CN113248530A - Active oxygen response antioxidant nitric oxide donor, preparation and application thereof - Google Patents
Active oxygen response antioxidant nitric oxide donor, preparation and application thereof Download PDFInfo
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- 230000003078 antioxidant effect Effects 0.000 title claims abstract description 44
- 239000003963 antioxidant agent Substances 0.000 title claims abstract description 42
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- 229910052760 oxygen Inorganic materials 0.000 title claims abstract description 34
- 239000001301 oxygen Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 230000004044 response Effects 0.000 title abstract description 9
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- 230000035484 reaction time Effects 0.000 claims description 25
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- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
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Abstract
The invention relates to the field of medicinal chemistry, in particular to an active oxygen response antioxidant nitric oxide donor, a preparation method and an application thereof, wherein the donor has the following structural formula, and the preparation method comprises the steps of reacting PBAP with CDI to obtain PBAP-CDI; and then reacts with ISN under the action of a catalyst to obtain the antioxidant nitric oxide donor. The active oxygen response antioxidant nitric oxide donor has good stability and long half-life period in physiological environment, can be decomposed only under the stimulation of high-concentration active oxygen in inflammatory tissues to release the antioxidant and the nitric oxide donor, and cannot generate the antioxidant and the nitric oxide donor to normal tissuesSide effects are produced. Meanwhile, active oxygen can be effectively removed, and an anti-oxidation effect is achieved; promotes the growth of endothelial cells and inhibits the growth of smooth muscle cells, is beneficial to the rapid endothelialization of cardiovascular, has diversified functions, can be widely applied to the development of medicaments, and has popularization and application values.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to an active oxygen response antioxidant nitric oxide donor, and preparation and application thereof.
Background
Nitric Oxide (NO) is an important gas signaling molecule in the living body, and it can participate in the regulation of various physiological functions in the living body and exert extremely important functions in the body. For example, nitric oxide is involved in processes such as vascular regulation, neurotransmission, inflammation and immune response. Nitric oxide also induces apoptosis of macrophages, cardiac myocytes, vascular smooth muscle cells, pancreatic islet cells, and the like. In addition, a number of studies have shown that nitric oxide is closely related to tumors, low concentrations of nitric oxide promote tumor growth, and high concentrations of nitric oxide inhibit tumor growth.
The research on the nitric oxide donor has received extensive attention to the problems of low endogenous nitric oxide concentrations in the body or abnormal nitric oxide metabolism. Nitric oxide donor drugs play a positive role in both basic research and clinical disease treatment, and nitric oxide donors such as 5-mononitroisosorbide, nitroglycerin, and the like have been widely used clinically for cardiovascular disease treatment. Nitric oxide donors can rapidly release high-concentration nitric oxide under physiological conditions, exert the physiological action of nitric oxide, and become one of the hot spots and frontiers of research in the biomedical field.
For example, CN107459482A discloses a nitric oxide donor, its preparation and application, which discloses the chemical formula of the following structure,
R2is H, C3-C8 cycloalkyl, or optionally substituted by 1-2 substituents selected from C1-4 alkoxy, -S (O)2-OH, and C1-6 alkyl substituted with a substituent of a hydroxyl group wherein N is attached to the phenyl ring of the fluorophore molecule, the compounds are useful as nitric oxide donors for hypertension and related diseases.
CN104119295A discloses a phenothiazine nitric oxide donor, a preparation method and application thereofThe structural formula of the compound is
n is 0, 1 or 2; r1Comprises the following steps: hydrogen, halogen, C1-C4 branched or straight chain alkyl, and C1-C4 halogenated branched or straight chain alkyl; r2Comprises the following steps: hydrogen, C1-C4 branched or straight chain alkyl. The compound is used as the active component of the medicine composition and the antitumor medicine, and may be used in preparing medicine for treating breast cancer, lung cancer and gastric cancer.
The nitric oxide donor can prolong the half-life period of nitric oxide and can be used as a carrier of NO to realize in vivo transportation. However, most NO donors are very unstable and the half-life typically varies from seconds to hours, which causes great trouble for storage and biomedical applications of NO donors. On the other hand, the half-life period of nitric oxide in vivo is only 3-6 seconds, and the diffusion radius is only 40-200 μm, so that the nitric oxide donor is required to be capable of converting into NO to play a role preferably at a focus part.
