WO2018232805A1 - 葛根素衍生物及其制备方法和在预防、治疗心脑血管疾病或糖尿病及其并发症中的用途 - Google Patents

葛根素衍生物及其制备方法和在预防、治疗心脑血管疾病或糖尿病及其并发症中的用途 Download PDF

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WO2018232805A1
WO2018232805A1 PCT/CN2017/093148 CN2017093148W WO2018232805A1 WO 2018232805 A1 WO2018232805 A1 WO 2018232805A1 CN 2017093148 W CN2017093148 W CN 2017093148W WO 2018232805 A1 WO2018232805 A1 WO 2018232805A1
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compound
formula
puerarin
pharmaceutically acceptable
group
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French (fr)
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娄红祥
孙斌
崔昌义
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山东大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D493/14—Ortho-condensed systems

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  • the present invention relates to the field of cardiovascular and vascular treatment of diabetes and the field of preparation of compounds, in particular, the present invention relates to the structure of novel derivatives of puerarin and a preparation method thereof, and the treatment and prevention of cardiovascular and cerebrovascular diseases or diabetes Use in complications.
  • Puerarin is a flavonoid compound distributed in the leguminous plants of kudzu and kudzu root, and is one of the main active ingredients of the Chinese medicine Pueraria.
  • puerarin is a class of beta blockers and calcium antagonists, with pharmacological effects such as dilatation of coronary arteries, blood pressure lowering, antiarrhythmia, hypoglycemic, hypolipidemic, diastolic smooth muscle, inhibition of platelet aggregation and antioxidants.
  • it is mainly used for the treatment of cardiovascular and cerebrovascular diseases such as hypertension, coronary heart disease, angina pectoris, acute cerebral infarction and hyperviscosity.
  • puerarin has a similar structure to the hypoglycemic substance phlorizin, both of which are flavonoids. Studies have shown that puerarin also has a certain blood sugar lowering function. Puerarin has important clinical application value because of its low toxicity, wide safety range and good curative effect.
  • puerarin has shortcomings such as poor water solubility and low oral bioavailability during clinical use, which limits its clinical use.
  • puerarin has a low water solubility of only 4.5 g/L.
  • puerarin injection requires the addition of high concentrations of propylene glycol and lysine, arginine, histidine and nicotinamide.
  • Solvents, and such cosolvents have limited effects, and may also cause toxic side effects such as allergic reactions and liver and kidney damage in the human body. Therefore, structural modification and modification of puerarin, development of new cardiovascular and cerebrovascular protective drugs and hypoglycemic drugs to enhance their water solubility, improve bioavailability and biological activity, have significant application value and market potential.
  • the prior art also discloses various derivatives which are structurally modified or modified to enhance the water solubility of puerarin and corresponding preparation methods, such as CN101712676A, which discloses the design and synthesis of a highly water-soluble puerarin derivative prodrug such as puerarin phosphate. Salt, sulfonate, etc. to enhance the water solubility of the drug; CN103382203A discloses improving the water solubility and fat solubility of puerarin by enhancing the targeted modification of the drug; CN103694229A prepares a water-soluble and fat-soluble puerarin derivative. There is a glucopyranose in the 8th position of puerarin, and a phenolic hydroxyl group in the 7th and 4' positions. It is the active group of puerarin and is the concentrated site of puerarin structure modification.
  • the present invention uses puerarin as a raw material, firstly by modifying its skeleton, reducing C ring ⁇ , ⁇ unsaturated double bonds, and destroying the molecular rigid structure. To improve its solubility; secondly, to further improve the molecular polarity and water solubility by further reducing the ketone carbonyl group to a hydroxyl group. Finally, several water-soluble puerarin derivatives were obtained.
  • the invention provides a novel derivative of puerarin, which has good water solubility, It has high activity and low preparation cost, and can be used as a promising drug for preventing and treating cardiovascular and cerebrovascular diseases.
  • the present invention relates to the following technical solutions:
  • R 1 represents an oxygen atom, a hydrogen atom, a hydroxyl group, an alkoxy group and a halogen atom
  • R 2 and R 3 represent a hydrogen atom, a hydroxyl group, a hydroxymethyl group or a halogen atom, respectively.
  • R 4 and R 5 may be independently selected from a hydrogen atom, a (C 1 -C 4 )alkyl group, an amino group Metal ions such as sodium ions, potassium ions, magnesium ions, calcium ions or zinc ions.
  • the puerarin derivative of the invention transforms the puerarin skeleton, reduces the C-ring ⁇ , ⁇ unsaturated double bond, destroys the molecular rigid structure, and improves the solubility thereof; further, by reducing the ketone carbonyl group to the hydroxyl group, Molecular polarity and water solubility.
  • the puerarin derivative (compound 1-10) of the present invention has a significantly improved water solubility (4.5 g/L) compared to puerarin, wherein the compounds 5 to 10 have the best water solubility of 20-25 g/L.
  • the solubility of the compounds 1 to 4 is slightly lower, both of which are about 10 g/L, but the solubility of puerarin is significantly improved.
  • the puerarin derivative of the present invention can effectively improve the water solubility and improve the bioavailability while maintaining or improving the physiological activity of puerarin, and is suitable for injection.
  • the compound may be a compound selected from the following structures:
  • the compounds of the invention are selected from the group consisting of compounds 5, 6, and 10.
