CN1269783C - 贯叶金丝桃素卤代衍生物、其用途和包含它们的制剂 - Google Patents

贯叶金丝桃素卤代衍生物、其用途和包含它们的制剂 Download PDF

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CN1269783C
CN1269783C CNB038089645A CN03808964A CN1269783C CN 1269783 C CN1269783 C CN 1269783C CN B038089645 A CNB038089645 A CN B038089645A CN 03808964 A CN03808964 A CN 03808964A CN 1269783 C CN1269783 C CN 1269783C
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chlorine
adhyperforin
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E·邦巴尔代利
P·莫拉佐尼
A·里瓦
N·菲扎提
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Abstract

式(I)的贯叶金丝桃素和加贯叶金丝桃素卤代衍生物,其中,X、R和R1如说明书中所定义,其制备方法及其在药学和/或营养学领域中的应用,特别是在治疗抑郁和阿尔茨海默病中的应用。

Description

贯叶金丝桃素卤代衍生物、其用途和包含它们的制剂
发明领域
本发明涉及贯叶金丝桃素和加贯叶金丝桃素(adhyperforin)卤代衍生物和其在药学和/或营养学领域中的应用,特别是在治疗抑郁和阿尔茨海默病中的应用。
背景技术
贯叶连翘的花枝(flowering tops)含有许多类结构不同的物质,它们直接或间接作用于中枢神经系统。这些化合物的作用机理各不相同,包括抗-MAO作用(Suzuki OR.等,Planta Med.,272-4,1984)、对5-羟色胺释放和再摄取的作用(Muller W.E.等,Pharmacopsychiatry,30,102-107,1997)以及苯二氮杂样活性(Coot J.M.Pharmacopsychiatry 30,108-112,1997)。
贯叶金丝桃素,一种floroglucin衍生物,是贯叶连翘花枝的亲脂性级分的主要成分之一;所述级分还包含加贯叶金丝桃素,它是贯叶金丝桃素的高级同系物,尽管其浓度比较低(Erdelmeier C.A.J.,Pharmacopsychiatry,31,2-6,1998)。
Figure C0380896400041
贯叶金丝桃素:R=CH3
加贯叶金丝桃素:R=CH2CH3
近年来,贯叶金丝桃素成为了许多研究工作的对象,这些研究工作确立了其作为抗抑郁药的重要作用(Pharmacopsychiatry,31 Suppl.1,1-60.1998)。此外,公认的是贯叶连翘的提取物能够用于预防和治疗神经变性疾病,尤其是阿尔茨海默病(WO/9940905,WO0057707)。特别地,记载了用于此目的的贯叶金丝桃素和加贯叶金丝桃素的无机阳离子盐或铵盐(WO 9941220)。
由文献可知,贯叶金丝桃素在常规的提取和贮存条件下稳定性较差;如WO97/13489所述,圣约翰草水-醇提取物中的贯叶金丝桃素含量在几个星期后就下降了。WO97/13489进一步叙述了为了获得贯叶金丝桃素稳定的提取物,必须在整个过程(提取、纯化和贮存)中存在抗氧化剂。因此显然,贯叶金丝桃素的高度不稳定性使得贯叶金丝桃素药物制剂的制备十分困难。为了克服这一缺陷,近来已经制备了比贯叶金丝桃素更加稳定的化合物,例如WO99/41220中公开的盐以及羟基官能化的衍生物(WO99/64388)。
此外,已知(Bystrov等,Bioorg.Khim,1978)通过对异戊二烯侧链的催化还原,贯叶金丝桃素和加贯叶金丝桃素能够转化成相应的八氢衍生物(IIa和IIb),
Figure C0380896400051
                        (IIa:R=CH3
                        IIb:R=CH2CH3)
