A magnesium complex with aspirin or its hypoxia-promoted derivative as ligand, preparation method and application

Abstract

The application discloses a magnesium complex taking aspirin or an oxygen-deficiency promoting derivative thereof as a ligand, a preparation method and application thereof in preparation of a medicine for treating coronary heart disease. The structural formula of the magnesium complex is shown in the following formula I-IV: the magnesium carbonate is reacted with nitric acid to obtain magnesium nitrate; the aspirin is reacted with sodium bicarbonate to obtain a neutral sodium salt of aspirin; the neutral sodium salt of aspirin is reacted with the magnesium nitrate according to a molar ratio of 1:1 or 2:1 to obtain the magnesium complex shown in the formula I or II. The aspirin is reacted with p-nitrobenzyl alcohol to obtain an oxygen-deficiency promoting derivative of aspirin; the oxygen-deficiency promoting derivative of aspirin is reacted with the magnesium nitrate according to a molar ratio of 1:1 or 2:1 to prepare the magnesium complex shown in the formula III or IV. The application has a remarkable repairing effect on heart damage caused by myocardial ischemia and the like.

Description

Technical Field

[0001] This invention relates to a magnesium complex with aspirin as a ligand or a hypoxia-induced magnesium complex with aspirin derivative as a ligand and its preparation method, and also to its application in the preparation of drugs for treating coronary heart disease, belonging to the field of new pharmaceutical technology. Background Technology

[0002] According to data from the World Health Organization, my country has as many as 330 million cardiovascular disease patients. Its incidence and mortality rates both exceed those of cancer, making it the leading cause of death from cardiovascular disease. Among these, coronary heart disease accounts for 47% of all cardiovascular disease deaths, and this number has been increasing year by year in recent years, making it the leading cause of death among cardiovascular disease patients.

[0003] Coronary artery stenosis and blockage leading to myocardial hypoxia is the common pathological basis for angina pectoris, myocardial infarction, ischemic cardiomyopathy, and even sudden cardiac death coronary heart disease. Magnesium plays a crucial role in the prevention and treatment of these diseases. First, magnesium helps maintain normal contraction and relaxation of the heart muscle, keeping the heart rhythm stable. Second, magnesium can dilate blood vessels, promote blood circulation, lower blood pressure, and reduce the risk of arteriosclerosis. Third, magnesium also has anti-inflammatory and antioxidant effects, playing a positive role in the prevention of cardiovascular diseases. Studies have shown that magnesium deficiency is common among patients with cardiovascular diseases, and adequate magnesium intake is essential for preventing cardiovascular diseases. However, the existing range of magnesium supplements is limited, and no magnesium supplements specifically for the treatment of cardiovascular diseases have been found. For example, magnesium sulfate and magnesium oxide are mainly used to treat digestive problems and do not have a good effect on blood magnesium supplementation. Magnesium glycine can reduce chronic inflammation, and magnesium citrate can calm the nerves and relieve stress, but their organic components are ordinary amino acids or organic acids, and they do not have the function of treating cardiovascular diseases. Summary of the Invention

[0004] Aspirin inhibits platelet aggregation and prevents thrombus formation, and is widely used in the treatment of myocardial infarction and coronary heart disease. When used in combination with magnesium, it not only has antithrombotic effects but also promises to dilate blood vessels, maintain cardiac contraction and relaxation, and enhance efficacy. Combining magnesium ions with functional organic small molecules such as aspirin to prepare functional magnesium complexes offers advantages over inorganic salt drugs and organic small molecule drugs in terms of efficacy, safety, and stability, representing an effective approach to obtaining ideal treatments for ischemic heart disease.

[0005] Based on this, the purpose of the present invention is to provide a magnesium complex with aspirin as a ligand or a hypoxia-induced magnesium complex with aspirin derivatives as ligands, a preparation method thereof, and its application in the preparation of drugs for coronary heart disease.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] In a first aspect, the present invention provides a magnesium complex, the structural formula of which is shown in formulas I to IV below:

[0008] .

[0009] In a second aspect, the present invention provides a method for preparing magnesium complexes represented by Formula I and Formula II, comprising the following steps:

[0010] Magnesium carbonate is reacted with nitric acid to produce magnesium nitrate;

[0011] Aspirin is reacted with sodium bicarbonate to obtain neutral sodium aspirin.

[0012] Neutral sodium aspirin was reacted with magnesium nitrate in a molar ratio of 1:1 or 2:1 to obtain the magnesium complexes shown in Formula I and Formula II, respectively.