In addition, most of the reported nitric oxide donors have single function, but the diseases are often the result of the combined action of multiple factors, especially many diseases are accompanied by inflammation, and active oxygen generated by inflammatory cells can damage normal cells, so that the disease condition is aggravated. Such as inflammation, have important promoting effects on the progression of cardiovascular diseases. Therefore, in the treatment of diseases, drugs are often required to have multiple functions. The development of the multifunctional nitric oxide donor has important significance in disease treatment and also has wide application prospect.
Disclosure of Invention
Based on the problems of poor stability, short half-life period and single function of a nitric oxide donor in the prior art, the invention provides an active oxygen response antioxidant nitric oxide donor, which can release an antioxidant p-hydroxybenzyl alcohol and a nitric oxide donor drug 5-mononitroisosorbide ester under the stimulation of high-concentration active oxygen at an inflammation part, and can remove the high-concentration active oxygen at the inflammation part while delivering nitric oxide, thereby realizing the multi-functionalization of the nitric oxide donor.
In order to achieve the purpose, the invention adopts the technical scheme that:
an active oxygen-responsive antioxidant nitric oxide donor having the formula:
the invention also provides a preparation method of the active oxygen response antioxidant nitric oxide donor, which comprises the following steps:
(1) 4-hydroxymethylphenylboronic acid pinacol ester (PBAP) and 2-azocarbonylimidazole (CDI) react to obtain 4-azocarbonylimidazolylboronic acid pinacol ester (PBAP-CDI); the reaction formula is as follows:
(2) reacting PBAP-CDI with 5-mononitroisosorbide ester (ISN) under the action of a catalyst to obtain 4-azocarbonyl- (5-mononitroisosorbide ester group) -benzoboronic acid pinacol ester (PBAP-ISN), namely the antioxidant nitric oxide donor, wherein the reaction formula of the step is as follows:
the solvent of the step (1) comprises any one or more of dichloromethane, chloroform, N-dimethylformamide, toluene, dioxane or dimethyl sulfoxide.
The solvent in the step (2) comprises any one or more of dichloromethane, chloroform, methanol, toluene, anisole, dioxane, cyclohexane or dimethyl sulfoxide.
The reaction conditions of the step (1) are as follows: the reaction time is more than 0.5 hour at the temperature of 0-60 ℃.
The reaction conditions of the step (2) are as follows: the reaction time is more than 2 hours at 20-90 ℃.
The catalyst in the step (2) comprises any one or more of benzimidazole, 4-Dimethylaminopyridine (DMAP), pyridine, triethylamine and trimethylamine; the molar ratio of the catalyst to the 4-N-carbonylimidazolyl phenylboronic acid pinacol ester is 0.1-5: 1.
Preferably, the reaction time of step (1) is more than 2 hours; the reaction time of the step (2) is more than 12 hours. The inventor finds that the yield can reach more than 95% after the reaction time of the step (1) is 2 hours, and the yield is not obviously increased after the reaction time is prolonged; in the step (2), when the reaction time is within 2 hours, the yield is very low and is only about 10%, and when the reaction time is 12 hours, the yield can reach about 60-80%, and the yield is not obviously increased after the reaction time is prolonged.
Further preferably, the reaction time of the step (1) is 2-12 hours, including 4 hours, 6 hours and 8 hours; the reaction time of the step (2) is 12-48 hours, including 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours and 36 hours.
Preferably, the solvent of step (1) is toluene, chloroform, dichloromethane.
Further preferably, the catalyst is 4-Dimethylaminopyridine (DMAP), and the molar ratio of the catalyst to the 4-N-carbonylimidazolyl-phenylboronic acid pinacol ester is 0.5-2: 1.
And (3) extracting, purifying and drying the products obtained in the step (1) and the step (2), wherein the drying agent is one or more of phosphorus pentoxide, anhydrous magnesium sulfate or anhydrous sodium sulfate.
The invention also provides the antioxidant nitric oxide donor with active oxygen response, which can be decomposed under the stimulation of high-concentration active oxygen in inflammatory tissues to release antioxidant p-hydroxybenzyl alcohol and nitric oxide donor 5-mononitroisosorbide, can be used for preparing medicaments for treating related diseases such as cardiovascular diseases and inflammations, can be prepared into subcutaneous, intramuscular or intravenous injections for treating cardiovascular diseases and inflammations, and can obtain good treatment effects. Can be widely applied to drug development and has popularization and application values.
