WO2011134119A1 - 7,2"-脱水葛根素及其盐类衍生物以及其制备方法与应用 - Google Patents
7,2"-脱水葛根素及其盐类衍生物以及其制备方法与应用 Download PDFInfo
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- the invention relates to a puerarin derivative and a preparation method and application thereof, in particular to 7, 2"-dehydrated puerarin and a salt derivative thereof, and a preparation method and application thereof, and belongs to the technical field of medicine.
- Puerarin is an isoflavone glycoside extracted from the leguminous plants of kudzu and kudzu root. It has been found to have free radical scavenging (J. Agric. Food Chem. 2002, 50, 7504-7509.), lowering serum cholesterol. (J. Nat. Prod. 2003, 66, 788-792.), anticoagulant and anti-allergic (Biol. Pharm. Bull. 2002, 25, 1328-1332.) and other activities, clinically used to treat coronary heart disease (Chinese Journal of Integrated Traditional Chinese and Western Medicine 2003, 23, 895-897.), Angina Pectoris (Chinese Journal of Integrated Traditional Chinese and Western Medicine 1998, 18, 282-284.), Myocardial Infarction (Chinese Med. J. 1992, 105, 11-17.) Sudden deafness (Journal of First Military Medical University 2002, 22, 1044- 1045) and alcoholism (Pharmacol. Biochem. Behav.
- puerarin has the above various pharmacological activities, causing widespread concern about puerarin and its derivatives.
- the puerarin oral absorption bioavailability is poor, which limits the application of oral dosage forms.
- the clinical application is mainly puerarin injection dosage form.
- the relevant literature reports mainly on structural modification or special dosage forms. Yang Ruolin et al. performed a series of derivatization of puerarin on methyl, methoxy, isopropyl, benzoyl, trityl, etc., and blood flow tests in rabbit eyes showed acetylation of the modified compound.
- Puerarin is an isoflavone carbon glycoside
- the hydroxyl group of the 4' position weak acid is its active group
- the isoflavone core is a planar structure
- Structural modification the 2" hydroxyl group Intramolecular Mi tsunobu reaction at the 7-position hydroxyl group, synthesis of 7, 2"-dehydrate puerarin (7, 2"-dehydrate puerarin;).
- one of the technical problems to be solved by the present invention is to provide a puerarin structural modified derivative 1-7, 2"- for the current situation of puerarin oral absorption bioavailability and clinical application only for injection.
- the second technical problem to be solved by the invention is to provide 7,2"-dehydrated puerarin and its salt derivatives in the preparation of therapeutic or/and prevention of cardiovascular and cerebrovascular diseases
- Applications of drugs including arrhythmias, coronary heart disease, angina pectoris, myocardial infarction, cerebral infarction and other cardiovascular and cerebrovascular diseases.
- the 7, 2"-dehydrated puerarin of the present invention has the following structural formula (I):
- 11 is 11.
- the 7, 2"-dehydrated puerarin salt derivative of the present invention refers to a hydroxyl group at the 4' position of 7, 2"-dehydrated kudzu root and various organic substances.
- a salt derivative formed by an inorganic base reaction for example, after the reaction, R may be Na+,
- the preparation method of 7, 2"-dehydrated puerarin of the invention is as follows: puerarin and strontium 3 and azo compound massage ratio
- the Y group in the PY 3 is any one of an aryl group, a fluorenyl group, a heteroaryl group or a decyloxy group.
- the azo compound is diisopropyl azodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD), hydrazine, hydrazine, hydrazine, ⁇ '-tetramethylazodicarbonamide (TMAD). Or any of azodiyldipiperidine (ADDP).
- the organic solvent is any one of tetrahydrofuran, dioxane, dichloromethane, chloroform, dimethylformamide, toluene, benzene or hexamethylphosphoric triamide.
