰基”优选的是指具有一或多个氨基或烷氧基的苯甲酰基或肉桂基。
“缩水甘油基”指通过醚键与吡喃糖基或呋喃糖基环的1-位上羟基连接的一个糖残基,同时糖的其它羟基被任意地甲基化或乙酰基化。
优选的R基团是乙酰基,一氯代乙酰基,丁酰基,γ-氨基丁酰基,对-氨基苄基,三甲氧基苯甲酰基,三甲氧基肉桂基,β-葡糖基以及β-半乳糖基。
本发明贯叶金丝桃素衍生物可用常规的羟基酰基化或糖基化反应来制备。
例如,可使贯叶金丝桃素纯品或富含金丝桃素的提取物在合适的溶剂中例如吡啶与RCOOH酸(R的定义同上)的酰氯或酸酐进行反应。
另一方面,可以采用所需糖(ROH)的适合保护的反应活性衍生物进行糖基化反应,例如α-D-吡喃葡糖四乙酸溴。
根据本发明一个非常便利的方面,可以在超临界条件下,用二氧化碳对贯叶连翘花顶部进行提取,随后使之在溶剂和生成的提取物中的衍生贯叶金丝桃素之间进行分配,从而制备得到式Ⅰ化合物。
在超临界条件下,压力为180-260巴范围内,优选的压力为240巴,温度为35-50℃,优选的是40℃下,用二氧化碳对分离或混合(主要是天然混合物)状态的St.-John’s-wort的叶子和花顶部进行提取。获得了含有约50%贯叶金丝桃素的亲脂性提取物。该提取物含有大量的呫吨酮、蜡、脂肪酸以及甘油三酯。根据本发明进一步的方面,将生成的提取物溶解于甲醇中或溶解于部分水性的乙腈中,然后用正己烷或脂肪烃提取,贯叶金丝桃素百分比会增加。烃相含有要除去的不需要物质;用约等体积的水和脂肪烃稀释亲水相。通过亲脂相浓缩得到的St.-John’s-wort提取物可以用来制备上述衍生物。
本发明衍生物在体外对受体不显示活性,而其在体内特别活跃,显示出强的与剂量有关的抗抑郁活性。
在小鼠和大鼠的体内实验中,本发明化合物比贯叶金丝桃素和金丝桃素的乙醇或甲醇提取物显示出更高的活性。
为了在体内实验中证实抗抑郁效果,根据文献中已知的模型,选择了逃避缺陷进展实验以及喜好醇的Sardinia大鼠乙醇消耗抑制实验。在逃跑缺陷进展实验中,本发明化合物显示比已知提取物更高的活性和可与已知药物(例如丙咪嗪)活性相比的活性。在这项研究中,使大鼠禁食,并受到温和的、短的、不可避免的电击50分钟(预实验)。24小时后,在不可能逃避的条件下,在动物尾部进行同样的刺激,测试它们的逃避能力。在30次刺激中大鼠出现了26次逃避(自然对照),而在进行过预实验的动物中,仅出现了1-3次逃避(ED对照)。这种由于预实验诱导的低反应性在预先用丙咪嗪或氟苯氧丙胺等抗抑郁药物处理过1-3周的大鼠中没有出现。在暴露于不可避免的刺激之前1小时给予大鼠的本发明化合物使得其对逃避实验的反应活性增加,当预处理持续1-2周时,活性即有所提高。
例如用化合物Ⅰ(其中R为乙酰基)处理大鼠,得到了下表中报告的结果:表-在具有两周预备性逃避实验的大鼠中金丝桃素乙酸酯的抗抑郁效果。
物质 剂量mg/kg 逃避次数
贯叶金丝桃素乙酸酯 6.25 12.6±2.8
贯叶金丝桃素乙酸酯 12.5 17.3±1.9
贯叶金丝桃素乙酸酯 25.0 21.2±1.3
金丝桃属醇提取物 1000 15.6±2.4
金丝桃属己烷提取物 600 16.9±1.2
Ed对照 2.6±0.7
自然对照 23.6±1.2统计分析:Kruskal-Wallis非参数ANOVA KW=13.462 p=0.0012金丝桃属醇提取物和己烷提取物对自然对照 p<0.01金丝桃素乙酸酯25mg对自然对照是 n.s.自然对照对于AND p<0.01
根据文献中已知的步骤,在Sardinia大鼠醇消耗降低实验(其为抑郁和焦虑的指标)中,给药两天后,与对照相比,本发明化合物可以引起60-75%的醇消耗降低且更倾向饮水。
式Ⅰ化合物可配制成软明胶胶囊、硬明胶胶囊、片剂、栓剂;优选的是将本发明化合物配制成软明胶胶囊或控释组合物。在常规组合物中,化合物的剂量为5-50mg/剂量,在控释组合物中,剂量上升至200mg,在这种情况下,优选的每日剂量为200mg。
实施例1-富含贯叶金丝桃素提取物的制备
根据下列所述方法,在一个配备有两个分离器的25L超临界气体提取装置中对10Kg生物量的贯叶连翘进行提取。
收集到10Kg贯叶连翘花顶部后,在不超过60℃的温度下对其进行机械干燥,然后挤压成立方体使细胞破裂,在下列实验条件下,用超临界条件下的CO2进行提取:
-温度:提取器内为45℃,第一个分离器中为30℃;第二个分离器中为20℃;
-压力:提取器内为240巴,第一个分离器中为100巴,第二个分离器中为50巴;
CO2的流速为10L/分钟,共计45分钟。提取物在第二个分离器中浓缩,事实上大部分存在于植物基质中的水份在第一个分离器被浓缩。将存在于第二个分离器中的提取物溶解于3.2L甲醇中,此溶液再用3×1.5L正己烷进行提取。
己烷提取相用98%的甲醇进行反相洗涤,以贯叶金丝桃素作为指示,其应留在甲醇相中。移去己烷相,用0.6L水对合并得到的甲醇溶液进行稀释,用2×0.6L正己烷进行再次提取。