或是通过将1和10位的酮基还原成羟基而转化成相应的四氢衍生物(IIc和IId)。
Figure C0380896400061
                    (IIc:R=CH3
                     IId:R=CH2CH3)
发明详述
现已发现,通过在贯叶金丝桃素、加贯叶金丝桃素或其还原衍生物的8-位上引入卤素而获得的化合物具有比贯叶金丝桃素和加贯叶金丝桃素更强的抗抑郁、抗焦虑和抗神经变性活性。
本发明具体涉及式(I)的化合物和其可药用盐或酯
Figure C0380896400062
其中,X为卤原子,R为甲基或乙基,并且:
a)R1为3-甲基-2-丁烯-1-基并且在1-和10-位存在氧代基团;或者
b)R1为3-甲基-丁-1-基并且在1-和10-位存在氧代基团;或者
c)R1为3-甲基-2-丁烯-1-基并且在1-和10-位存在羟基;或者
d)R1为3-甲基-丁-1-基并且在1-和10-位存在羟基。
本文中术语“卤素”是指氟或选自氯、溴和碘的卤素,更优选氯和溴,首选氯。
此外,在本发明中,“八氢”是指其中R1为3-甲基-丁-1-基并且在1-和10-位存在氧代基团的贯叶金丝桃素或加贯叶金丝桃素衍生物;“四氢”是指其中R1为3-甲基-2-丁烯-1-基并且在1-和10-位存在羟基的贯叶金丝桃素或加贯叶金丝桃素衍生物;“十二氢”是指其中R1为3-甲基-丁-1-基并且在1-和10-位存在羟基的贯叶金丝桃素或加贯叶金丝桃素衍生物。
本发明优选的化合物为如下式(I)的化合物,其中:X为氯或溴原子,R为甲基或乙基,R1为3-甲基-2-丁烯-1-基并且在1和10位存在氧代基团(在下文中定义为:8-氯贯叶金丝桃素Ia、8-氯加贯叶金丝桃素Ib、8-溴贯叶金丝桃素Ic、8-溴加贯叶金丝桃素Id)
Figure C0380896400071
(Ia:X=Cl,R=CH3Ib:X=Cl,R=CH2CH3Ic.X=Br,R=CH3Id:X=Br,R=CH2CH3)
此外,优选的式(I)化合物为如下化合物,其中:X为氯或溴原子,R为甲基或乙基,R1为3-甲基-丁-1-基并且在1和10位存在氧代基团(在下文中定义为:8-氯八氢贯叶金丝桃素Ie、8-氯八氢加贯叶金丝桃素If、8-溴八氢贯叶金丝桃素Ig、8-溴八氢加贯叶金丝桃素Ih)
Figure C0380896400072
(Ie:X=Cl,R=CH3If:X=Cl,R=CH2CH3Ig.X=Br,R=CH3Ih:X=Br,R=CH2CH3)。
特别优选8-氯贯叶金丝桃素(Ia)和8-氯八氢贯叶金丝桃素(Ie)。
式(I)化合物可这样制备:使贯叶金丝桃素、加贯叶金丝桃素或其四氢、八氢、十二氢衍生物与适宜的卤化剂反应,优选与N-氯琥珀酰亚胺或N-溴琥珀酰亚胺反应。
如上所述的四氢衍生物(IIa)和(IIb)通过用选自例如NaBH4、Redal、Vitride、LiAlH4的氢化物还原酮基而得到。
如上所述的八氢衍生物(IIc)和(IId)通过将异戊二烯侧链催化氢化还原,例如使用钯/木炭或阮内镍还原得到。
十二氢衍生物(十二氢贯叶金丝桃素IIe和十二氢加贯叶金丝桃素IIf)
                     (IIe:R=CH3
                     IIf:R=CH2CH3)
通过用上述氢化物处理八氢衍生物而得到。
十二氢衍生物(IIe)和(IIf)为新化合物,因此也是本发明的一部分。
以贯叶连翘花枝为原料制备本发明化合物的步骤概括如下:
贯叶连翘花枝可以单纯用醇或脂肪酮提取,或用其与水或超临界条件下的气体的混合物提取;将得到的提取物在正己烷和脂肪醇水溶液之间分配。己烷溶液用碱性甲醇萃取来提取出贯叶金丝桃素和加贯叶金丝桃素。酸化甲醇溶液,然后用弱碱性离子交换树脂处理,所述树脂可选择性地保留贯叶金丝桃素和加贯叶金丝桃素。用酸性甲醇洗脱树脂,并将洗脱液浓缩至小体积,然后用水稀释,以正己烷反萃取。将己烷溶液浓缩至小体积,得到的浓缩物即可用于衍生化。按照实施例记载的步骤,向残余物中加入含氯溶剂,然后加入适宜的反应物。
本发明还涉及式(I)的衍生物和其可药用盐或酯在制备用于治疗抑郁症和阿尔茨海默病的药物中的用途。
式(I)的化合物,特别是8-氯和8-溴贯叶金丝桃素以及8-氯和8-溴加贯叶金丝桃素显示出了抗抑郁活性。