  • the pharmaceutically acceptable salt of the compound of the present invention is also within the scope of the present invention, and the pharmaceutically acceptable salt of the compound is the compound and an inorganic base such as potassium hydroxide or sodium hydroxide. a salt formed by potassium carbonate, sodium carbonate, calcium chloride, calcium acetate or magnesium chloride, or a salt formed with an organic base such as tromethamine, aminoethanol, lysine or arginine.
  • a second object of the present invention is to provide a process for producing the above compound or a pharmaceutically acceptable salt thereof, which comprises the following reaction,
  • the compound represented by formula (IV) or formula (VI) is prepared by using puerarin (III) or formula 7, 2"-anhydropuerarin (V) as a starting material, respectively.
  • It is still another object of the present invention to provide a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof. It can be used either as a monomer or as a mixture of isomers.
  • the excipients used in the pharmaceutical compositions may be in solid or liquid form. Solid form preparations include powders, tablets, dispersion granules, capsules, pills, and suppositories. Powders and tablets may contain from about 5% to about 95% of the active ingredient. Suitable solid adjuvants can be magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, pills and capsules are solid dosage forms suitable for oral administration.
  • the liquid form preparations include solutions, suspensions and emulsions, and examples thereof are aqueous solutions for parenteral injection or water-propylene glycol solutions, or oral solutions in which sweeteners and contrast agents are added.
  • aqueous solutions for parenteral injection or water-propylene glycol solutions or oral solutions in which sweeteners and contrast agents are added.
  • it can also be used as a small water needle for injection, a freeze-dried powder for injection, a large infusion or a small infusion.
  • Another object of the present invention is to provide a compound of the above formula (I) or formula (II) or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for preventing and/or treating cardiovascular and cerebrovascular diseases or a hypoglycemic agent.
  • cardiovascular and cerebrovascular diseases include high blood Pressure, angina, heart failure, myocardial infarction, stroke and cerebral hemorrhage, in addition to diabetes and its complications.
  • Still another object of the present invention is to include a compound of the above formula (I) or formula (II) or a pharmaceutically acceptable salt thereof in combination with at least one other cardiovascular disease drug or hypoglycemic agent.
  • the atomic composition or structure of other cardiovascular disease drugs or hypoglycemic drugs covered is different from the compound of formula (I) or formula (II).
  • Other cardiovascular disease agents that can be used in combination with the novel compounds of the invention include those having antithrombotic, antiplatelet aggregation, antiatherosclerosis, anti-restenosis and/or anticoagulant, vasodilating activity, and diabetes and Its complications.
  • the present invention uses puerarin as a raw material to modify the skeleton thereof to reduce the C-ring ⁇ , ⁇ unsaturated double bond, thereby destroying the rigid structure of the molecule and improving its solubility; secondly, by further reducing the ketone carbonyl group to a hydroxyl group, Molecular polarity and water solubility, and finally obtained a number of well-water soluble puerarin derivatives.
  • composition of the present invention can increase the coronary blood flow of guinea pigs, relax the nociceptin-induced arterial contraction, and damage the rats with focal cerebral ischemia reperfusion injury. It has a protective effect and effectively maintains or enhances the physiological activity of puerarin while improving the bioavailability of puerarin.
  • the compound of the invention is simple and easy to prepare, has high compound activity and low preparation cost, and can be used as a promising drug for preventing and treating cardiovascular and cerebrovascular diseases.
  • Example 1 The structure of the compound of the present invention is as follows:
  • the pharmaceutically acceptable salt of the above compound is a salt of the compound with an inorganic base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, calcium chloride, calcium acetate or magnesium chloride, or with an organic base such as an amino group.
  • an inorganic base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, calcium chloride, calcium acetate or magnesium chloride, or with an organic base such as an amino group.
  • the compound puerarin (III) was weighed and placed in a dry round bottom flask, and dissolved in ethyl acetate. Then, 10% palladium carbon was added thereto, and the reaction was stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, palladium carbon was filtered off. The solvent was distilled off, and the obtained product was subjected to a flash reverse phase column, and the mobile phase was eluted with a gradient of methanol/water, and finally, the solvent was evaporated under reduced pressure to give Compounds 1 and 2 as white solid.
  • the compound puerarin (III) was weighed and placed in a dry round bottom flask, dissolved in ethyl acetate, and then 10% palladium on carbon was added thereto. The reaction was stirred at room temperature for 48 hours, and the progress of the reaction was monitored by TLC. After the reaction was completed, palladium carbon was filtered off. The solvent was distilled off, and the obtained product was subjected to a silica gel reversed phase column, and the mobile phase was eluted with a gradient of methanol/dichloromethane, and the solvent was evaporated under reduced pressure to give a mixture of compounds 5, 6, 7 and 8. Finally, through HPLC reverse phase column, the mobile phase was acetonitrile/water, and the pure products of compounds 5, 6, 7 and 8 were obtained, respectively.
  • the compound 3 was weighed and placed in a dry round bottom flask, dissolved in ethyl acetate, and then added with 10% palladium carbon. The reaction was stirred at room temperature for 36 hours. The reaction was monitored by TLC. After completion of the reaction, the palladium carbon was filtered off and the solvent was evaporated. The obtained product was passed through a silica gel reverse phase column, and the mobile phase was eluted with a gradient of methanol/dichloromethane, and the solvent was evaporated under reduced pressure to give a mixture of compounds 9 and 10. Finally, through HPLC reverse phase column, the mobile phase was acetonitrile/water, and the pure products 9 and 10 were obtained, respectively.
