WO2017124969A1 - 一种二咖啡酰亚精胺环化衍生物及其用途 - Google Patents

一种二咖啡酰亚精胺环化衍生物及其用途 Download PDF

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WO2017124969A1
WO2017124969A1 PCT/CN2017/071116 CN2017071116W WO2017124969A1 WO 2017124969 A1 WO2017124969 A1 WO 2017124969A1 CN 2017071116 W CN2017071116 W CN 2017071116W WO 2017124969 A1 WO2017124969 A1 WO 2017124969A1
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acid
pharmaceutically acceptable
disease
spermidine
volume ratio
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French (fr)
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高昊
姚新生
何蓉蓉
陈国栋
周正群
王传喜
胡丹
范红霞
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暨南大学
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Priority to EP17741000.8A priority Critical patent/EP3406620B1/en
Priority to JP2018555806A priority patent/JP6902757B2/ja
Priority to US16/070,667 priority patent/US10457702B2/en
Publication of WO2017124969A1 publication Critical patent/WO2017124969A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C07H1/08—Separation; Purification from natural products

Definitions

  • the invention belongs to the field of natural medicine, and more particularly relates to a bis-caffeospermine cyclized derivative and its use for preventing and treating neurodegenerative diseases.
  • Neurodegenerative diseases are a type of chronic, progressive neurological disease characterized by delayed regional neuronal degeneration and cell loss in specific areas, due to loss of neurons or their myelin, and over time. Deterioration and dysfunction, neurodegenerative diseases are generally divided into two categories according to their phenotype: one is affecting exercise, such as cerebellar ataxia, Parkinson's disease, etc., one is affecting memory and its related Dementia, the current treatment of neurodegenerative diseases is still less.
  • Alzheimer's disease is one of the neurodegenerative diseases. It is a multi-pathogenic heterogeneous disease characterized by progressive cognitive dysfunction and memory impairment.
  • the central nervous system degenerative disease syndrome is characterized by intelligence (including memory). Decline in learning ability, direction recognition ability, language ability, comprehension and judgment.
  • the disease is caused by a variety of factors (including biological and psychosocial factors), and there are more than 30 possible pathogenic factors and hypotheses, such as family history, head trauma, thyroid disease, and viral infection.
  • AD Alzheimer's disease
  • VA Vascular dementia
  • DLB Dementia with Lewybodies
  • FTD Frontotemporal dementia
  • Alzheimer's disease accounts for 50 to 70% of all dementia patients and is the most common type of Alzheimer's disease.
  • senile dementia is currently divided into: (1) symptomatic treatment of psychopathological conditions, including anti-anxiety drugs such as alprazolam, oxazepam, triazolam, antidepressants, Such as Baiyoujie, paroxetine, sertraline, etc., antipsychotic drugs, such as risperidone, olanzapine; (2) benefits Intelligence or improve cognitive function, mainly based on acetylcholinesterase inhibitors, N-methyl-D-aspartate receptor antagonist (NMDA), estrogen drugs and drugs that promote brain metabolism. These drugs can improve the symptoms of dementia in a certain degree, but can not prevent the deterioration of the disease and reverse the disease.
  • anti-anxiety drugs such as alprazolam, oxazepam, triazolam, antidepressants, Such as Baiyoujie, paroxetine, sertraline, etc.
  • antipsychotic drugs such as risperidone, olanzapine
  • Drosophila is one of the most well-known model organisms. Drosophila has advantages that other model animals cannot match. For example, the individual space is very small (usually one can be cultured in one reagent bottle). Drosophila), low cost of breeding, easy cultivation, rapid reproduction and strong reproductive capacity (high screening throughput), low sample consumption (5-50mg), short life cycle (about 50 days, short activity test cycle), Age-related neuronal degeneration is evident and is an ideal model for neurodegenerative disease research and drug screening for Alzheimer's disease.
  • the second caffeoyl spermine derivative is a rare class of plant constituents and is currently less studied.
  • the second caffeoyl spermine cyclic derivative has not been reported before.
  • the invention finds and isolates a class of bis-caffeospermine cyclized derivatives from scorpion, and proves that it has the activity of preventing and treating neurodegenerative diseases, especially senile dementia, by Drosophila model.
  • the optional substitution is optionally substituted with one or more of the following glycosyl groups: glucosyl, glucuronosyl, mannosyl, galactosyl, algose, fructosyl, sorbityl, furan
  • Various monosaccharide groups such as glycosyl, rhamnosyl, chicken glucosyl, arabinose, lysosyl, xylosyl, ribosyl, and various disaccharide groups and polysaccharides formed from the above monosaccharides base.
  • the compound of formula (I) is preferably a compound having the formula:
  • the pharmaceutically acceptable salt of the bis-caffeospermine cyclized derivative of the formula (I) is a bis-caffeoyl spermamine cyclized derivative of the formula (I), and hydrochloric acid or hydrobromic acid.
  • sulfuric acid sulfuric acid, nitric acid and other inorganic acids or trifluoroacetic acid, acetic acid, propionic acid, malonic acid, butyric acid, lactic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, maleic acid, benzoic acid, a salt formed from an organic acid such as succinic acid, picric acid, tartaric acid, citric acid or fumaric acid.