[0013] Furthermore, the molar ratio of magnesium carbonate to nitric acid is 1:2, the reaction temperature is room temperature, and the reaction time is 30 min.

[0014] Furthermore, the molar ratio of aspirin to sodium bicarbonate was 1:1, the reaction temperature was room temperature, and the reaction time was 30 min;

[0015] Furthermore, the reaction temperature of neutral sodium aspirin with magnesium nitrate was room temperature, and the reaction time was 2 hours.

[0016] Thirdly, the present invention provides a method for preparing magnesium complexes represented by Formula III and Formula IV, comprising the following steps:

[0017] Magnesium carbonate is reacted with nitric acid to produce magnesium nitrate;

[0018] Aspirin was reacted with p-nitrobenzyl alcohol to obtain a hypoxia-induced aspirin derivative;

[0019] The hypoxia-induced aspirin derivative was reacted with magnesium nitrate in a molar ratio of 1:1 or 2:1 to obtain the corresponding magnesium complexes shown in Formula III and Formula IV, respectively.

[0020] Furthermore, the molar ratio of magnesium carbonate to nitric acid is 1:2, the reaction temperature is room temperature, and the reaction time is 30 min.

[0021] Furthermore, the molar ratio of aspirin to p-nitrobenzyl alcohol is 1:1.

[0022] Further, aspirin and p-nitrobenzyl alcohol were dissolved in dichloromethane, and a dichloromethane solution of N,N-diisopropylethylamine was added dropwise under nitrogen protection at 0°C. The mixture was stirred until the reaction was complete to obtain an anaerobic-induced aspirin derivative.

[0023] Furthermore, the reaction temperature of the hypoxia-induced aspirin derivative and magnesium nitrate was room temperature, and the reaction time was 2 hours.

[0024] The present invention also provides the application of the magnesium complex in the preparation of drugs for treating coronary heart disease.

[0025] The present invention also provides the use of the magnesium complex in the preparation of drugs for treating hypoxic cardiomyocyte injury or drugs for treating cardiac injury.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] This invention combines magnesium ions with functional organic small molecules of aspirin to prepare a functional magnesium complex. The antioxidant and vasodilatory functions of magnesium ions are synergistically enhanced with the platelet aggregation inhibition and antithrombotic functions of aspirin. Compared with aspirin, magnesium nitrate or the combination of the two, the repair effect on cardiac damage caused by myocardial hypoxia such as myocardial infarction is significantly improved, showing a synergistic effect and cardioprotective activity.

[0028] This invention designs a hypoxia-promoted prodrug that can be activated by hypoxic conditions, enabling concentrated release of the pharmacophore at the site of hypoxic injury. This improves drug bioavailability and reduces damage to normal tissues. Combining this design with a magnesium complex to synthesize a hypoxia-promoted magnesium complex further enhances the bioavailability of the magnesium complex. The synthesized hypoxia-promoted magnesium complex can effectively improve myocardial hypoxia injury in coronary heart disease, providing a novel, highly effective, and safe drug candidate for the treatment of coronary heart disease.

[0029] Furthermore, the complexes of this invention have advantages over inorganic salt drugs and organic small molecule drugs in terms of efficacy, safety, and stability, making them ideal drugs for the treatment of coronary heart disease. Attached Figure Description

[0030] Figure 1 A comparative graph showing the results of different concentrations of MgSO4, aspirin, and the combination of the two in improving the viability of damaged cardiomyocytes;

[0031] Figure 2 Comparative graph showing the results of detecting the levels of magnesium sulfate combined with aspirin and magnesium complexes AsMg (1:1), AsMg (2:1), AsMgP (1:1), and AsMgP (2:1) in improving the viability of hypoxic-damaged cardiomyocytes;

[0032] Figure 3 A comparison of the results of different concentrations of the magnesium complex AsMgP (1:1) in improving the viability of hypoxic-damaged cardiomyocytes;

[0033] Figure 4 Comparative graph showing the effects of MgSO4, magnesium sulfate combined with aspirin, and magnesium complex AsMgP (1:1) on improving heart weight in a mouse model of myocardial ischemia;

[0034] Figure 5 Comparison of detection results for the effects of MgSO4, magnesium sulfate combined with aspirin, and magnesium complex AsMgP (1:1) on troponin I (cTnI) levels. Detailed Implementation

[0035] The present invention will be further described below with reference to specific embodiments. These embodiments are only used to more clearly illustrate the technical solutions of the present invention and should not be construed as limiting the scope of protection of the present invention.

