WO2017185900A1 - 藏红花色素类化合物及其用途 - Google Patents
藏红花色素类化合物及其用途 Download PDFInfo
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- WO2017185900A1 WO2017185900A1 PCT/CN2017/076911 CN2017076911W WO2017185900A1 WO 2017185900 A1 WO2017185900 A1 WO 2017185900A1 CN 2017076911 W CN2017076911 W CN 2017076911W WO 2017185900 A1 WO2017185900 A1 WO 2017185900A1
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
- C07H13/06—Fatty acids
-
- 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
- A61K31/7024—Esters of saccharides
-
- 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
-
- 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 present invention relates to a series of saffron pigment compounds and related pharmacological applications in the prevention and treatment of Alzheimer's disease.
- Crocins are a class of structurally water-soluble carotenoids, including crocetin and its sugar esters combined with different glycosides. It is saffron (Crocus sativus L.) and gardenia (Gardenia jasminoides). A common pigment component in Ellis). Traditionally, saffron has been widely used as a gynecological medicine in Europe and Asia. Hazelnut yellow pigment has been used as a natural coloring agent. In recent years, many studies have shown that Crocus sativus L.
- CSE Cere Extracts
- crocin-1 alfalfa Pig yellow pigment and monomer component crocin crocin disaccharide
- crocetin crocetin
- CSE central nervous system protection
- cardiovascular and cerebrovascular system protection [5-6]
- antagonism of malignant tumors [7-9] and other aspects showed high pharmacological activity of low toxicity.
- AD Alzheimer's Disease
- cognitive impairment characterized by loss of memory, cognitive impairment, and personality changes.
- AD is the most common type of Alzheimer's disease.
- the initial symptoms of AD patients are forgetfulness, which leads to the decline of orientation, comprehension, judgment and memory.
- the patient enters a general recession in the late stage, and the intelligence is completely lost.
- the movement and language barriers tend to Obviously, eventually died of secondary infection and failure.
- AD amyloid ⁇ -protein
- a ⁇ amyloid ⁇ -protein
- intracellular poly-tau protein in the cerebral cortex and hippocampal neurons.
- pathological changes such as inflammation and oxidative stress.
- oxidative stress is an important mechanism for the development of AD. Therefore, targeting antioxidant damage has become an important way to find effective means of prevention and treatment of AD.
- Glutamate is an endogenous neurotransmitter in the cerebral cortex and hippocampus. Under normal physiological conditions, glutamate regulates the synaptic transmission of the central nervous system and participates in all functions of the normal brain, including learning, memory, exercise, cognition, and development. However, under pathological conditions, glutamate content is increased due to various reasons, and the receptor is overactivated, thereby causing neuronal damage and producing neurotoxicity. A growing number of studies have found that abnormal glutamate plays an important role in the etiology and pathophysiology of many neurological diseases including Alzheimer's disease, cerebral ischemia, and schizophrenia. Therefore, it can play a neuroprotective role by antagonizing the neurotoxicity of glutamate [10] .
- CSE has better anti-oxidation in vitro and inhibits the formation of A ⁇ fibrils.
- the main pigment-containing crocin-1 can inhibit the formation of A ⁇ fibrils at lower doses, suggesting that saffron and its pigments may inhibit A ⁇ aggregation in human brain. Deposition, thus having the relevant activity of preventing AD [2] .
- Crocin-1 by increasing glutathione (GSH) content, inhibition of lipid peroxide formation, retention superoxide dismutase (SOD) and so exert antioxidant activity, which play a protective role in PC-12 cells [11 ] .
- CSE (30 and 60 mg/kg) can improve the learning and memory ability of normal rats in the experiment, and can effectively inhibit the memory impairment caused by purine in rats [12] ; the saffron is made into capsules, The preparation was used in the clinical phase II treatment of mild to moderate AD.
- saffron capsules had the same therapeutic effect as the positive drug donepezil, and there was no significant difference between the adverse drug reactions and the positive drugs.
- side effects of vomiting were weakened [3] ; for the clinical phase II treatment of moderate to severe AD, the experimental group took the capsule 30mg/day, and the control group took the positive control drug memantine 30mg/day. The results showed that the experimental group could Produced the same therapeutic effect as the control group, and no significant adverse reactions [4] .
- Crocin prevents the death of rat pheochromyctoma (PC-12) cells by its antioxidant effects stronger than those of a-tocopherol [J].
- Neuroscience Letters.2004 362 (1), 61-64.
- the present invention relates to the following technical solutions.
- R 1 and R 2 each independently represent H, CH 3 , CH 2 CH 3 , a glycosyl group, a quinic acid group,
- the basic structure of quinic acid is:
- the hydroxyl groups at the 1, 3, 4, 5, and 7 positions can form different quinic acid groups after the hydrogen is removed.
- the common 3 and 5 positions can be expressed as:
- the glycosyl group is a glucosyl group, a gentiobiose group, a xylosyl group, a galactosyl group, a mannosyl group, an arabinose group, a rhamnosyl group, a ribosyl group, a lysyl group, a glucosyl group,
- the number of glycosyl groups is 0-2,
- the hydroxyl group of the glycosyl group may be acylated with an acylating group: succinoyl group, caffeoyl group, coumaroyl group, cinnamoyl group, CH 3 (CH 2 ) nCO, HOOC(CH 2 ) nCO,
- the hydroxyl group at the 3, 4, and 5 positions of the quinic acid group can be acylated with the following acylating group: succinyl group, caffeoyl group, coumaroyl group, cinnamoyl group, CH 3 (CH 2 ) nCO, HOOC (CH 2 ) nCO,
- the carboxyl group at the 1-position of the quinic acid group may be methylated or ethylated.