- the hydroxyl group of the 4'-position weak acid of 7,2"-dehydrated puerarin of the present invention can react with various organic and inorganic strong bases to form a salt derivative of 7,2"-dehydrated puerarin to increase water solubility. And stability, improve its pharmacokinetic parameters.
- the 7, 2"-dehydrated puerarin and its salt derivative of the present invention can be used in any of the pharmaceutically acceptable dosage forms, and an oral preparation or an injection is preferred among the dosage forms.
- the phenolic hydroxyl group of many flavonoid glycosides can undergo dehydration reaction with the hydroxyl group of its glycosyl moiety to form a dehydrative derivative with strong biological activity (Tetrahedron 2004, 60, 9357-9379 : Bioorg. Med Chera. Lett. 2004, 14, 3201-3203; Org. Lett. 2009, 11, 2233-2236.
- puerarin is an isoflavone carbon glycoside
- the hydroxyl group of the 4' position weak acid is its active group
- the isoflavone core is a planar structure, so the inventors chose the 8-position glucopyranose group which can change the puerarin spatial structure for structural modification, and the intramolecular Mitsunobu reaction of the 2'-position hydroxyl group and the 7-position hydroxyl group to synthesize 7, 2 "-Dehydrated puerarin.
- the 7, 2"-dehydrated puerarin derivative of the present invention has good prevention and treatment effects on various cardiovascular and cerebrovascular diseases such as arrhythmia, coronary heart disease, angina pectoris, myocardial infarction and cerebral infarction, like puerarin, and has been experimentally tested. It is proved that part of its activity is significantly stronger than puerarin.
- the 7, 2"-dehydrated puerarin derivative of the present invention changes the polarity and spatial structure of puerarin itself to affect the water solubility of the compound and improve the cell membrane permeability of the drug.
- Figure 1 shows the physiological saline group ECG
- puerarin 2.9 g (about 7 mmol) of puerarin was dissolved in 200 ml of anhydrous tetrahydrofuran under N 2 protection, and added under ice bath. 1. 6 ml (about 10. 5 mmol) of diethyl azodicarboxylate and 2 ⁇ 8 g (about 10.5 ⁇ ol) of triphenylphosphine, slowly warmed to room temperature, and stirred magnetically for 16 h. 5% ⁇ The condensed, conventional silica gel column chromatography (CH 2 C1 2 : CH3OH - 13 : 1, 8: 1) to obtain 2. 187, 2"-dehydrated puerarin, the yield was 77.5%.
- Test 1 7, 2"-anti-arrhythmia test for dehydrated puerarin:
- the saline group was given a corresponding volume of 0.9% sodium chloride injection; the propylene glycol solvent-administered group was administered with 14.3% propylene glycol 1 ml/lOOg; the propylene glycol-soluble intravenous group was administered with 40% propylene glycol 0.5 ml/100 g; puerarin
- the injection group was administered at a dose of 50 mg kg ; the 7,2"-dehydrated puerarin group was administered at a dose of 60 mg kg, and the 7, 2"-dehydrated puerarin intravenous group was administered at a dose of 30 mg kg.
- the rats were intraperitoneally injected with 10% chloral hydrate (0.35 ml/100 g) and fixed in the dorsal position.
- the 7, 2"-dehydrated puerarin-administered group and the 7,2"-dehydrated puerarin group had significant effects on the duration of arrhythmia, which significantly shortened the duration of arrhythmia (" ⁇ 0.01) compared with the positive control puerarin, significantly shorten the duration of arrhythmia, there is statistically significant (# # P ⁇ 0.01, V ⁇ 0.05) o
- 7, 2 "- dehydration puerarin ⁇ group, 7, 2"-dehydrated puerarin gavage group significantly shortened the duration of arrhythmia, more significant than the 7, 2"-dehydrated puerarin iv group.
- the 7, 2"-dehydrated puerarin derivative of the present invention can significantly shorten the duration of arrhythmia, has good water solubility, and has high bioavailability.
