CN1646462A - 贯叶金丝桃素衍生物,其应用以及包含它们的制剂 - Google Patents
贯叶金丝桃素衍生物,其应用以及包含它们的制剂 Download PDFInfo
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- CN1646462A CN1646462A CNA038089319A CN03808931A CN1646462A CN 1646462 A CN1646462 A CN 1646462A CN A038089319 A CNA038089319 A CN A038089319A CN 03808931 A CN03808931 A CN 03808931A CN 1646462 A CN1646462 A CN 1646462A
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- hyperforine
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- adhyperforin
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- 239000000203 mixture Substances 0.000 title description 9
- 238000009472 formulation Methods 0.000 title description 2
- 150000002448 hyperforins Chemical class 0.000 title 1
- IWBJJCOKGLUQIZ-HQKKAZOISA-N hyperforin Chemical compound OC1=C(CC=C(C)C)C(=O)[C@@]2(CC=C(C)C)C[C@H](CC=C(C)C)[C@](CCC=C(C)C)(C)[C@]1(C(=O)C(C)C)C2=O IWBJJCOKGLUQIZ-HQKKAZOISA-N 0.000 claims abstract description 48
- MGKCAFQXBAFOSW-ACJQSPJVSA-N O=C1C(CC=C(C)C)=C(O)[C@@]2(CC=C(C)C)C[C@H](CC=C(C)C)[C@](CCC=C(C)C)(C)[C@]1(C(=O)C(C)CC)C2=O Chemical compound O=C1C(CC=C(C)C)=C(O)[C@@]2(CC=C(C)C)C[C@H](CC=C(C)C)[C@](CCC=C(C)C)(C)[C@]1(C(=O)C(C)CC)C2=O MGKCAFQXBAFOSW-ACJQSPJVSA-N 0.000 claims abstract description 26
- RIISSLSXWPTKFE-UHFFFAOYSA-N adhyperforin Natural products CCC(C)C(=O)C12CC(CC=C(C)C)(CC(CC=C(C)C)C1CCC=C(C)C)C(=C(CC=C(C)C)C2=O)O RIISSLSXWPTKFE-UHFFFAOYSA-N 0.000 claims abstract description 21
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 33
- -1 acetyl Octahydrohyperforin Chemical compound 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 230000000994 depressogenic effect Effects 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000009467 reduction Effects 0.000 abstract description 6
- 150000003839 salts Chemical class 0.000 abstract description 4
- QOVWXXKVLJOKNW-UHFFFAOYSA-N hyperforin Natural products CC(C)C(=O)C12CC(CC=C(C)C)(CC(CC=C(C)C)C1CCC=C(C)C)C(=C(CC=C(C)C)C2=O)O QOVWXXKVLJOKNW-UHFFFAOYSA-N 0.000 abstract description 2
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- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
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- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 1
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- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
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- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
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- 230000002555 anti-neurodegenerative effect Effects 0.000 description 1
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- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
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- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 1