- neurodegenerative disease comprises vascular dementia, vascular cognitive impairment, Alzheimer's disease, memory loss, brain tissue degenerative disease syndrome or cholinergic nerve Degenerative lesions.
- a pharmaceutical composition comprising the compound according to any one of [1] to [12], and a pharmaceutically acceptable carrier.
- the inventor of the present application extracted a series of traditional Chinese medicine scorpions by various chemical means.
- the novel saffron pigments represented by the general formula (I) were identified by various spectroscopy methods, and the saffron pigment compounds were excellently protected by the cellular experiments.
- positions 13-14 are in the trans E configuration, R 1 represents a glucosyl group, and R 2 represents a quinic acid group.
- GJ-1 neocrocin B
- R 1 represents a gentiobiose group and R 2 represents a 3-caffeoylquinic acid-5-oxy group
- GJ-2 a new compound neocrocin C
- positions 13-14 are in the cis Z configuration, R 1 represents H, glucosyl or quinic acid groups, and R 2 represents glucosyl or quinic acid groups.
- R 1 represents H and R 2 represents a gentiobiose group
- a new compound having a chemical name of 13Z-saffron acid-8'-O- ⁇ -D-gentiobioside is obtained, abbreviated as GJ-5.
- positions 13-14 are in the trans E configuration, R 1 represents a glucosyl group, and R 2 represents a glucosyl group or H.
- R 1 represents a 6-O-trans-glucosylcholyl saccharide group and R 2 represents a gentiobiose group
- GJ-6 a new compound neocrocin G
- R 1 represents a 6-O-trans-glucosylcholyl saccharide group and R 2 represents H
- GJ-7 a new compound neocrocin F, abbreviated as GJ-7, is obtained.
- positions 13-14 are in the trans E configuration, R 1 represents a glucosyl group, and R 2 represents CH 2 CH 3 .
- a fifth preferred group of compounds is neocrocin I, abbreviated as GJ-9.
- 13-14 E represents trans-configuration
- R 1 represents glucosyl
- xylosyl R 2 represents H.
- R 1 represents H and R 2 represents a xylosyl-(1 ⁇ 6)-glucosyl group
- GJ-10 a new compound neocrocin J
- Example 1 Extraction and separation of saffron pigment components in gardenia
- the decomposed portion was about 4.5 kg, the 50% ethanol eluted portion was 710.0 g, the 70% ethanol eluted portion was 150.0 g, and the 95% ethanol eluted portion was 112.0 g, wherein the 70% ethanol eluted portion was the scorpion safflor pigment active site.
- the silica gel fraction Fr.7 was subjected to ODS column chromatography, eluting with a gradient of methanol-water 40%-80%, and the compound GJ-11 (16.0 mg) was eluted by HPLC, 55% methanol-acid water (0.1% acetic acid).
- the compound GJ-2 (6.3 mg) was obtained eluting with EtOAc (EtOAc:EtOAc)
- the silica gel fraction Fr.8 was subjected to ODS column chromatography, eluting with a gradient of methanol and water from 55% to 65%.
- Compound 16 143.7 mg was eluted and eluted with HPLC, 55% methanol-acid water (0.1% acetic acid) GJ-6 (59.1 mg), GJ-2 (21.9 mg); eluted with HPLC, 68% methanol-acid water (0.1% acetic acid) to afford compound GJ-1 (400.9 mg); Elution with acid water (0.1% acetic acid) gave compound GJ-17 (1.8 mg), GJ-18 (3.5 mg).
- the silica gel fraction Fr.6 was subjected to ODS column chromatography and eluted with a gradient of methanol-water 50%-90% to precipitate compound GJ-15 (315.7 mg); eluted by HPLC, 60% methanol-acid water (0.1% acetic acid).
- Compound GJ-10 (10.0 mg) was obtained eluting with EtOAc EtOAc EtOAc (EtOAc) Elution with methanol-acid water (0.1% acetic acid) gave Compound GJ-8 (10.0 mg).
- Example 2 Neuroprotective effect of safflor pigment monomer in scorpion in H 2 O 2 and L-glutamate-induced SH-SY5Y cell injury model
- the SH-SY5Y nerve cells were cultured in DMEM medium (containing a volume fraction of 5% fetal bovine serum), cultured at 37 ° C in an incubator containing 5% CO 2 , and passaged every 3 to 4 days. Experiments were performed on logarithmic growth phase cells.
- SH-SY5Y cells were seeded in a 96-well plate at a concentration of 5 ⁇ 10 3 , culture was continued for 24 h, and 100 ⁇ L of a liquid medium containing H 2 O 2 was added to a 96-well plate to obtain a final concentration of H 2 O 2 of 400 ⁇ M.
- the final concentration of the drug was 10 ⁇ M, 1 ⁇ M, and 0.1 ⁇ M, and three wells were set in parallel for each concentration, and the culture was continued for 24 hours. After 24 hours, the supernatant was aspirated, and 100 ⁇ L of MTT (0.5 mg/mL) was added to each well. Incubation was continued for 4 hours.