- test tube was gently tilted once every 30 s to observe the end point of the coagulation (to slowly tilt the tube and the blood did not flow out as the end point).
- the clotting time between groups was compared.
- Statistical analysis was performed using SPSS software, and P ⁇ 0.05 was considered statistically significant.
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Description
7, 2"-脱水葛根素及其盐类衍生物以及其制备方法与应用 技术领域
本发明涉及葛根素衍生物及其制备方法与应用,尤其涉及 7, 2"-脱水葛根素及其盐类衍生 物及其制备方法与应用, 属于医药技术领域。
背景技术
葛根素是从豆科植物野葛、 甘葛藤根中提取的一种异黄酮苷, 研究发现其具有清除自由 基 (J. Agric. Food Chem. 2002, 50, 7504-7509. )、 降低血清胆固醇(J. Nat. Prod. 2003, 66, 788-792. )、 抗凝血以及抗变态反应(Biol. Pharm. Bull. 2002, 25, 1328- 1332. )等活 性, 临床上用于治疗冠心病(中国中西医结合杂志 2003, 23, 895-897. ) , 心绞痛(中国中西医 结合杂志 1998, 18, 282-284. ) , 心肌梗死(Chinese Med. J. 1992, 105, 11-17. )、 突发性 耳聋(第一军医大学学报 2002, 22, 1044- 1045)以及酒精中毒(Pharmacol. Biochem. Behav.
2003, 75, 593-606 ; Alcohol Clin. Exp. Res. 2003, 27, 177—185. )等。
正因为葛根素具有上述多种药理活性, 引起人们对葛根素及其衍生物的广泛关注。 但是 葛根素口服吸收生物利用度较差, 使口服剂型的应用受到限制, 临床主要是用葛根素的注射 液剂型, 为方便应用, 需要改善葛根素溶解性和生物利用度。 目前相关文献报道主要在于进 行结构修饰或采用特殊剂型。 杨若林等曾对葛根素进行了一系列甲基、 甲氧基、 异丙基、 苯 甲酰基、 三苯甲基等衍生化, 进行兔眼血流量试验表明所得结构修饰后的化合物中乙酰化和 三苯甲基化衍生物可显著增加血流量(中国药科大学学报 1999, 30, 81-85. )。 Dan Li 等利 用酶法对葛根素进行了多种糖基化反应, 其衍生物水溶性得到明显改善 (Carbohydr. Res.
2004, 339, 2789-2797. ) o 娄红祥等对葛根素进行了一系列乙酰水杨酰基衍生化, 抑制血小 板凝集活性实验表明, 7-乙酰水杨酰基葛根素对人体外血小板聚集反应具有非常显著的剂量 依赖性的抑制作用(ICs„=0. 91mmol. L"1),且抑制作用显著地强于单用相当量的阿司匹林和葛根 素 (CN200410036070. 9)。