本发明化合物的抗抑郁作用在大鼠上通过强迫游泳试验来进行评价,评价参数:挣扎、漂浮和游泳,如Cervo等人,Neuropharmacology,26,14969-72,1987所述。化合物分3次给予:预试验后30分钟、试验前5小时和30分钟。下表所列的结果证明,本发明化合物比母体化合物贯叶金丝桃素的活性更高。
  处理   mg/Kg   挣扎(秒)   漂浮(秒)   游泳(秒)
  载体   7.0±2.4   174.5±15.9   118.5±15.8
  氯贯叶金丝桃素   3.125   46.9±5.9   72.1±6.7   181.0±11.3
  氯八氢贯叶金丝桃素   6.25   57.3±6.2   63.4±9.2   165.6±12.5
  贯叶金丝桃素   6.25   30.4±4.6   60.4±7.3   99.3±10.6
  地昔帕明   10   148.3±12.6   53.0±9.2   98.8±7.9
本发明化合物还表现出对抗阿尔茨海默病的显著活性,这归因于其提高APPs(阿尔茨海默前体蛋白(APP)的可溶、无害形式)的能力。事实上已知的是,阿尔茨海默前体蛋白(APP)的蛋白酶剪切既受β-和γ-分泌酶的调节,它们诱导淀粉样肽Ab1-42(其在阿尔茨海默病的表征中也具有中枢作用)产量的提高,又受α-分泌酶的调节,其可提高无致病活性的可溶性APPs的量(Eslr W.P.,Wolfe M.S.,Science,293,1449-54,2001)。
根据Galbete J.L.等,Biochem J.348,307-313,2000所记载的步骤,由培养基中的成神经细胞瘤细胞系(SH-SY5Y)评价本发明化合物对由α-分泌酶产生的APPs的释放的影响。
下表中所列的结果显示,实验化合物激活了α-分泌酶介导的APP代谢,诱导培养基中分泌的APPs增多。
                                APPs%
对照                            100
10μM贯叶金丝桃素               296
10μM氯贯叶金丝桃素             627
10μM氯八氢贯叶金丝桃素         855
本发明化合物可以根据常规的方法,例如根据Remington’sPharmaceutical Sciences Handbook,17版,Mack Pub.,N.Y.,U.S.A的描述,制成软明胶胶囊、硬明胶胶囊、片剂、栓剂;优选将本发明提取物制成软明胶胶囊或控释制剂。常规制剂的剂量范围是每单位剂量10到100mg,控释制剂可高达200mg,此处建议的剂量是200mg每剂/天。此外,可将化合物通过控释经皮途径,将制剂应用于大脑颈动脉分路的邻近区域来给药。这些制剂中化合物的剂量范围是10到100mg每剂/天。
下述记载的实施例对本发明作了更加详细的说明。
实施例
实施例1-贯叶金丝桃素的制备
将10kg贯叶连翘花枝用30L甲醇在50L的提取设备中进行提取,将内容物在室温下放置3小时;再重复提取3次,然后将合并后的提取液在真空下浓缩至5kg,将浓缩液用3×5L正己烷萃取。将有机层用KOH甲醇溶液萃取直至没有贯叶金丝桃素和加贯叶金丝桃素。
将该溶液中和,用弱碱性离子交换树脂过滤,其可选择性地保留贯叶金丝桃素和加贯叶金丝桃素;保留的产物再次用经磷酸酸化的甲醇洗脱;将甲醇洗脱液于25℃在真空下浓缩,用水稀释并用正己烷反萃取直至没有贯叶金丝桃素。
合并的有机层用0.3%木炭脱色,然后用Na2SO4干燥,并在低于40℃的温度下真空浓缩至油状。固化后油变为蜡状物(0.52kg),含有约90%的贯叶金丝桃素。
向残余物中加入3L二氯甲烷,在强烈搅拌下加入0.14kg N-氯琥珀酰亚胺。将溶液在室温及搅拌下放置3小时,通过TLC检测贯叶金丝桃素的消失,TLC采用硅胶板并用正己烷/乙酸乙酯9∶1混合物作为洗脱剂(Rf贯叶金丝桃素0.20;氯贯叶金丝桃素0.80)。反应完成后,加入3L水;有机层用硫代硫酸钠洗涤,然后用碳酸钠干燥。蒸出溶剂,将残余物用硅胶色谱处理,用正己烷/乙酸乙酯98∶2混合物洗脱。浓缩包含氯代衍生物的级分得到0.48kg产品,经石油醚结晶后,其具有下述物化特征和光谱特征:
[a]D+16(c=0.5CH2Cl2);
IRνmax(KBr)1722,1713,1446,1377,1230,1064,831cm-1