The decomposition process of the antioxidant nitric oxide donor under the stimulation of high-concentration active oxygen is as follows:
compared with the prior art, the invention has the following beneficial effects:
(1) the antioxidant nitric oxide donor responding to active oxygen has good stability and long half-life period (>30 days) in a physiological environment, and compared with the nitric oxide donor in the prior art, the half-life period of the nitric oxide donor in vivo is generally different from several seconds to several hours, so that the stability of the antioxidant nitric oxide donor responding to active oxygen is greatly improved.
(2) The active oxygen response antioxidant nitric oxide donor can be decomposed only under the stimulation of high-concentration active oxygen in inflammatory tissues, releases an antioxidant and the nitric oxide donor, stably exists in normal tissues and does not generate side effects on the normal tissues.
(3) The antioxidant nitric oxide donor prepared by the invention can effectively remove active oxygen and has an antioxidant effect; meanwhile, the growth of endothelial cells can be promoted, the growth of smooth muscle cells can be inhibited, the rapid endothelialization of cardiovascular is facilitated, the function diversification is realized, and the problem of single function of the nitric oxide donor in the prior art is solved.
Drawings
FIG. 1 shows the NMR hydrogen spectrum of 4-N-carbonylimidazolyl-phenylboronic acid pinacol ester (PBAP-CDI) obtained in example 1.
FIG. 2 shows the NMR hydrogen spectrum of 4-N-carbonyloxy- (5-mononitroisosorbide) phenylboronic acid pinacol ester (PBAP-ISN) obtained in example 1.
FIG. 3 is a graph comparing the decomposition curves of the antioxidant nitric oxide donor PBAP-ISN obtained in example 1 in different environments.
FIG. 4 is a graph of the active oxygen scavenging capacity of the antioxidant nitric oxide donor PBAP-ISN obtained in example 2.
FIG. 5 is a bar graph comparing the effect of antioxidant nitric oxide donor PBAP-ISN obtained in example 3 on endothelial cell (a) and smooth muscle cell (b) proliferation.
FIG. 6 is a graph of the half-life test of PBAP-ISN obtained in example 1 in different environments.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. Those skilled in the art should understand that they can make modifications and equivalents without departing from the spirit and scope of the present invention, and all such modifications and equivalents are intended to be included within the scope of the present invention.
The raw materials used in the following embodiments are all commercially available.
Example 1
Dissolving 15g of 4-hydroxymethylphenylboronic acid pinacol ester (PBAP) in 100mL of chloroform, adding 6g of 2-N-Carbonylimidazole (CDI), stirring at 25 ℃ for 2 hours, extracting the product with water, drying with anhydrous sodium sulfate, filtering, and carrying out reduced pressure rotary evaporation on the filtrate to obtain the 4-N-carbonylimidazolylboronic acid pinacol ester (PBAP-CDI), wherein the yield is 95% and the purity is 98%.
5g of PBAP-CDI was dissolved in 25mL of dichloromethane, 8.5g of 5-mononitroisosorbide (ISN) and 3.2g of 4-Dimethylaminopyridine (DMAP) were added, stirred at 20 ℃ for 72 hours, the product was extracted with water and dried with phosphorus pentoxide, the filtrate was rotary evaporated under reduced pressure and dried in a vacuum oven to give 4-N-carbonyl- (5-mononitroisosorbide ester) -pinacol phenylboronic acid ester (PBAP-ISN) in a yield of > 85% and a purity of > 98%.
The nuclear magnetic resonance hydrogen spectra of the PBAP-CDI and the PBAP-ISN are respectively shown in the figure 1 and the figure 2, and the 4-N-carbonyl imidazolyl phenyl boronic acid pinacol ester and the 4-N-carbonyl- (5-mononitro isosorbide ester) -phenyl boronic acid pinacol ester are successfully prepared.
Example 2
500g of 4-hydroxymethylphenylboronic acid pinacol ester (PBAP) is dissolved in 1000mL of toluene, 250g of 2-N-Carbonylimidazole (CDI) is added, stirring is carried out at 0 ℃ for 48 hours, the product is extracted by water, dried by anhydrous magnesium sulfate and filtered, and the filtrate is decompressed and evaporated to obtain the 4-N-carbonylimidazolyl phenylboronic acid pinacol ester (PBAP-CDI), wherein the yield is 95 percent and the purity is 98 percent.