  • Compound 1-10 was tested at room temperature (25 ° C) for water solubility.
  • the water solubility of puerarin derivatives (compounds 1-10) was significantly higher than that of puerarin (4.5 g/L), and the solubility of compounds 5 to 10 was the best. It is 20-25 g/L, and the water solubility of the compounds 1 to 4 is slightly lower, both of which are about 10 g/L, and the compound 10 and the compound 5 and 6 having good water solubility are subjected to subsequent tests.
  • Example 6 Effect of compound of formula (I) or formula (II) on coronary flow in isolated guinea pigs
  • Instruments thermostat, oxygen supply system, constant pressure device, aortic cannula, surgical instruments
  • Drugs Puerarin injection, Compound 10, Compounds 5 and 6 were dissolved in sterile saline to 10 mg/ml and 5 mg/ml, respectively, and the intraperitoneal injection and gavage volume was 0.5 mL/100 g.
  • guinea pigs half male and half female, weighing 250-350g, were randomly divided into normal group, puerarin group (50mg/kg), compound 10 low dose group (25mg/kg,), compound 10 high dose group (50mg/kg). , low dose group of compound 5 and 6 mixture (25mg/kg), compound 5 and 6 mixture high dose group (50mg/kg) 4-5 per group, respectively, intraperitoneal injection, once a day for 10 days.
  • the normal group, the compound 10 high dose group (50 mg/kg), and the compound 5 and 6 mixture high dose group (50 mg/kg) were intragastrically administered for 7 days.
  • the lobes, trachea, etc., which are connected to the heart, are trimmed, and the aorta is hung on the aortic cannula to provide ex vivo conditions. After 10 minutes of stabilization, the coronary flow per minute was measured continuously for 20 min.
  • Puerarin group (50mg/kg), compound 10 low dose group (25mg/kg,), compound 10 high dose group (50mg/kg), compound 5 and 6 mixture low dose group (25mg/kg), compounds 5 and 6
  • the high-dose group (50 mg/kg) increased coronary blood flow in guinea pigs compared with the normal group.
  • the high dose group (50 mg/kg) of the compound 5 and 6 mixture was statistically significant compared with the normal group (intraperitoneal injection *P0.05; gavage **P0.01).
  • the high dose group of compound 5 and 6 (50 mg/kg) increased the coronary blood flow of guinea pigs more obviously.
  • Table 1 The specific results are shown in Table 1.
  • Example 7 Effect of a compound of formula (I) or formula (II) on aortic rings in rabbits
  • Example 8 Pharmacodynamic observation of the protective effect of the compound of formula (I) or formula (II) on focal cerebral ischemia reperfusion injury in rats
  • Intravenous administration (puerarin, compound 10, compound 5 and 6 were 100 mg/kg, sham group and model group were given the same volume of NS; 402 was intraperitoneally injected), and neurological score was observed after 24 hours; cardiac blood sampling (4000 rpm / min centrifuge for 10 min, take serum for use), decapitate the brain, freeze the refrigerator for 30 min, cut the rat brain into 6 pieces, set the TTC dye solution, 37 ° water bath for 30 min, take out the photo, use Jetta 801 form