用0.3%的活性炭对合并的己烷相进行脱色,干燥(Na2SO4)并在不超过40℃下减压浓缩至油状物。最后得到0.22kg蜡状提取物,其中约含有70%的贯叶金丝桃素。实施例2-贯叶金丝桃素乙酸酯的合成
向实施例1中得到的植物提取物(12g)的吡啶溶液中加入Ac2O(9.8ml),并在室温下搅拌。用TLC来检测反应情况(己烷-EtOAc95:5;贯叶金丝桃素的Rf值:0.24;乙酸酯的Rf值:0.49)。24小时后,用水稀释反应混合物,并用己烷-乙醚混合物(3∶1)进行提取。有机相用稀HCl、饱和NaHCO3和盐水洗涤。干燥(Na2SO4)并蒸发,残余物用硅胶柱层析纯化(大约30g),先用石油醚洗脱除去脂肪,然后用己烷-EtOAc(95∶5)洗脱,直至开始洗脱出标题化合物,得到3.34g(0.28%)贯叶金丝桃素乙酸酯,其为无色膏状物。C37H54O5,MW 578CI-MS:579(M+H)+IR(liquid film):1779,1732,1660,1634,1447,1377,1339,1146 cm-1 1H NMR(200 MHz,CDCl3):5.03(br s,2H),5.00(br s,2H),3.05(dd,J=15,7Hz,1H),2.87(dd,J=15,7Hz,IH),2.22(s,OAc),1.66-1.53(br s,8 x 3H),1.08(d,J=6.5 Hz,3H),0.98(s,3H),0.85(d,J=6.5 Hz,3H).实施例3-贯叶金丝桃素3,4,5-三甲氧基苯甲酸酯的制备
向实施例1中植物提取物(1.0g)的吡啶溶液中加入3,4,5-三甲氧苯甲酰氯(323mg)并在室温下搅拌24小时。由于在不同的溶剂中起始原料和产品的Rf值非常接近,因此无法用TLC来检测反应情况。用水稀释反应混合物,并用乙醚-己烷混合物(3∶1)进行提取。有机相用稀HCl及饱和NaHCO3(用盐水洗涤会使之乳化)洗涤。干燥(Na2SO4)并蒸发,残余物用硅胶柱层析纯化(大约5g)先用石油醚洗脱除去脂肪,然后用己烷-EtOAc(95∶5)洗脱,得到贯叶金丝桃素三甲氧基苯甲酸酯(317mg),其为无色油状物。C45H62O8,MW 730CI-MS:731(M+H)+IR(liquid film):1732,1660,1634,1589,1465,1331,1153,1130.914cm-1 1H NMR(200 MHz,CDCl3):7.27(s,2H),5.04(br S,2H),5.02(br s,2H),3.86(s,OMe),3.82(s,2 x OMe),3.10(dd,J=15,7 Hz,1H),2.92(dd,J=15,7 Hz,1H),1.66-1.53(br s, 8 x 3H),1.13(d,J=6,5 Hz,3H),1.04(s,3H),0.99(d,J=6.5 Hz,3H).实施例4-含有实施例2产品的包衣片剂
贯叶金丝桃素乙酸酯 100mg
大豆多糖 18.25mg
交联的羧甲基纤维素钠 13.50mg
二氧化硅 6.50mg
聚乙烯吡咯烷酮 5.00mg
硬脂酸镁 0.50mg
包衣剂:
羟丙甲基纤维素 3.75mg
滑石 2.75mg
二氧化钛 1.25mg
三乙酸甘油酯 0.75mg
多乙氧基醚80 0.25mg
红铁氧化物 1.00mg
Claims (6)
2.权利要求1中所述的化合物,R选自乙酰基,一氯代乙酰基,丁酰基,γ-氨基丁酰基,对-氨基苄基,三甲氧基苯甲酰基,三甲氧基肉桂基,β-葡糖基以及β-半乳糖基。
3.含有权利要求1或2中化合物的贯叶连翘提取物。
4.制备权利要求3中提取物的方法,其包括:
a)用超临界二氧化碳对贯叶连翘花顶部进行提取;
b)将步骤a)中的亲脂性提取物溶解于甲醇或乙腈中,并用脂肪烃进行提取;
c)用水稀释亲水相并用脂肪烃进行反提取;
d)浓缩亲脂相;
e)用RCOOH酸或ROH糖的反应活性衍生物、其中R的定义同权利要求1,处理步骤b)中得到的浓缩物。
5.含有合适载体及作为活性成分的权利要求1-2中化合物或权利要求3-4中提取物的药物组合物。
6.作为抗抑郁药物的式Ⅰ化合物。
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WO2000025824A2 (de) * | 1998-11-04 | 2000-05-11 | Dr. Willmar Schwabe Gmbh & Co. | Stabile zubereitungen mit hyperforin |
ITMI20020871A1 (it) | 2002-04-23 | 2003-10-23 | Indena Spa | Derivati alogenati dell'iperforina loro uso e formulazioni che li contengono |