[0036] It should be noted that, unless otherwise stated, the technical or scientific terms used in this application should have the ordinary meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0037] Example 1 Preparation of magnesium complexes AsMg (1:1) and AsMg (2:1)

[0038]

[0039] The synthesis circuit is as follows:

[0040]

[0041] The preparation steps include:

[0042] Step 1: Mix MgCO3 (84, 0.42 g) aqueous solution with HNO3 (63, 0.63 g) and stir at room temperature to prepare Mg(NO3)2;

[0043] Step 2: Mix the aspirin (180, 1.8g) ethanol solution with the NaHCO3 (84, 0.84g) aqueous solution, stir at room temperature, deprotonate the aspirin to obtain the neutral sodium aspirin.

[0044] Step 3: Mix aspirin neutral sodium salt with Mg(NO3)2 in a molar ratio of 1:1 or 2:1, stir at room temperature for 2 hours to obtain aspirin-magnesium complex AsMg (1:1) or AsMg (2:1), concentrate and add ethanol to precipitate solid products with yields of 77.3% and 75.5%, respectively.

[0045] AsMg (1:1): 1H NMR (600 MHz, DMSO- d 6) δ 2.23 (s, 3H), 7.20 (d, 1H),7.36 (t, 1H), 7.62 (t, 1H), 7.91 (d, 1H). MS calcd for C9H 10 MgNO8[M + H] + :284.02, found 284.2.

[0046] AsMg (2:1): 1 H NMR (600 MHz, DMSO- d 6) δ 2.25 (s, 6H), 7.21 (d, 2H), 7.38 (t, 2H), 7.64 (t, 2H), 7.93 (d, 2H). MS calcd for C 18 H 15 MgO8[M + H] + 383.6, found 382.9.

[0047] Example 2: Preparation of magnesium complexes AsMgP (1:1) and AsMgP (2:1)

[0048]

[0049] The synthetic route is as follows:

[0050]

[0051] The preparation steps include:

[0052] Step 1: Preparation of hypoxia-induced aspirin derivative 4-nitrobenzyl-2-acetoxybenzoate:

[0053]

[0054] p-Nitrobenzyl alcohol and aspirin were dissolved in dichloromethane at a 1:1 molar ratio. A dichloromethane solution of N,N-diisopropylethylamine (DIPEA / DCM) was added dropwise under nitrogen protection at 0°C, and the mixture was stirred for at least 4 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure, and the product was purified by silica gel column chromatography to obtain a white solid product with a yield of 79.6%.

[0055] 1 H NMR (600 MHz, DMSO- d6) δ 2.26 (s, 3H), 5.02 (s, 2H), 7.25 (d, 2H),7.39 (t, 1H), 7.67 (t, 1H), 7.70 (t, 1H), 7.81 (d, 1H), 7.98 (d, 2H). MScalcd for C 16 H 14 NO6[M + H] + : 315.07, found 315.5.

[0056] Step 2, Preparation of AsMgP (1:1) and AsMgP (2:1):

[0057] 4-Nitrobenzyl-2-acetylsalicylate was mixed with Mg(NO3)2 at a molar ratio of 1:1 or 2:1 and stirred at room temperature for 2 h to prepare hypoxia-induced aspirin-magnesium complexes AsMgP (1:1) and AsMgP (2:1). After concentration, ethanol was added to precipitate solid products with yields of 70.4% and 66.7%, respectively.

[0058] AsMgP (1:1): 1 H NMR (600 MHz, DMSO- d 6) δ 2.31 (s, 3H), 5.02 (s, 2H), 7.35 (d, 2H), 7.62 (t, 1H), 7.64 (t, 1H), 7.70 (t, 1H), 7.86 (d, 1H), 8.01(d, 2H). MS calcd for C 16 H 16 MgN2O 10 [M + H] + : 420.02, found 419.9.

[0059] AsMgP (2:1): 1 H NMR (600 MHz, DMSO- d 6) δ 2.31 (s, 6H), 5.05 (s, 4H), 7.37 (d, 4H), 7.65 (t, 2H), 7.66 (t, 2H), 7.73 (t, 2H), 7.87 (d, 2H), 8.03(d, 4H). MS calcd for C 32 H 27 MgN2O 12 [M + H] +: 655.13, found 655.6.

[0060] Experiment 1: Detection of the levels of MgSO4, aspirin, and the combination of the two in improving the viability of damaged cardiomyocytes.