  • the analysis software calculates the percentage of infarcts. The SOD and MDA contents were measured by biochemical methods.
  • Table 3 Effects of Compound 10, Compounds 5 and 6 on serum SOD and MDA in cerebral ischemia-reperfusion injury
  • Compound 10, compound 5 and mixture 6 can reduce the area of cerebral infarction caused by focal cerebral ischemia-reperfusion injury in rats and reduce the neurological score.
  • Compound 10, compound 5 and mixture 6 can increase serum SOD content and reduce MDA content caused by focal cerebral ischemia-reperfusion injury.

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Abstract

提供了式(I)或式(II)所示的葛根素衍生物或其药学上可接受的盐、其制备方法和在预防、治疗心脑血管疾病或糖尿病及其并发症中的用途。其中，（III）可代表是单键或双键；R1代表：氧原子、氢原子、羟基、烷氧基和卤素原子；R2和R3分别代表：氢原子、羟基、羟甲基、卤素原子、-O(O)CR4、-OSOR4、-OSO2R4、-O(O)PO2R4R5；上述化合物及其盐的医疗组合物可用于心脑血管疾病、糖尿病及并发症的预防和治疗，可以所述化合物作为主要成分制备相应的口服制剂和注射剂等，也可用于与其他心脑血管疾病治疗药物的联合治疗法。

Description

葛根素衍生物及其制备方法和在预防、治疗心脑血管疾病或糖尿病及其并发症中的用途 技术领域
本发明涉及心脑血管和糖尿病治疗领域以及化合物的制备领域，具体的，本发明涉及葛根素新型衍生物的结构及其制备方法以及这类衍生物在治疗和预防心脑血管疾病或糖尿病及其并发症中的用途。
背景技术
葛根素是从分布于豆科植物野葛和甘葛藤根中的一种黄酮类化合物，是中药葛根的主要活性成分之一。研究表明，葛根素是一类β受体阻断剂和钙离子拮抗剂，具有扩张冠状动脉、降血压、抗心律失常、降血糖、降血脂、舒张平滑肌、抑制血小板聚集和抗氧化等药理作用，临床上主要用于高血压、冠心病、心绞痛、急性脑梗死和高粘血症等心脑血管疾病的治疗。此外，葛根素与降糖物质根皮苷结构相似，两者均为黄酮类化合物，有研究证明葛根素也具有一定的降血糖功能。葛根素因其毒性低、安全范围广、疗效好等特点而具有重要的临床应用价值。
目前，葛根素在临床使用过程中存在水溶性差和口服生物利用度低等缺点，限制了其在临床上的使用范围。尤其是葛根素的水溶性较低，仅为4.5g/L，在临床使用中葛根素注射液大多需要加入高浓度的丙二醇以及赖氨酸、精氨酸、组氨酸和烟酰胺等作为助溶剂，而且这类助溶剂效果有限，同时还可能会引起人体的过敏反应以及肝肾损伤等毒副作用。因此，对葛根素进行结构改造和修饰，开发新型心脑血管保护药物以及降血糖药物，以增强其水溶性，提高生物利用度和生物学活性，具有重大应用价值和市场潜力。现有技术也公开了多种对葛根素进行结构修饰或改造来增强其水溶性的衍生物及相应制备方法，如CN101712676A公开了通过设计和合成高水溶新葛根素衍生物前药如葛根素磷酸盐、磺酸盐等来增强药物水溶性；CN103382203A公开了通过增强药物靶点性修饰改善葛根素水溶性和脂溶性；CN103694229A制备了水溶性和脂溶性良好的葛根素衍生物。葛根素的8位上连有一个吡喃葡萄糖碳苷，7，4′位上各有一个酚羟基，为葛根素的活性基团，是目前葛根素结构修饰的集中位点。
发明内容
针对现有技术存在的问题，为了克服葛根素水溶性差的缺点和不足，本发明以葛根素为原料，首先通过对其骨架进行改造，还原C环α，β不饱和双键，破坏分子刚性结构，提高其溶解性；其次，通过进一步还原酮羰基为羟基，提高分子极性和水溶性。最终得到了若干个水溶性良好的葛根素衍生物。本发明提供了一种葛根素新型衍生物，该药物具有水溶性好， 活性高，制备成本低廉等特点，可以作为预防和治疗心脑血管疾病很有前景的药物。
具体的，本发明涉及以下技术方案：
首先，本发明的一个目的在于，提供一种式(I)或式(II)所示的化合物或其药学上可接受的盐，
Figure PCTCN2017093148-appb-000001
其中，
Figure PCTCN2017093148-appb-000002
可代表是单键，也可代表双键；R1代表：氧原子、氢原子、羟基、烷氧基和卤素原子；R2和R3分别代表：氢原子、羟基、羟甲基、卤素原子，-O(O)CR4、-OSO3R4、-O(O)PO2R4R5；R4和R5可以独立选自氢原子、(C1-C4)烷基、氨基、金属离子，如钠离子、钾离子、镁离子、钙离子或锌离子等。
本发明优选的实施方案中，
Figure PCTCN2017093148-appb-000003
仅代表是单键。
本发明所述葛根素衍生物，是对葛根素骨架进行改造，还原C环α，β不饱和双键，破坏分子刚性结构，提高了其溶解性；进一步的，通过还原酮羰基为羟基，提高分子极性和水溶性。其中示例性的，本发明葛根素衍生物(化合物1-10)的水溶性较葛根素有显著提高(4.5g/L)，其中化合物5至10的水溶性最好，为20-25g/L，化合物1至4的水溶性略低，均为10g/L左右，但较葛根素溶解性有明显提升。本发明所述葛根素衍生物，在保持或提高葛根素生理活性的同时，有效的改善了其水溶性，提高生物利用度，适于做注射剂。
本发明优选的实施方案中，所述化合物可以是选自下列结构的化合物：
Figure PCTCN2017093148-appb-000004
更为优选的实施方案中，本发明所示的化合物选自化合物5、6、10。