  • Another object of the present invention is to provide a use of a bis-caffeoyl spermine cyclized derivative and a pharmaceutically acceptable salt thereof for preventing or treating a neurodegenerative disease, including but not limited to the elderly
  • a neurodegenerative disease including but not limited to the elderly
  • dementia Parkinson's disease, multiple sclerosis and Huntington's disease; preferably senile dementia, more preferably the senile dementia is Alzheimer's disease, vascular dementia, Lewy body dementia Ill and dementia.
  • the above two caffeoyl spermidine cyclized derivatives are fruits from Lycium barbarum Separated from the scorpion.
  • the scorpion was collected from Zhongning County, Ningxia Hui Autonomous Region, China.
  • the sample was stored in the Institute of Traditional Chinese Medicine and Natural Medicine of Jinan University School of Pharmacy (No.: LYBA-2013-NX-ZN, Venue: School of Pharmacy, Jinan University, 601 West Huangpu Road, Guangzhou, China, 510632).
  • the preparation method of the above-mentioned two caffeoyl spermidine cyclized derivatives and pharmaceutically acceptable salts thereof specifically comprises the following steps:
  • fraction F2 obtained by eluting ethanol-water in a volume ratio of 30:70 is subjected to atmospheric pressure silica gel column chromatography, and the volume ratio is 95:5:0, 90:10:1, 85:15:1.5. , 80:20:2, 70:30:3, 60:40:4, 50:50:5, 40:60:6 and 0:100:0 chloroform-methanol-water elution, get F2.1, 10 sub-fractions of F2.2, F2.3, F2.4, F2.5, F2.6, F2.7, F2.8, F2.9 and F2.10;
  • Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating a neurodegenerative disease, which comprises, as an active ingredient, a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof Accessories.
  • Preferred compounds of formula (I) are compounds of formula (II) or formula (III) or a pharmaceutically acceptable salt thereof.
  • Pharmaceutically acceptable excipients include, but are not limited to, diluents, lubricants, binders, disintegrants, stabilizers, solvents, and the like.
  • the diluent of the present invention includes, but is not limited to, starch, microcrystalline cellulose, sucrose, dextrin, lactose, powdered sugar, glucose, and the like;
  • the lubricant includes, but is not limited to, magnesium stearate, stearic acid, sodium chloride, sodium oleate, sodium lauryl sulfate, poloxamer, and the like;
  • the binder includes, but is not limited to, water, ethanol, starch syrup, syrup, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, sodium alginate, polyvinylpyrrolidone, and the like;
  • the disintegrant includes, but is not limited to, a starch effervescent mixture, namely sodium hydrogencarbonate and citric acid, tartaric acid, low-substituted hydroxypropyl cellulose, and the like;
  • the stabilizer includes, but is not limited to, polysaccharides such as acacia gum, agar, alginic acid, cellulose ether, and carboxymethyl chitosan;
  • the solvent includes, but is not limited to, water, a balanced salt solution, and the like.
  • the pharmaceutical composition of the present invention may be administered orally or by injection, and the corresponding dosage forms of the pharmaceutical composition include, but are not limited to, solid oral preparations, liquid oral preparations, injections, and the like;
  • the solid oral preparation comprises a tablet, a granule, a capsule, a pill, a powder, etc.
  • the liquid oral preparation includes an oral liquid, an emulsion, etc.
  • the injection includes: a small water injection, a large infusion, a freeze-dried powder, and the like;
  • More preferred such tablets include dispersible tablets, enteric coated tablets and the like.
  • Each of the preparations of the present invention can be prepared according to a conventional process in the field of medicine.
  • the amount of the active ingredient (i.e., the compound of the present invention) contained in the pharmaceutical preparation of the present invention can be specifically determined depending on the condition of the patient and the condition diagnosed by the doctor, and the dose or concentration of the active compound is adjusted within a wide range, and the active compound is The content ranges from 1% to 90% by weight of the pharmaceutical composition.
  • the present invention has the following advantages and beneficial effects: the dicaffeyl spermidine cyclized derivative represented by the present invention is a novel bis-caffeospermine cyclized derivative, and the present invention is biologically active.
  • sexual test experiments show that the bis-caffeoyl spermine cyclized derivative of the present invention has anti-dementia activity and antioxidant activity, and its activity is even better than that of the positive control drug or the positive control drug, which can significantly improve the senile dementia patients.
  • Cognitive function suitable for the prevention and treatment of senile dementia and neurodegenerative diseases.
  • the mass spectrometer was an LCQ Advantage MAX mass spectrometer manufactured by Finnigan, Germany.
  • the superconducting nuclear magnetic resonance instrument is Bruker AV-600.
  • Column chromatography HP-20 macroporous resin is a product of Mitsubishi Corporation of Japan.
  • Silica gel GF254 and column chromatography silica gel (200-300 mesh) for thin layer chromatography are products of Qingdao Ocean Chemical Plant.
  • the reverse phase ODS packing (50 ⁇ m) is a product of YMC Corporation of Japan.
  • the medium and low pressure liquid chromatograph is a product of Shanghai Lisui Electronic Technology Co., Ltd.
  • the preparative column used for liquid phase separation was Cosmosil Packed C 18 column (20.0 x 250 mm, 5 ⁇ m).
  • the liquid chromatography is chromatographically pure with methanol, the water is double distilled water, and the other reagents are of analytical grade.