[0061] (a) Medicines and reagents

[0062] CCK-8 assay kit (Beyotime Biotechnology Co., Ltd., Shanghai), MgSO4, aspirin, AsMg (1:1), AsMg (2:1), AsMgP (1:1), AsMgP (2:1), DMEM medium, fetal bovine serum, PBS.

[0063] (b) Experimental Principle

[0064] CCK-8 contains WST-8 and the electron carrier 1-methoxyPMS. WST-8 is reduced by intracellular dehydrogenase to produce water-soluble orange-yellow formazan, which dissolves in the cell culture medium. The formazan content is directly proportional to the number of viable cells. The absorbance of formazan at 450 nm was measured using a microplate reader, and changes in cell viability were calculated based on the absorbance values.

[0065] (c) Experimental procedures

[0066] (1) Cardiac cells were cultured in DMEM medium containing 10% fetal bovine serum in 96-well plates. After the cells adhered, ISO modeling agent was added and the cells were placed in a three-gas incubator for hypoxia (1% O2) for 4 hours to establish the model.

[0067] (2) At the same time as the model was established, the drug administration group was given different concentrations of MgSO4, aspirin or a combination of the two;

[0068] (3) Take out the 96-well plate, add 10 μL of CCK8 to each well and incubate in a normal incubator for 1-2 hours, and then detect with an enzyme-linked immunosorbent assay (ELISA) reader.

[0069] (d) Experimental results

[0070] Figure 1 A comparative graph showing the results of detecting the improvement of damaged cardiomyocyte viability by different concentrations of MgSO4 (mgs), aspirin (asp), and the combination of the two (asp & mgs). Figure 1 As shown in the two-way ANOVA, magnesium sulfate or aspirin alone can improve the cell viability of ISO-modeled cardiomyocytes. The main effect of the effect on cell viability exists. Further interaction effect analysis shows that there is an interaction between the two, which can synergistically enhance the activity.

[0071] Experimental Example 2: Magnesium complexes improve the viability of hypoxic-damaged cardiomyocytes.

[0072] (a) Medicines and reagents

[0073] CCK-8 assay kit (Beyotime Biotechnology Co., Ltd., Shanghai), MgSO4, aspirin, AsMg (1:1), AsMg (2:1), AsMgP (1:1), AsMgP (2:1), DMEM medium, fetal bovine serum, PBS.

[0074] (b) Experimental Principle

[0075] CCK-8 contains WST-8 and the electron carrier 1-methoxyPMS. WST-8 is reduced by intracellular dehydrogenase to produce water-soluble orange-yellow formazan, which dissolves in the cell culture medium. The formazan content is directly proportional to the number of viable cells. The absorbance of formazan at 450 nm was measured using a microplate reader, and changes in cell viability were calculated based on the absorbance values.

[0076] (c) Experimental procedures

[0077] (1) Cardiac cells were cultured in DMEM medium containing 10% fetal bovine serum in 96-well plates. After the cells adhered, the cells were placed in a three-gas incubator for hypoxia (1% O2) for 4 hours after the addition of modeling agent LPS.

[0078] (2) During the modeling process, the drug administration group was given different concentrations of MgSO4, aspirin or complex AsMg.

[0079] (3) Take out the 96-well plate, add 10 μL of CCK8 to each well and incubate in a normal incubator for 1-2 hours, and then detect with an enzyme-linked immunosorbent assay (ELISA) reader.

[0080] (d) Experimental results

[0081] Figure 2 Comparative graph showing the results of detecting the levels of magnesium sulfate combined with aspirin and magnesium complexes AsMg (1:1), AsMg (2:1), AsMgP (1:1), and AsMgP (2:1) in improving the viability of hypoxic-damaged cardiomyocytes; Figure 3 This figure compares the results of different concentrations of the magnesium complex AsMgP (1:1) in improving the viability of hypoxic-injured cardiomyocytes. As can be seen from the figure, in the hypoxic cardiomyocyte injury model, at a dosage concentration of 10 μM, the overall activity of the magnesium complex was superior to that of magnesium sulfate or aspirin alone, with AsMgP (1:1) showing the best activity, and this activity exhibited a concentration-dependent effect.

[0082] Experimental Example 3: The effect of magnesium complex AsMgP (1:1) on improving myocardial injury in a mouse model of myocardial ischemia.

[0083] (a) Medicines and reagents

[0084] Isoproterenol (ISO), PBS, MgSO4, aspirin, AsMgP (1:1).