200g of PBAP-CDI is dissolved in 200mL of dioxane, 300g of 5-mononitroisosorbide (ISN) and 72g of pyridine are added, stirring is carried out for 2 hours at 75 ℃, the product is extracted by water and dried by anhydrous magnesium sulfate, then the filtrate is decompressed and steamed in a rotary manner and dried in a vacuum oven to obtain the 4-azocarbonyl- (5-mononitroisosorbide ester group) -benzoboronic acid pinacol ester (PBAP-ISN) with the yield of less than 20 percent and the purity of more than 90 percent.
Example 3
Dissolving 5g of 4-hydroxymethylphenylboronic acid pinacol ester (PBAP) in 50mL of dimethyl sulfoxide, adding 10g of 2-N-Carbonylimidazole (CDI), stirring at 60 ℃ for 24 hours, extracting the product with water, drying with phosphorus pentoxide, filtering, and carrying out reduced pressure rotary evaporation on the filtrate to obtain the 4-N-carbonylimidazolylboronic acid pinacol ester (PBAP-CDI). The yield is less than 50 percent, and the purity is more than 98 percent
Dissolving 2g of PBAP-CDI in 10mL of anisole, adding 3g of 5-mononitroisosorbide (ISN) and 5.7g of 4-Dimethylaminopyridine (DMAP), stirring at 90 ℃ for 24 hours, extracting the product with water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation on the filtrate, and drying in a vacuum oven to obtain 4-azocarbonyl- (5-mononitroisosorbide ester group) -benzoboronic acid pinacol ester (PBAP-ISN), wherein the yield is 95% and the purity is 98%.
Example 4
Dissolving 100g of 4-hydroxymethylphenylboronic acid pinacol ester (PBAP) in 500mL of dichloromethane, adding 30g of 2-N-Carbonylimidazole (CDI), stirring at 50 ℃ for 6 hours, extracting a product with water, drying with anhydrous sodium sulfate, filtering, and carrying out reduced pressure rotary evaporation on a filtrate to obtain the 4-N-carbonylimidazolyl-phenylboronic acid pinacol ester (PBAP-CDI) with the rate of 95% and the purity of 98%.
10g of PBAP-CDI was dissolved in 30mL of chloroform, 5g of 5-mononitroisosorbide (ISN) and 3.1g of triethylamine were added, the mixture was stirred at 50 ℃ for 48 hours, the product was extracted with water and dried over anhydrous magnesium sulfate, and then the filtrate was rotary-distilled under reduced pressure and dried in a vacuum oven to obtain 4-N-carbonyl- (5-mononitroisosorbide ester group) -pinacol phenylboronic acid ester (PBAP-ISN) in a yield of < 65% and a purity of > 98%.
Example 5
Dissolving 10g of 4-hydroxymethylphenylboronic acid pinacol ester (PBAP) in 30mL of N, N-dimethylformamide, adding 5g of 2-N-Carbonylimidazole (CDI), stirring at 60 ℃ for 12 hours, extracting a product with water, drying with phosphorus pentoxide, filtering, and carrying out reduced pressure rotary evaporation on a filtrate to obtain the 4-N-carbonylimidazolylboronic acid pinacol ester (PBAP-CDI) with the yield of 50% and the purity of 98%.
Dissolving 7g of PBAP-CDI in 20mL of toluene, adding 6g of 5-mononitroisosorbide (ISN) and 0.9g of triethylamine, stirring at 25 ℃ for 24 hours, extracting the product with water, drying with anhydrous magnesium sulfate, carrying out reduced pressure rotary evaporation on the filtrate, and drying in a vacuum oven to obtain 4-azocarbonyl- (5-mononitroisosorbide ester group) -benzoboronic acid pinacol ester (PBAP-ISN), wherein the yield is less than 65% and the purity is more than 98%. From the product results of the above examples, the yield 1>4>3>5>2 and the product purity 1 ≈ 3 ≈ 5 ≈ 4>2 of PBAP-ISN in the above examples are optimal considering the overall example 1. In the preparation of PBAP-CDI, the reaction solvent has a lower miscibility with water, the easier it is to extract the product into the organic phase, the higher the yield, but without affecting the product purity (the yield is greater than water-miscible DMSO and DMF in the case of toluene, chloroform, dichloromethane solvents). In the process of preparing PBAP-ISN, DMAP is much more catalytic than triethylamine, so the yield is higher in the presence of DMAP than triethylamine, than without any catalyst.