- SH-SY5Y cells were seeded in 96-well plates at a concentration of 5 ⁇ 10 3 , cultured for 24 h, and 100 ⁇ L of L-glutamic acid-containing medicinal medium was added to a 96-well plate to make L-glutamic acid
- the concentration was 160 mM
- the final concentration of the drug was 10 ⁇ M, 1 ⁇ M, and 0.1 ⁇ M
- three wells in parallel were set for each concentration, and the culture was continued for 24 hours. After 24 hours, the supernatant was aspirated, and 100 ⁇ L of MTT (0.5 mg/mL) was added to each well. Incubation was continued for 4 hours.
- the compounds GJ-1 to GJ-10 showed good protection in the H 2 O 2 induced SY5Y cell injury model.
- the compounds GJ-6, GJ-10 and GJ-8 showed more Excellent protective effect; compounds GJ-1 to GJ-10 also showed good protection in L-glutamic acid-induced SY5Y cell injury model, among which compounds GJ-1, GJ-6, GJ-7 GJ-10, GJ-9, and GJ-8 showed superior protection.
- the effectiveness of each compound in different injury models is different, which may be due to the mechanism of H 2 O 2 induced damage being oxidative stress, and the mechanism of L-glutamate-induced damage is through excitement. Sexual amino acids cause excitotoxic damage, and the compounds exert damage protection through different mechanisms.
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Abstract
提供一系列藏红花色素类化合物及其在防治阿尔茨海默症方面的相关药理应用。以中药栀子为原料，通过多种分离方法得到一系列藏红花色素类化合物，以体外细胞实验筛选具有保护过氧化氢(H 2O 2)引起的氧化损伤和 L-谷氨酸所引起的兴奋性氨基酸损伤的化合物，结果显示，这些藏红花色素类化合物具有良好的保护H 2O 2和 L-谷氨酸所致细胞损伤的作用，由于氧化应激、兴奋性氨基酸显著升高是阿尔茨海默症神经损伤的重要因素，故这些化合物具有良好的防治阿尔茨海默症的作用并具有广阔的开发利用前景。
Description
本发明涉及一系列藏红花色素类化合物及其在防治阿尔茨海默症方面的相关药理应用。
藏红花色素(crocins)是一类结构独特的水溶性类胡萝卜素，包括藏红花酸(crocetin)及其与不同糖基结合而成的糖酯，是藏红花(Crocus sativus L.)和栀子(Gardenia jasminoides Ellis)中的共有色素成分。传统应用上，藏红花作为妇科良药在欧洲和亚洲广泛应用，栀子黄色素多被用作天然的着色剂，近年来多项研究表明，藏红花粗提物(Crocus sativus L.Extracts，CSE)、栀子黄色素以及单体成分藏红花素双龙胆二糖苷(crocin-1)、藏红花酸(crocetin)在中枢神经系统保护[1-4]、心脑血管系统的保护[5-6]、拮抗恶性肿瘤[7-9]等方面表现出高效低毒的药理活性。
阿尔茨海默症(Alzheimer’s Disease，AD)，是一种与衰老相关，以记忆缺失、认知障碍、人格改变为特征的渐进性神经退行性疾病。AD是老年痴呆中最常见的类型，AD患者最初的症状是健忘，进而发展为定向力、理解力、判断力和记忆力的下降，患者晚期进入全面衰退状态，智能完全丧失，运动和语言障碍日趋明显，最终多死于继发性感染和衰竭。
随着世界老龄化进程的加剧，AD的发病率呈逐年迅速上升的趋势，给各个国家尤其是发展中国家的社会和人民带来沉重的经济和家庭负担。自1906年德国医生Alzheimer首次描述该病迄今100多年来，国际上公认暂无治愈此病的方法和药物。可见，在尚无理想治疗药物的情况下，抗老年痴呆药物的筛选和研发具有十分广阔的
市场前景和深远的社会意义。
AD显著的病理学特征为大脑皮质和海马神经细胞外的β-淀粉样蛋白沉积(amyloid β-protein，Aβ)和细胞内多聚的tau蛋白缠结。目前大多数学者认为，Aβ的大量沉积是导致AD发病的直接原因，在此过程中，主要存在炎症、氧化应激等病理变化。大量研究证实氧化应激是AD发生发展的重要机制。因此以抗氧化损伤为靶点已经成为寻找AD防治有效手段的重要途径。
谷氨酸是大脑皮层和海马部位的内源性神经递质。正常生理条件下，谷氨酸调节中枢神经系统的突触传递，参与正常脑内的所有功能，包括学习、记忆、运动、认知和发育。但是在病理条件下，由于各种原因使得谷氨酸含量增高，过度激活受体，从而引起神经元损伤，产生神经毒性。越来越多的研究发现，非正常谷氨酸在许多神经疾病包括阿尔茨海默症、脑缺血、精神分裂症等的病因学和病理生理学过程中发挥重要作用。因此，通过拮抗谷氨酸的神经毒性可以起到神经保护的作用[10]。
CSE具有较好的体外抗氧化以及抑制Aβ原纤维形成的作用，主含色素crocin-1在较低剂量下可抑制Aβ原纤维形成，提示藏红花及其所含色素可能具有抑制人体脑部Aβ聚集沉积，从而具有防治AD的相关活性[2]。Crocin-1可通过提高谷胱甘肽(GSH)含量、抑制过氧化脂质形成、保留过氧化物歧化酶(SOD)活力等发挥抗氧化作用，从而对PC-12细胞起到保护作用[11]。
在动物实验中，CSE(30和60mg/kg)，可提高正常大鼠在实验中的学习记忆能力，并能有效抑制莨菪碱造成的大鼠记忆障碍[12]；将藏红花制成胶囊剂，将该制剂用于轻中度AD临床II期治疗研究，在为期22周的随机双盲试验中，藏红花胶囊剂与阳性药多奈哌齐具有同等的治疗作用，且药物不良反应与阳性药无明显差异，并且治呕副作用减弱[3]；用于中重度AD的临床II期治疗研究，实验组患者服用该胶囊剂30mg/day，对照组服用阳性对照药美金刚30mg/day，结果表明，实验组可产生与对照组同等的治疗作用，且无
明显不良反应[4]。
【参考文献】
[1]Karakani A.-M.，Riazi G.，Mahmood G.-S.，et al.Inhibitory effect of corcin on aggregation of 1N/4R human tau protein in vitro[J].Iranian journal of basic medical sciences.2015，18(5)，485-92.