据文献报道, 许多黄酮碳苷类化合物的酚羟基可与其糖基部分的羟基发生分子内脱水反 应生成具有较强的生物学活性的脱水衍生物 (Tetrahedron 2004, 60, 9357-9379 ; Bioorg. Med. Chem. Lett. 2004, 14, 3201-3203 ; Org. Lett. 2009, 11, 2233-2236· )。 但是, 经 检索, 目前尚未发现有 7, 2"-脱水葛根素衍生物的报道。
葛根素为异黄酮碳苷, 4'位显弱酸的羟基为其活性基团, 且由于异黄酮母核为平面结构, 因此我们选择了可改变葛根素空间结构的 8位吡喃葡萄糖基团进行结构改造, 将 2"位羟基与
7位羟基发生分子内 Mi tsunobu反应, 合成 7, 2"-脱水葛根素 (7, 2"-dehydrate puerarin;)。
发明内容
针对上述现有技术, 本发明要解决的技术问题之一是针对葛根素口服吸收生物利用度较 差、临床只有注射剂应用的现状, 提供一种葛根素结构修饰衍生物一一 7, 2"-脱水葛根素及其 盐类衍生物及其制备方法;本发明要解决的技术问题之二是提供 7, 2"-脱水葛根素及其盐类衍 生物在制备治疗或 /和预防心脑血管疾病的药物中的应用, 包括心律失常、 冠心病、 心绞痛、 心肌梗死、 脑梗死等心脑血管疾病。
本发明是通过以下技术方案实现的:
本发明的 7, 2"-脱水葛根素结构式如下式 ( I ):
( I )
其中, 11为11。
本发明的 7, 2"-脱水葛根素盐类衍生物, 是指 7, 2"-脱水葛根 4'位羟基与各种有机、
等离子中的任一种。
本发明的 7, 2"-脱水葛根素的制备方法为: 将葛根素与 ΡΥ3以及偶氮类化合物按摩尔比
1: ( 1〜4): ( 1 -4)混合, 在有机溶剂中, 发生分子内 Mitsunobu反应, 制得式 I化合物, 常规过滤、 浓縮、 硅胶柱层析, 将得到的 7, 2"-脱水葛根素分离纯化; 其合成反应示意如下:
所述 PY3中 Y基团为芳基、 垸基、 杂芳基或垸氧基中的任一种
所述偶氮类化合物为偶氮二甲酸二异丙酯 (DIAD)、偶氮二甲酸二乙酯 (DEAD)、 Ν,Ν,Ν',Ν'- 四甲基偶氮二甲酰胺 (TMAD)或偶氮二甲酰二哌啶 (ADDP)中的任一种。
所述有机溶剂为四氢呋喃、 二噁烷、 二氯甲垸、 氯仿、 二甲基甲酰胺、 甲苯、 苯或六甲 基磷酰三胺中的任一种。
本发明的的 7, 2"-脱水葛根素中 4'位显弱酸的羟基可与各种有机、 无机强碱反应, 生成 7, 2"-脱水葛根素的盐类衍生物, 以增加水溶性和稳定性, 改善其药代动力学参数。
本发明的的 7, 2"-脱水葛根素及其盐类衍生物在制备治疗或 /和预防心脑血管疾病的药物 中的应用, 包括心律失常、 冠心病、 心绞痛、 心肌梗死、 脑梗死等心脑血管疾病。
用本发明的 7, 2"-脱水葛根素及其盐类衍生物可制成任何一种药剂学上所述的剂型的药 物, 在所述的剂型中优选口服制剂或注射剂。
根据文献报道, 许多黄酮碳苷类化合物的酚羟基可与其糖基部分的羟基发生分子内脱水 反应生成具有较强的生物学活性的脱水衍生物 (Tetrahedron 2004, 60, 9357-9379 : Bioorg. Med. Chera. Lett. 2004, 14, 3201-3203; Org. Lett. 2009, 11, 2233-2236. ) 0 葛根素为 异黄酮碳苷, 4'位显弱酸的羟基为其活性基团, 且由于异黄酮母核为平面结构, 因此发明人 选择了可改变葛根素空间结构的 8位吡喃葡萄糖基团进行结构改造, 将 2"位羟基与 7位羟基 发生分子内 Mitsunobu反应, 合成 7, 2"-脱水葛根素。