  • fraction F2 eluted by ethanol-water having a volume ratio of 30:70 was taken, and 70.0 g of F2 was taken for atmospheric pressure silica gel column chromatography, and the volume ratio was 95:5:0, 90:10:1, 85 in order. :15:1.5, 80:20:2, 70:30:3, 60:40:4, 50:50:5, 40:60:6 and 0:100:0 chloroform-methanol-water elution F2.1, F2.2, F2.3, F2.4, F2.5, F2.6, F2.7, F2.8, F2.9 and F2.10 have 10 sub-fractions.
  • the subfraction F2.9.6 (105.5 mg) obtained by eluting methanol-water-trifluoroacetic acid at a volume ratio of 15:85:0.1 was prepared by reverse phase preparative HPLC using methanol-water-three at a flow rate of 8 mL/min.
  • the fluoroacetic acid (20:80:0.1, v/v/v) was eluted to give the compound of the formula (II) (t R : 24.5 min, 12.3 mg, purity 95%) and the compound of the formula (III) (t R : 29.2 Min, 5.1 mg, purity 95%) of trifluoroacetate.
  • a trifluoroacetate salt of a compound of formula (II) a green oily liquid; -23.8 (c 0.50, MeOH); UV (MeOH) ⁇ max (log ⁇ ) 204 (4.33), 294 (3.95), 320 (3.92) nm; IR (KBr) v max 3375, 2933, 2873, 1679, 1508, 1432, 1287, 1200, 1132, 1077, 801, 722 cm -1 ; ESIMS (positive) m/z 632.6; ESIMS (negative) m/z 630.4; HRESIMS (positive) m/z 632.2820 (calcd. for C 31 H 42 N 3 O 11 , 632.2819), the molecular formula of the compound (II) was determined to be C 31 H 41 N 3 O 11 ; 13 C and 1 H NMR are shown in Table 1.
  • a trifluoroacetate salt of a compound of formula (III) a green oily liquid; -25.0 (c 0.50, MeOH); UV (MeOH) ⁇ max (log ⁇ ) 204 (4.29), 293 (3.85), 319 (3.82) nm; IR (KBr) v max 3347, 2935, 2874, 1678, 1508, 1432, 1282, 1199, 1132, 1073, 801, 722 cm -1 ; ESIMS (positive) m/z 794.7; ESIMS (negative) m/z 792.6; HRESIMS (positive) m/z 794.3362 (calcd. for C 37 H 52 N 3 O 16 , 794.3348), the molecular formula of the compound (III) was determined to be C 37 H 51 N 3 O 16 ; 13 C and 1 H NMR are shown in Table 1.
  • Example 2 Test method for learning and memory activity of Drosophila melanogaster by cyclized derivative of caffeoyl spermidine
  • w 1118 was used as the control background of the experimental fruit fly, abbreviated as "2U”.
  • the fruit fly that successfully transferred to the pathogenic A ⁇ 42 protein was (UAS-A ⁇ 42 ; abbreviated as “H29.3”).
  • the strain, Drosophila obtained a Drosophila strain carrying elav-GAL4 c155 (P35) and A ⁇ 42 by crossing with the whole brain expressing the Gal4 promoter Drosophila.
  • All the parents of the tested fruit flies were raised and propagated in a fly house at a constant temperature of 24 ° C and a constant humidity of 42% RH (Relative humidity).
  • RH relative humidity
  • the control fruit fly and the disease group Drosophila and the Drosophila group to be fed were subjected to carbon dioxide anesthesia, and the correct traits of the fruit flies were selected in the glass tube containing the food.
  • all tested fruit flies were housed in a 28 ° C constant temperature and 42% constant humidity incubator to ensure the efficiency of Drosophila medication.
  • the daily fruit fly was administered for 4 hours, and the second day from the picking of the fruit fly, the drug was administered until the 8th day.
  • the drug was administered on the second day of the fly and fed to the fruit fly on the day of preparation. 100% DMSO was dissolved to a concentration of 10 mM. When preparing the working solution, the 10 mM mother liquor was diluted to 100 ⁇ M with 4% sucrose. In addition, the control fruit flies were fed syrup containing 1% DMSO. For each Performance Index, two tube fly groups are required, each containing approximately 100 fruit flies.
  • the same genetic background healthy fly (2U*H29.3), the untreated dementia disease fly (P35*H29.3), and the test substance of the Alzheimer's disease flies Short-term memory deficit tests were performed to calculate their total learning and memory behavior index (PI).
  • Genotype/drug PI (100 ⁇ M) 2U*H29.3 50.2 ⁇ 1.2
  • 2U*H29.3 represents healthy fruit flies; P35*H29.3 represents diseased fruit flies; and memantine represents a positive control drug treatment group.
  • the drug treatment group was administered at a concentration of 100 ⁇ M.
  • Group and 2U * H29.3, # P ⁇ 0.001 ; and P35 * H29.3 group, ** P ⁇ 0.01, *** P ⁇ 0.001; n 6, One-way analysis of variance (ANOVA).
  • the experimental results in Table 2 indicate that the compound of formula II and formula III of the present invention can significantly improve the learning and memory function of Drosophila melanogaster, wherein the compound of formula III is superior to the positive control drug in improving the learning and memory function of Drosophila melanogaster.
  • the inventive dicaffeyl spermidine cyclized derivative has better effects in preventing and treating senile dementia.
  • the antioxidant activity of the compounds was evaluated using the oxygen radical absorbance capacity (ORAC) experiment.