[2]Papandreou M.-A.，Kanakis C.-D.，Polissiou M.-G.，et al.Inhibitory Activity on Amyloid-β Aggregation and Antioxidant Properties of Crocus sativus Stigmas Extract and Its Crocin Constituents[J].douranl of Agriculture and Food Chemistry.2006，54(23)，8762-8768.
[3]Akhondzadeh S.，Sabet M.-S.，Harirchian M.-H.，et al.A 22-week，multicenter，randomized，double-blind controlled trial of Crocus sativus in the treatment of mild-to-moderate Alzheimer’s disease[J].Psychopharmacology.2010，207(4)，637-643.
[4]Farokhnia M.，Shafiee S.-M.，Iranpour N.，et al.Comparing the efficacy and safety of Crocus sativus L.With memantine in patients with moderate to severe Alzheimer’s disease：a double-blind randomized clinical trial[J].Human Psychopharmacology.2014，29(4)，351-359.
[5]Zheng Y.-Q.，Liu J.-X.，Wang J.-N.，et al.Effects of crocin on reperfusion-induced oxidative_nitrative injury to cerebral microvessels after global cerebral ischemia[J].Brain Research.2007，1138，86-94.
[6]Higashino S.，Sasaki Y.，Giddings J.-C.，et al.Crocetin，a Carotenoid from Gardenia jasminoides Ellis，Protects against Hypertension and Cerebral Thrombogenesis in Stroke-prone Spontaneously Hypertensive Rats[J].Phytotherapy Research.2014，28(9)，1315-1319.
[7]董盛宇，刘付梅，李祥勇.藏红花素对CNE2细胞的增殖及迁移抑制作用[J].湖北民族学院学报·医学版.2013，30(2)，6-12.
[8]王新星，于正洪，侍述碌等.藏红花素对人肺腺癌SPC-A1细胞的增殖抑制作用及机制研究[J].临床肿瘤学杂志.2013，18(4)，295-299.
[9]陈福雄，陶佳，黄穗等.儿童EB病毒感染相关IM和EBV-AHS的临床研究和病毒感染特征[A].中华医学会、中华医学会儿科学分会.中华医学会第十七次全国儿科学术大会论文汇编(上册)[C].中华医学会、中华医学会儿科学分会：，2012：1.
[10]Lau A.，Tymianski M..Glutamate receptors，neurotoxicity and neurodegeneration[J].European Journal of Physiology.2010，460(2)，525-542.
[11]Ochiai T.，Ohno S.，Soeda S.，et al.Crocin prevents the death of rat pheochromyctoma(PC-12)cells by its antioxidant effects stronger than those of a-tocopherol[J].Neuroscience Letters.2004，362(1)，61-64.
[12]Pitsikas N.，Sakellaridis N..Crocus sativus L.extracts antagonize memory impairments in different behavioural tasks in the rat[J].Behavioural Brain Research.2006，173(1)，112-115.
发明内容
本发明涉及下述技术方案。
[1]一种通式(I)表示的藏红花色素类化合物或其药学上容许的盐，
其中，13-14位双键的构型为反式E或者顺式Z，
R1、R2各自独立表示H、CH3、CH2CH3、糖基、奎宁酸基，
奎宁酸的基本结构为：
其中，1，3，4，5，7位的羟基去掉氢后，可形成不同的奎宁酸基，如常见的3位、5位可表示为：
所述糖基为葡萄糖基、龙胆二糖基、木糖基、半乳糖基、甘露糖基、阿拉伯糖基、鼠李糖基、核糖基、来苏糖基、夫糖基，
所述糖基个数为0-2个，
所述糖基的羟基可被以下酰化基团酰化：芥子酰基、咖啡酰基、香豆酰基、肉桂酰基、CH3(CH2)nCO、HOOC(CH2)nCO，
所述奎宁酸基的3、4、5位羟基可被以下酰化基团酰化：芥子酰基、咖啡酰基、香豆酰基、肉桂酰基、CH3(CH2)nCO、HOOC(CH2)nCO，