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- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical class OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 description 1
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Abstract
贯叶金丝桃素和加贯叶金丝桃素的还原产物及其药学上可接受的盐或酯在药学和/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
发明领域
本发明涉及贯叶金丝桃素和加贯叶金丝桃素(adhyperforin)衍生物以及其在药学和/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。
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)。
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,即八氢贯叶金丝桃素(Ia)和八氢加贯叶金丝桃素(Ib),
(Ia:R=CH3
Ib:R=CH2CH3)或是用金属氢化物将1和10位的酮基还原成羟基而转化成相应的四氢衍生物,即四氢贯叶金丝桃素(Ic)和四氢加贯叶金丝桃素(Id)。
(Ic:R=CH3
Id:R=CH2CH3)
发明详述
现已发现,通过将异戊二烯链的所有双键还原和/或通过将1和10位的酮基还原成羟基而得到的贯叶金丝桃素和加贯叶金丝桃素衍生物,不仅具有较高的稳定性,而且其抗抑郁、抗焦虑和抗神经变性的活性也出人意料地高于贯叶金丝桃素和加贯叶金丝桃素。
因此,本发明的目的是式(I)的贯叶金丝桃素和加贯叶金丝桃素衍生物用于制备药物的用途,特别是用于制备用来治疗抑郁和阿尔茨海默病的药物的用途,
其中R是甲基或乙基,R2是氢、药学上可接受的无机或有机碱阳离子或直链或支链C2-C5酰基残基,并且其中:
a)R1是3-甲基-丁-1-基并且在1和10位存在氧代基团;或者
b)R1是3-甲基-2-丁烯-1-基并且在1和10位存在羟基基团;或者
c)R1是3-甲基-丁-1-基并且在1和10位存在羟基基团。
a)中所定义的优选的式(I)化合物是那些其中R2是氢的化合物,即以下定义的八氢贯叶金丝桃素(Ia)和八氢加贯叶金丝桃素(Ib):
(Ia:R=CH3
Ib:R=CH2CH3)
b)中所定义的优选的式(I)化合物是那些其中R2是氢的化合物(以下定义的四氢贯叶金丝桃素Ic和四氢加贯叶金丝桃素Id),最优选四氢贯叶金丝桃素(Ic):
(Ic:R=CH3
Id:R=CH2CH3)
c)中所定义的优选的式(I)化合物是那些其中R2是氢的化合物(以下定义的十二氢贯叶金丝桃素Ie和十二氢加贯叶金丝桃素If),最优选十二氢贯叶金丝桃素(Ie):
(Ie):R=CH3
(If):R=CH2CH3
a)中所定义的进一步优选的式(I)化合物是那些其中R2是锂的化合物(八氢贯叶金丝桃素锂盐Ig和八氢加贯叶金丝桃素锂盐Ih),最优选八氢贯叶金丝桃素锂盐(Ig):
(Ig:R=CH3
Ih:R=CH2CH3)
a)中所定义的进一步优选的式(I)化合物是那些其中R2是乙酰基的化合物(乙酰八氢贯叶金丝桃素Ii和乙酰八氢加贯叶金丝桃素Il),最优选乙酰八氢贯叶金丝桃素(Ii):
(Ii:R=CH3
Il:R=CH2CH3)
十二氢贯叶金丝桃素(Ie)、十二氢加贯叶金丝桃素(If)、乙酰八氢贯叶金丝桃素(Ii)和乙酰八氢加贯叶金丝桃素(Il)是新化合物,也是本发明的一部分。
式(Ia)和(Ib)化合物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。
式(Ic)和(Id)化合物通过用选自例如NaBH4、Redal、Vitride、LiAlH4的氢化物还原1和10位的酮基而获得。
式(Ie)和(If)化合物通过按照以上描述,先还原异戊二烯侧链,再还原1和10位的酮基而获得。
其中R2是无机或有机碱阳离子或酰基残基的式(I)化合物,可以由其中R2是氢的式(I)化合物,通过常规方法经成盐或酯化来制备。
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。
本发明化合物已经显示出抗抑郁的作用,其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 |
八氢贯叶金丝桃素锂盐6.25 | 63.1±5.8 | 59.5±11.3 | 177.4±14.9 |
四氢贯叶金丝桃素 6.25 | 51.4±4.1 | 68.4±7.6 | 193.4±13.2 |
十二氢贯叶金丝桃素 6.25 | 62.13±5.1 | 55.1±6.2 | 169.5±10.1 |
乙酰八氢贯叶金丝桃素6.25 | 73.9±5.9 | 68.4±5.7 | 171.9±11.4 |
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八氢贯叶金丝桃素锂盐 | 1383 |
10μM四氢贯叶金丝桃素 | 926 |
10μM十二氢贯叶金丝桃素 | 879 |
10μM乙酰八氢贯叶金丝桃素 | 954 |
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己烷萃取。弃去水-甲醇溶液,而己烷溶液用碱性甲醇(KOH)反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。
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3-四氢贯叶金丝桃素的制备
将2g贯叶金丝桃素(M.W.=536,01)在磁力搅拌下溶于20ml THF中;在溶液中加入大大过量的LiAlH4(1g,0.026mol,M.W.=38)。反应进程由TLC监控(洗脱液:石油醚/EtOAc 9∶1)。十分钟后反应完成。
加入附着在硅藻土上的Na2S2O4·10H2O(3∶1重量比)来破坏过量的反应物:该反应高度放热,因此需要用冰冷却。部分溶剂由于产生的热而蒸发。将混合物用硅藻土过滤,滤液用20ml AcOEt洗涤三次。将溶液置于150ml圆底带颈烧瓶中,将溶剂彻底蒸发。
