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WO2018232805A1 - Dérivé de puérarine, son procédé de préparation et son utilisation pour la prévention et le traitement de maladies cardiovasculaires et cérébrovasculaires ou du diabète et de leurs complications - Google Patents

Dérivé de puérarine, son procédé de préparation et son utilisation pour la prévention et le traitement de maladies cardiovasculaires et cérébrovasculaires ou du diabète et de leurs complications Download PDF

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Publication number
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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Prior art keywords
compound
formula
puerarin
pharmaceutically acceptable
group
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English (en)
Chinese (zh)
Inventor
娄红祥
孙斌
崔昌义
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Shandong University
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Shandong University
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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

Definitions

  • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un dérivé de puérarine représenté par la formule (I) ou la formule (II) ou son sel pharmaceutiquement acceptable, son procédé de préparation, et son utilisation pour la prévention et le traitement de maladies cardiovasculaires et cérébrovasculaires ou du diabète et de leurs complications. (III) peut représenter une liaison simple ou une liaison double ; R1 représente un atome d'oxygène, un atome d'hydrogène, un groupe hydroxyle, un groupe alcoxy, ou un atome d'halogène ; et R2 et R3 représentent individuellement un atome d'hydrogène, un groupe hydroxyle, un groupe hydroxyméthyle, un atome d'halogène, -O(O)CR4, -OSOR4, -OSO2R4, ou -O(O)PO2R4R5. Une composition médicale du composé ci-dessus et son sel peuvent être utilisés pour la prévention et le traitement de maladies cardiovasculaires et cérébrovasculaires ou du diabète et de leurs complications. Le composé peut être utilisé comme ingrédient principal pour la préparation d'une formulation orale correspondante et d'une injection. Le composé peut également être utilisé avec d'autres médicaments dans des régimes de polytraitement pour traiter des maladies cardiovasculaires et cérébrovasculaires.
PCT/CN2017/093148 2017-06-19 2017-07-17 Dérivé de puérarine, son procédé de préparation et son utilisation pour la prévention et le traitement de maladies cardiovasculaires et cérébrovasculaires ou du diabète et de leurs complications Ceased WO2018232805A1 (fr)

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CN201710464386.5A CN107311991B (zh) 2017-06-19 2017-06-19 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
CN201710464386.5 2017-06-19

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CN101921282A (zh) * 2010-04-29 2010-12-22 山东大学 7,2"-脱水葛根素及其盐类衍生物以及其制备方法与应用
CN107098893A (zh) * 2017-05-31 2017-08-29 陕西中医药大学 一种葛根素衍生物及其制备方法和应用

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CN101353346A (zh) * 2007-07-23 2009-01-28 北京美倍他药物研究有限公司 葛根素的氨基酸酯衍生物及其医药用途

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CN101921282A (zh) * 2010-04-29 2010-12-22 山东大学 7,2"-脱水葛根素及其盐类衍生物以及其制备方法与应用
CN107098893A (zh) * 2017-05-31 2017-08-29 陕西中医药大学 一种葛根素衍生物及其制备方法和应用

Non-Patent Citations (3)

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HE, XIANZHI ET AL.: "A Genomic Approach to Isoflavone Biosynthesis in Kudzu (Pueraria Lobata)", PLANTA, vol. 233, 11 January 2011 (2011-01-11), pages 843 - 855, XP055555276 *
KATO, EISUKE ET AL.: "Glucose Uptake Enhancing Activity of Puerarin and the Role of C-glucoside Suggested From Activity of Related Compounds", BIOORG. MED. CHEM. LETT., vol. 20, 17 June 2010 (2010-06-17), pages 4333 - 4336, XP027137488 *

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