所述奎宁酸基的1位羧基可发生甲酯化或乙酯化，
其中，所述通式(I)化合物不包括以下化合物：
[2]如项[1]所述的化合物，其中，13-14位双键的构型为反式E构型，R1表示葡萄糖基，R2表示奎宁酸基。
[3]如项[2]所述的化合物，其中，所述化合物是
[4]如项[1]所述的化合物，其中，13-14位双键的构型为顺式Z构型，R1表示H、葡萄糖基或奎宁酸基，R2表示H、葡萄糖基或奎宁酸基。
[5]如项[4]所述的化合物，其中，所述化合物是
[6]如项[1]所述的化合物，其中，13-14位双键的构型为反式E构型，R1表示葡萄糖基，R2表示葡萄糖基或H。
[7]如项[6]所述的化合物，其中，所述化合物是
[8]如项[1]所述的化合物，其中，13-14位双键的构型为反式E构型，R1表示葡萄糖基，R2表示CH2CH3。
[9]如项[8]所述的化合物，其中，所述化合物是
[10]如项[1]所述的化合物，其中，13-14位双键的构型为反式E构型，R1表示葡萄糖基、木糖基，R2表示H。
[11]如项[10]所述的化合物，其中，所述化合物是
[12]一种藏红花色素类化合物，其结构式为
[13]项[1]～[12]中任一项所述的化合物在制备用于预防和治疗神经退行性疾病药物中的用途。
[14]如项[13]所述的用途，所述神经退行性疾病包括血管性痴呆、血管性认知障碍、阿尔茨海默症、记忆力减退、脑组织退行性病变症候群或胆碱能神经退行性病变。
[15]一种组合物，所述组合物包括项[1]～[12]中任一项所述的化合物和其他藏红花色素类化合物，所述其他藏红花色素类化合物为，
[16]一种药物组合物，所述药物组合物包括项[1]～[12]中任一项所述的化合物和可药用载体。
[17]一种制备项[1]～[12]中任一项所述的化合物的方法，所述方法包括：采用中药栀子为原料，用乙醇、甲醇或者水，采用不同提取次数和时间，通过热提取或者超声提取的方法进行提取，减压浓缩提取液，得到栀子总提取物。
[18]如项[17]所述的方法，其中，用适量水溶解栀子总提物，离心，将上清液通过大孔吸附树脂开放柱色谱，用水洗脱和/或30％-95％的乙醇洗脱适量的柱床体积，收集洗脱液，减压浓缩得到栀子藏红花色素活性部位，进一步采用各种柱色谱进行分离。
19、如项[17]所述的方法，其中，采用4倍量的60％乙醇，加热回流提取3次，每次2小时。
20、如项[18]所述的方法，其中，用水洗脱，然后用30％、50％、70％、95％乙醇依次洗脱，每个梯度洗脱4个柱床体积，减压浓缩70％乙醇液得到栀子藏红花色素活性部位。
21、如项[18]所述的方法，其中，所述柱色谱包括硅胶柱色谱、ODS开放柱色谱、Sephadex LH-20开放柱色谱以及Pre-HPLC柱色谱。
本申请发明人通过多种化学手段从中药栀子中提取得到了一系
列通式(I)表示的新型藏红花色素类化合物，运用多种波谱学方法进行了鉴定，并通过细胞实验证明了这些藏红花色素类化合物对中枢神经系统具有优异的保护作用。
各取代基的定义如前文所述。
第一组优选的化合物中，13-14位为反式E构型，R1表示葡萄糖基，R2表示奎宁酸基。
其中，当R1表示Glc-(1→6)-Glc(龙胆二糖基)、R2表示3-咖啡酰奎宁酸-4-氧基时，得到新化合物neocrocin B，简称GJ-1。
其中，当R1表示龙胆二糖基、R2表示3-咖啡酰奎宁酸-5-氧基时，得到新化合物neocrocin C，简称GJ-2。
第二组优选的化合物中，13-14位为顺式Z构型，R1表示H、葡萄糖基或奎宁酸基，R2表示葡萄糖基或奎宁酸基。
其中，当R1表示龙胆二糖基、R2表示3-咖啡酰奎宁酸-4-氧基时，得到新化合物neocrocin D，简称GJ-3。
其中，当R1表示3-咖啡酰奎宁酸-4-氧基、R2表示龙胆二糖基时，得到新化合物neocrocin E，简称GJ-4。
其中，当R1表示H，R2表示龙胆二糖基时，得到化学名为13Z-藏红花酸-8′-O-β-D-龙胆二糖苷的新化合物，简称GJ-5。
第三组优选的化合物中，13-14位为反式E构型，R1表示葡萄糖基，R2表示葡萄糖基或H。
其中，当R1表示6-O-反-芥子酰基龙胆二糖基、R2表示龙胆二糖基时，得到新化合物neocrocin G，简称GJ-6。
其中，当R1表示6-O-反-芥子酰基龙胆二糖基、R2表示H时，得到新化合物neocrocin F，简称GJ-7。
第四组优选的化合物中，13-14位为反式E构型，R1表示葡萄糖基，R2表示CH2CH3。
其中，当R1表示龙胆二糖基、R2表示CH2CH3时，得到新化合物neocrocin H，简称GJ-8。
第五组优选的化合物为neocrocin I，简称GJ-9。
第六组优选的化合物中，13-14表示反式E构型，R1表示葡萄糖基、木糖基，R2表示H。
其中，当R1表示H、R2表示木糖基-(1→6)-葡萄糖基时，得到新化合物neocrocin J，简称GJ-10。
另外，在通式(I)范围内的下述表1所示的化合物是已知的。
[表1]
[实施例]
实施例1：栀子中藏红花色素成分的提取分离
取栀子干燥成熟果实40.0kg，经适当粉碎后，用4倍量的60％乙醇加热回流提取3次，每次2小时。合并提取液，减压除去溶剂，得到栀子总提物6.2kg(收率为15.5％)；以适量水溶解提取物，离心，上清液进行大孔树脂开放柱层析(20.0×90cm)，依次用4倍柱床体积的水、30％、50％、70％、95％的乙醇梯度洗脱，收集各部分洗脱液，分别减压回收溶剂，得到水洗脱、30％乙醇洗脱组合部分约4.5kg，50％乙醇洗脱部分710.0g，70％乙醇洗脱部分150.0g，95％乙醇洗脱部分112.0g，其中70％乙醇洗脱部分即为栀子藏红花色素活性部位。