ITMI20020872A1 (it) | 2002-04-23 | 2003-10-23 | Indena Spa | Derivati dell'iperforina loro uso e formulazioni che li contengono |
US20060115556A1 (en) * | 2004-12-01 | 2006-06-01 | Foulger Sidney W | Nutritional supplement drink containing xanthone extracts |
US20060115555A1 (en) * | 2004-12-01 | 2006-06-01 | Foulger Sidney W | Nutritional supplements containing xanthone extracts |
BRPI0900614A2 (pt) | 2009-02-13 | 2011-06-28 | Univ Fed Do Rio Grande Do Sul Ufrgs | extrato vegetal neuroativo, composição farmacêutica compreendendo o mesmo e processo para sua produção |
BR112013030986A2 (pt) * | 2011-06-03 | 2016-12-06 | Harvard College | análogos de hiperforina, métodos de síntese e usos dos mesmos |
ITMI20131012A1 (it) | 2013-06-19 | 2014-12-20 | Indena Spa | Derivati dell'iperforina e loro uso nella malattia di alzheimer |
RU2676100C1 (ru) * | 2018-10-05 | 2018-12-26 | федеральное государственное автономное образовательное учреждение высшего образования "Санкт-Петербургский политехнический университет Петра Великого" (ФГАОУ ВО "СПбПУ") | Применение производных пиперазина для лечения болезни Альцгеймера и деменций альцгеймеровского типа с нарушенной внутриклеточной кальциевой сигнализацией |
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US2550266A (en) * | 1948-12-11 | 1951-04-24 | Swift & Co | Preservation of food products |
DE4239959A1 (de) * | 1992-11-27 | 1994-06-01 | Schwabe Willmar Gmbh & Co | Johanniskraut-Trockenextrakt, Verfahren zu seiner Herstellung und seine Verwendung |
DE19646977A1 (de) * | 1995-09-29 | 1998-01-15 | Schwabe Willmar Gmbh & Co | Stabiler Extrakt aus Hypericum perforatum L., Verfahren zu seiner Herstellung und pharmazeutische Zubereitungen |
DE19714450A1 (de) * | 1997-04-08 | 1998-10-15 | Schwabe Willmar Gmbh & Co | Stabiler Extrakt aus Hypericum perforatum L., Verfahren zu seiner Herstellung und pharmazeutische Zubereitung |
JP2002509111A (ja) * | 1998-01-13 | 2002-03-26 | レクソール サンダウン インコーポレイテッド | オトギリソウ及びメチル供与体組成物、並びにその使用 |
US6224906B1 (en) * | 1999-08-31 | 2001-05-01 | Natreon Inc. | St. John's wort composition |
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