得到的混合物经柱色谱纯化,使用200ml装有100ml硅胶的柱子,用石油醚/EtOAc 95∶5作为洗脱混合物。收集约20ml洗脱液级分,通过TLC(石油醚/EtOAc 9∶1)检测其成分。从甲醇中结晶出的含量较高的产物其光谱性质如下:
1H-NMR(300MHz CDCl3):δ5.11(1H,m,H-22),5.00(3H,m,H-17,H-27,H-32),3.11(1H,dd,J=14.0,7.4Hz,CH2-26),2.92(1H,dd,J=14.0,7.0Hz,CH2-26),2.50-1.35(12H,m,H-4,H-11,CH2-5,CH2-15,CH2-16,CH2-21,CH2-31),1.80-1.52(24H,s,CH3-19,CH3-20,CH3-24,CH3-25,CH3-29,CH3-30,CH3-34,CH3-35),1.19-0.95(9H,d,CH3-12,CH3-13,CH3-14)。
13C-NMR(75MHz CDCl3):δ200.5,174.3,134.1,132.6,131.2 130.6,125.8,123.9,122.6,120.5,119.4,79.2,73.1,39.6,37.2,30.5,32.8,31.3,30.2,26.1,26.0,25.8,23.5,23.1,21.9,20.0,18.3,18.1,17.8,15.6。
ESIMS m/z 1103[2M+Na+](100),541[M+H+](25),563[M+Na+](12)。
实施例4-八氢加贯叶金丝桃素锂盐的制备
将15g八氢贯叶金丝桃素二环己基铵盐在酸性树脂上(Dowex50×8,300g)用600ml甲醇洗脱。得到11.01g八氢贯叶金丝桃素,向其中加入0.8745g溶于水的LiOH一水合物。蒸发混合物至干燥,得到11.41g锂盐,其光谱特征如下:
1H-NMR(300MHz CDCl3):δ1.93-1.00(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),1.00-0.80(24H,d,CH3-19,CH3-20,CH3-24,CH3-25,CH3-29,CH3-30,CH3-34,CH3-35),1.20,1.06(6H,d,J=6.3Hz,CH3-12,CH3-13),0.91(3H,s,CH3-14)。
13C-NMR(75MHz CDCl3):δ211.4,191.3,184.6,82.7,61.5,51.3,47.7,41.5,40.5,38.2,37.9,37.7,33.9,30.5,29.6,28.7,28.3,28.1,27.1,23.3,23.1,23.0,22.8,22.7,22.4,22.0,14.0。
ESIMS m/z 551[M+H+](100),557[M+Li+](40),1102 [2M+H+](71),
1108[M+Li+](75)。
实施例5-十二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(M.W.=38;0.092mol)。反应进程通过TLC监测(洗脱液:石油醚/EtOAc9∶1)。十分钟后反应完成。
按照实施例5的描述破坏过量的反应物。过滤混合物,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,其光谱特征如下:
EIMS m/z 548[M]+。
实施例6-乙酰八氢贯叶金丝桃素的制备
将300mg乙酰贯叶金丝桃素(M.W.=578;0.52mmol)溶于3ml置于双颈圆底烧瓶中的MeOH中,然后加入催化剂(5%钯/木炭)。反应通过TLC监测(石油醚/EtOAc 95∶5 Rfp=0.43;Rfa=0.52)。四小时后反应完成。通过硅藻土层滤去催化剂,然后蒸除甲醇。
反应产物用30g硅胶通过柱色谱进行纯化,用石油醚/乙酸乙酯9∶1混合物洗脱。用甲醇结晶得到150mg所需化合物,其光谱特征如下:
EIMS m/z 586[M]+。
Claims (9)
2.用于制备用来治疗抑郁和阿尔茨海默病的药物的权利要求1所述的衍生物。
3.权利要求1或2所述的衍生物,其中R2是氢。
4.权利要求1或2所述的衍生物,其中R2是锂,R1是3-甲基-丁-1-基,并且在1-和10-位存在氧代基团。
5.权利要求4所述的衍生物,其中R是甲基。
6.权利要求1或2所述的衍生物,其中R2是乙酰基,R1是3-甲基-丁-1-基,并且在1-和10-位存在氧代基团。
7.权利要求6所述的衍生物,其中R是甲基。
8.一种化合物,选自十二氢贯叶金丝桃素(Ie)、十二氢加贯叶金丝桃素(If)、乙酰八氢贯叶金丝桃素(Ih)和乙酰八氢加贯叶金丝桃素(Ii)。
9.含有权利要求4所述化合物的药物组合物。
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CN103732568A (zh) * | 2011-06-03 | 2014-04-16 | 哈佛大学的校长及成员们 | 贯叶金丝桃素类似物、其合成方法及其用途 |
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---|---|---|---|---|
CA2320091A1 (en) * | 1998-02-13 | 1999-08-19 | Dr. Willmar Schwabe Gmbh & Co. | Stable hyperforin salts, methods of manufacturing them, and their use for the treatment of alzheimer's disease |
WO1999040905A2 (de) | 1998-02-13 | 1999-08-19 | Dr. Willmar Schwabe Gmbh & Co. | Verwendung von hyperforin und hyperforinhaltigen extrakten zur behandlung und prophylaxe von demenzerkrankungen |
IT1301679B1 (it) | 1998-06-10 | 2000-07-07 | Indena Spa | Derivati dell'iperforina, loro uso e formulazioni che licontengono. |
-
2002
- 2002-04-23 IT IT2002MI000872A patent/ITMI20020872A1/it unknown
-
2003