70％乙醇洗脱部位150g经硅胶柱色谱
氯仿-甲醇-水99∶1-6∶4∶0.8梯度洗脱，化合物GJ-11(49.1mg)、GJ-12(136.5mg)、GJ-13(7.0g)分别析出。
硅胶子馏分Fr.9经ODS柱色谱，甲醇-水30％-70％梯度洗脱，化合物GJ-19(545.1mg)析出，经HPLC，60％甲醇-水洗脱，得到化合物GJ-20(265.7mg)；经HPLC，68％甲醇-酸水(0.1％乙酸)洗脱，得到化合物GJ-1(120.0mg)、及GJ-3和GJ-4的混合物104.8mg(1∶2混合)，进而采用水(0.3％TEAA)∶乙腈＝55∶45分离化合物GJ-3和GJ-4。
硅胶子馏分Fr.7经ODS柱色谱，甲醇-水40％-80％梯度洗脱，析出化合物GJ-11(16.0mg)，经HPLC，55％甲醇-酸水(0.1％乙酸)洗脱，得到化合物GJ-2(6.3mg)；经HPLC，42％乙腈-酸水(0.1％乙酸)洗脱，得到化合物GJ-13(8.0mg)、化合物GJ-5(16.0mg)。
硅胶子馏分Fr.8经ODS柱色谱，甲醇-水55％-65％梯度洗脱，化合物16(143.7mg)析出，经HPLC，55％甲醇-酸水(0.1％乙酸)洗脱，得到化合物GJ-6(59.1mg)、GJ-2(21.9mg)；经HPLC，68％甲醇-酸水(0.1％乙酸)洗脱，得到化合物GJ-1(400.9mg)；经HPLC，32％乙腈-酸水(0.1％乙酸)洗脱，得到化合物GJ-17(1.8mg)、GJ-18
(3.5mg)。
硅胶子馏分Fr.6经ODS柱色谱，甲醇-水50％-90％梯度洗脱，析出化合物GJ-15(315.7mg)；经HPLC，60％甲醇-酸水(0.1％乙酸)洗脱，得到化合物GJ-10(10.0mg)；经HPLC，65％甲醇-酸水(0.1％乙酸)洗脱，得到化合物GJ-9(2.0mg)、GJ-7(66.2mg)；经HPLC，70％甲醇-酸水(0.1％乙酸)洗脱，得到化合物GJ-8(10.0mg)。
所获得化合物的结构信息如表2所示。
[表2]
所获得的化合物的物理化学数据如下：
化合物GJ-1：红色无定型粉末；ESI-MS(positive)：m/z 1011[M+Na]+；HR-ESI-MS：m/z 989.3642[M+H]+(calcd for C48H61O22，989.3654)，确认化合物GJ-1的分子式为C48H60O22；UV(MeOH)λmax(logε)：433(5.32)，458(5.28)，331(4.68)，253(4.52)nm；IR(KBr)νmax968，1061，1224，1268，1576，1610，1694，2920，3401cm-1；13C NMR
(DMSO-d6，150MHz)见表3。
化合物GJ-2：红色无定型粉末；ESI-MS(positive)：m/z 1011[M+Na]+；HR-ESI-MS：m/z 989.3646[M+H]+(calcd for C48H61O22，989.3654)，确认化合物GJ-2的分子式为C48H60O22；UV(MeOH)λmax(logε)：431(4.63)，457(4.56)，331(4.12)，249(3.85)；IR(KBr)νmax1064，1230，1279，1602，1698，2921，3417cm-1；13C NMR(DMSO-d6150MHz)见表3。
化合物GJ-3：红色无定型粉末；ESI-MS(positive)：m/z 1011[M+Na]+；HR-ESI-MS：m/z 1011.3471[M+Na]+(calcd for C48H60O22Na，1011.3474)，确认化合物GJ-3的分子是为C48H60O22；UV(MeOH)λmax(logε)：429(5.04)，453(4.99)，324(4.68)，251(4.04)nm；IR(KBr)νmax969，1062，1229，1277，1607，1693，2920，3368cm-1；13C NMR(DMSO-d6，150MHz)见表3。
化合物GJ-4：红色无定型粉末；ESI-MS(positive)：m/z 1011[M+Na]+；HR-ESI-MS：m/z 1011.3471[M+Na]+(calcd for C48H60O22Na，1011.3474)，确认化合物GJ-4的分子式是C48H60O22；UV(MeOH)λmax(logε)：429(5.04)，453(4.99)，324(4.68)，251(4.04)nm；IR(KBr)νmax969，1062，1229，1277，1607，1693，2920，3368cm-1；13C NMR(DMSO-d6，150MHz)见表3。
化合物GJ-5：红色无定型粉末，ESI-MS(positive)：m/z 675[M+Na]+，m/z 1327[2M+Na]+，推测化合物GJ-14分子量为652；HR-ESI-MS：675.2617[M+Na+](计算值为675.2629)，确定化合物GJ-14分子式为C32H44O14。13C NMR(DMSO-d6，150MHz)见表3。