  • ORAC oxygen radical absorbance capacity
  • the specific experimental procedure is as follows. 0.248 g of AAPH (2,2'-azobisisobutylphosphonium dihydrochloride) was added to a 50 mL phosphate buffer system to prepare a 18.3 mM AAPH stock solution. 20 ⁇ L of phosphate buffer, 20 ⁇ L of the sample to be tested or the standard substance Trolox solution (concentration of 6.25 ⁇ M) and 20 ⁇ L of the fluorescent substance disodium fluorescein (FL, concentration 630 nM) were sequentially added to the wells of a 96-well plate.
  • AUC sample refers to the integrated area under the fluorescence decay curve of the test sample
  • AUC trolox refers to the integrated area under the fluorescence decay curve of the standard substance Trolox
  • AUC blank refers to the fluorescence decay when the test sample or the standard substance Trolox is not added.
  • the integrated area under the curve The specific results are shown in Table 3:
  • EGCG epigallocatechin gallate

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Abstract

提供一种二咖啡酰亚精胺环化衍生物和用途，生物活性实验显示了该二咖啡酰亚精胺环化衍生物具有抗老年痴呆活性和抗氧化活性，且其活性甚至还优于阳性对照药物，可用于老年痴呆等神经退行性疾病的预防及治疗。并且提供从枸杞子中制备该二咖啡酰亚精胺环化衍生物的方法。

Description

一种二咖啡酰亚精胺环化衍生物及其用途 技术领域
本发明属于天然药物领域，更具体的涉及一种二咖啡酰亚精胺环化衍生物及其预防和治疗神经退行性疾病的用途。
背景技术
神经退行性疾病是一类慢性、进行性神经疾病，以特定区域的迟发性神经细胞退行性病变、细胞丢失为共同特征，是由于神经元或其髓鞘的丧失导致的，并随着时间的推移而恶化，导致功能障碍，神经退行性疾病按照其表型一般分为两类：一类是影响运动的，如小脑性共济失调，帕金森病等，一类是影响记忆及其相关的痴呆症，目前神经退行性疾病的治疗药物仍然较少。
老年痴呆是神经退行性疾病中的一种，为多病机异质性疾病，以进行性认知功能障碍和记忆损害为特征的中枢神经系统退行性疾病综合征，其表现为智力(包括记忆力、学习能力、方向辨认能力、语言能力、理解能力以及判断力)上的减退。该病在多种因素(包括生物和社会心理因素)作用下发病，可能的发病因素和假说多达30余种，如家族史、头部外伤、甲状腺病、病毒感染等。老年痴呆一般常见的有阿尔茨海默病(Alzheimer’s disease，AD)、血管性痴呆病(Vasculardementia，VA)、路易体痴呆病(Dementia with Lewybodies，DLB)以及额颞痴呆(Frontotemporal dementia，FTD)等。在所有的痴呆患者中，阿尔茨海默病患者占50～70％，是老年痴呆中最常见的类型。
对于老年痴呆的治疗目前主要分为：(1)控制伴发精神病理状态的对症治疗，用药主要包括抗焦虑药，如阿普唑仑、奥沙西泮、三唑仑等，抗抑郁药，如百优解、帕罗西汀、舍曲林等，抗精神病药，如利培酮、奥氮平等；(2)益 智或改善认知功能，用药主要以乙酰胆碱酯酶抑制剂、N-甲基-D-天门冬氨酸受体拮抗剂(NMDA)、雌激素类药物和促进脑代谢药物为主。以上这些药物能在一定程度上改善患者的痴呆症状，但不能从根本上阻止病情的恶化、逆转病情，因此寻找抗老年痴呆症药物的研制已经引起全世界的重视，并已建立许多相关的生物活性筛选和评价体系。在现有众多整体动物模型中，果蝇是人们最为熟知的模式生物之一，果蝇有着其它模式动物不能比拟的优势，如：个体空间占位极小(一般一个试剂瓶中可以培养上千只果蝇)、饲养成本低、易培养、繁殖速度快且繁殖能力强(筛选通量高)、样品消耗量少(5-50mg)、寿命周期短(约50天，活性测试周期短)、与年龄相关的神经元退化明显，是老年痴呆症等神经退行性疾病研究和药物筛选的理想模型。