- 2003-04-18 PT PT03718778T patent/PT1497250E/pt unknown
- 2003-04-18 EP EP03718778A patent/EP1497250B1/en not_active Expired - Lifetime
- 2003-04-18 DE DE60322871T patent/DE60322871D1/de not_active Expired - Lifetime
- 2003-04-18 AT AT03718778T patent/ATE404519T1/de active
- 2003-04-18 KR KR1020047016491A patent/KR100944052B1/ko not_active IP Right Cessation
- 2003-04-18 DK DK03718778T patent/DK1497250T3/da active
- 2003-04-18 SI SI200331386T patent/SI1497250T1/sl unknown
- 2003-04-18 RU RU2004131210/04A patent/RU2320636C2/ru not_active IP Right Cessation
- 2003-04-18 JP JP2003587762A patent/JP4315818B2/ja not_active Expired - Fee Related
- 2003-04-18 CA CA2483205A patent/CA2483205C/en not_active Expired - Fee Related
- 2003-04-18 WO PCT/EP2003/004100 patent/WO2003091194A1/en active IP Right Grant
- 2003-04-18 US US10/512,067 patent/US7105705B2/en not_active Ceased
- 2003-04-18 PL PL371347A patent/PL205829B1/pl unknown
- 2003-04-18 US US12/896,158 patent/USRE43280E1/en not_active Expired - Fee Related
- 2003-04-18 CN CNB038089319A patent/CN1290816C/zh not_active Expired - Fee Related
- 2003-04-18 ES ES03718778T patent/ES2311697T3/es not_active Expired - Lifetime
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2004
- 2004-10-21 IL IL164763A patent/IL164763A/en not_active IP Right Cessation
- 2004-10-21 NO NO20044519A patent/NO329176B1/no not_active IP Right Cessation
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102772461A (zh) * | 2011-05-11 | 2012-11-14 | 成都康弘药业集团股份有限公司 | 药物组合物在制备预防或治疗老年性痴呆的药物中的应用 |
CN103732568A (zh) * | 2011-06-03 | 2014-04-16 | 哈佛大学的校长及成员们 | 贯叶金丝桃素类似物、其合成方法及其用途 |
CN105283434A (zh) * | 2013-06-19 | 2016-01-27 | 因德纳有限公司 | 贯叶金丝桃素衍生物及其在阿尔茨海默病中的应用 |
Also Published As
Publication number | Publication date |
---|---|
SI1497250T1 (sl) | 2008-12-31 |
ITMI20020872A0 (it) | 2002-04-23 |
DK1497250T3 (da) | 2008-12-01 |
CA2483205C (en) | 2011-07-05 |
CN1290816C (zh) | 2006-12-20 |
IL164763A (en) | 2010-02-17 |
HK1075654A1 (en) | 2005-12-23 |
JP2005523917A (ja) | 2005-08-11 |
ATE404519T1 (de) | 2008-08-15 |
USRE43280E1 (en) | 2012-03-27 |
RU2320636C2 (ru) | 2008-03-27 |
KR100944052B1 (ko) | 2010-02-24 |
PL371347A1 (en) | 2005-06-13 |
NO329176B1 (no) | 2010-09-06 |
KR20040111519A (ko) | 2004-12-31 |
US7105705B2 (en) | 2006-09-12 |
JP4315818B2 (ja) | 2009-08-19 |
US20050165117A1 (en) | 2005-07-28 |
EP1497250A1 (en) | 2005-01-19 |
WO2003091194A1 (en) | 2003-11-06 |
CA2483205A1 (en) | 2003-11-06 |
RU2004131210A (ru) | 2005-04-10 |
AU2003222828A1 (en) | 2003-11-10 |
NO20044519L (no) | 2004-11-02 |
DE60322871D1 (de) | 2008-09-25 |
PT1497250E (pt) | 2008-11-12 |
ITMI20020872A1 (it) | 2003-10-23 |
PL205829B1 (pl) | 2010-05-31 |
EP1497250B1 (en) | 2008-08-13 |
IL164763A0 (en) | 2005-12-18 |
ES2311697T3 (es) | 2009-02-16 |
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