优选的实施方案中，本发明所述化合物药学上可接受的盐，也是本发明的保护范围，所述化合物药学上可接受的盐为所述化合物与无机碱，例如氢氧化钾、氢氧化钠、碳酸钾、碳酸钠、氯化钙、醋酸钙或氯化镁形成的盐，或者与有机碱，例如氨基丁三醇、氨基乙醇、赖氨酸或精氨酸等形成的盐。
其次，本发明的目的之二在于提供上述化合物或其药学上可接受的盐的制备方法，所述化合物的制备方法包括如下反应，
Figure PCTCN2017093148-appb-000005
通过式(III)或(V)所示的化合物经催化氢化反应得到式(IV)或式(VI)所示的化合物，其中
Figure PCTCN2017093148-appb-000006
可代表是单键，也可代表双键；R1代表：氧原子、氢原子、羟基、烷氧基和卤素原子。
优选的实施方案中，式(IV)或式(VI)所示的化合物的制备分别是以葛根素(III)或式7,2”-脱水葛根素(V)为起始原料，通过以下方法制得：葛根素或脱水葛根素在钯碳催化下，在甲醇或乙酸乙酯溶液中，通过控制反应时间得到不同还原程度的如式(IV)或式(VI)所示的化合物，其中
Figure PCTCN2017093148-appb-000007
可代表是单键，也可代表双键；R1代表：氧原子、氢原子和羟基。
本发明的再一个目的在于，提供一种包含上述化合物或其药学上可接受的盐的药物组合物。既可以作为单体使用，也可以作为异构体的混合物使用。医药组合物所用的辅料可为固态或液态。固态形式的制剂包括粉剂、片剂、分散颗粒、胶囊、药丸及栓剂。粉剂及片剂可包含约5％至约95％的活性成分。适当的固体辅料可以是碳酸镁、硬脂酸镁、滑石粉、糖或者乳糖。片剂、粉剂、药丸及胶囊为适于口服用的固态剂型。液态形式的制剂包括溶液、悬浮液及乳液，其实施例为非经肠注射用水溶液或水-丙二醇溶液，或添加甜味剂及造影剂的口服溶液。此外，还可制成注射用小水针、注射用冻干粉针、大输液或小输液。
本发明的另一个目的在于，提供上述式(I)或式(II)化合物或其药学上可接受的盐在制备预防和/或治疗心脑血管疾病药物或降血糖药物中的用途。这些心脑血管疾病包括高血 压、心绞痛、心脏衰竭、心肌梗死、中风和脑出血疾病等，此外还有糖尿病及其并发症。
本发明的又有一个目的在于，包括上述式(I)或式(II)化合物或其药学上可接受的盐与至少一种其它心血管疾病药物或降糖药物合用。所涵盖的其它心血管疾病药物或降糖药物的原子组成或结构均异于式(I)或式(II)的化合物。可与本发明新颖化合物组合使用的其它心血管疾病药物包括具有抗血栓形成、抗血小板聚集、抗动脉粥样硬化、抗再狭窄症及/或抗凝血、血管舒张活性的药物，以及糖尿病及其并发症。
本发明取得了以下有益效果：
(1)本发明以葛根素为原料，通过对其骨架进行改造，还原C环α，β不饱和双键，破坏分子刚性结构，提高其溶解性；其次，通过进一步还原酮羰基为羟基，提高分子极性和水溶性，最终得到了若干个水溶性良好的葛根素衍生物。
(2)通过动物实验证实，本发明所述组合物能增加豚鼠的冠脉血流量、对去甲肾上腺素所致的动脉收缩有舒张作用、对大鼠局灶性脑缺血再灌住损伤具有保护作用，在提高葛根素生物利用性的同时，有效的保持或提高了葛根素生理活性。
(3)本发明所述化合物制备简单易行，具有化合物活性高，制备成本低廉等特点，可以作为预防和治疗心脑血管疾病很有前景的药物。
附图说明
图1：去甲肾上腺素对动脉收缩的影响—空白对照
图2：葛根素对由去甲肾上腺素引起的动脉收缩的舒张作用
图3：化合物10对由去甲肾上腺素引起的动脉收缩的舒张作用
图4：化合物5和6混合物对由去甲肾上腺素引起的动脉收缩的舒张作用
具体实施方式
本发明列举实施例如下,对本发明作进一步详细说明,但本发明的实施方式不限于此。对于本领域的技术人员来说,本发明可以有各种更改和变化,凡在本发明的精神和原则之内,所作的任何修改、等同替换或改进等,均应包含在本发明的保护范围之内。
实施例一：本发明所述化合物的结构如下：
Figure PCTCN2017093148-appb-000008
上述化合物药学上可接受的盐为所述化合物与无机碱，例如氢氧化钾、氢氧化钠、碳酸钾、碳酸钠、氯化钙、醋酸钙或氯化镁形成的盐，或者与有机碱，例如氨基丁三醇、氨基乙醇、赖氨酸或精氨酸等形成的盐。
实施例二：化合物1和2的制备
Figure PCTCN2017093148-appb-000009
称取化合物葛根素(III)置于干燥圆底烧瓶中，加入乙酸乙酯加以溶解，随后加入10％鈀碳，室温下搅拌反应6小时，TLC监测反应进程，反应结束后，滤除鈀碳，蒸除溶剂，所得产物过Flash反相柱，流动相为甲醇/水梯度洗脱，最后减压蒸去溶剂，得白色固体化合物1和2。
化合物1：MS m/z:419(M+1)；1H NMR(400MHz,MeOD)δ7.75(d,J＝8.8Hz,1H),7.08(d,J＝8.6Hz,2H),6.75(d,J＝8.5Hz,2H),6.54(d,J＝8.8Hz,1H),4.93–4.88(m,2H),4.63–4.52(m,2H),4.04(s,1H),3.87(dd,J＝11.9,1.9Hz,1H),3.73(dd,J＝11.9,4.9Hz,1H),3.50–3.36(m,3H).
化合物2：MS m/z:419(M+1)；1H NMR(400MHz,MeOD)δ7.75(d,J＝8.8Hz,1H),7.12(d,J＝8.5Hz,2H),6.74(d,J＝8.5Hz,2H),6.55(d,J＝8.8Hz,1H),4.95–4.89(m,2H),4.64–4.54(m,2H),4.01(s,1H),3.87(dd,J＝12.0,2.0Hz,1H),3.77–3.70(m,1H),3.50–3.37(m,3H).
实施例三：化合物3和4的制备
Figure PCTCN2017093148-appb-000010
称取化合物脱水葛根素(V)置于干燥圆底烧瓶中，加入乙酸乙酯加以溶解，随后加入10％鈀碳，室温下搅拌反应6小时，TLC监测反应进程，反应结束后，滤除鈀碳，蒸除溶剂，所得产物过Flash反相柱，流动相为甲醇/水梯度洗脱，最后减压蒸去溶剂，得白色固体化合物3和4。
化合物3：MS m/z:401(M+1)；1H NMR(600MHz,CD3OD)δ7.92(d,J＝8.6Hz,1H),7.08(d,J＝8.6Hz,2H),6.77(d,J＝8.6Hz,2H),6.68(d,J＝8.6Hz,1H),5.18(d,J＝3.3Hz,1H),4.70–4.55(m,3H),4.00-3.97(m,2H),3.84(dd,J＝12.1,2.5Hz,1H),3.64(dd,J＝12.1,5.7Hz,1H),3.60(t,J＝9.4Hz,1H),3.35(ddd,J＝9.3,5.7,2.3Hz,1H).