二咖啡酰亚精胺衍生物是一类稀少的植物成分，目前研究较少。二咖啡酰亚精胺环状衍生物以前未见任何报道。本发明即为从枸杞子中发现并分离了一类二咖啡酰亚精胺环化衍生物，经果蝇模型证明了其具有预防及治疗神经退行性疾病，尤其是老年痴呆的活性。
发明内容
本发明的一个目的是提供一类二咖啡酰亚精胺环化衍生物或其药学上可接受的盐，其结构式如下：
Figure PCTCN2017071116-appb-000001
其中：
R1、R2和R3为羟基、甲氧基或任选取代的糖基，R4和R5同为-CH＝或-CH2-，R6和R7同为-CH＝或-CH2-。所述任选取代为任选被下述糖基中的一个或多个取代：葡萄糖基、葡萄糖醛酸基、甘露糖基、半乳糖基、阿洛糖基、果糖基、山梨糖基、呋喃糖基、鼠李糖基、鸡纳糖基、阿拉伯糖基、来苏糖基、木糖基、核糖基等各种单糖基，以及由上述单糖所形成的各种二糖基及多糖基。
在本发明进一步地实施方案中，所述式(I)化合物优选为具有以下结构式的化合物：
Figure PCTCN2017071116-appb-000002
在本发明中，式(I)的二咖啡酰亚精胺环化衍生物的药学上可接受的盐，为式(I)的二咖啡酰亚精胺环化衍生物与盐酸、氢溴酸、硫酸、硝酸等无机酸或三氟乙酸、乙酸、丙酸、丙二酸、丁酸、乳酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、马来酸，苯甲酸、琥珀酸、苦味酸、酒石酸、柠檬酸、富马酸等有机酸形成的盐。
本发明的另一个目的是提供二咖啡酰亚精胺环化衍生物及其药学上可接受的盐在预防或治疗神经退行性疾病药物中的应用，所述神经退行性疾病包括但不限于老年痴呆、帕金森氏症、多发性硬化症和亨廷顿氏病中一种或几种；优选的为老年痴呆，更优选的所述老年痴呆为阿尔茨海默病、血管性痴呆病、路易体痴呆病以及额颞痴呆。
上述二咖啡酰亚精胺环化衍生物是从宁夏枸杞(Lycium barbarum)的果实 枸杞子中分离得到。枸杞子采自中国宁夏回族自治区中宁县。样品保存于暨南大学药学院中药及天然药物研究所(编号：LYBA-2013-NX-ZN，地点：中国广州市黄埔大道西601号暨南大学药学院，510632)。
上述二咖啡酰亚精胺环化衍生物及其药学上可接受的盐的制备方法具体包括以下步骤：
(1)枸杞子用体积比为60:40的乙醇-水加热回流提取3次，每次2小时，过滤后，滤液经减压浓缩得浓缩液；
(2)浓缩液经大孔树脂柱层析，依次用体积比为0:100、30:70、50:50、70:30和95:5的乙醇-水洗脱，得到5个馏分F1、F2、F3、F4、F5；
(3)将体积比为30:70的乙醇-水洗脱得到的馏分F2进行常压硅胶柱层析，依次用体积比为95:5:0、90:10:1、85:15:1.5、80:20:2、70:30:3、60:40:4、50:50:5、40:60:6和0:100:0的氯仿-甲醇-水洗脱，得到F2.1、F2.2、F2.3、F2.4、F2.5、F2.6、F2.7、F2.8、F2.9和F2.10共10个子馏分；
(4)将体积比40:60:6氯仿-甲醇-水洗脱得到的子馏分F2.9，过中低压液相ODS柱层析，依次用体积比为5:95:0.1、10:90:0.1、15:85:0.1、20:80:0.1、25:75:0.1、30:70:0.1、40:60:0.1和100:0:0的甲醇-水-三氟乙酸洗脱，得到F2.9.1、F2.9.2、F2.9.3、F2.9.4、F2.9.5、F2.9.6、F2.9.7、F2.9.8和F2.9.9共9个子馏分；
(5)将体积比为15:85:0.1的甲醇-水-三氟乙酸洗脱得到的子馏分F2.9.6，经过反相制备级HPLC制备，使用流速为8mL/min的体积比为20:80:0.1的甲醇-水-三氟乙酸进行洗脱，即得本发明所述的二咖啡酰亚精胺环化衍生物。
本发明的再一个目的是提供一种预防或治疗神经退行性疾病的药物组合物，所述药物组合物包括作为活性成分的式(I)化合物或其药学上可接受的盐和药学上可接受的辅料。
优选的式(I)化合物为式(II)或式(III)化合物或其药学上可接受的盐， 药学上可接受的辅料包括但不限于稀释剂、润滑剂、粘合剂、崩解剂、稳定剂、溶剂等。
本发明所述稀释剂包括但不限于淀粉、微晶纤维素、蔗糖、糊精、乳糖、糖粉、葡萄糖等；
所述润滑剂包括但不限于硬脂酸镁、硬脂酸、氯化钠、油酸钠、月桂醇硫酸钠、泊洛沙母等；
所述粘合剂包括但不限于水、乙醇、淀粉浆、糖浆、羟丙基甲基纤维素、羧甲基纤维素钠、海藻酸钠、聚乙烯吡咯烷酮等；
所述崩解剂包括但不限于淀粉泡腾混合物即碳酸氢钠和枸橼酸、酒石酸、低取代羟丙基纤维素等；
所述稳定剂包括但不限于多糖如金合欢胶、琼脂、藻酸、纤维素醚和羧甲基甲壳酯等；
所述溶剂包括但不限于水、平衡的盐溶液等。
本发明的药物组合物可以口服给药或注射给药，相应的所述药物组合物的剂型包括但不限于固体口服制剂、液体口服制剂、注射剂等；
优选的所述固体口服制剂包括片剂、颗粒剂、胶囊剂、滴丸剂、散剂等，液体口服制剂包括口服液、乳剂等；注射剂有：小水针剂、大输液、冻干粉针等；
更优选的所述片剂包括分散片、肠溶片等。
本发明的各制剂可以根据药物领域的常规工艺制备而成。
本发明药物制剂中含有的活性成份(即本发明化合物)的量可以根据患者的病情、医生诊断的情况特定的加以应用，活性化合物的剂量或浓度在一个较宽的范围内调节，活性化合物的含量范围为药物组合物的1％～90％(重量)。