Example 6
Following the reaction conditions of example 1, replacing only the reaction time for the preparation of PBAP-CDI by 0.5 hours, 1 hour, 3 hours and 24 hours, yields of PBAP-CDI of 43%, 70%, > 95% and purities of 55%, 84%, > 98% and > 98% were obtained, respectively.
The influence degree of the reaction time of the step on the result can be seen, when the reaction time is less than 2 hours, the reaction yield gradually increases along with the increase of the time, but when the reaction time is less than 2 hours, the yield can reach more than 95 percent, and then the reaction time is continuously prolonged, and the yield is not qualitatively changed.
Example 7
Following the reaction conditions of example 1, replacing only the reaction time for the preparation of PBAP-ISN with 6 hours, 12 hours, 24 hours, 48 hours, yields of PBAP-ISN of 15%, 50%, > 70%, and > 85%%, respectively, and purities of 10%, 33%, > 85%, and > 98% were obtained.
It can also be seen that in this step, when the reaction time is within 12 hours, even within 24 hours, the yield gradually increases with the increase of the reaction time, but the rising trend is moderate, and when the reaction time is above 24 hours, the reaction time is continued to be prolonged, and the yield is not qualitatively changed.
Application example 1
To study the stability of the antioxidant nitric oxide donor, a stability test experiment was performed:
hydrogen peroxide was used to simulate the high active oxygen environment of inflamed tissues, PBAP-ISN prepared in example 1 was added to different solutions (A: phosphate buffered saline PBS; B:5mM hydrogen peroxide solution) respectively, the concentration of PBAP-ISN in the final solution was 2mM, and the decomposition rate of PBAP-ISN was determined.
The results are shown in fig. 3, which shows that the antioxidant nitric oxide donor PBAP-ISN is hardly decomposed in phosphate buffer solution PBS simulating physiological environment, showing excellent physiological environment stability; in the presence of 5mM hydrogen peroxide simulating high active oxygen environment of inflammatory tissues, PBAP-ISN can be rapidly decomposed to release antioxidant p-hydroxybenzyl alcohol and nitric oxide donor 5-mononitroisosorbide.
Application example 2
To investigate the antioxidant capacity of the nitric oxide donor PBAP-ISN, a test of the active oxygen scavenging capacity was performed: PBAP-ISN prepared in example 2 was added to a 5mM hydrogen peroxide solution, the concentration of PBAP-ISN in the final solution was 10mM, and hydrogen peroxide in the solution was measured at regular intervals by the xylenol orange method.
The result is shown in figure 4, which shows that the antioxidant nitric oxide donor PBAP-ISN can effectively remove hydrogen peroxide in the solution, has antioxidant effect and has multiple functions.
Application example 3
To investigate the effect of antioxidant nitric oxide donors on the growth of endothelial cells and smooth muscle cells, cell proliferation behavior test experiments were performed: when the HUVEC of the endothelial cells grow to 80% -90% fusion, the HUVEC is subjected to digestion centrifugation and culture medium dispersion, the HUVEC is inoculated into a 24-well cell culture plate at the density of 5000 cells per well, after 4 hours of adhesion, 1mL of cell culture medium containing 0 muM, 5 muM and 10 muM of PBAP-ISN prepared in example 3 is added every 12 hours, wherein the cell culture medium of 0 muM of cyclodextrin-based nitric oxide donor is a PBS control group; after 1 day and 3 days of culture, statistics on cell density were performed on the cells.
The smooth muscle cells were subjected to the same procedure as described above.
The results are shown in FIG. 5, (a) showing that PBAP-ISN is effective in promoting endothelial cell proliferation, and (b) showing that PBAP-ISN inhibits smooth muscle cell proliferation.
Application example 4
To study the half-life of the antioxidant nitric oxide donor under simulated physiological conditions, a drug stability test was performed: PBAP-ISN prepared in example 1 was dissolved in DMSO, blended 1:100 with PBS (phosphate buffered saline) solution, PBS solution containing 10% BSA (bovine serum albumin), and PBS solution containing 10% FBS (fetal bovine serum), UV absorption at 276nm of PBAP-ISN was measured at various time points (6 hours, 12 hours, 24 hours, 2 days, 3 days, 6 days, 12 days, 20 days, and 30 days), and the remaining concentration of PBAP-ISN (C.sub.concentration) was calculated from a standard curveRemainder ofmg·L-1) Calculating the concentration (C) of the compoundOriginal) Is the remaining percentage RRemainder of：
RRemainder of＝(CRemainder of÷COriginal)×100％
The results are shown in fig. 6, the remaining percentage of PBAP-ISN in different solutions at different time points, and it can be seen that PBAP-ISN of the present invention remains stable at > 90% after 30 days of incubation in various solutions simulating physiological environments.