本发明的 7, 2"-脱水葛根素衍生物与葛根素一样, 对心律失常、冠心病、心绞痛、心肌梗 死、 脑梗死等多种心脑血管疾病具有良好的预防与治疗作用, 且经实验证明, 其部分活性明 显强于葛根素。本发明的 7, 2"-脱水葛根素衍生物改变了葛根素本身的极性和空间结构, 以影 响化合物的水溶性, 改善药物的细胞膜通透功能, 增强在胃肠道中的吸收, 提高葛根素的口 服生物利用度, 克服了目前临床上葛根素口服吸收生物利用度较差的缺陷, 在制备心脑血管 疾病治疗与预防药物方面应具有良好的应用前景。
附图说明
图 1为生理盐水组 ECG;
图 2丙二醇溶媒灌胃组 ECG;
图 3丙二醇溶媒 iv组 ECG;
图 4葛根素注射液组 ECG;
图 5 7, 2"-脱水葛根素灌胃组 ECG;
图 6 7, 2"-脱水葛根素 iv组 ECG;
图 7 7, 2"-脱水葛根素 ^NMR;
图 87, 2"-脱水葛根素 l3C NMR;
注: 图 1〜6中上方标记分别为开始给予 0.1%BaCl2时的心电图、 给予 0.1%BaCl2后开始 出现心律失常的心电图、 以及从开始给予 0.1%BaCl2记录 30 min时的心电图。
具体实施方式
实施例 1: 7, 2"-脱水葛根素的制备:
将 2.9g (约 7匪01)葛根素在 N2保护下溶于 200ml无水四氢呋喃中, 冰浴条件下, 加入 3.5ml (约 17.5醒 ol) 偶氮二甲酸二异丙酯和 4.6g (约 17.5醒 ol)三苯基磷, 缓慢升至室温, 磁力搅拌 16h。 浓縮、 常规硅胶柱层析 (CH2C12: CH3OH= 13:l, 8: 1)得 2.4g 7, 2"-脱水葛根素, 收率为 87.1%。
7, 2"-脱水葛根素为白色粉末,分子式为 C21Hl808,结构式见式 I ,分子量 398, mp 258.4〜 260. ΓΟ; Ή NMR (600 MHz, CD30D): δ 8.23 (d, 1Η, / = 8.4 Hz) , 8.21(s, 1H), 7.39 (d, 2H, 8.4 Hz), 7.13 (d, 1H, 8.4 Hz), 6.87 (d, 2H, 8.4 Hz), 5.45 (d, 1H, J = 3.6 Hz), 4.81(t, 1H, = 3.6 Hz), 4.07 (dd, 1H, J = 4.8, 9.6 Hz), 3.87 (dd, 1H, / = 2,4, 12.0 Hz), 3.65 (m, 2H), 3.43 (m, 1H); 13C NMR (150 MHz, CD30D) : δ 61.8, 68.1, 72.1, 73.6, 79.1, 87.6, 110.1, 115.2, 116.2, 118.9, 122.9, 125.3, 129.9, 130.4, 153.3, 154, 1, 157.8, 166.2, 176.8; HRMS(ESI) m/z calcd for C21Hl80e[M+Na]+ 421.0894, found 421.0893. ( 7、 图 8所示)。
( I ).
实施例 2: 7, 2"-脱水葛根素的制备:
将 2.9g (约 7匪 ol)葛根素在 N2保护下溶于 200ml无水四氢呋喃中, 冰浴条件下, 加入 2.4g (约 14.0ramol) Ν,Ν,Ν',Ν'-四甲基偶氮二甲酰胺和 3.4ral (约 14. Ommol)三正丁基磷, 缓 慢升至室温, 磁力搅拌 16h。 浓縮、 常规硅胶柱层析 (CH2C12: CH30H = 13:1, 8: 1)得 2.2g 7, 2"- 脱水葛根素, 收率为 81.4%。