有益效果：
本发明相对于现有技术，具有以下的优点和有益效果：本发明所示的二咖啡酰亚精胺环化衍生物是新的二咖啡酰亚精胺环化衍生物，本发明通过生物活 性测试实验表明本发明的二咖啡酰亚精胺环化衍生物具有抗老年痴呆活性和抗氧化活性，其活性甚至还优于阳性对照药物或与阳性对照药物相当，可显著改善老年痴呆患者的认知功能，适合用于老年痴呆及神经退行性疾病的预防及治疗。
具体实施方式
以下实施例旨在说明本发明而不是本发明进一步的限定，本发明可以按发明内容所述的任一方式实施。
下列实施例中，质谱仪为德国Finnigan公司生产的LCQAdvantage MAX质谱仪。超导核磁共振仪为BrukerAV-600。柱色谱HP-20大孔树脂为日本Mitsubishi公司产品。薄层色谱用硅胶GF254和柱色谱硅胶(200-300目)均为青岛海洋化工厂产品。反相ODS填料(50μm)为日本YMC公司产品。中低压液相色谱仪为上海利穗电子科技有限公司产品。液相分离所使用制备级色谱柱为Cosmosil Packed C18 column(20.0×250mm,5μm)。液相色谱用甲醇为色谱纯，水为双重蒸馏水，其他试剂均为分析纯。
实施例1 式(II)和式(III)化合物的制备
19.5kg枸杞子用100L乙醇-水(60:40,v/v)加热回流提取3次，每次2小时。过滤后，滤液经减压浓缩得浓缩液。浓缩液经大孔树脂柱层析，依次用体积比为0:100、30:70、50:50、70:30和95:5的乙醇-水洗脱，得到5个馏分F1、F2、F3、F4、F5。接下来对体积比为30:70的乙醇-水洗脱得到的馏分F2，取70.0克F2进行常压硅胶柱层析，依次用体积比为95:5:0、90:10:1、85:15:1.5、80:20:2、70:30:3、60:40:4、50:50:5、40:60:6和0:100:0的氯仿-甲醇-水洗脱，得到F2.1、F2.2、F2.3、F2.4、F2.5、F2.6、F2.7、F2.8、F2.9和F2.10共10个子馏分。然后将体积比40:60:6氯仿-甲醇-水洗脱得到的子馏分F2.9(3.8g)过中低压液相 ODS柱层析，依次用体积比为5:95:0.1、10:90:0.1、15:85:0.1、20:80:0.1、25:75:0.1、30:70:0.1、40:60:0.1和100:0:0的甲醇-水-三氟乙酸洗脱，得到F2.9.1、F2.9.2、F2.9.3、F2.9.4、F2.9.5、F2.9.6、F2.9.7、F2.9.8和F2.9.9共9个子馏分。将体积比为15:85:0.1的甲醇-水-三氟乙酸洗脱得到的子馏分F2.9.6(105.5mg)经过反相制备级HPLC制备，使用流速为8mL/min的甲醇-水-三氟乙酸(20:80:0.1,v/v/v)进行洗脱，得到式(II)化合物(tR:24.5min,12.3mg，纯度95％)和式(III)化合物(tR:29.2min,5.1mg，纯度95％)的三氟乙酸盐。
理化常数如下：
式(II)化合物的三氟乙酸盐：绿色油状液体；
Figure PCTCN2017071116-appb-000003
-23.8(c 0.50,MeOH)；UV(MeOH)λmax(logε)204(4.33),294(3.95),320(3.92)nm；IR(KBr)vmax 3375,2933,2873,1679,1508,1432,1287,1200,1132,1077,801,722cm-1；ESIMS(positive)m/z 632.6；ESIMS(negative)m/z 630.4；HRESIMS(positive)m/z 632.2820(calcd.for C31H42N3O11,632.2819)，确定该化合物(II)的分子式为C31H41N3O11；13C和1H NMR见表1。
式(III)化合物的三氟乙酸盐：绿色油状液体；
Figure PCTCN2017071116-appb-000004
-25.0(c 0.50,MeOH)；UV(MeOH)λmax(logε)204(4.29),293(3.85),319(3.82)nm；IR(KBr)vmax 3347,2935,2874,1678,1508,1432,1282,1199,1132,1073,801,722cm-1；ESIMS(positive)m/z 794.7；ESIMS(negative)m/z 792.6；HRESIMS(positive)m/z 794.3362(calcd.for C37H52N3O16,794.3348)，确定该化合物(III)的分子式为C37H51N3O16；13C和1H NMR见表1。
表1 式(II)和式(III)化合物的13CNMR及1H NMR数据和归属
Figure PCTCN2017071116-appb-000005
Figure PCTCN2017071116-appb-000006
aδ in ppm,J in Hz,1H NMR(600MHz),13C NMR(150MHz),in DMSO-d6.
*Assignment may be interchanged.