化合物4：MS m/z:401(M+1)；1H NMR(600MHz,CD3OD)δ7.92(d,J＝8.6Hz,1H),7.09(d,J＝8.6Hz,2H),6.74(d,J＝8.6Hz,2H),6.68(d,J＝8.5Hz,1H),5.18(d,J＝3.3Hz,1H),4.71–4.63(m,3H),3.98(dd,J＝9.5,4.8Hz,1H),3.88(dd,J＝7.4,5.3Hz,1H),3.84(dd,J＝12.0,2.4Hz,1H),3.64(dd,J＝12.1,5.8Hz,1H),3.59(t,J＝9.4Hz,1H),3.35(ddd,J＝8.0,5.8,2.4Hz,1H).
实施例四：化合物5-8的制备
Figure PCTCN2017093148-appb-000011
称取化合物葛根素(III)置于干燥圆底烧瓶中，加入乙酸乙酯加以溶解，随后加入10％鈀碳，室温下搅拌反应48小时，TLC监测反应进程，反应结束后，滤除鈀碳，蒸除溶剂，所得产物过硅胶反相柱，流动相为甲醇/二氯甲烷梯度洗脱，减压蒸去溶剂，得化合物5、6、7和8的混合物。最后通过HPLC反相柱，流动相为乙腈/水，分别得到化合物5、6、7和8纯品。
化合物5：MS m/z:421(M+1)；1H NMR(400MHz,MeOD)δ7.24(d,J＝8.6Hz,1H),7.07(d,J＝8.5Hz,2H),6.73(d,J＝8.5Hz,2H),6.46(d,J＝8.5Hz,1H),4.77(d,J＝7.2Hz,1H),4.29(dd,J＝11.1,3.6Hz,1H),4.17(dd,J＝11.0,8.6Hz,1H),4.01–3.91(m,1H),3.84(dd,J＝11.8,1.8Hz,1H),3.74(dd,J＝12.1,5.0Hz,1H),3.46(t,J＝7.3Hz,2H),3.40-3.36(m,1H),3.01(td,J＝8.1,3.5Hz,1H).
化合物6：MS m/z:421(M+1)；1H NMR(400MHz,MeOD)δ7.12(d,J＝8.6Hz,2H),7.08(d,J＝8.5Hz,1H),6.76(d,J＝8.6Hz,2H),6.44(d,J＝8.4Hz,1H),4.60(d,J＝2.2Hz,1H),4.47(dd,J＝11.9,10.7Hz,1H),4.22(dd,J＝10.3,2.6,1H),3.99(t,J＝8.9Hz,1H),3.85(dd,J＝12.1,2.2Hz,1H),3.75(dd,J＝12.1,4.9Hz,1H),3.49(t,J＝7.3Hz,2H),3.40-3.36(m,1H),3.11(dt,J＝12.0,3.2Hz,1H).
化合物7：MS m/z:421(M+1)；1H NMR(400MHz,MeOD)δ7.12(d,J＝8.5Hz,2H),7.09(d,J＝8.4Hz,1H),6.76(d,J＝8.5Hz,2H),6.44(d,J＝8.4Hz,1H),4.61(d,J＝2.1Hz,1H),4.45(dd,J＝12.0,10.5Hz,1H),4.25(dd,J＝10.3,2.4Hz,1H),3.99(t,J＝8.7Hz,1H),3.85(dd,J＝12.0,2.1Hz,1H),3.76(dd,J＝12.0,4.8Hz,1H),3.48(t,J＝8.3Hz,2H),3.43–3.37(m,1H),3.15(dt,J＝12.1,3.2Hz,1H).
化合物8：MS m/z:421(M+1)；1H NMR(400MHz,MeOD)δ7.21(d,J＝8.6Hz,1H),7.11(d,J＝8.3,2H),6.73(d,J＝8.3Hz,2H),6.45(dd,J＝8.4,3.1Hz,1H),4.71(d,J＝6.8Hz,1H),4.30(dd,J＝11.1,3.7Hz,1H),4.22(dd,J＝11.1,7.8Hz,1H),3.96(t,J＝8.9Hz,1H),3.85(dd,J＝12.0,2.2Hz,1H),3.76(dd,J＝12.1,4.7Hz,1H),3.48(t,J＝8.1Hz,2H),3.43–3.37(m,1H),2.99(td,J＝7.4,3.7Hz,1H).