化合物GJ-6：红色无定型粉末；ESI-MS(positive)：m/z 1205[M+Na]+；HR-ESI-MS：m/z 1183.4479[M+H]+(calcd for C55H75O28，1183.4445)，确认化合物GJ-6的分子式是C55H74O28；UV(MeOH)λmax(logε)：434(5.22)，459(5.17)，330(4.78)，242(4.65)；IR(KBr)νmax1059，1119，1225，1273，1610，1701，2920，3385cm-1；13C NMR(DMSO-d6，150MHz)见表3。
化合物GJ-7：红色无定型粉末；ESI-MS(positive)：m/z 881[M+Na]+；HR-ESI-MS：m/z 881.3188[M+Na]+(calcd for C43H54O18Na，881.3208)，确认化合物GJ-7的分子式是C43H54O18；UV(MeOH)λmax(logε)：430(5.33)，454(5.28)，326(4.80)，242(4.78)；IR(KBr)νmax 972，1069，1179，1227，1284，1610，1697，2922，3391cm-1；13C NMR(DMSO-d6，150MHz)见表3。
化合物GJ-8：红色无定型粉末；ESI-MS(positive)：m/z 703[M+Na]+；HR-ESI-MS：m/z 703.2904[M+Na]+(calcd for C34H48O14Na，703.2942)，确认化合物GJ-8的分子式是C34H48O14；UV(MeOH)λmax(logε)：430(4.64)，456(4.59)，322(3.84)，257(3.95)；IR(KBr)νmax1074，1229，1697，2925，3400cm-1；13C NMR(DMSO-d6，150MHz)参见表3。
化合物GJ-9：红色无定型粉末；ESI-MS(positive)：m/z 659[M+Na]+；HR-ESI-MS：m/z 659.2657[M+Na]+(calcd for C32H44O13Na，659.2680)，确认化合物GJ-9的分子式是C32H44O13；UV(MeOH)λmax(logε)：438(4.63)，462(4.60)，328(3.90)，261(3.94)；IR(KBr)νmax1071，1515，1694，2921，3277cm-1；13C NMR(DMSO-d6，150MHz)参见表3。
化合物GJ-10：红色无定型粉末；ESI-MS(positive)：m/z 645[M+Na]+；HR-ESI-MS：m/z 645.2519[M+Na]+(calcd for C31H42O13Na，645.2523)，确认化合物GJ-10的分子式是C31H42O13；UV(MeOH)λmax(logε)：428(4.56)，453(4.50)，320(4.11)，257(4.10)；IR(KBr)νmax1072，1230，1700，2924，3416cm-1；13C NMR(DMSO-d6，150MHz)参见表3。
[表3]
a means signals could be interchangeable with the corresponding position in one compound
实施例2：栀子中的藏红花色素单体在H2O2和L-谷氨酸致SH-SY5Y细胞损伤模型中的神经保护作用
2.1 SH-SY5Y神经细胞培养方法
SH-SY5Y神经细胞培养于DMEM培养基(含体积分数为5％胎牛血清)中，置于37℃，含5％CO2的培养箱中培养，每3～4天传代一次。选取对数生长期细胞进行实验。
2.2过氧化氢损伤模型筛选方法
将SH-SY5Y细胞以5×103的浓度接种于96孔板中，继续培养24h，加入含H2O2的药液培养基100μL至96孔板中，使H2O2终浓度为400μM，药物终浓度为10μM、1μM、0.1μM，每个浓度设定平行的3个孔，继续培养24h。24h后，吸弃上清液，每孔加MTT(0.5mg/mL)100μL，继续孵育4h，吸弃上清液，每孔加入150μL的DMSO，震荡10min，选择570nm波长，在酶标仪上测定吸光度值[12]。(有效率％＝(OD药物-OD模型)/(OD对照-OD模型)*100)，筛选结果见表4。
2.3 L-谷氨酸损伤模型筛选方法
将SH-SY5Y细胞以5×103的浓度接种于96孔板中，继续培养24h，加入含L-谷氨酸的药液培养基100μL至96孔板中，使L-谷氨酸的终浓度为160mM，药物终浓度为10μM、1μM、0.1μM，每个浓度设定平行的3个孔，继续培养24h。24h后，吸弃上清液，每孔加MTT(0.5mg/mL)100μL，继续孵育4h，吸弃上清液，每孔加入150μL的DMSO，震荡10min，选择570nm波长，在酶标仪上测定吸光度值[13]。(有效率％＝(OD药物-OD模型)/(OD对照-OD模
型)*100)，结果见表5。
[表4]
*P＜0.1，**P＜0.05，***P＜0.01。
[表5]
*P＜0.1，**P＜0.05，***P＜0.01。
实验结果表明：在H2O2诱导的SY5Y细胞损伤模型上，化合物GJ-1到GJ-10均表现出良好的保护作用，其中，化合物GJ-6、GJ-10、GJ-8表现出更加优异的保护作用；在L-谷氨酸诱导的SY5Y细胞损伤模型上，化合物GJ-1到GJ-10也都表现出良好的保护作用，其中，