实施例2 二咖啡酰亚精胺环化衍生物提高老年痴呆果蝇学习记忆活性测试方法
(1)老年痴呆果蝇的培育
w1118(isoCJ1)作为实验的对照组背景果蝇，简记为“2U”。成功转入致病性Aβ42蛋白的果蝇为(UAS-Aβ42；简记为“H29.3”)。该品系果蝇通过与全脑表达Gal4启动子果蝇进行杂交，获得携带elav-GAL4c155(P35)与Aβ42的果蝇品系。
(2)老年痴呆果蝇的给药
试验设置健康果蝇无药对照、疾病果蝇无药对照和疾病果蝇给药的三种组别。
所有测试果蝇的亲本均在恒温24℃，恒湿42％RH(Relative humidity)的蝇房饲养和繁殖。果蝇羽化后的第一天将对照组果蝇及疾病组果蝇和待喂药组果蝇通过二氧化碳麻醉之后，挑选正确性状的果蝇在含有食物的玻璃管中。在给药阶段，所有测试果蝇在28℃恒温和42％恒湿的保温箱内饲养，以保证果蝇吃药的效率。每日果蝇喂药4小时，从挑出果蝇的第二天一直喂药到第8天。
所喂药物在挑蝇第二天配制并与配制当天给果蝇喂药。100％DMSO溶解使其浓度为10mM。在配制工作液时，利用含有4％的蔗糖将10mM母液稀释至100μM。另外，对照组果蝇喂含有1％DMSO的糖水。对于每个行为指数(Performance Index)，需要有2管果蝇组，每管中含有约100只果蝇。
实验在恒温25℃、恒湿70％，避光的行为房中进行，方法可见参考文献[1-3]。
1)在训练阶段，将100只左右的果蝇装入安置有铜网交叉电极的训练管，先后通入辛醇(OCT)和甲基环己醇(MCH)两种气味各60s，中间间隔45s的新鲜空气。在通入第一种气味(CS+)的同时给予果蝇60V的脉冲电击刺激(US，脉 冲时长1.5s，间隔3.5s)。通入第二种气味(CS-)时不给予电击。如此完成一个训练周期。
2)在瞬时记忆(学习)能力测试中，完成一个训练周期的果蝇被立即转移到T-Maze的选择点，同时从相对的两个方向通入CS+和CS-。经过2min的选择后两侧的果蝇被分别收集，麻醉或处死后进行计数。行为指数(Performance index，PI)的计算公式如下：PI＝[(CS-)-(CS+)]/[(CS-)+(CS+)]×100。
分别使用OCT和MCH作为CS+进行训练和测试，得到的两个PI的平均值作为一次实验的PI使用。PI＝0表示测试中果蝇对于两种气味的选择为50:50，即没有形成记忆；PI＝100表示测试中果蝇全部逃避伴随电击的气味，即完美记忆。进行活性测试时，同时进行不喂药的同遗传背景健康蝇(2U*H29.3)、不喂药的老年痴呆疾病蝇(P35*H29.3)、喂测试药的老年痴呆疾病蝇的嗅觉短期记忆缺陷测试，分别计算它们的总学习记忆行为指数(PI)。将喂测试药的老年痴呆疾病蝇学习记忆行为指数与不喂药的同遗传背景健康蝇(2U*H29.3)行为指数、不喂药的老年痴呆疾病蝇(P35*H29.3)行为指数相比较，评价测试药物抗老年痴呆的作用。喂食测试物的老年痴呆疾病蝇学习记忆行为指数相对越高则说明测试物抗老年痴呆作用越强。采用One-way analysis of variance(ANOVA)比较，喂食测试物的老年痴呆疾病蝇学习记忆行为指数和不喂药(仅给不含药样品的溶剂)的老年痴呆疾病蝇学习记忆行为指数，P<0.05为有明显差别，P<0.01为有显著差别，P<0.001为有极显著差别。
数据分析和图形展示通过GraphPad Prism 5.01进行处理；具体结果见表2。
表2 二咖啡酰亚精胺环化衍生物提高老年痴呆果蝇学习记忆活性结果
Genotype/drug PI(100μM)
2U*H29.3 50.2±1.2
P35*H29.3 23.3±3.4#
美金刚 44.2±2.1***
式II 37.1±2.2**
式III 45.9±1.9***
2U*H29.3代表健康果蝇；P35*H29.3代表疾病果蝇；美金刚代表阳性对照药治疗组。药物治疗组给药浓度为100μM。与2U*H29.3组比较，#P<0.001；与P35*H29.3组比较，**P<0.01，***P<0.001；n＝6，One-way analysis of variance(ANOVA)。
表2的实验结果表明本发明的式II、式III化合物可明显提高老年痴呆果蝇的学习记忆功能，其中式III化合物对于老年痴呆果蝇学习记忆功能的提高优于阳性对照药物，表明了本发明的二咖啡酰亚精胺环化衍生物具有更好的预防和治疗老年痴呆的效果。
实施例3 二咖啡酰亚精胺环化衍生物抗氧化活性结果
化合物的抗氧化活性是采用oxygen radical absorbance capacity(ORAC)实验来评价的，具体实验流程如下。将0.248g AAPH(2,2'-偶氮二异丁基脒二盐酸盐)加入到50mL磷酸缓冲液体系中配置成18.3mM的AAPH储备溶液。依次将20μL磷酸缓冲液、20μL待检测样品或标准物质Trolox溶液(浓度为6.25μM)和20μL荧光物质disodium fluorescein(FL，浓度为630nM)加入到96孔板板孔中。接下来，迅速将140μL AAPH(浓度为18.3mM)加入到96孔板板孔中，并即刻将96孔板置于瑞士Tecan公司生产的GENios Luciferase-based微孔板读数仪中，设定激发波长为485nm，发射波长为527nm，每2分钟测定其荧光强度，共记录100min。
活性物质的抗氧化能力如下计算公式：Relative ORAC value＝(AUCsample–AUCblank)/(AUCtrolox–AUCblank)。其中，AUCsample指的是测试样品的荧光衰退曲 线下积分面积，AUCtrolox指的是标准物质Trolox的荧光衰退曲线下积分面积，AUCblank指的是未加入测试样品或标准物质Trolox时的荧光衰退曲线下积分面积。具体结果如表3：
表3 二咖啡酰亚精胺环化衍生物抗氧化活性结果
Figure PCTCN2017071116-appb-000007
EGCG(epigallocatechin gallate)代表阳性对照药治疗组。
表3的实验结果显示了本发明的二咖啡酰亚精胺环化衍生物具有明显的抗氧化活性，其中式II化合物的抗氧化效果与阳性对照药相当。
本发明内容仅仅举例说明了要求保护的一些具体实施方案，其中一个或更多个技术方案中所记载的技术特征可以与任意的一个或多个技术方案相组合，这些经组合而得到的技术方案也在本申请保护范围内，就像这些经组合而得到的技术方案已经在本发明公开内容中具体记载一样。
参考文献：
[1]Tully T,et al.J.Comp.Physiol.A 1985,157,263-277.