实施例五：化合物9和10的制备
Figure PCTCN2017093148-appb-000012
称取化合物3置于干燥圆底烧瓶中，加入乙酸乙酯加以溶解，随后加入10％鈀碳，室温下搅拌反应36小时，TLC监测反应进程，反应结束后，滤除鈀碳，蒸除溶剂，所得产物过硅胶反相柱，流动相为甲醇/二氯甲烷梯度洗脱，减压蒸去溶剂，得化合物9和10的混合物。最后通过HPLC反相柱，流动相为乙腈/水，分别得到化合物9和10纯品。
化合物9：MS m/z:403(M+1)；1H NMR(600MHz,CD3OD)δ7.36(d,J＝8.3Hz,1H),7.08(d,J＝8.5Hz,2H),6.73(d,J＝8.6Hz,2H),6.53(d,J＝8.3Hz,1H),5.07(d,J＝3.3Hz,1H),4.80(d,J＝7.3Hz,1H),4.52(dd,J＝4.7,3.4Hz,1H),4.35(dd,J＝11.1,3.7Hz,1H),4.27(dd,J＝11.1,8.4Hz,1H),3.93(dd,J＝9.5,4.8Hz,1H),3.84(dd,J＝12.0,2.3Hz,1H),3.60(dd,J＝12.1,6.1Hz,1H),3.55(t,J＝9.4Hz,1H),3.34–3.32(m,1H),3.03(td,J＝7.9,3.6Hz,1H).
化合物10：MS m/z:403(M+1)；1H NMR(400MHz,CD3OD)δ7.09(d,J＝8.3Hz,2H),7.08(d,J＝8.4Hz,1H),6.68(d,J＝8.5Hz,2H),6.43(d,J＝8.1Hz,1H),4.92(d,J＝3.1Hz,1H),4.52–4.40(m,3H),4.35(dd,J＝4.8,3.1Hz,1H),4.21–4.10(m,1H),3.76(dd,J＝9.4,4.7Hz,1H),3.68–3.55(m,1H),3.42-3.38(m,1H),3.13(ddd,J＝8.9,5.3,1.9Hz,1H),3.05(dt,J＝12.3,2.9Hz,1H).
化合物1-10室温(25℃)进行水溶性试验，葛根素衍生物(化合物1-10)的水溶性较葛根素有显著提高(4.5g/L)，其中化合物5至10的水溶性最好，为20-25g/L，化合物1至4的水溶性略低，均为10g/L左右，取水溶性较好的化合物10、化合物5、6进行后续试验。
实施例六：式(I)或式(II)化合物对离体豚鼠冠脉流量的影响
1.材料：
动物：豚鼠
仪器：恒温装置、供氧***、恒压装置、主动脉套管、手术器械
药品：葛根素注射液、化合物10、化合物5和6混合物，分别用无菌生理盐水溶解成10mg/ml和5mg/ml，腹腔注射和灌胃体积为0.5mL/100g。
2.方法：
(1)豚鼠雌雄各半，体重250-350g，随机分为正常组、葛根素组(50mg/kg)，化合物10低剂量组(25mg/kg,)、化合物10高剂量组(50mg/kg)、化合物5和6混合物低剂量组 (25mg/kg)、化合物5和6混合物高剂量组(50mg/kg)每组4-5只，分别腹腔注射，每天一次，共10天。
另外还有正常组、化合物10高剂量组(50mg/kg)、化合物5和6混合物高剂量组(50mg/kg)分别灌胃给药，共7天。
(2)采用Langendorff法观察化合物对冠脉流量的影响，调节恒温恒压灌流仪器：温度37±0.5℃，氧气2-3个/s，压力40-60cm水柱。
(3)于末次给药30min后，20％乌拉坦(0.5ml/100g)麻醉，剪胸部皮肤，自剑突处剪开胸骨，迅速打开胸腔，暴露心脏，左手轻轻拿住心脏，剪断上下腔静脉、肺动脉、主动脉及心脏周围的组织，摘出心脏。置于充氧的4℃任洛氏液的培养皿中，用手指轻轻挤压心脏，使心室内残血排出，去除心包膜，找到主动脉。修剪连接在心脏上的肺叶、气管等累赘物，主动脉挂在主动脉套管上，供给离体条件。稳定10min后连续测定20min的每分冠脉流量。
3.结果：
葛根素组(50mg/kg)，化合物10低剂量组(25mg/kg,)、化合物10高剂量组(50mg/kg)、化合物5和6混合物低剂量组(25mg/kg)、化合物5和6混合物高剂量组(50mg/kg)与正常组相比，都能增加豚鼠的冠脉血流量。化合物5和6混合物高剂量组(50mg/kg)与正常组相比有统计学意义(腹腔注射*P0.05；灌胃**P0.01)。与葛根素组相比，化合物5和6混合物高剂量组(50mg/kg)对豚鼠的冠脉血流量的增加更明显，具体结果见表1。
表1：葛根素衍生物对离体豚鼠冠脉流量的影响
Figure PCTCN2017093148-appb-000013
与相同给药途径的正常组相比：*P0.05，**P0.01。
4.结论：葛根素衍生物5和6混合物对豚鼠的冠脉血流量的增加更明显。
实施例七：式(I)或式(II)化合物对家兔主动脉环的作用
1.方法：
取家兔，棒击致昏，颈动脉放血致死，迅速开胸取出胸主动脉，置冷克亨氏液中，分离周围的组织，剪成0.5mm大小的环，备用，将其动脉环置恒温浴槽中(内有10ml克亨氏液)，并与压力换能器链接，(前负荷定为2g)，将其电信号传入电脑。37度恒温，通O2，稳定2小时后，给予10-6mmol/L去甲肾上腺素，待其是动脉收缩达高峰后，分别加入累加浓度的葛根素、化合物10、化合物5和6混合物0.1mg/ml、0.5mg/ml、1mg/ml、2mg/ml(生理盐水组加入同体积的生理盐水)，观察血管的舒张情况。
2.结果
具体结果如图1至图4所示，其中纵坐标代表动脉血管收缩张力，数值越高，血管收缩力越大。横坐标代表时间。由结果可知，化合物10以及化合物5和6混合物对去甲肾上腺素所致的动脉收缩有舒张作用。