[0085] (b) Laboratory animals

[0086] Male C57 mice aged 6-8 weeks.

[0087] (c) Experimental Principle

[0088] Isoproterenol is a catecholamine drug and a β-adrenergic receptor agonist. It increases myocardial contractility and oxygen consumption, thereby increasing myocardial workload and myocardial microcirculation disorders, leading to ischemic and hypoxic damage to the heart.

[0089] (d) Experimental procedures

[0090] (1) A mouse model of myocardial infarction was constructed by injecting isoproterenol (ISO).

[0091] (2) After modeling, the drugs were administered intraperitoneally for 3 days (15 mg / kg). The drug administration groups included magnesium sulfate, magnesium sulfate combined with aspirin, and magnesium complex AsMgP (1:1). After modeling and drug administration, the heart was weighed and analyzed, and the level of troponin I (cTnI) in each group was detected.

[0092] (e) Experimental Results

[0093] Figure 4 This figure compares the effects of MgSO4, magnesium sulfate combined with aspirin, and the magnesium complex AsMgP (1:1) on improving heart weight in a mouse model of myocardial ischemia. The figure shows that ISO-induced myocardial ischemia leads to cardiac swelling and increased heart weight. In the treatment groups, the complex AsMgP (1:1) showed the best effect in reducing heart weight, superior to the control group (magnesium sulfate and the combined treatment), indicating its superior effect in reducing cardiac swelling.

[0094] Figure 5 This is a comparison of the results of MgSO4, magnesium sulfate combined with aspirin, and the magnesium complex AsMgP (1:1) in improving troponin I (cTnI) levels. The figure shows that the troponin I (cTnI) test, used to assess the degree of myocardial injury, again demonstrates that the magnesium complex AsMgP (1:1) has a better anti-myocardial injury effect than magnesium sulfate or the combined treatment group.

[0095] This invention combines magnesium ions with functional organic small molecules of aspirin to prepare a functional magnesium complex. The antioxidant and vasodilatory functions of magnesium ions are synergistically enhanced with the platelet aggregation inhibition and antithrombotic functions of aspirin. Furthermore, the design of a hypoxia-promoting prodrug is combined with the magnesium complex to synthesize a hypoxia-promoting magnesium complex, which improves the bioavailability of the magnesium complex. The repair effect on cardiac damage caused by myocardial hypoxia, such as myocardial infarction, is significantly improved compared with aspirin, magnesium nitrate, or the combination of the two, showing a synergistic effect.

[0096] The present invention has been disclosed above with reference to preferred embodiments, but it is not intended to limit the present invention. All technical solutions obtained by adopting equivalent substitutions or equivalent transformations fall within the protection scope of the present invention.

Claims

1. A magnesium complex, characterized in that, Its structural formula is shown in Equation III below: 。 2. The method for preparing the magnesium complex according to claim 1, characterized in that, The magnesium complex shown in Formula III is prepared according to the following steps: Magnesium carbonate is reacted with nitric acid to produce magnesium nitrate; Aspirin was reacted with p-nitrobenzyl alcohol to obtain a hypoxia-induced aspirin derivative; The hypoxia-induced aspirin derivative was reacted with magnesium nitrate in a 1:1 molar ratio to obtain the corresponding magnesium complex shown in Formula III.

3. The method for preparing the magnesium complex according to claim 2, characterized in that, The molar ratio of magnesium carbonate to nitric acid was 1:2, the reaction temperature was room temperature, and the reaction time was 30 min.

4. The method for preparing the magnesium complex according to claim 2, characterized in that, The molar ratio of aspirin to p-nitrobenzyl alcohol is 1:

1.

5. The method for preparing the magnesium complex according to claim 2, characterized in that, Aspirin and p-nitrobenzyl alcohol were dissolved in dichloromethane, and a dichloromethane solution of N,N-diisopropylethylamine was added dropwise under nitrogen protection at 0°C. The mixture was stirred until the reaction was complete to obtain an anaerobic-induced aspirin derivative.

6. The method for preparing the magnesium complex according to claim 2, characterized in that, The reaction temperature of hypoxia-induced aspirin derivative and magnesium nitrate was room temperature, and the reaction time was 2 hours.

7. The use of the magnesium complex according to claim 1 in the preparation of a drug for treating coronary heart disease.

8. The use of the magnesium complex according to claim 1 in the preparation of drugs for treating hypoxic cardiomyocyte injury or drugs for treating cardiac injury.

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