实施例 3: 7, 2"-脱水葛根素的制备:
将 2.9g (约 7mmol)葛根素在 N2保护下溶于 200ml无水四氢呋喃中, 冰浴条件下, 加入
1. 6ml (约 10. 5mmol) 偶氮二甲酸二乙酯和 2· 8g (约 10. 5匪 ol)三苯基磷, 缓慢升至室温, 磁力搅拌 16h。 浓缩、 常规硅胶柱层析 (CH2C12: CH3OH - 13 : 1, 8: 1)得2. 187,2"-脱水葛根素, 收率为 77. 5%。
试验 1 : 7, 2"-脱水葛根素的抗心律失常试验:
( 1 ) 方法: 取健康成年 Wistar大鼠 60只, 雄性, 180-220g, 按体重随机分为生理盐水 组,丙二醇溶媒灌胃组, 丙二醇溶媒 iv组,葛根素注射液组, 7, 2"-脱水葛根素灌胃组, 7,2"- 脱水葛根素 iv组, 10只 /组。 静脉注射组每天给药一次, 连续三天; 灌胃组每天给药两次, 给药三天。 生理盐水组给予相应体积的 0.9%氯化钠注射液; 丙二醇溶媒灌胃组给药剂量为 14.3%丙二醇 lml/lOOg;丙二醇溶媒静脉注射组给药剂量为 40%丙二醇 0.5ml/100g;葛根素注 射液组给药剂量为 50mg kg; 7,2"-脱水葛根素灌胃组给药剂量为 60mg kg, 7, 2"-脱水葛根素 静脉注射液组给药剂量为 30mg kg。 大鼠腹腔注射 10%水合氯醛麻醉(0.35ml/100g), 背位固 定。连接 BL~410生物机能实验系统, 监测心电变化。暴露股静脉, 插入头皮针, 连接恒速注 射泵, 以恒速注入 0.1%BaCl2, 0.1ml/100g,速度为 0.6ml/min。 注射时开始计算时间, 监测并 记录 30min内心电图 (ECG), 记录心律失常潜伏时间, 心律失常的持续时间 (30min内未恢复 记录为 30min)。 比较各组大鼠间差异, 并用 SPSS软件进行统计学分析, Ρ<0.05认为有统计 学差异。
(2)结果: 心电图如图 1〜图 6所示, 数据如表 1所示, 与生理盐水组比较, 7, 2"-脱水 葛根素灌胃组与 7, 2"-脱水葛根素 iv组对 0.1%BaCl2诱导的心律失常潜伏时间有所延长, 但 无统计学意义。 与生理盐水组比较, 7, 2"-脱水葛根素灌胃组与 7,2"-脱水葛根素^组对心律 失常持续时间有明显作用, 可显著縮短心律失常持续时间 ("Ρ<0.01 )。 与阳性对照葛根素 注射液比较, 也显著缩短心律失常持续时间, 有显著统计学意义 (# #P<0.01, V<0.05)o 此外, 与 7, 2"-脱水葛根素 ίν组比较, 7, 2"-脱水葛根素灌胃组更明显的缩短心律失常持续时 间, 较 7, 2"-脱水葛根素 iv组效果更显著。
表 1 7, 2"-脱水葛根素预防给药对大鼠心律失常的影响 (r±SD) 心律失常潜伏时间 心律失常持续时间
组别 剂量
(s) (min)
生理盐水组 NS 21.50±8.58 30
丙二醇溶媒灌胃组 1.4ml/kg 39.75±11.44 30
丙二醇溶媒 iv组 2ml/kg 75.75±20.35** 30
葛根素注射液组 SOmg kg 86.75±42.55" 30
7, 2"-脱水葛根素灌胃组 60mg/kg 29.25±5.12"* 2.09±0.98**"*
7, 2"-脱水葛根素 iv组 30mg/kg 47.25±19.87* 17.75±4.61 ***
与生理盐水组比较: *尸<0.05, *V<0.01.
与葛根素注射液组比较: ·><0.05, "V<0.01.