[2]Tully T,et al.Cell 1994,79,35-47.
[3]Yin JC,et al.Cell 1994,79,49-58.

Claims (10)

  1. 一种二咖啡酰亚精胺环化衍生物或其药学上可接受的盐，其特征在于具有如下结构：
    Figure PCTCN2017071116-appb-100001
    其中：
    R1、R2和R3为羟基、甲氧基或任选取代的糖基，R4和R5同为-CH＝或-CH2-，R6和R7同为-CH＝或-CH2-；
    所述任选取代为任选被下述糖基中的一个或多个单糖基以及由下述单糖所形成的二糖基或多糖基取代，所述单糖选自：葡萄糖基、葡萄糖醛酸基、甘露糖基、半乳糖基、阿洛糖基、果糖基、山梨糖基、呋喃糖基、鼠李糖基、鸡纳糖基、阿拉伯糖基、来苏糖基、木糖基、核糖基。
  2. 根据权利要求1所述的二咖啡酰亚精胺环化衍生物或其药学上可接受的盐，其特征在于所述药学上可接受的盐为式(I)的二咖啡酰亚精胺环化衍生物与无机酸或有机酸形成的盐。
  3. 根据权利要求2所述的二咖啡酰亚精胺环化衍生物或其药学上可接受的盐，其特征在于所述无机酸为盐酸、氢溴酸、硫酸或硝酸，所述有机酸为三氟乙酸、乙酸、丙酸、丙二酸、丁酸、乳酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、马来酸，苯甲酸、琥珀酸、苦味酸、酒石酸、柠檬酸或富马酸。
  4. 根据权利要求1-3任一项所述的二咖啡酰亚精胺环化衍生物或其药学上可接受的盐，其特征在于所述式(I)化合物为
    Figure PCTCN2017071116-appb-100002
  5. 权利要求1-4任一项所述的二咖啡酰亚精胺环化衍生物或其药学上可接受的盐在制备预防及治疗神经退行性疾病的药物中的用途。
  6. 根据权利要求5所述的用途，其特征在于所述神经退行性疾病为老年痴呆、帕金森氏症、多发性硬化症和亨廷顿氏病中一种或几种。
  7. 根据权利要求6所述的用途，其特征在于：所述神经退行性疾病为老年痴呆，所述老年痴呆为阿尔茨海默病、血管性痴呆病、路易体痴呆病或额颞痴呆。
  8. 一种预防及治疗退行性疾病的药物组合物，其特征在于包括权利要求1-4任一项所述的二咖啡酰亚精胺环化衍生物或其药学上可接受的盐作为活性成分和药学上可接受的辅料。
  9. 根据权利要求1所述的预防及治疗退行性疾病的药物组合物，其特征在于作为活性成分的二咖啡酰亚精胺环化衍生物或其药学上可接受的盐的含量为药物组合物的1％～90％重量。
  10. 权利要求1-4任一项所述的二咖啡酰亚精胺环化衍生物或其药学上可接受的盐的制备方法，其特征在于包括以下步骤：
    (1)枸杞子用体积比为60:40的乙醇-水加热回流提取3次，每次2小时，过滤后，滤液经减压浓缩得浓缩液；
    (2)浓缩液经大孔树脂柱层析，依次用体积比为0:100、30:70、50:50、70:30和95:5的乙醇-水洗脱，得到5个馏分F1、F2、F3、F4、F5；
    (3)将体积比为30:70的乙醇-水洗脱得到的馏分F2进行常压硅胶柱层析，依次用体积比为95:5:0、90:10:1、85:15:1.5、80:20:2、70:30:3、60:40:4、50:50:5、40:60:6和0:100:0的氯仿-甲醇-水洗脱，得到F2.1、F2.2、F2.3、F2.4、F2.5、F2.6、F2.7、F2.8、F2.9和F2.10共10个子馏分；
    (4)将体积比40:60:6氯仿-甲醇-水洗脱得到的子馏分F2.9，过中低压液相ODS柱层析，依次用体积比为5:95:0.1、10:90:0.1、15:85:0.1、20:80:0.1、25:75:0.1、30:70:0.1、40:60:0.1和100:0:0的甲醇-水-三氟乙酸洗脱，得到F2.9.1、F2.9.2、F2.9.3、F2.9.4、F2.9.5、F2.9.6、F2.9.7、F2.9.8和F2.9.9共9个子馏分；
    (5)将体积比为15:85:0.1的甲醇-水-三氟乙酸洗脱得到的子馏分F2.9.6，经过反相制备级HPLC制备，使用流速为8mL/min的体积比为20:80:0.1的甲醇-水-三氟乙酸进行洗脱，即得。
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