化合物GJ-1、GJ-6、GJ-7、GJ-10、GJ-9、GJ-8表现出更加优异的保护作用。由上述实验结果还可获知，各化合物在不同损伤模型中的有效性不同，这可能是由于H2O2诱导损伤的机理是氧化应激，而L-谷氨酸诱导损伤的机制是通过兴奋性氨基酸造成兴奋性毒性损伤，化合物通过不同机制发挥损伤保护作用。
Claims (21)
- 一种通式(I)表示的藏红花色素类化合物或其药学上容许的盐，
其中，13-14位双键的构型为反式E或者顺式Z，R1、R2各自独立表示H、CH3、CH2CH3、糖基、奎宁酸基，所述糖基为葡萄糖基、龙胆二糖基、木糖基、半乳糖基、甘露糖基、阿拉伯糖基、鼠李糖基、核糖基、来苏糖基、夫糖基，所述糖基个数为0-2个，所述糖基的羟基可被以下酰化基团酰化：芥子酰基、咖啡酰基、香豆酰基、肉桂酰基、CH3(CH2)nCO、HOOC(CH2)nCO，所述奎宁酸基的3、4、5位羟基可被以下酰化基团酰化：芥子酰基、咖啡酰基、香豆酰基、肉桂酰基、CH3(CH2)nCO、HOOC(CH2)nCO，所述奎宁酸基的1位羧基可发生甲酯化或乙酯化，其中，所述通式(I)化合物不包括以下化合物：
- 如权利要求1所述的化合物，其中，13-14位双键的构型为反式E构型，R1表示葡萄糖基，R2表示奎宁酸基。
- 如权利要求2所述的化合物，其中，所述化合物是
- 如权利要求1所述的化合物，其中，13-14位双键的构型为顺式Z构型，R1表示H、葡萄糖基或奎宁酸基，R2表示H、葡萄糖基或奎宁酸基。
- 如权利要求4所述的化合物，其中，所述化合物是
- 如权利要求1所述的化合物，其中，13-14位双键的构型为反式E构型，R1表示葡萄糖基，R2表示葡萄糖基或H。
- 如权利要求6所述的化合物，其中，所述化合物是
- 如权利要求1所述的化合物，其中，13-14位双键的构型为反式E构型，R1表示葡萄糖基，R2表示CH2CH3。
- 如权利要求8所述的化合物，其中，所述化合物是
- 如权利要求1所述的化合物，其中，13-14位双键的构型为反式E构型，R1表示葡萄糖基、木糖基，R2表示H。
- 如权利要求10所述的化合物，其中，所述化合物是
- 一种藏红花色素类化合物，其结构式为
- 权利要求1～12中任一项所述的化合物在制备用于预防和治疗神经退行性疾病药物中的用途。
- 如权利要求13所述的用途，所述神经退行性疾病包括血管性痴呆、血管性认知障碍、阿尔茨海默症、记忆力减退、脑组织退行性病变症候群或胆碱能神经退行性病变。
- 一种组合物，所述组合物包括权利要求1～12中任一项所述的化合物和其他藏红花色素类化合物，所述其他藏红花色素类化合 物为，
- 一种药物组合物，所述药物组合物包括权利要求1～12中任一项所述的化合物和可药用载体。
- 一种制备权利要求1～12中任一项所述的化合物的方法，所述方法包括：采用中药栀子为原料，用乙醇、甲醇或者水，采用不同提取次数和时间，通过热提取或者超声提取的方法进行提取，减压浓缩提取液，得到栀子总提取物。
- 如权利要求17所述的方法，其中，用适量水溶解栀子总提物，离心，将上清液通过大孔吸附树脂开放柱色谱，用水洗脱和/或30％-95％的乙醇洗脱适量的柱床体积，收集洗脱液，减压浓缩得到栀子藏红花色素活性部位，进一步采用各种柱色谱进行分离。
- 如权利要求17所述的方法，其中，采用4倍量的60％乙醇，加热回流提取3次，每次2小时。
- 如权利要求18所述的方法，其中，用水洗脱，然后用30％、50％、70％、95％乙醇依次洗脱，每个梯度洗脱4个柱床体积，减压浓缩70％乙醇液得到栀子藏红花色素活性部位。
- 如权利要求18所述的方法，其中，所述柱色谱包括硅胶柱色谱、ODS开放柱色谱、Sephadex LH-20开放柱色谱以及Pre-HPLC柱色谱。
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| AU2019218153B2 (en) | 2018-02-06 | 2023-01-19 | Shanghai Pharmaceuticals Holding Co., Ltd. | Therapeutic drug for neurodegenerative disease and application thereof |
| CN112082960A (zh) * | 2019-06-13 | 2020-12-15 | 上海崇明农联西红花研究发展中心 | 一种西红花苷含量的检测方法 |
| TWI703980B (zh) * | 2019-07-12 | 2020-09-11 | 鴻元生技股份有限公司 | 梔子萃取物、其製備方法及其用於護眼之用途 |
| CN110330537B (zh) * | 2019-08-23 | 2020-08-21 | 郑州中科新兴产业技术研究院 | 一种从栀子果中提取高纯度藏红花素工艺的方法 |
| KR102592445B1 (ko) * | 2019-10-18 | 2023-10-23 | 서울대학교산학협력단 | 크로신 배당체 및 상기 크로신 배당체의 제조방법 |
| CN111171087B (zh) * | 2020-02-17 | 2023-09-08 | 天津理工大学 | 一种高纯度西红花苷i的提纯方法和应用 |
| CN116617238A (zh) * | 2023-05-29 | 2023-08-22 | 中国科学院水生生物研究所 | 中草药西红花苷 ⅰ 在鱼类抗病毒中的应用 |
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