实施例八：式(I)或式(II)化合物对大鼠局灶性脑缺血再灌住损伤保护作用的药效学观察
1.方法：
取90只SD雄性大鼠，体重280-320g，随机分为5组，实验前12小时，禁食不禁水。2％戊巴比妥钠溶液0.2ml/100g腹腔注射麻醉，仰位固定，用栓线法制作局灶性脑缺血再灌注损伤模型(缺血2小时再灌注24小时)，缺血后即刻静脉注射给药(葛根素、化合物10、化合物5和6混合物均为100mg/kg，sham组和模型组给予同容量的NS；402为腹腔注射)，24小时后观察神经学评分；心脏取血(4000转/min离心10min，取血清备用)，断头取脑，冰箱冷冻30min，将鼠脑横切成6片，置TTC染液中，37度水浴中30min，取出拍照，用捷达801形态分析软件计算梗塞面机百分比。用生化法检测SOD和MDA含量。
2.结果
具体实验结果如表2和表3所示：
表2：化合物10、化合物5和6混合物对脑缺血再灌注损伤的保护作用
Figure PCTCN2017093148-appb-000014
Figure PCTCN2017093148-appb-000015
注：###p<0.001，vs假手术组；*p<0.05,**p<0.01,***p<0.001，vs模型组。
表3：化合物10、化合物5和6混合物对脑缺血再灌注损伤血清SOD、MDA的影响
Figure PCTCN2017093148-appb-000016
注：###p<0.001，vs假手术组；***p<0.001，vs模型组。
3.结论
(1)化合物10、化合物5和6混合物都可以减小大鼠局灶性脑缺血再灌注损伤所致的脑梗塞面积，降低神经学评分。
(2)化合物10、化合物5和6混合物都可以升高局灶性脑缺血再灌注损伤所致的血清SOD含量，降低其MDA含量。

Claims (10)

  1. 一种结构如式(I)或式(II)所示的化合物或其药学上可接受的盐；
    Figure PCTCN2017093148-appb-100001
    其中，
    Figure PCTCN2017093148-appb-100002
    可代表是单键，也可代表双键；R1代表：氧原子、氢原子、羟基、烷氧基和卤素原子中的一种；R2和R3分别代表：氢原子、羟基、羟甲基、卤素原子，-O(O)CR4、-OSO3R4、-O(O)PO2R4R5，R4和R5可以独立选自氢原子、(C1-C4)烷基、钠离子、钾离子、镁离子、钙离子、锌离子或氨基。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，所述化合物是选自下列结构的化合物：
    Figure PCTCN2017093148-appb-100003
  3. 根据权利要求1或2任意一项所述的化合物或其药学上可接受的盐，其特征在于，所述化合物药学上可接受的盐为所述化合物与无机碱形成的盐，或者与有机碱形成的盐，优选的，无机碱选自氢氧化钾、氢氧化钠、碳酸钾、碳酸钠、氯化钙、醋酸钙或氯化镁，有机碱选自氨基丁三醇、氨基乙醇、赖氨酸或精氨酸。
  4. 一种权利要求1-3中任一项所述的化合物或其药学上可接受的盐的制备方法，其特征在于，所述化合物的制备方法包括如下反应，
    Figure PCTCN2017093148-appb-100004
    通过式(III)或(V)所示的化合物经催化氢化反应得到式(IV)或式(VI)所示的化合物，其中
    Figure PCTCN2017093148-appb-100005
    可代表是单键，也可代表双键；R1代表：氧原子、氢原子、羟基、烷氧基和卤素原子。
  5. 根据权利要求4所述的制备方法，其特征在于，式(IV)或式(VI)所示的化合物的制备分别是以葛根素(III)或7,2”-脱水葛根素(V)为起始原料，通过以下方法制得：葛根素或7,2”-脱水葛根素在钯碳催化下，在甲醇或乙酸乙酯溶液中，通过控制反应时间得到不同还原程度的如式(IV)或式(VI)所示的化合物。
  6. 一种药物组合物，其包含权利要求1-3中任一项所述的化合物或其药学上可接受的盐，其作为单体使用，或者作为异构体混合物使用。
  7. 根据权利6所述的药物组合物，其特征在于，所述药物组合物还包括一种或多种药学上可接受的载体、赋形剂、助溶剂和/或稀释剂。
  8. 根据权利要求6或7所述的药物组合物，其特征在于，所述药物组合物为固体口服制剂、液体口服制剂或注射剂。
  9. 根据权利要求6至8中任一项所述的药物组合物，其特征在于，所属药物组合物为片剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小水针、注射用冻干粉针、大输液或小输液。
  10. 根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐或者权利要求6-9任一项所述的药物组合物的用途，所述用途为在制备预防和/治疗心脑血管疾病和/糖尿病及其并发症药物中的应用，
    优选的，心脑血管疾病选自动脉粥样硬化、再狭窄症、高血压、心绞痛、心脏衰竭、心肌梗死、中风和脑出血；
    优选的，权利要求1至3中任一项所述的化合物或其药学上可接受的盐或者权利要求6-9任一项所述的药物组合物与其他心脑血管疾病治疗药物或其他糖尿病治疗药物在临床上的联合应用。
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