1H-NMR(300MHz CDCl3):1.41(m,H-4),2.16(m,H-5),1.70(m,H-5′),2.80(m,H-11),1.18(d,J=7Hz,H-12),1.02(d,J=7Hz,H-13),1.06(s,H-14),2.01(m,H-15),1.06(m,H-15′),5.03(m,H-17),1.66(br s,H-19),1.60(br s,H-20),2.05(m,H-21),1.65(m,H-21′),4.76(m,H-22),1.66(s,H-24),1.52(s,H-25),3.18(s,H-26),4.96(m,H-27),1.63(br s,H-29),1.69(br s,H-30),2.60(m,H-31),5.17(dd,J 13.6,H-32),1.66(s,H-35)。
13C-NMR(75MHz CDCl3):δ207.6,205.4,198.7,195.9,139.2,135.0,134.1,131.8,124.5,121.8,118.9,116.8,85.1,67.2,65.1,56.2,45.7,40.1,38.5,37.5,31.6,31.5,28.2,26.4,26.1,26.0,25.9,25.5,22.2,20.6,18.6,18.2,18.1,17.9,13.9。
ESIMS m/z 593,595[M+Na+](100.38),1163,1165[2M+Na+](32,28)。
与上述化合物一起,相同的色谱分离还获得了0.049kg的氯加贯叶金丝桃素,其具有下述物化特征和光谱特征:
1H-NMR(300MHz CDCl3):δ5.27-4.75(4H,m,H-18,H-23,H-28,H-33),2.23,3.09(2-H,dd,J=13.4,8.4Hz,CH2-32),2.63(2H,m,CH2-27),2.80-1.42(10H,m,H-4,H-11,CH2-5,CH2-16,CH2-17,CH2-22),1.82-1.55(27H,s,CH3-20,CH3-21,CH3-25,CH3-26,CH3-29,CH3-30,CH3-31,CH3-35,CH3-36),1.21(3H,d,J=6.6Hz,CH3-14),0.87(3H,d,J=6.6Hz,CH3-13),1.07(3H,s,CH3-15)。
13C-NMR(75MHz CDCl3):δ206.9,205.4,198.7,196.7,139.2,135.0,134.1,131.9,124.5,121.8,118.9,116.8,85.1,67.2,65.1,56.2,46.7,45.7,45.2,37.5,31.6,31.5,28.5,28.2,26.4,26.1,26.0,25.9,25.5,18.6,18.2,18.1,18.0,16.8,13.9,11.6。
ESIMS m/z 607,609[M+Na+](100,34),1191,1193[2M+Na+](21,20)。
实施例2-八氢贯叶金丝桃素二环己基铵盐的制备
将50g按照实施例1的描述获得的贯叶金丝桃素在2g 5%钯/木炭的存在下溶于500ml乙酸乙酯并氢化直至氢吸收完全。滤除催化剂,真空下将溶液浓缩至干燥,将残余物溶于正己烷。向溶液中加入化学计量的二环己基胺,从而选择性地使相应的盐形成结晶。
得到了62g八氢贯叶金丝桃素二环己基铵盐,其光谱特征如下:
1H-NMR(300MHz CDCl3):δ3.03(2H,m,CH-DCHA),2.55-2.30,2.10-1.76(20H,m,CH2-DCHA),1.70-1.10(22H,m,H-4,H-11,CH2-5,CH2-15,CH2-16,CH2-17,CH2-21,CH2-22,CH2-26,CH2-27,CH2-31,CH2-32),0.97-0.83(24H,d,CH3-19,CH3-20,CH3-24,CH3-25,CH3-29,CH3-30,CH3-34,CH3-35),1.19,1.12(6H,d,J=6.5Hz,CH3-12,CH3-13),0.91(3H,s,CH3-14)。