(3)结论: 本发明的 7, 2"-脱水葛根素衍生物可显著缩短心律失常持续时间, 水溶性良 好, 生物利用度高。
试验 2: 7, 2"-脱水葛根素的抗凝血试验:
( 1 ) 方法: 取家兔一只, 称重, 耳缘静脉注射 3%戊巴比妥钠 lml/kg。 麻醉后, 分离颈 动脉, 结扎远心端, 近心端插管, 取血 25ml。 分别放入预先加入 50mg ml草酸钾 0.5 ml的试 管中, 混匀。 另取预先加入相应药物 0.25ml的小试管 24只, 向每只小试管中加入上述兔血 0.9 ml,再各加 2mg/ml CaCl2 0.1ml,摇匀后立即放入 37±0.5°C的恒温水浴锅中。 每隔 30s, 将 试管轻轻倾斜一次, 观察记录凝血终点时间(以将试管慢慢倾斜, 血液不致流出为终点)。 比 较各组之间的凝血时间。 用 SPSS软件进行统计学分析, P<0.05认为有统计学差异。
(2) 结果: 数据如表 2所示, 与生理盐水组比较, 溶媒组及药物组明显延长凝血时间, 有统计学差异。 与阳性对照葛根素组比较, 7, 2"-脱水葛根素药物中, 高剂量组显著延长凝血 时间, 有显著统计学差异(##P<0.01 )。 与丙二醇溶媒组比较, 葛根素组及 7, 2"-脱水葛根素 中, 高剂量组显著延长凝血时间, 有统计学差异 (ΑΡ<0.05, ΑΑ <0.01, ΛΑΡ<0.01 )
表 2 7, 2"-脱水葛根素体外抗凝血作用研宄(r±SD) 组别 浓度 凝血时间 (min)
生理盐水组 NS 3.8±0.4
丙二醇溶媒组 20 % (v/v) il.7±1.5"
葛根素组 3mg ml : 15.3±2.4"A
7, 2"-脱水葛根素低剂量组 0.75mg ml 14.7±1.6**
7, 2"-脱水葛根素中剂量组 l.Smg ml 22.7±2.6""""
7, 2"-脱水葛根素高剂量组 3mg ml
与生理盐水组比较: *尸<0.05, "尸<0.01。
与葛根素组比较: "尸 <0.05, "" <0.01.
与丙二醇溶媒组比较: <0.05, AAP<0.01.
Claims
1. 7, 2"-脱水葛根素及其盐类衍生物, 其特征在于, 是指结构式如下式 ( I ) 的化合物, 及
( I )
其中, R为 H;
所述 7, 2"-脱水葛根素盐类衍生物, 是指 7, 2"-脱水葛根素的 4'位羟基与各种有机、 无机 碱反应生成的盐类衍生物。
2. 权利要求 1所述的 7, 2"-脱水葛根素及其盐类衍生物的制备方法,其特征在于,所述 7, 2"- 脱水葛根素的制备方法如下:将葛根素与 PY3以及偶氮类化合物按摩尔比 1: ( 1〜4 ): ( 1 ~ 4)混合, 在有机溶剂中, 发生分子内 Mitsunobu反应, 制得化合物 7, 2"-脱水葛根素, 常 规过滤、 浓縮、 硅胶柱层析, 将得到的 7, 2"-脱水葛根素分离纯化; 其中, PY3中 Y基团 为芳基、 垸基、 杂芳基或焼氧基中的任一种。
3. 根据权利要求 2所述的制备方法,其特征在于:所述偶氮类化合物为偶氮二甲酸二异丙酯、 偶氮二甲酸二乙酯、 Ν,Ν,Ν',Ν'-四甲基偶氮二甲酰胺或偶氮二甲酰二哌啶中的任一种。
4. 根据权利要求 2所述的制备方法, 其特征在于: 所述有机溶剂为四氢呋喃、二噁烷、二氯 甲垸、 氯仿、 二甲基甲酰胺、 甲苯、 苯或六甲基磷酰三胺中的任一种。
5. 权利要求 1所述的 7, 2"-脱水葛根素及其盐类衍生物在制备治疗或 /和预防心脑血管疾病的 药物中的应用。
6. 根据权利要求 5所述的应用, 其特征在于: 应用时, 制成口服制剂或注射剂。
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