Claims (10)
1. An active oxygen-responsive antioxidant nitric oxide donor having the formula:
2. the method of preparing an active oxygen-responsive antioxidant nitric oxide donor of claim 1, comprising the steps of:
(1) 4-N-carbonylimidazolyl phenylboronic acid pinacol ester is obtained by reacting 4-hydroxymethyl phenylboronic acid pinacol ester with 2-N-carbonylimidazole;
(2) 4-azocarbonyl imidazolyl phenylboronic acid pinacol ester and 5-mononitro isosorbide ester react under the action of a catalyst to obtain the antioxidant nitric oxide donor.
3. The method for preparing an active oxygen-responsive, antioxidant nitric oxide donor as claimed in claim 2, wherein the solvent of step (1) comprises any one or more of dichloromethane, chloroform, N-dimethylformamide, toluene, dioxane or dimethylsulfoxide.
4. The method for preparing an active oxygen-responsive antioxidant nitric oxide donor as claimed in claim 2, wherein the solvent of step (2) comprises one or more of dichloromethane, chloroform, methanol, toluene, anisole, dioxane, cyclohexane or dimethyl sulfoxide.
5. The method for preparing an active oxygen-responsive antioxidant nitric oxide donor as claimed in claim 2, wherein the reaction conditions of step (1) are: the reaction time is more than 0.5 hour at the temperature of 0-60 ℃.
6. The method for preparing an active oxygen-responsive antioxidant nitric oxide donor as claimed in claim 2, wherein the reaction conditions of step (2) are: the reaction time is more than 2 hours at 20-90 ℃.
7. The method for preparing an active oxygen-responsive antioxidant nitric oxide donor as claimed in claim 2, wherein the catalyst in step (2) comprises one or more of benzimidazole, 4-dimethylaminopyridine, pyridine, triethylamine, and trimethylamine; the molar ratio of the catalyst to the 4-N-carbonylimidazolyl phenylboronic acid pinacol ester is 0.1-5: 1.
8. The method for preparing an active oxygen-responsive antioxidant nitric oxide donor as claimed in claim 2, wherein the reaction time of step (1) is 2 hours or more; the solvent in the step (1) is toluene, chloroform and dichloromethane;
the reaction time of the step (2) is more than 12 hours; the catalyst is 4-dimethylamino pyridine; the molar ratio of the catalyst to the 4-N-carbonylimidazolyl phenylboronic acid pinacol ester is 0.5-2: 1.
9. The method for preparing the active oxygen-responsive antioxidant nitric oxide donor of claim 2, wherein the products obtained in step (1) and step (2) are extracted, purified and dried, and the drying agent is one or more of phosphorus pentoxide, anhydrous magnesium sulfate and anhydrous sodium sulfate.
10. Use of the reactive oxygen species-responsive antioxidant nitric oxide donor of claim 1 in the manufacture of a medicament for the treatment of cardiovascular disease, inflammation.
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| CN103819483A (en) * | 2014-02-18 | 2014-05-28 | 中国人民解放军第四军医大学 | Drug for preventing and treating pulmonary artery hypertension, synthesis and applications thereof |
| WO2018045335A1 (en) * | 2016-09-02 | 2018-03-08 | Nusirt Sciences, Inc. | Nitrogen oxide donors and uses thereof |
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| CN103755839A (en) * | 2014-01-21 | 2014-04-30 | 张建祥 | Active oxygen free radical sensitive cyclodextrin material as drug delivery carrier and preparation method thereof |
| CN103819483A (en) * | 2014-02-18 | 2014-05-28 | 中国人民解放军第四军医大学 | Drug for preventing and treating pulmonary artery hypertension, synthesis and applications thereof |
| WO2018045335A1 (en) * | 2016-09-02 | 2018-03-08 | Nusirt Sciences, Inc. | Nitrogen oxide donors and uses thereof |
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