13C-NMR(75MHz CDCl3):δ213.1,211.1,186.3,183.6,119.0,82.5,60.8,53.5,47.5,44.2,41.3,41.0,40.9,38.2,38.1,37.8,33.8,31.0,30.7,30.0,29.4,28.8,28.3,27.9,27.1,25.4,25.1,24.9,23.5,23.2,23.1,22.9,22.8,22.7,22.5,13.7。ESIMS m/z 567[M+Na+](100),1111[2M+Na+](91)。
实施例3-氯八氢贯叶金丝桃素的制备
在10g八氢贯叶金丝桃素二环己基铵盐的60ml二氯甲烷溶液中加入1.89g N-氯琥珀酰亚胺,将混合物搅拌30分钟。向有机相中加入60ml水,用饱和硫代硫酸钠溶液洗涤,用硫酸钠干燥;浓缩至干后,将残余物用硅胶柱纯化,用乙酸乙酯/己烷95∶5混合物洗脱所需的化合物。将得到的级分蒸发至干得到白色粉末状的所需化合物,在用甲醇重结晶后得到6.27g氯代衍生物,其具有下述光谱特征:
1H-NMR(300MHz CDCl3):δ3.04-1.04(22H,m,H-4,H-11,CH2-5,CH2-15,CH2-16,CH2-17,CH2-21,CH2-22,CH2-26,CH2-27,CH2-31,CH2-32),1.05-0.83(24H,d,CH3-19,CH3-20,CH3-24,CH3-25,CH3-29,CH3-30,CH3-34,CH3-35),1.19,1.03(6H,d,J=6.6Hz,CH3-12,CH3-13),1-03(3H,s,CH3-14)。
13C-NMR(75MHz CDCl3):δ207.6,205.1,199.3,195.8,84.9,68.7,64.5,56.8,46.1,43.3,40.2,39.9,38.1,37.8,34.8,33.5,31.3,30.7,29.0,28.8,28.2,27.0,24.8,23.0,22.9,22.8,22.7,22.5,22.4,22.1,20.6,14.2。
ESIMS m/z 601,603[M+Na+](100.38),1179,1181[2M+Na+](62,48)。
实施例4-十二氢贯叶金丝桃素的制备
将1.72g八氢贯叶金丝桃素二环己基铵盐(M.W.=716;2.41mmol)在磁力搅拌下溶于20ml THF;在溶液中加入大大过量(3.5g)的LiAlH4(0.092mol)。反应进程通过TLC监测(洗脱液:石油醚/EtOAc 9∶1,Rfp=0.6;Rfa=0.6;Rfc=0.52;Rfd=0.18)。十分钟后反应完成。
按照实施例3的描述破坏过量的反应物。过滤半固体反应混合物,残余物用乙酸乙酯充分洗涤。蒸发溶液至干燥,将反应粗品溶于15ml石油醚/乙醚3∶1中,将溶液置于150ml分液漏斗中。有机相用2N硫酸洗涤三次,然后用盐水洗涤。弃去水相,有机相用Na2SO4干燥并浓缩至干。得到的产品用75g硅胶通过柱色谱纯化,用石油醚/乙酸乙酯99∶1洗脱所需化合物。得到0.9g十二氢贯叶金丝桃素,其物化和光谱特征如下:
EIMS m/z 548[M]+

Claims (6)

1.式(I)的化合物
其中,X为卤原子,R为甲基或乙基,并且:
a)R1为3-甲基-2-丁烯-1-基并且在1-和10-位存在氧代基团;或者
b)R1为3-甲基-丁-1-基并且在1-和10-位存在氧代基团;或者
c)R1为3-甲基-2-丁烯-1-基并且在1-和10-位存在羟基;或者
d)R1为3-甲基-丁-1-基并且在1-和10-位存在羟基。
2.权利要求1的化合物,其中,X为氯或溴。
3.权利要求1的化合物,其中,X为氯。
4.权利要求1的化合物,其选自:8-氯贯叶金丝桃素(Ia)、8-氯加贯叶金丝桃素(Ib)、8-溴贯叶金丝桃素(Ic)、8-溴加贯叶金丝桃素(Id)
Ia:X=Cl,R=CH3
Ib:X=Cl,R=CH2CH3
Ic:X=Br,R=CH3
Id:X=Br,R=CH2CH3
8-氯八氢贯叶金丝桃素(Ie)、8-氯八氢加贯叶金丝桃素(If)、8-溴八氢贯叶金丝桃素(Ig)、8-溴八氢加贯叶金丝桃素(Ih)
Ie:X=Cl,R=CH3
If:X=Cl,R=CH2CH3
Ig:X=Br,R=CH3
Ih:X=Br,R=CH2CH3
5.权利要求1-4任一项的化合物在制备用于治疗抑郁症和阿尔茨海默病的药物中的用途。
6.药物组合物,其包含权利要求1-4任一项的化合物和适宜的赋形剂或载体。
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